On an orthotropic model for progressive degradation

DEFF Research Database (Denmark)

Hammer, Velaja B.; Pedersen, Pauli

1999-01-01

Progressive degradation in orthotropic materials is modelled from a smear-out point of view, and physical measurable quantities are used as the describing parameters. Evolution of stiffness and evolution of strength are kept uncoupled. For plane problems the stiffness evolution is modelled...

A CASE STUDY OF STUDENT’S PROGRESS IN PIANO PLAYING: THE ROLE OF TRAINING MODEL IN STUDENT’S EXPERTISE

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Maja Marijan

2016-02-01

Full Text Available A case study of student’s progress in piano playing was carried out as an empirical research investigating student’s progress in piano performance. The research was outlined as a multiple process carrying out in three phases. The paper discusses the valuation of the training model through the assessment of the student’s level of attainment. The analysis included descriptive statistics for all the variables, and correlations between variables and the level of attainment. Factors that influence the student’s progress in piano playing, student’s individual characteristics (traits,and cognitive abilities, were measured objectively and were related to significant aspect of musical behavior. These items were assessed at the commencement of the student’s tuition program and at the cut-off date set for the study period. Findings confirmed that the change of training model has significant impact on the student’s progress in very short period, in this case three-week research period. Introduction of organized, and intuitive training model influenced cognitive abilities and motor skills, and personality constructs, such as anxiety, motivation, sense of contentment, self confidence, energy and effort. The difference is large enough to permit the conclusion that the proper training model leads to an important progress in student’s piano playing.

In silico ADME-Tox modeling: progress and prospects.

Science.gov (United States)

Alqahtani, Saeed

2017-11-01

Although significant progress has been made in high-throughput screening of absorption, distribution, metabolism and excretion, and toxicity (ADME-Tox) properties in drug discovery and development, in silico ADME-Tox prediction continues to play an important role in facilitating the appropriate selection of candidate drugs by pharmaceutical companies prior to expensive clinical trials. Areas covered: This review provides an overview of the available in silico models that have been used to predict the ADME-Tox properties of compounds. It also provides a comprehensive overview and summarization of the latest modeling methods and algorithms available for the prediction of physicochemical characteristics, ADME properties, and drug toxicity issues. Expert opinion: The in silico models currently available have greatly contributed to the knowledge of screening approaches in the early stages of drug discovery and the development process. As the definitive goal of in silico molding is to predict the pharmacokinetics and disposition of compounds in vivo by assembling all kinetic processes within one global model, PBPK models can serve this purpose. However, much work remains to be done in this area to generate more data and input parameters to build more reliable and accurate prediction models.

Prediction of autoignition in a lifted methane/air flame using an unsteady flamelet/progress variable model

Energy Technology Data Exchange (ETDEWEB)

Ihme, Matthias; See, Yee Chee [Department of Aerospace Engineering, University of Michigan, Ann Arbor, MI 48109 (United States)

2010-10-15

An unsteady flamelet/progress variable (UFPV) model has been developed for the prediction of autoignition in turbulent lifted flames. The model is a consistent extension to the steady flamelet/progress variable (SFPV) approach, and employs an unsteady flamelet formulation to describe the transient evolution of all thermochemical quantities during the flame ignition process. In this UFPV model, all thermochemical quantities are parameterized by mixture fraction, reaction progress parameter, and stoichiometric scalar dissipation rate, eliminating the explicit dependence on a flamelet time scale. An a priori study is performed to analyze critical modeling assumptions that are associated with the population of the flamelet state space. For application to LES, the UFPV model is combined with a presumed PDF closure to account for subgrid contributions of mixture fraction and reaction progress variable. The model was applied in LES of a lifted methane/air flame. Additional calculations were performed to quantify the interaction between turbulence and chemistry a posteriori. Simulation results obtained from these calculations are compared with experimental data. Compared to the SFPV results, the unsteady flamelet/progress variable model captures the autoignition process, and good agreement with measurements is obtained for mixture fraction, temperature, and species mass fractions. From the analysis of scatter data and mixture fraction-conditional results it is shown that the turbulence/chemistry interaction delays the ignition process towards lower values of scalar dissipation rate, and a significantly larger region in the flamelet state space is occupied during the ignition process. (author)

IAEA Mission Sees Significant Progress in Georgia’s Regulatory Framework, Challenges Ahead

International Nuclear Information System (INIS)

2018-01-01

An International Atomic Energy Agency (IAEA) team of experts said Georgia has made significant progress in strengthening its regulatory framework for nuclear and radiation safety. The team also pointed to challenges ahead as Georgia seeks to achieve further progress. The Integrated Regulatory Review Service (IRRS) team concluded a 10-day mission on 28 February to assess the regulatory safety framework in Georgia. The mission was conducted at the request of the Government and hosted by the Agency of Nuclear and Radiation Safety (ANRS), which is responsible for regulatory oversight in the country. IRRS missions are designed to strengthen the effectiveness of the national safety regulatory infrastructure, while recognizing the responsibility of each State to ensure nuclear and radiation safety. Georgia uses radioactive sources in medicine and industry and operates radioactive waste management facilities. It has decommissioned its only research reactor and has no nuclear power plants. In recent years, the Government and ANRS, with assistance from the IAEA, introduced new safety regulations and increased the number of regulatory inspections.

Changes in gene expression and cellular architecture in an ovarian cancer progression model.

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Amy L Creekmore

Full Text Available BACKGROUND: Ovarian cancer is the fifth leading cause of cancer deaths among women. Early stage disease often remains undetected due the lack of symptoms and reliable biomarkers. The identification of early genetic changes could provide insights into novel signaling pathways that may be exploited for early detection and treatment. METHODOLOGY/PRINCIPAL FINDINGS: Mouse ovarian surface epithelial (MOSE cells were used to identify stage-dependent changes in gene expression levels and signal transduction pathways by mouse whole genome microarray analyses and gene ontology. These cells have undergone spontaneous transformation in cell culture and transitioned from non-tumorigenic to intermediate and aggressive, malignant phenotypes. Significantly changed genes were overrepresented in a number of pathways, most notably the cytoskeleton functional category. Concurrent with gene expression changes, the cytoskeletal architecture became progressively disorganized, resulting in aberrant expression or subcellular distribution of key cytoskeletal regulatory proteins (focal adhesion kinase, α-actinin, and vinculin. The cytoskeletal disorganization was accompanied by altered patterns of serine and tyrosine phosphorylation as well as changed expression and subcellular localization of integral signaling intermediates APC and PKCβII. CONCLUSIONS/SIGNIFICANCE: Our studies have identified genes that are aberrantly expressed during MOSE cell neoplastic progression. We show that early stage dysregulation of actin microfilaments is followed by progressive disorganization of microtubules and intermediate filaments at later stages. These stage-specific, step-wise changes provide further insights into the time and spatial sequence of events that lead to the fully transformed state since these changes are also observed in aggressive human ovarian cancer cell lines independent of their histological type. Moreover, our studies support a link between aberrant cytoskeleton

Progressive IRP Models for Power Resources Including EPP

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Yiping Zhu

2017-01-01

Full Text Available In the view of optimizing regional power supply and demand, the paper makes effective planning scheduling of supply and demand side resources including energy efficiency power plant (EPP, to achieve the target of benefit, cost, and environmental constraints. In order to highlight the characteristics of different supply and demand resources in economic, environmental, and carbon constraints, three planning models with progressive constraints are constructed. Results of three models by the same example show that the best solutions to different models are different. The planning model including EPP has obvious advantages considering pollutant and carbon emission constraints, which confirms the advantages of low cost and emissions of EPP. The construction of progressive IRP models for power resources considering EPP has a certain reference value for guiding the planning and layout of EPP within other power resources and achieving cost and environmental objectives.

Novel AAV-based rat model of forebrain synucleinopathy shows extensive pathologies and progressive loss of cholinergic interneurons.

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Patrick Aldrin-Kirk

Full Text Available Synucleinopathies, characterized by intracellular aggregation of α-synuclein protein, share a number of features in pathology and disease progression. However, the vulnerable cell population differs significantly between the disorders, despite being caused by the same protein. While the vulnerability of dopamine cells in the substantia nigra to α-synuclein over-expression, and its link to Parkinson's disease, is well studied, animal models recapitulating the cortical degeneration in dementia with Lewy-bodies (DLB are much less mature. The aim of this study was to develop a first rat model of widespread progressive synucleinopathy throughout the forebrain using adeno-associated viral (AAV vector mediated gene delivery. Through bilateral injection of an AAV6 vector expressing human wild-type α-synuclein into the forebrain of neonatal rats, we were able to achieve widespread, robust α-synuclein expression with preferential expression in the frontal cortex. These animals displayed a progressive emergence of hyper-locomotion and dysregulated response to the dopaminergic agonist apomorphine. The animals receiving the α-synuclein vector displayed significant α-synuclein pathology including intra-cellular inclusion bodies, axonal pathology and elevated levels of phosphorylated α-synuclein, accompanied by significant loss of cortical neurons and a progressive reduction in both cortical and striatal ChAT positive interneurons. Furthermore, we found evidence of α-synuclein sequestered by IBA-1 positive microglia, which was coupled with a distinct change in morphology. In areas of most prominent pathology, the total α-synuclein levels were increased to, on average, two-fold, which is similar to the levels observed in patients with SNCA gene triplication, associated with cortical Lewy body pathology. This study provides a novel rat model of progressive cortical synucleinopathy, showing for the first time that cholinergic interneurons are vulnerable

The Significance of Trust in the Political System and Motivation for Pupils' Learning Progress in Politics Lessons

Science.gov (United States)

Landwehr, Barbara; Weisseno, Georg

2016-01-01

Very little research has been conducted on the contribution of political education to learning progress in Germany. Hence, there is a need for intervention studies measuring performance against the theoretical background of a political competence model. This model comprises three constructs: subject knowledge, motivation and attitudes. According…

Electric power and its significance as the energy for innovation and progress

International Nuclear Information System (INIS)

Klinger, H.; Boehmer, T.

1999-01-01

The significance of electric power as the essential form of energy to support innovation and progress well into the future is explained with respect to four major domains of application: 1. Innovative activities in microelectronics and semiconductor technology, for applications such as automation and computer technology, instrumentation and control technology, facility and systems management and control. 2. Energy efficiency programmes and schemes for increasing the penetration of energiy from renewable sources in the market. Example: Heat pump technology. 3. Electric power as an energy boosting innovation in industrial production processes. Examples are given from the transportation sector. (orig./CB) [de

The Progressive BSSG Rat Model of Parkinson's: Recapitulating Multiple Key Features of the Human Disease.

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Jackalina M Van Kampen

Full Text Available The development of effective neuroprotective therapies for Parkinson's disease (PD has been severely hindered by the notable lack of an appropriate animal model for preclinical screening. Indeed, most models currently available are either acute in nature or fail to recapitulate all characteristic features of the disease. Here, we present a novel progressive model of PD, with behavioural and cellular features that closely approximate those observed in patients. Chronic exposure to dietary phytosterol glucosides has been found to be neurotoxic. When fed to rats, β-sitosterol β-d-glucoside (BSSG triggers the progressive development of parkinsonism, with clinical signs and histopathology beginning to appear following cessation of exposure to the neurotoxic insult and continuing to develop over several months. Here, we characterize the progressive nature of this model, its non-motor features, the anatomical spread of synucleinopathy, and response to levodopa administration. In Sprague Dawley rats, chronic BSSG feeding for 4 months triggered the progressive development of a parkinsonian phenotype and pathological events that evolved slowly over time, with neuronal loss beginning only after toxin exposure was terminated. At approximately 3 months following initiation of BSSG exposure, animals displayed the early emergence of an olfactory deficit, in the absence of significant dopaminergic nigral cell loss or locomotor deficits. Locomotor deficits developed gradually over time, initially appearing as locomotor asymmetry and developing into akinesia/bradykinesia, which was reversed by levodopa treatment. Late-stage cognitive impairment was observed in the form of spatial working memory deficits, as assessed by the radial arm maze. In addition to the progressive loss of TH+ cells in the substantia nigra, the appearance of proteinase K-resistant intracellular α-synuclein aggregates was also observed to develop progressively, appearing first in the

Progressive significance map and its application to error-resilient image transmission.

Science.gov (United States)

Hu, Yang; Pearlman, William A; Li, Xin

2012-07-01

Set partition coding (SPC) has shown tremendous success in image compression. Despite its popularity, the lack of error resilience remains a significant challenge to the transmission of images in error-prone environments. In this paper, we propose a novel data representation called the progressive significance map (prog-sig-map) for error-resilient SPC. It structures the significance map (sig-map) into two parts: a high-level summation sig-map and a low-level complementary sig-map (comp-sig-map). Such a structured representation of the sig-map allows us to improve its error-resilient property at the price of only a slight sacrifice in compression efficiency. For example, we have found that a fixed-length coding of the comp-sig-map in the prog-sig-map renders 64% of the coded bitstream insensitive to bit errors, compared with 40% with that of the conventional sig-map. Simulation results have shown that the prog-sig-map can achieve highly competitive rate-distortion performance for binary symmetric channels while maintaining low computational complexity. Moreover, we note that prog-sig-map is complementary to existing independent packetization and channel-coding-based error-resilient approaches and readily lends itself to other source coding applications such as distributed video coding.

Progress and Overview on Neutronics Modelling Development in RTP

International Nuclear Information System (INIS)

Mohamad Hairie Rabir; Muhammad Rawi Mohamed Zin; Julia Abdul Karim

2016-01-01

Reactor calculation and simulation are significantly important to ensure safety and better utilization of a research reactor. The Malaysian PUSPATI TRIGA Reactor (RTP) achieved initial criticality on June 28, 1982. The reactor is designed to effectively implement the various fields of basic nuclear research, manpower training, and production of radioisotopes. Since early 90s, neutronics modelling were used as part of its routine in-core fuel management activities. The are several computer codes have been used in RTP since then, based on 1D neutron diffusion, 2D neutron diffusion and 3D Monte Carlo neutron transport method. This paper describes current progress and overview on neutronics modelling development in RTP. Several important parameters were analysed such as k_e_f_f, reactivity, neutron flux, power distribution, B_e_f_f, and fission product build-up for the latest core configuration. The developed core neutronics model was validated by means of comparison with experimental and measurement data. Along with the RTP core model, the calculation procedure also developed to establish better prediction capability of RTP behaviour. (author)

Progression of Diabetic Capillary Occlusion: A Model.

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Xiao Fu

2016-06-01

Full Text Available An explanatory computational model is developed of the contiguous areas of retinal capillary loss which play a large role in diabetic maculapathy and diabetic retinal neovascularization. Strictly random leukocyte mediated capillary occlusion cannot explain the occurrence of large contiguous areas of retinal ischemia. Therefore occlusion of an individual capillary must increase the probability of occlusion of surrounding capillaries. A retinal perifoveal vascular sector as well as a peripheral retinal capillary network and a deleted hexagonal capillary network are modelled using Compucell3D. The perifoveal modelling produces a pattern of spreading capillary loss with associated macular edema. In the peripheral network, spreading ischemia results from the progressive loss of the ladder capillaries which connect peripheral arterioles and venules. System blood flow was elevated in the macular model before a later reduction in flow in cases with progression of capillary occlusions. Simulations differing only in initial vascular network structures but with identical dynamics for oxygen, growth factors and vascular occlusions, replicate key clinical observations of ischemia and macular edema in the posterior pole and ischemia in the retinal periphery. The simulation results also seem consistent with quantitative data on macular blood flow and qualitative data on venous oxygenation. One computational model applied to distinct capillary networks in different retinal regions yielded results comparable to clinical observations in those regions.

Demonstrating the benefits of fuel cells: further significant progress towards commercialisation

Energy Technology Data Exchange (ETDEWEB)

Anon,

1995-01-01

The fourteenth Fuel Cell Seminar held in San Diego, California in 1994 is reported. The phosphoric acid fuel cell (PAFC) is the closest to widespread commercialization. PAFC cogeneration plants have to be shown to compare favourable in reliability with current mature natural gas-fuelled engine and turbine technologies. Although highly efficient, further development is necessary to produce cost effective generators. Progress is being made on proton exchange membrane fuel cell (PEMFC) stationary power plants, too, which may prove to be cost effective. In view of its lower operating temperature, at below 100[sup o]C compared with about 200[sup o]C for the PAFC, the principal use of the PEMFC has been identified as powering vehicles. Fuel cells have significant environmental advantages but further capital cost reductions are necessary if they are to compete with established technologies. (UK)

Interleukin-1 may link helplessness-hopelessness with cancer progression: A proposed model

OpenAIRE

Argaman, M; Gidron, Y; Ariad, S

2005-01-01

A model of the relations between psychological factors and cancer progression should include brain and systemic components and their link with critical cellular stages in cancer progression. We present a psychoneuroimmunological (PNI) model that links helplessness-hopelessness (HH) with cancer progression via interleukin-1β (IL-1β). IL-1β was elevated in the brain following exposure to inescapable shock, and HH was minimized by antagonizing cerebral IL-1β. Elevated cerebral IL-1β increased ca...

Progressive Damage Modeling of Durable Bonded Joint Technology

Science.gov (United States)

Leone, Frank A.; Davila, Carlos G.; Lin, Shih-Yung; Smeltzer, Stan; Girolamo, Donato; Ghose, Sayata; Guzman, Juan C.; McCarville, Duglas A.

2013-01-01

The development of durable bonded joint technology for assembling composite structures for launch vehicles is being pursued for the U.S. Space Launch System. The present work is related to the development and application of progressive damage modeling techniques to bonded joint technology applicable to a wide range of sandwich structures for a Heavy Lift Launch Vehicle. The joint designs studied in this work include a conventional composite splice joint and a NASA-patented Durable Redundant Joint. Both designs involve a honeycomb sandwich with carbon/epoxy facesheets joined with adhesively bonded doublers. Progressive damage modeling allows for the prediction of the initiation and evolution of damage. For structures that include multiple materials, the number of potential failure mechanisms that must be considered increases the complexity of the analyses. Potential failure mechanisms include fiber fracture, matrix cracking, delamination, core crushing, adhesive failure, and their interactions. The joints were modeled using Abaqus parametric finite element models, in which damage was modeled with user-written subroutines. Each ply was meshed discretely, and layers of cohesive elements were used to account for delaminations and to model the adhesive layers. Good correlation with experimental results was achieved both in terms of load-displacement history and predicted failure mechanisms.

Progress in modeling hypersonic turbulent boundary layers

Science.gov (United States)

Zeman, Otto

1993-01-01

A good knowledge of the turbulence structure, wall heat transfer, and friction in turbulent boundary layers (TBL) at high speeds is required for the design of hypersonic air breathing airplanes and reentry space vehicles. This work reports on recent progress in the modeling of high speed TBL flows. The specific research goal described here is the development of a second order closure model for zero pressure gradient TBL's for the range of Mach numbers up to hypersonic speeds with arbitrary wall cooling requirements.

Maximum standard uptake value on pre-chemotherapeutic FDG-PET is a significant parameter for disease progression of newly diagnosed lymphoma

International Nuclear Information System (INIS)

Eo, Jae Seon; Lee, Won Woo; Chung, June Key; Lee, Myung Chul; Kim, Sang Eun

2005-01-01

F-18 FDG-PET is useful for detection and staging of lymphoma. We investigated the prognostic significance of maximum standard uptake (maxSUV) value of FDG-PET for newly diagnosed lymphoma patients before chemotherapy. Twenty-seven patients (male: female = 17: 10: age: 49±19 years) with newly diagnosed lymphoma were enrolled. Nine-teen patients suffered from B cell lymphoma, 6 Hodgkins disease and 2 T cell lymphoma. One patient was stage I, 9 stage II, 3 stage III, 1 stage IV and 13 others. All patients underwent FDG-PET before initiation of chemotherapy. MaxSUV values using lean body weight were obtained for main and largest lesion to represent maxSUV of the patients. The disease progression was defined as total change of the chemotherapeutic regimen or addition of new chemotherapeutic agent during follow up period. The observed period was 389±224 days. The value of maxSUV ranged from 3 to 18 (mean±SD = 10.6±4.4). The disease progressions occurred in 6 patients. Using Cox proportional-hazard regression analysis, maxSUV was identified as a significant parameter for the disease progression free survival (p=0.044). Kaplan-Meier survival curve analysis revealed that the group with higher maxSUV (=10.6, n=5) suffered from shorter disease progression free survival (median 299 days) than the group with lower maxSUV (<10.6, n = 22) (median 378 days, p=0.0146). We found that maxSUV on pre-chemotherapeutic F-18 FDG-PET for newly diagnosed lymphoma patients is a significant parameter for disease progression. Lymphoma patients can be stratified before initiation of chemotherapy in terms of disease progression by the value of maxSUV 10.6

Does significant renal ablation truly and invariably lead to hyperfiltration and progressive chronic kidney disease?

Science.gov (United States)

Wang, Andrew; Sam, Ramin

2017-06-01

It is generally believed that significant renal ablation leads to hyperfiltration and eventually progressively worsening chronic kidney disease. The data behind this belief have not been scrutinized intensively. More importantly, the above belief leads many physicians to manage patients differently than they otherwise would manage. Here, we examine the data behind whether hyperfiltration occurs when patients lose kidney mass (by excision or by disease) and whether the hyperfiltration is uniformly injurious.

Progress in D-brane model building

International Nuclear Information System (INIS)

Marchesano, F.

2007-01-01

The state of the art in D-brane model building is briefly reviewed, focusing on recent achievements in the construction of D=4 N=1 type II string vacua with semi-realistic gauge sectors. Such progress relies on a better understanding of the spectrum of BPS D-branes, the effective field theory obtained from them and the explicit construction of vacua. We first consider D-branes in standard Calabi-Yau compactifications, and then the more involved case of compactifications with fluxes. We discuss how the non-trivial interplay between D-branes and fluxes modifies the previous model-building rules, as well as provides new possibilities to connect string theory to particle physics. (Abstract Copyright [2007], Wiley Periodicals, Inc.)

A stochastic model for identifying differential gene pair co-expression patterns in prostate cancer progression

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Mao Yu

2009-07-01

Full Text Available Abstract Background The identification of gene differential co-expression patterns between cancer stages is a newly developing method to reveal the underlying molecular mechanisms of carcinogenesis. Most researches of this subject lack an algorithm useful for performing a statistical significance assessment involving cancer progression. Lacking this specific algorithm is apparently absent in identifying precise gene pairs correlating to cancer progression. Results In this investigation we studied gene pair co-expression change by using a stochastic process model for approximating the underlying dynamic procedure of the co-expression change during cancer progression. Also, we presented a novel analytical method named 'Stochastic process model for Identifying differentially co-expressed Gene pair' (SIG method. This method has been applied to two well known prostate cancer data sets: hormone sensitive versus hormone resistant, and healthy versus cancerous. From these data sets, 428,582 gene pairs and 303,992 gene pairs were identified respectively. Afterwards, we used two different current statistical methods to the same data sets, which were developed to identify gene pair differential co-expression and did not consider cancer progression in algorithm. We then compared these results from three different perspectives: progression analysis, gene pair identification effectiveness analysis, and pathway enrichment analysis. Statistical methods were used to quantify the quality and performance of these different perspectives. They included: Re-identification Scale (RS and Progression Score (PS in progression analysis, True Positive Rate (TPR in gene pair analysis, and Pathway Enrichment Score (PES in pathway analysis. Our results show small values of RS and large values of PS, TPR, and PES; thus, suggesting that gene pairs identified by the SIG method are highly correlated with cancer progression, and highly enriched in disease-specific pathways. From

Progress in transport modelling of internal transport barrier plasmas in JET

International Nuclear Information System (INIS)

Tala, T.; Bourdelle, C.; Imbeaux, F.; Moreau, D.; Garbet, X.; Joffrin, E.; Laborde, L.; Litaudon, X.; Mazon, D.; Parail, V.; Corrigan, G.; Heading, D.; Crisanti, F.; Mantica, P.; Salmi, A.; Strand, P.; Weiland, J.

2005-01-01

This paper will report on the recent progress in transport modelling of Internal Transport Barrier (ITB) plasmas. Two separate issues will be covered, fully predictive transport modelling of ITBs in the multi-tokamak database, including micro-stability analyses of ITBs, and predictive closed-loop (i.e. real-time control) transport simulations of the q-profile and ITBs. For the first time, the predictive capabilities of the mixed Bohm/GyroBohm and Weiland transport models are investigated with discharges from the ITPA ITB database by fully predictive transport simulations. The predictive transport simulations with the Bohm/GyroBohm model agree very well with experimental results from JET and JT-60U. In order to achieve a good agreement in DIII-D, the stabilisation had to be included into the model, showing the significant role played by the stabilisation in governing the physics of the ITBs. The significant role of the stabilisation is also emphasised by the gyrokinetic analysis. The Weiland transport model shows only limited agreement between the model predictions and experimental results with respect to the formation and location of the ITB. The fully predictive closed-loop simulations with real-time control of the q-profile and ITB show that it is possible to reach various set-point profiles for q and ITB and control them for longer than a current diffusion time in JET using the same real-time control technique as in the experiments. (author)

Progress in wall turbulence 2 understanding and modelling

CERN Document Server

Jimenez, Javier; Marusic, Ivan

2016-01-01

This is the proceedings of the ERCOFTAC Workshop on Progress in Wall Turbulence: Understanding and Modelling, that was held in Lille, France from June 18 to 20, 2014. The workshop brought together world specialists of near wall turbulence and stimulated exchanges between them around up-to-date theories, experiments, simulations and numerical models. This book contains a coherent collection of recent results on near wall turbulence including theory, new experiments, DNS, and modeling with RANS, LES.The fact that both physical understanding and modeling by different approaches are addressed by the best specialists in a single workshop is original.

A genetic model of progressively partial melting for uranium-bearing granites in south China

International Nuclear Information System (INIS)

Zhai Jianping.

1989-01-01

A genetic model of progressively partial and enrichment mechanism of uranium during partial melting of the sources of material studied and the significance of the genetic model in search of uranium deposits is elaborated. This model accounts better for some geological and geochemical features of uranium-bearing granties and suspects the traditional idea that igneous uranium-bearing granites were formed by fusion of U-rich strata surrounding these granites. Finally this paper points out that the infuence of U-rich strata of wall rocks of granites over uranium-bearing granites depends on variation of water solubility in the magma and assimilation of magma to wall rocks during its ascending and crystallization

Recent progress in biomass burning research: a perspective from analyses of satellite data and model studies. (Invited)

Science.gov (United States)

Logan, J. A.

2010-12-01

Significant progress has been made in using satellite data to provide bottom-up constraints on biomass burning (BB) emissions. However, inverse studies with CO satellite data imply that tropical emissions are underestimated by current inventories, while model simulations of the ARCTAS period imply that the FLAMBE estimates of extratropical emissions are significantly overestimated. Injection heights of emissions from BB have been quantified recently using MISR data, and these data provide some constraints on 1-d plume models. I will discuss recent results in these areas, highlighting future research needs.

Development of a Conceptual Model of Disease Progression for Use in Economic Modeling of Chronic Obstructive Pulmonary Disease.

Science.gov (United States)

Tabberer, Maggie; Gonzalez-McQuire, Sebastian; Muellerova, Hana; Briggs, Andrew H; Rutten-van Mölken, Maureen P M H; Chambers, Mike; Lomas, David A

2017-05-01

To develop and validate a new conceptual model (CM) of chronic obstructive pulmonary disease (COPD) for use in disease progression and economic modeling. The CM identifies and describes qualitative associations between disease attributes, progression and outcomes. A literature review was performed to identify any published CMs or literature reporting the impact and association of COPD disease attributes with outcomes. After critical analysis of the literature, a Steering Group of experts from the disciplines of health economics, epidemiology and clinical medicine was convened to develop a draft CM, which was refined using a Delphi process. The refined CM was validated by testing for associations between attributes using data from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). Disease progression attributes included in the final CM were history and occurrence of exacerbations, lung function, exercise capacity, signs and symptoms (cough, sputum, dyspnea), cardiovascular disease comorbidities, 'other' comorbidities (including depression), body composition (body mass index), fibrinogen as a biomarker, smoking and demographic characteristics (age, gender). Mortality and health-related quality of life were determined to be the most relevant final outcome measures for this model, intended to be the foundation of an economic model of COPD. The CM is being used as the foundation for developing a new COPD model of disease progression and to provide a framework for the analysis of patient-level data. The CM is available as a reference for the implementation of further disease progression and economic models.

Mapping of Students’ Learning Progression Based on Mental Model in Magnetic Induction Concepts

Science.gov (United States)

Hamid, R.; Pabunga, D. B.

2017-09-01

The progress of student learning in a learning process has not been fully optimally observed by the teacher. The concept being taught is judged only at the end of learning as a product of thinking, and does not assess the mental processes that occur in students’ thinking. Facilitating students’ thinking through new phenomena can reveal students’ variation in thinking as a mental model of a concept, so that students who are assimilative and or accommodative can be identified in achieving their equilibrium of thought as well as an indicator of progressiveness in the students’ thinking stages. This research data is obtained from the written documents and interviews of students who were learned about the concept of magnetic induction through Constructivist Teaching Sequences (CTS) models. The results of this study indicate that facilitating the students’ thinking processes on the concept of magnetic induction contributes to increasing the number of students thinking within the "progressive change" category, and it can be said that the progress of student learning is more progressive after their mental models were facilitated through a new phenomena by teacher.

Modeling Progress in AI

OpenAIRE

Brundage, Miles

2015-01-01

Participants in recent discussions of AI-related issues ranging from intelligence explosion to technological unemployment have made diverse claims about the nature, pace, and drivers of progress in AI. However, these theories are rarely specified in enough detail to enable systematic evaluation of their assumptions or to extrapolate progress quantitatively, as is often done with some success in other technological domains. After reviewing relevant literatures and justifying the need for more ...

Progress in modelling agricultural impacts of and adaptations to climate change.

Science.gov (United States)

Rötter, R P; Hoffmann, M P; Koch, M; Müller, C

2018-06-01

Modelling is a key tool to explore agricultural impacts of and adaptations to climate change. Here we report recent progress made especially referring to the large project initiatives MACSUR and AgMIP; in particular, in modelling potential crop impacts from field to global using multi-model ensembles. We identify two main fields where further progress is necessary: a more mechanistic understanding of climate impacts and management options for adaptation and mitigation; and focusing on cropping systems and integrative multi-scale assessments instead of single season and crops, especially in complex tropical and neglected but important cropping systems. Stronger linking of experimentation with statistical and eco-physiological crop modelling could facilitate the necessary methodological advances. Copyright © 2018 Elsevier Ltd. All rights reserved.

PET studies of brain energy metabolism in a model of subcortical dementia: progressive supranuclear Palsy

International Nuclear Information System (INIS)

Blin, J.; Baron, J.C.; Cambon, H.

1988-01-01

In 41 patients with clinically determined Progressive Supranuclear Palsy, a model of degenerative subcortical dementia, alterations in regional brain energy metabolism with respect to control subjects have been investigated using positron computed tomography and correlated to clinical and neuropsychological scores. A generalized significant reduction in brain metabolism was found, which predominated in the prefrontal cortex in accordance with, and statistically correlated to, the frontal neuropsychological score

Modelling T4 cell count as a marker of HIV progression in the ...

African Journals Online (AJOL)

Modelling T4 cell count as a marker of HIV progression in the absence of any defense mechanism. VSM Yadavalli, MMO Labeodan, S Udayabaskaran, N Forche. Abstract. The T4 cell count, which is considered one of the markers of disease progression in an HIV infected individual, is modelled in this paper. The World ...

Analysis of the effects of exposure to acute hypoxia on oxidative lesions and tumour progression in a transgenic mouse breast cancer model

Directory of Open Access Journals (Sweden)

Lunt Sarah

2008-05-01

Full Text Available Abstract Background Tumour hypoxia is known to be a poor prognostic indicator, predictive of increased risk of metastatic disease and reduced survival. Genomic instability has been proposed as one of the potential mechanisms for hypoxic tumour progression. Both of these features are commonly found in many cancer types, but their relationship and association with tumour progression has not been examined in the same model. Methods To address this issue, we determined the effects of 6 week in vivo acute hypoxic exposure on the levels of mutagenic lipid peroxidation product, malondialdehyde, and 8-oxo-7,8-dihydro-2'-deoxyguanosine DNA (8-oxo-dG lesions in the transgenic polyomavirus middle T (PyMT breast cancer mouse model. Results We observed significantly increased plasma lipid peroxidation and 8-oxo-dG lesion levels in the hypoxia-exposed mice. Consumption of malondialdehyde also induced a significant increase in the PyMT tumour DNA lesion levels, however, these increases did not translate into enhanced tumour progression. We further showed that the in vivo exposure to acute hypoxia induced accumulation of F4/80 positive tumour-associated macrophages (TAMs, demonstrating a relationship between hypoxia and macrophages in an experimental model. Conclusion These data suggest that although exposure to acute hypoxia causes an increase in 8-oxo-dG lesions and TAMs in the PyMT tumours, these increases do not translate into significant changes in tumour progression at the primary or metastatic levels in this strong viral oncogene-driven breast cancer model.

Explicit modeling the progressive interface damage in fibrous composite: Analytical vs. numerical approach

DEFF Research Database (Denmark)

Kushch, V.I.; Shmegera, S.V.; Mishnaevsky, Leon

2011-01-01

of the multiple inclusion problem by means of complex potentials. The second, finite element model of FRC is based on the cohesive zone model of interface. Simulation of progressive debonding in FRC using the many-fiber models of composite has been performed. The advantageous features and applicability areas...... of both models are discussed. It has been shown that the developed models provide detailed analysis of the progressive debonding phenomena including the interface crack cluster formation, overall stiffness reduction and induced anisotropy of the effective elastic moduli of composite....

Disease Progression/Clinical Outcome Model for Castration-Resistant Prostate Cancer in Patients Treated with Eribulin

NARCIS (Netherlands)

Van Hasselt, J. G C; Gupta, A.; Hussein, Z.; Beijnen, J. H.; Schellens, J. H M; Huitema, A. D R

2015-01-01

Frameworks that associate cancer dynamic disease progression models with parametric survival models for clinical outcome have recently been proposed to support decision making in early clinical development. Here we developed such a disease progression clinical outcome model for castration-resistant

Data-driven models of dominantly-inherited Alzheimer's disease progression.

Science.gov (United States)

Oxtoby, Neil P; Young, Alexandra L; Cash, David M; Benzinger, Tammie L S; Fagan, Anne M; Morris, John C; Bateman, Randall J; Fox, Nick C; Schott, Jonathan M; Alexander, Daniel C

2018-03-22

Dominantly-inherited Alzheimer's disease is widely hoped to hold the key to developing interventions for sporadic late onset Alzheimer's disease. We use emerging techniques in generative data-driven disease progression modelling to characterize dominantly-inherited Alzheimer's disease progression with unprecedented resolution, and without relying upon familial estimates of years until symptom onset. We retrospectively analysed biomarker data from the sixth data freeze of the Dominantly Inherited Alzheimer Network observational study, including measures of amyloid proteins and neurofibrillary tangles in the brain, regional brain volumes and cortical thicknesses, brain glucose hypometabolism, and cognitive performance from the Mini-Mental State Examination (all adjusted for age, years of education, sex, and head size, as appropriate). Data included 338 participants with known mutation status (211 mutation carriers in three subtypes: 163 PSEN1, 17 PSEN2, and 31 APP) and a baseline visit (age 19-66; up to four visits each, 1.1 ± 1.9 years in duration; spanning 30 years before, to 21 years after, parental age of symptom onset). We used an event-based model to estimate sequences of biomarker changes from baseline data across disease subtypes (mutation groups), and a differential equation model to estimate biomarker trajectories from longitudinal data (up to 66 mutation carriers, all subtypes combined). The two models concur that biomarker abnormality proceeds as follows: amyloid deposition in cortical then subcortical regions (∼24 ± 11 years before onset); phosphorylated tau (17 ± 8 years), tau and amyloid-β changes in cerebrospinal fluid; neurodegeneration first in the putamen and nucleus accumbens (up to 6 ± 2 years); then cognitive decline (7 ± 6 years), cerebral hypometabolism (4 ± 4 years), and further regional neurodegeneration. Our models predicted symptom onset more accurately than predictions that used familial estimates: root mean squared error of 1

Progressive sampling-based Bayesian optimization for efficient and automatic machine learning model selection.

Science.gov (United States)

Zeng, Xueqiang; Luo, Gang

2017-12-01

Machine learning is broadly used for clinical data analysis. Before training a model, a machine learning algorithm must be selected. Also, the values of one or more model parameters termed hyper-parameters must be set. Selecting algorithms and hyper-parameter values requires advanced machine learning knowledge and many labor-intensive manual iterations. To lower the bar to machine learning, miscellaneous automatic selection methods for algorithms and/or hyper-parameter values have been proposed. Existing automatic selection methods are inefficient on large data sets. This poses a challenge for using machine learning in the clinical big data era. To address the challenge, this paper presents progressive sampling-based Bayesian optimization, an efficient and automatic selection method for both algorithms and hyper-parameter values. We report an implementation of the method. We show that compared to a state of the art automatic selection method, our method can significantly reduce search time, classification error rate, and standard deviation of error rate due to randomization. This is major progress towards enabling fast turnaround in identifying high-quality solutions required by many machine learning-based clinical data analysis tasks.

Significant uncertainty in global scale hydrological modeling from precipitation data errors

Science.gov (United States)

Sperna Weiland, Frederiek C.; Vrugt, Jasper A.; van Beek, Rens (L.) P. H.; Weerts, Albrecht H.; Bierkens, Marc F. P.

2015-10-01

In the past decades significant progress has been made in the fitting of hydrologic models to data. Most of this work has focused on simple, CPU-efficient, lumped hydrologic models using discharge, water table depth, soil moisture, or tracer data from relatively small river basins. In this paper, we focus on large-scale hydrologic modeling and analyze the effect of parameter and rainfall data uncertainty on simulated discharge dynamics with the global hydrologic model PCR-GLOBWB. We use three rainfall data products; the CFSR reanalysis, the ERA-Interim reanalysis, and a combined ERA-40 reanalysis and CRU dataset. Parameter uncertainty is derived from Latin Hypercube Sampling (LHS) using monthly discharge data from five of the largest river systems in the world. Our results demonstrate that the default parameterization of PCR-GLOBWB, derived from global datasets, can be improved by calibrating the model against monthly discharge observations. Yet, it is difficult to find a single parameterization of PCR-GLOBWB that works well for all of the five river basins considered herein and shows consistent performance during both the calibration and evaluation period. Still there may be possibilities for regionalization based on catchment similarities. Our simulations illustrate that parameter uncertainty constitutes only a minor part of predictive uncertainty. Thus, the apparent dichotomy between simulations of global-scale hydrologic behavior and actual data cannot be resolved by simply increasing the model complexity of PCR-GLOBWB and resolving sub-grid processes. Instead, it would be more productive to improve the characterization of global rainfall amounts at spatial resolutions of 0.5° and smaller.

A Segmented Signal Progression Model for the Modern Streetcar System

Directory of Open Access Journals (Sweden)

Baojie Wang

2015-01-01

Full Text Available This paper is on the purpose of developing a segmented signal progression model for modern streetcar system. The new method is presented with the following features: (1 the control concept is based on the assumption of only one streetcar line operating along an arterial under a constant headway and no bandwidth demand for streetcar system signal progression; (2 the control unit is defined as a coordinated intersection group associated with several streetcar stations, and the control joints must be streetcar stations; (3 the objective function is built to ensure the two-way streetcar arrival times distributing within the available time of streetcar phase; (4 the available time of streetcar phase is determined by timing schemes, intersection structures, track locations, streetcar speeds, and vehicular accelerations; (5 the streetcar running speed is constant separately whether it is in upstream or downstream route; (6 the streetcar dwell time is preset according to historical data distribution or charging demand. The proposed method is experimentally examined in Hexi New City Streetcar Project in Nanjing, China. In the experimental results, the streetcar system operation and the progression impacts are shown to affect transit and vehicular traffic. The proposed model presents promising outcomes through the design of streetcar system segmented signal progression, in terms of ensuring high streetcar system efficiency and minimizing negative impacts on transit and vehicular traffic.

Progression of renal cell carcinoma is inhibited by genistein and radiation in an orthotopic model

International Nuclear Information System (INIS)

Hillman, Gilda G; Wang, Yu; Che, Mingxin; Raffoul, Julian J; Yudelev, Mark; Kucuk, Omer; Sarkar, Fazlul H

2007-01-01

We have previously reported the potentiation of radiotherapy by the soy isoflavone genistein for prostate cancer using prostate tumor cells in vitro and orthotopic prostate tumor models in vivo. However, when genistein was used as single therapy in animal models, it promoted metastasis to regional para-aortic lymph nodes. To clarify whether these intriguing adverse effects of genistein are intrinsic to the orthotopic prostate tumor model, or these results could also be recapitulated in another model, we used the orthotopic metastatic KCI-18 renal cell carcinoma (RCC) model established in our laboratory. The KCI-18 RCC cell line was generated from a patient with papillary renal cell carcinoma. Following orthotopic renal implantation of KCI-18 RCC cells and serial in vivo kidney passages in nude mice, we have established a reliable and predictable metastatic RCC tumor model. Mice bearing established kidney tumors were treated with genistein combined with kidney tumor irradiation. The effect of the therapy was assessed on the primary tumor and metastases to various organs. In this experimental model, the karyotype and histological characteristics of the human primary tumor are preserved. Tumor cells metastasize from the primary renal tumor to the lungs, liver and mesentery mimicking the progression of RCC in humans. Treatment of established kidney tumors with genistein demonstrated a tendency to stimulate the growth of the primary kidney tumor and increase the incidence of metastasis to the mesentery lining the bowel. In contrast, when given in conjunction with kidney tumor irradiation, genistein significantly inhibited the growth and progression of established kidney tumors. These findings confirm the potentiation of radiotherapy by genistein in the orthotopic RCC model as previously shown in orthotopic models of prostate cancer. Our studies in both RCC and prostate tumor models demonstrate that the combination of genistein with primary tumor irradiation is a more

The Model of Optimum Economic Growth with the Induced Scientific-Technological Progress

Directory of Open Access Journals (Sweden)

Dilenko Viktor A.

2017-07-01

Full Text Available On the basis of the economic dynamics of the Harrod – Domar model, a model of optimum economic growth in line with the induced scientific-technological progress (STP has been built. In order to reflect the induced scientific-technological progress, with this model is proposed to further allocate the income element that is specially used for the investment of innovation activity, implementation of which reduces the capital intensity in development of the discussed economy. For the simplest way of presenting an economic mechanism for the investment of induced STP, analytical solutions of an appropriate task in optimum management have been obtained. Studying these decisions allowed to reveal the characteristics of the impact of parameters of scientific-technological progress and the analyzed economic system on choosing the best trajectory for its evolution. Possible directions for further developing the results presented can be considered the tasks in building and analyzing models of optimum economic growth that implement different investment options for the induced STP, as well as the models in which this investment mechanism is not exogenouslyed, but rather the result of the corresponding economic-mathematical research.

3D Printing of Tissue Engineered Constructs for in vitro Modeling of Disease Progression and Drug Screening

Science.gov (United States)

Vanderburgh, Joseph; Sterling, Julie A.

2016-01-01

2D cell culture and preclinical animal models have traditionally been implemented for investigating the underlying cellular mechanisms of human disease progression. However, the increasing significance of 3D versus 2D cell culture has initiated a new era in cell culture research in which 3D in vitro models are emerging as a bridge between traditional 2D cell culture and in vivo animal models. Additive manufacturing (AM, also known as 3D printing), defined as the layer-by-layer fabrication of parts directed by digital information from a 3D computer-aided design (CAD) file, offers the advantages of simultaneous rapid prototyping and biofunctionalization as well as the precise placement of cells and extracellular matrix with high resolution. In this review, we highlight recent advances in 3D printing of tissue engineered constructs (TECs) that recapitulate the physical and cellular properties of the tissue microenvironment for investigating mechanisms of disease progression and for screening drugs. PMID:27169894

Modelling the Progression of Competitive Performance of an Academy's Soccer Teams.

Science.gov (United States)

Malcata, Rita M; Hopkins, Will G; Richardson, Scott

2012-01-01

Progression of a team's performance is a key issue in competitive sport, but there appears to have been no published research on team progression for periods longer than a season. In this study we report the game-score progression of three teams of a youth talent-development academy over five seasons using a novel analytic approach based on generalised mixed modelling. The teams consisted of players born in 1991, 1992 and 1993; they played totals of 115, 107 and 122 games in Asia and Europe between 2005 and 2010 against teams differing in age by up to 3 years. Game scores predicted by the mixed model were assumed to have an over-dispersed Poisson distribution. The fixed effects in the model estimated an annual linear pro-gression for Aspire and for the other teams (grouped as a single opponent) with adjustment for home-ground advantage and for a linear effect of age difference between competing teams. A random effect allowed for different mean scores for Aspire and opposition teams. All effects were estimated as factors via log-transformation and presented as percent differences in scores. Inferences were based on the span of 90% confidence intervals in relation to thresholds for small factor effects of x/÷1.10 (+10%/-9%). Most effects were clear only when data for the three teams were combined. Older teams showed a small 27% increase in goals scored per year of age difference (90% confidence interval 13 to 42%). Aspire experienced a small home-ground advantage of 16% (-5 to 41%), whereas opposition teams experienced 31% (7 to 60%) on their own ground. After adjustment for these effects, the Aspire teams scored on average 1.5 goals per match, with little change in the five years of their existence, whereas their opponents' scores fell from 1.4 in their first year to 1.0 in their last. The difference in progression was trivial over one year (7%, -4 to 20%), small over two years (15%, -8 to 44%), but unclear over >2 years. In conclusion, the generalized mixed model

A theoretical model to describe progressions and regressions for exercise rehabilitation.

Science.gov (United States)

Blanchard, Sam; Glasgow, Phil

2014-08-01

This article aims to describe a new theoretical model to simplify and aid visualisation of the clinical reasoning process involved in progressing a single exercise. Exercise prescription is a core skill for physiotherapists but is an area that is lacking in theoretical models to assist clinicians when designing exercise programs to aid rehabilitation from injury. Historical models of periodization and motor learning theories lack any visual aids to assist clinicians. The concept of the proposed model is that new stimuli can be added or exchanged with other stimuli, either intrinsic or extrinsic to the participant, in order to gradually progress an exercise whilst remaining safe and effective. The proposed model maintains the core skills of physiotherapists by assisting clinical reasoning skills, exercise prescription and goal setting. It is not limited to any one pathology or rehabilitation setting and can adapted by any level of skilled clinician. Copyright © 2014 Elsevier Ltd. All rights reserved.

Progress in tritium retention and release modeling for ceramic breeders

International Nuclear Information System (INIS)

Raffray, A.R.; Federici, G.; Billone, M.C.; Tanaka, S.

1994-01-01

Tritium behavior in ceramic breeder blankets is a key design issue for this class of blanket because of its impact on safety and fuel self-sufficiency. Over the past 10-15 years, substantial theoretical and experimental efforts have been dedicated world-wide to develop a better understanding of tritium transport in ceramic breeders. Models that are available today seem to cover reasonably well all the key physical transport and trapping mechanisms. They have allowed for reasonable interpretation and reproduction of experimental data and have helped in pointing out deficiencies in material property data base, in providing guidance for future experiments, and in analyzing blanket tritium behavior. This paper highlights the progress in tritium modeling over the last decade. Key tritium transport mechanisms are briefly described along with the more recent and sophisticated models developed to help understand them. Recent experimental data are highlighted and model calibration and validation discussed. Finally, example applications to blanket cases are shown as illustration of progress in the prediction of ceramic breeder blanket tritium inventory

MUC1 enhances tumor progression and contributes toward immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma.

Science.gov (United States)

Tinder, Teresa L; Subramani, Durai B; Basu, Gargi D; Bradley, Judy M; Schettini, Jorge; Million, Arefayene; Skaar, Todd; Mukherjee, Pinku

2008-09-01

MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic adenocarcinoma. However, the role of MUC1 in pancreatic cancer has been elusive, partly due to the lack of an appropriate model. We report the characterization of a novel mouse model that expresses human MUC1 as a self molecule (PDA.MUC1 mice). Pancreatic tumors arise in an appropriate MUC1-tolerant background within an immune-competent host. Significant enhancement in the development of pancreatic intraepithelial preneoplastic lesions and progression to adenocarcinoma is observed in PDA.MUC1 mice, possibly due to increased proliferation. Tumors from PDA.MUC1 mice express higher levels of cyclooxygenase-2 and IDO compared with PDA mice lacking MUC1, especially during early stages of tumor development. The increased proinflammatory milieu correlates with an increased percentage of regulatory T cells and myeloid suppressor cells in the pancreatic tumor and tumor draining lymph nodes. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease, which in turn regulate the immune responses. Thus, the mouse model is ideally suited for testing novel chemopreventive and therapeutic strategies against pancreatic cancer.

MUC1 enhances tumor progression and contributes towards immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma

Science.gov (United States)

Tinder, Teresa L.; Subramani, Durai B.; Basu, Gargi D.; Bradley, Judy M.; Schettini, Jorge; Million, Arefayene; Skaar, Todd

2008-01-01

MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic adenocarcinoma. However, the role of MUC1 in pancreatic cancer has been elusive, partly due to the lack of an appropriate model. We report the characterization of a novel mouse model that expresses human MUC1 as a self molecule (PDA.MUC1 mice). Pancreatic tumors arise in an appropriate MUC1-tolerant background within an immune competent host. Significant enhancement in the development of pancreatic intraepithelial pre-neoplastic lesions (PanINs) and progression to adenocarcinoma is observed in PDA.MUC1 mice, possibly due to increased proliferation. Tumors from PDA.MUC1 mice express higher levels of cyclooxygenase-2 and indoleamine 2,3, dioxygenase compared to PDA mice lacking MUC1, especially during early stages of tumor development. The increased pro-inflammatory milieu correlates with an increased percentage of regulatory T cells and myeloid suppressor cells in the pancreatic tumor and tumor draining lymph nodes. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease which in turn regulate the immune responses. Thus, the mouse model is ideally-suited for testing novel chemopreventive and therapeutic strategies against pancreatic cancer. PMID:18713982

Interleukin-1 may link helplessness-hopelessness with cancer progression: a proposed model.

Science.gov (United States)

Argaman, Miriam; Gidron, Yori; Ariad, Shmuel

2005-01-01

A model of the relations between psychological factors and cancer progression should include brain and systemic components and their link with critical cellular stages in cancer progression. We present a psychoneuroimmunological (PNI) model that links helplessness-hopelessness (HH) with cancer progression via interleukin-1beta (IL-1beta). IL-1beta was elevated in the brain following exposure to inescapable shock, and HH was minimized by antagonizing cerebral IL-1beta. Elevated cerebral IL-1beta increased cancer metastasis in animals. Inescapable shock was associated with systemic elevations of IL-1beta and peripheral IL-1beta was associated with escape from apoptosis, angiogenesis, and metastasis. Involvement of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis are discussed. Future studies need to identify the role of additional factors in this PNI pathway.

Using Rasch models to develop and validate an environmental thinking learning progression

Science.gov (United States)

Hashimoto-Martell, Erin A.

Environmental understanding is highly relevant in today's global society. Social, economic, and political structures are connected to the state of environmental degradation and exploitation, and disproportionately affect those in poor or urban communities (Brulle & Pellow, 2006; Executive Order No. 12898, 1994). Environmental education must challenge the way we live, and our social and ecological quality of life, with the goal of responsible action. The development of a learning progression in environmental thinking, along with a corresponding assessment, could provide a tool that could be used across environmental education programs to help evaluate and guide programmatic decisions. This study sought to determine if a scale could be constructed that allowed individuals to be ordered along a continuum of environmental thinking. First, I developed the Environmental Thinking Learning Progression, a scale of environmental thinking from novice to advanced, based on the current available research and literature. The scale consisted of four subscales, each measuring a different aspect of environmental thinking: place consciousness, human connection, agency, and science concepts. Second, a measurement instrument was developed, so that the data appropriately fit the model using Rasch analysis. A Rasch analysis of the data placed respondents along a continuum, given the range of item difficulty for each subscale. Across three iterations of instrument revision and data collection, findings indicated that the items were ordered in a hierarchical way that corresponded to the construct of environmental thinking. Comparisons between groups showed that the average score of respondents who had participated in environmental education programs was significantly higher than those who had not. A comparison between males and females showed no significant difference in average measure, however, there were varied significant differences between how racial/ethnic groups performed. Overall

MODELLING THE PROGRESSION OF COMPETITIVE PERFORMANCE OF AN ACADEMY'S SOCCER TEAMS

Directory of Open Access Journals (Sweden)

Rita M. Malcata

2012-09-01

Full Text Available Progression of a team's performance is a key issue in competitive sport, but there appears to have been no published research on team progression for periods longer than a season. In this study we report the game-score progression of three teams of a youth talent-development academy over five seasons using a novel analytic approach based on generalised mixed modelling. The teams consisted of players born in 1991, 1992 and 1993; they played totals of 115, 107 and 122 games in Asia and Europe between 2005 and 2010 against teams differing in age by up to 3 years. Game scores predicted by the mixed model were assumed to have an over-dispersed Poisson distribution. The fixed effects in the model estimated an annual linear pro-gression for Aspire and for the other teams (grouped as a single opponent with adjustment for home-ground advantage and for a linear effect of age difference between competing teams. A random effect allowed for different mean scores for Aspire and opposition teams. All effects were estimated as factors via log-transformation and presented as percent differences in scores. Inferences were based on the span of 90% confidence intervals in relation to thresholds for small factor effects of x/÷1.10 (+10%/-9%. Most effects were clear only when data for the three teams were combined. Older teams showed a small 27% increase in goals scored per year of age difference (90% confidence interval 13 to 42%. Aspire experienced a small home-ground advantage of 16% (-5 to 41%, whereas opposition teams experienced 31% (7 to 60% on their own ground. After adjustment for these effects, the Aspire teams scored on average 1.5 goals per match, with little change in the five years of their existence, whereas their opponents' scores fell from 1.4 in their first year to 1.0 in their last. The difference in progression was trivial over one year (7%, -4 to 20%, small over two years (15%, -8 to 44%, but unclear over >2 years. In conclusion, the generalized

Progress towards localization in the attractive Hubbard model

Science.gov (United States)

Morong, W.; Xu, W.; Demarco, B.

2017-04-01

The interplay between fermionic superfluidity and disorder is a topic of long-standing interest that has recently come within reach of ultracold gas experiments. Outstanding questions include the fate of Cooper pairs in a localized superfluid and the effect of disorder on the superfluid transition temperature. We report progress on tackling this problem using a realization of the Hubbard model with attractive interactions. Our system consists of two spin states of fermionic potassium-40 trapped in a cubic optical lattice. Disorder is introduced using an optical speckle potential, and interactions are controlled via a Feshbach resonance. We study the binding and unbinding of Cooper pairs in this system using rf spectroscopy, changes in Tc by measuring the condensate fraction, and transport properties by observing the response to an applied impulse. We will discuss progress towards these measurements.

A model to predict progression in brain-injured patients.

Science.gov (United States)

Tommasino, N; Forteza, D; Godino, M; Mizraji, R; Alvarez, I

2014-11-01

The study of brain death (BD) epidemiology and the acute brain injury (ABI) progression profile is important to improve public health programs, organ procurement strategies, and intensive care unit (ICU) protocols. The purpose of this study was to analyze the ABI progression profile among patients admitted to ICUs with a Glasgow Coma Score (GCS) ≤8, as well as establishing a prediction model of probability of death and BD. This was a retrospective analysis of prospective data that included all brain-injured patients with GCS ≤8 admitted to a total of four public and private ICUs in Uruguay (N = 1447). The independent predictor factors of death and BD were studied using logistic regression analysis. A hierarchical model consisting of 2 nested logit regression models was then created. With these models, the probabilities of death, BD, and death by cardiorespiratory arrest were analyzed. In the first regression, we observed that as the GCS decreased and age increased, the probability of death rose. Each additional year of age increased the probability of death by 0.014. In the second model, however, BD risk decreased with each year of age. The presence of swelling, mass effect, and/or space-occupying lesion increased BD risk for the same given GCS. In the presence of injuries compatible with intracranial hypertension, age behaved as a protective factor that reduced the probability of BD. Based on the analysis of the local epidemiology, a model to predict the probability of death and BD can be developed. The organ potential donation of a country, region, or hospital can be predicted on the basis of this model, customizing it to each specific situation.

Setting a research agenda for progressive multiple sclerosis: the International Collaborative on Progressive MS.

Science.gov (United States)

Fox, Robert J; Thompson, Alan; Baker, David; Baneke, Peer; Brown, Doug; Browne, Paul; Chandraratna, Dhia; Ciccarelli, Olga; Coetzee, Timothy; Comi, Giancarlo; Feinstein, Anthony; Kapoor, Raj; Lee, Karen; Salvetti, Marco; Sharrock, Kersten; Toosy, Ahmed; Zaratin, Paola; Zuidwijk, Kim

2012-11-01

Despite significant progress in the development of therapies for relapsing MS, progressive MS remains comparatively disappointing. Our objective, in this paper, is to review the current challenges in developing therapies for progressive MS and identify key priority areas for research. A collaborative was convened by volunteer and staff leaders from several MS societies with the mission to expedite the development of effective disease-modifying and symptom management therapies for progressive forms of multiple sclerosis. Through a series of scientific and strategic planning meetings, the collaborative identified and developed new perspectives on five key priority areas for research: experimental models, identification and validation of targets and repurposing opportunities, proof-of-concept clinical trial strategies, clinical outcome measures, and symptom management and rehabilitation. Our conclusions, tackling the impediments in developing therapies for progressive MS will require an integrated, multi-disciplinary approach to enable effective translation of research into therapies for progressive MS. Engagement of the MS research community through an international effort is needed to address and fund these research priorities with the ultimate goal of expediting the development of disease-modifying and symptom-relief treatments for progressive MS.

Setting a research agenda for progressive multiple sclerosis: The International Collaborative on Progressive MS

Science.gov (United States)

Thompson, Alan; Baker, David; Baneke, Peer; Brown, Doug; Browne, Paul; Chandraratna, Dhia; Ciccarelli, Olga; Coetzee, Timothy; Comi, Giancarlo; Feinstein, Anthony; Kapoor, Raj; Lee, Karen; Salvetti, Marco; Sharrock, Kersten; Toosy, Ahmed; Zaratin, Paola; Zuidwijk, Kim

2012-01-01

Despite significant progress in the development of therapies for relapsing MS, progressive MS remains comparatively disappointing. Our objective, in this paper, is to review the current challenges in developing therapies for progressive MS and identify key priority areas for research. A collaborative was convened by volunteer and staff leaders from several MS societies with the mission to expedite the development of effective disease-modifying and symptom management therapies for progressive forms of multiple sclerosis. Through a series of scientific and strategic planning meetings, the collaborative identified and developed new perspectives on five key priority areas for research: experimental models, identification and validation of targets and repurposing opportunities, proof-of-concept clinical trial strategies, clinical outcome measures, and symptom management and rehabilitation. Our conclusions, tackling the impediments in developing therapies for progressive MS will require an integrated, multi-disciplinary approach to enable effective translation of research into therapies for progressive MS. Engagement of the MS research community through an international effort is needed to address and fund these research priorities with the ultimate goal of expediting the development of disease-modifying and symptom-relief treatments for progressive MS. PMID:22917690

Progress in integrated energy-economy-environment model system development

International Nuclear Information System (INIS)

Yasukawa, Shigeru; Mankin, Shuichi; Sato, Osamu; Tadokoro, Yoshihiro; Nakano, Yasuyuki; Nagano, Takao

1987-11-01

The Integrated Energy-Economy-Environment Model System has been developed for providing analytical tools for the system analysis and technology assessments in the field of nuclear research and development. This model system consists of the following four model groups. The first model block installs 5 models and can serve to analyze and generate long-term scenarios on economy-energy-environment evolution. The second model block installs 2 models and can serve to analyze the structural transition phenomena in energy-economy-environment interactions. The third model block installs 2 models and can handle power reactor installation strategy problem and long-term fuel cycle analysis. The fourth model block installs 5 models and codes and can treats cost-benefit-risk analysis and assessments. This report describes mainly the progress and the outlines of application of the model system in these years after the first report on the research and development of the model system (JAERI-M 84 - 139). (author)

Direct modeling of regression effects for transition probabilities in the progressive illness-death model

DEFF Research Database (Denmark)

Azarang, Leyla; Scheike, Thomas; de Uña-Álvarez, Jacobo

2017-01-01

In this work, we present direct regression analysis for the transition probabilities in the possibly non-Markov progressive illness–death model. The method is based on binomial regression, where the response is the indicator of the occupancy for the given state along time. Randomly weighted score...

Effect of fluoxetine on disease progression in a mouse model of ALS

Science.gov (United States)

Koschnitzky, J. E.; Quinlan, K. A.; Lukas, T. J.; Kajtaz, E.; Kocevar, E. J.; Mayers, W. F.; Siddique, T.

2014-01-01

Selective serotonin reuptake inhibitors (SSRIs) and other antidepressants are often prescribed to amyotrophic lateral sclerosis (ALS) patients; however, the impact of these prescriptions on ALS disease progression has not been systematically tested. To determine whether SSRIs impact disease progression, fluoxetine (Prozac, 5 or 10 mg/kg) was administered to mutant superoxide dismutase 1 (SOD1) mice during one of three age ranges: neonatal [postnatal day (P)5–11], adult presymptomatic (P30 to end stage), and adult symptomatic (P70 to end stage). Long-term adult fluoxetine treatment (started at either P30 or P70 and continuing until end stage) had no significant effect on disease progression. In contrast, neonatal fluoxetine treatment (P5-11) had two effects. First, all animals (mutant SOD1G93A and control: nontransgenic and SOD1WT) receiving the highest dose (10 mg/kg) had a sustained decrease in weight from P30 onward. Second, the high-dose SOD1G93A mice reached end stage ∼8 days (∼6% decrease in life span) sooner than vehicle and low-dose animals because of an increased rate of motor impairment. Fluoxetine increases synaptic serotonin (5-HT) levels, which is known to increase spinal motoneuron excitability. We confirmed that 5-HT increases spinal motoneuron excitability during this neonatal time period and therefore hypothesized that antagonizing 5-HT receptors during the same time period would improve disease outcome. However, cyproheptadine (1 or 5 mg/kg), a 5-HT receptor antagonist, had no effect on disease progression. These results show that a brief period of antidepressant treatment during a critical time window (the transition from neonatal to juvenile states) can be detrimental in ALS mouse models. PMID:24598527

Risk estimation of multiple recurrence and progression of non muscle invasive bladder carcinoma using new mathematical models.

Science.gov (United States)

Luján, S; Santamaría, C; Pontones, J L; Ruiz-Cerdá, J L; Trassierra, M; Vera-Donoso, C D; Solsona, E; Jiménez-Cruz, F

2014-12-01

To apply new mathematical models according to Non Muscle Invasive Bladder Carcinoma (NMIBC) biological characteristics and enabling an accurate risk estimation of multiple recurrences and tumor progression. The classical Cox model is not valid for the assessment of this kind of events becausethe time betweenrecurrencesin the same patientmay be stronglycorrelated. These new models for risk estimation of recurrence/progression lead to individualized monitoring and treatment plan. 960 patients with primary NMIBC were enrolled. The median follow-up was 48.1 (3-160) months. Results obtained were validated in 240 patients from other center. Transurethral resection of the bladder (TURB) and random bladder biopsy were performed. Subsequently, adjuvant localized chemotherapy was performed. The variables analyzed were: number and tumor size, age, chemotherapy and histopathology. The endpoints were time to recurrence and time to progression. Cox model and its extensions were used as joint frailty model for multiple recurrence and progression. Model accuracy was calculated using Harrell's concordance index (c-index). 468 (48.8%) patients developed at least one tumor recurrence and tumor progression was reported in 52 (5.4%) patients. Variables for multiple-recurrence risk are: age, grade, number, size, treatment and the number of prior recurrences. All these together with age, stage and grade are the variables for progression risk. Concordance index was 0.64 and 0.85 for multiple recurrence and progression respectively. the high concordance reported besides to the validation process in external source, allow accurate multi-recurrence/progression risk estimation. As consequence, it is possible to schedule a follow-up and treatment individualized plan in new and recurrent NMCB cases. Copyright © 2014 AEU. Published by Elsevier Espana. All rights reserved.

Cell-based multi-parametric model of cleft progression during submandibular salivary gland branching morphogenesis.

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Shayoni Ray

Full Text Available Cleft formation during submandibular salivary gland branching morphogenesis is the critical step initiating the growth and development of the complex adult organ. Previous experimental studies indicated requirements for several epithelial cellular processes, such as proliferation, migration, cell-cell adhesion, cell-extracellular matrix (matrix adhesion, and cellular contraction in cleft formation; however, the relative contribution of each of these processes is not fully understood since it is not possible to experimentally manipulate each factor independently. We present here a comprehensive analysis of several cellular parameters regulating cleft progression during branching morphogenesis in the epithelial tissue of an early embryonic salivary gland at a local scale using an on lattice Monte-Carlo simulation model, the Glazier-Graner-Hogeweg model. We utilized measurements from time-lapse images of mouse submandibular gland organ explants to construct a temporally and spatially relevant cell-based 2D model. Our model simulates the effect of cellular proliferation, actomyosin contractility, cell-cell and cell-matrix adhesions on cleft progression, and it was used to test specific hypotheses regarding the function of these parameters in branching morphogenesis. We use innovative features capturing several aspects of cleft morphology and quantitatively analyze clefts formed during functional modification of the cellular parameters. Our simulations predict that a low epithelial mitosis rate and moderate level of actomyosin contractility in the cleft cells promote cleft progression. Raising or lowering levels of contractility and mitosis rate resulted in non-progressive clefts. We also show that lowered cell-cell adhesion in the cleft region and increased cleft cell-matrix adhesions are required for cleft progression. Using a classifier-based analysis, the relative importance of these four contributing cellular factors for effective cleft

Basic fibroblast growth factor in an animal model of spontaneous mammary tumor progression.

Science.gov (United States)

Kao, Steven; Mo, Jeffrey; Baird, Andrew; Eliceiri, Brian P

2012-06-01

Although basic fibroblast growth factor (FGF2) was the first pro-angiogenic molecule discovered, it has numerous activities on the growth and differentiation of non-vascular cell types. FGF2 is both stimulatory and inhibitory, depending on the cell type evaluated, the experimental design used and the context in which it is tested. Here, we investigated the effects of manipulating endogenous FGF2 on the development of mammary cancer to determine whether its endogenous contribution in vivo is pro- or anti-tumorigenic. Specifically, we examined the effects of FGF2 gene dosing in a cross between a spontaneous breast tumor model (PyVT+ mice) and FGF2-/- (FGF KO) mice. Using these mice, the onset and progression of mammary tumors was determined. As predicted, female FGF2 WT mice developed mammary tumors starting around 60 days after birth and by 80 days, 100% of FGF2 WT female mice had mammary tumors. In contrast, 80% of FGF2 KO female mice had no palpable tumors until nearly three weeks later (85 days) at times when 100% of the WT cohort was tumor positive. All FGF KO mice were tumor-bearing by 115 days. When we compared the onset of mammary tumor development and the tumor progression curves between FGF het and FGF KO mice, we observed a difference, which suggested a gene dosing effect. Analysis of the tumors demonstrated that there were significant differences in tumor size depending on FGF2 status. The delay in tumor onset supports a functional role for FGF2 in mammary tumor progression, but argues against an essential role for FGF2 in overall mammary tumor progression.

Progress report on SYVAC chemical modelling studies during 1984/85

International Nuclear Information System (INIS)

Cross, J.E.; Read, D.; Smith, G.L.; Williams, D.R.

1985-05-01

This report summarises progress made from April 1984 to May 1985 on chemical modelling within the DOE SYVAC project. Three new computer programs; the reaction path codes, PHREEQE and EQ3/6, and the chemical transport simulator CHEMTRN, have been acquired. Their applicability, overall capabilities, ease of use and database requirements are assessed. Coupled approaches to geochemical - hydrological modelling and the use of CHEMTRN is discussed. Modelling has been performed in connection with the ''Dry Run Assessment''. Speciation and solubilities of the actinides were simulated, assuming the vault to be a concrete solution and the geosphere to be represented by Harwell site groundwater analyses. Model verification and validation by collaboration with experimentalists and other modellers is discussed. (author)

A joint frailty-copula model between tumour progression and death for meta-analysis.

Science.gov (United States)

Emura, Takeshi; Nakatochi, Masahiro; Murotani, Kenta; Rondeau, Virginie

2017-12-01

Dependent censoring often arises in biomedical studies when time to tumour progression (e.g., relapse of cancer) is censored by an informative terminal event (e.g., death). For meta-analysis combining existing studies, a joint survival model between tumour progression and death has been considered under semicompeting risks, which induces dependence through the study-specific frailty. Our paper here utilizes copulas to generalize the joint frailty model by introducing additional source of dependence arising from intra-subject association between tumour progression and death. The practical value of the new model is particularly evident for meta-analyses in which only a few covariates are consistently measured across studies and hence there exist residual dependence. The covariate effects are formulated through the Cox proportional hazards model, and the baseline hazards are nonparametrically modeled on a basis of splines. The estimator is then obtained by maximizing a penalized log-likelihood function. We also show that the present methodologies are easily modified for the competing risks or recurrent event data, and are generalized to accommodate left-truncation. Simulations are performed to examine the performance of the proposed estimator. The method is applied to a meta-analysis for assessing a recently suggested biomarker CXCL12 for survival in ovarian cancer patients. We implement our proposed methods in R joint.Cox package.

The complex model of risk and progression of AMD estimation

Directory of Open Access Journals (Sweden)

V. S. Akopyan

2012-01-01

Full Text Available Purpose: to develop a method and a statistical model to estimate individual risk of AMD and the risk for progression to advanced AMD using clinical and genetic risk factors.Methods: A statistical risk assessment model was developed using stepwise binary logistic regression analysis. to estimate the population differences in the prevalence of allelic variants of genes and for the development of models adapted to the population of Moscow region genotyping and assessment of the influence of other risk factors was performed in two groups: patients with differ- ent stages of AMD (n = 74, and control group (n = 116. Genetic risk factors included in the study: polymorphisms in the complement system genes (C3 and CFH, genes at 10q26 locus (ARMS2 and HtRA1, polymorphism in the mitochondrial gene Mt-ND2. Clinical risk factors included in the study: age, gender, high body mass index, smoking history.Results: A comprehensive analysis of genetic and clinical risk factors for AMD in the study group was performed. Compiled statis- tical model assessment of individual risk of AMD, the sensitivity of the model — 66.7%, specificity — 78.5%, AUC = 0.76. Risk factors of late AMD, compiled a statistical model describing the probability of late AMD, the sensitivity of the model — 66.7%, specificity — 78.3%, AUC = 0.73. the developed system allows determining the most likely version of the current late AMD: dry or wet.Conclusion: the developed test system and the mathematical algorhythm for determining the risk of AMD, risk of progression to advanced AMD have fair diagnostic informative and promising for use in clinical practice.

Progressive Conversion from B-rep to BSP for Streaming Geometric Modeling.

Science.gov (United States)

Bajaj, Chandrajit; Paoluzzi, Alberto; Scorzelli, Giorgio

2006-01-01

We introduce a novel progressive approach to generate a Binary Space Partition (BSP) tree and a convex cell decomposition for any input triangles boundary representation (B-rep), by utilizing a fast calculation of the surface inertia. We also generate a solid model at progressive levels of detail. This approach relies on a variation of standard BSP tree generation, allowing for labeling cells as in, out and fuzzy, and which permits a comprehensive representation of a solid as the Hasse diagram of a cell complex. Our new algorithm is embedded in a streaming computational framework, using four types of dataflow processes that continuously produce, transform, combine or consume subsets of cells depending on their number or input/output stream. A varied collection of geometric modeling techniques are integrated in this streaming framework, including polygonal, spline, solid and heterogeneous modeling with boundary and decompositive representations, Boolean set operations, Cartesian products and adaptive refinement. The real-time B-rep to BSP streaming results we report in this paper are a large step forward in the ultimate unification of rapid conceptual and detailed shape design methodologies.

Loss of Ikbkap Causes Slow, Progressive Retinal Degeneration in a Mouse Model of Familial Dysautonomia.

Science.gov (United States)

Ueki, Yumi; Ramirez, Grisela; Salcedo, Ernesto; Stabio, Maureen E; Lefcort, Frances

2016-01-01

Familial dysautonomia (FD) is an autosomal recessive congenital neuropathy that is caused by a mutation in the gene for inhibitor of kappa B kinase complex-associated protein ( IKBKAP ). Although FD patients suffer from multiple neuropathies, a major debilitation that affects their quality of life is progressive blindness. To determine the requirement for Ikbkap in the developing and adult retina, we generated Ikbkap conditional knockout (CKO) mice using a TUBA1a promoter-Cre ( Tα1-Cre ). In the retina, Tα1-Cre expression is detected predominantly in retinal ganglion cells (RGCs). At 6 months, significant loss of RGCs had occurred in the CKO retinas, with the greatest loss in the temporal retina, which is the same spatial phenotype observed in FD, Leber hereditary optic neuropathy, and dominant optic atrophy. Interestingly, the melanopsin-positive RGCs were resistant to degeneration. By 9 months, signs of photoreceptor degeneration were observed, which later progressed to panretinal degeneration, including RGC and photoreceptor loss, optic nerve thinning, Müller glial activation, and disruption of layers. Taking these results together, we conclude that although Ikbkap is not required for normal development of RGCs, its loss causes a slow, progressive RGC degeneration most severely in the temporal retina, which is later followed by indirect photoreceptor loss and complete retinal disorganization. This mouse model of FD is not only useful for identifying the mechanisms mediating retinal degeneration, but also provides a model system in which to attempt to test therapeutics that may mitigate the loss of vision in FD patients.

Toward a Progress Indicator for Machine Learning Model Building and Data Mining Algorithm Execution: A Position Paper

Science.gov (United States)

Luo, Gang

2017-01-01

For user-friendliness, many software systems offer progress indicators for long-duration tasks. A typical progress indicator continuously estimates the remaining task execution time as well as the portion of the task that has been finished. Building a machine learning model often takes a long time, but no existing machine learning software supplies a non-trivial progress indicator. Similarly, running a data mining algorithm often takes a long time, but no existing data mining software provides a nontrivial progress indicator. In this article, we consider the problem of offering progress indicators for machine learning model building and data mining algorithm execution. We discuss the goals and challenges intrinsic to this problem. Then we describe an initial framework for implementing such progress indicators and two advanced, potential uses of them, with the goal of inspiring future research on this topic. PMID:29177022

A new model of progressive pulmonary fibrosis in rats

Energy Technology Data Exchange (ETDEWEB)

Last, J.A.; Gelzleichter, T.R.; Pinkerton, K.E.; Walker, R.M.; Witschi, H. (Univ. of California, Davis (United States))

1993-08-01

Sprague-Dawley rats were exposed for 6 h daily to 0.8 ppm of ozone and 14.4 ppm of nitrogen dioxide. Approximately 7 to 10 wk after the initiation of exposure, animals began to demonstrate respiratory insufficiency and severe weight loss. About half of the rats died between Days 55 and 78 of exposure; no overt ill effects were observed in animals exposed to filtered air, to ozone alone, or to nitrogen dioxide. Biochemical findings in animals exposed to ozone and nitrogen dioxide included increased lung content of DNA, protein, collagen, and elastin, which was about 300% higher than the control values. The collagen-specific crosslink hydroxy-pyridinium, a biomarker for mature collagen in the lung, was decreased by about 40%. These results are consistent with extensive breakdown and remodeling of the lung parenchyma and its associated vasculature. Histopathologic evaluation showed severe fibrosis, alveolar collapse, honeycombing, macrophage and mast cell accumulation, vascular smooth muscle hypertrophy, and other indications of severe progressive interstitial pulmonary fibrosis and end-stage lung disease. This unique animal model of progressive pulmonary fibrosis resembles the final stages of human idiopathic pulmonary fibrosis and should facilitate studying underlying mechanisms and potential therapy of progressive pulmonary fibrosis.

Evaluating significance in linear mixed-effects models in R.

Science.gov (United States)

Luke, Steven G

2017-08-01

Mixed-effects models are being used ever more frequently in the analysis of experimental data. However, in the lme4 package in R the standards for evaluating significance of fixed effects in these models (i.e., obtaining p-values) are somewhat vague. There are good reasons for this, but as researchers who are using these models are required in many cases to report p-values, some method for evaluating the significance of the model output is needed. This paper reports the results of simulations showing that the two most common methods for evaluating significance, using likelihood ratio tests and applying the z distribution to the Wald t values from the model output (t-as-z), are somewhat anti-conservative, especially for smaller sample sizes. Other methods for evaluating significance, including parametric bootstrapping and the Kenward-Roger and Satterthwaite approximations for degrees of freedom, were also evaluated. The results of these simulations suggest that Type 1 error rates are closest to .05 when models are fitted using REML and p-values are derived using the Kenward-Roger or Satterthwaite approximations, as these approximations both produced acceptable Type 1 error rates even for smaller samples.

Significant progress towards development of the low-level radioactive waste disposal facility in Illinois

International Nuclear Information System (INIS)

Klebe, M.; Henry, T.L.; Corpstein, P.

1996-01-01

Development of disposal sites for low-level radioactive waste is a complicated legal, regulatory and public sector process. Development of the low-level radioactive waste disposal facility to support generators in Illinois and Kentucky is well under way. Significant progress has been made to re-engineer the siting development process capitalizing on prior lessons learned and a recommitment from Illinois state leadership assuring the future success of the program. Comparisons of why this new process will succeed are the major focus of this paper. Specific changes in approach from the previous process including changes in the Illinois Management Act (Management Act), creation of the Illinois Low-Level Radioactive Waste Siting Task Group (Task Group), new roles for the Illinois State Geologic Survey and Illinois State Water Survey (Scientific Surveys) and the Illinois Department of Nuclear Safety (IDNS), a new contractor reliance approach and increased confidence on the open-quote science close-quote are the major contrasts between the previous process and the new process currently underway

Progress on nuclear data work at Nankai University in 1995

Energy Technology Data Exchange (ETDEWEB)

Chonghai, Cai; Ziqiang, Yu; Yixin, Zuo [Nankai Univ., Tianjin (China)

1996-06-01

The research work on nuclear model programs and QMD theory are reported. Two nuclear models programs CCRMN and OMHF have finished in 1995. The theoretical research on quantum molecular dynamics (QMD) have made significant progress in 1995.

Evaluation of F8-TNF-α in Models of Early and Progressive Metastatic Osteosarcoma

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Bernhard Robl

2017-06-01

Full Text Available The targeted delivery of tumor necrosis factor-α (TNF-α with antibodies specific to splice isoforms of fibronectin [e.g., F8-TNF, specific to the extra-domain A (EDA domain of fibronectin] has already shown efficacy against experimental sarcomas but has not yet been investigated in orthotopic sarcomas. Here, we investigated F8-TNF in a syngeneic K7 M2–derived orthotopic model of osteosarcoma as a treatment against pulmonary metastases, the most frequent cause of osteosarcoma-related death. Immunofluorescence on human osteosarcoma tissue confirmed the presence of EDA in primary tumors (PTs as well as metastases. In mice, the efficacy of F8-TNF against PTs and early pulmonary metastases was evaluated. Intratibial PT growth was not affected by F8-TNF, yet early micrometastases were reduced possibly due to an F8-TNF–dependent attraction of pulmonary CD4+, CD8+, and natural killer cells. Furthermore, immunofluorescence revealed stronger expression of EDA in early pulmonary metastases compared with PT tissue. To study progressing pulmonary metastases, a hind limb amputation model was established, and the efficacy of F8-TNF, alone or combined with doxorubicin, was investigated. Despite the presence of EDA in metastases, no inhibition of progressive metastatic growth was detected. No significant differences in numbers of CD4+ or CD8+ cells or F4/80+ and Ly6G+ myeloid-derived cells were observed, although a strong association between metastatic growth and presence of pulmonary Ly6G+ myeloid-derived cells was detected. In summary, these findings demonstrate the potential of F8-TNF in activating the immune system and reducing early metastatic growth yet suggest a lack of efficacy of F8-TNF alone or combined with doxorubicin against progressing osteosarcoma metastases.

Evaluation of F8-TNF-α in Models of Early and Progressive Metastatic Osteosarcoma.

Science.gov (United States)

Robl, Bernhard; Botter, Sander Martijn; Boro, Aleksandar; Meier, Daniela; Neri, Dario; Fuchs, Bruno

2017-06-01

The targeted delivery of tumor necrosis factor-α (TNF-α) with antibodies specific to splice isoforms of fibronectin [e.g., F8-TNF, specific to the extra-domain A (EDA) domain of fibronectin] has already shown efficacy against experimental sarcomas but has not yet been investigated in orthotopic sarcomas. Here, we investigated F8-TNF in a syngeneic K7 M2-derived orthotopic model of osteosarcoma as a treatment against pulmonary metastases, the most frequent cause of osteosarcoma-related death. Immunofluorescence on human osteosarcoma tissue confirmed the presence of EDA in primary tumors (PTs) as well as metastases. In mice, the efficacy of F8-TNF against PTs and early pulmonary metastases was evaluated. Intratibial PT growth was not affected by F8-TNF, yet early micrometastases were reduced possibly due to an F8-TNF-dependent attraction of pulmonary CD4 + , CD8 + , and natural killer cells. Furthermore, immunofluorescence revealed stronger expression of EDA in early pulmonary metastases compared with PT tissue. To study progressing pulmonary metastases, a hind limb amputation model was established, and the efficacy of F8-TNF, alone or combined with doxorubicin, was investigated. Despite the presence of EDA in metastases, no inhibition of progressive metastatic growth was detected. No significant differences in numbers of CD4 + or CD8 + cells or F4/80 + and Ly6G + myeloid-derived cells were observed, although a strong association between metastatic growth and presence of pulmonary Ly6G + myeloid-derived cells was detected. In summary, these findings demonstrate the potential of F8-TNF in activating the immune system and reducing early metastatic growth yet suggest a lack of efficacy of F8-TNF alone or combined with doxorubicin against progressing osteosarcoma metastases. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Modeling Freedom From Progression for Standard-Risk Medulloblastoma: A Mathematical Tumor Control Model With Multiple Modes of Failure

International Nuclear Information System (INIS)

Brodin, N. Patrik; Vogelius, Ivan R.; Björk-Eriksson, Thomas; Munck af Rosenschöld, Per; Bentzen, Søren M.

2013-01-01

Purpose: As pediatric medulloblastoma (MB) is a relatively rare disease, it is important to extract the maximum information from trials and cohort studies. Here, a framework was developed for modeling tumor control with multiple modes of failure and time-to-progression for standard-risk MB, using published pattern of failure data. Methods and Materials: Outcome data for standard-risk MB published after 1990 with pattern of relapse information were used to fit a tumor control dose-response model addressing failures in both the high-dose boost volume and the elective craniospinal volume. Estimates of 5-year event-free survival from 2 large randomized MB trials were used to model the time-to-progression distribution. Uncertainty in freedom from progression (FFP) was estimated by Monte Carlo sampling over the statistical uncertainty in input data. Results: The estimated 5-year FFP (95% confidence intervals [CI]) for craniospinal doses of 15, 18, 24, and 36 Gy while maintaining 54 Gy to the posterior fossa was 77% (95% CI, 70%-81%), 78% (95% CI, 73%-81%), 79% (95% CI, 76%-82%), and 80% (95% CI, 77%-84%) respectively. The uncertainty in FFP was considerably larger for craniospinal doses below 18 Gy, reflecting the lack of data in the lower dose range. Conclusions: Estimates of tumor control and time-to-progression for standard-risk MB provides a data-driven setting for hypothesis generation or power calculations for prospective trials, taking the uncertainties into account. The presented methods can also be applied to incorporate further risk-stratification for example based on molecular biomarkers, when the necessary data become available

Inhibition of 5-Lipoxygenase inhibitor zileuton in high-fat diet-induced nonalcoholic fatty liver disease progression model

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Kuifen Ma

2017-11-01

Full Text Available Objective(s: Arachidonic Acid/5-lipoxygenase (AA/5-LOX pathway connects lipid metabolism and proinflammatory cytokine, which are both related to the development and progression of nonalcoholic fatty liver disease (NAFLD. Therefore, the present study was designed to investigate the role of AA/5-LOX pathway in progression of NAFLD, and the effect of zileuton, an inhibitor of 5-LOX, in this model. Materials and Methods: Animal model for progression of NAFLD was established via feeding high saturated fat diet (HFD. Liver function, HE staining, NAFLD activity score (NAS were used to evaluate NAFLD progression. We detected the lipid metabolism substrates: free fatty acids (FFA and AA, products: cysteinyl-leukotrienes (CysLTs, and changes in gene and protein level of key enzyme in AA/5-LOX pathway including PLA2 and 5-LOX. Furthermore, we determined whether NAFLD progression pathway was delayed or reversed when zileuton (1-[1-(1-benzothiophen-2-ylethyl]-1-hydroxyurea was administrated. Results: Rat model for progression of NAFLD was well established as analyzed by liver transaminase activities, hematoxylin-eosin (HE staining and NAS. The concentrations of substrates and products in AA/5-LOX pathway were increased with the progression of NAFLD. mRNA and protein expression of PLA2 and 5-LOX were all enhanced. Moreover, administration of zileuton inhibited AA/5-LOX pathway and reversed the increased transamine activities and NAS. Conclusion: AA/5-LOX pathway promotes the progression of NAFLD, which can be reversed by zileuton.

An Innovative Academic Progression in Nursing Model in New York State.

Science.gov (United States)

Markowitz, Marianne; Bastable, Susan B

2017-05-01

The Dual Degree Partnership in Nursing (DDPN) is a unique articulation model created in 2005 between two nursing programs that provides a seamless pathway for students to earn both an associate's degree and a bachelor's degree in nursing while benefiting from the strengths of each program. Archival data has been systematically collected for a decade on admission, progression, retention, satisfaction, graduation, and NCLEX-RN pass rates to measure the reliability, validity, and integrity of this DDPN model for nursing education. The findings demonstrate consistent performance and positive outcomes on all factors measured, which have been benchmarked against available state and national results. This innovative approach to academic progression in nursing is replicable and serves as a prototype to educate more nurses at the baccalaureate level, which directly contributes to the Institute of Medicine's goal of 80% of RNs having a minimum of a bachelor's degree by 2020. [J Nurs Educ. 2017;56(5):266-273.]. Copyright 2017, SLACK Incorporated.

Accessing key steps of human tumor progression in vivo by using an avian embryo model

Science.gov (United States)

Hagedorn, Martin; Javerzat, Sophie; Gilges, Delphine; Meyre, Aurélie; de Lafarge, Benjamin; Eichmann, Anne; Bikfalvi, Andreas

2005-02-01

Experimental in vivo tumor models are essential for comprehending the dynamic process of human cancer progression, identifying therapeutic targets, and evaluating antitumor drugs. However, current rodent models are limited by high costs, long experimental duration, variability, restricted accessibility to the tumor, and major ethical concerns. To avoid these shortcomings, we investigated whether tumor growth on the chick chorio-allantoic membrane after human glioblastoma cell grafting would replicate characteristics of the human disease. Avascular tumors consistently formed within 2 days, then progressed through vascular endothelial growth factor receptor 2-dependent angiogenesis, associated with hemorrhage, necrosis, and peritumoral edema. Blocking of vascular endothelial growth factor receptor 2 and platelet-derived growth factor receptor signaling pathways by using small-molecule receptor tyrosine kinase inhibitors abrogated tumor development. Gene regulation during the angiogenic switch was analyzed by oligonucleotide microarrays. Defined sample selection for gene profiling permitted identification of regulated genes whose functions are associated mainly with tumor vascularization and growth. Furthermore, expression of known tumor progression genes identified in the screen (IL-6 and cysteine-rich angiogenic inducer 61) as well as potential regulators (lumican and F-box-only 6) follow similar patterns in patient glioma. The model reliably simulates key features of human glioma growth in a few days and thus could considerably increase the speed and efficacy of research on human tumor progression and preclinical drug screening. angiogenesis | animal model alternatives | glioblastoma

Tumour model with intrusive morphology, progressive phenotypical heterogeneity and memory

Science.gov (United States)

Atangana, Abdon; Alqahtani, Rubayyi T.

2018-03-01

The model of a tumour, taking into account invasive morphology, progressive phenotypical heterogeneity and also memory, is developed and analyzed in this paper. Three models are investigated: first we consider the model describing the proliferation concentrates in proximity of tumour boundaries, in which the oxygen levels are pronounced. Then we consider the model where the oxygen around the tumour is considered to be unchanged by the vascular system. Finally, we investigate the model of growth of tumours using the concept of non-local operators with the Mittag-Leffler kernel. We provide the numerical solution using the extended 3/8 Simpson method for the new trends of fractional integration for the proliferation concentrates in the proximity of the tumour model. Then we provide the exact solutions of the Gompertz model with three different fractional differentiations involving power law, exponential decay law and the Mittag-Leffler law.

Modelling gas migration in fractured rock. A contribution to the EU's PROGRESS project

International Nuclear Information System (INIS)

Humm, J.; Robinson, P.; Clark, K.

2001-01-01

make comparison of results uninformative. Despite this disagreement, the developed approach of using a time-step approach to move fluid mass, with a steady-state pressure calculation at each step, appears to be capable of producing realistic behaviour. The dynamic model also produces behaviours, such as intermittence, which would not be expected of simpler models. The calculation time for the model allows a single fracture calculation to be undertaken in tens of minutes to hours, depending on the problem size and the chosen time-step. Clearly, scaling this to a fracture network would be impractical. Moreover, the data requirements cannot be met in any precise way. The limited modelling work carried out here supports the existing understanding that gas will find its way through heterogeneous systems by the easiest route. As far as gas migration through the geosphere in general is concerned, it may be considered conservative to assume that there is no significant delay and that gas will tend to reach the surface quickly. A comparison with the FRAC model is also made. The uncertainties in the measurements of aperture and gas fractions within the fracture that was modelled make it impossible to determine which model is most appropriate for such systems. Both models support the existing understanding that gas will find its way through heterogeneous systems by the easiest route available, i.e. through fractures with the greatest apertures. Finally, a summary is given of the key results from the PROGRESS Project (Research into Gas Generation and Migration in Radioactive Waste Repository Systems, carried out as part of the European Commission's IV th framework R and D programme)

Increased diacylglycerols characterize hepatic lipid changes in progression of human nonalcoholic fatty liver disease; comparison to a murine model.

Science.gov (United States)

Gorden, D Lee; Ivanova, Pavlina T; Myers, David S; McIntyre, J Oliver; VanSaun, Michael N; Wright, J Kelly; Matrisian, Lynn M; Brown, H Alex

2011-01-01

The spectrum of nonalcoholic fatty liver disease (NAFLD) includes steatosis, nonalcoholic steatohepatitis (NASH), and progression to cirrhosis. While differences in liver lipids between disease states have been reported, precise composition of phospholipids and diacylglycerols (DAG) at a lipid species level has not been previously described. The goal of this study was to characterize changes in lipid species through progression of human NAFLD using advanced lipidomic technology and compare this with a murine model of early and advanced NAFLD. Utilizing mass spectrometry lipidomics, over 250 phospholipid and diacylglycerol species (DAGs) were identified in normal and diseased human and murine liver extracts. Significant differences between phospholipid composition of normal and diseased livers were demonstrated, notably among DAG species, consistent with previous reports that DAG transferases are involved in the progression of NAFLD and liver fibrosis. In addition, a novel phospholipid species (ether linked phosphatidylinositol) was identified in human cirrhotic liver extracts. Using parallel lipidomics analysis of murine and human liver tissues it was determined that mice maintained on a high-fat diet provide a reproducible model of NAFLD in regards to specificity of lipid species in the liver. These studies demonstrated that novel lipid species may serve as markers of advanced liver disease and importantly, marked increases in DAG species are a hallmark of NAFLD. Elevated DAGs may contribute to altered triglyceride, phosphatidylcholine (PC), and phosphatidylethanolamine (PE) levels characteristic of the disease and specific DAG species might be important lipid signaling molecules in the progression of NAFLD.

Gradient models in molecular biophysics: progress, challenges, opportunities

Science.gov (United States)

Bardhan, Jaydeep P.

2013-12-01

In the interest of developing a bridge between researchers modeling materials and those modeling biological molecules, we survey recent progress in developing nonlocal-dielectric continuum models for studying the behavior of proteins and nucleic acids. As in other areas of science, continuum models are essential tools when atomistic simulations (e.g., molecular dynamics) are too expensive. Because biological molecules are essentially all nanoscale systems, the standard continuum model, involving local dielectric response, has basically always been dubious at best. The advanced continuum theories discussed here aim to remedy these shortcomings by adding nonlocal dielectric response. We begin by describing the central role of electrostatic interactions in biology at the molecular scale, and motivate the development of computationally tractable continuum models using applications in science and engineering. For context, we highlight some of the most important challenges that remain, and survey the diverse theoretical formalisms for their treatment, highlighting the rigorous statistical mechanics that support the use and improvement of continuum models. We then address the development and implementation of nonlocal dielectric models, an approach pioneered by Dogonadze, Kornyshev, and their collaborators almost 40 years ago. The simplest of these models is just a scalar form of gradient elasticity, and here we use ideas from gradient-based modeling to extend the electrostatic model to include additional length scales. The review concludes with a discussion of open questions for model development, highlighting the many opportunities for the materials community to leverage its physical, mathematical, and computational expertise to help solve one of the most challenging questions in molecular biology and biophysics.

From goal motivation to goal progress: the mediating role of coping in the Self-Concordance Model.

Science.gov (United States)

Gaudreau, Patrick; Carraro, Natasha; Miranda, Dave

2012-01-01

The present studies examined the mediating role of self-regulatory mechanisms in the relationship between goal motivation and goal progress in the Self-Concordance Model. First, a systematic review, using meta-analytical path analysis, supported the mediating role of effort and action planning in the positive association between autonomous goal motivation and goal progress. Second, results from two additional empirical studies, using structural equation modeling, lent credence to the mediating role of coping in the relationship between goal motivation and goal progress of university students. Autonomous goal motivation was positively associated with task-oriented coping, which predicted greater goal progress during midterm exams (Study 1, N=702) and at the end of the semester in a different sample (Study 2, N=167). Controlled goal motivation was associated with greater disengagement-oriented coping (Study 1 and Study 2) and lesser use of task-oriented coping (Study 2), which reduced goal progress. These results held up after controlling for perceived stress (Study 2). Our findings highlight the importance of coping in the "inception-to-attainment" goal process because autonomous goal motivation indirectly rather than directly predicts goal progress of university students through their usage of task-oriented coping.

A simplified baseline prediction model for joint damage progression in rheumatoid arthritis: a step toward personalized medicine.

Science.gov (United States)

de Punder, Yvonne M R; van Riel, Piet L C M; Fransen, Jaap

2015-03-01

To compare the performance of an extended model and a simplified prognostic model for joint damage in rheumatoid arthritis (RA) based on 3 baseline risk factors: anticyclic citrullinated peptide antibodies (anti-CCP), erosions, and acute-phase reaction. Data were used from the Nijmegen early RA cohort. An extended model and a simplified baseline prediction model were developed to predict joint damage progression between 0 and 3 years. Joint damage progression was assessed using the Ratingen score. In the extended model, prediction factors were positivity for anti-CCP and/or rheumatoid factor, the level of erythrocyte sedimentation rate, and the quantity of erosions. The prediction score was calculated as the sum of the regression coefficients. In the simplified model, the prediction factors were dichotomized and the number of risk factors was counted. Performances of both models were compared using discrimination and calibration. The models were internally validated using bootstrapping. The extended model resulted in a prediction score between 0 and 5.6 with an area under the receiver-operation characteristic (ROC) curve of 0.77 (95% CI 0.72-0.81). The simplified model resulted in a prediction score between 0 and 3. This model had an area under the ROC curve of 0.75 (95% CI 0.70-0.80). In internal validation, the 2 models showed reasonably well the agreement between observed and predicted probabilities for joint damage progression (Hosmer-Lemeshow test p > 0.05 and calibration slope near 1.0). A simple prediction model for joint damage progression in early RA, by only counting the number of risk factors, has adequate performance. This facilitates the translation of the theoretical prognostic models to daily clinical practice.

Quo natas, Danio?—Recent Progress in Modeling Cancer in Zebrafish

Directory of Open Access Journals (Sweden)

Stefanie Kirchberger

2017-08-01

Full Text Available Over the last decade, zebrafish has proven to be a powerful model in cancer research. Zebrafish form tumors that histologically and genetically resemble human cancers. The live imaging and cost-effective compound screening possible with zebrafish especially complement classic mouse cancer models. Here, we report recent progress in the field, including genetically engineered zebrafish cancer models, xenotransplantation of human cancer cells into zebrafish, promising approaches toward live investigation of the tumor microenvironment, and identification of therapeutic strategies by performing compound screens on zebrafish cancer models. Given the recent advances in genome editing, personalized zebrafish cancer models are now a realistic possibility. In addition, ongoing automation will soon allow high-throughput compound screening using zebrafish cancer models to be part of preclinical precision medicine approaches.

EGFR inhibitor erlotinib delays disease progression but does not extend survival in the SOD1 mouse model of ALS.

Directory of Open Access Journals (Sweden)

Claire E Le Pichon

Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal neurodegenerative disease that causes progressive paralysis due to motor neuron death. Several lines of published evidence suggested that inhibition of epidermal growth factor receptor (EGFR signaling might protect neurons from degeneration. To test this hypothesis in vivo, we treated the SOD1 transgenic mouse model of ALS with erlotinib, an EGFR inhibitor clinically approved for oncology indications. Although erlotinib failed to extend ALS mouse survival it did provide a modest but significant delay in the onset of multiple behavioral measures of disease progression. However, given the lack of protection of motor neuron synapses and the lack of survival extension, the small benefits observed after erlotinib treatment appear purely symptomatic, with no modification of disease course.

A model to calculate the progression of the centre of pressure under the foot during gait analysis.

Science.gov (United States)

Louey, Melissa Gar Yee; Mudge, Anita; Wojciechowski, Elizabeth; Sangeux, Morgan

2017-09-01

Pedobarography and the centre of pressure (COP) progression is useful to understand foot function. Pedobarography is often unavailable in gait laboratories or completed asynchronously to kinematic and kinetic data collection. This paper presents a model that allows calculation of COP progression synchronously using force plate data. The model is an adjunct to Plug-In-Gait and was applied to 49 typically developing children to create reference COP data. COP progressions were noted to spend 8% of stance behind the ankle joint centre, traverse lateral of the longitudinal axis of the foot through the midfoot for 76% of stance and finishing past the second metatarsal head on the medial side for 16% of stance. It is hoped the model will bridge the information gap for gait laboratories lacking pedobarography during foot assessments and will open up the possibility of retrospective research into COP progression based indices on kinematic data. Copyright © 2017 Elsevier B.V. All rights reserved.

Measurements and models for hazardous chemical and mixed wastes. 1998 annual progress report

International Nuclear Information System (INIS)

Holcomb, C.; Louie, B.; Mullins, M.E.; Outcalt, S.L.; Rogers, T.N.; Watts, L.

1998-01-01

'Aqueous waste of various chemical compositions constitutes a significant fraction of the total waste produced by industry in the US. A large quantity of the waste generated by the US chemical process industry is waste water. In addition, the majority of the waste inventory at DoE sites previously used for nuclear weapons production is aqueous waste. Large quantities of additional aqueous waste are expected to be generated during the clean-up of those sites. In order to effectively treat, safely handle, and properly dispose of these wastes, accurate and comprehensive knowledge of basic thermophysical property information is paramount. This knowledge will lead to huge savings by aiding in the design and optimization of treatment and disposal processes. The main objectives of this project are: Develop and validate models that accurately predict the phase equilibria and thermodynamic properties of hazardous aqueous systems necessary for the safe handling and successful design of separation and treatment processes for hazardous chemical and mixed wastes. Accurately measure the phase equilibria and thermodynamic properties of a representative system (water + acetone + isopropyl alcohol + sodium nitrate) over the applicable ranges of temperature, pressure, and composition to provide the pure component, binary, ternary, and quaternary experimental data required for model development. As of May, 1998, nine months into the first year of a three year project, the authors have made significant progress in the database development, have begun testing the models, and have been performance testing the apparatus on the pure components.'

Gradient Models in Molecular Biophysics: Progress, Challenges, Opportunities.

Science.gov (United States)

Bardhan, Jaydeep P

2013-12-01

In the interest of developing a bridge between researchers modeling materials and those modeling biological molecules, we survey recent progress in developing nonlocal-dielectric continuum models for studying the behavior of proteins and nucleic acids. As in other areas of science, continuum models are essential tools when atomistic simulations (e.g. molecular dynamics) are too expensive. Because biological molecules are essentially all nanoscale systems, the standard continuum model, involving local dielectric response, has basically always been dubious at best. The advanced continuum theories discussed here aim to remedy these shortcomings by adding features such as nonlocal dielectric response, and nonlinearities resulting from dielectric saturation. We begin by describing the central role of electrostatic interactions in biology at the molecular scale, and motivate the development of computationally tractable continuum models using applications in science and engineering. For context, we highlight some of the most important challenges that remain and survey the diverse theoretical formalisms for their treatment, highlighting the rigorous statistical mechanics that support the use and improvement of continuum models. We then address the development and implementation of nonlocal dielectric models, an approach pioneered by Dogonadze, Kornyshev, and their collaborators almost forty years ago. The simplest of these models is just a scalar form of gradient elasticity, and here we use ideas from gradient-based modeling to extend the electrostatic model to include additional length scales. The paper concludes with a discussion of open questions for model development, highlighting the many opportunities for the materials community to leverage its physical, mathematical, and computational expertise to help solve one of the most challenging questions in molecular biology and biophysics.

Gradient Models in Molecular Biophysics: Progress, Challenges, Opportunities

Science.gov (United States)

Bardhan, Jaydeep P.

2014-01-01

In the interest of developing a bridge between researchers modeling materials and those modeling biological molecules, we survey recent progress in developing nonlocal-dielectric continuum models for studying the behavior of proteins and nucleic acids. As in other areas of science, continuum models are essential tools when atomistic simulations (e.g. molecular dynamics) are too expensive. Because biological molecules are essentially all nanoscale systems, the standard continuum model, involving local dielectric response, has basically always been dubious at best. The advanced continuum theories discussed here aim to remedy these shortcomings by adding features such as nonlocal dielectric response, and nonlinearities resulting from dielectric saturation. We begin by describing the central role of electrostatic interactions in biology at the molecular scale, and motivate the development of computationally tractable continuum models using applications in science and engineering. For context, we highlight some of the most important challenges that remain and survey the diverse theoretical formalisms for their treatment, highlighting the rigorous statistical mechanics that support the use and improvement of continuum models. We then address the development and implementation of nonlocal dielectric models, an approach pioneered by Dogonadze, Kornyshev, and their collaborators almost forty years ago. The simplest of these models is just a scalar form of gradient elasticity, and here we use ideas from gradient-based modeling to extend the electrostatic model to include additional length scales. The paper concludes with a discussion of open questions for model development, highlighting the many opportunities for the materials community to leverage its physical, mathematical, and computational expertise to help solve one of the most challenging questions in molecular biology and biophysics. PMID:25505358

Development and Validation of a Model to Determine Risk of Progression of Barrett's Esophagus to Neoplasia.

Science.gov (United States)

Parasa, Sravanthi; Vennalaganti, Sreekar; Gaddam, Srinivas; Vennalaganti, Prashanth; Young, Patrick; Gupta, Neil; Thota, Prashanthi; Cash, Brooks; Mathur, Sharad; Sampliner, Richard; Moawad, Fouad; Lieberman, David; Bansal, Ajay; Kennedy, Kevin F; Vargo, John; Falk, Gary; Spaander, Manon; Bruno, Marco; Sharma, Prateek

2018-04-01

A system is needed to determine the risk of patients with Barrett's esophagus for progression to high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). We developed and validated a model to determine of progression to HGD or EAC in patients with BE, based on demographic data and endoscopic and histologic findings at the time of index endoscopy. We performed a longitudinal study of patients with BE at 5 centers in United States and 1 center in Netherlands enrolled in the Barrett's Esophagus Study database from 1985 through 2014. Patients were excluded from the analysis if they had less than 1 year of follow-up, were diagnosed with HGD or EAC within the past year, were missing baseline histologic data, or had no intestinal metaplasia. Seventy percent of the patients were used to derive the model and 30% were used for the validation study. The primary outcome was development of HGD or EAC during the follow-up period (median, 5.9 years). Survival analysis was performed using the Kaplan-Meier method. We assigned a specific number of points to each BE risk factor, and point totals (scores) were used to create categories of low, intermediate, and high risk. We used Cox regression to compute hazard ratios and 95% confidence intervals to determine associations between risk of progression and scores. Of 4584 patients in the database, 2697 were included in our analysis (84.1% men; 87.6% Caucasian; mean age, 55.4 ± 20.1 years; mean body mass index, 27.9 ± 5.5 kg/m 2 ; mean length of BE, 3.7 ± 3.2 cm). During the follow-up period, 154 patients (5.7%) developed HGD or EAC, with an annual rate of progression of 0.95%. Male sex, smoking, length of BE, and baseline-confirmed low-grade dysplasia were significantly associated with progression. Scores assigned identified patients with BE that progressed to HGD or EAC with a c-statistic of 0.76 (95% confidence interval, 0.72-0.80; P Esophagus score) based on male sex, smoking, length of BE, and baseline low-grade dysplasia

Inference of type-specific HPV transmissibility, progression and clearance rates: a mathematical modelling approach.

Directory of Open Access Journals (Sweden)

Helen C Johnson

Full Text Available Quantifying rates governing the clearance of Human Papillomavirus (HPV and its progression to clinical disease, together with viral transmissibility and the duration of naturally-acquired immunity, is essential in estimating the impact of vaccination programmes and screening or testing regimes. However, the complex natural history of HPV makes this difficult. We infer the viral transmissibility, rate of waning natural immunity and rates of progression and clearance of infection of 13 high-risk and 2 non-oncogenic HPV types, making use of a number of rich datasets from Sweden. Estimates of viral transmissibility, clearance of initial infection and waning immunity were derived in a Bayesian framework by fitting a susceptible-infectious-recovered-susceptible (SIRS transmission model to age- and type-specific HPV prevalence data from both a cross-sectional study and a randomised controlled trial (RCT of primary HPV screening. The models fitted well, but over-estimated the prevalence of four high-risk types with respect to the data. Three of these types (HPV-33, -35 and -58 are among the most closely related phylogenetically to the most prevalent HPV-16. The fourth (HPV-45 is the most closely related to HPV-18; the second most prevalent type. We suggest that this may be an indicator of cross-immunity. Rates of progression and clearance of clinical lesions were additionally estimated from longitudinal data gathered as part of the same RCT. Our estimates of progression and clearance rates are consistent with the findings of survival analysis studies and we extend the literature by estimating progression and clearance rates for non-16 and non-18 high-risk types. We anticipate that such type-specific estimates will be useful in the parameterisation of further models and in developing our understanding of HPV natural history.

Coupled Atmosphere-Wave-Ocean Modeling of Tropical Cyclones: Progress, Challenges, and Ways Forward

Science.gov (United States)

Chen, Shuyi

2015-04-01

It has long been recognized that air-sea interaction plays an important role in tropical cyclones (TC) intensity change. However, most current numerical weather prediction (NWP) models are deficient in predicting TC intensity. The extreme high winds, intense rainfall, large ocean waves, and copious sea spray in TCs push the surface-exchange parameters for temperature, water vapor, and momentum into untested regimes. Parameterizations of air-sea fluxes in NWP models are often crude and create "manmade" energy source/sink that does not exist, especially in the absence of a fully interactive ocean in the model. The erroneous surface heat, moisture, and momentum fluxes can cause compounding errors in the model (e.g., precipitation, water vapor, boundary layer properties). The energy source (heat and moisture fluxes from the ocean) and sink (surface friction and wind-induced upper ocean cooling) are critical to TC intensity. However, observations of air-sea fluxes in TCs are very limited, especially in extreme high wind conditions underneath of the eyewall region. The Coupled Boundary Layer Air-Sea Transfer (CBLAST) program was designed to better understand the air-sea interaction, especially in high wind conditions, which included laboratory and coupled model experiments and field campaign in 2003-04 hurricane seasons. Significant progress has been made in better understanding of air-sea exchange coefficients up to 30 m/s, i.e., a leveling off in drag coefficient and relatively invariant exchange coefficient of enthalpy with wind speed. More recently, the Impact of Typhoon on the Ocean in the Pacific (ITOP) field campaign in 2010 has provided an unprecedented data set to study the air-sea fluxes in TCs and their impact on TC structure and intensity. More than 800 GPS dropsondes and 900 AXBTs/AXCTs as well as drifters, floats, and moorings were deployed in TCs, including Typhoons Fanapi and Malakas, and Supertyphoon Megi with a record peak wind speed of more than 80 m

Progress towards Continental River Dynamics modeling

Science.gov (United States)

Yu, Cheng-Wei; Zheng, Xing; Liu, Frank; Maidment, Daivd; Hodges, Ben

2017-04-01

The high-resolution National Water Model (NWM), launched by U.S. National Oceanic and Atmospheric Administration (NOAA) in August 2016, has shown it is possible to provide real-time flow prediction in rivers and streams across the entire continental United States. The next step for continental-scale modeling is moving from reduced physics (e.g. Muskingum-Cunge) to full dynamic modeling with the Saint-Venant equations. The Simulation Program for River Networks (SPRNT) provides a computational approach for the Saint-Venant equations, but obtaining sufficient channel bathymetric data and hydraulic roughness is seen as a critical challenge. However, recent work has shown the Height Above Nearest Drainage (HAND) method can be applied with the National Elevation Dataset (NED) to provide automated estimation of effective channel bathymetry suitable for large-scale hydraulic simulations. The present work examines the use of SPRNT with the National Hydrography Dataset (NHD) and HAND-derived bathymetry for automated generation of rating curves that can be compared to existing data. The approach can, in theory, be applied to every stream reach in the NHD and thus provide flood guidance where none is available. To test this idea we generated 2000+ rating curves in two catchments in Texas and Alabama (USA). Field data from the USGS and flood records from an Austin, Texas flood in May 2015 were used as validation. Large-scale implementation of this idea requires addressing several critical difficulties associated with numerical instabilities, including ill-posed boundary conditions generated in automated model linkages and inconsistencies in the river geometry. A key to future progress is identifying efficient approaches to isolate numerical instability contributors in a large time-space varying solution. This research was supported in part by the National Science Foundation under grant number CCF-1331610.

Filtering data from the collaborative initial glaucoma treatment study for improved identification of glaucoma progression.

Science.gov (United States)

Schell, Greggory J; Lavieri, Mariel S; Stein, Joshua D; Musch, David C

2013-12-21

Open-angle glaucoma (OAG) is a prevalent, degenerate ocular disease which can lead to blindness without proper clinical management. The tests used to assess disease progression are susceptible to process and measurement noise. The aim of this study was to develop a methodology which accounts for the inherent noise in the data and improve significant disease progression identification. Longitudinal observations from the Collaborative Initial Glaucoma Treatment Study (CIGTS) were used to parameterize and validate a Kalman filter model and logistic regression function. The Kalman filter estimates the true value of biomarkers associated with OAG and forecasts future values of these variables. We develop two logistic regression models via generalized estimating equations (GEE) for calculating the probability of experiencing significant OAG progression: one model based on the raw measurements from CIGTS and another model based on the Kalman filter estimates of the CIGTS data. Receiver operating characteristic (ROC) curves and associated area under the ROC curve (AUC) estimates are calculated using cross-fold validation. The logistic regression model developed using Kalman filter estimates as data input achieves higher sensitivity and specificity than the model developed using raw measurements. The mean AUC for the Kalman filter-based model is 0.961 while the mean AUC for the raw measurements model is 0.889. Hence, using the probability function generated via Kalman filter estimates and GEE for logistic regression, we are able to more accurately classify patients and instances as experiencing significant OAG progression. A Kalman filter approach for estimating the true value of OAG biomarkers resulted in data input which improved the accuracy of a logistic regression classification model compared to a model using raw measurements as input. This methodology accounts for process and measurement noise to enable improved discrimination between progression and nonprogression

Modeling the impacts of climate change and technical progress on the wheat yield in inland China: An autoregressive distributed lag approach.

Science.gov (United States)

Zhai, Shiyan; Song, Genxin; Qin, Yaochen; Ye, Xinyue; Lee, Jay

2017-01-01

This study aims to evaluate the impacts of climate change and technical progress on the wheat yield per unit area from 1970 to 2014 in Henan, the largest agricultural province in China, using an autoregressive distributed lag approach. The bounded F-test for cointegration among the model variables yielded evidence of a long-run relationship among climate change, technical progress, and the wheat yield per unit area. In the long run, agricultural machinery and fertilizer use both had significantly positive impacts on the per unit area wheat yield. A 1% increase in the aggregate quantity of fertilizer use increased the wheat yield by 0.19%. Additionally, a 1% increase in machine use increased the wheat yield by 0.21%. In contrast, precipitation during the wheat growth period (from emergence to maturity, consisting of the period from last October to June) led to a decrease in the wheat yield per unit area. In the short run, the coefficient of the aggregate quantity of fertilizer used was negative. Land size had a significantly positive impact on the per unit area wheat yield in the short run. There was no significant short-run or long-run impact of temperature on the wheat yield per unit area in Henan Province. The results of our analysis suggest that climate change had a weak impact on the wheat yield, while technical progress played an important role in increasing the wheat yield per unit area. The results of this study have implications for national and local agriculture policies under climate change. To design well-targeted agriculture adaptation policies for the future and to reduce the adverse effects of climate change on the wheat yield, climate change and technical progress factors should be considered simultaneously. In addition, adaptive measures associated with technical progress should be given more attention.

Modeling the impacts of climate change and technical progress on the wheat yield in inland China: An autoregressive distributed lag approach.

Directory of Open Access Journals (Sweden)

Shiyan Zhai

Full Text Available This study aims to evaluate the impacts of climate change and technical progress on the wheat yield per unit area from 1970 to 2014 in Henan, the largest agricultural province in China, using an autoregressive distributed lag approach. The bounded F-test for cointegration among the model variables yielded evidence of a long-run relationship among climate change, technical progress, and the wheat yield per unit area. In the long run, agricultural machinery and fertilizer use both had significantly positive impacts on the per unit area wheat yield. A 1% increase in the aggregate quantity of fertilizer use increased the wheat yield by 0.19%. Additionally, a 1% increase in machine use increased the wheat yield by 0.21%. In contrast, precipitation during the wheat growth period (from emergence to maturity, consisting of the period from last October to June led to a decrease in the wheat yield per unit area. In the short run, the coefficient of the aggregate quantity of fertilizer used was negative. Land size had a significantly positive impact on the per unit area wheat yield in the short run. There was no significant short-run or long-run impact of temperature on the wheat yield per unit area in Henan Province. The results of our analysis suggest that climate change had a weak impact on the wheat yield, while technical progress played an important role in increasing the wheat yield per unit area. The results of this study have implications for national and local agriculture policies under climate change. To design well-targeted agriculture adaptation policies for the future and to reduce the adverse effects of climate change on the wheat yield, climate change and technical progress factors should be considered simultaneously. In addition, adaptive measures associated with technical progress should be given more attention.

Polyyne-Enriched Extract from Oplopanax elatus Significantly Ameliorates the Progression of Colon Carcinogenesis in ApcMin/+ Mice

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Xin Qiao

2017-09-01

Full Text Available Colorectal cancer (CRC is the third most common cancer in the world. Oplopanax elatus is widely used in traditional medicine. However, little is known about its pharmacological effects and bioactive compounds. We evaluated the effects of the polyyne-enriched extract from O. elatus (PEO on the progression of colon carcinogenesis in ApcMin/+ mice. In addition, these effects were also investigated in HCT116 and SW480 cells. After PEO oral administration (0.2% diet for 12 weeks, PEO significantly improved body weight changes and reduced the tumor burden and tumor multiplicity compared with the untreated mice. Meanwhile, western blot and immunohistochemistry results showed PEO significantly reduced the expression of β-catenin and cyclinD1 in both small intestine and the colon tissues compared with the untreated mice. In addition, PEO treatment significant decreased the cell viability in both HCT116 and SW480 cell lines. It also decreased the levels of β-catenin, cyclinD1, c-myc and p-GSK-3β in HCT116 and SW480 cells at 25 μM. These results indicate that PEO may have potential value in prevention of colon cancer by down-regulating Wnt-related protein.

Building a progressive vertical integration

International Nuclear Information System (INIS)

Charette, D.

2008-01-01

AAER Inc. is a Quebec-based company that manufactures turbines using proven European designs. This presentation discussed the company's business model. The company places an emphasis on identifying strategic and key components currently available for its turbines. Market analyses are performed in order to determine ideal suppliers and define business strategies and needs. The company invests in long-term relationships with its suppliers. Business partners for AAER are of a similar size and have a mutual understanding and respect for the company's business practices. Long-term agreements with suppliers are signed in order to ensure reliability and control over costs. Progressive vertical integration has been achieved by progressively manufacturing key components and integrating a North American supply chain. The company's secure supply chain and progressive vertical integration has significantly reduced financial costs and provided better quality control. It was concluded that vertical integration has also allowed AAER to provide better customer service and reduce transportation costs. tabs., figs

Longitudinal quantification of the gingival crevicular fluid proteome during progression from gingivitis to periodontitis in a canine model.

Science.gov (United States)

Davis, Ian J; Jones, Andrew W; Creese, Andrew J; Staunton, Ruth; Atwal, Jujhar; Chapple, Iain L C; Harris, Stephen; Grant, Melissa M

2016-07-01

Inflammatory periodontal disease is widespread in dogs. This study evaluated site-specific changes in the canine gingival crevicular fluid (GCF) proteome during longitudinal progression from very mild gingivitis to mild periodontitis. Periodontitis diagnosis in dogs requires general anaesthesia with associated risks and costs; our ultimate aim was to develop a periodontitis diagnostic for application in conscious dogs. The objective of this work was to identify potential biomarkers of periodontal disease progression in dogs. Gingival crevicular fluid was sampled from a total of 10 teeth in eight dogs at three different stages of health/disease and samples prepared for quantitative mass spectrometry (data available via ProteomeXchange; identifier PXD003337). A univariate mixed model analysis determined significantly altered proteins between health states and six were evaluated by ELISA. Four hundred and six proteins were identified with 84 present in all samples. The prevalence of 40 proteins was found to be significantly changed in periodontitis relative to gingivitis. ELISA measurements confirmed that haptoglobin was significantly increased. This study demonstrates for the first time that proteins detected by mass spectrometry have potential to identify novel biomarkers for canine periodontal disease. Further work is required to validate additional biomarkers for a periodontitis diagnostic. © 2016 The Authors. Journal of Clinical Periodontology Published by John Wiley & Sons Ltd.

Curcumin slows osteoarthritis progression and relieves osteoarthritis-associated pain symptoms in a post-traumatic osteoarthritis mouse model.

Science.gov (United States)

Zhang, Zhuo; Leong, Daniel J; Xu, Lin; He, Zhiyong; Wang, Angela; Navati, Mahantesh; Kim, Sun J; Hirsh, David M; Hardin, John A; Cobelli, Neil J; Friedman, Joel M; Sun, Hui B

2016-06-03

Curcumin has been shown to have chondroprotective potential in vitro. However, its effect on disease and symptom modification in osteoarthritis (OA) is largely unknown. This study aimed to determine whether curcumin could slow progression of OA and relieve OA-related pain in a mouse model of destabilization of the medial meniscus (DMM). Expression of selected cartilage degradative-associated genes was evaluated in human primary chondrocytes treated with curcumin and curcumin nanoparticles and assayed by real-time PCR. The mice subjected to DMM surgery were orally administered curcumin or topically administered curcumin nanoparticles for 8 weeks. Cartilage integrity was evaluated by Safranin O staining and Osteoarthritis Research Society International (OARSI) score, and by immunohistochemical staining of cleaved aggrecan and type II collagen, and levels of matrix metalloproteinase (MMP)-13 and ADAMTS5. Synovitis and subchondral bone thickness were scored based on histologic images. OA-associated pain and symptoms were evaluated by von Frey assay, and locomotor behavior including distance traveled and rearing. Both curcumin and nanoparticles encapsulating curcumin suppressed mRNA expression of pro-inflammatory mediators IL-1β and TNF-α, MMPs 1, 3, and 13, and aggrecanase ADAMTS5, and upregulated the chondroprotective transcriptional regulator CITED2, in primary cultured chondrocytes in the absence or presence of IL-1β. Oral administration of curcumin significantly reduced OA disease progression, but showed no significant effect on OA pain relief. Curcumin was detected in the infrapatellar fat pad (IPFP) following topical administration of curcumin nanoparticles on the skin of the injured mouse knee. Compared to vehicle-treated controls, topical treatment led to: (1) reduced proteoglycan loss and cartilage erosion and lower OARSI scores, (2) reduced synovitis and subchondral plate thickness, (3) reduced immunochemical staining of type II collagen and aggrecan

A MATHEMATICAL MODEL OF CHP 2000 TYPE PROGRESSIVE GEAR

Directory of Open Access Journals (Sweden)

Paweł Lonkwic

2016-12-01

Full Text Available The project of CHP2000 type progressive gear has been presented in the article. The offered solution from its construction point of view differs from the existing solutions due to the application of Belleville springs packets supporting the braking roller cam and achieving a flexible range of the gear loading. The standard concept of the gear loading within a mathematical and a geometrical model has been presented in the article. The proposed solution can be used in the friction lifts with the loading capacity from 8500 up to 20000 N.

Dose-dependent striatal changes in dopaminergic terminals and alpha-synuclein reactivity in a porcine model of progressive Parkinson’s disease

DEFF Research Database (Denmark)

Nielsen, Mette Slot; Glud, Andreas Nørgaard; Møller, Arne

2011-01-01

to discover effective compounds halting PD progression have so far failed in clinical trials, perhaps because current animal models do not imitate the neuropathological progression of PD well enough. We recently established a progressive large animal PD model in Göttingen minipigs based on chronic infusion......Parkinson disease (PD) is a common neurodegenerative disorder, resulting from a progressive dopaminergic neuron loss in the substantia nigra (SN). Alpha-synuclein positive neuronal inclusion bodies and progressive loss of dopaminergic striatal terminals is also well described in PD. Attempts...... the SN were paraffin embedded and immunohistochemically stained for tyrosine hydroxylase (TH) and alpha-synuclein. Stereological examination of the SN showed progressive nigral neuron loss with increased MPTP dosages. Occasional neuronal staining confined to the cytoplasm and cell membrane was observed...

Recent progress in sorption mechanisms and models

International Nuclear Information System (INIS)

Fedoroff, M.; Lefevre, G.

2005-01-01

reactivity of the different faces. Finally, we know more about the sorption processes and are able to model them with a better agreement with the real sorption mechanisms. However, this progress concerns a few simple systems and a further task will be the application of this knowledge to more complex systems. (authors)

Joint modelling of longitudinal CEA tumour marker progression and survival data on breast cancer

Science.gov (United States)

Borges, Ana; Sousa, Inês; Castro, Luis

2017-06-01

This work proposes the use of Biostatistics methods to study breast cancer in patients of Braga's Hospital Senology Unit, located in Portugal. The primary motivation is to contribute to the understanding of the progression of breast cancer, within the Portuguese population, using a more complex statistical model assumptions than the traditional analysis that take into account a possible existence of a serial correlation structure within a same subject observations. We aim to infer which risk factors aect the survival of Braga's Hospital patients, diagnosed with breast tumour. Whilst analysing risk factors that aect a tumour markers used on the surveillance of disease progression the Carcinoembryonic antigen (CEA). As survival and longitudinal processes may be associated, it is important to model these two processes together. Hence, a joint modelling of these two processes to infer on the association of these was conducted. A data set of 540 patients, along with 50 variables, was collected from medical records of the Hospital. A joint model approach was used to analyse these data. Two dierent joint models were applied to the same data set, with dierent parameterizations which give dierent interpretations to model parameters. These were used by convenience as the ones implemented in R software. Results from the two models were compared. Results from joint models, showed that the longitudinal CEA values were signicantly associated with the survival probability of these patients. A comparison between parameter estimates obtained in this analysis and previous independent survival[4] and longitudinal analysis[5][6], lead us to conclude that independent analysis brings up bias parameter estimates. Hence, an assumption of association between the two processes in a joint model of breast cancer data is necessary. Results indicate that the longitudinal progression of CEA is signicantly associated with the probability of survival of these patients. Hence, an assumption of

Association between metformin use and progression of monoclonal gammopathy of undetermined significance to multiple myeloma in US veterans with diabetes mellitus: a population-based retrospective cohort study.

Science.gov (United States)

Chang, Su-Hsin; Luo, Suhong; O'Brian, Katiuscia K; Thomas, Theodore S; Colditz, Graham A; Carlsson, Nils P; Carson, Kenneth R

2015-01-01

Multiple myeloma is one of the most common haematological malignancies in the USA and is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS). We aimed to assess the association between metformin use and progression of MGUS to multiple myeloma. We did a retrospective cohort study of patients registered in the US Veterans Health Administration database and diagnosed with MGUS between Oct 1, 1999, and Dec 31, 2009. We included patients (aged >18 years) with at least one International Classification of Diseases (9th revision) code for diabetes mellitus and one treatment for their diabetes before MGUS diagnosis. We reviewed patient-level clinical data to verify diagnoses and extract any available data for size of baseline M-protein and type of MGUS. We defined metformin users as patients with diabetes who were given metformin consistently for 4 years after their diabetes diagnosis and before multiple myeloma development, death, or censorship. Our primary outcome was time from MGUS diagnosis to multiple myeloma diagnosis. We used Kaplan-Meier curves and Cox models to analyse the association between metformin use and MGUS progression. We obtained data for 3287 patients, of whom 2003 (61%) were included in the final analytical cohort. Median follow-up was 69 months (IQR 49–96). 463 (23%) participants were metformin users and 1540 (77%) participants were non-users. 13 (3%) metformin users progressed to multiple myeloma compared with 74 (5%) non-users. After adjustment, metformin use was associated with a reduced risk of progression to multiple myeloma (hazard ratio 0·47, 95% CI 0·25–0·87). For patients with diabetes diagnosed with MGUS, metformin use for 4 years or longer was associated with a reduced risk of progression of MGUS to multiple myeloma. Prospective studies are needed to establish whether this association is causal and whether these results can be extrapolated to non-diabetic individuals. Barnes-Jewish Hospital Foundation

Localization of aPKC lambda/iota and its interacting protein, Lgl2, is significantly associated with lung adenocarcinoma progression.

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Imamura, Naoko; Horikoshi, Yosuke; Matsuzaki, Tomohiko; Toriumi, Kentaro; Kitatani, Kanae; Ogura, Go; Masuda, Ryota; Nakamura, Naoya; Takekoshi, Susumu; Iwazaki, Masayuki

2013-12-20

Atypical protein kinase C lambda/iota (aPKC λ/ι) is expressed in several human cancers; however, the correlation between aPKC λ/ι localization and cancer progression in human lung adenocarcinoma (LAC) remains to be clarified. We found that patients with a high level of aPKC λ/ι expression in LAC had significantly shorter overall survival than those with a low level of aPKC λ/ι expression. In addition, localization of aPKC λ/ι in the apical membrane or at the cell-cell contact was associated with both lymphatic invasion and metastasis. The intercellular adhesion molecule, E-cadherin, was decreased in LACs with highly expressed aPKC λ/ι at the invasion site of tumor cells. This result suggested that the expression levels of aPKC λ/ι and E-cadherin reflect the progression of LAC. On double-immunohistochemical analysis, aPKC λ/ι and Lgl2, a protein that interacts with aPKC λ/ι, were co-localized within LACs. Furthermore, we found that Lgl2 bound the aPKC λ/ι-Par6 complex in tumor tissue by immune-cosedimentation analysis. Apical membrane localization of Lgl2 was correlated with lymphatic invasion and lymph node metastasis. These results thus indicate that aPKC λ/ι expression is altered upon the progression of LAC. This is also the first evidence to show aPKC λ/ι overexpression in LAC and demonstrates that aPKC λ/ι localization at the apical membrane or cell-cell contact is associated with lymphatic invasion and metastasis of the tumor.

Comparing clinical attachment level and pocket depth for predicting periodontal disease progression in healthy sites of patients with chronic periodontitis using multi-state Markov models.

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Mdala, Ibrahimu; Olsen, Ingar; Haffajee, Anne D; Socransky, Sigmund S; Thoresen, Magne; de Blasio, Birgitte Freiesleben

2014-09-01

To understand degeneration of healthy sites and identify factors associated with disease progression in patients with chronic periodontitis. Data on healthy sites from 163 American and Swedish subjects were analysed using two-three-state (health, gingivitis, chronic periodontitis) Markov models based on bleeding on probing (BOP), and either clinical attachment level (CAL) + BOP or pocket depth (PD) + BOP. In 2 years, 10% (CAL + BOP) and 3% (PD + BOP) of healthy sites developed chronic periodontitis. On average, healthy sites remained healthy for 32 months before transiting in both models. Most transitions (87-97%) from health were to the gingivitis state. The expected duration of the gingivitis lesion was 4-5 months and sites recovered with a high probability (96-98%). Disease severity as measured by number of sites with CAL/PD > 4 mm at baseline and smoking, were associated with fast progression from health to chronic periodontitis within 6 months as were gingival redness in the PD + BOP model only. With age, the rate of disease progression to gingivitis decreased. Transition probabilities for gingivitis and chronic periodontitis were higher with CAL + BOP than with PD + BOP. Smoking and disease severity were significant predictors for fast progression. © 2014 The Authors. Journal of Clinical Periodontology Published by John Wiley & Sons Ltd.

Comparing clinical attachment level and pocket depth for predicting periodontal disease progression in healthy sites of patients with chronic periodontitis using multi-state Markov models

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Mdala, Ibrahimu; Olsen, Ingar; Haffajee, Anne D; Socransky, Sigmund S; Thoresen, Magne; de Blasio, Birgitte Freiesleben

2014-01-01

Aim To understand degeneration of healthy sites and identify factors associated with disease progression in patients with chronic periodontitis. Material and Methods Data on healthy sites from 163 American and Swedish subjects were analysed using two-three-state (health, gingivitis, chronic periodontitis) Markov models based on bleeding on probing (BOP), and either clinical attachment level (CAL) + BOP or pocket depth (PD) + BOP. Results In 2 years, 10% (CAL + BOP) and 3% (PD + BOP) of healthy sites developed chronic periodontitis. On average, healthy sites remained healthy for 32 months before transiting in both models. Most transitions (87–97%) from health were to the gingivitis state. The expected duration of the gingivitis lesion was 4–5 months and sites recovered with a high probability (96–98%). Disease severity as measured by number of sites with CAL/PD > 4 mm at baseline and smoking, were associated with fast progression from health to chronic periodontitis within 6 months as were gingival redness in the PD + BOP model only. With age, the rate of disease progression to gingivitis decreased. Conclusion Transition probabilities for gingivitis and chronic periodontitis were higher with CAL + BOP than with PD + BOP. Smoking and disease severity were significant predictors for fast progression. PMID:24888705

Modeling freedom from progression for standard-risk medulloblastoma: a mathematical tumor control model with multiple modes of failure

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Brodin, Nils Patrik; Vogelius, Ivan R.; Bjørk-Eriksson, Thomas

2013-01-01

As pediatric medulloblastoma (MB) is a relatively rare disease, it is important to extract the maximum information from trials and cohort studies. Here, a framework was developed for modeling tumor control with multiple modes of failure and time-to-progression for standard-risk MB, using published...

Biomedical Progress Rates as New Parameters for Models of Economic Growth in Developed Countries

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Alex Zhavoronkov

2013-11-01

Full Text Available While the doubling of life expectancy in developed countries during the 20th century can be attributed mostly to decreases in child mortality, the trillions of dollars spent on biomedical research by governments, foundations and corporations over the past sixty years are also yielding longevity dividends in both working and retired population. Biomedical progress will likely increase the healthy productive lifespan and the number of years of government support in the old age. In this paper we introduce several new parameters that can be applied to established models of economic growth: the biomedical progress rate, the rate of clinical adoption and the rate of change in retirement age. The biomedical progress rate is comprised of the rejuvenation rate (extending the productive lifespan and the non-rejuvenating rate (extending the lifespan beyond the age at which the net contribution to the economy becomes negative. While staying within the neoclassical economics framework and extending the overlapping generations (OLG growth model and assumptions from the life cycle theory of saving behavior, we provide an example of the relations between these new parameters in the context of demographics, labor, households and the firm.

Biomedical progress rates as new parameters for models of economic growth in developed countries.

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Zhavoronkov, Alex; Litovchenko, Maria

2013-11-08

While the doubling of life expectancy in developed countries during the 20th century can be attributed mostly to decreases in child mortality, the trillions of dollars spent on biomedical research by governments, foundations and corporations over the past sixty years are also yielding longevity dividends in both working and retired population. Biomedical progress will likely increase the healthy productive lifespan and the number of years of government support in the old age. In this paper we introduce several new parameters that can be applied to established models of economic growth: the biomedical progress rate, the rate of clinical adoption and the rate of change in retirement age. The biomedical progress rate is comprised of the rejuvenation rate (extending the productive lifespan) and the non-rejuvenating rate (extending the lifespan beyond the age at which the net contribution to the economy becomes negative). While staying within the neoclassical economics framework and extending the overlapping generations (OLG) growth model and assumptions from the life cycle theory of saving behavior, we provide an example of the relations between these new parameters in the context of demographics, labor, households and the firm.

Atypical squamous cells of undetermined significance in patients with HPV positive DNA testing and correlation with disease progression by age group: an institutional experience.

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Rodriguez, Erika F; Reynolds, Jordan P; Jenkins, Sarah M; Winter, Stephanie M; Henry, Michael R; Nassar, Aziza

2012-01-01

Atypical squamous cells of undetermined significance (ASC-US) is a broad diagnostic category that could be attributed to human papillomavirus infection (HPV), malignant neoplasia and reactive conditions. We evaluated our institutional experience with ASC-US in women who are positive for high risk HPV (HRHPV+) by the Digene hybrid capture method from 2005-2009 to identify the risk of progression to squamous intraepithelial lesion (SIL) and cervical intraepithelial neoplasia (CIN) in association with age. We reviewed cytologic and follow-up surgical pathology reports for all specimens available. Progression was defined as a diagnosis of at least CINI on follow-up biopsy or resection or SIL on cytology. We identified 2613 cases and follow-up was available in 1839 (70.4%). Of these 74.2% had just one follow-up, 16.2% had a total of 2 follow-ups, 5.3% had a total of 3 follow-ups, and the remaining had as many as 6 follow-ups. Among the 1839 patients, 69.4% were age 30 or younger, 16.0% were between 31 to 40, 9.0% were between 41 to 50, and 5.6% were 51 or older. Among these, 25-30% progressed to dysplasia. The risk of progression varied by age (p=0.04) and was lowest among women between the ages of 41-50. Our findings highlight the importance of continued cytologic follow-up in women with HRHPV+ ASC-US in order to detect progression of disease, although the risk of progression is age dependent.

CKD Progression and Mortality among Hispanics and Non-Hispanics.

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Fischer, Michael J; Hsu, Jesse Y; Lora, Claudia M; Ricardo, Ana C; Anderson, Amanda H; Bazzano, Lydia; Cuevas, Magdalena M; Hsu, Chi-Yuan; Kusek, John W; Renteria, Amada; Ojo, Akinlolu O; Raj, Dominic S; Rosas, Sylvia E; Pan, Qiang; Yaffe, Kristine; Go, Alan S; Lash, James P

2016-11-01

Although recommended approaches to CKD management are achieved less often in Hispanics than in non-Hispanics, whether long-term outcomes differ between these groups is unclear. In a prospective longitudinal analysis of participants enrolled into the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic-CRIC Studies, we used Cox proportional hazards models to determine the association between race/ethnicity, CKD progression (50% eGFR loss or incident ESRD), incident ESRD, and all-cause mortality, and linear mixed-effects models to assess differences in eGFR slope. Among 3785 participants, 13% were Hispanic, 43% were non-Hispanic white (NHW), and 44% were non-Hispanic black (NHB). Over a median follow-up of 5.1 years for Hispanics and 6.8 years for non-Hispanics, 27.6% of all participants had CKD progression, 21.3% reached incident ESRD, and 18.3% died. Hispanics had significantly higher rates of CKD progression, incident ESRD, and mean annual decline in eGFR than did NHW (P<0.05) but not NHB. Hispanics had a mortality rate similar to that of NHW but lower than that of NHB (P<0.05). In adjusted analyses, the risk of CKD progression did not differ between Hispanics and NHW or NHB. However, among nondiabetic participants, compared with NHB, Hispanics had a lower risk of CKD progression (hazard ratio, 0.61; 95% confidence interval, 0.39 to 0.95) and incident ESRD (hazard ratio, 0.50; 95% confidence interval, 0.30 to 0.84). At higher levels of urine protein, Hispanics had a significantly lower risk of mortality than did non-Hispanics (P<0.05). Thus, important differences in CKD progression and mortality exist between Hispanics and non-Hispanics and may be affected by proteinuria and diabetes. Copyright © 2016 by the American Society of Nephrology.

Iron overload in a murine model of hereditary hemochromatosis is associated with accelerated progression of osteoarthritis under mechanical stress.

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Camacho, A; Simão, M; Ea, H-K; Cohen-Solal, M; Richette, P; Branco, J; Cancela, M L

2016-03-01

Hereditary hemochromatosis (HH) is a disease caused by mutations in the Hfe gene characterised by systemic iron overload and associated with an increased prevalence of osteoarthritis (OA) but the role of iron overload in the development of OA is still undefined. To further understand the molecular mechanisms involved we have used a murine model of HH and studied the progression of experimental OA under mechanical stress. OA was surgically induced in the knee joints of 10-week-old C57BL6 (wild-type) mice and Hfe-KO mice. OA progression was assessed using histology, micro CT, gene expression and immunohistochemistry at 8 weeks after surgery. Hfe-KO mice showed a systemic iron overload and an increased iron accumulation in the knee synovial membrane following surgery. The histological OA score was significantly higher in the Hfe-KO mice at 8 weeks after surgery. Micro CT study of the proximal tibia revealed increased subchondral bone volume and increased trabecular thickness. Gene expression and immunohistochemical analysis showed a significant increase in the expression of matrix metallopeptidase 3 (MMP-3) in the joints of Hfe-KO mice compared with control mice at 8 weeks after surgery. HH was associated with an accelerated development of OA in mice. Our findings suggest that synovial iron overload has a definite role in the progression of HH-related OA. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Local ASIC3 modulates pain and disease progression in a rat model of osteoarthritis

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Izumi Masashi

2012-08-01

Full Text Available Abstract Background Recent data have suggested a relationship between acute arthritic pain and acid sensing ion channel 3 (ASIC3 on primary afferent fibers innervating joints. The purpose of this study was to clarify the role of ASIC3 in a rat model of osteoarthritis (OA which is considered a degenerative rather than an inflammatory disease. Methods We induced OA via intra-articular mono-iodoacetate (MIA injection, and evaluated pain-related behaviors including weight bearing measured with an incapacitance tester and paw withdrawal threshold in a von Frey hair test, histology of affected knee joint, and immunohistochemistry of knee joint afferents. We also assessed the effect of ASIC3 selective peptide blocker (APETx2 on pain behavior, disease progression, and ASIC3 expression in knee joint afferents. Results OA rats showed not only weight-bearing pain but also mechanical hyperalgesia outside the knee joint (secondary hyperalgesia. ASIC3 expression in knee joint afferents was significantly upregulated approximately twofold at Day 14. Continuous intra-articular injections of APETx2 inhibited weight distribution asymmetry and secondary hyperalgesia by attenuating ASIC3 upregulation in knee joint afferents. Histology of ipsilateral knee joint showed APETx2 worked chondroprotectively if administered in the early, but not late phase. Conclusions Local ASIC3 immunoreactive nerve is strongly associated with weight-bearing pain and secondary hyperalgesia in MIA-induced OA model. APETx2 inhibited ASIC3 upregulation in knee joint afferents regardless of the time-point of administration. Furthermore, early administration of APETx2 prevented cartilage damage. APETx2 is a novel, promising drug for OA by relieving pain and inhibiting disease progression.

The significance of MMP-9 examination in serum from embryo of gastric cancer model

International Nuclear Information System (INIS)

Liu Zhan; Zhao Xuejian; Wang Lu; Li Yulin; Zhang Lihong; Zhang Hong

2003-01-01

Objective: To investigate the changes matrix metalloproteinase-9 (MMP-9) content from sera of chick embryos during the progression of transformed models of gastric cancer cells on chorioallantoic membrane (CAM). Methods: Morphometric investigation method was used to study the tumor generation on CAM; Enzyme-linked immunosorbent assay (ELISA) method was used to test MMP-9 concentrations in chick embryos'sera transferred by cancer cells at different points of time; the relationship between MMP-9 and cancer biological characteristics was analyzed. Results: In the group of 1 x 10 6 ·ml -1 gastric cancer cells, a single clot which could be seen by naked eyes appeared at 72 hours after inoculation. With the time going on, the volumes of the clot became larger and larger, and the neovessels on CAM accumulated to the clot. In the group of 1 x 10 6 ·ml -1 gastric cancer cells, the MMP-9 content in sera extremely increased at 72 hours after inoculation and increased continuously till the maxim at 7 days after inoculation. Conclusion: The whole progression of cancer development is accompanied with the increase of MMP-9 concentration. This model is feasible to study the characteristics of gastric cancer

Targeting fibroblast growth factor receptor signaling inhibits prostate cancer progression.

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Feng, Shu; Shao, Longjiang; Yu, Wendong; Gavine, Paul; Ittmann, Michael

2012-07-15

Extensive correlative studies in human prostate cancer as well as studies in vitro and in mouse models indicate that fibroblast growth factor receptor (FGFR) signaling plays an important role in prostate cancer progression. In this study, we used a probe compound for an FGFR inhibitor, which potently inhibits FGFR-1-3 and significantly inhibits FGFR-4. The purpose of this study is to determine whether targeting FGFR signaling from all four FGFRs will have in vitro activities consistent with inhibition of tumor progression and will inhibit tumor progression in vivo. Effects of AZ8010 on FGFR signaling and invasion were analyzed using immortalized normal prostate epithelial (PNT1a) cells and PNT1a overexpressing FGFR-1 or FGFR-4. The effect of AZ8010 on invasion and proliferation in vitro was also evaluated in prostate cancer cell lines. Finally, the impact of AZ8010 on tumor progression in vivo was evaluated using a VCaP xenograft model. AZ8010 completely inhibits FGFR-1 and significantly inhibits FGFR-4 signaling at 100 nmol/L, which is an achievable in vivo concentration. This results in marked inhibition of extracellular signal-regulated kinase (ERK) phosphorylation and invasion in PNT1a cells expressing FGFR-1 and FGFR-4 and all prostate cancer cell lines tested. Treatment in vivo completely inhibited VCaP tumor growth and significantly inhibited angiogenesis and proliferation and increased cell death in treated tumors. This was associated with marked inhibition of ERK phosphorylation in treated tumors. Targeting FGFR signaling is a promising new approach to treating aggressive prostate cancer.

[RESEARCH PROGRESS OF EXPERIMENTAL ANIMAL MODELS OF AVASCULAR NECROSIS OF FEMORAL HEAD].

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Yu, Kaifu; Tan, Hongbo; Xu, Yongqing

2015-12-01

To summarize the current researches and progress on experimental animal models of avascular necrosis of the femoral head. Domestic and internation literature concerning experimental animal models of avascular necrosis of the femoral head was reviewed and analyzed. The methods to prepare the experimental animal models of avascular necrosis of the femoral head can be mainly concluded as traumatic methods (including surgical, physical, and chemical insult), and non-traumatic methods (including steroid, lipopolysaccharide, steroid combined with lipopolysaccharide, steroid combined with horse serum, etc). Each method has both merits and demerits, yet no ideal methods have been developed. There are many methods to prepare the experimental animal models of avascular necrosis of the femoral head, but proper model should be selected based on the aim of research. The establishment of ideal experimental animal models needs further research in future.

Expression status and clinical significance of lncRNA APPAT in the progression of atherosclerosis

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Fanming Meng

2018-01-01

Full Text Available Background Long non-coding RNAs (lncRNAs have been reported to modulate cardiovascular diseases, and expression dynamics of lncRNAs in the bloodstream were proposed to be potential biomarkers for clinical diagnosis. However, few cardiovascular diseases-related circulating lncRNAs were identified and their prediction power has not been investigated in depth. Here we report a new circulating lncRNA, atherosclerotic plaque pathogenesis associated transcript (APPAT, and evaluated its role and predicting ability in atherosclerotic development. Methods APPAT was analyzed and screened by high-throughput sequencing, and then detected in vitro and in vivo. Immunofluorescence-fluorescence in situ hybridization (IF-FISH was utilized to explore distribution and subcellular location of APPAT. The expressing alteration of APPAT in samples of healthy and pathological coronary artery was explored further. We also assessed the level of circulating APPAT in blood samples from healthy individuals, and patients with angina pectoris (AP or myocardial infarction (MI. Additionally, we predicted and validated microRNA targets of APPAT, then showed the expression level of a candidate target which was primarily measured in human VSMCs cell line, coronary artery, and blood samples. Lastly, we examined the potential indicating ability of APPAT for the risk of AP or MI. Results APPAT showed significant reduction in ox-LDL treated human VSMCs in vitro. It enriched in contractile VSMCs of artery tunica media and mainly existed in cytoplasm. Significant down-regulation of APPAT was found in coronary artery samples with severe stenosis. More importantly, we observed decreased expression of APPAT in blood samples accompanying disease progression. ROC and correlation analyses further verified the relatively high predicting ability of APPAT. We also observed the predicted miRNA exhibited opposite expression direction to that of APPAT. Conclusions This study revealed that

Formal modeling and analysis of the hexosamine biosynthetic pathway: role of O-linked N-acetylglucosamine transferase in oncogenesis and cancer progression

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Muhammad Tariq Saeed

2016-09-01

Full Text Available The alteration of glucose metabolism, through increased uptake of glucose and glutamine addiction, is essential to cancer cell growth and invasion. Increased flux of glucose through the Hexosamine Biosynthetic Pathway (HBP drives increased cellular O-GlcNAcylation (hyper-O-GlcNAcylation and contributes to cancer progression by regulating key oncogenes. However, the association between hyper-O-GlcNAcylation and activation of these oncogenes remains poorly characterized. Here, we implement a qualitative modeling framework to analyze the role of the Biological Regulatory Network in HBP activation and its potential effects on key oncogenes. Experimental observations are encoded in a temporal language format and model checking is applied to infer the model parameters and qualitative model construction. Using this model, we discover step-wise genetic alterations that promote cancer development and invasion due to an increase in glycolytic flux, and reveal critical trajectories involved in cancer progression. We compute delay constraints to reveal important associations between the production and degradation rates of proteins. O-linked N-acetylglucosamine transferase (OGT, an enzyme used for addition of O-GlcNAc during O-GlcNAcylation, is identified as a key regulator to promote oncogenesis in a feedback mechanism through the stabilization of c-Myc. Silencing of the OGT and c-Myc loop decreases glycolytic flux and leads to programmed cell death. Results of network analyses also identify a significant cycle that highlights the role of p53-Mdm2 circuit oscillations in cancer recovery and homeostasis. Together, our findings suggest that the OGT and c-Myc feedback loop is critical in tumor progression, and targeting these mediators may provide a mechanism-based therapeutic approach to regulate hyper-O-GlcNAcylation in human cancer.

Androgen receptor levels during progression of prostate cancer in the transgenic adenocarcinoma of mouse prostate model

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Krisna Murti

2010-02-01

Full Text Available Aim To construct tissue microarrays (TMAs that consisted of prostate tumours from the transgenic adenocarcinoma of mouse prostate (TRAMP mice and non-transgenic murine prostates and to assess androgen receptor (AR levels during progression of prostate cancer in TRAMP mice by immunohistochemistry.Methods Haematoxylin and eosin (H&E sections from the ventral and dorso-lateral prostate lobes of non-transgenic, intact TRAMP and castrated TRAMP were used to demarcate regions of interest for TMAs construction. The samples on TMAs were used to evaluate AR expression using video image analysis (VIA.Results AR was expressed during cancer progression, but AR levels were reduced or absent in late stage disease. Furthermore, when AR levels were compared in tumours from intact and castrate animals, a significant increase in AR levels was observed following androgen ablation.Conclusion Similar to clinical prostate cancer, in the TRAMP model, prostate tumours evolve mechanisms to maintain AR expression and AR responsive gene pathways following castration to facilitate continued tumour growth. (Med J Indones 2010; 19:5-13Keywords : androgen ablation therapy, tissue microarrays, haematoxylin and eosin, video image analysis

Three-tiered risk stratification model to predict progression in Barrett's esophagus using epigenetic and clinical features.

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Fumiaki Sato

2008-04-01

Full Text Available Barrett's esophagus predisposes to esophageal adenocarcinoma. However, the value of endoscopic surveillance in Barrett's esophagus has been debated because of the low incidence of esophageal adenocarcinoma in Barrett's esophagus. Moreover, high inter-observer and sampling-dependent variation in the histologic staging of dysplasia make clinical risk assessment problematic. In this study, we developed a 3-tiered risk stratification strategy, based on systematically selected epigenetic and clinical parameters, to improve Barrett's esophagus surveillance efficiency.We defined high-grade dysplasia as endpoint of progression, and Barrett's esophagus progressor patients as Barrett's esophagus patients with either no dysplasia or low-grade dysplasia who later developed high-grade dysplasia or esophageal adenocarcinoma. We analyzed 4 epigenetic and 3 clinical parameters in 118 Barrett's esophagus tissues obtained from 35 progressor and 27 non-progressor Barrett's esophagus patients from Baltimore Veterans Affairs Maryland Health Care Systems and Mayo Clinic. Based on 2-year and 4-year prediction models using linear discriminant analysis (area under the receiver-operator characteristic (ROC curve: 0.8386 and 0.7910, respectively, Barrett's esophagus specimens were stratified into high-risk (HR, intermediate-risk (IR, or low-risk (LR groups. This 3-tiered stratification method retained both the high specificity of the 2-year model and the high sensitivity of the 4-year model. Progression-free survivals differed significantly among the 3 risk groups, with p = 0.0022 (HR vs. IR and p<0.0001 (HR or IR vs. LR. Incremental value analyses demonstrated that the number of methylated genes contributed most influentially to prediction accuracy.This 3-tiered risk stratification strategy has the potential to exert a profound impact on Barrett's esophagus surveillance accuracy and efficiency.

Transgenic Monkey Model of the Polyglutamine Diseases Recapitulating Progressive Neurological Symptoms

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Ishibashi, Hidetoshi; Minakawa, Eiko N.; Motohashi, Hideyuki H.; Takayama, Osamu; Popiel, H. Akiko; Puentes, Sandra; Owari, Kensuke; Nakatani, Terumi; Nogami, Naotake; Yamamoto, Kazuhiro; Yonekawa, Takahiro; Tanaka, Yoko; Fujita, Naoko; Suzuki, Hikaru; Aizawa, Shu; Nagano, Seiichi; Yamada, Daisuke; Wada, Keiji; Kohsaka, Shinichi

2017-01-01

Abstract Age-associated neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and the polyglutamine (polyQ) diseases, are becoming prevalent as a consequence of elongation of the human lifespan. Although various rodent models have been developed to study and overcome these diseases, they have limitations in their translational research utility owing to differences from humans in brain structure and function and in drug metabolism. Here, we generated a transgenic marmoset model of the polyQ diseases, showing progressive neurological symptoms including motor impairment. Seven transgenic marmosets were produced by lentiviral introduction of the human ataxin 3 gene with 120 CAG repeats encoding an expanded polyQ stretch. Although all offspring showed no neurological symptoms at birth, three marmosets with higher transgene expression developed neurological symptoms of varying degrees at 3–4 months after birth, followed by gradual decreases in body weight gain, spontaneous activity, and grip strength, indicating time-dependent disease progression. Pathological examinations revealed neurodegeneration and intranuclear polyQ protein inclusions accompanied by gliosis, which recapitulate the neuropathological features of polyQ disease patients. Consistent with neuronal loss in the cerebellum, brain MRI analyses in one living symptomatic marmoset detected enlargement of the fourth ventricle, which suggests cerebellar atrophy. Notably, successful germline transgene transmission was confirmed in the second-generation offspring derived from the symptomatic transgenic marmoset gamete. Because the accumulation of abnormal proteins is a shared pathomechanism among various neurodegenerative diseases, we suggest that this new marmoset model will contribute toward elucidating the pathomechanisms of and developing clinically applicable therapies for neurodegenerative diseases. PMID:28374014

Riboflavin and ultraviolet A irradiation for the prevention of progressive myopia in a guinea pig model.

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Li, Xiaoxia; Wu, Miaoqin; Zhang, Luyi; Liu, Hui; Zhang, Lan; He, Jinjing

2017-12-01

In this study, we evaluated the effect of oral administration of riboflavin combined with whole-body ultraviolet A (UVA) irradiation on the biochemical and biomechanical properties of sclera in a guinea pig model to control the progression of myopia. Experimental groups were administered 0.1% riboflavin solution with or without vitamin C by gavage from 3 days before myopic modeling and during the modeling process. Guinea pigs underwent 30 min of whole-body UVA irradiation after each gavage for 2 weeks. For control groups, guinea pigs were administered vitamin C and underwent either whole-body UVA irradiation without 0.1% riboflavin solution or whole-body fluorescent lamp irradiation with or without 0.1% riboflavin solution. Resultantly, myopia models were established with an increased axial length and myopic diopter. Compared with myopic eyes in the control groups, the net increase in axial length, diopter and strain assessment decreased significantly, and the net decrease in sclera thickness, ultimate load, and stress assessment decreased significantly in experimental groups. MMP-2 expression showed a lower net increase, while TIMP-2 expression showed a lower net decrease. In addition, hyperplasia of scleral fibroblasts was more active in myopic eyes of experimental groups. Overall, our results showed that oral administration of riboflavin with whole-body UVA irradiation could increase the strength and stiffness of sclera by altering the biochemical and biomechanical properties, and decreases in axial elongation and myopic diopter are greater in the guinea pig myopic model. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Recent progress and modern challenges in applied mathematics, modeling and computational science

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Makarov, Roman; Belair, Jacques

2017-01-01

This volume is an excellent resource for professionals in various areas of applications of mathematics, modeling, and computational science. It focuses on recent progress and modern challenges in these areas. The volume provides a balance between fundamental theoretical and applied developments, emphasizing the interdisciplinary nature of modern trends and detailing state-of-the-art achievements in Applied Mathematics, Modeling, and Computational Science.  The chapters have been authored by international experts in their respective fields, making this book ideal for researchers in academia, practitioners, and graduate students. It can also serve as a reference in the diverse selected areas of applied mathematics, modelling, and computational sciences, and is ideal for interdisciplinary collaborations.

Integrating evolutionary game theory into an agent-based model of ductal carcinoma in situ: Role of gap junctions in cancer progression.

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Malekian, Negin; Habibi, Jafar; Zangooei, Mohammad Hossein; Aghakhani, Hojjat

2016-11-01

There are many cells with various phenotypic behaviors in cancer interacting with each other. For example, an apoptotic cell may induce apoptosis in adjacent cells. A living cell can also protect cells from undergoing apoptosis and necrosis. These survival and death signals are propagated through interaction pathways between adjacent cells called gap junctions. The function of these signals depends on the cellular context of the cell receiving them. For instance, a receiver cell experiencing a low level of oxygen may interpret a received survival signal as an apoptosis signal. In this study, we examine the effect of these signals on tumor growth. We make an evolutionary game theory component in order to model the signal propagation through gap junctions. The game payoffs are defined as a function of cellular context. Then, the game theory component is integrated into an agent-based model of tumor growth. After that, the integrated model is applied to ductal carcinoma in situ, a type of early stage breast cancer. Different scenarios are explored to observe the impact of the gap junction communication and parameters of the game theory component on cancer progression. We compare these scenarios by using the Wilcoxon signed-rank test. The Wilcoxon signed-rank test succeeds in proving a significant difference between the tumor growth of the model before and after considering the gap junction communication. The Wilcoxon signed-rank test also proves that the tumor growth significantly depends on the oxygen threshold of turning survival signals into apoptosis. In this study, the gap junction communication is modeled by using evolutionary game theory to illustrate its role at early stage cancers such as ductal carcinoma in situ. This work indicates that the gap junction communication and the oxygen threshold of turning survival signals into apoptosis can notably affect cancer progression. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Malignant progressive tumor cell clone exhibits significant up-regulation of cofilin-2 and 27-kDa modified form of cofilin-1 compared to regressive clone.

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Kuramitsu, Yasuhiro; Wang, Yufeng; Okada, Futoshi; Baron, Byron; Tokuda, Kazuhiro; Kitagawa, Takao; Akada, Junko; Nakamura, Kazuyuki

2013-09-01

QR-32 is a regressive murine fibrosarcoma cell clone which cannot grow when they are transplanted in mice; QRsP-11 is a progressive malignant tumor cell clone derived from QR-32 which shows strong tumorigenicity. A recent study showed there to be differentially expressed up-regulated and down-regulated proteins in these cells, which were identified by proteomic differential display analyses by using two-dimensional gel electrophoresis and mass spectrometry. Cofilins are small proteins of less than 20 kDa. Their function is the regulation of actin assembly. Cofilin-1 is a small ubiquitous protein, and regulates actin dynamics by means of binding to actin filaments. Cofilin-1 plays roles in cell migration, proliferation and phagocytosis. Cofilin-2 is also a small protein, but it is mainly expressed in skeletal and cardiac muscles. There are many reports showing the positive correlation between the level of cofilin-1 and cancer progression. We have also reported an increased expression of cofilin-1 in pancreatic cancer tissues compared to adjacent paired normal tissues. On the other hand, cofilin-2 was significantly less expressed in pancreatic cancer tissues. Therefore, the present study investigated the comparison of the levels of cofilin-1 and cofilin-2 in regressive QR-32 and progressive QRsP-11cells by western blotting. Cofilin-2 was significantly up-regulated in QRsP-11 compared to QR-32 cells (p<0.001). On the other hand, the difference of the intensities of the bands of cofilin-1 (18 kDa) in QR-32 and QRsP-11 was not significant. However, bands of 27 kDa showed a quite different intensity between QR-32 and QRsP-11, with much higher intensities in QRsP-11 compared to QR-32 (p<0.001). These results suggested that the 27-kDa protein recognized by the antibody against cofilin-1 is a possible biomarker for progressive tumor cells.

Progress in sensor performance testing, modeling and range prediction using the TOD method: an overview

Science.gov (United States)

Bijl, Piet; Hogervorst, Maarten A.; Toet, Alexander

2017-05-01

The Triangle Orientation Discrimination (TOD) methodology includes i) a widely applicable, accurate end-to-end EO/IR sensor test, ii) an image-based sensor system model and iii) a Target Acquisition (TA) range model. The method has been extensively validated against TA field performance for a wide variety of well- and under-sampled imagers, systems with advanced image processing techniques such as dynamic super resolution and local adaptive contrast enhancement, and sensors showing smear or noise drift, for both static and dynamic test stimuli and as a function of target contrast. Recently, significant progress has been made in various directions. Dedicated visual and NIR test charts for lab and field testing are available and thermal test benches are on the market. Automated sensor testing using an objective synthetic human observer is within reach. Both an analytical and an image-based TOD model have recently been developed and are being implemented in the European Target Acquisition model ECOMOS and in the EOSTAR TDA. Further, the methodology is being applied for design optimization of high-end security camera systems. Finally, results from a recent perception study suggest that DRI ranges for real targets can be predicted by replacing the relevant distinctive target features by TOD test patterns of the same characteristic size and contrast, enabling a new TA modeling approach. This paper provides an overview.

The Process-Oriented Simulation (POS) model for common cause failures: recent progress

International Nuclear Information System (INIS)

Berg, H.P.; Goertz, R.; Schimetschka, E.; Kesten, J.

2006-01-01

A common-cause failure (CCF) model based on stochastic simulation has been developed to complement the established approaches and to overcome some of their shortcomings. Reflecting the models proximity to the CCF process it was called Process Oriented Simulation (POS) Model. In recent years, some progress has been made to render the POS model fit for practical applications comprising the development of parameter estimates and a number of test applications in areas where results were already available - especially from CCF benchmarks - and comparison can provide insights in strong and weak points of the different approaches. In this paper, a detailed description of the POS model is provided together with the approach to parameter estimation and representative test applications. It is concluded, that the POS model has a number of strengths - especially the feature to provide reasonable extrapolation to CCF groups with high degrees of redundancy - and thus a considerable potential to complement the insights obtained from existing modeling. (orig.)

Adjustment modes in the trajectory of progressive multiple sclerosis: a qualitative study and conceptual model.

Science.gov (United States)

Bogosian, Angeliki; Morgan, Myfanwy; Bishop, Felicity L; Day, Fern; Moss-Morris, Rona

2017-03-01

We examined cognitive and behavioural challenges and adaptations for people with progressive multiple sclerosis (MS) and developed a preliminary conceptual model of changes in adjustment over time. Using theoretical sampling, 34 semi-structured interviews were conducted with people with MS. Participants were between 41 and 77 years of age. Thirteen were diagnosed with primary progressive MS and 21 with secondary progressive MS. Data were analysed using a grounded theory approach. Participants described initially bracketing the illness off and carrying on their usual activities but this became problematic as the condition progressed and they employed different adjustment modes to cope with increased disabilities. Some scaled back their activities to live a more comfortable life, others identified new activities or adapted old ones, whereas at times, people disengaged from the adjustment process altogether and resigned to their condition. Relationships with partners, emotional reactions, environment and perception of the environment influenced adjustment, while people were often flexible and shifted among modes. Adjusting to a progressive condition is a fluid process. Future interventions can be tailored to address modifiable factors at different stages of the condition and may involve addressing emotional reactions concealing/revealing the condition and perceptions of the environment.

An observation-based progression modeling approach to spring and autumn deciduous tree phenology

Science.gov (United States)

Yu, Rong; Schwartz, Mark D.; Donnelly, Alison; Liang, Liang

2016-03-01

It is important to accurately determine the response of spring and autumn phenology to climate change in forest ecosystems, as phenological variations affect carbon balance, forest productivity, and biodiversity. We observed phenology intensively throughout spring and autumn in a temperate deciduous woodlot at Milwaukee, WI, USA, during 2007-2012. Twenty-four phenophase levels in spring and eight in autumn were recorded for 106 trees, including white ash, basswood, white oak, boxelder, red oak, and hophornbeam. Our phenological progression models revealed that accumulated degree-days and day length explained 87.9-93.4 % of the variation in spring canopy development and 75.8-89.1 % of the variation in autumn senescence. In addition, the timing of community-level spring and autumn phenophases and the length of the growing season from 1871 to 2012 were reconstructed with the models developed. All simulated spring phenophases significantly advanced at a rate from 0.24 to 0.48 days/decade ( p ≤ 0.001) during the 1871-2012 period and from 1.58 to 2.00 days/decade ( p coloration) and 0.50 (full-leaf coloration) days/decade ( p coloration and leaf fall, and suggested accelerating simulated ecosystem responses to climate warming over the last four decades in comparison to the past 142 years.

Endogenous Technological Progress with Uncertainty and Carbon Abatement Polices

Energy Technology Data Exchange (ETDEWEB)

Cho, G.L. [Korea Energy Economics Institute, Euiwang (Korea)

2001-11-01

Most greenhouse gas abatement policy models tend to neglect a potentially important element that is relevant to the induced technology changes(ITC). These models that incorporate technological change treat such a change as autonomous, that is, unaffected by changes in prices brought about by policy reforms. However, climate change policies can create economic incentives to engage in more extensive R and D oriented toward the discovery of new production techniques that mitigate a reliance on convectional fuels, ultimately resulting in impacts on the policies themselves. In order to investigate the significance of induced technology for the attractiveness of abatement policies, this study develop the multi-sectoral dynamic CGE model by incorporating two characteristics of technological progress: the endogenous growth model with externality of technology in Romer (1986) and Lucas(1988) and the technological changes resulting from profit maximizing investment in R and D in Rebelo(1991) and Jones and Manuelli(1990). Furthermore, technological progress is affected by not only the economical factors but also the political and institutional system that cannot be captured in this model. This study considers such uncertainty in the technological progress as technology shock as in RBC school. This study shows that the presence of ITC implies lower costs of achieving a given abatement target in terms of the reduction cost per ton of carbon and GDP losses. The presence of ITC reduces the GDP losses by 0.9%p{approx}1.5%p compared with the absence of the ITC. As the abatement target is substantially high, R and D is reduced significantly even in the presence of ITC. Therefore, it is necessary to seriously consider the tax recycling for enhancing R and D investment, which minimizes the GDP losses. The reduction cost is highly sensitive to the uncertainty in technological progress. The technology shock leads the reduction cost to widely vary, in terms of standard deviation, 3

Generalizability of the Disease State Index Prediction Model for Identifying Patients Progressing from Mild Cognitive Impairment to Alzheimer's Disease

NARCIS (Netherlands)

Hall, A.; Munoz-Ruiz, M.; Mattila, J.; Koikkalainen, J.; Tsolaki, M.; Mecocci, P.; Kloszewska, I.; Vellas, B.; Lovestone, S.; Visser, P.J.; Lotjonen, J.; Soininen, H.

2015-01-01

Background: The Disease State Index (DSI) prediction model measures the similarity of patient data to diagnosed stable and progressive mild cognitive impairment (MCI) cases to identify patients who are progressing to Alzheimer's disease. Objectives: We evaluated how well the DSI generalizes across

Progress in MELCOR development and assessment

International Nuclear Information System (INIS)

Summers, R.M.; Kmetyk, L.N.; Cole, R.K. Jr.; Smith, R.C.; Elsbernd, A.E.; Stuart, D.S.; Thompson, S.L.

1995-01-01

MELCOR models the progression of severe accidents in light water reactor nuclear power plants. Recent efforts in MELCOR development to incorporate CORCON-Mod3 models for core-concrete interactions, new models for advanced reactors, and improvements to several other existing models have resulted in release of MELCOR 1.8.3. In addition, continuing efforts to expand the code assessment database have filled in many of the gaps in phenomenological coverage. Efforts are now under way to develop models for chemical interactions of fission products with structural surfaces and for reactions of iodine in the presence of water, and work is also in progress to improve models for the scrubbing of fission products by water pools, the chemical reactions of boron carbide with steam, and the coupling of flow blockages with the hydrodynamics. Several code assessment analyses are in progress, and more are planned

Earnings progression, human capital and incentives

DEFF Research Database (Denmark)

Frederiksen, Anders

progression by investigating the effects of on-the-job human capital acquisition, explicit short-run incentives and career concern incentives on earnings progression. The model leads to predictions about the incentive structure and the progression in both cross-sectional and individual earnings which...

Vision deficits precede structural losses in a mouse model of mitochondrial dysfunction and progressive retinal degeneration.

Science.gov (United States)

Laliberté, Alex M; MacPherson, Thomas C; Micks, Taft; Yan, Alex; Hill, Kathleen A

2011-12-01

Current animal models of retinal disease often involve the rapid development of a retinal disease phenotype; however, this is at odds with age-related diseases that take many years to manifest clinical symptoms. The present study was performed to examine an apoptosis-inducing factor (Aif)-deficient model, the harlequin carrier mouse (X(hq)X), and determine how mitochondrial dysfunction and subsequent accelerated aging affect the function and structure of the mouse retina. Vision and eye structure for cohorts of 6 X(hq)X and 6 wild type mice at 3, 11, and 15 months of age were studied using in vivo electroretinography (ERG), and optical coherence tomography (OCT). Retinal superoxide levels were determined in situ using dihydroethidium (DHE) histochemistry. Retinal cell counts were quantified post mortem using hematoxylin and eosin (H&E) staining. ERG analysis of X(hq)X retinal function indicated a reduction in b-wave amplitude significant at 3 months of age (p retina (p retina may account for the early and significant reduction in retinal function. This remodeling of retinal neurochemistry in response to stress may be a relevant mechanism in the progression of normal retinal aging and early stages of some retinal degenerative diseases. Copyright © 2011 Elsevier Ltd. All rights reserved.

A spray flamelet/progress variable approach combined with a transported joint PDF model for turbulent spray flames

Science.gov (United States)

Hu, Yong; Olguin, Hernan; Gutheil, Eva

2017-05-01

A spray flamelet/progress variable approach is developed for use in spray combustion with partly pre-vaporised liquid fuel, where a laminar spray flamelet library accounts for evaporation within the laminar flame structures. For this purpose, the standard spray flamelet formulation for pure evaporating liquid fuel and oxidiser is extended by a chemical reaction progress variable in both the turbulent spray flame model and the laminar spray flame structures, in order to account for the effect of pre-vaporised liquid fuel for instance through use of a pilot flame. This new approach is combined with a transported joint probability density function (PDF) method for the simulation of a turbulent piloted ethanol/air spray flame, and the extension requires the formulation of a joint three-variate PDF depending on the gas phase mixture fraction, the chemical reaction progress variable, and gas enthalpy. The molecular mixing is modelled with the extended interaction-by-exchange-with-the-mean (IEM) model, where source terms account for spray evaporation and heat exchange due to evaporation as well as the chemical reaction rate for the chemical reaction progress variable. This is the first formulation using a spray flamelet model considering both evaporation and partly pre-vaporised liquid fuel within the laminar spray flamelets. Results with this new formulation show good agreement with the experimental data provided by A.R. Masri, Sydney, Australia. The analysis of the Lagrangian statistics of the gas temperature and the OH mass fraction indicates that partially premixed combustion prevails near the nozzle exit of the spray, whereas further downstream, the non-premixed flame is promoted towards the inner rich-side of the spray jet since the pilot flame heats up the premixed inner spray zone. In summary, the simulation with the new formulation considering the reaction progress variable shows good performance, greatly improving the standard formulation, and it provides new

White matter lesion progression

DEFF Research Database (Denmark)

Hofer, Edith; Cavalieri, Margherita; Bis, Joshua C

2015-01-01

10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current......BACKGROUND AND PURPOSE: White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants...... associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. METHODS: Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from...

Recent Progresses in Incorporating Human Land-Water Management into Global Land Surface Models Toward Their Integration into Earth System Models

Science.gov (United States)

Pokhrel, Yadu N.; Hanasaki, Naota; Wada, Yoshihide; Kim, Hyungjun

2016-01-01

The global water cycle has been profoundly affected by human land-water management. As the changes in the water cycle on land can affect the functioning of a wide range of biophysical and biogeochemical processes of the Earth system, it is essential to represent human land-water management in Earth system models (ESMs). During the recent past, noteworthy progress has been made in large-scale modeling of human impacts on the water cycle but sufficient advancements have not yet been made in integrating the newly developed schemes into ESMs. This study reviews the progresses made in incorporating human factors in large-scale hydrological models and their integration into ESMs. The study focuses primarily on the recent advancements and existing challenges in incorporating human impacts in global land surface models (LSMs) as a way forward to the development of ESMs with humans as integral components, but a brief review of global hydrological models (GHMs) is also provided. The study begins with the general overview of human impacts on the water cycle. Then, the algorithms currently employed to represent irrigation, reservoir operation, and groundwater pumping are discussed. Next, methodological deficiencies in current modeling approaches and existing challenges are identified. Furthermore, light is shed on the sources of uncertainties associated with model parameterizations, grid resolution, and datasets used for forcing and validation. Finally, representing human land-water management in LSMs is highlighted as an important research direction toward developing integrated models using ESM frameworks for the holistic study of human-water interactions within the Earths system.

A Simple Diet- and Chemical-Induced Murine NASH Model with Rapid Progression of Steatohepatitis, Fibrosis and Liver Cancer.

Science.gov (United States)

Tsuchida, Takuma; Lee, Youngmin A; Fujiwara, Naoto; Ybanez, Maria; Allen, Brittany; Martins, Sebastiao; Fiel, M Isabel; Goossens, Nicolas; Chou, Hsin-I; Hoshida, Yujin; Friedman, Scott L

2018-03-20

Although the majority of patients with nonalcoholic fatty liver disease (NAFLD) have only steatosis without progression, a sizable fraction develop non-alcoholic steatohepatitis (NASH), which can lead to cirrhosis and hepatocellular carcinoma (HCC). Many established diet-induced mouse models for NASH require 24-52 weeks, which makes testing for drug response costly and time consuming. We have sought to establish a murine NASH model with rapid progression of extensive fibrosis and HCC by using a western diet (WD), which is high-fat, high-fructose and high-cholesterol, combined with low dose weekly intraperitoneal carbon tetrachloride (CCl 4 ), which served as an accelerator. C57BL/6J mice were fed a normal chow diet (ND) ± CCl 4 or WD ± CCl 4 for 12 and 24 weeks. Addition of CCl 4 exacerbated histological features of NASH, fibrosis, and tumor development induced by WD, which resulted in stage 3 fibrosis at 12 weeks and HCC development at 24 weeks. Furthermore, whole liver transcriptomic analysis indicated that dysregulated molecular pathways in WD/CCl 4 mice and immunologic features were closely similar to those of human NASH. Our mouse NASH model exhibits rapid progression of advanced fibrosis and HCC, and mimics histological, immunological and transcriptomic features of human NASH, suggesting that it will be a useful experimental tool for preclinical drug testing. A carefully characterized model has been developed in mice that recapitulates the progressive stages of human fatty liver disease, from simple steatosis, to inflammation, fibrosis and cancer. The functional pathways of gene expression and immune abnormalities in this model closely resemble human disease. The ease and reproducibility of this model makes it ideal to study disease pathogenesis and test new treatments. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Sludge Treatment Evaluation: 1992 Technical progress

International Nuclear Information System (INIS)

Silva, L.J.; Felmy, A.R.; Ding, E.R.

1993-01-01

This report documents Fiscal Year 1992 technical progress on the Sludge Treatment Evaluation Task, which is being conducted by Pacific Northwest Laboratory. The objective of this task is to develop a capability to predict the performance of pretreatment processes for mixed radioactive and hazardous waste stored at Hanford and other US Department of Energy (DOE) sites. Significant cost savings can be achieved if radionuclides and other undesirable constituents can be effectively separated from the bulk waste prior to final treatment and disposal. This work is initially focused on chemical equilibrium prediction of water washing and acid or base dissolution of Hanford single-shell tank (SST) sludges, but may also be applied to other steps in pretreatment processes or to other wastes. Although SST wastes contain many chemical species, there are relatively few constituents -- Na, Al, NO 3 , NO 2 , PO 4 , SO 4 , and F -- contained in the majority of the waste. These constituents comprise 86% and 74% of samples from B-110 and U-110 SSTS, respectively. The major radionuclides of interest (Cs, Sr, Tc, U) are present in the sludge in small molal quantities. For these constituents, and other important components that are present in small molal quantities, the specific ion-interaction terms used in the Pitzer or NRTL equations may be assumed to be zero for a first approximation. Model development can also be accelerated by considering only the acid or base conditions that apply for the key pretreatment steps. This significantly reduces the number of chemical species and chemical reactions that need to be considered. Therefore, significant progress can be made by developing all the specific ion interactions for a base model and an acid dissolution model

Sludge Treatment Evaluation: 1992 Technical progress

Energy Technology Data Exchange (ETDEWEB)

Silva, L J; Felmy, A R; Ding, E R

1993-01-01

This report documents Fiscal Year 1992 technical progress on the Sludge Treatment Evaluation Task, which is being conducted by Pacific Northwest Laboratory. The objective of this task is to develop a capability to predict the performance of pretreatment processes for mixed radioactive and hazardous waste stored at Hanford and other US Department of Energy (DOE) sites. Significant cost savings can be achieved if radionuclides and other undesirable constituents can be effectively separated from the bulk waste prior to final treatment and disposal. This work is initially focused on chemical equilibrium prediction of water washing and acid or base dissolution of Hanford single-shell tank (SST) sludges, but may also be applied to other steps in pretreatment processes or to other wastes. Although SST wastes contain many chemical species, there are relatively few constituents -- Na, Al, NO[sub 3], NO[sub 2], PO[sub 4], SO[sub 4], and F -- contained in the majority of the waste. These constituents comprise 86% and 74% of samples from B-110 and U-110 SSTS, respectively. The major radionuclides of interest (Cs, Sr, Tc, U) are present in the sludge in small molal quantities. For these constituents, and other important components that are present in small molal quantities, the specific ion-interaction terms used in the Pitzer or NRTL equations may be assumed to be zero for a first approximation. Model development can also be accelerated by considering only the acid or base conditions that apply for the key pretreatment steps. This significantly reduces the number of chemical species and chemical reactions that need to be considered. Therefore, significant progress can be made by developing all the specific ion interactions for a base model and an acid dissolution model.

Progress in the improved lattice calculation of direct CP-violation in the Standard Model

Science.gov (United States)

Kelly, Christopher

2018-03-01

We discuss the ongoing effort by the RBC & UKQCD collaborations to improve our lattice calculation of the measure of Standard Model direct CP violation, ɛ', with physical kinematics. We present our progress in decreasing the (dominant) statistical error and discuss other related activities aimed at reducing the systematic errors.

Dietary manipulation and social isolation alter disease progression in a murine model of coronary heart disease.

Directory of Open Access Journals (Sweden)

Yumiko Nakagawa-Toyama

Full Text Available BACKGROUND: Mice with a deficiency in the HDL receptor SR-BI and low expression of a modified apolipoprotein E gene (SR-BI KO/ApoeR61(h/h called 'HypoE' when fed an atherogenic, 'Paigen' diet develop occlusive, atherosclerotic coronary arterial disease (CHD, myocardial infarctions (MI, and heart dysfunction and die prematurely (50% mortality ~40 days after initiation of this diet. Because few murine models share with HypoE mice these cardinal, human-like, features of CHD, HypoE mice represent a novel, small animal, diet-inducible and genetically tractable model for CHD. To better describe the properties of this model, we have explored the effects of varying the composition and timing of administration of atherogenic diets, as well as social isolation vs. group housing, on these animals. METHODOLOGY/PRINCIPAL FINDINGS: HypoE mice were maintained on a standard lab chow diet (control until two months of age. Subsequently they received one of three atherogenic diets (Paigen, Paigen without cholate, Western or control diet for varying times and were housed in groups or singly, and we determined the plasma cholesterol levels, extent of cardiomegaly and/or survival. The rate of disease progression could be reduced by lowering the severity of the atherogenic diet and accelerated by social isolation. Disease could be induced by Paigen diets either containing or free of cholate. We also established conditions under which CHD could be initiated by an atherogenic diet and then subsequently, by replacing this diet with standard lab chow, hypercholesterolemia could be reduced and progression to early death prevented. CONCLUSIONS/SIGNIFICANCE: HypoE mice provide a powerful, surgery-free, diet-'titratable' small animal model that can be used to study the onset of recovery from occlusive, atherosclerotic CHD and heart failure due to MI. HypoE mice can be used for the analysis of the effects of environment (diet, social isolation on a variety of features of

The Association of Unintentional Changes in Weight, Body Composition, and Homeostasis Model Assessment Index with Glycemic Progression in Non-Diabetic Healthy Subjects

Directory of Open Access Journals (Sweden)

Eun-Jung Rhee

2011-04-01

Full Text Available BackgroundWe performed a retrospective longitudinal study on the effects of changes in weight, body composition, and homeostasis model assessment (HOMA indices on glycemic progression in subjects without diabetes during a four-year follow-up period in a community cohort without intentional intervention.MethodsFrom 28,440 non-diabetic subjects who participated in a medical check-up program in 2004, data on anthropometric and metabolic parameters were obtained after four years in 2008. Body composition analyses were performed with a bioelectrical impedance analyzer. Skeletal muscle index (SMI, % was calculated with lean mass/weight×100. Subjects were divided into three groups according to weight change status in four years: weight loss (≤-5.0%, stable weight (-5.0 to 5.0%, weight gain (≥5.0%. Progressors were defined as the subjects who progressed to impaired fasting glucose or diabetes.ResultsProgressors showed worse baseline metabolic profiles compared with non-progressors. In logistic regression analyses, the increase in changes of HOMA-insulin resistance (HOMA-IR in four years presented higher odds ratios for glycemic progression compared with other changes during that period. Among the components of body composition, a change in waist-hip ratio was the strongest predictor, and SMI change in four years was a significant negative predictor for glycemic progression. Changes in HOMA β-cell function in four years was a negative predictor for glycemic progression.ConclusionIncreased interval changes in HOMA-IR, weight gain and waist-hip ratio was associated with glycemic progression during a four-year period without intentional intervention in non-diabetic Korean subjects.

THE EFFECTS OF SINGLE LEG HOP PROGRESSION AND DOUBLE LEGS HOP PROGRESSION EXERCISE TO INCREASE SPEED AND EXPLOSIVE POWER OF LEG MUSCLE

Directory of Open Access Journals (Sweden)

Nining W. Kusnanik

2015-05-01

Full Text Available The main purpose of this study was to determine the effect of single leg hop progression and double legs hop progression exercise to increase speed and explosive power of leg muscles. Plyometric is one of the training methods that can increase explosive power. There are many models of plyometric training including single leg hop progression and double leg hop progression. This research was experimental using match subject design techniques. The subjects of this study were 39 students who joined basketball school club. There were 3 groups in this study: Group 1 were 13 students who given sin¬gle leg hop progression exercise, Group 2 were 13 students who given double legs hop progression exercise, Group 3 were 13 students who given conventional exercise. The data was collected during pre test and post test by testing 30m speed running and vertical jump. The data was analyzed using Analysis of Varians (Anova. It was found that there were significantly increased on speed and explosive power of leg muscles of Group 1 and Group 2. It can be stated that single leg hop progression exercise was more effective than double leg hop progression exercise. The recent findings supported the hypothesis that single leg hop progression and double legs hop progression exercise can increase speed and explosive power of leg muscles. These finding were supported by some previous studies (Singh, et al, 2011; Shallaby, H.K., 2010. The single leg hop progression is more effective than double legs hop progression. This finding was consistent with some previous evidences (McCurdy, et al, 2005; Makaruk et al, 2011.

A single dose of a neuron-binding human monoclonal antibody improves brainstem NAA concentrations, a biomarker for density of spinal cord axons, in a model of progressive multiple sclerosis.

Science.gov (United States)

Wootla, Bharath; Denic, Aleksandar; Watzlawik, Jens O; Warrington, Arthur E; Rodriguez, Moses

2015-04-29

Intracerebral infection of susceptible mouse strains with Theiler's murine encephalomyelitis virus (TMEV) results in chronic demyelinating disease with progressive axonal loss and neurologic dysfunction similar to progressive forms of multiple sclerosis (MS). We previously showed that as the disease progresses, a marked decrease in brainstem N-acetyl aspartate (NAA; metabolite associated with neuronal integrity) concentrations, reflecting axon health, is measured. We also demonstrated stimulation of neurite outgrowth by a neuron-binding natural human antibody, IgM12. Treatment with either the serum-derived or recombinant human immunoglobulin M 12 (HIgM12) preserved functional motor activity in the TMEV model. In this study, we examined IgM-mediated changes in brainstem NAA concentrations and central nervous system (CNS) pathology. (1)H-magnetic resonance spectroscopy (MRS) showed that treatment with HIgM12 significantly increased brainstem NAA concentrations compared to controls in TMEV-infected mice. Pathologic analysis demonstrated a significant preservation of axons in the spinal cord of animals treated with HIgM12. This study links drug efficacy of slowing deficits with axon preservation and NAA concentrations in the brainstem in a model of progressive MS. HIgM12-mediated changes of NAA concentrations in the brainstem are a surrogate marker of axon injury/preservation throughout the spinal cord. This study provides proof-of-concept that a neuron-reactive human IgM can be therapeutic and provides a biomarker for clinical trials.

Early Prediction of Disease Progression in Small Cell Lung Cancer: Toward Model-Based Personalized Medicine in Oncology.

Science.gov (United States)

Buil-Bruna, Núria; Sahota, Tarjinder; López-Picazo, José-María; Moreno-Jiménez, Marta; Martín-Algarra, Salvador; Ribba, Benjamin; Trocóniz, Iñaki F

2015-06-15

Predictive biomarkers can play a key role in individualized disease monitoring. Unfortunately, the use of biomarkers in clinical settings has thus far been limited. We have previously shown that mechanism-based pharmacokinetic/pharmacodynamic modeling enables integration of nonvalidated biomarker data to provide predictive model-based biomarkers for response classification. The biomarker model we developed incorporates an underlying latent variable (disease) representing (unobserved) tumor size dynamics, which is assumed to drive biomarker production and to be influenced by exposure to treatment. Here, we show that by integrating CT scan data, the population model can be expanded to include patient outcome. Moreover, we show that in conjunction with routine medical monitoring data, the population model can support accurate individual predictions of outcome. Our combined model predicts that a change in disease of 29.2% (relative standard error 20%) between two consecutive CT scans (i.e., 6-8 weeks) gives a probability of disease progression of 50%. We apply this framework to an external dataset containing biomarker data from 22 small cell lung cancer patients (four patients progressing during follow-up). Using only data up until the end of treatment (a total of 137 lactate dehydrogenase and 77 neuron-specific enolase observations), the statistical framework prospectively identified 75% of the individuals as having a predictable outcome in follow-up visits. This included two of the four patients who eventually progressed. In all identified individuals, the model-predicted outcomes matched the observed outcomes. This framework allows at risk patients to be identified early and therapeutic intervention/monitoring to be adjusted individually, which may improve overall patient survival. ©2015 American Association for Cancer Research.

Progress test utopia.

Science.gov (United States)

van der Vleuten, Cees; Freeman, Adrian; Collares, Carlos Fernando

2018-04-01

This paper discusses the advantages of progress testing. A utopia is described where medical schools would work together to develop and administer progress testing. This would lead to a significant reduction of cost, an increase in the quality of measurement and phenomenal feedback to learner and school. Progress testing would also provide more freedom and resources for more creative in-school assessment. It would be an educationally attractive alternative for the creation of cognitive licensing exams. A utopia is always far away in the future, but by formulating a vision for that future we may engage in discussions on how to get there.

Progression of pancreatic adenocarcinoma is significantly impeded with a combination of vaccine and COX-2 inhibition.

Science.gov (United States)

Mukherjee, Pinku; Basu, Gargi D; Tinder, Teresa L; Subramani, Durai B; Bradley, Judy M; Arefayene, Million; Skaar, Todd; De Petris, Giovanni

2009-01-01

With a 5-year survival rate of <5%, pancreatic cancer is one of the most rapidly fatal malignancies. Current protocols for the treatment of pancreas cancer are not as effective as we desire. In this study, we show that a novel Mucin-1 (MUC1)-based vaccine in combination with a cyclooxygenase-2 inhibitor (celecoxib), and low-dose chemotherapy (gemcitabine) was effective in preventing the progression of preneoplastic intraepithelial lesions to invasive pancreatic ductal adenocarcinomas. The study was conducted in an appropriate triple transgenic model of spontaneous pancreatic cancer induced by the KRAS(G12D) mutation and that expresses human MUC1 as a self molecule. The combination treatment elicited robust antitumor cellular and humoral immune responses and was associated with increased apoptosis in the tumor. The mechanism for the increased immune response was attributed to the down-regulation of circulating prostaglandin E(2) and indoleamine 2, 3,-dioxygenase enzymatic activity, as well as decreased levels of T regulatory and myeloid suppressor cells within the tumor microenvironment. The preclinical data provide the rationale to design clinical trials with a combination of MUC1-based vaccine, celecoxib, and gemcitabine for the treatment of pancreatic cancer.

Influence of model assumptions about HIV disease progression after initiating or stopping treatment on estimates of infections and deaths averted by scaling up antiretroviral therapy

Science.gov (United States)

Sucharitakul, Kanes; Boily, Marie-Claude; Dimitrov, Dobromir

2018-01-01

Background Many mathematical models have investigated the population-level impact of expanding antiretroviral therapy (ART), using different assumptions about HIV disease progression on ART and among ART dropouts. We evaluated the influence of these assumptions on model projections of the number of infections and deaths prevented by expanded ART. Methods A new dynamic model of HIV transmission among men who have sex with men (MSM) was developed, which incorporated each of four alternative assumptions about disease progression used in previous models: (A) ART slows disease progression; (B) ART halts disease progression; (C) ART reverses disease progression by increasing CD4 count; (D) ART reverses disease progression, but disease progresses rapidly once treatment is stopped. The model was independently calibrated to HIV prevalence and ART coverage data from the United States under each progression assumption in turn. New HIV infections and HIV-related deaths averted over 10 years were compared for fixed ART coverage increases. Results Little absolute difference (ART coverage (varied between 33% and 90%) if ART dropouts reinitiated ART at the same rate as ART-naïve MSM. Larger differences in the predicted fraction of HIV-related deaths averted were observed (up to 15pp). However, if ART dropouts could only reinitiate ART at CD4ART interruption did not affect the fraction of HIV infections averted with expanded ART, unless ART dropouts only re-initiated ART at low CD4 counts. Different disease progression assumptions had a larger influence on the fraction of HIV-related deaths averted with expanded ART. PMID:29554136

Accident progression event tree analysis for postulated severe accidents at N Reactor

International Nuclear Information System (INIS)

Wyss, G.D.; Camp, A.L.; Miller, L.A.; Dingman, S.E.; Kunsman, D.M.; Medford, G.T.

1990-06-01

A Level II/III probabilistic risk assessment (PRA) has been performed for N Reactor, a Department of Energy (DOE) production reactor located on the Hanford reservation in Washington. The accident progression analysis documented in this report determines how core damage accidents identified in the Level I PRA progress from fuel damage to confinement response and potential releases the environment. The objectives of the study are to generate accident progression data for the Level II/III PRA source term model and to identify changes that could improve plant response under accident conditions. The scope of the analysis is comprehensive, excluding only sabotage and operator errors of commission. State-of-the-art methodology is employed based largely on the methods developed by Sandia for the US Nuclear Regulatory Commission in support of the NUREG-1150 study. The accident progression model allows complex interactions and dependencies between systems to be explicitly considered. Latin Hypecube sampling was used to assess the phenomenological and systemic uncertainties associated with the primary and confinement system responses to the core damage accident. The results of the analysis show that the N Reactor confinement concept provides significant radiological protection for most of the accident progression pathways studied

Application of a prediction model for the progression of rheumatoid arthritis in patients with undifferentiated arthritis.

Science.gov (United States)

Arana-Guajardo, Ana; Pérez-Barbosa, Lorena; Vega-Morales, David; Riega-Torres, Janett; Esquivel-Valerio, Jorge; Garza-Elizondo, Mario

2014-01-01

Different prediction rules have been applied to patients with undifferentiated arthritis (UA) to identify those that progress to rheumatoid arthritis (RA). The Leiden Prediction Rule (LPR) has proven useful in different UA cohorts. To apply the LPR to a cohort of patients with UA of northeastern Mexico. We included 47 patients with UA, LPR was applied at baseline. They were evaluated and then classified after one year of follow-up into two groups: those who progressed to RA (according to ACR 1987) and those who did not. 43% of the AI patients developed RA. In the RA group, 56% of patients obtained a score ≤ 6 and only 15% ≥ 8. 70% who did not progress to RA had a score between 6 and ≤ 8. There was no difference in median score of LPR between groups, p=0.940. Most patients who progressed to RA scored less than 6 points in the LPR. Unlike what was observed in other cohorts, the model in our population did not allow us to predict the progression of the disease. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

Significance of Selective Predation and Development of Prey Protection Measures for Juvenile Salmonids in the Columbia and Snake River Reservoirs: Annual Progress Report, February 1991-February 1992.

Energy Technology Data Exchange (ETDEWEB)

Poe, Thomas P.

1992-12-31

This document is the 1991 annual report of progress for the Bonneville Power Administration (BPA) research Project conducted by the US Fish and Wildlife Service (FWS). Our approach was to present the progress achieved during 1991 in a series of separate reports for each major project task. Each report is prepared in the format of a scientific paper and is able to stand alone, whatever the state of progress or completion. This project has two major goals. One is to understand the significance of selective predation and prey vulnerability by determining if substandard juvenile salmonids (dead, injured, stressed, diseased, or naive) are more vulnerable to predation by northern squawfish, than standard or normal juvenile salmonids. The second goal is to develop and test prey protection measures to control predation on juvenile salmonids by reducing predator-smolt encounters or predator capture efficiency.

Progress Report on SAM Reduced-Order Model Development for Thermal Stratification and Mixing during Reactor Transients

Energy Technology Data Exchange (ETDEWEB)

Hu, R. [Argonne National Lab. (ANL), Argonne, IL (United States)

2017-09-01

This report documents the initial progress on the reduced-order flow model developments in SAM for thermal stratification and mixing modeling. Two different modeling approaches are pursued. The first one is based on one-dimensional fluid equations with additional terms accounting for the thermal mixing from both flow circulations and turbulent mixing. The second approach is based on three-dimensional coarse-grid CFD approach, in which the full three-dimensional fluid conservation equations are modeled with closure models to account for the effects of turbulence.

An efficient numerical progressive diagonalization scheme for the quantum Rabi model revisited

International Nuclear Information System (INIS)

Pan, Feng; Bao, Lina; Dai, Lianrong; Draayer, Jerry P

2017-01-01

An efficient numerical progressive diagonalization scheme for the quantum Rabi model is revisited. The advantage of the scheme lies in the fact that the quantum Rabi model can be solved almost exactly by using the scheme that only involves a finite set of one variable polynomial equations. The scheme is especially efficient for a specified eigenstate of the model, for example, the ground state. Some low-lying level energies of the model for several sets of parameters are calculated, of which one set of the results is compared to that obtained from the Braak’s exact solution proposed recently. It is shown that the derivative of the entanglement measure defined in terms of the reduced von Neumann entropy with respect to the coupling parameter does reach the maximum near the critical point deduced from the classical limit of the Dicke model, which may provide a probe of the critical point of the crossover in finite quantum many-body systems, such as that in the quantum Rabi model. (paper)

Determining significant endpoints for ecological risk analyses. 1997 annual progress report

Energy Technology Data Exchange (ETDEWEB)

Hinton, T.G.; Congdon, J.; Rowe, C.; Scott, D. [Univ. of Georgia, Aiken, SC (US). Savannah River Ecology Lab.; Bedford, J.; Whicker, F.W. [Colorado State Univ., Fort Collins, CO (US)

1997-11-01

'This report summarizes the first year''s progress of research funded under the Department of Energy''s Environmental Management Science Program. The research was initiated to better determine ecological risks from toxic and radioactive contaminants. More precisely, the research is designed to determine the relevancy of sublethal cellular damage to the performance of individuals and to identify characteristics of non-human populations exposed to chronic, low-level radiation, as is typically found on many DOE sites. The authors propose to establish a protocol to assess risks to non-human species at higher levels of biological organization by relating molecular damage to more relevant responses that reflect population health. They think that they can achieve this by coupling changes in metabolic rates and energy allocation patterns to meaningful population response variables, and by using novel biological dosimeters in controlled, manipulative dose/effects experiments. They believe that a scientifically defensible endpoint for measuring ecological risks can only be determined once its understood the extent to which molecular damage from contaminant exposure is detrimental at the individual and population levels of biological organization.'

Climate Reanalysis: Progress and Future Prospects

Science.gov (United States)

Gelaro, Ron

2018-01-01

Reanalysis is the process whereby an unchanging data assimilation system is used to provide a consistent reprocessing of observations, typically spanning an extended segment of the historical data record. The process relies on an underlying model to combine often-disparate observations in a physically consistent manner, enabling production of gridded data sets for a broad range of applications including the study of historical weather events, preparation of climatologies, business sector development and, more recently, climate monitoring. Over the last few decades, several generations of reanalyses of the global atmosphere have been produced by various operational and research centers, focusing more or less on the period of regular conventional and satellite observations beginning in the mid to late twentieth century. There have also been successful efforts to extend atmospheric reanalyses back to the late nineteenth and early twentieth centuries, using mostly surface observations. Much progress has resulted from (and contributed to) advancements in numerical weather prediction, especially improved models and data assimilation techniques, increased computing capacity, the availability of new observation types and efforts to recover and improve the quality of historical ones. The recent extension of forecast systems that allow integrated modeling of meteorological, oceanic, land surface, and chemical variables provide the basic elements for coupled data assimilation. This has opened the door to the development of a new generation of coupled reanalyses of the Earth system, or integrated Earth system analyses (IESA). Evidence so far suggests that this approach can improve the analysis of currently uncoupled components of the Earth system, especially at their interface, and lead to increased predictability. However, extensive analysis coupling as envisioned for IESA, while progressing, still presents significant challenges. These include model biases that can be

An epidemic model for the future progression of the current Haiti cholera epidemic

Science.gov (United States)

Bertuzzo, E.; Mari, L.; Righetto, L.; Casagrandi, R.; Gatto, M.; Rodriguez-Iturbe, I.; Rinaldo, A.

2012-04-01

As a major cholera epidemic progresses in Haiti, and the figures of the infection, up to December 2011, climb to 522,000 cases and 7,000 deaths, the development of general models to track and predict the evolution of the outbreak, so as to guide the allocation of medical supplies and staff, is gaining notable urgency. We propose here a spatially explicit epidemic model that accounts for the dynamics of susceptible and infected individuals as well as the redistribution of Vibrio cholera, the causative agent of the disease, among different human communities. In particular, we model two spreading pathways: the advection of pathogens through hydrologic connections and the dissemination due to human mobility described by means of a gravity-like model. To this end the country has been divided into hydrologic units based on drainage directions derived from a digital terrain model. Moreover the population of each unit has been estimated from census data downscaled to 1 km x 1 km resolution via remotely sensed geomorphological information (LandScan project). The model directly accounts for the role of rainfall patterns in driving the seasonality of cholera outbreaks. The two main outbreaks in fact occurred during the rainy seasons (October and May) when extensive floodings severely worsened the sanitation conditions and, in turn, raised the risk of infection. The model capability to reproduce the spatiotemporal features of the epidemic up to date grants robustness to the foreseen future development. To this end, we generate realistic scenario of future precipitation in order to forecast possible epidemic paths up to the end of the 2013. In this context, the duration of acquired immunity, a hotly debated topic in the scientific community, emerges as a controlling factor for progression of the epidemic in the near future. The framework presented here can straightforwardly be used to evaluate the effectiveness of alternative intervention strategies like mass vaccinations

Designing and Implementing the Model of Public Assessment of Social and Cultural Progress in Universities

Directory of Open Access Journals (Sweden)

Gholamreza Khaje Sarvi

2013-03-01

Full Text Available Implementing Investigations, analyzes and performance measurements in special and qualitative social/cultural arena in our country, needs local and special methodologies. Thus the aim of present article is investigating these issues: the concept of culture, classification of cultural organizations in Islamic Republic of Iran, the Pyramidal structure of cultural hierarchy, the process of development and mutual influences of institutions, reviewing related literature of policy making in cultural issues, compatibility of strategies to existing realities in cultural performance structure, double division in measures and analyzing and elaborating suggested measures in elaborating weighting model and assessment method and investigating progress measures by focusing on Islamic-Iranian pattern of progress and investigating the effects of implementing this pattern plus weighting method and using related measures and studying some university cases which are implemented in three phases in universities and high education centers overall the country. This research has shown a linear model by considering weighting coefficients.

Progress report 1981

International Nuclear Information System (INIS)

Chalupka, A.; Dirninger, G.

1982-01-01

The progress report describes the scientific work and research results of the institute for radium research and nuclear physics of the Austrian Academy of Sciences for the period of 1981. The progress report covers the subject areas of nuclear theory, nuclear model calculations, experimental nuclear physics and neutron involved reactions, medium energy physics, instrumentation and detectors, evaluation of nuclear data and numerical data processing, dating, applications in medicine, dosimetry and environmental studies. A list of publications of this institute is given. (A.N.)

Progress report 1982

International Nuclear Information System (INIS)

Chalupka, A.; Wild, E.; Dirninger, G.

1983-01-01

The progress report describes the scientific work and research results of the institute for radium research and nuclear physics of the Austrian Academy of Sciences for the period of 1982. The progress report covers the subject areas of nuclear theory, nuclear model calculations, experimental nuclear physics and neutron involved reactions, medium energy physics, instrumentation and detectors, evaluation of nuclear data and numerical data processing, dating, applications in medicine, dosimetry and environmental studies. A list of publications of this institute is given. (A.N.)

A spatially explicit model for the future progression of the current Haiti cholera epidemic

Science.gov (United States)

Bertuzzo, E.; Mari, L.; Righetto, L.; Gatto, M.; Casagrandi, R.; Rodriguez-Iturbe, I.; Rinaldo, A.

2011-12-01

As a major cholera epidemic progresses in Haiti, and the figures of the infection, up to July 2011, climb to 385,000 cases and 5,800 deaths, the development of general models to track and predict the evolution of the outbreak, so as to guide the allocation of medical supplies and staff, is gaining notable urgency. We propose here a spatially explicit epidemic model that accounts for the dynamics of susceptible and infected individuals as well as the redistribution of textit{Vibrio cholera}, the causative agent of the disease, among different human communities. In particular, we model two spreading pathways: the advection of pathogens through hydrologic connections and the dissemination due to human mobility described by means of a gravity-like model. To this end the country has been divided into hydrologic units based on drainage directions derived from a digital terrain model. Moreover the population of each unit has been estimated from census data downscaled to 1 km x 1 km resolution via remotely sensed geomorphological information (LandScan texttrademark project). The model directly account for the role of rainfall patterns in driving the seasonality of cholera outbreaks. The two main outbreaks in fact occurred during the rainy seasons (October and May) when extensive floodings severely worsened the sanitation conditions and, in turn, raised the risk of infection. The model capability to reproduce the spatiotemporal features of the epidemic up to date grants robustness to the foreseen future development. In this context, the duration of acquired immunity, a hotly debated topic in the scientific community, emerges as a controlling factor for progression of the epidemic in the near future. The framework presented here can straightforwardly be used to evaluate the effectiveness of alternative intervention strategies like mass vaccinations, clean water supply and educational campaigns, thus emerging as an essential component of the control of future cholera

Selective expression of long non-coding RNAs in a breast cancer cell progression model.

Science.gov (United States)

Tracy, Kirsten M; Tye, Coralee E; Page, Natalie A; Fritz, Andrew J; Stein, Janet L; Lian, Jane B; Stein, Gary S

2018-02-01

Long non-coding RNAs (lncRNAs) are acknowledged as regulators of cancer biology and pathology. Our goal was to perform a stringent profiling of breast cancer cell lines that represent disease progression. We used the MCF-10 series, which includes the normal-like MCF-10A, HRAS-transformed MCF-10AT1 (pre-malignant), and MCF-10CA1a (malignant) cells, to perform transcriptome wide sequencing. From these data, we have identified 346 lncRNAs with dysregulated expression across the progression series. By comparing lncRNAs from these datasets to those from an additional set of cell lines that represent different disease stages and subtypes, MCF-7 (early stage, luminal), and MDA-MB-231 (late stage, basal), 61 lncRNAs that are associated with breast cancer progression were identified. Querying breast cancer patient data from The Cancer Genome Atlas, we selected a lncRNA, IGF-like family member 2 antisense RNA 1 (IGFL2-AS1), of potential clinical relevance for functional characterization. Among the 61 lncRNAs, IGFL2-AS1 was the most significantly decreased. Our results indicate that this lncRNA plays a role in downregulating its nearest neighbor, IGFL1, and affects migration of breast cancer cells. Furthermore, the lncRNAs we identified provide a valuable resource to mechanistically and clinically understand the contribution of lncRNAs in breast cancer progression. © 2017 Wiley Periodicals, Inc.

Estimating past hepatitis C infection risk from reported risk factor histories: implications for imputing age of infection and modeling fibrosis progression

Directory of Open Access Journals (Sweden)

Busch Michael P

2007-12-01

Full Text Available Abstract Background Chronic hepatitis C virus infection is prevalent and often causes hepatic fibrosis, which can progress to cirrhosis and cause liver cancer or liver failure. Study of fibrosis progression often relies on imputing the time of infection, often as the reported age of first injection drug use. We sought to examine the accuracy of such imputation and implications for modeling factors that influence progression rates. Methods We analyzed cross-sectional data on hepatitis C antibody status and reported risk factor histories from two large studies, the Women's Interagency HIV Study and the Urban Health Study, using modern survival analysis methods for current status data to model past infection risk year by year. We compared fitted distributions of past infection risk to reported age of first injection drug use. Results Although injection drug use appeared to be a very strong risk factor, models for both studies showed that many subjects had considerable probability of having been infected substantially before or after their reported age of first injection drug use. Persons reporting younger age of first injection drug use were more likely to have been infected after, and persons reporting older age of first injection drug use were more likely to have been infected before. Conclusion In cross-sectional studies of fibrosis progression where date of HCV infection is estimated from risk factor histories, modern methods such as multiple imputation should be used to account for the substantial uncertainty about when infection occurred. The models presented here can provide the inputs needed by such methods. Using reported age of first injection drug use as the time of infection in studies of fibrosis progression is likely to produce a spuriously strong association of younger age of infection with slower rate of progression.

SIGNIFICANT PROGRESS IN THE DEPLOYMENT OF NEW TECHNOLOGIES FOR THE RETRIEVAL OF HANFORD RADIOACTIVE WASTE STORAGE TANKS

International Nuclear Information System (INIS)

RAYMOND RE; DODD RA; CARPENTER KE; STURGES MH

2008-01-01

Significant enhancements in the development and deployment of new technologies for removing waste from storage tanks at the Hanford Site have resulted in accelerated progress and reduced costs for tank cleanup. CH2M HILL Hanford Group, Inc. is the U.S. Department of Energy, Office of River Protection's prime contractor responsible for safely storing and retrieving approximately 53 million gallons of highly-radioactive and hazardous waste stored in 177 underground tanks. The waste is stored in 149 older single-shell tanks (SST) and 28 newer double-shell tanks (DST) that are grouped in 18 so-called farms near the center of the Hanford Site, located in southeastern Washington State. Tank contents include materials from years of World-War II and post-war weapons production, which account for 60 percent by volume of the nation's high-level radioactive waste. A key strategy for improved cleanup is the development and deployment of innovative technologies, which enhance worker safety, resolve technical challenges, streamline retrieval processes, and cut project costs and durations. During the past seven years of tank cleanout projects we have encountered conditions and waste chemistry that defy conventional approaches, requiring a variety of new tools and techniques. Through the deployment of advanced technology and the creative application of resources, we are finding ways to accomplish the retrieval process safely, swiftly, and economically. To date, retrieval operations have been completed in seven tanks, including a record six tanks in a two-year period. Retrieval operations are in progress for another three tanks. This paper describes the following tank cleanup technologies deployed at Hanford in the past few years: Modified waste sluicing, High pressure water lance, Mobile retrieval tools, Saltcake dissolution, Vacuum retrieval, Sparging of wastes, Selective dissolution for waste treatment, Oxalic acid dissolution, High-pressure water mixers, Variable height pumps

Differentiating Tumor Progression from Pseudoprogression in Patients with Glioblastomas Using Diffusion Tensor Imaging and Dynamic Susceptibility Contrast MRI.

Science.gov (United States)

Wang, S; Martinez-Lage, M; Sakai, Y; Chawla, S; Kim, S G; Alonso-Basanta, M; Lustig, R A; Brem, S; Mohan, S; Wolf, R L; Desai, A; Poptani, H

2016-01-01

Early assessment of treatment response is critical in patients with glioblastomas. A combination of DTI and DSC perfusion imaging parameters was evaluated to distinguish glioblastomas with true progression from mixed response and pseudoprogression. Forty-one patients with glioblastomas exhibiting enhancing lesions within 6 months after completion of chemoradiation therapy were retrospectively studied. All patients underwent surgery after MR imaging and were histologically classified as having true progression (>75% tumor), mixed response (25%-75% tumor), or pseudoprogression (<25% tumor). Mean diffusivity, fractional anisotropy, linear anisotropy coefficient, planar anisotropy coefficient, spheric anisotropy coefficient, and maximum relative cerebral blood volume values were measured from the enhancing tissue. A multivariate logistic regression analysis was used to determine the best model for classification of true progression from mixed response or pseudoprogression. Significantly elevated maximum relative cerebral blood volume, fractional anisotropy, linear anisotropy coefficient, and planar anisotropy coefficient and decreased spheric anisotropy coefficient were observed in true progression compared with pseudoprogression (P < .05). There were also significant differences in maximum relative cerebral blood volume, fractional anisotropy, planar anisotropy coefficient, and spheric anisotropy coefficient measurements between mixed response and true progression groups. The best model to distinguish true progression from non-true progression (pseudoprogression and mixed) consisted of fractional anisotropy, linear anisotropy coefficient, and maximum relative cerebral blood volume, resulting in an area under the curve of 0.905. This model also differentiated true progression from mixed response with an area under the curve of 0.901. A combination of fractional anisotropy and maximum relative cerebral blood volume differentiated pseudoprogression from

Cumulative Significance of Hyporheic Exchange and Biogeochemical Processing in River Networks

Science.gov (United States)

Harvey, J. W.; Gomez-Velez, J. D.

2014-12-01

Biogeochemical reactions in rivers that decrease excessive loads of nutrients, metals, organic compounds, etc. are enhanced by hydrologic interactions with microbially and geochemically active sediments of the hyporheic zone. The significance of reactions in individual hyporheic flow paths has been shown to be controlled by the contact time between river water and sediment and the intrinsic reaction rate in the sediment. However, little is known about how the cumulative effects of hyporheic processing in large river basins. We used the river network model NEXSS (Gomez-Velez and Harvey, submitted) to simulate hyporheic exchange through synthetic river networks based on the best available models of network topology, hydraulic geometry and scaling of geomorphic features, grain size, hydraulic conductivity, and intrinsic reaction rates of nutrients and metals in river sediment. The dimensionless reaction significance factor, RSF (Harvey et al., 2013) was used to quantify the cumulative removal fraction of a reactive solute by hyporheic processing. SF scales reaction progress in a single pass through the hyporheic zone with the proportion of stream discharge passing through the hyporheic zone for a specified distance. Reaction progress is optimal where the intrinsic reaction timescale in sediment matches the residence time of hyporheic flow and is less efficient in longer residence time hyporheic flow as a result of the decreasing proportion of river flow that is processed by longer residence time hyporheic flow paths. In contrast, higher fluxes through short residence time hyporheic flow paths may be inefficient because of the repeated surface-subsurface exchanges required to complete the reaction. Using NEXSS we found that reaction efficiency may be high in both small streams and large rivers, although for different reasons. In small streams reaction progress generally is dominated by faster pathways of vertical exchange beneath submerged bedforms. Slower exchange

Progressive Impairment of Lactate-based Gluconeogenesis in the Huntington's Disease Mouse Model R6/2

DEFF Research Database (Denmark)

Nielsen, Signe Marie Borch; Hasholt, Lis; Nørremølle, Anne

2015-01-01

of impairment of lactate-based hepatic gluconeogenesis in the transgenic HD mouse model R6/2 and determine that the defect manifests very early and progresses in severity with disease development, indicating a potential to explore this defect in a biomarker context. Moreover, R6/2 animals displayed lower blood...

An ETP model (exclusion-tolerance-progression for multi drug resistance

Directory of Open Access Journals (Sweden)

Kannan Subburaj

2005-04-01

Full Text Available Abstract Background It is known that sensitivity or resistance of tumor cells to a given chemotherapeutic agent is an acquired characteristic(s, depending on the heterogeneity of the tumor mass subjected to the treatment. The clinical success of a chemotherapeutic regimen depends on the ratio of sensitive to resistant cell populations. Results Based on findings from clinical and experimental studies, a unifying model is proposed to delineate the potential mechanism by which tumor cells progress towards multi drug resistance, resulting in failure of chemotherapy. Conclusion It is suggested that the evolution of multi drug resistance is a developmentally orchestrated event. Identifying stage-specific time windows during this process would help to identify valid therapeutic targets for the effective elimination of malignancy.

Recent progress of GEANT4 electromagnetic physics for LHC and other applications

NARCIS (Netherlands)

Bagulya, A.; Brown, J.M.C.; Burkhardt, H.; Grichine, V.; Guatelli, S.; Incerti, S.; Ivanchenko, V. N.; Kadri, O.; Karamitros, M.; Maire, M.; Mashtakov, K.; Novak, M; Pandola, L.; Rancoita, P. G.; Sawkey, D.; Tacconi, M.; Urban, L.

2017-01-01

We report on the recent progress within the Geant4 electromagnetic physics subpackages. Several new interfaces and models recently introduced are already used in LHC applications and may be useful for any type of simulation. Significant developments were carried out to improve the user interface,

Damaging role of neutrophilic infiltration in a mouse model of progressive tuberculosis.

Science.gov (United States)

Marzo, Elena; Vilaplana, Cristina; Tapia, Gustavo; Diaz, Jorge; Garcia, Vanessa; Cardona, Pere-Joan

2014-01-01

Tuberculosis was studied using an experimental model based on the C3HeB/FeJ mouse strain, which mimics the liquefaction of caseous necrosis occurring during active disease in immunocompetent adults. Mice were intravenously infected with 2 × 10(4) Colony Forming Units of Mycobacterium tuberculosis and their histopathology, immune response, bacillary load, and survival were evaluated. The effects of the administration of drugs with anti-inflammatory activity were examined, and the C3H/HeN mouse strain was also included for comparative purposes. Massive intra-alveolar neutrophilic infiltration led to rapid granuloma growth and coalescence of lesions into superlesions. A central necrotic area appeared showing progressive cellular destruction, the alveoli cell walls being initially conserved (caseous necrosis) but finally destroyed (liquefactive necrosis). Increasing levels of pro-inflammatory mediators were detected in lungs. C3HeB/FeJ treated with anti-inflammatory drugs and C3H/HeN animals presented lower levels of pro-inflammatory mediators such as TNF-α, IL-17, IL-6 and CXCL5, a lower bacillary load, better histopathology, and increased survival compared with untreated C3HeB/FeJ. The observation of massive neutrophilic infiltration suggests that inflammation may be a key factor in progression towards active tuberculosis. On the basis of our findings, we consider that the C3HeB/FeJ mouse model would be useful for evaluating new therapeutic strategies against human tuberculosis. Copyright © 2013 Elsevier Ltd. All rights reserved.

Developing and validating a predictive model for stroke progression

OpenAIRE

Craig, L.E.; Wu, Olivia; Gilmour, H.; Barber, M.; Langhorne, P.

2011-01-01

Background: Progression is believed to be a common and important complication in acute stroke, and has been associated with increased mortality and morbidity. Reliable identification of predictors of early neurological deterioration could potentially benefit routine clinical care. The aim of this study was to identify predictors of early stroke progression using two independent patient cohorts. \\ud \\ud Methods: Two patient cohorts were used for this study – the first cohort formed the trainin...

A 3-D model of tumor progression based on complex automata driven by particle dynamics.

Science.gov (United States)

Wcisło, Rafał; Dzwinel, Witold; Yuen, David A; Dudek, Arkadiusz Z

2009-12-01

The dynamics of a growing tumor involving mechanical remodeling of healthy tissue and vasculature is neglected in most of the existing tumor models. This is due to the lack of efficient computational framework allowing for simulation of mechanical interactions. Meanwhile, just these interactions trigger critical changes in tumor growth dynamics and are responsible for its volumetric and directional progression. We describe here a novel 3-D model of tumor growth, which combines particle dynamics with cellular automata concept. The particles represent both tissue cells and fragments of the vascular network. They interact with their closest neighbors via semi-harmonic central forces simulating mechanical resistance of the cell walls. The particle dynamics is governed by both the Newtonian laws of motion and the cellular automata rules. These rules can represent cell life-cycle and other biological interactions involving smaller spatio-temporal scales. We show that our complex automata, particle based model can reproduce realistic 3-D dynamics of the entire system consisting of the tumor, normal tissue cells, blood vessels and blood flow. It can explain phenomena such as the inward cell motion in avascular tumor, stabilization of tumor growth by the external pressure, tumor vascularization due to the process of angiogenesis, trapping of healthy cells by invading tumor, and influence of external (boundary) conditions on the direction of tumor progression. We conclude that the particle model can serve as a general framework for designing advanced multiscale models of tumor dynamics and it is very competitive to the modeling approaches presented before.

Optimization of electronic enclosure design for thermal and moisture management using calibrated models of progressive complexity

DEFF Research Database (Denmark)

Mohanty, Sankhya; Staliulionis, Zygimantas; Shojaee Nasirabadi, Parizad

2016-01-01

the development of rigorous calibrated CFD models as well as simple predictive numerical tools, the current paper tackles the optimization of critical features of a typical two-chamber electronic enclosure. The progressive optimization strategy begins the design parameter selection by initially using simpler...

Apple Peel Supplemented Diet Reduces Parameters of Metabolic Syndrome and Atherogenic Progression in ApoE−/− Mice

Directory of Open Access Journals (Sweden)

Jaime Gonzalez

2015-01-01

Full Text Available Cardiovascular Diseases (CVD represent about 30% of all causes of death worldwide. The development of CVD is related in many cases with the previous existence of metabolic syndrome (MS. It is known that apple consumption has a cardiovascular protecting effect, containing phenolic compounds with antioxidant effect, which are concentrated in the fruit peel. The objective of this study was to test the effect of apple peel consumption in a murine model of MS and apoE−/− mice. Apple supplemented diets reduced the biochemical parameters (glycaemia, total cholesterol, HDL-cholesterol, LDL-cholesterol, ureic nitrogen, triglycerides, insulin, and asymmetric dimethylarginine (ADMA of MS model in CF1 mice significantly. The model apoE−/− mouse was used to evaluate the capacity of the apple peel to revert the progression of the atherogenesis. FD with HAP reverts cholesterol significantly and slows down the progression of the plate diminishing the cholesterol accumulation area. With these results, it can be concluded that the consumption of apple peel reduces several MS parameters and the atherogenic progression in mice.

Fear Extinction as a Model for Translational Neuroscience: Ten Years of Progress

Science.gov (United States)

Milad, Mohammed R.; Quirk, Gregory J.

2016-01-01

The psychology of extinction has been studied for decades. Approximately 10 years ago, however, there began a concerted effort to understand the neural circuits of extinction of fear conditioning, in both animals and humans. Progress during this period has been facilitated by an unusual degree of coordination between rodent and human researchers examining fear extinction. This successful research program could serve as a model for translational research in other areas of behavioral neuroscience. Here we review the major advances and highlight new approaches to understanding and exploiting fear extinction. PMID:22129456

Progression of motor symptoms in Parkinson's disease

Institute of Scientific and Technical Information of China (English)

Ruiping Xia; Zhi-Hong Mao

2012-01-01

Parkinson's disease (PD) is a chronic progressive neurodegenerative disease that is clinically manifested by a triad of cardinal motor symptoms - rigidity,bradykinesia and tremor - due to loss of dopaminergic neurons.The motor symptoms of PD become progressively worse as the disease advances.PD is also a heterogeneous disease since rigidity and bradykinesia are the major complaints in some patients whereas tremor is predominant in others.In recent years,many studies have investigated the progression of the hallmark symptoms over time,and the cardinal motor symptoms have different rates of progression,with the disease usually progressing faster in patients with rigidity and bradykinesia than in those with predominant tremor.The current treatment regime of dopamine-replacement therapy improves motor symptoms and alleviates disability.Increasing the dosage of dopaminergic medication is commonly used to combat the worsenirtg symptoms.However,the drug-induced involuntary body movements and motor comphcations can significantly contribute to overall disability.Further,none of the currently-available therapies can slow or halt the disease progression.Significant research efforts have been directed towards developing neuroprotective or disease-modifying agents that are intended to slow the progression.In this article,the most recent clinical studies investigating disease progression and current progress on the development of disease-modifying drug trials are reviewed.

Adult Neurogenesis in the Mammalian Brain: Significant Answers and Significant Questions

Science.gov (United States)

Ming, Guo-li; Song, Hongjun

2011-01-01

Summary Adult neurogenesis, a process of generating functional neurons from adult neural precursors, occurs throughout life in restricted brain regions in mammals. The past decade has witnessed tremendous progress in addressing questions related to almost every aspect of adult neurogenesis in the mammalian brain. Here we review major advances in our understanding of adult mammalian neurogenesis in the dentate gyrus of the hippocampus and from the subventricular zone of the lateral ventricle, the rostral migratory stream to the olfactory bulb. We highlight emerging principles that have significant implications for stem cell biology, developmental neurobiology, neural plasticity, and disease mechanisms. We also discuss remaining questions related to adult neural stem cells and their niches, underlying regulatory mechanisms and potential functions of newborn neurons in the adult brain. Building upon the recent progress and aided by new technologies, the adult neurogenesis field is poised to leap forward in the next decade. PMID:21609825

High beta and second stability region transport and stability analysis: Technical progress report

International Nuclear Information System (INIS)

Hughes, M.H.; Phillips, M.W.

1995-03-01

This report summarizes MHD equilibrium and stability studies carried out at Northrop Grumman's Advanced Technology and Development Center during the 12 month period starting March 1, 1994. Progress is reported in both ideal and resistive MHD modeling of TFTR plasmas. The development of codes to calculate the significant effects of highly anisotropic pressure distributions is discussed along with results from this model

High beta and second stability region transport and stability analysis. Technical progress report

International Nuclear Information System (INIS)

Hughes, M.H.; Phillips, M.W.

1994-09-01

This report summarizes MHD equilibrium and stability studies carried out at Grumman's Corporate Research Center during the 6 month period starting March 1, 1994. Progress is reported in both ideal and resistive MHD modeling of TFTR plasmas. The development of codes to calculate the significant effects of highly anisotropic pressure distributions is discussed along with initial results from this model

Progress in computational toxicology.

Science.gov (United States)

Ekins, Sean

2014-01-01

Computational methods have been widely applied to toxicology across pharmaceutical, consumer product and environmental fields over the past decade. Progress in computational toxicology is now reviewed. A literature review was performed on computational models for hepatotoxicity (e.g. for drug-induced liver injury (DILI)), cardiotoxicity, renal toxicity and genotoxicity. In addition various publications have been highlighted that use machine learning methods. Several computational toxicology model datasets from past publications were used to compare Bayesian and Support Vector Machine (SVM) learning methods. The increasing amounts of data for defined toxicology endpoints have enabled machine learning models that have been increasingly used for predictions. It is shown that across many different models Bayesian and SVM perform similarly based on cross validation data. Considerable progress has been made in computational toxicology in a decade in both model development and availability of larger scale or 'big data' models. The future efforts in toxicology data generation will likely provide us with hundreds of thousands of compounds that are readily accessible for machine learning models. These models will cover relevant chemistry space for pharmaceutical, consumer product and environmental applications. Copyright © 2013 Elsevier Inc. All rights reserved.

Progression of biopsy-measured liver fibrosis in untreated patients with hepatitis C infection: non-Markov multistate model analysis.

Directory of Open Access Journals (Sweden)

Peter Bacchetti

Full Text Available BACKGROUND: Fibrosis stages from liver biopsies reflect liver damage from hepatitis C infection, but analysis is challenging due to their ordered but non-numeric nature, infrequent measurement, misclassification, and unknown infection times. METHODS: We used a non-Markov multistate model, accounting for misclassification, with multiple imputation of unknown infection times, applied to 1062 participants of whom 159 had multiple biopsies. Odds ratios (OR quantified the estimated effects of covariates on progression risk at any given time. RESULTS: Models estimated that progression risk decreased the more time participants had already spent in the current stage, African American race was protective (OR 0.75, 95% confidence interval 0.60 to 0.95, p = 0.018, and older current age increased risk (OR 1.33 per decade, 95% confidence interval 1.15 to 1.54, p = 0.0002. When controlled for current age, older age at infection did not appear to increase risk (OR 0.92 per decade, 95% confidence interval 0.47 to 1.79, p = 0.80. There was a suggestion that co-infection with human immunodeficiency virus increased risk of progression in the era of highly active antiretroviral treatment beginning in 1996 (OR 2.1, 95% confidence interval 0.97 to 4.4, p = 0.059. Other examined risk factors may influence progression risk, but evidence for or against this was weak due to wide confidence intervals. The main results were essentially unchanged using different assumed misclassification rates or imputation of age of infection. DISCUSSION: The analysis avoided problems inherent in simpler methods, supported the previously suspected protective effect of African American race, and suggested that current age rather than age of infection increases risk. Decreasing risk of progression with longer time already spent in a stage was also previously found for post-transplant progression. This could reflect varying disease activity, with recent progression indicating

Some Approaches to the Accounting and Analysis of the Impact of Scientific and Technological Progress in the Harrod-Domar Economic Growth Model

Directory of Open Access Journals (Sweden)

Dilenko Viktor O.

2016-11-01

Full Text Available The paper presents methods for the accounting of autonomous and induced scientific and technological progress in the Harrod-Domar model of economic dynamics that imply determining the incremental capital/output ratio of the model in the form of special functions of time. As part of the received version of the Harrod-Domar model, on the basis of conditional data there conducted a numerical study of some aspects of the impact of parameters of scientific and technological progress and the initial state of the economy being modeled on peculiarities of corresponding trajectories of its dynamics. A simple economic and mathematical problem of determining an optimal value of investments in the implementation of the induced STP is formulated, and content interpretation of the obtained solution is carried out. Possible directions of development of the obtained results may be associated with the application of the proposed modification of the Harrod-Domar model to build and analyze mathematical models of optimal economic growth in view of the induced STP, as well as with the prospective use of these results to improve dynamic models of the Leontief type in terms of considering innovation processes (scientific and technical progress of various kinds.

Progression of Pancreatic Adenocarcinoma Is Significantly Impeded with a Combination of Vaccine and COX-2 Inhibition1

Science.gov (United States)

Mukherjee, Pinku; Basu, Gargi D.; Tinder, Teresa L.; Subramani, Durai B.; Bradley, Judy M.; Arefayene, Million; Skaar, Todd; De Petris, Giovanni

2013-01-01

With a 5-year survival rate of <5%, pancreatic cancer is one of the most rapidly fatal malignancies. Current protocols for the treatment of pancreas cancer are not as effective as we desire. In this study, we show that a novel Mucin-1 (MUC1)-based vaccine in combination with a cyclooxygenase-2 inhibitor (celecoxib), and low-dose chemotherapy (gemcitabine) was effective in preventing the progression of preneoplastic intraepithelial lesions to invasive pancreatic ductal adenocarcinomas. The study was conducted in an appropriate triple transgenic model of spontaneous pancreatic cancer induced by the KRASG12D mutation and that expresses human MUC1 as a self molecule. The combination treatment elicited robust antitumor cellular and humoral immune responses and was associated with increased apoptosis in the tumor. The mechanism for the increased immune response was attributed to the down-regulation of circulating prostaglandin E2 and indoleamine 2, 3,-dioxygenase enzymatic activity, as well as decreased levels of T regulatory and myeloid suppressor cells within the tumor microenvironment. The preclinical data provide the rationale to design clinical trials with a combination of MUC1-based vaccine, celecoxib, and gemcitabine for the treatment of pancreatic cancer. PMID:19109152

Discovery of CDH23 as a Significant Contributor to Progressive Postlingual Sensorineural Hearing Loss in Koreans.

Directory of Open Access Journals (Sweden)

Bong Jik Kim

Full Text Available CDH23 mutations have mostly been associated with prelingual severe-to-profound sensorineural hearing loss (SNHL in either syndromic or nonsyndromic SNHL (DFNB12. Herein, we demonstrate the contribution of CDH23 mutations to postlingual nonsyndromic SNHL (NS-SNHL. We screened 32 Korean adult probands with postlingual NS-SNHL sporadically or in autosomal recessive fashion using targeted panel or whole exome sequencing. We identified four (12.5%, 4/32 potential postlingual DFNB12 families that segregated the recessive CDH23 variants, qualifying for our criteria along with rapidly progressive SNHL. Three of the four families carried one definite pathogenic CDH23 variant previously known as the prelingual DFNB12 variant in a trans configuration with rare CDH23 variants. To determine the contribution of rare CDH23 variants to the postlingual NS-SNHL, we checked the minor allele frequency (MAF of CDH23 variants detected from our postlingual NS-SNHL cohort and prelingual NS-SNHL cohort, among the 2040 normal control chromosomes. The allele frequency of these CDH23 variants in our postlingual cohort was 12.5%, which was significantly higher than that of the 2040 control chromosomes (5.53%, confirming the contribution of these rare CDH23 variants to postlingual NS-SNHL. Furthermore, MAF of rare CDH23 variants from the postlingual NS-SNHL group was significantly higher than that from the prelingual NS-SNHL group. This study demonstrates an important contribution of CDH23 mutations to poslingual NS-SNHL and shows that the phenotypic spectrum of DFNB12 can be broadened even into the presbycusis, depending on the pathogenic potential of variants. We also propose that pathogenic potential of CDH23 variants and the clinical fate of DFNB12 may be predicted by MAF.

A Progress Review on Soot Experiments and Modeling in the Engine Combustion Network (ECN)

KAUST Repository

Skeen, Scott A.

2016-04-05

The 4th Workshop of the Engine Combustion Network (ECN) was held September 5-6, 2015 in Kyoto, Japan. This manuscript presents a summary of the progress in experiments and modeling among ECN contributors leading to a better understanding of soot formation under the ECN “Spray A” configuration and some parametric variants. Relevant published and unpublished work from prior ECN workshops is reviewed. Experiments measuring soot particle size and morphology, soot volume fraction (fv), and transient soot mass have been conducted at various international institutions providing target data for improvements to computational models. Multiple modeling contributions using both the Reynolds Averaged Navier-Stokes (RANS) Equations approach and the Large-Eddy Simulation (LES) approach have been submitted. Among these, various chemical mechanisms, soot models, and turbulence-chemistry interaction (TCI) methodologies have been considered.

A Progress Review on Soot Experiments and Modeling in the Engine Combustion Network (ECN)

KAUST Repository

Skeen, Scott A.; Manin, Julien; Pickett, Lyle M.; Cenker, Emre; Bruneaux, Gilles; Kondo, Katsufumi; Aizawa, Tets; Westlye, Fredrik; Dalen, Kristine; Ivarsson, Anders; Xuan, Tiemin; Garcia-Oliver, Jose M; Pei, Yuanjiang; Som, Sibendu; Hu, Wang; Reitz, Rolf D.; Lucchini, Tommaso; D'Errico, Gianluca; Farrace, Daniele; Pandurangi, Sushant S.; Wright, Yuri M.; Chishty, Muhammad Aqib; Bolla, Michele; Hawkes, Evatt

2016-01-01

The 4th Workshop of the Engine Combustion Network (ECN) was held September 5-6, 2015 in Kyoto, Japan. This manuscript presents a summary of the progress in experiments and modeling among ECN contributors leading to a better understanding of soot formation under the ECN “Spray A” configuration and some parametric variants. Relevant published and unpublished work from prior ECN workshops is reviewed. Experiments measuring soot particle size and morphology, soot volume fraction (fv), and transient soot mass have been conducted at various international institutions providing target data for improvements to computational models. Multiple modeling contributions using both the Reynolds Averaged Navier-Stokes (RANS) Equations approach and the Large-Eddy Simulation (LES) approach have been submitted. Among these, various chemical mechanisms, soot models, and turbulence-chemistry interaction (TCI) methodologies have been considered.

Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma.

Science.gov (United States)

Avet-Loiseau, Hervé; Fonseca, Rafael; Siegel, David; Dimopoulos, Meletios A; Špička, Ivan; Masszi, Tamás; Hájek, Roman; Rosiñol, Laura; Goranova-Marinova, Vesselina; Mihaylov, Georgi; Maisnar, Vladimír; Mateos, Maria-Victoria; Wang, Michael; Niesvizky, Ruben; Oriol, Albert; Jakubowiak, Andrzej; Minarik, Jiri; Palumbo, Antonio; Bensinger, William; Kukreti, Vishal; Ben-Yehuda, Dina; Stewart, A Keith; Obreja, Mihaela; Moreau, Philippe

2016-09-01

The presence of certain high-risk cytogenetic abnormalities, such as translocations (4;14) and (14;16) and deletion (17p), are known to have a negative impact on survival in multiple myeloma (MM). The phase 3 study ASPIRE (N = 792) demonstrated that progression-free survival (PFS) was significantly improved with carfilzomib, lenalidomide, and dexamethasone (KRd), compared with lenalidomide and dexamethasone (Rd) in relapsed MM. This preplanned subgroup analysis of ASPIRE was conducted to evaluate KRd vs Rd by baseline cytogenetics according to fluorescence in situ hybridization. Of 417 patients with known cytogenetic risk status, 100 patients (24%) were categorized with high-risk cytogenetics (KRd, n = 48; Rd, n = 52) and 317 (76%) were categorized with standard-risk cytogenetics (KRd, n = 147; Rd, n = 170). For patients with high-risk cytogenetics, treatment with KRd resulted in a median PFS of 23.1 months, a 9-month improvement relative to treatment with Rd. For patients with standard-risk cytogenetics, treatment with KRd led to a 10-month improvement in median PFS vs Rd. The overall response rates for KRd vs Rd were 79.2% vs 59.6% (high-risk cytogenetics) and 91.2% vs 73.5% (standard-risk cytogenetics); approximately fivefold as many patients with high- or standard-risk cytogenetics achieved a complete response or better with KRd vs Rd (29.2% vs 5.8% and 38.1% vs 6.5%, respectively). KRd improved but did not abrogate the poor prognosis associated with high-risk cytogenetics. This regimen had a favorable benefit-risk profile in patients with relapsed MM, irrespective of cytogenetic risk status, and should be considered a standard of care in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01080391. © 2016 by The American Society of Hematology.

Escherichia coli DinB inhibits replication fork progression without significantly inducing the SOS response.

Science.gov (United States)

Mori, Tetsuya; Nakamura, Tatsuro; Okazaki, Naoto; Furukohri, Asako; Maki, Hisaji; Akiyama, Masahiro Tatsumi

2012-01-01

The SOS response is readily triggered by replication fork stalling caused by DNA damage or a dysfunctional replicative apparatus in Escherichia coli cells. E. coli dinB encodes DinB DNA polymerase and its expression is upregulated during the SOS response. DinB catalyzes translesion DNA synthesis in place of a replicative DNA polymerase III that is stalled at a DNA lesion. We showed previously that DNA replication was suppressed without exogenous DNA damage in cells overproducing DinB. In this report, we confirm that this was due to a dose-dependent inhibition of ongoing replication forks by DinB. Interestingly, the DinB-overproducing cells did not significantly induce the SOS response even though DNA replication was perturbed. RecA protein is activated by forming a nucleoprotein filament with single-stranded DNA, which leads to the onset of the SOS response. In the DinB-overproducing cells, RecA was not activated to induce the SOS response. However, the SOS response was observed after heat-inducible activation in strain recA441 (encoding a temperature-sensitive RecA) and after replication blockage in strain dnaE486 (encoding a temperature-sensitive catalytic subunit of the replicative DNA polymerase III) at a non-permissive temperature when DinB was overproduced in these cells. Furthermore, since catalytically inactive DinB could avoid the SOS response to a DinB-promoted fork block, it is unlikely that overproduced DinB takes control of primer extension and thus limits single-stranded DNA. These observations suggest that DinB possesses a feature that suppresses DNA replication but does not abolish the cell's capacity to induce the SOS response. We conclude that DinB impedes replication fork progression in a way that does not activate RecA, in contrast to obstructive DNA lesions and dysfunctional replication machinery.

Evaluation of an unsteady flamelet progress variable model for autoignition and flame development in compositionally stratified mixtures

Science.gov (United States)

Mukhopadhyay, Saumyadip; Abraham, John

2012-07-01

The unsteady flamelet progress variable (UFPV) model has been proposed by Pitsch and Ihme ["An unsteady/flamelet progress variable method for LES of nonpremixed turbulent combustion," AIAA Paper No. 2005-557, 2005] for modeling the averaged/filtered chemistry source terms in Reynolds averaged simulations and large eddy simulations of reacting non-premixed combustion. In the UFPV model, a look-up table of source terms is generated as a function of mixture fraction Z, scalar dissipation rate χ, and progress variable C by solving the unsteady flamelet equations. The assumption is that the unsteady flamelet represents the evolution of the reacting mixing layer in the non-premixed flame. We assess the accuracy of the model in predicting autoignition and flame development in compositionally stratified n-heptane/air mixtures using direct numerical simulations (DNS). The focus in this work is primarily on the assessment of accuracy of the probability density functions (PDFs) employed for obtaining averaged source terms. The performance of commonly employed presumed functions, such as the dirac-delta distribution function, the β distribution function, and statistically most likely distribution (SMLD) approach in approximating the shapes of the PDFs of the reactive and the conserved scalars is evaluated. For unimodal distributions, it is observed that functions that need two-moment information, e.g., the β distribution function and the SMLD approach with two-moment closure, are able to reasonably approximate the actual PDF. As the distribution becomes multimodal, higher moment information is required. Differences are observed between the ignition trends obtained from DNS and those predicted by the look-up table, especially for smaller gradients where the flamelet assumption becomes less applicable. The formulation assumes that the shape of the χ(Z) profile can be modeled by an error function which remains unchanged in the presence of heat release. We show that this

Theoretical aspects of electroweak and other interactions in medium energy nuclear physics. Interim progress report

International Nuclear Information System (INIS)

Mukhopadhyay, N.C.

1994-01-01

Significant progress has been made in the current project year in the development of chiral soliton model and its applications to the electroweak structure of the nucleon and the Delta (1232) resonance. Further progress also has been made in the application of the perturbative QCD (pQCD) and the study of physics beyond the standard model. The postdoctoral associate and the graduate student working towards his Ph.D. degree have both made good progress. The review panel of the DOE has rated this program as a ''strong, high priority'' one. A total of fifteen research communications -- eight journal papers and, conference reports and seven other communications -- have been made during the project year so far. The principal investigator is a member of the Physics Advisory Committee of two nuclear accelerator facilities

Rare sugar D-psicose prevents progression and development of diabetes in T2DM model Otsuka Long-Evans Tokushima Fatty rats.

Science.gov (United States)

Hossain, Akram; Yamaguchi, Fuminori; Hirose, Kayoko; Matsunaga, Toru; Sui, Li; Hirata, Yuko; Noguchi, Chisato; Katagi, Ayako; Kamitori, Kazuyo; Dong, Youyi; Tsukamoto, Ikuko; Tokuda, Masaaki

2015-01-01

The fundamental cause of overweight and obesity is consumption of calorie-dense foods. We have introduced a zero-calorie sweet sugar, d-psicose (d-allulose), a rare sugar that has been proven to have strong antihyperglycemic and antihyperlipidemic effects, and could be used as a replacement of natural sugar for the obese and diabetic subjects. Above mentioned efficacy of d-psicose (d-allulose) has been confirmed in our previous studies on type 2 diabetes mellitus (T2DM) model Otsuka Long-Evans Tokushima Fatty (OLETF) rats with short-term treatment. In this study we investigated the long-term effect of d-psicose in preventing the commencement and progression of T2DM with the mechanism of preservation of pancreatic β-cells in OLETF rats. Treated OLETF rats were fed 5% d-psicose dissolved in water and control rats only water. Nondiabetic control rats, Long-Evans Tokushima Otsuka (LETO), were taken as healthy control and fed water. To follow the progression of diabetes, periodic measurements of blood glucose, plasma insulin, and body weight changes were continued till sacrifice at 60 weeks. Periodic in vivo body fat mass was measured. On sacrifice, pancreas, liver, and abdominal adipose tissues were collected for various staining tests. d-Psicose prevented the commencement and progression of T2DM till 60 weeks through the maintenance of blood glucose levels, decrease in body weight gain, and the control of postprandial hyperglycemia, with decreased levels of HbA1c in comparison to nontreated control rats. This improvement in glycemic control was accompanied by the maintenance of plasma insulin levels and the preservation of pancreatic β-cells with the significant reduction in inflammatory markers. Body fat accumulation was significantly lower in the treatment group, with decreased infiltration of macrophages in the abdominal adipose tissue. Our findings suggest that the rare sugar d-psicose could be beneficial for the prevention and control of obesity and

The Significance of α-Synuclein, Amyloid-β and Tau Pathologies in Parkinson’s Disease Progression and Related Dementia

Science.gov (United States)

Compta, Y.; Parkkinen, L.; Kempster, P.; Selikhova, M.; Lashley, T.; Holton, J.L.; Lees, A.J.; Revesz, T.

2014-01-01

Background Dementia is one of the milestones of advanced Parkinson’s disease (PD), with its neuropathological substrate still being a matter of debate, particularly regarding its potential mechanistic implications. Objective The aim of this study was to review the relative importance of Lewy-related α-synuclein and Alzheimer’s tau and amyloid-β (Aβ) pathologies in disease progression and dementia in PD. Methods We reviewed studies conducted at the Queen Square Brain Bank, Institute of Neurology, University College London, using large PD cohorts. Results Cortical Lewy- and Alzheimer-type pathologies are associated with milestones of poorer prognosis and with non-tremor predominance, which have been, in turn, linked to dementia. The combination of these pathologies is the most robust neuropathological substrate of PD-related dementia, with cortical Aβ burden determining a faster progression to dementia. Conclusion The shared relevance of these pathologies in PD progression and dementia is in line with experimental data suggesting synergism between α-synuclein, tau and Aβ and with studies testing these proteins as disease biomarkers, hence favouring the eventual testing of therapeutic strategies targeting these proteins in PD. PMID:24028925

Theoretical progress at CNDC theory group

International Nuclear Information System (INIS)

Lu Zhongdao

1993-01-01

In 1992, CNDC (Chinese Nuclear Data Center) theory group has made progress in model study, code making and data calculations for low energy nuclear reaction, intermediate and high energy nuclear reaction. It has also made progress in parameter library establishment. The brief explanations are presented

Emphysema Distribution and Diffusion Capacity Predict Emphysema Progression in Human Immunodeficiency Virus Infection

Science.gov (United States)

Leung, Janice M; Malagoli, Andrea; Santoro, Antonella; Besutti, Giulia; Ligabue, Guido; Scaglioni, Riccardo; Dai, Darlene; Hague, Cameron; Leipsic, Jonathon; Sin, Don D.; Man, SF Paul; Guaraldi, Giovanni

2016-01-01

Background Chronic obstructive pulmonary disease (COPD) and emphysema are common amongst patients with human immunodeficiency virus (HIV). We sought to determine the clinical factors that are associated with emphysema progression in HIV. Methods 345 HIV-infected patients enrolled in an outpatient HIV metabolic clinic with ≥2 chest computed tomography scans made up the study cohort. Images were qualitatively scored for emphysema based on percentage involvement of the lung. Emphysema progression was defined as any increase in emphysema score over the study period. Univariate analyses of clinical, respiratory, and laboratory data, as well as multivariable logistic regression models, were performed to determine clinical features significantly associated with emphysema progression. Results 17.4% of the cohort were emphysema progressors. Emphysema progression was most strongly associated with having a low baseline diffusion capacity of carbon monoxide (DLCO) and having combination centrilobular and paraseptal emphysema distribution. In adjusted models, the odds ratio (OR) for emphysema progression for every 10% increase in DLCO percent predicted was 0.58 (95% confidence interval [CI] 0.41–0.81). The equivalent OR (95% CI) for centrilobular and paraseptal emphysema distribution was 10.60 (2.93–48.98). Together, these variables had an area under the curve (AUC) statistic of 0.85 for predicting emphysema progression. This was an improvement over the performance of spirometry (forced expiratory volume in 1 second to forced vital capacity ratio), which predicted emphysema progression with an AUC of only 0.65. Conclusion Combined paraseptal and centrilobular emphysema distribution and low DLCO could identify HIV patients who may experience emphysema progression. PMID:27902753

Lattice-based model of ductal carcinoma in situ suggests rules for breast cancer progression to an invasive state.

Science.gov (United States)

Boghaert, Eline; Radisky, Derek C; Nelson, Celeste M

2014-12-01

Ductal carcinoma in situ (DCIS) is a heterogeneous group of non-invasive lesions of the breast that result from abnormal proliferation of mammary epithelial cells. Pathologists characterize DCIS by four tissue morphologies (micropapillary, cribriform, solid, and comedo), but the underlying mechanisms that distinguish the development and progression of these morphologies are not well understood. Here we explored the conditions leading to the emergence of the different morphologies of DCIS using a two-dimensional multi-cell lattice-based model that incorporates cell proliferation, apoptosis, necrosis, adhesion, and contractility. We found that the relative rates of cell proliferation and apoptosis governed which of the four morphologies emerged. High proliferation and low apoptosis favored the emergence of solid and comedo morphologies. In contrast, low proliferation and high apoptosis led to the micropapillary morphology, whereas high proliferation and high apoptosis led to the cribriform morphology. The natural progression between morphologies cannot be investigated in vivo since lesions are usually surgically removed upon detection; however, our model suggests probable transitions between these morphologies during breast cancer progression. Importantly, cribriform and comedo appear to be the ultimate morphologies of DCIS. Motivated by previous experimental studies demonstrating that tumor cells behave differently depending on where they are located within the mammary duct in vivo or in engineered tissues, we examined the effects of tissue geometry on the progression of DCIS. In agreement with our previous experimental work, we found that cells are more likely to invade from the end of ducts and that this preferential invasion is regulated by cell adhesion and contractility. This model provides additional insight into tumor cell behavior and allows the exploration of phenotypic transitions not easily monitored in vivo.

Immediate treatment with bicalutamide 150mg as adjuvant therapy significantly reduces the risk of PSA progression in early prostate cancer

DEFF Research Database (Denmark)

See, W; Iversen, P; Wirth, M

2003-01-01

To evaluate the effect of bicalutamide ('Casodex') 150mg (in addition to standard care), on the risk of prostate-specific antigen (PSA) progression, in patients with early prostate cancer.......To evaluate the effect of bicalutamide ('Casodex') 150mg (in addition to standard care), on the risk of prostate-specific antigen (PSA) progression, in patients with early prostate cancer....

Damage-Based Time-Dependent Modeling of Paraglacial to Postglacial Progressive Failure of Large Rock Slopes

Science.gov (United States)

Riva, Federico; Agliardi, Federico; Amitrano, David; Crosta, Giovanni B.

2018-01-01

Large alpine rock slopes undergo long-term evolution in paraglacial to postglacial environments. Rock mass weakening and increased permeability associated with the progressive failure of deglaciated slopes promote the development of potentially catastrophic rockslides. We captured the entire life cycle of alpine slopes in one damage-based, time-dependent 2-D model of brittle creep, including deglaciation, damage-dependent fluid occurrence, and rock mass property upscaling. We applied the model to the Spriana rock slope (Central Alps), affected by long-term instability after Last Glacial Maximum and representing an active threat. We simulated the evolution of the slope from glaciated conditions to present day and calibrated the model using site investigation data and available temporal constraints. The model tracks the entire progressive failure path of the slope from deglaciation to rockslide development, without a priori assumptions on shear zone geometry and hydraulic conditions. Complete rockslide differentiation occurs through the transition from dilatant damage to a compacting basal shear zone, accounting for observed hydraulic barrier effects and perched aquifer formation. Our model investigates the mechanical role of deglaciation and damage-controlled fluid distribution in the development of alpine rockslides. The absolute simulated timing of rock slope instability development supports a very long "paraglacial" period of subcritical rock mass damage. After initial damage localization during the Lateglacial, rockslide nucleation initiates soon after the onset of Holocene, whereas full mechanical and hydraulic rockslide differentiation occurs during Mid-Holocene, supporting a key role of long-term damage in the reported occurrence of widespread rockslide clusters of these ages.

Progress with lossy compression of data from the Community Earth System Model

Science.gov (United States)

Xu, H.; Baker, A.; Hammerling, D.; Li, S.; Clyne, J.

2017-12-01

Climate models, such as the Community Earth System Model (CESM), generate massive quantities of data, particularly when run at high spatial and temporal resolutions. The burden of storage is further exacerbated by creating large ensembles, generating large numbers of variables, outputting at high frequencies, and duplicating data archives (to protect against disk failures). Applying lossy compression methods to CESM datasets is an attractive means of reducing data storage requirements, but ensuring that the loss of information does not negatively impact science objectives is critical. In particular, test methods are needed to evaluate whether critical features (e.g., extreme values and spatial and temporal gradients) have been preserved and to boost scientists' confidence in the lossy compression process. We will provide an overview on our progress in applying lossy compression to CESM output and describe our unique suite of metric tests that evaluate the impact of information loss. Further, we will describe our processes how to choose an appropriate compression algorithm (and its associated parameters) given the diversity of CESM data (e.g., variables may be constant, smooth, change abruptly, contain missing values, or have large ranges). Traditional compression algorithms, such as those used for images, are not necessarily ideally suited for floating-point climate simulation data, and different methods may have different strengths and be more effective for certain types of variables than others. We will discuss our progress towards our ultimate goal of developing an automated multi-method parallel approach for compression of climate data that both maximizes data reduction and minimizes the impact of data loss on science results.

NMR-based lipidomic analysis of blood lipoproteins differentiates the progression of coronary heart disease.

Science.gov (United States)

Kostara, Christina E; Papathanasiou, Athanasios; Psychogios, Nikolaos; Cung, Manh Thong; Elisaf, Moses S; Goudevenos, John; Bairaktari, Eleni T

2014-05-02

Abnormal lipid composition and metabolism of plasma lipoproteins play a crucial role in the pathogenesis of coronary heart disease (CHD). A (1)H NMR-based lipidomic approach was used to investigate the correlation of coronary artery stenosis with the atherogenic (non-HDL) and atheroprotective (HDL) lipid profiles in 99 patients with CHD of various stages of disease and compared with 60 patients with normal coronary arteries (NCA), all documented in coronary angiography. The pattern recognition models created from lipid profiles predicted the presence of CHD with a sensitivity of 87% and a specificity of 88% in the HDL model and with 90% and 89% in the non-HDL model, respectively. Patients with mild, moderate, and severe coronary artery stenosis were progressively differentiated from those with NCA in the non-HDL model with a statistically significant separation of severe stage from both mild and moderate. In the HDL model, the progressive differentiation of the disease stages was statistically significant only between patients with mild and severe coronary artery stenosis. The lipid constituents of lipoproteins that mainly characterized the initial stages and then the progression of the disease were the high levels of saturated fatty acids in lipids in both HDL and non-HDL particles, the low levels of HDL-phosphatidylcholine, HDL-sphingomyelin, and omega-3 fatty acids and linoleic acid in lipids in non-HDL particles. The conventional lipid marker, total cholesterol, found in low levels in HDL and in high levels in non-HDL, also contributed to the onset of the disease but with a much lower coefficient of significance. (1)H NMR-based lipidomic analysis of atherogenic and atheroprotective lipoproteins could contribute to the early evaluation of the onset of coronary artery disease and possibly to the establishment of an appropriate therapeutic option.

2D model for melt progression through rods and debris

International Nuclear Information System (INIS)

Fichot, F.

2001-01-01

During the degradation of a nuclear core in a severe accident scenario, the high temperatures reached lead to the melting of materials. The formation of liquid mixtures at various elevations is followed by the flow of molten materials through the core. Liquid mixture may flow under several configurations: axial relocation along the rods, horizontal motion over a plane surface such as the core support plate or a blockage of material, 2D relocation through a debris bed, etc.. The two-dimensional relocation of molten material through a porous debris bed, implemented for the simulation of late degradation phases, has opened a new way to the elaboration of the relocation model for the flow of liquid mixture along the rods. It is based on a volume averaging method, where wall friction and capillary effects are taken into account by introducing effective coefficients to characterize the solid matrix (rods, grids, debris, etc.). A local description of the liquid flow is necessary to derive the effective coefficients. Heat transfers are modelled in a similar way. The derivation of the conservation equations for the liquid mixture falling flow (momentum) in two directions (axial and radial-horizontal) and for the heat exchanges (energy) are the main points of this new model for simulating melt progression. In this presentation, the full model for the relocation and solidification of liquid materials through a rod bundle or a debris bed is described. It is implemented in the ICARE/CATHARE code, developed by IPSN in Cadarache. The main improvements and advantages of the new model are: A single formulation for liquid mixture relocation, in 2D, either through a rod bundle or a porous debris bed, Extensions to complex structures (grids, by-pass, etc..), The modeling of relocation of a liquid mixture over plane surfaces. (author)

How Often Is the Misfit of Item Response Theory Models Practically Significant?

Science.gov (United States)

Sinharay, Sandip; Haberman, Shelby J.

2014-01-01

Standard 3.9 of the Standards for Educational and Psychological Testing ([, 1999]) demands evidence of model fit when item response theory (IRT) models are employed to data from tests. Hambleton and Han ([Hambleton, R. K., 2005]) and Sinharay ([Sinharay, S., 2005]) recommended the assessment of practical significance of misfit of IRT models, but…

Modelling the tumour microenvironment in long-term microencapsulated 3D co-cultures recapitulates phenotypic features of disease progression.

Science.gov (United States)

Estrada, Marta F; Rebelo, Sofia P; Davies, Emma J; Pinto, Marta T; Pereira, Hugo; Santo, Vítor E; Smalley, Matthew J; Barry, Simon T; Gualda, Emilio J; Alves, Paula M; Anderson, Elizabeth; Brito, Catarina

2016-02-01

3D cell tumour models are generated mainly in non-scalable culture systems, using bioactive scaffolds. Many of these models fail to reflect the complex tumour microenvironment and do not allow long-term monitoring of tumour progression. To overcome these limitations, we have combined alginate microencapsulation with agitation-based culture systems, to recapitulate and monitor key aspects of the tumour microenvironment and disease progression. Aggregates of MCF-7 breast cancer cells were microencapsulated in alginate, either alone or in combination with human fibroblasts, then cultured for 15 days. In co-cultures, the fibroblasts arranged themselves around the tumour aggregates creating distinct epithelial and stromal compartments. The presence of fibroblasts resulted in secretion of pro-inflammatory cytokines and deposition of collagen in the stromal compartment. Tumour cells established cell-cell contacts and polarised around small lumina in the interior of the aggregates. Over the culture period, there was a reduction in oestrogen receptor and membranous E-cadherin alongside loss of cell polarity, increased collective cell migration and enhanced angiogenic potential in co-cultures. These phenotypic alterations, typical of advanced stages of cancer, were not observed in the mono-cultures of MCF-7 cells. The proposed model system constitutes a new tool to study tumour-stroma crosstalk, disease progression and drug resistance mechanisms. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Stress Exposure in Significant Relationships Is Associated with Lymph Node Status in Breast Cancer.

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Chiara Renzi

Full Text Available Life stress exposure may impact on health and disease. Previous literature showed that stressful life events are associated with cancer incidence, survival and mortality. In animal models, patterns of maternal care have been shown to critically affect stress sensitivity and immunity trajectories later in life, by modifying DNA methylation during critical periods early in life. However, the role of parental care in breast cancer progression and survival has only limitedly been explored. Here, we investigated whether these factors may be linked to biological prognostic variables.One hundred twenty-three women hospitalized for surgery of primary breast cancer completed a questionnaire assessing parental bonding. Stressful events throughout the life span were also assessed.We found that the absence of optimal parental relationships is significantly associated with an increased risk of lymph node involvement, adjusting for confounders, while cumulative stress in the area of sentimental relationships is borderline significantly associated with the same prognostic factor.Our results suggest that parental bonding and sentimental relations may have a role in breast cancer progression. These variables represent an important evolutionary aspect which may modulate cancer progression through psycho-physiological stress pathways and influence the immune system.

Forecasting of Radiation Belts: Results From the PROGRESS Project.

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Balikhin, M. A.; Arber, T. D.; Ganushkina, N. Y.; Walker, S. N.

2017-12-01

Forecasting of Radiation Belts: Results from the PROGRESS Project. The overall goal of the PROGRESS project, funded in frame of EU Horizon2020 programme, is to combine first principles based models with the systems science methodologies to achieve reliable forecasts of the geo-space particle radiation environment.The PROGRESS incorporates three themes : The propagation of the solar wind to L1, Forecast of geomagnetic indices, and forecast of fluxes of energetic electrons within the magnetosphere. One of the important aspects of the PROGRESS project is the development of statistical wave models for magnetospheric waves that affect the dynamics of energetic electrons such as lower band chorus, hiss and equatorial noise. The error reduction ratio (ERR) concept has been used to optimise the set of solar wind and geomagnetic parameters for organisation of statistical wave models for these emissions. The resulting sets of parameters and statistical wave models will be presented and discussed. However the ERR analysis also indicates that the combination of solar wind and geomagnetic parameters accounts for only part of the variance of the emissions under investigation (lower band chorus, hiss and equatorial noise). In addition, advances in the forecast of fluxes of energetic electrons, exploiting empirical models and the first principles IMPTAM model achieved by the PROGRESS project is presented.

BWR core melt progression phenomena: Experimental analyses

International Nuclear Information System (INIS)

Ott, L.J.

1992-01-01

In the BWR Core Melt in Progression Phenomena Program, experimental results concerning severe fuel damage and core melt progression in BWR core geometry are used to evaluate existing models of the governing phenomena. These include control blade eutectic liquefaction and the subsequent relocation and attack on the channel box structure; oxidation heating and hydrogen generation; Zircaloy melting and relocation; and the continuing oxidation of zirconium with metallic blockage formation. Integral data have been obtained from the BWR DF-4 experiment in the ACRR and from BWR tests in the German CORA exreactor fuel-damage test facility. Additional integral data will be obtained from new CORA BWR test, the full-length FLHT-6 BWR test in the NRU test reactor, and the new program of exreactor experiments at Sandia National Laboratories (SNL) on metallic melt relocation and blockage formation. an essential part of this activity is interpretation and use of the results of the BWR tests. The Oak Ridge National Laboratory (ORNL) has developed experiment-specific models for analysis of the BWR experiments; to date, these models have permitted far more precise analyses of the conditions in these experiments than has previously been available. These analyses have provided a basis for more accurate interpretation of the phenomena that the experiments are intended to investigate. The results of posttest analyses of BWR experiments are discussed and significant findings from these analyses are explained. The ORNL control blade/canister models with materials interaction, relocation and blockage models are currently being implemented in SCDAP/RELAP5 as an optional structural component

Progression from acute to chronic pancreatitis

DEFF Research Database (Denmark)

Nøjgaard, Camilla; Becker, Ulrik; Matzen, Peter

2011-01-01

Objectives: Knowledge of the natural course of acute pancreatitis (AP) and risk of progression to chronic pancreatitis (CP) is limited. The aims were to describe: (1) the incidence of progression from AP to CP, (2) prognostic factors for progression, and (3) the natural course and mortality.......1%) during follow-up; 48.2% developed from alcoholic AP, 47.0% from idiopathic AP, and 4.8% from other causes. The mortality rate for patients with progressive AP was 2.7 times higher than in patients with nonprogressive acute pancreatitis, and 5.3 to 6.5 times higher than in the background population....... In Cox regression analyses corrected for age, only smoking was of significance for the progression from AP to CP. Conclusions: Acute pancreatitis can progress to CP, not only from alcoholic but also from nonalcoholic AP. Smoking was the strongest risk factor associated with progression. The mortality...

Progressive Decrease of Peripapillary Angioflow Vessel Density During Structural and Visual Field Progression in Early Primary Open-angle Glaucoma.

Science.gov (United States)

Holló, Gábor

2017-07-01

To present a case of early primary open-angle glaucoma in which retinal nerve fiber layer thickness (RNFLT), ganglion cell complex (GCC), and visual field progression were accompanied with significant progression of peripapillary angioflow vessel density (PAFD) measured with optical coherence tomographic angiography. A 68-year-old female patient who was under topical intraocular pressure (IOP) lowering medication for 20 years for ocular hypertension of the right and preperimetric primary open-angle glaucoma of the left eye (with reproducible inferotemporal and superotemporal neuroretinal rim and RNFL loss) was prospectively imaged with the AngioVue OCT for RNFLT, GCC thickness, and PAFD, and investigated with the Octopus Normal G2 visual field test on the same days at 6-month intervals for 18 months, while the IOP of the left eye escaped from control. IOP of the left eye fluctuated between 14 and 30 mm Hg in the study period. RNFLT, GCC thickness, and peripapillary PAFD all decreased significantly (linear regression analysis, P=0.030, 0.040, and 0.020, respectively), and a significant 2.1 dB/y progression was seen for a superior visual field cluster. The RNFLT, peripapillary PAFD, and visual field of the right eye remained normal and unchanged. In our case IOP elevation, glaucomatous visual field conversion, and structural progression were accompanied with significant progressive decrease of peripapillary PAFD. The simultaneous thinning of RNFLT and GCC and decrease of peripapillary PAFD suggest that PAFD may potentially be an additional indicator of early progression in primary open-angle glaucoma.

Fluor Hanford Project Focused Progress at Hanford

International Nuclear Information System (INIS)

HANSON, R.D.

2000-01-01

Fluor Hanford is making significant progress in accelerating cleanup at the Hanford site. This progress consistently aligns with a new strategic vision established by the U.S. Department of Energy's Richland Operations Office (RL)

Metformin blocks progression of obesity-activated thyroid cancer in a mouse model.

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Park, Jeongwon; Kim, Won Gu; Zhao, Li; Enomoto, Keisuke; Willingham, Mark; Cheng, Sheue-Yann

2016-06-07

Compelling epidemiologic evidence indicates that obesity is associated with a high risk of human malignancies, including thyroid cancer. We previously demonstrated that a high fat diet (HFD) effectively induces the obese phenotype in a mouse model of aggressive follicular thyroid cancer (ThrbPV/PVPten+/-mice). We showed that HFD promotes cancer progression through aberrant activation of the leptin-JAK2-STAT3 signaling pathway. HFD-promoted thyroid cancer progression allowed us to test other molecular targets for therapeutic opportunity for obesity-induced thyroid cancer. Metformin is a widely used drug to treat patients with type II diabetes. It has been shown to reduce incidences of neoplastic diseases and cancer mortality in type II diabetes patients. The present study aimed to test whether metformin could be a therapeutic for obesity-activated thyroid cancer. ThrbPV/PVPten+/-mice were fed HFD together with metformin or vehicle-only, as controls, for 20 weeks. While HFD-ThrbPV/PVPten+/-mice had shorter survival than LFD-treated mice, metformin had no effects on the survival of HFD-ThrbPV/PVPten+/-mice. Remarkably, metformin markedly decreased occurrence of capsular invasion and completely blocked vascular invasion and anaplasia in HFD-ThrbPV/PVPten+/-mice without affecting thyroid tumor growth. The impeded cancer progression was due to the inhibitory effect of metformin on STAT3-ERK-vimentin and fibronectin-integrin signaling to decrease tumor cell invasion and de-differentiation. The present studies provide additional molecular evidence to support the link between obesity and thyroid cancer risk. Importantly, our findings suggest that metformin could be used as an adjuvant in combination with antiproliferative modalities to improve the outcome of patients with obesity-activated thyroid cancer.

The Chronic Kidney Disease Model: A General Purpose Model of Disease Progression and Treatment

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Patel Uptal D

2011-06-01

Full Text Available Abstract Background Chronic kidney disease (CKD is the focus of recent national policy efforts; however, decision makers must account for multiple therapeutic options, comorbidities and complications. The objective of the Chronic Kidney Disease model is to provide guidance to decision makers. We describe this model and give an example of how it can inform clinical and policy decisions. Methods Monte Carlo simulation of CKD natural history and treatment. Health states include myocardial infarction, stroke with and without disability, congestive heart failure, CKD stages 1-5, bone disease, dialysis, transplant and death. Each cycle is 1 month. Projections account for race, age, gender, diabetes, proteinuria, hypertension, cardiac disease, and CKD stage. Treatment strategies include hypertension control, diabetes control, use of HMG-CoA reductase inhibitors, use of angiotensin converting enzyme inhibitors, nephrology specialty care, CKD screening, and a combination of these. The model architecture is flexible permitting updates as new data become available. The primary outcome is quality adjusted life years (QALYs. Secondary outcomes include health state events and CKD progression rate. Results The model was validated for GFR change/year -3.0 ± 1.9 vs. -1.7 ± 3.4 (in the AASK trial, and annual myocardial infarction and mortality rates 3.6 ± 0.9% and 1.6 ± 0.5% vs. 4.4% and 1.6% in the Go study. To illustrate the model's utility we estimated lifetime impact of a hypothetical treatment for primary prevention of vascular disease. As vascular risk declined, QALY improved but risk of dialysis increased. At baseline, 20% and 60% reduction: QALYs = 17.6, 18.2, and 19.0 and dialysis = 7.7%, 8.1%, and 10.4%, respectively. Conclusions The CKD Model is a valid, general purpose model intended as a resource to inform clinical and policy decisions improving CKD care. Its value as a tool is illustrated in our example which projects a relationship between

Lattice-based model of ductal carcinoma in situ suggests rules for breast cancer progression to an invasive state.

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Eline Boghaert

2014-12-01

Full Text Available Ductal carcinoma in situ (DCIS is a heterogeneous group of non-invasive lesions of the breast that result from abnormal proliferation of mammary epithelial cells. Pathologists characterize DCIS by four tissue morphologies (micropapillary, cribriform, solid, and comedo, but the underlying mechanisms that distinguish the development and progression of these morphologies are not well understood. Here we explored the conditions leading to the emergence of the different morphologies of DCIS using a two-dimensional multi-cell lattice-based model that incorporates cell proliferation, apoptosis, necrosis, adhesion, and contractility. We found that the relative rates of cell proliferation and apoptosis governed which of the four morphologies emerged. High proliferation and low apoptosis favored the emergence of solid and comedo morphologies. In contrast, low proliferation and high apoptosis led to the micropapillary morphology, whereas high proliferation and high apoptosis led to the cribriform morphology. The natural progression between morphologies cannot be investigated in vivo since lesions are usually surgically removed upon detection; however, our model suggests probable transitions between these morphologies during breast cancer progression. Importantly, cribriform and comedo appear to be the ultimate morphologies of DCIS. Motivated by previous experimental studies demonstrating that tumor cells behave differently depending on where they are located within the mammary duct in vivo or in engineered tissues, we examined the effects of tissue geometry on the progression of DCIS. In agreement with our previous experimental work, we found that cells are more likely to invade from the end of ducts and that this preferential invasion is regulated by cell adhesion and contractility. This model provides additional insight into tumor cell behavior and allows the exploration of phenotypic transitions not easily monitored in vivo.

Curcumin ameliorates liver damage and progression of NASH in NASH-HCC mouse model possibly by modulating HMGB1-NF-κB translocation.

Science.gov (United States)

Afrin, Rejina; Arumugam, Somasundaram; Rahman, Azizur; Wahed, Mir Imam Ibne; Karuppagounder, Vengadeshprabhu; Harima, Meilei; Suzuki, Hiroshi; Miyashita, Shizuka; Suzuki, Kenji; Yoneyama, Hiroyuki; Ueno, Kazuyuki; Watanabe, Kenichi

2017-03-01

Curcumin, a phenolic compound, has a wide spectrum of therapeutic effects such as antitumor, anti-inflammatory, anti-cancer and so on. The study aimed to investigate the underlying mechanisms of curcumin to protect liver damage and progression of non-alcoholic steatohepatitis (NASH) in a novel NASH-hepatocellular carcinoma (HCC) mouse model. To induce this model neonatal C57BL/6J male mice were exposed to low-dose streptozotocin and were fed a high-fat diet (HFD) from the age of 4weeks to 14weeks. Curcumin was given at 100mg/kg dose daily by oral gavage started at the age of 10weeks and continued until 14weeks along with HFD feeding. We found that curcumin improved the histopathological changes of the NASH liver via reducing the level of steatosis, fibrosis associated with decreasing serum aminotransferases. In addition, curcumin treatment markedly reduced the hepatic protein expression of oxidative stress, pro-inflammatory cytokines, and chemokines including interferon (IFN) γ, interleukin-1β and IFNγ-inducible protein 10, in NASH mice. Furthermore, curcumin treatment significantly reduced the cytoplasmic translocation of high mobility group box 1 (HMGB1) and the protein expression of toll like receptor 4. Nuclear translocation of nuclear factor kappa B (NF-κB) was also dramatically attenuated by the curcumin in NASH liver. Curcumin treatment effectively reduced the progression of NASH to HCC by suppressing the protein expression of glypican-3, vascular endothelial growth factor, and prothrombin in the NASH liver. Our data suggest that curcumin reduces the progression of NASH and liver damage, which may act via inhibiting HMGB1-NF-κB translocation. Copyright © 2017 Elsevier B.V. All rights reserved.

Vision for the Future of FIA: Paean to Progress, Possibilities, and Partners

Science.gov (United States)

Susan L. King; Charles T. Scott

2006-01-01

The Forest Inventory and Analysis (FIA) program of the U.S. Department of Agriculture Forest Service has made significant progress implementing the annualized inventory in 46 States in 2004. Major increases in program performance included the availability of plot data and the plots? corresponding approximate coordinates. A mill site study and biomass models were used...

Taurine Alleviates the Progression of Diabetic Nephropathy in Type 2 Diabetic Rat Model

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Jang Hyun Koh

2014-01-01

Full Text Available The overexpression of vascular endothelial growth factor (VEGF is known to be involved in the pathogenesis of diabetic nephropathy. In this study, the protective effects of taurine on diabetic nephropathy along with its underlying mechanism were investigated. Experimental animals were divided into three groups: LETO rats as normal group (n=10, OLETF rats as diabetic control group (n=10, and OLETF rats treated with taurine group (n=10. We treated taurine (200 mg/kg/day for 20 weeks and treated high glucose (HG, 30 mM with or without taurine (30 mM in mouse cultured podocyte. After taurine treatment, blood glucose level was decreased and insulin secretion was increased. Taurine significantly reduced albuminuria and ACR. Also it decreased glomerular volume, GBM thickness and increased open slit pore density through decreased VEGF and increased nephrin mRNA expressions in renal cortex. The antioxidant effects of taurine were confirmed by the reduction of urine MDA in taurine treated diabetic group. Also reactive oxygen species (ROS levels were decreased in HG condition with taurine treated podocytes compared to without taurine. These results indicate that taurine lowers glucose level via increased insulin secretion and ameliorates the progression of diabetic nephropathy through antifibrotic and antioxidant effects in type 2 diabetes rat model.

Mental Model Progression in Learning the Electron Transport Chain: Effects of Instructional Strategies and Cognitive Flexibility

Science.gov (United States)

Darabi, Aubteen; Hemphill, Jennifer; Nelson, David W.; Boulware, Wilma; Liang, Xinya

2010-01-01

This study investigated the effect of two instructional strategies, segmented and holistic, on the progression over time of learners' mental models toward that of an expert with the moderator of cognitive flexibility. Sixty-four juniors and seniors in a college metabolism course were randomly assigned to one of the two strategies for instruction…

Targeting ECM Disrupts Cancer Progression

DEFF Research Database (Denmark)

Venning, Freja A; Wullkopf, Lena; Erler, Janine T

2015-01-01

, the extracellular matrix (ECM). Many ECM proteins are significantly deregulated during the progression of cancer, causing both biochemical and biomechanical changes that together promote the metastatic cascade. In this review, the influence of several ECM proteins on these multiple steps of cancer spread...... is summarized. In addition, we highlight the promising (pre-)clinical data showing benefits of targeting these ECM macromolecules to prevent cancer progression....

Stimulation of ganglionated plexus attenuates cardiac neural remodeling and heart failure progression in a canine model of acute heart failure post-myocardial infarction.

Science.gov (United States)

Luo, Da; Hu, Huihui; Qin, Zhiliang; Liu, Shan; Yu, Xiaomei; Ma, Ruisong; He, Wenbo; Xie, Jing; Lu, Zhibing; He, Bo; Jiang, Hong

2017-12-01

Heart failure (HF) is associated with autonomic dysfunction. Vagus nerve stimulation has been shown to improve cardiac function both in HF patients and animal models of HF. The purpose of this present study is to investigate the effects of ganglionated plexus stimulation (GPS) on HF progression and autonomic remodeling in a canine model of acute HF post-myocardial infarction. Eighteen adult mongrel male dogs were randomized into the control (n=8) and GPS (n=10) groups. All dogs underwent left anterior descending artery ligation followed by 6-hour high-rate (180-220bpm) ventricular pacing to induce acute HF. Transthoracic 2-dimensional echocardiography was performed at different time points. The plasma levels of norepinephrine, B-type natriuretic peptide (BNP) and Ang-II were measured using ELISA kits. C-fos and nerve growth factor (NGF) proteins expressed in the left stellate ganglion as well as GAP43 and TH proteins expressed in the peri-infarct zone were measured using western blot. After 6h of GPS, the left ventricular end-diastolic volume, end-systolic volume and ejection fraction showed no significant differences between the 2 groups, but the interventricular septal thickness at end-systole in the GPS group was significantly higher than that in the control group. The plasma levels of norepinephrine, BNP, Ang-II were increased 1h after myocardial infarction while the increase was attenuated by GPS. The expression of c-fos and NGF proteins in the left stellate ganglion as well as GAP43 and TH proteins in cardiac peri-infarct zone in GPS group were significantly lower than that in control group. GPS inhibits cardiac sympathetic remodeling and attenuates HF progression in canines with acute HF induced by myocardial infarction and ventricular pacing. Copyright © 2017 Elsevier B.V. All rights reserved.

Introducing errors in progress ratios determined from experience curves

NARCIS (Netherlands)

van Sark, W.G.J.H.M.

2008-01-01

Progress ratios (PRs) derived from historical data in experience curves are used for forecasting development of many technologies as a means to model endogenous technical change in for instance climate–economy models. These forecasts are highly sensitive to uncertainties in the progress ratio. As a

Rate Dependent Multicontinuum Progressive Failure Analysis of Woven Fabric Composite Structures under Dynamic Impact

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James Lua

2004-01-01

Full Text Available Marine composite materials typically exhibit significant rate dependent response characteristics when subjected to extreme dynamic loading conditions. In this work, a strain-rate dependent continuum damage model is incorporated with multicontinuum technology (MCT to predict damage and failure progression for composite material structures. MCT treats the constituents of a woven fabric composite as separate but linked continua, thereby allowing a designer to extract constituent stress/strain information in a structural analysis. The MCT algorithm and material damage model are numerically implemented with the explicit finite element code LS-DYNA3D via a user-defined material model (umat. The effects of the strain-rate hardening model are demonstrated through both simple single element analyses for woven fabric composites and also structural level impact simulations of a composite panel subjected to various impact conditions. Progressive damage at the constituent level is monitored throughout the loading. The results qualitatively illustrate the value of rate dependent material models for marine composite materials under extreme dynamic loading conditions.

Progression of MDS-UPDRS Scores Over Five Years in De Novo Parkinson Disease from the Parkinson's Progression Markers Initiative Cohort.

Science.gov (United States)

Holden, Samantha K; Finseth, Taylor; Sillau, Stefan H; Berman, Brian D

2018-01-01

The Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UDPRS) is a commonly used tool to measure Parkinson disease (PD) progression. Longitudinal changes in MDS-UPDRS scores in de novo PD have not been established. Determine progression rates of MDS-UPDRS scores in de novo PD. 362 participants from the Parkinson's Progression Markers Initiative, a multicenter longitudinal cohort study of de novo PD, were included. Longitudinal progression of MDS-UPDRS total and subscale scores were modeled using mixed model regression. MDS-UPDRS scores increased in a linear fashion over five years in de novo PD. MDS-UPDRS total score increased an estimated 4.0 points/year, Part I 0.25 points/year, Part II 1.0 points/year, and Part III 2.4 points/year. The expected average progression of MDS-UPDRS scores in de novo PD from this study can assist in clinical monitoring and provide comparative data for detection of disease modification in treatment trials.

Recent Progress in Large-Scale Structure

CERN Multimedia

CERN. Geneva

2014-01-01

I will discuss recent progress in the understanding of how to model galaxy clustering. While recent analyses have focussed on the baryon acoustic oscillations as a probe of cosmology, galaxy redshift surveys contain a lot more information than the acoustic scale. In extracting this additional information three main issues need to be well understood: nonlinear evolution of matter fluctuations, galaxy bias and redshift-space distortions. I will present recent progress in modeling these three effects that pave the way to constraining cosmology and galaxy formation with increased precision.

Progress toward generating a ferret model of cystic fibrosis by somatic cell nuclear transfer

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Engelhardt John F

2003-11-01

Full Text Available Abstract Mammalian cloning by nuclear transfer from somatic cells has created new opportunities to generate animal models of genetic diseases in species other than mice. Although genetic mouse models play a critical role in basic and applied research for numerous diseases, often mouse models do not adequately reproduce the human disease phenotype. Cystic fibrosis (CF is one such disease. Targeted ablation of the cystic fibrosis transmembrane conductance regulator (CFTR gene in mice does not adequately replicate spontaneous bacterial infections observed in the human CF lung. Hence, several laboratories are pursuing alternative animal models of CF in larger species such as the pig, sheep, rabbits, and ferrets. Our laboratory has focused on developing the ferret as a CF animal model. Over the past few years, we have investigated several experimental parameters required for gene targeting and nuclear transfer (NT cloning in the ferret using somatic cells. In this review, we will discuss our progress and the hurdles to NT cloning and gene-targeting that accompany efforts to generate animal models of genetic diseases in species such as the ferret.

How do psychological factors influence adolescent smoking progression? The evidence for indirect effects through tobacco advertising receptivity.

Science.gov (United States)

Audrain-McGovern, Janet; Rodriguez, Daniel; Patel, Vaishali; Faith, Myles S; Rodgers, Kelli; Cuevas, Jocelyn

2006-04-01

To determine whether novelty seeking and depressive symptoms had mediated or indirect effects on adolescent smoking progression through tobacco advertising receptivity. More than 1000 adolescents were monitored from 9th grade to 12th grade and completed annual surveys that measured demographic characteristics, smoking behavior, tobacco advertising receptivity, novelty-seeking personality, depressive symptoms, family and peer smoking, alcohol use, and marijuana use. Latent growth modeling indicated that novelty seeking had a significant indirect effect on smoking progression through baseline tobacco advertising receptivity. For each 1-SD increase in novelty seeking, the odds of being more receptive to tobacco advertising increased by 12% (ie, being in a specific category or higher), which in turn resulted in an 11% increase in the odds of smoking progression from 9th grade to 12th grade. The indirect effect from depressive symptoms to smoking progression did not reach significance. These findings may inform future research on other factors that influence tobacco advertising receptivity, as well as programs aimed at preventing adolescent smoking initiation and progression.

Influence of Modelling Options in RELAP5/SCDAPSIM and MAAP4 Computer Codes on Core Melt Progression and Reactor Pressure Vessel Integrity

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Siniša Šadek

2010-01-01

Full Text Available RELAP5/SCDAPSIM and MAAP4 are two widely used severe accident computer codes for the integral analysis of the core and the reactor pressure vessel behaviour following the core degradation. The objective of the paper is the comparison of code results obtained by application of different modelling options and the evaluation of influence of thermal hydraulic behaviour of the plant on core damage progression. The analysed transient was postulated station blackout in NPP Krško with a leakage from reactor coolant pump seals. Two groups of calculations were performed where each group had a different break area and, thus, a different leakage rate. Analyses have shown that MAAP4 results were more sensitive to varying thermal hydraulic conditions in the primary system. User-defined parameters had to be carefully selected when the MAAP4 model was developed, in contrast to the RELAP5/SCDAPSIM model where those parameters did not have any significant impact on final results.

Using hemoglobin A1C as a predicting model for time interval from pre-diabetes progressing to diabetes.

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Chen-Ling Huang

Full Text Available The early identification of subjects at high risk for diabetes is essential, thus, random rather than fasting plasma glucose is more useful. We aim to evaluate the time interval between pre-diabetes to diabetes with anti-diabetic drugs by using HbA1C as a diagnostic tool, and predicting it using a mathematic model.We used the Taipei Medical University Affiliated Hospital Patient Profile Database (AHPPD from January-2007 to June-2011. The patients who progressed and were prescribed anti-diabetic drugs were selected from AHPPD. The mathematical model used to predict the time interval of HbA1C value ranged from 5.7% to 6.5% for diabetes progression.We predicted an average overall time interval for all participants in between 5.7% to 6.5% during a total of 907 days (standard error, 103 days. For each group found among 5.7% to 6.5% we determined 1169.3 days for the low risk group (i.e. 3.2 years, 1080.5 days (i.e. 2.96 years for the increased risk group and 729.4 days (i.e. 1.99 years for the diabetes group. This indicates the patients will take an average of 2.49 years to reach 6.5%.This prediction model is very useful to help prioritize the diagnosis at an early stage for targeting individuals with risk of diabetes. Using patients' HbA1C before anti-diabetes drugs are used we predicted the time interval from pre-diabetes progression to diabetes is 2.49 years without any influence of age and gender. Additional studies are needed to support this model for a long term prediction.

Blood Transcriptional Signatures for Disease Progression in a Rat Model of Osteoarthritis

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Michał Korostyński

2017-01-01

Full Text Available Biomarkers of osteoarthritis (OA that can accurately diagnose the disease at the earliest stage would significantly support efforts to develop treatments for prevention and early intervention. We have sought to determine the time course of alterations in peripheral blood gene expression profile associated with the development of OA. Blood samples were collected from a tail vein of individual rats with monosodium iodoacetate- (MIA- induced OA (2, 14, 21, and 28 days after the treatment. We used whole-genome microarrays to reveal OA-related transcriptional alterations of 72 transcripts. Three main groups of coexpressed genes revealed diverse time-dependent profiles of up- and downregulation. Functional links that connect expression of the gradually downregulated genes to the G13 signaling pathway were indicated. The mRNA abundance levels of the identified transcripts were further analyzed in publicly available gene expression dataset obtained from a GARP study cohort of OA patients. We revealed three-gene signature differentially expressed in both rat and human blood (TNK2, KCTD2, and WDR37. The alterations in expression of the selected transcripts in peripheral blood samples of the patients indicate heterogeneity of the OA profiles potentially related to disease progress and severity of clinical symptoms. Our study identifies several potential stage-specific biomarkers of OA progression.

Brain viscoelasticity alteration in chronic-progressive multiple sclerosis.

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Kaspar-Josche Streitberger

Full Text Available INTRODUCTION: Viscoelastic properties indicate structural alterations in biological tissues at multiple scales with high sensitivity. Magnetic Resonance Elastography (MRE is a novel technique that directly visualizes and quantitatively measures biomechanical tissue properties in vivo. MRE recently revealed that early relapsing-remitting multiple sclerosis (MS is associated with a global decrease of the cerebral mechanical integrity. This study addresses MRE and MR volumetry in chronic-progressive disease courses of MS. METHODS: We determined viscoelastic parameters of the brain parenchyma in 23 MS patients with primary or secondary chronic progressive disease course in comparison to 38 age- and gender-matched healthy individuals by multifrequency MRE, and correlated the results with clinical data, T2 lesion load and brain volume. Two viscoelastic parameters, the shear elasticity μ and the powerlaw exponent α, were deduced according to the springpot model and compared to literature values of relapsing-remitting MS. RESULTS: In chronic-progressive MS patients, μ and α were reduced by 20.5% and 6.1%, respectively, compared to healthy controls. MR volumetry yielded a weaker correlation: Total brain volume loss in MS patients was in the range of 7.5% and 1.7% considering the brain parenchymal fraction. All findings were significant (P<0.001. CONCLUSIONS: Chronic-progressive MS disease courses show a pronounced reduction of the cerebral shear elasticity compared to early relapsing-remitting disease. The powerlaw exponent α decreased only in the chronic-progressive stage of MS, suggesting an alteration in the geometry of the cerebral mechanical network due to chronic neuroinflammation.

What progress have we made with tinnitus? The Tonndorf Lecture 2005.

Science.gov (United States)

Baguley, David M

2006-12-01

The field of tinnitus research is vibrant and active. Prospects for progress are high, but would be optimized by the growth of inter-disciplinary collaborations. Tinnitus remains a source of urgent scientific investigation, and truly effective treatments continue to be elusive. The Tonndorf Lecture of the International Tinnitus Seminars represents an opportunity to reflect upon progress to date regarding tinnitus, and the actions needed to further that progress in future. Progress regarding tinnitus mechanisms is reviewed, with particular regard to the conceptual distinction between ignition sites for tinnitus, and the physiological mechanisms that then promote the tinnitus through the central auditory pathway. The current status of both the Jastreboff neurophysiological model and the psychological model of tinnitus is reviewed. Some concerns regarding each model are raised, and the need for models that integrate the insights of both perspectives is identified as urgent. There are clear indications of progress in tinnitus, specifically regarding mechanisms, models and treatments. For knowledge to progress further, however, there is a pressing need for an inter-disciplinary approach to tinnitus, more involvement in teaching at a postgraduate level, and the development of experimental models of tinnitus that are both congruent with, and represent the complexity of, human experience of tinnitus.

Scientific progress as increasing verisimilitude.

Science.gov (United States)

Niiniluoto, Ilkka

2014-06-01

According to the foundationalist picture, shared by many rationalists and positivist empiricists, science makes cognitive progress by accumulating justified truths. Fallibilists, who point out that complete certainty cannot be achieved in empirical science, can still argue that even successions of false theories may progress toward the truth. This proposal was supported by Karl Popper with his notion of truthlikeness or verisimilitude. Popper's own technical definition failed, but the idea that scientific progress means increasing truthlikeness can be expressed by defining degrees of truthlikeness in terms of similarities between states of affairs. This paper defends the verisimilitude approach against Alexander Bird who argues that the "semantic" definition (in terms of truth or truthlikeness alone) is not sufficient to define progress, but the "epistemic" definition referring to justification and knowledge is more adequate. Here Bird ignores the crucial distinction between real progress and estimated progress, explicated by the difference between absolute (and usually unknown) degrees of truthlikeness and their evidence-relative expected values. Further, it is argued that Bird's idea of returning to the cumulative model of growth requires an implausible trick of transforming past false theories into true ones.

Capital accumulation and embodied technological progress

NARCIS (Netherlands)

Grass, D.; Hartl, R.F.; Kort, P.M.

This paper combines technology adoption with capital accumulation taking into account technological progress. We model this as a multi-stage optimal control problem and solve it using the corresponding maximum principle. The model with linear revenue can be solved analytically, while the model with

Impact of Environmental Regulation and Technical Progress on Industrial Carbon Productivity: An Approach Based on Proxy Measure

Directory of Open Access Journals (Sweden)

Huan Zhang

2016-08-01

Full Text Available This research aims to study the main influencing factors of China’s industrial carbon productivity by incorporating environmental regulation and technical progress into an econometric model. The paper focuses on data from 35 of China’s industrial sectors and covers the period from 2006 to 2014, in order to examine the impact of environmental regulation and technical progress on carbon productivity. Methods applied include panel fixed effect model, panel random effect model and two stage least squares with instrumental variables (IV-2SLS. The effect of environmental regulation and technical progress has industrial heterogeneity. The paper subdivides industrial sectors into capital and technology intensive, resource intensive and labor intensive sectors according to factor intensiveness. The estimation results of the subgroups have uncovered that for capital and technology intensive and resource intensive sectors, environmental regulation has a more significant impact than technical progress; while for labor intensive sectors, innovation more significantly influences carbon productivity. In addition, foreign direct investment (FDI and industrialization level facilitate improving carbon productivity for the full sample. By contrast, industrial structure inhibits the overall industrial carbon productivity. The industry-specific results indicate that for capital and technology intensive sectors, optimizing of the industrial structure can improve carbon productivity; for resource intensive sectors, FDI and energy consumption structure should be emphasized more; for labor intensive sectors, industrialization levels help enhance carbon productivity. Finally the industrial sector-specific policy suggestions are proposed.

Increased common carotid artery wall thickness is associated with rapid progression of asymptomatic carotid stenosis.

Science.gov (United States)

Diomedi, Marina; Scacciatelli, Daria; Misaggi, Giulia; Balestrini, Simona; Balucani, Clotilde; Sallustio, Fabrizio; Di Legge, Silvia; Stanzione, Paolo; Silvestrini, Mauro

2014-01-01

This study aimed to identify clinical and ultrasound imaging predictors of progression of carotid luminal narrowing in subjects with asymptomatic moderate internal carotid artery (ICA) stenosis. A total of 571 subjects with asymptomatic moderate (50-69%) ICA stenoses were enrolled. They underwent ultrasound examination at baseline and after 12 months. Demographics, vascular risk factors, medications, plaque characteristics (surface and echogenicity) and common carotid intima-media thickness (IMT) were collected. At the follow-up examination, any change of ICA stenosis was graded in three categories (i) ≥70% to near occlusion, (ii) near occlusion, and (iii) occlusion. Progression of stenosis was defined as an increase in the stenosis degree by at least one category from baseline to follow-up. At 12 months, progression occurred in 142 subjects (prevalence rate 25%). At the multivariable logistic model, pathological IMT values (considered as binary variable: normal: ≤1 mm vs. pathologic: >1 mm) significantly predicted the risk for plaque progression after adjusting the model for possible confounders (OR 2.28, 95% CI 1.18-4.43, P = .014, multivariable logistic model). Our results confirm the role of carotid wall thickening as a marker of atherosclerosis. Carotid IMT measurement should be considered to implement risk stratification in patients with asymptomatic carotid disease.

Kolb's Experiential Learning Model: Critique from a Modeling Perspective

Science.gov (United States)

Bergsteiner, Harald; Avery, Gayle C.; Neumann, Ruth

2010-01-01

Kolb's experiential learning theory has been widely influential in adult learning. The theory and associated instruments continue to be criticized, but rarely is the graphical model itself examined. This is significant because models can aid scientific understanding and progress, as well as theory development and research. Applying accepted…

Communication of nuclear data progress

International Nuclear Information System (INIS)

2006-07-01

This is the 30th issue of Communication of Nuclear Data Progress (CNDP), in which the progress and achievements in nuclear data field in China during 2004 are carried. It includes the evaluations and model calculations of neutron data for n+ 31 P, 59 Co, 92-106 Mo, Nat-116 Cd, 233 U and the covariance data evaluation of experimental data for 27 Al, update the decay data for radionuclide 7 Be. Some results of studies for nuclear evaluation tool and model are also included in this issue, i.e. reaction mechanism studies of 5 He, a new method of evaluating the discrepant data, linear fit of correlative data by least squared method et al. (authors)

A Unique Model System for Tumor Progression in GBM Comprising Two Developed Human Neuro-Epithelial Cell Lines with Differential Transforming Potential and Coexpressing Neuronal and Glial Markers

Directory of Open Access Journals (Sweden)

Anjali Shiras

2003-11-01

Full Text Available The molecular mechanisms involved in tumor progression from a low-grade astrocytoma to the most malignant glioblastoma multiforme (GBM have been hampered due to lack of suitable experimental models. We have established a model of tumor progression comprising of two cell lines derived from the same astrocytoma tumor with a set of features corresponding to low-grade glioma (as in HNGC-1 and high-grade GBM (as in HNGC-2. The HNGC-1 cell line is slowgrowing, contact-inhibited, nontumorigenic, and noninvasive, whereas HNGC-2 is a rapidly proliferating, anchorage-independent, highly tumorigenic, and invasive cell line. The proliferation of cell lines is independent of the addition of exogenous growth factors. Interestingly, the HNGC-2 cell line displays a near-haploid karyotype except for a disomy of chromosome 2. The two cell lines express the neuronal precursor and progenitor markers vimentin, nestin, MAP-2, and NFP160, as well as glial differentiation protein S100μ. The HNGC-1 cell line also expresses markers of mature neurons like Tuj1 and GFAP, an astrocytic differentiation marker, hence contributing toward a more morphologically differentiated phenotype with a propensity for neural differentiation in vitro. Additionally, overexpression of epidermal growth factor receptor and c-erbB2, and loss of fibronectin were observed only in the HNGC-2 cell line, implicating the significance of these pathways in tumor progression. This in vitro model system assumes importance in unraveling the cellular and molecular mechanisms in differentiation, transformation, and gliomagenesis.

Enforcement actions: significant actions resolved. Quarterly progress report, July-September 1982

International Nuclear Information System (INIS)

1982-10-01

This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (July to September 1982) and includes copies of letters, notices, and orders sent by the Nuclear Regulatory Commission to the licensee with respect to the enforcement action. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, in the interest of promoting public health and safety as well as common defense and security. This publication is issued on a quarterly basis to include significant enforcement actions resolved during the preceding quarter

Three new genetic loci (R1210C in CFH, variants in COL8A1 and RAD51B) are independently related to progression to advanced macular degeneration.

Science.gov (United States)

Seddon, Johanna M; Reynolds, Robyn; Yu, Yi; Rosner, Bernard

2014-01-01

To assess the independent impact of new genetic variants on conversion to advanced stages of AMD, controlling for established risk factors, and to determine the contribution of genes in predictive models. In this prospective longitudinal study of 2765 individuals, 777 subjects progressed to neovascular disease (NV) or geographic atrophy (GA) in either eye over 12 years. Recently reported genetic loci were assessed for their independent effects on incident advanced AMD after controlling for 6 established loci in 5 genes, and demographic, behavioral, and macular characteristics. New variants which remained significantly related to progression were then added to a final multivariate model to assess their independent effects. The contribution of genes to risk models was assessed using reclassification tables by determining risk within cross-classified quintiles for alternative models. THREE NEW GENETIC VARIANTS WERE SIGNIFICANTLY RELATED TO PROGRESSION: rare variant R1210C in CFH (hazard ratio (HR) 2.5, 95% confidence interval [CI] 1.2-5.3, P = 0.01), and common variants in genes COL8A1 (HR 2.0, 95% CI 1.1-3.5, P = 0.02) and RAD51B (HR 0.8, 95% CI 0.60-0.97, P = 0.03). The area under the curve statistic (AUC) was significantly higher for the 9 gene model (.884) vs the 0 gene model (.873), P = .01. AUC's for the 9 vs 6 gene models were not significantly different, but reclassification analyses indicated significant added information for more genes, with adjusted odds ratios (OR) for progression within 5 years per one quintile increase in risk score of 2.7, Padvanced AMD beyond macular and behavioral phenotypes.

Progressive neurologic and somatic disease in a novel mouse model of human mucopolysaccharidosis type IIIC

Directory of Open Access Journals (Sweden)

Sara Marcó

2016-09-01

Full Text Available Mucopolysaccharidosis type IIIC (MPSIIIC is a severe lysosomal storage disease caused by deficiency in activity of the transmembrane enzyme heparan-α-glucosaminide N-acetyltransferase (HGSNAT that catalyses the N-acetylation of α-glucosamine residues of heparan sulfate. Enzyme deficiency causes abnormal substrate accumulation in lysosomes, leading to progressive and severe neurodegeneration, somatic pathology and early death. There is no cure for MPSIIIC, and development of new therapies is challenging because of the unfeasibility of cross-correction. In this study, we generated a new mouse model of MPSIIIC by targeted disruption of the Hgsnat gene. Successful targeting left LacZ expression under control of the Hgsnat promoter, allowing investigation into sites of endogenous expression, which was particularly prominent in the CNS, but was also detectable in peripheral organs. Signs of CNS storage pathology, including glycosaminoglycan accumulation, lysosomal distension, lysosomal dysfunction and neuroinflammation were detected in 2-month-old animals and progressed with age. Glycosaminoglycan accumulation and ultrastructural changes were also observed in most somatic organs, but lysosomal pathology seemed most severe in liver. Furthermore, HGSNAT-deficient mice had altered locomotor and exploratory activity and shortened lifespan. Hence, this animal model recapitulates human MPSIIIC and provides a useful tool for the study of disease physiopathology and the development of new therapeutic approaches.

An imbalance in progenitor cell populations reflects tumour progression in breast cancer primary culture models

LENUS (Irish Health Repository)

Donatello, Simona

2011-04-26

Abstract Background Many factors influence breast cancer progression, including the ability of progenitor cells to sustain or increase net tumour cell numbers. Our aim was to define whether alterations in putative progenitor populations could predict clinicopathological factors of prognostic importance for cancer progression. Methods Primary cultures were established from human breast tumour and adjacent non-tumour tissue. Putative progenitor cell populations were isolated based on co-expression or concomitant absence of the epithelial and myoepithelial markers EPCAM and CALLA respectively. Results Significant reductions in cellular senescence were observed in tumour versus non-tumour cultures, accompanied by a stepwise increase in proliferation:senescence ratios. A novel correlation between tumour aggressiveness and an imbalance of putative progenitor subpopulations was also observed. Specifically, an increased double-negative (DN) to double-positive (DP) ratio distinguished aggressive tumours of high grade, estrogen receptor-negativity or HER2-positivity. The DN:DP ratio was also higher in malignant MDA-MB-231 cells relative to non-tumourogenic MCF-10A cells. Ultrastructural analysis of the DN subpopulation in an invasive tumour culture revealed enrichment in lipofuscin bodies, markers of ageing or senescent cells. Conclusions Our results suggest that an imbalance in tumour progenitor subpopulations imbalances the functional relationship between proliferation and senescence, creating a microenvironment favouring tumour progression.

Clinical significance of pretreatment FDG PET/CT IN MOBG-avid pediatric neuroblastoma

Energy Technology Data Exchange (ETDEWEB)

Kang, Seo Young; Kim, Yong Il; Cheon, Gi Jeong; Kang, Keon Wook; Chung, June Key; Lee, Dong Soo; Kang, Hyoung Jin; Shin, Hee Young [Seoul National University Hospital, Seoul (Korea, Republic of); Kim, E. Edmund [Seoul National University, Seoul (Korea, Republic of); Rahim, Muhammad Kashif [Nishtar Medical College and Hospital, Multan (Pakistan)

2017-06-15

{sup 18}F-fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging is well known to have clinical significance in the initial staging and response evaluation of the many kinds of neoplasms. However, its role in the pediatric neuroblastoma is not clearly defined. In the present study, the clinical significance of FDG-PET/computed tomography (CT) in 123I- or 131I-metaiodobenzylguanidine (MIBG)-avid pediatric neuroblastoma was investigated. Twenty patients with neuroblastoma who undertook pretreatment FDG PET/CT at our institute between 2008 and 2015 and showed MIBG avidity were retrospectively enrolled in the present study. Clinical information—including histopathology, and serum markers—and several PET parameters—including SUVmax of the primary lesion (Psuv), target-to-background ratio (TBR), metabolic tumor volume (MTV), and coefficient of variation (CV)—were analyzed. The prognostic effect of PET parameters was evaluated in terms of progression-free survival (PFS). Total 20 patients (4.5 ± 3.5 years) were divided as two groups by disease progression. Six patients (30.0 %) experienced disease progression and one patient (5.0 %) died during follow-up period. There were not statistically significant in age, stage, MYCN status, primary tumor size, serum lactate dehydrogenase (LDH), neuron-specific enolase (NSE), and ferritin level between two groups with progression or no progression. However, Psuv (p = 0.017), TBR (p = 0.09), MTV (p = 0.02), and CV (p = 0.036) showed significant differences between two groups. In univariate analysis, PFS was significantly associated with Psuv (p = 0.021) and TBR (p = 0.023). FDG-PET parameters were significantly related with progression of neuroblastoma. FDG-PET/CT may have the potential as a valuable modality for evaluating prognosis in the patients with MIBG-avid pediatric neuroblastoma.

Development and reliability of a multi-modality scoring system for evaluation of disease progression in pre-clinical models of osteoarthritis: celecoxib may possess disease-modifying properties.

Science.gov (United States)

Panahifar, A; Jaremko, J L; Tessier, A G; Lambert, R G; Maksymowych, W P; Fallone, B G; Doschak, M R

2014-10-01

We sought to develop a comprehensive scoring system for evaluation of pre-clinical models of osteoarthritis (OA) progression, and use this to evaluate two different classes of drugs for management of OA. Post-traumatic OA (PTOA) was surgically induced in skeletally mature rats. Rats were randomly divided in three groups receiving either glucosamine (high dose of 192 mg/kg) or celecoxib (clinical dose) or no treatment. Disease progression was monitored utilizing micro-magnetic resonance imaging (MRI), micro-computed tomography (CT) and histology. Pertinent features such as osteophytes, subchondral sclerosis, joint effusion, bone marrow lesion (BML), cysts, loose bodies and cartilage abnormalities were included in designing a sensitive multi-modality based scoring system, termed the rat arthritis knee scoring system (RAKSS). Overall, an inter-observer correlation coefficient (ICC) of greater than 0.750 was achieved for each scored feature. None of the treatments prevented cartilage loss, synovitis, joint effusion, or sclerosis. However, celecoxib significantly reduced osteophyte development compared to placebo. Although signs of inflammation such as synovitis and joint effusion were readily identified at 4 weeks post-operation, we did not detect any BML. We report the development of a sensitive and reliable multi-modality scoring system, the RAKSS, for evaluation of OA severity in pre-clinical animal models. Using this scoring system, we found that celecoxib prevented enlargement of osteophytes in this animal model of PTOA, and thus it may be useful in preventing OA progression. However, it did not show any chondroprotective effect using the recommended dose. In contrast, high dose glucosamine had no measurable effects. Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Effect of self-assembled peptide–mesenchymal stem cell complex on the progression of osteoarthritis in a rat model

Directory of Open Access Journals (Sweden)

Kim JE

2014-05-01

Full Text Available Ji Eun Kim,1 Sang Mok Lee,2 Soo Hyun Kim,1 Phil Tatman,3 Albert O Gee,4 Deok-Ho Kim,3,5 Kyung Eun Lee,6 Youngmee Jung,1 Sang Jun Kim21Biomaterials Research Center, Korea Institute of Science and Technology, Seoul, South Korea; 2Department of Physical and Rehabilitation Medicine, Samsung Medical Center, Seoul, South Korea; 3Department of Bioengineering, 4Department of Orthopaedics and Sports Medicine, 5Institute for Stem Cell and Regenerative Medicine and Center for Cardiovascular Biology, University of Washington, Seattle, WA, USA; 6Advanced Analysis Center, Korea Institute of Science and Technology, Seoul, South KoreaPurpose: To evaluate the efficacy of mesenchymal stem cells (MSCs encapsulated in self-assembled peptide (SAP hydrogels in a rat knee model for the prevention of osteoarthritis (OA progression.Materials and methods: Nanostructured KLD-12 SAPs were used as the injectable hydrogels. Thirty-three Sprague Dawley rats were used for the OA model. Ten rats were used for the evaluation of biotin-tagged SAP disappearance. Twenty-three rats were divided into four groups: MSC (n=6, SAP (n=6, SAP-MSC (n=6, and no treatment (n=5. MSCs, SAPs, and SAP-MSCs were injected into the knee joints 3 weeks postsurgery. Histologic examination, immunofluorescent staining, measurement of cytokine levels, and micro-computed tomography analysis were conducted 6 weeks after injections. Behavioral studies were done to establish baseline measurements before treatment, and repeated 3 and 6 weeks after treatment to measure the efficacy of SAP-MSCs.Results: Concentration of biotinylated SAP at week 1 was not significantly different from those at week 3 and week 6 (P=0.565. Bone mineral density was significantly lower in SAP-MSC groups than controls (P=0.002. Significant differences in terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling staining between the control group and all other groups were observed. Caspase-8, tissue inhibitor of

Enforcement actions: significant actions resolved. Quarterly progress report, January-June 1982

International Nuclear Information System (INIS)

1982-09-01

This compilation summarizes significant enforcement actions that have been resolved during two quarterly periods (January to June 1982) and includes copies of letters, notices, and orders sent by the Nuclear Regulatory Commission to the licensee with respect to the enforcement action. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, in the interest of promoting public health and safety as well as common defense and security. The intention is that this publication will be issued on a quarterly basis to include significant enforcement actions resolved during the preceding quarter

v-Ha-ras oncogene insertion: A model for tumor progression of human small cell lung cancer

International Nuclear Information System (INIS)

Mabry, M.; Nakagawa, Toshitaro; Nelkin, B.D.; McDowell, E.; Gesell, M.; Eggleston, J.C.; Casero, R.A. Jr.; Baylin, S.B.

1988-01-01

Small cell lung cancer (SCLC) manifests a range of phenotypes in culture that may be important in understanding its relationship to non-SCLCs and to tumor progression events in patients. Most SCLC-derived cell lines, termed classic SCLC lines, have properties similar to SCLC tumors in patients. To delineate further the relationships between these phenotypes and the molecular events involved, the authors inserted the v-Ha-ras gene in SCLC cell lines with (biochemical variant) and without (classic) an amplified c-myc gene. These two SCLC subtypes had markedly different phenotypic responses to similar levels of expression of v-Ha-ras RNA. No biochemical or morphologic changes were observed in classic SCLC cells. In contrast, in biochemical variant SCLC cells, v-Ha-ras expression induced features typical of large cell undifferentiated lung carcinoma. Expression of v-Ha-ras in biochemical variant SCLC cells directly demonstrates that important transitions can occur between phenotypes of human lung cancer cells and that these may play a critical role in tumor progression events in patients. The finding provide a model system to study molecular events involved in tumor progression steps within a series of related tumor types

Chronic lymphocytic leukemia disease progression is accelerated by APRIL-TACI interaction in the TCL1 transgenic mouse model

NARCIS (Netherlands)

Lascano, Valeria; Guadagnoli, Marco; Schot, Jan G.; Luijks, Dieuwertje M.; Guikema, Jeroen E. J.; Cameron, Katherine; Hahne, Michael; Pals, Steven; Slinger, Erik; Kipps, Thomas J.; van Oers, Marinus H. J.; Eldering, Eric; Medema, Jan Paul; Kater, Arnon P.

2013-01-01

Although in vitro studies pointed to the tumor necrosis factor family member APRIL (a proliferation-inducing ligand) in mediating survival of chronic lymphocytic leukemia (CLL) cells, clear evidence for a role in leukemogenesis and progression in CLL is lacking. APRIL significantly prolonged in

Detection of Progressive Retinal Nerve Fiber Layer Loss in Glaucoma Using Scanning Laser Polarimetry with Variable Corneal Compensation

Science.gov (United States)

Medeiros, Felipe A.; Alencar, Luciana M.; Zangwill, Linda M.; Bowd, Christopher; Vizzeri, Gianmarco; Sample, Pamela A.; Weinreb, Robert N.

2010-01-01

Purpose To evaluate the ability of scanning laser polarimetry with variable corneal compensation to detect progressive retinal nerve fiber layer (RNFL) loss in glaucoma patients and patients suspected of having the disease. Methods This was an observational cohort study that included 335 eyes of 195 patients. Images were obtained annually with the GDx VCC scanning laser polarimeter, along with optic disc stereophotographs and standard automated perimetry (SAP) visual fields. The median follow-up time was 3.94 years. Progression was determined using commercial software for SAP and by masked assessment of optic disc stereophotographs performed by expert graders. Random coefficient models were used to evaluate the relationship between RNFL thickness measurements over time and progression as determined by SAP and/or stereophotographs. Results From the 335 eyes, 34 (10%) showed progression over time by stereophotographs and/or SAP. Average GDx VCC measurements decreased significantly over time for both progressors as well as non-progressors. However, the rate of decline was significantly higher in the progressing group (−0.70 μm/year) compared to the non-progressing group (−0.14 μm/year; P = 0.001). Black race and male sex were significantly associated with higher rates of RNFL loss during follow-up. Conclusions The GDx VCC scanning laser polarimeter was able to identify longitudinal RNFL loss in eyes that showed progression in optic disc stereophotographs and/or visual fields. These findings suggest that this technology could be useful to detect and monitor progressive disease in patients with established diagnosis of glaucoma or suspected of having the disease. PMID:19029038

Body composition during early infancy and developmental progression from 1 to 5 years of age

DEFF Research Database (Denmark)

Abera, Mubarek; Tesfaye, Markos; Admassu, Bitiya

2018-01-01

aimed to examine the relation between fat mass (FM) or fat-free mass (FFM) tissues at birth and their accretion during early infancy, and later developmental progression. In a birth cohort from Ethiopia, 455 children who have BC measurement at birth and 416 who have standardised rate of BC growth during...... variables was examined using linear-mixed regression model. The finding revealed that FFM at birth was positively associated with global developmental progression from 1 to 5 years (β=1·75; 95 % CI 0·11, 3·39) and from 4 to 5 years (β=1·34; 95 % CI 0·23, 2·44) in the adjusted model. Furthermore, the rate...... of postnatal FFM tissue accretion was positively associated with development at 1 year of age (β=0·50; 95 % CI 0·01, 0·99). Neither fetal nor postnatal FM showed a significant association. In conclusion, fetal, rather than postnatal, FFM tissue accretion was associated with developmental progression...

Experimental verification of a progressive damage model for composite laminates based on continuum damage mechanics. M.S. Thesis Final Report

Science.gov (United States)

Coats, Timothy William

1994-01-01

Progressive failure is a crucial concern when using laminated composites in structural design. Therefore the ability to model damage and predict the life of laminated composites is vital. The purpose of this research was to experimentally verify the application of the continuum damage model, a progressive failure theory utilizing continuum damage mechanics, to a toughened material system. Damage due to tension-tension fatigue was documented for the IM7/5260 composite laminates. Crack density and delamination surface area were used to calculate matrix cracking and delamination internal state variables, respectively, to predict stiffness loss. A damage dependent finite element code qualitatively predicted trends in transverse matrix cracking, axial splits and local stress-strain distributions for notched quasi-isotropic laminates. The predictions were similar to the experimental data and it was concluded that the continuum damage model provided a good prediction of stiffness loss while qualitatively predicting damage growth in notched laminates.

TU-D-207B-01: A Prediction Model for Distinguishing Radiation Necrosis From Tumor Progression After Gamma Knife Radiosurgery Based On Radiomics Features From MR Images

International Nuclear Information System (INIS)

Zhang, Z; Ho, A; Wang, X; Brown, P; Guha-Thakurta, N; Ferguson, S; Fave, X; Zhang, L; Mackin, D; Court, L; Li, J; Yang, J

2016-01-01

Purpose: To develop and validate a prediction model using radiomics features extracted from MR images to distinguish radiation necrosis from tumor progression for brain metastases treated with Gamma knife radiosurgery. Methods: The images used to develop the model were T1 post-contrast MR scans from 71 patients who had had pathologic confirmation of necrosis or progression; 1 lesion was identified per patient (17 necrosis and 54 progression). Radiomics features were extracted from 2 images at 2 time points per patient, both obtained prior to resection. Each lesion was manually contoured on each image, and 282 radiomics features were calculated for each lesion. The correlation for each radiomics feature between two time points was calculated within each group to identify a subset of features with distinct values between two groups. The delta of this subset of radiomics features, characterizing changes from the earlier time to the later one, was included as a covariate to build a prediction model using support vector machines with a cubic polynomial kernel function. The model was evaluated with a 10-fold cross-validation. Results: Forty radiomics features were selected based on consistent correlation values of approximately 0 for the necrosis group and >0.2 for the progression group. In performing the 10-fold cross-validation, we narrowed this number down to 11 delta radiomics features for the model. This 11-delta-feature model showed an overall prediction accuracy of 83.1%, with a true positive rate of 58.8% in predicting necrosis and 90.7% for predicting tumor progression. The area under the curve for the prediction model was 0.79. Conclusion: These delta radiomics features extracted from MR scans showed potential for distinguishing radiation necrosis from tumor progression. This tool may be a useful, noninvasive means of determining the status of an enlarging lesion after radiosurgery, aiding decision-making regarding surgical resection versus conservative medical

TU-D-207B-01: A Prediction Model for Distinguishing Radiation Necrosis From Tumor Progression After Gamma Knife Radiosurgery Based On Radiomics Features From MR Images

Energy Technology Data Exchange (ETDEWEB)

Zhang, Z [Central South University Xiangya Hospital, Changsha, Hunan (China); MD Anderson Cancer Center, Houston, TX (United States); Ho, A [University of Houston, Houston, TX (United States); Wang, X; Brown, P; Guha-Thakurta, N; Ferguson, S; Fave, X; Zhang, L; Mackin, D; Court, L; Li, J; Yang, J [MD Anderson Cancer Center, Houston, TX (United States)

2016-06-15

Purpose: To develop and validate a prediction model using radiomics features extracted from MR images to distinguish radiation necrosis from tumor progression for brain metastases treated with Gamma knife radiosurgery. Methods: The images used to develop the model were T1 post-contrast MR scans from 71 patients who had had pathologic confirmation of necrosis or progression; 1 lesion was identified per patient (17 necrosis and 54 progression). Radiomics features were extracted from 2 images at 2 time points per patient, both obtained prior to resection. Each lesion was manually contoured on each image, and 282 radiomics features were calculated for each lesion. The correlation for each radiomics feature between two time points was calculated within each group to identify a subset of features with distinct values between two groups. The delta of this subset of radiomics features, characterizing changes from the earlier time to the later one, was included as a covariate to build a prediction model using support vector machines with a cubic polynomial kernel function. The model was evaluated with a 10-fold cross-validation. Results: Forty radiomics features were selected based on consistent correlation values of approximately 0 for the necrosis group and >0.2 for the progression group. In performing the 10-fold cross-validation, we narrowed this number down to 11 delta radiomics features for the model. This 11-delta-feature model showed an overall prediction accuracy of 83.1%, with a true positive rate of 58.8% in predicting necrosis and 90.7% for predicting tumor progression. The area under the curve for the prediction model was 0.79. Conclusion: These delta radiomics features extracted from MR scans showed potential for distinguishing radiation necrosis from tumor progression. This tool may be a useful, noninvasive means of determining the status of an enlarging lesion after radiosurgery, aiding decision-making regarding surgical resection versus conservative medical

Enhanced expression of melanoma progression markers in mouse model of sleep apnea

Directory of Open Access Journals (Sweden)

S. Perini

2016-07-01

Full Text Available Introduction: Obstructive sleep apnea has been associated with higher cancer incidence and mortality. Increased melanoma aggressivity was reported in obstructive sleep apnea patients. Mice exposed to intermittent hypoxia (IH mimicking sleep apnea show enhanced melanoma growth. Markers of melanoma progression have not been investigated in this model. Objective: The present study examined whether IH affects markers of melanoma tumor progression. Methods: Mice were exposed to isocapnic IH to a nadir of 8% oxygen fraction for 14 days. One million B16F10 melanoma cells were injected subcutaneously. Immunohistochemistry staining for Ki-67, PCNA, S100-beta, HMB-45, Melan-A, TGF-beta, Caspase-1, and HIF-1alpha were quantified using Photoshop. Results: Percentage of positive area stained was higher in IH than sham IH group for Caspase-1, Ki-67, PCNA, and Melan-A. The greater expression of several markers of tumor aggressiveness, including markers of ribosomal RNA transcription (Ki-67 and of DNA synthesis (PCNA, in mice exposed to isocapnic IH than in controls provide molecular evidence for a apnea–cancer relationship. Conclusions: These findings have potential repercussions in the understanding of differences in clinical course of tumors in obstructive sleep apnea patients. Further investigation is necessary to confirm mechanisms of these descriptive results. Keywords: Apnea, Melanoma, Biological markers

A whole-brain computational modeling approach to explain the alterations in resting-state functional connectivity during progression of Alzheimer's disease

Directory of Open Access Journals (Sweden)

Murat Demirtaş

2017-01-01

Full Text Available Alzheimer's disease (AD is the most common dementia with dramatic consequences. The research in structural and functional neuroimaging showed altered brain connectivity in AD. In this study, we investigated the whole-brain resting state functional connectivity (FC of the subjects with preclinical Alzheimer's disease (PAD, mild cognitive impairment due to AD (MCI and mild dementia due to Alzheimer's disease (AD, the impact of APOE4 carriership, as well as in relation to variations in core AD CSF biomarkers. The synchronization in the whole-brain was monotonously decreasing during the course of the disease progression. Furthermore, in AD patients we found widespread significant decreases in functional connectivity (FC strengths particularly in the brain regions with high global connectivity. We employed a whole-brain computational modeling approach to study the mechanisms underlying these alterations. To characterize the causal interactions between brain regions, we estimated the effective connectivity (EC in the model. We found that the significant EC differences in AD were primarily located in left temporal lobe. Then, we systematically manipulated the underlying dynamics of the model to investigate simulated changes in FC based on the healthy control subjects. Furthermore, we found distinct patterns involving CSF biomarkers of amyloid-beta (Aβ1−42 total tau (t-tau and phosphorylated tau (p-tau. CSF Aβ1−42 was associated to the contrast between healthy control subjects and clinical groups. Nevertheless, tau CSF biomarkers were associated to the variability in whole-brain synchronization and sensory integration regions. These associations were robust across clinical groups, unlike the associations that were found for CSF Aβ1−42. APOE4 carriership showed no significant correlations with the connectivity measures.

Communication of nuclear data progress

Energy Technology Data Exchange (ETDEWEB)

NONE

2006-07-15

This is the 30th issue of Communication of Nuclear Data Progress (CNDP), in which the progress and achievements in nuclear data field in China during 2004 are carried. It includes the evaluations and model calculations of neutron data for n+{sup 31}P, {sup 59}Co, {sup 92-106}Mo, {sup Nat-116}Cd, {sup 233}U and the covariance data evaluation of experimental data for {sup 27}Al, update the decay data for radionuclide {sup 7}Be. Some results of studies for nuclear evaluation tool and model are also included in this issue, i.e. reaction mechanism studies of {sup 5}He, a new method of evaluating the discrepant data, linear fit of correlative data by least squared method et al. (authors)

L-carnitine prevents progression of non-alcoholic steatohepatitis in a mouse model with upregulation of mitochondrial pathway.

Directory of Open Access Journals (Sweden)

Hisashi Ishikawa

Full Text Available Non-alcoholic steatohepatitis (NASH is a severe form of non-alcoholic fatty liver disease characterized by lobular inflammation, hepatocellular ballooning, and fibrosis with an inherent risk for progression to cirrhosis and hepatocellular carcinoma (HCC. Mitochondrial dysfunction appears to play a role in the progression from simple steatosis to NASH. L-carnitine (L-b-hydroxy-g-N-trimethylaminobutyric acid, an essential nutrient that converts fat into energy in mitochondria, has been shown to ameliorate liver damage. The aim of the present study was to explore the preventive and therapeutic effect of L-carnitine in NASH model mice. Eight-week-old male STAM mice, a NASH-cirrhosis-hepatocarcinogenic model, were divided into 3 experimental groups and fed as follows: 1 high-fat diet (HFD (control group; 2 HFD mixed with 0.28% L-carnitine (L-carnitine group; and 3 HFD mixed with 0.01% α-tocopherol (α-tocopherol group. After 4 or 8 weeks, mice were sacrificed. Blood samples and livers were collected, and hepatic tumors were counted and measured. Livers were subjected to histological study, immunohistochemical staining of 4-hydroxynonenal and ferritin, determination of 8-OHdG levels, mRNA and protein expressions for multiple genes, and metabolomic analysis. The intestinal microbiome was also analyzed. L-carnitine increased hepatic expression of genes related to long-chain fatty acid transport, mitochondrial β-oxidation, and antioxidant enzymes following suppression of hepatic oxidative stress markers and inflammatory cytokines in NASH, and mice treated with L-carnitine developed fewer liver tumors. Although α-tocopherol resulted in NASH improvement in the same manner as L-carnitine, it increased periodontitis-related microbiotic changes and hepatic iron transport-related gene expression and led to less effective for anti-hepatocarcinogenesis. Conclusion: L-carnitine prevents progression of non-alcoholic steatohepatitis in a mouse model by

Ocular hemodynamics and glaucoma: the role of mathematical modeling.

Science.gov (United States)

Harris, Alon; Guidoboni, Giovanna; Arciero, Julia C; Amireskandari, Annahita; Tobe, Leslie A; Siesky, Brent A

2013-01-01

To discuss the role of mathematical modeling in studying ocular hemodynamics, with a focus on glaucoma. We reviewed recent literature on glaucoma, ocular blood flow, autoregulation, the optic nerve head, and the use of mathematical modeling in ocular circulation. Many studies suggest that alterations in ocular hemodynamics play a significant role in the development, progression, and incidence of glaucoma. Although there is currently a limited number of studies involving mathematical modeling of ocular blood flow, regulation, and diseases (such as glaucoma), preliminary modeling work shows the potential of mathematical models to elucidate the mechanisms that contribute most significantly to glaucoma progression. Mathematical modeling is a useful tool when used synergistically with clinical and laboratory data in the study of ocular blood flow and glaucoma. The development of models to investigate the relationship between ocular hemodynamic alterations and glaucoma progression will provide a unique and useful method for studying the pathophysiology of glaucoma.

Are Forecast Updates Progressive?

NARCIS (Netherlands)

C-L. Chang (Chia-Lin); Ph.H.B.F. Franses (Philip Hans); M.J. McAleer (Michael)

2010-01-01

textabstractMacro-economic forecasts typically involve both a model component, which is replicable, as well as intuition, which is non-replicable. Intuition is expert knowledge possessed by a forecaster. If forecast updates are progressive, forecast updates should become more accurate, on average,

Severe Accident Progression and Consequence Assessment Methodology Upgrades in ISAAC for Wolsong CANDU6

International Nuclear Information System (INIS)

Song, Y.M.; Kim, D.H.; Nijhawan, Sunil

2015-01-01

Amongst the applications of integrated severe accident analysis codes like ISAAC, the principal are to a) help develop an understanding of the severe accident progression and its consequences; b) support the design of mitigation measures by providing for them the state of the reactor following an accident; and c) to provide a training platform for accident management actions. After Fukushima accident there is an increased awareness of the need to implement effective and appropriate mitigation measures and empower the operators with training and understanding about severe accident progression and control opportunities. An updated code with reduced uncertainties can better serve these needs of the utility making decisions about mitigation measures and corrective actions. Optimal deployment of systems such as PARS and filtered containment venting require information on reactor transients for a number of critical parameters. Thus there is a greater consensus now for a demonstrated ability to perform accident progression and consequence assessment analyses with reduced uncertainties. Analyses must now provide source term transients that represent the best in available understanding and so meaningfully support mitigation measures. This requires removal of known simplifications and inclusion of all quantifiable and risk significant phenomena. Advances in understanding of CANDU6 severe accident progression reflected in the severe accident integrated code ROSHNI are being incorporated into ISAAC using CANDU specific component and system models developed and verified for Wolsong CANDU 6 reactors. A significant and comprehensive upgrade of core behavior models is being implemented in ISAAC to properly reflect the large variability amongst fuel channels in feeder geometry, fuel thermal powers and burnup. The paper summarizes the models that have been added and provides some results to illustrate code capabilities. ISAAC is being updated to meet the current requirements and

Severe Accident Progression and Consequence Assessment Methodology Upgrades in ISAAC for Wolsong CANDU6

Energy Technology Data Exchange (ETDEWEB)

Song, Y.M.; Kim, D.H. [KAERI, Daejeon (Korea, Republic of); Nijhawan, Sunil [Prolet Inc. 98 Burbank Drive, Toronto (Canada)

2015-05-15

Amongst the applications of integrated severe accident analysis codes like ISAAC, the principal are to a) help develop an understanding of the severe accident progression and its consequences; b) support the design of mitigation measures by providing for them the state of the reactor following an accident; and c) to provide a training platform for accident management actions. After Fukushima accident there is an increased awareness of the need to implement effective and appropriate mitigation measures and empower the operators with training and understanding about severe accident progression and control opportunities. An updated code with reduced uncertainties can better serve these needs of the utility making decisions about mitigation measures and corrective actions. Optimal deployment of systems such as PARS and filtered containment venting require information on reactor transients for a number of critical parameters. Thus there is a greater consensus now for a demonstrated ability to perform accident progression and consequence assessment analyses with reduced uncertainties. Analyses must now provide source term transients that represent the best in available understanding and so meaningfully support mitigation measures. This requires removal of known simplifications and inclusion of all quantifiable and risk significant phenomena. Advances in understanding of CANDU6 severe accident progression reflected in the severe accident integrated code ROSHNI are being incorporated into ISAAC using CANDU specific component and system models developed and verified for Wolsong CANDU 6 reactors. A significant and comprehensive upgrade of core behavior models is being implemented in ISAAC to properly reflect the large variability amongst fuel channels in feeder geometry, fuel thermal powers and burnup. The paper summarizes the models that have been added and provides some results to illustrate code capabilities. ISAAC is being updated to meet the current requirements and

Histone Demethylase RBP2 Is Critical for Breast Cancer Progression and Metastasis

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Jian Cao

2014-03-01

Full Text Available Metastasis is a major clinical challenge for cancer treatment. Emerging evidence suggests that aberrant epigenetic modifications contribute significantly to tumor formation and progression. However, the drivers and roles of such epigenetic changes in tumor metastasis are still poorly understood. Using bioinformatic analysis of human breast cancer gene-expression data sets, we identified histone demethylase RBP2 as a putative mediator of metastatic progression. By using both human breast cancer cells and genetically engineered mice, we demonstrated that RBP2 is critical for breast cancer metastasis to the lung in multiple in vivo models. Mechanistically, RBP2 promotes metastasis as a pleiotropic positive regulator of many metastasis genes, including TNC. In addition, RBP2 loss suppresses tumor formation in MMTV-neu transgenic mice. These results suggest that therapeutic targeting of RBP2 is a potential strategy for inhibition of tumor progression and metastasis.

Zebrafish as a model to assess cancer heterogeneity, progression and relapse

Science.gov (United States)

Blackburn, Jessica S.; Langenau, David M.

2014-01-01

Clonal evolution is the process by which genetic and epigenetic diversity is created within malignant tumor cells. This process culminates in a heterogeneous tumor, consisting of multiple subpopulations of cancer cells that often do not contain the same underlying mutations. Continuous selective pressure permits outgrowth of clones that harbor lesions that are capable of enhancing disease progression, including those that contribute to therapy resistance, metastasis and relapse. Clonal evolution and the resulting intratumoral heterogeneity pose a substantial challenge to biomarker identification, personalized cancer therapies and the discovery of underlying driver mutations in cancer. The purpose of this Review is to highlight the unique strengths of zebrafish cancer models in assessing the roles that intratumoral heterogeneity and clonal evolution play in cancer, including transgenesis, imaging technologies, high-throughput cell transplantation approaches and in vivo single-cell functional assays. PMID:24973745

Progress and bottleneck in induced pluripotency

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Zhang Zhen-Ning

2012-07-01

Full Text Available Abstract With their capability to undergo unlimited self-renewal and to differentiate into all cell types in the body, induced pluripotent stem cells (iPSCs, reprogrammed from somatic cells of individual patients with defined factors, have unlimited potential in cell therapy and in modeling complex human diseases. Significant progress has been achieved to improve the safety of iPSCs and the reprogramming efficiency. To avoid the cancer risk and spontaneous reactivation of the reprogramming factors associated with the random integration of viral vectors into the genome, several approaches have been established to deliver the reprogramming factors into the somatic cells without inducing genetic modification. In addition, a panel of small molecule compounds, many of which targeting the epigenetic machinery, have been identified to increase the reprogramming efficiency. Despite these progresses, recent studies have identified genetic and epigenetic abnormalities of iPSCs as well as the immunogenicity of some cells derived from iPSCs. In addition, due to the oncogenic potential of the reprogramming factors and the reprogramming-induced DNA damage, the critical tumor suppressor pathways such as p53 and ARF are activated to act as the checkpoints that suppress induced pluripotency. The inactivation of these tumor suppression pathways even transiently during reprogramming processes could have significant adverse impact on the genome integrity. These safety concerns must be resolved to improve the feasibility of the clinic development of iPSCs into human cell therapy.

ARMA modeling of stochastic processes in nuclear reactor with significant detection noise

International Nuclear Information System (INIS)

Zavaljevski, N.

1992-01-01

The theoretical basis of ARMA modelling of stochastic processes in nuclear reactor was presented in a previous paper, neglecting observational noise. The identification of real reactor data indicated that in some experiments the detection noise is significant. Thus a more rigorous theoretical modelling of stochastic processes in nuclear reactor is performed. Starting from the fundamental stochastic differential equations of the Langevin type for the interaction of the detector with neutron field, a new theoretical ARMA model is developed. preliminary identification results confirm the theoretical expectations. (author)

Achieving efficient RNAi therapy: progress and challenges

Directory of Open Access Journals (Sweden)

Kun Gao

2013-07-01

Full Text Available RNA interference (RNAi has been harnessed to produce a new class of drugs for treatment of various diseases. This review summarizes the most important parameters that govern the silencing efficiency and duration of the RNAi effect such as small interfering RNA (siRNA stability and modification, the type of delivery system and particle sizing methods. It also discusses the predominant barriers for siRNA delivery, such as off-target effects and introduces internalization, endosomal escape and mathematical modeling in RNAi therapy and combinatorial RNAi. At present, effective delivery of RNAi therapeutics in vivo remains a challenge although significant progress has been made in this field.

Impacts of fresh lime juice and peel on atherosclerosis progression in an animal model.

Science.gov (United States)

Boshtam, Maryam; Asgary, Sedigheh; Moshtaghian, Jamal; Naderi, Gholamali; Jafari-Dinani, Narges

2013-11-01

The main protective role of antioxidants in the progression of atherosclerosis has been shown in some studies. Therefore, this project evaluated the effects of Citrus aurantifolia (Christm) juice and peel on antioxidant activity and atherosclerosis progression in rabbits receiving a hypercholesterolemic diet. Forty white New Zealand male rabbits were randomly allocated to four groups. All groups were on hypercholesterolemic diet for two months. While the first group was considered as the hypercholesterolemic control, groups 2 and 3 (intervention groups) received 5 ml/day lime juice and 1 g/day dried lime peel powder, respectively. Group 4 was fed a normal diet (normal control). Before and after the study, weight was measured and a fasting blood specimen was taken from the rabbits. Serum lipids analyses and antioxidant activity evaluations were then performed. The rabbits' aorta and coronary arteries were separated and the presence of fatty streaks was studied. Comparing to the hypercholesterolemic control group (-25.2 ± 7.0), only the plasma total antioxidant capacity change was significantly more in rabbits supplemented with lime juice (16.3 ± 14.7) and peel (8.6 ± 7.1) (P = 0.008). The presence of fatty streaks in coronary arteries and aorta of the intervention groups [juice (0.2 ± 0.01); peel (0.0 ± 0.00)] was significantly decreased compared to the hypercholesterolemic control group (1.2 ± 0.4) (P lime peel is more effective than lime juice.

A Progressive Damage Model for Predicting Permanent Indentation and Impact Damage in Composite Laminates

Science.gov (United States)

Ji, Zhaojie; Guan, Zhidong; Li, Zengshan

2017-10-01

In this paper, a progressive damage model was established on the basis of ABAQUS software for predicting permanent indentation and impact damage in composite laminates. Intralaminar and interlaminar damage was modelled based on the continuum damage mechanics (CDM) in the finite element model. For the verification of the model, low-velocity impact tests of quasi-isotropic laminates with material system of T300/5228A were conducted. Permanent indentation and impact damage of the laminates were simulated and the numerical results agree well with the experiments. It can be concluded that an obvious knee point can be identified on the curve of the indentation depth versus impact energy. Matrix cracking and delamination develops rapidly with the increasing impact energy, while considerable amount of fiber breakage only occurs when the impact energy exceeds the energy corresponding to the knee point. Predicted indentation depth after the knee point is very sensitive to the parameter μ which is proposed in this paper, and the acceptable value of this parameter is in range from 0.9 to 1.0.

Clinical and MRI models predicting amyloid deposition in progressive aphasia and apraxia of speech.

Science.gov (United States)

Whitwell, Jennifer L; Weigand, Stephen D; Duffy, Joseph R; Strand, Edythe A; Machulda, Mary M; Senjem, Matthew L; Gunter, Jeffrey L; Lowe, Val J; Jack, Clifford R; Josephs, Keith A

2016-01-01

Beta-amyloid (Aβ) deposition can be observed in primary progressive aphasia (PPA) and progressive apraxia of speech (PAOS). While it is typically associated with logopenic PPA, there are exceptions that make predicting Aβ status challenging based on clinical diagnosis alone. We aimed to determine whether MRI regional volumes or clinical data could help predict Aβ deposition. One hundred and thirty-nine PPA (n = 97; 15 agrammatic, 53 logopenic, 13 semantic and 16 unclassified) and PAOS (n = 42) subjects were prospectively recruited into a cross-sectional study and underwent speech/language assessments, 3.0 T MRI and C11-Pittsburgh Compound B PET. The presence of Aβ was determined using a 1.5 SUVR cut-point. Atlas-based parcellation was used to calculate gray matter volumes of 42 regions-of-interest across the brain. Penalized binary logistic regression was utilized to determine what combination of MRI regions, and what combination of speech and language tests, best predicts Aβ (+) status. The optimal MRI model and optimal clinical model both performed comparably in their ability to accurately classify subjects according to Aβ status. MRI accurately classified 81% of subjects using 14 regions. Small left superior temporal and inferior parietal volumes and large left Broca's area volumes were particularly predictive of Aβ (+) status. Clinical scores accurately classified 83% of subjects using 12 tests. Phonological errors and repetition deficits, and absence of agrammatism and motor speech deficits were particularly predictive of Aβ (+) status. In comparison, clinical diagnosis was able to accurately classify 89% of subjects. However, the MRI model performed well in predicting Aβ deposition in unclassified PPA. Clinical diagnosis provides optimum prediction of Aβ status at the group level, although regional MRI measurements and speech and language testing also performed well and could have advantages in predicting Aβ status in unclassified PPA subjects.

Clinical and MRI models predicting amyloid deposition in progressive aphasia and apraxia of speech

Directory of Open Access Journals (Sweden)

Jennifer L. Whitwell

2016-01-01

Full Text Available Beta-amyloid (Aβ deposition can be observed in primary progressive aphasia (PPA and progressive apraxia of speech (PAOS. While it is typically associated with logopenic PPA, there are exceptions that make predicting Aβ status challenging based on clinical diagnosis alone. We aimed to determine whether MRI regional volumes or clinical data could help predict Aβ deposition. One hundred and thirty-nine PPA (n = 97; 15 agrammatic, 53 logopenic, 13 semantic and 16 unclassified and PAOS (n = 42 subjects were prospectively recruited into a cross-sectional study and underwent speech/language assessments, 3.0 T MRI and C11-Pittsburgh Compound B PET. The presence of Aβ was determined using a 1.5 SUVR cut-point. Atlas-based parcellation was used to calculate gray matter volumes of 42 regions-of-interest across the brain. Penalized binary logistic regression was utilized to determine what combination of MRI regions, and what combination of speech and language tests, best predicts Aβ (+ status. The optimal MRI model and optimal clinical model both performed comparably in their ability to accurately classify subjects according to Aβ status. MRI accurately classified 81% of subjects using 14 regions. Small left superior temporal and inferior parietal volumes and large left Broca's area volumes were particularly predictive of Aβ (+ status. Clinical scores accurately classified 83% of subjects using 12 tests. Phonological errors and repetition deficits, and absence of agrammatism and motor speech deficits were particularly predictive of Aβ (+ status. In comparison, clinical diagnosis was able to accurately classify 89% of subjects. However, the MRI model performed well in predicting Aβ deposition in unclassified PPA. Clinical diagnosis provides optimum prediction of Aβ status at the group level, although regional MRI measurements and speech and language testing also performed well and could have advantages in predicting Aβ status in unclassified

A novel quantitative model of cell cycle progression based on cyclin-dependent kinases activity and population balances.

Science.gov (United States)

Pisu, Massimo; Concas, Alessandro; Cao, Giacomo

2015-04-01

Cell cycle regulates proliferative cell capacity under normal or pathologic conditions, and in general it governs all in vivo/in vitro cell growth and proliferation processes. Mathematical simulation by means of reliable and predictive models represents an important tool to interpret experiment results, to facilitate the definition of the optimal operating conditions for in vitro cultivation, or to predict the effect of a specific drug in normal/pathologic mammalian cells. Along these lines, a novel model of cell cycle progression is proposed in this work. Specifically, it is based on a population balance (PB) approach that allows one to quantitatively describe cell cycle progression through the different phases experienced by each cell of the entire population during its own life. The transition between two consecutive cell cycle phases is simulated by taking advantage of the biochemical kinetic model developed by Gérard and Goldbeter (2009) which involves cyclin-dependent kinases (CDKs) whose regulation is achieved through a variety of mechanisms that include association with cyclins and protein inhibitors, phosphorylation-dephosphorylation, and cyclin synthesis or degradation. This biochemical model properly describes the entire cell cycle of mammalian cells by maintaining a sufficient level of detail useful to identify check point for transition and to estimate phase duration required by PB. Specific examples are discussed to illustrate the ability of the proposed model to simulate the effect of drugs for in vitro trials of interest in oncology, regenerative medicine and tissue engineering. Copyright © 2015 Elsevier Ltd. All rights reserved.

The quest for significance model of radicalization: implications for the management of terrorist detainees.

Science.gov (United States)

Dugas, Michelle; Kruglanski, Arie W

2014-01-01

Radicalization and its culmination in terrorism represent a grave threat to the security and stability of the world. A related challenge is effective management of extremists who are detained in prison facilities. The major aim of this article is to review the significance quest model of radicalization and its implications for management of terrorist detainees. First, we review the significance quest model, which elaborates on the roles of motivation, ideology, and social processes in radicalization. Secondly, we explore the implications of the model in relation to the risks of prison radicalization. Finally, we analyze the model's implications for deradicalization strategies and review preliminary evidence for the effectiveness of a rehabilitation program targeting components of the significance quest. Based on this evidence, we argue that the psychology of radicalization provides compelling reason for the inclusion of deradicalization efforts as an essential component of the management of terrorist detainees. Copyright © 2014 John Wiley & Sons, Ltd.

Co-firing biomass and coal-progress in CFD modelling capabilities

DEFF Research Database (Denmark)

Kær, Søren Knudsen; Rosendahl, Lasse Aistrup; Yin, Chungen

2005-01-01

This paper discusses the development of user defined FLUENT™ sub models to improve the modelling capabilities in the area of large biomass particle motion and conversion. Focus is put on a model that includes the influence from particle size and shape on the reactivity by resolving intra-particle......This paper discusses the development of user defined FLUENT™ sub models to improve the modelling capabilities in the area of large biomass particle motion and conversion. Focus is put on a model that includes the influence from particle size and shape on the reactivity by resolving intra......-particle gradients. The advanced reaction model predicts moisture and volatiles release characteristics that differ significantly from those found from a 0-dimensional model partly due to the processes occurring in parallel rather than sequentially. This is demonstrated for a test case that illustrates single...

Progressive irreversible hearing loss is caused by stria vascularis degeneration in an Slc26a4-insufficient mouse model of large vestibular aqueduct syndrome.

Science.gov (United States)

Ito, T; Nishio, A; Wangemann, P; Griffith, A J

2015-12-03

Hearing loss of patients with enlargement of the vestibular aqueduct (EVA) can fluctuate or progress, with overall downward progression. The most common detectable cause of EVA is mutations of SLC26A4. We previously described a transgenic Slc26a4-insufficient mouse model of EVA in which Slc26a4 expression is controlled by doxycycline administration. Mice that received doxycycline from conception until embryonic day 17.5 (DE17.5; doxycycline discontinued at embryonic day 17.5) had fluctuating hearing loss between 1 and 6 months of age with an overall downward progression after 6 months of age. In this study, we characterized the cochlear functional and structural changes underlying irreversible hearing loss in DE17.5 mice at 12 months of age. The endocochlear potential was decreased and inversely correlated with auditory brainstem response thresholds. The stria vascularis was thickened and edematous in ears with less severe hearing loss, and thinned and atrophic in ears with more severe hearing loss. There were pathologic changes in marginal cell morphology and gene expression that were not observed at 3 months. We conclude that strial dysfunction and degeneration are the primary causes of irreversible progressive hearing loss in our Slc26a4-insufficient mouse model of EVA. This model of primary strial atrophy may be used to explore the mechanisms of progressive hearing loss due to strial dysfunction. Published by Elsevier Ltd.

Cloud ice: A climate model challenge with signs and expectations of progress

Science.gov (United States)

Waliser, Duane E.; Li, Jui-Lin F.; Woods, Christopher P.; Austin, Richard T.; Bacmeister, Julio; Chern, Jiundar; Del Genio, Anthony; Jiang, Jonathan H.; Kuang, Zhiming; Meng, Huan; Minnis, Patrick; Platnick, Steve; Rossow, William B.; Stephens, Graeme L.; Sun-Mack, Szedung; Tao, Wei-Kuo; Tompkins, Adrian M.; Vane, Deborah G.; Walker, Christopher; Wu, Dong

2009-04-01

Present-day shortcomings in the representation of upper tropospheric ice clouds in general circulation models (GCMs) lead to errors in weather and climate forecasts as well as account for a source of uncertainty in climate change projections. An ongoing challenge in rectifying these shortcomings has been the availability of adequate, high-quality, global observations targeting ice clouds and related precipitating hydrometeors. In addition, the inadequacy of the modeled physics and the often disjointed nature between model representation and the characteristics of the retrieved/observed values have hampered GCM development and validation efforts from making effective use of the measurements that have been available. Thus, even though parameterizations in GCMs accounting for cloud ice processes have, in some cases, become more sophisticated in recent years, this development has largely occurred independently of the global-scale measurements. With the relatively recent addition of satellite-derived products from Aura/Microwave Limb Sounder (MLS) and CloudSat, there are now considerably more resources with new and unique capabilities to evaluate GCMs. In this article, we illustrate the shortcomings evident in model representations of cloud ice through a comparison of the simulations assessed in the Intergovernmental Panel on Climate Change Fourth Assessment Report, briefly discuss the range of global observational resources that are available, and describe the essential components of the model parameterizations that characterize their "cloud" ice and related fields. Using this information as background, we (1) discuss some of the main considerations and cautions that must be taken into account in making model-data comparisons related to cloud ice, (2) illustrate present progress and uncertainties in applying satellite cloud ice (namely from MLS and CloudSat) to model diagnosis, (3) show some indications of model improvements, and finally (4) discuss a number of

Central Blood Pressure and Chronic Kidney Disease Progression

Directory of Open Access Journals (Sweden)

Debbie L. Cohen

2011-01-01

Full Text Available Hypertension, diabetes, and proteinuria are well-recognized risk factors for progressive kidney function loss. However, despite excellent antihypertensive and antidiabetic drug therapies, which also often lower urinary protein excretion, there remains a significant reservoir of patients with chronic kidney disease who are at high risk for progression to end-stage kidney disease. This has led to the search for less traditional cardiovascular risk factors that will help stratify patients at risk for more rapid kidney disease progression. Among these are noninvasive estimates of vascular structure and function. Arterial stiffness, manifested by the pulse wave velocity in the aorta, has been established in a number of studies as a significant risk factor for kidney disease progression and cardiovascular endpoints. Much less well studied in chronic kidney disease are measures of central arterial pressures. In this paper we cover the physiology behind the generation of the central pulse wave contour and the studies available using these approaches and conclude with some speculations on the rationale for why measurements of central pressure may be informative for the study of chronic kidney disease progression.

[Riboflavin UVA crosslinking in progressive keratoconus].

Science.gov (United States)

Maier, P; Reinhard, T

2017-06-01

In patients with keratoconus, a progressive, ectatic disease of the cornea, the shape of the cornea is continuously changing leading to a reduction in visual acuity by progressive myopia and more and more (irregular) astigmatism. The symptomatic treatment consists of the prescription of glasses or special gas-permeable rigid contact lenses. Corneal tomography is generally used for diagnosis. After initial diagnosis of keratoconus, regular tomographic follow-ups should be performed. If clinically significant progression is found and confirmed by repeated measurements, riboflavin UVA collagen crosslinking should be offered to the patients. The aim of riboflavin UVA collagen crosslinking is to halt the progression of the disease to avoid further complications. The therapeutic principle is a combined effect of the photosensitizer riboflavin and UVA light. This stiffening effect of the corneal tissue halts the progression of keratoconus. The efficacy of this treatment has been demonstrated in various randomized, controlled trials.

Metabolic Disturbances in the Striatum and Substantia Nigra in the Onset and Progression of MPTP-Induced Parkinsonism Model

Directory of Open Access Journals (Sweden)

Yi Lu

2018-02-01

Full Text Available Metabolic confusion has been linked to the pathogenesis of Parkinson's disease (PD, while the dynamic changes associated with the onset and progression of PD remain unclear. Herein, dynamic changes in metabolites were detected from the initiation to the development of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP -induced Parkinsonism model to elucidate its potential metabolic mechanism. Ex vivo1H nuclear magnetic resonance (NMR spectroscopy was used to measure metabolite changes in the striatum and substantia nigra (SN of mice at 1, 7, and 21 days after injection of MPTP. Metabolomic analysis revealed a clear separation of the overall metabolites between PD and control mice at different time points. Glutamate (Glu in the striatum was significantly elevated at induction PD day 1 mice, which persisted to day 21. N-acetylaspartate (NAA increased in the striatum of induction PD mice on days 1 and 7, but no significant difference was found in striatum on day 21. Myo-Inositol (mI and taurine (Tau were also disturbed in the striatum in induction PD day 1 mice. Additionally, key enzymes in the glutamate-glutamine cycle were significantly increased in PD mice. These findings suggest that neuron loss and motor function impairment in induction PD mice may be linked to overactive glutamate-glutamine cycle and altered membrane metabolism.

Predicting the multi-domain progression of Parkinson's disease: a Bayesian multivariate generalized linear mixed-effect model.

Science.gov (United States)

Wang, Ming; Li, Zheng; Lee, Eun Young; Lewis, Mechelle M; Zhang, Lijun; Sterling, Nicholas W; Wagner, Daymond; Eslinger, Paul; Du, Guangwei; Huang, Xuemei

2017-09-25

It is challenging for current statistical models to predict clinical progression of Parkinson's disease (PD) because of the involvement of multi-domains and longitudinal data. Past univariate longitudinal or multivariate analyses from cross-sectional trials have limited power to predict individual outcomes or a single moment. The multivariate generalized linear mixed-effect model (GLMM) under the Bayesian framework was proposed to study multi-domain longitudinal outcomes obtained at baseline, 18-, and 36-month. The outcomes included motor, non-motor, and postural instability scores from the MDS-UPDRS, and demographic and standardized clinical data were utilized as covariates. The dynamic prediction was performed for both internal and external subjects using the samples from the posterior distributions of the parameter estimates and random effects, and also the predictive accuracy was evaluated based on the root of mean square error (RMSE), absolute bias (AB) and the area under the receiver operating characteristic (ROC) curve. First, our prediction model identified clinical data that were differentially associated with motor, non-motor, and postural stability scores. Second, the predictive accuracy of our model for the training data was assessed, and improved prediction was gained in particularly for non-motor (RMSE and AB: 2.89 and 2.20) compared to univariate analysis (RMSE and AB: 3.04 and 2.35). Third, the individual-level predictions of longitudinal trajectories for the testing data were performed, with ~80% observed values falling within the 95% credible intervals. Multivariate general mixed models hold promise to predict clinical progression of individual outcomes in PD. The data was obtained from Dr. Xuemei Huang's NIH grant R01 NS060722 , part of NINDS PD Biomarker Program (PDBP). All data was entered within 24 h of collection to the Data Management Repository (DMR), which is publically available ( https://pdbp.ninds.nih.gov/data-management ).

Longitudinal analysis of progression in glaucoma using spectral-domain optical coherence tomography.

Science.gov (United States)

Wessel, Julia M; Horn, Folkert K; Tornow, Ralf P; Schmid, Matthias; Mardin, Christian Y; Kruse, Friedrich E; Juenemann, Anselm G; Laemmer, Robert

2013-05-01

To compare the longitudinal loss of RNFL thickness measurements by SD-OCT in healthy individuals and glaucoma patients with or without progression concerning optic disc morphology. A total of 62 eyes, comprising 38 glaucomatous eyes with open angle glaucoma and 24 healthy controls, were included in the study (Erlangen Glaucoma Registry, NTC00494923). All patients were investigated annually over a period of 3 years by Spectralis SD-OCT measuring peripapillary RNFL thickness. By masked comparative analysis of photographs, the eyes were classified into nonprogressive and progressive glaucoma cases. Longitudinal loss of RNFL thickness was compared with morphological changes of optic disc morphology. Mixed model analysis of annual OCT scans revealed an estimated annual decrease of the RNFL thickness by 2.12 μm in glaucoma eyes with progression, whereas glaucoma eyes without progression in optic disc morphology lost 1.18 μm per year in RNFL thickness (P = 0.002). The rate of change in healthy eyes was 0.60 μm and thereby also significantly lower than in glaucoma eyes with progression (P < 0.001). The intrasession variability of three successive measurements without head repositioning was 1.5 ± 0.7 μm. The loss of mean RNFL thickness exceeded the intrasession variability in 60% of nonprogressive eyes, and in 85% of progressive eyes after 3 years. LONGITUDINAL MEASUREMENTS OF RNFL THICKNESS USING SD-OCT SHOW A MORE PRONOUNCED REDUCTION OF RNFL THICKNESS IN PATIENTS WITH PROGRESSION COMPARED WITH PATIENTS WITHOUT PROGRESSION IN GLAUCOMATOUS OPTIC DISC CHANGES. (www.clinicaltrials.gov number, NTC00494923.).

Environmentally-induced malignancies: An in vivo model to evaluate the health impact of chemicals in mixed waste. 1997 annual progress report

International Nuclear Information System (INIS)

Pallavicini, M.

1997-01-01

'Occupational or environmental exposure to organic ligands, solvents, fuel hydrocarbons, and polychlorinated biphenyls is linked to increased risk of developing leukemia, a blood cancer. The long term health effects of exposure to complex mixtures of chemicals and radionuclides are of particular concern because their biologic effects may synergize to increase risk of malignancy. Increased understanding of steps in the progression pathway of a normal cell to a cancer cell is important for biomonitoring, risk assessment and intervention in exposed individuals. Leukemias are characterized by multiple genetic aberrations. Accumulation of multiple genomic changes may reflect genomic instability in the affected ceils. Thus agents that induce DNA damage or genomic instability may increase accumulation of genomic alterations, thereby predisposing cells to transformation. However, not all DNA damaging agents predispose to transformation. Other factors such as genetic susceptibility, cell and tissue response to genotoxicity and cytotoxicity, DNA repair, etc. will impact malignant progression. The author proposed a progression model (Figure 1) of environmentally-induced leukemia that can be evaluated using mouse models.'

WHEN MODEL MEETS REALITY – A REVIEW OF SPAR LEVEL 2 MODEL AGAINST FUKUSHIMA ACCIDENT

Energy Technology Data Exchange (ETDEWEB)

Zhegang Ma

2013-09-01

The Standardized Plant Analysis Risk (SPAR) models are a set of probabilistic risk assessment (PRA) models used by the Nuclear Regulatory Commission (NRC) to evaluate the risk of operations at U.S. nuclear power plants and provide inputs to risk informed regulatory process. A small number of SPAR Level 2 models have been developed mostly for feasibility study purpose. They extend the Level 1 models to include containment systems, group plant damage states, and model containment phenomenology and accident progression in containment event trees. A severe earthquake and tsunami hit the eastern coast of Japan in March 2011 and caused significant damages on the reactors in Fukushima Daiichi site. Station blackout (SBO), core damage, containment damage, hydrogen explosion, and intensive radioactivity release, which have been previous analyzed and assumed as postulated accident progression in PRA models, now occurred with various degrees in the multi-units Fukushima Daiichi site. This paper reviews and compares a typical BWR SPAR Level 2 model with the “real” accident progressions and sequences occurred in Fukushima Daiichi Units 1, 2, and 3. It shows that the SPAR Level 2 model is a robust PRA model that could very reasonably describe the accident progression for a real and complicated nuclear accident in the world. On the other hand, the comparison shows that the SPAR model could be enhanced by incorporating some accident characteristics for better representation of severe accident progression.

Clinical Significance of HER-2 Splice Variants in Breast Cancer Progression and Drug Resistance

Directory of Open Access Journals (Sweden)

Claire Jackson

2013-01-01

Full Text Available Overexpression of human epidermal growth factor receptor (HER-2 occurs in 20–30% of breast cancers and confers survival and proliferative advantages on the tumour cells making HER-2 an ideal therapeutic target for drugs like Herceptin. Continued delineation of tumour biology has identified splice variants of HER-2, with contrasting roles in tumour cell biology. For example, the splice variant 16HER-2 (results from exon 16 skipping increases transformation of cancer cells and is associated with treatment resistance; conversely, Herstatin (results from intron 8 retention and p100 (results from intron 15 retention inhibit tumour cell proliferation. This review focuses on the potential clinical implications of the expression and coexistence of HER-2 splice variants in cancer cells in relation to breast cancer progression and drug resistance. “Individualised” strategies currently guide breast cancer management; in accordance, HER-2 splice variants may prove valuable as future prognostic and predictive factors, as well as potential therapeutic targets.

Numerical simulation of progressive debonding in fiber reinforced composite under transverse loading

DEFF Research Database (Denmark)

Kushch, V.; Shmegera, S.V.; Brøndsted, Povl

2011-01-01

. Then, the effect on debonding progress of local stress redistribution due to interaction between the fibers was studied in the framework of two-inclusion model. Simulation of progressive debonding in fiber reinforced composite using the many-fiber models of composite has been performed. It has been...... shown that the developed model provides detailed analysis of the progressive debonding phenomenon including the interface crack cluster formation, overall stiffness reduction and induced anisotropy of the effective elastic moduli of composite....

Three new genetic loci (R1210C in CFH, variants in COL8A1 and RAD51B are independently related to progression to advanced macular degeneration.

Directory of Open Access Journals (Sweden)

Johanna M Seddon

Full Text Available To assess the independent impact of new genetic variants on conversion to advanced stages of AMD, controlling for established risk factors, and to determine the contribution of genes in predictive models.In this prospective longitudinal study of 2765 individuals, 777 subjects progressed to neovascular disease (NV or geographic atrophy (GA in either eye over 12 years. Recently reported genetic loci were assessed for their independent effects on incident advanced AMD after controlling for 6 established loci in 5 genes, and demographic, behavioral, and macular characteristics. New variants which remained significantly related to progression were then added to a final multivariate model to assess their independent effects. The contribution of genes to risk models was assessed using reclassification tables by determining risk within cross-classified quintiles for alternative models.THREE NEW GENETIC VARIANTS WERE SIGNIFICANTLY RELATED TO PROGRESSION: rare variant R1210C in CFH (hazard ratio (HR 2.5, 95% confidence interval [CI] 1.2-5.3, P = 0.01, and common variants in genes COL8A1 (HR 2.0, 95% CI 1.1-3.5, P = 0.02 and RAD51B (HR 0.8, 95% CI 0.60-0.97, P = 0.03. The area under the curve statistic (AUC was significantly higher for the 9 gene model (.884 vs the 0 gene model (.873, P = .01. AUC's for the 9 vs 6 gene models were not significantly different, but reclassification analyses indicated significant added information for more genes, with adjusted odds ratios (OR for progression within 5 years per one quintile increase in risk score of 2.7, P<0.001 for the 9 vs 6 loci model, and OR 3.5, P<0.001 for the 9 vs. 0 gene model. Similar results were seen for NV and GA.Rare variant CFH R1210C and common variants in COL8A1 and RAD51B plus six genes in previous models contribute additional predictive information for advanced AMD beyond macular and behavioral phenotypes.

Optimal tax progressivity in imperfect labour markets

DEFF Research Database (Denmark)

Sørensen, Peter Birch

1999-01-01

that there may be an optimal degree of tax progressivity where the marginal welfare gain from reduced involuntary unemployment is just offset by the marginal welfare loss from lower productivity. This paper sets up four different models of an imperfect labour market in order to identify the degree of tax......All modern labour market theories capable of explaining involuntary unemployment as an equilibrium phenomenon imply that increased income tax progressivity reduces unemployment, but they also imply that higher progressivity tends to reduce work effort and labour productivity. This suggests...

Large-scale identification of clinical and genetic predictors of motor progression in patients with newly diagnosed Parkinson's disease: a longitudinal cohort study and validation.

Science.gov (United States)

Latourelle, Jeanne C; Beste, Michael T; Hadzi, Tiffany C; Miller, Robert E; Oppenheim, Jacob N; Valko, Matthew P; Wuest, Diane M; Church, Bruce W; Khalil, Iya G; Hayete, Boris; Venuto, Charles S

2017-11-01

Better understanding and prediction of progression of Parkinson's disease could improve disease management and clinical trial design. We aimed to use longitudinal clinical, molecular, and genetic data to develop predictive models, compare potential biomarkers, and identify novel predictors for motor progression in Parkinson's disease. We also sought to assess the use of these models in the design of treatment trials in Parkinson's disease. A Bayesian multivariate predictive inference platform was applied to data from the Parkinson's Progression Markers Initiative (PPMI) study (NCT01141023). We used genetic data and baseline molecular and clinical variables from patients with Parkinson's disease and healthy controls to construct an ensemble of models to predict the annual rate of change in combined scores from the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts II and III. We tested our overall explanatory power, as assessed by the coefficient of determination (R 2 ), and replicated novel findings in an independent clinical cohort from the Longitudinal and Biomarker Study in Parkinson's disease (LABS-PD; NCT00605163). The potential utility of these models for clinical trial design was quantified by comparing simulated randomised placebo-controlled trials within the out-of-sample LABS-PD cohort. 117 healthy controls and 312 patients with Parkinson's disease from the PPMI study were available for analysis, and 317 patients with Parkinson's disease from LABS-PD were available for validation. Our model ensemble showed strong performance within the PPMI cohort (five-fold cross-validated R 2 41%, 95% CI 35-47) and significant-albeit reduced-performance in the LABS-PD cohort (R 2 9%, 95% CI 4-16). Individual predictive features identified from PPMI data were confirmed in the LABS-PD cohort. These included significant replication of higher baseline MDS-UPDRS motor score, male sex, and increased age, as well as a novel Parkinson's disease

Progressive taxation, income inequality, and happiness.

Science.gov (United States)

Oishi, Shigehiro; Kushlev, Kostadin; Schimmack, Ulrich

2018-01-01

Income inequality has become one of the more widely debated social issues today. The current article explores the role of progressive taxation in income inequality and happiness. Using historical data in the United States from 1962 to 2014, we found that income inequality was substantially smaller in years when the income tax was more progressive (i.e., a higher tax rate for higher income brackets), even when controlling for variables like stock market performance and unemployment rate. Time lag analyses further showed that higher progressive taxation predicted increasingly lower income inequality up to 5 years later. Data from the General Social Survey (1972-2014; N = 59,599) with U.S. residents (hereafter referred to as "Americans") showed that during years with higher progressive taxation rates, less wealthy Americans-those in the lowest 40% of the income distribution-tended to be happier, whereas the richest 20% were not significantly less happy. Mediational analyses confirmed that the association of progressive taxation with the happiness of less wealthy Americans can be explained by lower income inequality in years with higher progressive taxation. A separate sample of Americans polled online (N = 373) correctly predicted the positive association between progressive taxation and the happiness of poorer Americans but incorrectly expected a strong negative association between progressive taxation and the happiness of richer Americans. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

White Adipose Tissue Cells Are Recruited by Experimental Tumors and Promote Cancer Progression in Mouse Models

Science.gov (United States)

Zhang, Yan; Daquinag, Alexes; Traktuev, Dmitry O.; Amaya-Manzanares, Felipe; Simmons, Paul J.; March, Keith L.; Pasqualini, Renata; Arap, Wadih; Kolonin, Mikhail G.

2010-01-01

The connection between obesity and accelerated cancer progression has been established, but the mediating mechanisms are not well understood. We have shown that stromal cells from white adipose tissue (WAT) cooperate with the endothelium to promote blood vessel formation through the secretion of soluble trophic factors. Here, we hypothesize that WAT directly mediates cancer progression by serving as a source of cells that migrate to tumors and promote neovascularization. To test this hypothesis, we have evaluated the recruitment of WAT-derived cells by tumors and the effect of their engraftment on tumor growth by integrating a transgenic mouse strain engineered for expansion of traceable cells with established allograft and xenograft cancer models. Our studies show that entry of adipose stromal and endothelial cells into systemic circulation leads to their homing to and engraftment into tumor stroma and vasculature, respectively. We show that recruitment of adipose stromal cells by tumors is sufficient to promote tumor growth. Finally, we show that migration of stromal and vascular progenitor cells from WAT grafts to tumors is also associated with acceleration of cancer progression. These results provide a biological insight for the clinical association between obesity and cancer, thus outlining potential avenues for preventive and therapeutic strategies. PMID:19491274

Quantitative Reasoning in Environmental Science: A Learning Progression

Science.gov (United States)

Mayes, Robert Lee; Forrester, Jennifer Harris; Christus, Jennifer Schuttlefield; Peterson, Franziska Isabel; Bonilla, Rachel; Yestness, Nissa

2014-01-01

The ability of middle and high school students to reason quantitatively within the context of environmental science was investigated. A quantitative reasoning (QR) learning progression was created with three progress variables: quantification act, quantitative interpretation, and quantitative modeling. An iterative research design was used as it…

Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies.

Science.gov (United States)

Korde, Neha; Kristinsson, Sigurdur Y; Landgren, Ola

2011-05-26

Monoclonal gammopathy of unknown significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic plasma cell dyscrasias, with a propensity to progress to symptomatic MM. In recent years there have been improvements in risk stratification models (involving molecular markers) of both disorders, which have led to better understanding of the biology and probability of progression of MGUS and SMM. In the context of numerous molecular events and heterogeneous risk of progression, developing individualized risk profiles for patients with MGUS and SMM represents an ongoing challenge that has to be addressed by prospective clinical monitoring and extensive correlative science. In this review we discuss the current standard of care of patients with MGUS and SMM, the use of risk models, including flow cytometry and free-light chain analyses, for predicting risk of progression. Emerging evidence from molecular studies on MGUS and SMM, involving cytogenetics, gene-expression profiling, and microRNA as well as molecular imaging is described. Finally, future directions for improving individualized management of MGUS and SMM patients, as well as the potential for developing early treatment strategies designed to delay and prevent development of MM are discussed.

Progression of motor axon dysfunction and ectopic Na(v)1.8 expression in a mouse model of Charcot-Marie-Tooth disease 1B

DEFF Research Database (Denmark)

Rosberg, Mette R.; Alvarez Herrero, Susana; Klein, Dennis

2016-01-01

Mice heterozygously deficient for the myelin protein P0 gene (P0+/-) develop a slowly progressing neuropathy modeling demyelinating Charcot-Marie-Tooth disease (CMT1B). The aim of the study was to investigate the long-term progression of motor dysfunction in P0+/- mice at 3, 7, 12 and 20months...... pharmacologic block of NaV1.8 in P0+/-. Mathematical modeling indicated an association of altered passive cable properties with a depolarizing shift in resting membrane potential and increase in the persistent Na(+) current in P0+/-. Our data suggest that ectopic NaV1.8 expression precipitates depolarizing...

A Multiscale Agent-Based in silico Model of Liver Fibrosis Progression

International Nuclear Information System (INIS)

Dutta-Moscato, Joyeeta; Solovyev, Alexey; Mi, Qi; Nishikawa, Taichiro; Soto-Gutierrez, Alejandro; Fox, Ira J.; Vodovotz, Yoram

2014-01-01

Chronic hepatic inflammation involves a complex interplay of inflammatory and mechanical influences, ultimately manifesting in a characteristic histopathology of liver fibrosis. We created an agent-based model (ABM) of liver tissue in order to computationally examine the consequence of liver inflammation. Our liver fibrosis ABM (LFABM) is comprised of literature-derived rules describing molecular and histopathological aspects of inflammation and fibrosis in a section of chemically injured liver. Hepatocytes are modeled as agents within hexagonal lobules. Injury triggers an inflammatory reaction, which leads to activation of local Kupffer cells and recruitment of monocytes from circulation. Portal fibroblasts and hepatic stellate cells are activated locally by the products of inflammation. The various agents in the simulation are regulated by above-threshold concentrations of pro- and anti-inflammatory cytokines and damage-associated molecular pattern molecules. The simulation progresses from chronic inflammation to collagen deposition, exhibiting periportal fibrosis followed by bridging fibrosis, and culminating in disruption of the regular lobular structure. The ABM exhibited key histopathological features observed in liver sections from rats treated with carbon tetrachloride (CCl 4 ). An in silico “tension test” for the hepatic lobules predicted an overall increase in tissue stiffness, in line with clinical elastography literature and published studies in CCl 4 -treated rats. Therapy simulations suggested differential anti-fibrotic effects of neutralizing tumor necrosis factor alpha vs. enhancing M2 Kupffer cells. We conclude that a computational model of liver inflammation on a structural skeleton of physical forces can recapitulate key histopathological and macroscopic properties of CCl 4 -injured liver. This multiscale approach linking molecular and chemomechanical stimuli enables a model that could be used to gain translationally relevant insights into

Relationship of computed tomography perfusion and positron emission tomography to tumour progression in malignant glioma

International Nuclear Information System (INIS)

Yeung, Timothy P C; Yartsev, Slav; Lee, Ting-Yim; Wong, Eugene; He, Wenqing; Fisher, Barbara; VanderSpek, Lauren L; Macdonald, David; Bauman, Glenn

2014-01-01

Introduction: This study aimed to explore the potential for computed tomography (CT) perfusion and 18-Fluorodeoxyglucose positron emission tomography (FDG-PET) in predicting sites of future progressive tumour on a voxel-by-voxel basis after radiotherapy and chemotherapy. Methods: Ten patients underwent pre-radiotherapy magnetic resonance (MR), FDG-PET and CT perfusion near the end of radiotherapy and repeated post-radiotherapy follow-up MR scans. The relationships between these images and tumour progression were assessed using logistic regression. Cross-validation with receiver operating characteristic (ROC) analysis was used to assess the value of these images in predicting sites of tumour progression. Results: Pre-radiotherapy MR-defined gross tumour; near-end-of-radiotherapy CT-defined enhancing lesion; CT perfusion blood flow (BF), blood volume (BV) and permeability-surface area (PS) product; FDG-PET standard uptake value (SUV); and SUV:BF showed significant associations with tumour progression on follow-up MR imaging (P < 0.0001). The mean sensitivity (±standard deviation), specificity and area under the ROC curve (AUC) of PS were 0.64 ± 0.15, 0.74 ± 0.07 and 0.72 ± 0.12 respectively. This mean AUC was higher than that of the pre-radiotherapy MR-defined gross tumour and near-end-of-radiotherapy CT-defined enhancing lesion (both AUCs = 0.6 ± 0.1, P ≤ 0.03). The multivariate model using BF, BV, PS and SUV had a mean AUC of 0.8 ± 0.1, but this was not significantly higher than the PS only model. Conclusion: PS is the single best predictor of tumour progression when compared to other parameters, but voxel-based prediction based on logistic regression had modest sensitivity and specificity

Relationship of computed tomography perfusion and positron emission tomography to tumour progression in malignant glioma

Energy Technology Data Exchange (ETDEWEB)

Yeung, Timothy P C [London Regional Cancer Program, London Health Sciences Centre, Ontario, Canada, N6A 4L6 (Canada); Robarts Research Institute, The University of Western Ontario, Ontario, Canada, N6A 5B7 (Canada); Department of Medical Biophysics, The University of Western Ontario, Ontario, Canada, N6A 5C1 (Canada); Yartsev, Slav [London Regional Cancer Program, London Health Sciences Centre, Ontario, Canada, N6A 4L6 (Canada); Department of Medical Biophysics, The University of Western Ontario, Ontario, Canada, N6A 5C1 (Canada); Department of Oncology, The University of Western Ontario, London Health Sciences Centre, London Regional Cancer Program, Ontario, Canada, N6A 4L6 (Canada); Lee, Ting-Yim [Robarts Research Institute, The University of Western Ontario, Ontario, Canada, N6A 5B7 (Canada); Department of Medical Biophysics, The University of Western Ontario, Ontario, Canada, N6A 5C1 (Canada); Department of Oncology, The University of Western Ontario, London Health Sciences Centre, London Regional Cancer Program, Ontario, Canada, N6A 4L6 (Canada); Department of Medical Imaging, The University of Western Ontario, London Health Sciences Centre, Victoria Hospital, Ontario, Canada, N6A 5W9 (Australia); Lawson Health Research Institute, St. Joseph' s Health Care London, Ontario, Canada, N6A 4V2 (Canada); Wong, Eugene [London Regional Cancer Program, London Health Sciences Centre, Ontario, Canada, N6A 4L6 (Canada); Department of Oncology, The University of Western Ontario, London Health Sciences Centre, London Regional Cancer Program, Ontario, Canada, N6A 4L6 (Canada); Department of Physics and Astronomy, The University of Western Ontario, Ontario, Canada, N6A 3K7 (Canada); He, Wenqing [Department of Statistical and Actuarial Sciences, The University of Western Ontario, Ontario, Canada, N6A 5B7 (Canada); Fisher, Barbara; VanderSpek, Lauren L [London Regional Cancer Program, London Health Sciences Centre, Ontario, Canada, N6A 4L6 (Canada); Department of Oncology, The University of Western Ontario, London Health Sciences Centre, London Regional Cancer Program, Ontario, Canada, N6A 4L6 (Canada); Macdonald, David [London Regional Cancer Program, London Health Sciences Centre, Ontario, Canada, N6A 4L6 (Canada); Department of Oncology, The University of Western Ontario, London Health Sciences Centre, London Regional Cancer Program, Ontario, Canada, N6A 4L6 (Canada); Department of Clinical Neurological Sciences, The University of Western Ontario, London Health Sciences Centre, University Hospital, Ontario, Canada, N6A 5A5 (Canada); Bauman, Glenn, E-mail: glenn.bauman@lhsc.on.ca [London Regional Cancer Program, London Health Sciences Centre, Ontario, Canada, N6A 4L6 (Canada); Department of Medical Biophysics, The University of Western Ontario, Ontario, Canada, N6A 5C1 (Canada); Department of Oncology, The University of Western Ontario, London Health Sciences Centre, London Regional Cancer Program, Ontario, Canada, N6A 4L6 (Canada)

2014-02-15

Introduction: This study aimed to explore the potential for computed tomography (CT) perfusion and 18-Fluorodeoxyglucose positron emission tomography (FDG-PET) in predicting sites of future progressive tumour on a voxel-by-voxel basis after radiotherapy and chemotherapy. Methods: Ten patients underwent pre-radiotherapy magnetic resonance (MR), FDG-PET and CT perfusion near the end of radiotherapy and repeated post-radiotherapy follow-up MR scans. The relationships between these images and tumour progression were assessed using logistic regression. Cross-validation with receiver operating characteristic (ROC) analysis was used to assess the value of these images in predicting sites of tumour progression. Results: Pre-radiotherapy MR-defined gross tumour; near-end-of-radiotherapy CT-defined enhancing lesion; CT perfusion blood flow (BF), blood volume (BV) and permeability-surface area (PS) product; FDG-PET standard uptake value (SUV); and SUV:BF showed significant associations with tumour progression on follow-up MR imaging (P < 0.0001). The mean sensitivity (±standard deviation), specificity and area under the ROC curve (AUC) of PS were 0.64 ± 0.15, 0.74 ± 0.07 and 0.72 ± 0.12 respectively. This mean AUC was higher than that of the pre-radiotherapy MR-defined gross tumour and near-end-of-radiotherapy CT-defined enhancing lesion (both AUCs = 0.6 ± 0.1, P ≤ 0.03). The multivariate model using BF, BV, PS and SUV had a mean AUC of 0.8 ± 0.1, but this was not significantly higher than the PS only model. Conclusion: PS is the single best predictor of tumour progression when compared to other parameters, but voxel-based prediction based on logistic regression had modest sensitivity and specificity.

Progress report on SYVAC chemical speciation modelling studies during 1983/4

International Nuclear Information System (INIS)

Cross, J.; Smith, G.L.; Williams, D.R.

1984-01-01

This report summarises progress made on the SYVAC (System Variability Analysis program) chemical speciation project during 1983-4. Chemical speciation is defined and its importance in the SYVAC approach to Radioactive Waste Management is discussed. Computer modelling of chemical equilibria is described and the two programs presently operational at UWIST - SOLMNQ and MINEQL - are compared and discussed in detail. In view of the shortcomings of the databases supplied with these programs, a new database of equilibrium constants has been compiled containing 483 aqueous species and 329 solid phases, including data for the radionuclides uranium, plutonium, americium, neptunium and thorium. The collaborative work with AERE, Harwell, is reported. A leaching experiment carried out at Harwell has been modelled using the chemical speciation programs. The results for uranium, plutonium, americium and neptunium, are presented. However, the experimental data provided by AERE is insufficient for accurate simulations. Chemical speciation studies relating to specific sites require accurate characterisation of the groundwater, i.e. chemical composition, Eh and pH. In the absence of such information, preliminary studies have been made using an average granite groundwater. The results of these studies are presented and include solubility and speciation plots for uranium, plutonium, thorium and neptunium. The future aims of the project are discussed. (author)

Aspirations, Progress and Perceptions of Boys from a Single Sex School Following the Changeover to Coeducation

Science.gov (United States)

Yates, Shirley M.

2004-01-01

Career and further education aspirations, educational progress and perceptions of the learning environment were measured annually over three years in primary and secondary boys from a single sex non-government school, following the changeover to coeducation. Hierarchical Linear Modelling analyses revealed the significant role played by the career…

Decision-Making Accuracy of CBM Progress-Monitoring Data

Science.gov (United States)

Hintze, John M.; Wells, Craig S.; Marcotte, Amanda M.; Solomon, Benjamin G.

2018-01-01

This study examined the diagnostic accuracy associated with decision making as is typically conducted with curriculum-based measurement (CBM) approaches to progress monitoring. Using previously published estimates of the standard errors of estimate associated with CBM, 20,000 progress-monitoring data sets were simulated to model student reading…

Progressive Impairment of Lactate-based Gluconeogenesis in the Huntington?s Disease Mouse Model R6/2

OpenAIRE

Nielsen, Signe Marie Borch; Hasholt, Lis; N?rrem?lle, Anne; Josefsen, Knud

2015-01-01

Huntington?s disease (HD) is a neurodegenerative illness, where selective neuronal loss in the brain caused by expression of mutant huntingtin protein leads to motor dysfunction and cognitive decline in addition to peripheral metabolic changes. In this study we confirm our previous observation of impairment of lactate-based hepatic gluconeogenesis in the transgenic HD mouse model R6/2 and determine that the defect manifests very early and progresses in severity with disease development, indic...

Progress in modeling and simulation.

Science.gov (United States)

Kindler, E

1998-01-01

For the modeling of systems, the computers are more and more used while the other "media" (including the human intellect) carrying the models are abandoned. For the modeling of knowledges, i.e. of more or less general concepts (possibly used to model systems composed of instances of such concepts), the object-oriented programming is nowadays widely used. For the modeling of processes existing and developing in the time, computer simulation is used, the results of which are often presented by means of animation (graphical pictures moving and changing in time). Unfortunately, the object-oriented programming tools are commonly not designed to be of a great use for simulation while the programming tools for simulation do not enable their users to apply the advantages of the object-oriented programming. Nevertheless, there are exclusions enabling to use general concepts represented at a computer, for constructing simulation models and for their easy modification. They are described in the present paper, together with true definitions of modeling, simulation and object-oriented programming (including cases that do not satisfy the definitions but are dangerous to introduce misunderstanding), an outline of their applications and of their further development. In relation to the fact that computing systems are being introduced to be control components into a large spectrum of (technological, social and biological) systems, the attention is oriented to models of systems containing modeling components.

The Agricultural Model Intercomparison and Improvement Project (AgMIP): Progress and Preliminary Results

Science.gov (United States)

Rosenzweig, C.

2011-12-01

The Agricultural Model Intercomparison and Improvement Project (AgMIP) is a distributed climate-scenario simulation exercise for historical model intercomparison and future climate change conditions with participation of multiple crop and agricultural trade modeling groups around the world. The goals of AgMIP are to improve substantially the characterization of risk of hunger and world food security due to climate change and to enhance adaptation capacity in both developing and developed countries. Recent progress and the current status of AgMIP will be presented, highlighting three areas of activity: preliminary results from crop pilot studies, outcomes from regional workshops, and emerging scientific challenges. AgMIP crop modeling efforts are being led by pilot studies, which have been established for wheat, maize, rice, and sugarcane. These crop-specific initiatives have proven instrumental in testing and contributing to AgMIP protocols, as well as creating preliminary results for aggregation and input to agricultural trade models. Regional workshops are being held to encourage collaborations and set research activities in motion for key agricultural areas. The first of these workshops was hosted by Embrapa and UNICAMP and held in Campinas, Brazil. Outcomes from this meeting have informed crop modeling research activities within South America, AgMIP protocols, and future regional workshops. Several scientific challenges have emerged and are currently being addressed by AgMIP researchers. Areas of particular interest include geospatial weather generation, ensemble methods for climate scenarios and crop models, spatial aggregation of field-scale yields to regional and global production, and characterization of future changes in climate variability.

Mapping the Most Significant Computer Hacking Events to a Temporal Computer Attack Model

OpenAIRE

Heerden , Renier ,; Pieterse , Heloise; Irwin , Barry

2012-01-01

Part 4: Section 3: ICT for Peace and War; International audience; This paper presents eight of the most significant computer hacking events (also known as computer attacks). These events were selected because of their unique impact, methodology, or other properties. A temporal computer attack model is presented that can be used to model computer based attacks. This model consists of the following stages: Target Identification, Reconnaissance, Attack, and Post-Attack Reconnaissance stages. The...

Progressive Finland sees progress with nuclear projects

Energy Technology Data Exchange (ETDEWEB)

Dalton, David [NucNet, Brussels (Belgium)

2016-02-15

The Finnish Hanhikivi-1 reactor project is firmly on track and a licence has been granted for construction of a final disposal facility for spent nuclear fuel - the first final repository in the world to enter the construction phase. Significant progress has been made with plans for Finland to build its sixth nuclear reactor unit at Hanhikivi. Fennovoima's licensing manager Janne Liuko said the company expects to receive the construction licence for the Generation III+ Hanhikivi-1 plant in late 2017. The application was submitted to the Finnish Ministry of Employment and the Economy in June 2015.

Reduced estimated glomerular filtration rate (eGFR 73 m2 ) at first transurethral resection of bladder tumour is a significant predictor of subsequent recurrence and progression.

Science.gov (United States)

Blute, Michael L; Kucherov, Victor; Rushmer, Timothy J; Damodaran, Shivashankar; Shi, Fangfang; Abel, E Jason; Jarrard, David F; Richards, Kyle A; Messing, Edward M; Downs, Tracy M

2017-09-01

To evaluate if moderate chronic kidney disease [CKD; estimated glomerular filtration rate (eGFR) 73 m 2 ] is associated with high rates of non-muscle-invasive bladder cancer (NMIBC) recurrence or progression. A multi-institutional database identified patients with serum creatinine values prior to first transurethral resection of bladder tumour (TURBT). The CKD-epidemiology collaboration formula calculated patient eGFR. Cox proportional hazards models evaluated associations with recurrence-free (RFS) and progression-free survival (PFS). In all, 727 patients were identified with a median (interquartile range [IQR]) patient age of 69.8 (60.1-77.6) years. Data for eGFR were available for 632 patients. During a median (IQR) follow-up of 3.7 (1.5-6.5) years, 400 (55%) patients had recurrence and 145 (19.9%) patients had progression of tumour stage or grade. Moderate or severe CKD was identified in 183 patients according to eGFR. Multivariable analysis identified an eGFR of 73 m 2 (hazard ratio [HR] 1.5, 95% confidence interval [CI]: 1.2-1.9; P = 0.002) as a predictor of tumour recurrence. The 5-year RFS rate was 46% for patients with an eGFR of ≥60 mL/min/1.73 m 2 and 27% for patients with an eGFR of 73 m 2 (P 73 m 2 (HR 3.7, 95% CI: 1.75-7.94; P = 0.001) was associated with progression to muscle-invasive disease. The 5-year PFS rate was 83% for patients with an eGFR of ≥60 mL/min/1.73 m 2 and 71% for patients with an eGFR of 73 m 2 (P = 0.01). Moderate CKD at first TURBT is associated with reduced RFS and PFS. Patients with reduced renal function should be considered for increased surveillance. © 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.

Inflammation in Lafora Disease: Evolution with Disease Progression in Laforin and Malin Knock-out Mouse Models.

Science.gov (United States)

López-González, Irene; Viana, Rosa; Sanz, Pascual; Ferrer, Isidre

2017-07-01

Lafora progressive myoclonus epilepsy (Lafora disease, LD) is a fatal rare autosomal recessive neurodegenerative disorder characterized by the accumulation of insoluble ubiquitinated polyglucosan inclusions in the cytoplasm of neurons, which is most commonly associated with mutations in two genes: EPM2A, encoding the glucan phosphatase laforin, and EPM2B, encoding the E3-ubiquitin ligase malin. The present study analyzes possible inflammatory responses in the mouse lines Epm2a -/- (laforin knock-out) and Epm2b -/- (malin knock-out) with disease progression. Increased numbers of reactive astrocytes (expressing the GFAP marker) and microglia (expressing the Iba1 marker) together with increased expression of genes encoding cytokines and mediators of the inflammatory response occur in both mouse lines although with marked genotype differences. C3ar1 and CxCl10 messenger RNAs (mRNAs) are significantly increased in Epm2a -/- mice aged 12 months when compared with age-matched controls, whereas C3ar1, C4b, Ccl4, CxCl10, Il1b, Il6, Tnfα, and Il10ra mRNAs are significantly upregulated in Epm2b -/- at the same age. This is accompanied by increased protein levels of IL1-β, IL6, TNFα, and Cox2 particularly in Epm2b -/- mice. The severity of inflammatory changes correlates with more severe clinical symptoms previously described in Epm2b -/- mice. These findings show for the first time increased innate inflammatory responses in a neurodegenerative disease with polyglucosan intraneuronal deposits which increase with disease progression, in a way similar to what is seen in neurodegenerative diseases with abnormal protein aggregates. These findings also point to the possibility of using anti-inflammatory agents to mitigate the degenerative process in LD.

On the significance of magnetospheric research for progress in astrophysics

International Nuclear Information System (INIS)

Faelthammar, C-G.; Akasofu, S-I.; Alfen, H.

1978-04-01

Recent discoveries by means of in situ measurements have led to a substantial revision of our picture of the magnetosphere and parts of the heliosphere. This concerns such essential aspects as the character and distribution of electric fields and currents, the ways in which charged particles are energized, and the chemical composition of the magnetospheric plasma. This revision reflects the fact that even in fundamental respects, real cosmical plasmas behave in different ways than predicted by the idealized models that have traditionally been used in magnetospheric physics as well as in astrophysics. The new understanding of the general properties of cosmical plasma that has been, and continues to be, provided by in situ measurements gives us a much improved basis on which to interpret astrophysical observations

Violet Light Exposure Can Be a Preventive Strategy Against Myopia Progression

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Hidemasa Torii

2017-02-01

Full Text Available Prevalence of myopia is increasing worldwide. Outdoor activity is one of the most important environmental factors for myopia control. Here we show that violet light (VL, 360–400 nm wavelength suppresses myopia progression. First, we confirmed that VL suppressed the axial length (AL elongation in the chick myopia model. Expression microarray analyses revealed that myopia suppressive gene EGR1 was upregulated by VL exposure. VL exposure induced significantly higher upregulation of EGR1 in chick chorioretinal tissues than blue light under the same conditions. Next, we conducted clinical research retrospectively to compare the AL elongation among myopic children who wore eyeglasses (VL blocked and two types of contact lenses (partially VL blocked and VL transmitting. The data showed the VL transmitting contact lenses suppressed myopia progression most. These results suggest that VL is one of the important outdoor environmental factors for myopia control. Since VL is apt to be excluded from our modern society due to the excessive UV protection, VL exposure can be a preventive strategy against myopia progression.

The DIAN-TU Next Generation Alzheimer’s prevention trial: adaptive design and disease progression model

Science.gov (United States)

Bateman, Randall J.; Benzinger, Tammie L.; Berry, Scott; Clifford, David B.; Duggan, Cynthia; Fagan, Anne M.; Fanning, Kathleen; Farlow, Martin R.; Hassenstab, Jason; McDade, Eric M.; Mills, Susan; Paumier, Katrina; Quintana, Melanie; Salloway, Stephen P.; Santacruz, Anna; Schneider, Lon S.; Wang, Guoqiao; Xiong, Chengjie

2016-01-01

INTRODUCTION The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) trial is an adaptive platform trial testing multiple drugs to slow or prevent the progression of Alzheimer’s disease in autosomal dominant Alzheimer’s disease (ADAD) families. With completion of enrollment of the first two drug arms, the DIAN-TU now plans to add new drugs to the platform, designated as the Next Generation Prevention Trial (NexGen). METHODS In collaboration with ADAD families, philanthropic organizations, academic leaders, the DIAN-TU Pharma Consortium, the NIH, and regulatory colleagues, the DIAN-TU developed innovative clinical study designs for the DIAN-TU NexGen trial. RESULTS Our expanded trials toolbox consists of a Disease Progression Model for ADAD, primary endpoint DIAN-TU cognitive performance composite, biomarker development, self-administered cognitive assessments, adaptive dose adjustments, and blinded data collection through the last participant completion. CONCLUSION These steps represent elements to improve efficacy of the adaptive platform trial and a continued effort to optimize prevention and treatment trials in ADAD. PMID:27583651

Models for poloidal divertors

International Nuclear Information System (INIS)

Post, D.E.; Heifetz, D.; Petravic, M.

1982-07-01

Recent progress in models for poloidal divertors has both helped to explain current divertor experiments and contributed significantly to design efforts for future large tokamak (INTOR, etc.) divertor systems. These models range in sophistication from zero-dimensional treatments and dimensional analysis to two-dimensional models for plasma and neutral particle transport which include a wide variety of atomic and molecular processes as well as detailed treatments of the plasma-wall interaction. This paper presents a brief review of some of these models, describing the physics and approximations involved in each model. We discuss the wide variety of physics necessary for a comprehensive description of poloidal divertors. To illustrate the progress in models for poloidal divertors, we discuss some of our recent work as typical examples of the kinds of calculations being done

Models for poloidal divertors

Energy Technology Data Exchange (ETDEWEB)

Post, D.E.; Heifetz, D.; Petravic, M.

1982-07-01

Recent progress in models for poloidal divertors has both helped to explain current divertor experiments and contributed significantly to design efforts for future large tokamak (INTOR, etc.) divertor systems. These models range in sophistication from zero-dimensional treatments and dimensional analysis to two-dimensional models for plasma and neutral particle transport which include a wide variety of atomic and molecular processes as well as detailed treatments of the plasma-wall interaction. This paper presents a brief review of some of these models, describing the physics and approximations involved in each model. We discuss the wide variety of physics necessary for a comprehensive description of poloidal divertors. To illustrate the progress in models for poloidal divertors, we discuss some of our recent work as typical examples of the kinds of calculations being done.

Multi-state Markov models for disease progression in the presence of informative examination times: an application to hepatitis C.

Science.gov (United States)

Sweeting, M J; Farewell, V T; De Angelis, D

2010-05-20

In many chronic diseases it is important to understand the rate at which patients progress from infection through a series of defined disease states to a clinical outcome, e.g. cirrhosis in hepatitis C virus (HCV)-infected individuals or AIDS in HIV-infected individuals. Typically data are obtained from longitudinal studies, which often are observational in nature, and where disease state is observed only at selected examinations throughout follow-up. Transition times between disease states are therefore interval censored. Multi-state Markov models are commonly used to analyze such data, but rely on the assumption that the examination times are non-informative, and hence the examination process is ignorable in a likelihood-based analysis. In this paper we develop a Markov model that relaxes this assumption through the premise that the examination process is ignorable only after conditioning on a more regularly observed auxiliary variable. This situation arises in a study of HCV disease progression, where liver biopsies (the examinations) are sparse, irregular, and potentially informative with respect to the transition times. We use additional information on liver function tests (LFTs), commonly collected throughout follow-up, to inform current disease state and to assume an ignorable examination process. The model developed has a similar structure to a hidden Markov model and accommodates both the series of LFT measurements and the partially latent series of disease states. We show through simulation how this model compares with the commonly used ignorable Markov model, and a Markov model that assumes the examination process is non-ignorable. Copyright 2010 John Wiley & Sons, Ltd.

Molecular and metabolic pattern classification for detection of brain glioma progression

Energy Technology Data Exchange (ETDEWEB)

Imani, Farzin, E-mail: imanif@upmc.edu [Department of Radiology, University of Pittsburgh Medical Center, PA (United States); Boada, Fernando E. [Department of Radiology, University of Pittsburgh Medical Center, PA (United States); Lieberman, Frank S. [Department of Neurology, University of Pittsburgh Medical Center, PA (United States); Davis, Denise K.; Mountz, James M. [Department of Radiology, University of Pittsburgh Medical Center, PA (United States)

2014-02-15

Objectives: The ability to differentiate between brain tumor progression and radiation therapy induced necrosis is critical for appropriate patient management. In order to improve the differential diagnosis, we combined fluorine-18 2-fluoro-deoxyglucose positron emission tomography ({sup 18}F-FDG PET), proton magnetic resonance spectroscopy ({sup 1}H MRS) and histological data to develop a multi-parametric machine-learning model. Methods: We enrolled twelve post-therapy patients with grade 2 and 3 gliomas that were suspicious of tumor progression. All patients underwent {sup 18}F-FDG PET and {sup 1}H MRS. Maximal standardized uptake value (SUVmax) of the tumors and reference regions were obtained. Multiple 2D maps of choline (Cho), creatine (Cr), and N-acetylaspartate (NAA) of the tumors were generated. A support vector machine (SVM) learning model was established to take imaging biomarkers and histological data as input vectors. A combination of clinical follow-up and multiple sequential MRI studies served as the basis for assessing the clinical outcome. All vector combinations were evaluated for diagnostic accuracy and cross validation. The optimal cutoff value of individual parameters was calculated using Receiver operating characteristic (ROC) plots. Results: The SVM and ROC analyses both demonstrated that SUVmax of the lesion was the most significant single diagnostic parameter (75% accuracy) followed by Cho concentration (67% accuracy). SVM analysis of all paired parameters showed SUVmax and Cho concentration in combination could achieve 83% accuracy. SUVmax of the lesion paired with SUVmax of the white matter as well as the tumor Cho paired with the tumor Cr both showed 83% accuracy. These were the most significant paired diagnostic parameters of either modality. Combining all four parameters did not improve the results. However, addition of two more parameters, Cho and Cr of brain parenchyma contralateral to the tumor, increased the accuracy to 92

Progression-free survival/time to progression as a potential surrogate for overall survival in HR+, HER2– metastatic breast cancer

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Forsythe A

2018-05-01

Full Text Available Anna Forsythe,1 David Chandiwana,2 Janina Barth,3 Marroon Thabane,4 Johan Baeck,2 Gabriel Tremblay1 1Purple Squirrel Economics, New York, NY, 2Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 3Novartis Pharma GmbH, Nuremberg, Germany; 4Novartis Pharmaceuticals Incorporated, Dorval, QC, Canada Background: Several recent randomized controlled trials (RCTs in hormone receptor-positive (HR+, human epidermal growth factor receptor 2-negative (HER2– metastatic breast cancer (MBC have demonstrated significant improvements in progression-free survival (PFS; however, few have reported improvement in overall survival (OS. The surrogacy of PFS or time to progression (TTP for OS has not been formally investigated in HR+, HER2– MBC.Methods: A systematic literature review of RCTs in HR+, HER2– MBC was conducted to identify studies that reported both median PFS/TTP and OS. The correlation between PFS/TTP and OS was evaluated using Pearson’s product–moment correlation and Spearman’s rank correlation. Subgroup analyses were performed to explore possible reasons for heterogeneity. Errors-in-variables weighted least squares regression (LSR was used to model incremental OS months as a function of incremental PFS/TTP months. An exploratory analysis investigated the impact of three covariates (chemotherapy vs hormonal/targeted therapy, PFS vs TTP, and first-line therapy vs second-line therapy or greater on OS prediction. The lower 95% prediction band was used to determine the minimum incremental PFS/TTP months required to predict OS benefit (surrogate threshold effect [STE].Results: Forty studies were identified. There was a statistically significant correlation between median PFS/TTP and OS (Pearson =0.741, P=0.000; Spearman =0.650, P=0.000. These results proved consistent for chemotherapy and hormonal/targeted therapy. Univariate LSR analysis yielded an R2 of 0.354 with 1 incremental PFS/TTP month corresponding to 1.13 incremental OS months

Arginase-1 expressing microglia in close proximity to motor neurons were increased early in disease progression in canine degenerative myelopathy, a model of amyotrophic lateral sclerosis.

Science.gov (United States)

Toedebusch, Christine M; Snyder, John C; Jones, Maria R; Garcia, Virginia B; Johnson, Gayle C; Villalón, Eric L; Coates, Joan R; Garcia, Michael L

2018-04-01

Toxicity within superoxide dismutase-1 (SOD1)-associated familial amyotrophic lateral sclerosis (ALS) is non-cell autonomous with direct contribution from microglia. Microglia exhibit variable expression of neuroprotective and neurotoxic molecules throughout disease progression. The mechanisms regulating microglial phenotype within ALS are not well understood. This work presents a first study to examine the specific microglial phenotypic response in close association to motor neurons in a naturally occurring disease model of ALS, canine degenerative myelopathy (DM). Microglia closely associated with motor neurons were increased in all stages of DM progression, although only DM Late reached statistical significance. Furthermore, the number of arginase-1 expressing microglia per motor neuron were significantly increased in early stages of DM, whereas the number of inducible nitric oxide synthase (iNOS)-expressing microglia per motor neuron was indistinguishable from aged controls at all stages of disease. Fractalkine, a chemotactic molecule for microglia, was expressed in motor neurons, and the fractalkine receptor was specifically localized to microglia. However, we found no correlation between microglial response and lumbar spinal cord fractalkine levels. Taken together, these data suggest that arginase-1-expressing microglia are recruited to the motor neuron early in DM disease through a fractalkine-independent mechanism. Copyright © 2018 Elsevier Inc. All rights reserved.

Incidence and progression of aortic valve calcium in the Multi-ethnic Study of Atherosclerosis (MESA).

Science.gov (United States)

Owens, David S; Katz, Ronit; Takasu, Junichiro; Kronmal, Richard; Budoff, Matthew J; O'Brien, Kevin D

2010-03-01

Aortic valve calcium (AVC) is common among older adults and shares epidemiologic and histopathologic similarities to atherosclerosis. However, prospective studies have failed to identify meaningful risk associations with incident ("new") AVC or its progression. In the present study, AVC was quantified from serial computed tomographic images from 5,880 participants (aged 45 to 84 years) in the Multi-Ethnic Study of Atherosclerosis, using the Agatston method. Multivariate backward selection modeling was used to identify the risk factors for incident AVC and AVC progression. During a mean follow-up of 2.4 +/- 0.9 years, 210 subjects (4.1%) developed incident AVC. The incidence rate (mean 1.7%/year) increased significantly with age (p AVC included age, male gender, body mass index, current smoking, and the use of lipid-lowering and antihypertensive medications. Among those with AVC at baseline, the median rate of AVC progression was 2 Agatston units/year (interquartile range -21 to 37). The baseline Agatston score was a strong, independent predictor of progression, especially among those with high calcium scores at baseline. In conclusion, in this ethnically diverse, preclinical cohort, the rate of incident AVC increased significantly with age. The incident AVC risk was associated with several traditional cardiovascular risk factors, specifically age, male gender, body mass index, current smoking, and the use of both antihypertensive and lipid-lowering medications. AVC progression risk was associated with male gender and the baseline Agatston score. Additional research is needed to determine whether age- and stage-specific mechanisms underlie the risk of AVC progression. Copyright 2010 Elsevier Inc. All rights reserved.

Smoldering multiple myeloma risk factors for progression

DEFF Research Database (Denmark)

Sørrig, Rasmus; Klausen, Tobias W; Salomo, Morten

2016-01-01

Several risk scores for disease progression in Smoldering Multiple Myeloma (SMM) patients have been proposed, however, all have been developed using single center registries. To examine risk factors for time to progression (TTP) to Multiple Myeloma (MM) for SMM we analyzed a nationwide population......-based cohort of 321 newly diagnosed SMM patients registered within the Danish Multiple Myeloma Registry between 2005 and 2014. Significant univariable risk factors for TTP were selected for multivariable Cox regression analyses. We found that both an M-protein ≥ 30g/l and immunoparesis significantly influenced......-high risk of transformation to MM. Using only immunoparesis and M-protein ≥ 30g/l, we created a scoring system to identify low, intermediate and high risk SMM. This first population-based study of SMM patients confirms that an M-protein ≥ 30g/l and immunoparesis remain important risk factors for progression...

Behavioral and Academic Progress of Children Displaying Substantive ADHD Behaviors in Special Education: A 1-Year Follow-up.

Science.gov (United States)

Stoutjesdijk, Regina; Scholte, Evert M; Swaab, Hanna

2016-01-01

Exploring differences in behavioral and academic progress between children displaying substantive ADHD behaviors (M age of 9.4 years) in special schools (n = 38) and in inclusive education (n = 26). The contribution of pedagogical strategies to positive outcomes was also examined. Measurements used were the Teachers' Report Form, the Social Emotional Questionnaire, assessments of academic achievement, and the Pedagogical Methods Questionnaire. Mixed-model ANOVAs and Pearson's correlations were used to analyze the data. Significant progress was found regarding disorder-specific problem behavior and in all academic areas, but no interaction effect was found between time and setting. Correlations indicated that positive behavior reinforcement and emotional support are the pedagogical strategies that contributed most to behavioral adaptation. Children displaying substantive ADHD behaviors in both groups develop equally well in the areas of behavioral and academic functioning where significant progress was found. © The Author(s) 2013.

Long-term exposure to hypoxia inhibits tumor progression of lung cancer in rats and mice

International Nuclear Information System (INIS)

Yu, Lunyin; Hales, Charles A

2011-01-01

Hypoxia has been identified as a major negative factor for tumor progression in clinical observations and in animal studies. However, the precise role of hypoxia in tumor progression has not been fully explained. In this study, we extensively investigated the effect of long-term exposure to hypoxia on tumor progression in vivo. Rats bearing transplanted tumors consisting of A549 human lung cancer cells (lung cancer tumor) were exposed to hypoxia for different durations and different levels of oxygen. The tumor growth and metastasis were evaluated. We also treated A549 lung cancer cells (A549 cells) with chronic hypoxia and then implanted the hypoxia-pretreated cancer cells into mice. The effect of exposure to hypoxia on metastasis of Lewis lung carcinoma in mice was also investigated. We found that long-term exposure to hypoxia a) significantly inhibited lung cancer tumor growth in xenograft and orthotopic models in rats, b) significantly reduced lymphatic metastasis of the lung cancer in rats and decreased lung metastasis of Lewis lung carcinoma in mice, c) reduced lung cancer cell proliferation and cell cycle progression in vitro, d) decreased growth of the tumors from hypoxia-pretreated A549 cells, e) decreased Na + -K + ATPase α1 expression in hypoxic lung cancer tumors, and f) increased expression of hypoxia inducible factors (HIF1α and HIF2α) but decreased microvessel density in the lung cancer tumors. In contrast to lung cancer, the growth of tumor from HCT116 human colon cancer cells (colon cancer tumor) was a) significantly enhanced in the same hypoxia conditions, accompanied by b) no significant change in expression of Na + -K + ATPase α1, c) increased HIF1α expression (no HIF2α was detected) and d) increased microvessel density in the tumor tissues. This study demonstrated that long-term exposure to hypoxia repressed tumor progression of the lung cancer from A549 cells and that decreased expression of Na + -K + ATPase was involved in hypoxic

A Multiscale Agent-Based in silico Model of Liver Fibrosis Progression

Energy Technology Data Exchange (ETDEWEB)

Dutta-Moscato, Joyeeta [Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA (United States); Department of Surgery, University of Pittsburgh, Pittsburgh, PA (United States); Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Solovyev, Alexey [Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Department of Mathematics, University of Pittsburgh, Pittsburgh, PA (United States); Mi, Qi [Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Department of Sports Medicine and Nutrition, University of Pittsburgh, Pittsburgh, PA (United States); Nishikawa, Taichiro [McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Department of Surgery, Children’s Hospital of Pittsburgh, Pittsburgh, PA (United States); Soto-Gutierrez, Alejandro [McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Department of Pathology, University of Pittsburgh, Pittsburgh, PA (United States); Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA (United States); Fox, Ira J. [McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Department of Surgery, Children’s Hospital of Pittsburgh, Pittsburgh, PA (United States); Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA (United States); Vodovotz, Yoram, E-mail: vodovotzy@upmc.edu [Department of Surgery, University of Pittsburgh, Pittsburgh, PA (United States); Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA (United States)

2014-05-30

Chronic hepatic inflammation involves a complex interplay of inflammatory and mechanical influences, ultimately manifesting in a characteristic histopathology of liver fibrosis. We created an agent-based model (ABM) of liver tissue in order to computationally examine the consequence of liver inflammation. Our liver fibrosis ABM (LFABM) is comprised of literature-derived rules describing molecular and histopathological aspects of inflammation and fibrosis in a section of chemically injured liver. Hepatocytes are modeled as agents within hexagonal lobules. Injury triggers an inflammatory reaction, which leads to activation of local Kupffer cells and recruitment of monocytes from circulation. Portal fibroblasts and hepatic stellate cells are activated locally by the products of inflammation. The various agents in the simulation are regulated by above-threshold concentrations of pro- and anti-inflammatory cytokines and damage-associated molecular pattern molecules. The simulation progresses from chronic inflammation to collagen deposition, exhibiting periportal fibrosis followed by bridging fibrosis, and culminating in disruption of the regular lobular structure. The ABM exhibited key histopathological features observed in liver sections from rats treated with carbon tetrachloride (CCl{sub 4}). An in silico “tension test” for the hepatic lobules predicted an overall increase in tissue stiffness, in line with clinical elastography literature and published studies in CCl{sub 4}-treated rats. Therapy simulations suggested differential anti-fibrotic effects of neutralizing tumor necrosis factor alpha vs. enhancing M2 Kupffer cells. We conclude that a computational model of liver inflammation on a structural skeleton of physical forces can recapitulate key histopathological and macroscopic properties of CCl{sub 4}-injured liver. This multiscale approach linking molecular and chemomechanical stimuli enables a model that could be used to gain translationally relevant

A B Cell-Driven Autoimmune Pathway Leading to Pathological Hallmarks of Progressive Multiple Sclerosis in the Marmoset Experimental Autoimmune Encephalomyelitis Model

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Bert A. ’t Hart

2017-07-01

Full Text Available The absence of pathological hallmarks of progressive multiple sclerosis (MS in commonly used rodent models of experimental autoimmune encephalomyelitis (EAE hinders the development of adequate treatments for progressive disease. Work reviewed here shows that such hallmarks are present in the EAE model in marmoset monkeys (Callithrix jacchus. The minimal requirement for induction of progressive MS pathology is immunization with a synthetic peptide representing residues 34–56 from human myelin oligodendrocyte glycoprotein (MOG formulated with a mineral oil [incomplete Freund’s adjuvant (IFA]. Pathological aspects include demyelination of cortical gray matter with microglia activation, oxidative stress, and redistribution of iron. When the peptide is formulated in complete Freund’s adjuvant, which contains mycobacteria that relay strong activation signals to myeloid cells, oxidative damage pathways are strongly boosted leading to more intensive pathology. The proven absence of immune potentiating danger signals in the MOG34–56/IFA formulation implies that a narrow population of antigen-experienced T cells present in the monkey’s immune repertoire is activated. This novel pathway involves the interplay of lymphocryptovirus-infected B cells with MHC class Ib/Caja-E restricted CD8+ CD56+ cytotoxic T lymphocytes.

Recent progress in safety-related applications of reactor noise analysis

International Nuclear Information System (INIS)

Hirota, Jitsuya; Shinohara, Yoshikuni; Saito, Keiichi

1982-01-01

Recent progress in safety-related applications of reactor noise analysis is reviewed, mainly referring to various papers presented at the Third Specialists' Meeting on Reactor Noise (SMORN-III) held in Tokyo in 1981. Advances in application of autoregressive model, coherence analysis and pattern recognition technique are significant since SMORN-II in 1977. Development of reactor diagnosis systems based on noise analysis is in progress. Practical experiences in the safety-related applications to power plants are being accumulated. Advances in quantitative monitoring of vibration of internal structures in PWR and diagnosis of core stability and control system characteristics in BWR are notable. Acoustic methods are also improved to detect sodium boiling in LMFBR. The Reactor Noise Analysis Benchmark Test performed by Japan in connection with SMORN-III is successful so that it is possible to proceed to the second stage of the benchmark test. (author)

Progression og underviserkompetencer

Directory of Open Access Journals (Sweden)

Lene Tortzen Bager

2014-03-01

Full Text Available På baggrund af en kvalitativ interviewundersøgelse af undervisere ved Aarhus Universitet lavet i 2012, tematiserer artiklen, hvordan undervisere udvikler deres faglige og pædagogiske kompetencer i forhold til at kunne skabe progression inden for innovation og entreprenørskab forstået enten som didaktik, arbejdsformer i faglige forløb eller som fag på universitetet. I arbejdet med progression er det en udfordring at integrere de nye faglige dimensioner i det kernefaglige felt. Den seneste model for progression inden for innovation og entreprenør-skab siger, at det er den lærendes generelle erfaringsniveau, der er den afgørende progressionsskabende faktor (Progressionsmodellen, Fonden for Entreprenørskab, 2013b. Samtidig skelner international forskning inden for studiekompetenceområdet mellem niveauer, hvor indlejret viden er det mest avancerede kompetenceniveau (Barrie, 2002.Ifølge progressionsmodellen og den nævnte kompetenceforskning er erfaring og dybt integreret læring altså centrale dimensioner i progression. Men hvad er underviserens rolle heri? Underviserens professionelle udviklingsarbejde forekommer at være underbelyst i forhold til, at underviseren er den legitime garant for integrationen af nye faglige dimensioner og for den studerendes kompetenceniveau. Interviewundersøgelsen forholder sig til spørgsmålet om progression gennem de deltagende underviseres beskrivelse af betydningslag i entreprenørskabsbegrebet koblet til de praksisformer i undervisningen, der knytter sig hertil samt et indblik i undervisernes refleksioner over deres kompetenceudviklingsprocesser. Artiklens bidrag til progression er at se underviserens motivation og kompetenceudvikling som forudsætninger herfor.     Based on a qualitative study of five teachers in the Faculty of Arts at Aarhus University that took place during 2012, the article thematizes how teachers develop their professional and educational qualifications in innovation and

PREDICTIVE FACTORS FOR THE PROGRESSION OF CHRONIC CHAGAS CARDIOMYOPATHY IN PATIENTS WITHOUT LEFT VENTRICULAR DYSFUNCTION

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Silvana de Araújo SILVA

2015-04-01

Full Text Available The identification of predictors for the progression of chronic Chagas cardiomyopathy (CCC is essential to ensure adequate patient management. This study looked into a non-concurrent cohort of 165 CCC patients between 1985 and 2010 for independent predictors for CCC progression. The outcomes were worsening of the CCC scores and the onset of left ventricular dysfunction assessed by means of echo-Doppler cardiography. Patients were analyzed for social, demographic, epidemiologic, clinical and workup-related variables. A descriptive analysis was conducted, followed by survival curves based on univariate (Kaplan-Meier and Cox’s univariate model and multivariate (Cox regression model analysis. Patients were followed from two to 20 years (mean: 8.2. Their mean age was 44.8 years (20-77. Comparing both iterations of the study, in the second there was a statistically significant increase in the PR interval and in the QRS duration, despite a reduction in heart rates (Wilcoxon < 0.01. The predictors for CCC progression in the final regression model were male gender (HR = 2.81, Holter monitoring showing pauses equal to or greater than two seconds (HR = 3.02 increased cardiothoracic ratio (HR = 7.87 and time of use of digitalis (HR = 1.41. Patients with multiple predictive factors require stricter follow-up and treatment.

Empirical Refinements of a Molecular Genetics Learning Progression: The Molecular Constructs

Science.gov (United States)

Todd, Amber; Kenyon, Lisa

2016-01-01

This article describes revisions to four of the eight constructs of the Duncan molecular genetics learning progression [Duncan, Rogat, & Yarden, (2009)]. As learning progressions remain hypothetical models until validated by multiple rounds of empirical studies, these revisions are an important step toward validating the progression. Our…

Disease progression and phasic changes in gene expression in a mouse model of osteoarthritis.

Directory of Open Access Journals (Sweden)

Richard F Loeser

Full Text Available Osteoarthritis (OA is the most common form of arthritis and has multiple risk factors including joint injury. The purpose of this study was to characterize the histologic development of OA in a mouse model where OA is induced by destabilization of the medial meniscus (DMM model and to identify genes regulated during different stages of the disease, using RNA isolated from the joint "organ" and analyzed using microarrays. Histologic changes seen in OA, including articular cartilage lesions and osteophytes, were present in the medial tibial plateaus of the DMM knees beginning at the earliest (2 week time point and became progressively more severe by 16 weeks. 427 probe sets (371 genes from the microarrays passed consistency and significance filters. There was an initial up-regulation at 2 and 4 weeks of genes involved in morphogenesis, differentiation, and development, including growth factor and matrix genes, as well as transcription factors including Atf2, Creb3l1, and Erg. Most genes were off or down-regulated at 8 weeks with the most highly down-regulated genes involved in cell division and the cytoskeleton. Gene expression increased at 16 weeks, in particular extracellular matrix genes including Prelp, Col3a1 and fibromodulin. Immunostaining revealed the presence of these three proteins in cartilage and soft tissues including ligaments as well as in the fibrocartilage covering osteophytes. The results support a phasic development of OA with early matrix remodeling and transcriptional activity followed by a more quiescent period that is not maintained. This implies that the response to an OA intervention will depend on the timing of the intervention. The quiescent period at 8 weeks may be due to the maturation of the osteophytes which are thought to temporarily stabilize the joint.

How cold was Europe at the Last Glacial Maximum? A synthesis of the progress achieved since the first PMIP model-data comparison

Directory of Open Access Journals (Sweden)

G. Ramstein

2007-06-01

Full Text Available The Last Glacial Maximum has been one of the first foci of the Paleoclimate Modelling Intercomparison Project (PMIP. During its first phase, the results of 17 atmosphere general circulation models were compared to paleoclimate reconstructions. One of the largest discrepancies in the simulations was the systematic underestimation, by at least 10°C, of the winter cooling over Europe and the Mediterranean region observed in the pollen-based reconstructions. In this paper, we investigate the progress achieved to reduce this inconsistency through a large modelling effort and improved temperature reconstructions. We show that increased model spatial resolution does not significantly increase the simulated LGM winter cooling. Further, neither the inclusion of a vegetation cover compatible with the LGM climate, nor the interactions with the oceans simulated by the atmosphere-ocean general circulation models run in the second phase of PMIP result in a better agreement between models and data. Accounting for changes in interannual variability in the interpretation of the pollen data does not result in a reduction of the reconstructed cooling. The largest recent improvement in the model-data comparison has instead arisen from a new climate reconstruction based on inverse vegetation modelling, which explicitly accounts for the CO₂ decrease at LGM and which substantially reduces the LGM winter cooling reconstructed from pollen assemblages. As a result, the simulated and observed LGM winter cooling over Western Europe and the Mediterranean area are now in much better agreement.

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.

Attenuation of radiological consequences from CDA's by radiation. Progress report, October 1, 1976--September 31, 1977

International Nuclear Information System (INIS)

Chan, S.H.

1977-01-01

This technical progress report summarizes the research work accomplished during the first six months of the investigation on the significance of radiation heat transfer in attenuating the radiological consequences from LMFBR core disruptive accidents. Considerable progress has been made in modeling and computing the effects of radiative cooling on a rising HCDA bubble buoyant through a sodium pool. Our results reveal that most of the fuel vapor within the bubble can be effectively condensed out by radiating cooling. The finding has a profound implication as it could lead to a substantial reduction in subsequent aerosal releases

An Argument for Formative Assessment with Science Learning Progressions

Science.gov (United States)

Alonzo, Alicia C.

2018-01-01

Learning progressions--particularly as defined and operationalized in science education--have significant potential to inform teachers' formative assessment practices. In this overview article, I lay out an argument for this potential, starting from definitions for "formative assessment practices" and "learning progressions"…

Use of dispersion modelling for Environmental Impact Assessment of biological air pollution from composting: Progress, problems and prospects.

Science.gov (United States)

Douglas, P; Hayes, E T; Williams, W B; Tyrrel, S F; Kinnersley, R P; Walsh, K; O'Driscoll, M; Longhurst, P J; Pollard, S J T; Drew, G H

2017-12-01

With the increase in composting asa sustainable waste management option, biological air pollution (bioaerosols) from composting facilities have become a cause of increasing concern due to their potential health impacts. Estimating community exposure to bioaerosols is problematic due to limitations in current monitoring methods. Atmospheric dispersion modelling can be used to estimate exposure concentrations, however several issues arise from the lack of appropriate bioaerosol data to use as inputs into models, and the complexity of the emission sources at composting facilities. This paper analyses current progress in using dispersion models for bioaerosols, examines the remaining problems and provides recommendations for future prospects in this area. A key finding is the urgent need for guidance for model users to ensure consistent bioaerosol modelling practices. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Usefulness of optic nerve ultrasound to predict clinical progression in multiple sclerosis.

Science.gov (United States)

Pérez Sánchez, S; Eichau Madueño, S; Rus Hidalgo, M; Domínguez Mayoral, A M; Vilches-Arenas, A; Navarro Mascarell, G; Izquierdo, G

2018-03-21

Progressive neuronal and axonal loss are considered the main causes of disability in patients with multiple sclerosis (MS). The disease frequently involves the visual system; the accessibility of the system for several functional and structural tests has made it a model for the in vivo study of MS pathogenesis. Orbital ultrasound is a non-invasive technique that enables various structures of the orbit, including the optic nerve, to be evaluated in real time. We conducted an observational, ambispective study of MS patients. Disease progression data were collected. Orbital ultrasound was performed on all patients, with power set according to the 'as low as reasonably achievable' (ALARA) principle. Optical coherence tomography (OCT) data were also collected for those patients who underwent the procedure. Statistical analysis was conducted using SPSS version 22.0. Disease progression was significantly correlated with ultrasound findings (P=.041 for the right eye and P=.037 for the left eye) and with Expanded Disability Status Scale (EDSS) score at the end of the follow-up period (P=.07 for the right eye and P=.043 for the left eye). No statistically significant differences were found with relation to relapses or other clinical variables. Ultrasound measurement of optic nerve diameter constitutes a useful, predictive factor for the evaluation of patients with MS. Smaller diameters are associated with poor clinical progression and greater disability (measured by EDSS). Copyright © 2018 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Study of progressive depigmentation of dog′s muzzle

OpenAIRE

Shah K

1991-01-01

A new animal model is developed using dog′s muzzle to demonstrate progressive depigmen-tation after birth. Dog′s muzzle is heavily pigmented with pigment melanin and looks black in colour. Progressive depigmentation was observed two months after birth in a pup born with a depigmented mucous membrane of the mouth and lips. This resembles the vitiligo of humans.

Fe model predicting the increase in seismic resistance induced by the progressive FRP strengthening on already damaged masonry arches subjected to settlement

Science.gov (United States)

Stockdale, G.; Milani, G.

2017-11-01

In seismic regions, the retrofitting of masonry structures subjected to differential foundation settlements is of the upmost importance. This practice however poses significant challenges, most notably in the consideration of historical monuments where the integrity of the original structure must be weighted alongside public safety. Fiber reinforced polymers (FRPs), when appropriately applied, provide the potential to balance this duality of heritage preservation and modern safety. Using an advanced FE point of view, this work studies the seismic response of a progressive reinforcement strategy aimed at strengthening and controlling the failure mechanism for masonry arches that exist in a damaged state induced through a differential abutment settlement. A heterogeneous FE approach of a semi-circular block and mortar arch on continuously spreading supports is examined. In this model hinge formation is obtained by assigning a damage plasticity behavior to the mortar joints. Strategically placed FRPs, designed through the utilization of the Italian CNR recommendations for externally bonded FRP systems, are applied through the Abaqus birth and death approach and introduced to the spreading support model after settlement. Finally, the structural behavior of the reinforced and unreinforced models are examined for a seismic response.

Using Markov Chains to predict the natural progression of diabetic retinopathy.

Science.gov (United States)

Srikanth, Priyanka

2015-01-01

To study the natural progression of diabetic retinopathy in patients with type 2 diabetes. This was an observational study of 153 cases with type 2 diabetes from 2010 to 2013. The state of patient was noted at end of each year and transition matrices were developed to model movement between years. Patients who progressed to severe non-proliferative diabetic retinopathy (NPDR) were treated. Markov Chains and Chi-square test were used for statistical analysis. We modelled the transition of 153 patients from NPDR to blindness on an annual basis. At the end of year 3, we compared results from the Markov model versus actual data. The results from Chi-square test confirmed that there was statistically no significant difference (P=0.70) which provided assurance that the model was robust to estimate mean sojourn times. The key finding was that a patient entering the system in mild NPDR state is expected to stay in that state for 5y followed by 1.07y in moderate NPDR, be in the severe NPDR state for 1.33y before moving into PDR for roughly 8y. It is therefore expected that such a patient entering the model in a state of mild NPDR will enter blindness after 15.29y. Patients stay for long time periods in mild NPDR before transitioning into moderate NPDR. However, they move rapidly from moderate NPDR to proliferative diabetic retinopathy (PDR) and stay in that state for long periods before transitioning into blindness.

Technological Progress, Exit and Trade

DEFF Research Database (Denmark)

Schröder, Philipp; Sørensen, Allan

productivity exporters are more likely to continue to export, and market exit is typically preceded by periods of contracting market shares. We show that the simple inclusion of exogenous economy wide technological progress into the standard Melitz (2003) model generates a tractable dynamic framework...

Azimuth cut-off model for significant wave height investigation along coastal water of Kuala Terengganu, Malaysia

Science.gov (United States)

Marghany, Maged; Ibrahim, Zelina; Van Genderen, Johan

2002-11-01

The present work is used to operationalize the azimuth cut-off concept in the study of significant wave height. Three ERS-1 images have been used along the coastal waters of Terengganu, Malaysia. The quasi-linear transform was applied to map the SAR wave spectra into real ocean wave spectra. The azimuth cut-off was then used to model the significant wave height. The results show that azimuth cut-off varied with the different period of the ERS-1 images. This is because of the fact that the azimuth cut-off is a function of wind speed and significant wave height. It is of interest to find that the significant wave height modeled from azimuth cut-off is in good relation with ground wave conditions. It can be concluded that ERS-1 can be used as a monitoring tool in detecting the significant wave height variation. The azimuth cut-off can be used to model the significant wave height. This means that the quasi-linear transform could be a good application to significant wave height variation during different seasons.

Significance of settling model structures and parameter subsets in modelling WWTPs under wet-weather flow and filamentous bulking conditions.

Science.gov (United States)

Ramin, Elham; Sin, Gürkan; Mikkelsen, Peter Steen; Plósz, Benedek Gy

2014-10-15

Current research focuses on predicting and mitigating the impacts of high hydraulic loadings on centralized wastewater treatment plants (WWTPs) under wet-weather conditions. The maximum permissible inflow to WWTPs depends not only on the settleability of activated sludge in secondary settling tanks (SSTs) but also on the hydraulic behaviour of SSTs. The present study investigates the impacts of ideal and non-ideal flow (dry and wet weather) and settling (good settling and bulking) boundary conditions on the sensitivity of WWTP model outputs to uncertainties intrinsic to the one-dimensional (1-D) SST model structures and parameters. We identify the critical sources of uncertainty in WWTP models through global sensitivity analysis (GSA) using the Benchmark simulation model No. 1 in combination with first- and second-order 1-D SST models. The results obtained illustrate that the contribution of settling parameters to the total variance of the key WWTP process outputs significantly depends on the influent flow and settling conditions. The magnitude of the impact is found to vary, depending on which type of 1-D SST model is used. Therefore, we identify and recommend potential parameter subsets for WWTP model calibration, and propose optimal choice of 1-D SST models under different flow and settling boundary conditions. Additionally, the hydraulic parameters in the second-order SST model are found significant under dynamic wet-weather flow conditions. These results highlight the importance of developing a more mechanistic based flow-dependent hydraulic sub-model in second-order 1-D SST models in the future. Copyright © 2014 Elsevier Ltd. All rights reserved.

Progress in InP solar cell research

International Nuclear Information System (INIS)

Weinberg, I.; Brinker, D.J.

1988-01-01

Progress, in the past year, in InP solar cell research is reviewed. Small area cells with AMO, total area efficiencies of 18.8 percent were produced by OMCVD and Ion Implantation. Larger area cells (2 and 4 sq cm) were processed on a production basis. One thousand of the 2 sq cm cells will be used to supply power to a small piggyback lunar orbiter scheduled for launch in February 1990. Laboratory tests of ITO/InP cells, under 10 MeV proton irradiation, indicate radiation resistance comparable to InP n/p homojunction cells. Computer modeling studies indicate that, for identical geometries and dopant concentrations, InP solar cells are significantly more radiation resistant than GaAs under 1 MeV electron irradiation. Additional computer modeling calculations were used to produce rectangular and circular InP concentrator cell designs for both the low concentration SLATS and higher concentration Cassegrainian Concentrators

Progressive polyuria without vasopressin neuron loss in a mouse model for familial neurohypophysial diabetes insipidus.

Science.gov (United States)

Hayashi, Masayuki; Arima, Hiroshi; Ozaki, Noriyuki; Morishita, Yoshiaki; Hiroi, Maiko; Ozaki, Nobuaki; Nagasaki, Hiroshi; Kinoshita, Noriaki; Ueda, Masatsugu; Shiota, Akira; Oiso, Yutaka

2009-05-01

Familial neurohypophysial diabetes insipidus (FNDI), an autosomal dominant disorder, is mostly caused by mutations in the gene of neurophysin II (NPII), the carrier protein of arginine vasopressin (AVP). Previous studies suggest that loss of AVP neurons might be the cause of polyuria in FNDI. Here we analyzed knockin mice expressing mutant NPII that causes FNDI in humans. The heterozygous mice manifested progressive polyuria as do patients with FNDI. Immunohistochemical analyses revealed that inclusion bodies that were not immunostained with antibodies for mutant NPII, normal NPII, or AVP were present in the AVP cells in the supraoptic nucleus (SON), and that the size of inclusion bodies gradually increased in parallel with the increases in urine volume. Electron microscopic analyses showed that aggregates existed in the endoplasmic reticulum (ER) as well as in the nucleus of AVP neurons in 1-mo-old heterozygous mice. At 12 mo, dilated ER filled with aggregates occupied the cytoplasm of AVP cells, while few aggregates were found in the nucleus. Analyses with in situ hybridization revealed that expression of AVP mRNA was significantly decreased in the SON in the heterozygous mice compared with that in wild-type mice. Counting cells expressing AVP mRNA in the SON indicated that polyuria had progressed substantially in the absence of neuronal loss. These data suggest that cell death is not the primary cause of polyuria in FNDI, and that the aggregates accumulated in the ER might be involved in the dysfunction of AVP neurons that lead to the progressive polyuria.

Topical Loperamide-Encapsulated Liposomal Gel Increases the Severity of Inflammation and Accelerates Disease Progression in the Adjuvant-Induced Model of Experimental Rheumatoid Arthritis

Directory of Open Access Journals (Sweden)

Susan Hua

2017-08-01

Full Text Available This study evaluates the prophylactic effect of the peripherally-selective mu-opioid receptor agonist, loperamide, administered topically in a liposomal gel formulation on pain, inflammation, and disease progression in the adjuvant-induced model of experimental rheumatoid arthritis in female Lewis rats. In a randomized, blinded and controlled animal trial, AIA rats were divided into six groups consisting of eleven rats per group based on the following treatments: loperamide liposomal gel, free loperamide gel, empty liposomal gel, diclofenac gel (Voltaren®, no treatment, and naive control. Topical formulations were applied daily for a maximum of 17 days—starting from day 0 at the same time as immunization. The time course of the effect of the treatments on antinocieption and inflammation was assessed using a paw pressure analgesiometer and plethysmometer, respectively. Arthritis progression was scored daily using an established scoring protocol. At the end of the study, hind paws were processed for histological analysis. Administration of loperamide liposomal gel daily across the duration of the study produced significant peripheral antinociception as expected; however, increased the severity of inflammation and accelerated arthritis progression. This was indicated by an increase in paw volume, behavioral and observational scoring, and histological analysis compared to the control groups. In particular, histology results showed an increase in pannus formation and synovial inflammation, as well as an upregulation of markers of inflammation and angiogenesis. These findings may have implications for the use of loperamide and other opioids in arthritis and potentially other chronic inflammatory diseases.

Psychosocial predictors of coronary artery calcification progression in postmenopausal women.

Science.gov (United States)

Low, Carissa A; Matthews, Karen A; Kuller, Lewis H; Edmundowicz, Daniel

2011-01-01

Coronary artery calcification (CAC) has been associated with psychosocial factors in some but not all cross-sectional analyses. The goal of this study was to determine whether positive and negative psychosocial factors prospectively predict CAC progression in postmenopausal women. Participants from the Healthy Women Study who also participated in the Pittsburgh Mind-Body Center protocol (n = 149) completed self-report psychosocial measures before two electron beam computed tomographic scans of CAC separated by an average of 3.3 years. Results of exploratory factor analysis were used to create aggregate psychosocial indices: psychological risk (depressive symptoms, perceived stress, cynicism, and anger-in) and psychosocial resources (optimism, purpose in life, mastery, self-esteem, and social support). The psychological risk index predicted significantly greater CAC progression over 3 years (β = 0.16, p = .035, ΔR(2) = 0.03), whereas the psychosocial resources index was not predictive of CAC progression (β = -0.08, p = .30, ΔR(2) = 0.01). On individual scales, higher scores on cynicism emerged as a significant predictor of CAC progression, along with a trend linking anger-in to atherosclerosis progression. A post hoc analysis showed a significant interaction between cynicism and anger-in (β = 0.20, p = .01, ΔR(2) = 0.03), such that women reporting high levels of both cynicism and anger suppression exhibited the most CAC progression. These findings highlight psychosocial risk factors that may accelerate the progression of subclinical atherosclerosis in older women, suggest the potential importance of examining combinations of psychosocial risk factors, and identify potential targets for psychological interventions to reduce cardiovascular risk.

Progressive Classification Using Support Vector Machines

Science.gov (United States)

Wagstaff, Kiri; Kocurek, Michael

2009-01-01

An algorithm for progressive classification of data, analogous to progressive rendering of images, makes it possible to compromise between speed and accuracy. This algorithm uses support vector machines (SVMs) to classify data. An SVM is a machine learning algorithm that builds a mathematical model of the desired classification concept by identifying the critical data points, called support vectors. Coarse approximations to the concept require only a few support vectors, while precise, highly accurate models require far more support vectors. Once the model has been constructed, the SVM can be applied to new observations. The cost of classifying a new observation is proportional to the number of support vectors in the model. When computational resources are limited, an SVM of the appropriate complexity can be produced. However, if the constraints are not known when the model is constructed, or if they can change over time, a method for adaptively responding to the current resource constraints is required. This capability is particularly relevant for spacecraft (or any other real-time systems) that perform onboard data analysis. The new algorithm enables the fast, interactive application of an SVM classifier to a new set of data. The classification process achieved by this algorithm is characterized as progressive because a coarse approximation to the true classification is generated rapidly and thereafter iteratively refined. The algorithm uses two SVMs: (1) a fast, approximate one and (2) slow, highly accurate one. New data are initially classified by the fast SVM, producing a baseline approximate classification. For each classified data point, the algorithm calculates a confidence index that indicates the likelihood that it was classified correctly in the first pass. Next, the data points are sorted by their confidence indices and progressively reclassified by the slower, more accurate SVM, starting with the items most likely to be incorrectly classified. The user

Static Progressive Orthoses for Elbow Contracture: A Systematic Review

Directory of Open Access Journals (Sweden)

Bin Chen

2017-01-01

Full Text Available Background. As one of the most common musculoskeletal complications following trauma, elbow contracture is a frequent source of disabled daily activities. Conventional interventions are inadequate to provide favorable outcome. The static progressive orthoses are getting popular in the treatment of this problem. Objective. The purpose of this review was to assess the effectiveness of static progressive orthoses for elbow contracture. Methods. Literatures when written in English published during 1 January 1997 and 31 January 2017 were searched in the following databases: Web of Science, Cochrane Library, PubMed, and EBSCOhost. Articles are quality-assessed by two assessors, each article was summarized in evidence tables, and a narrative synthesis was also performed. Results. Ten clinical trials were included. The study design and outcome measures used varied. Significant immediate improvement in the range of motion was reported by all studies, and those effects were still significant at follow-up. No significant difference was shown between static progressive and dynamic orthoses for elbow contracture in one randomized control trial. Conclusions. Current low-quality evidence suggested that static progressive orthoses provided assistance for elbow contracture through improving range of motion. Further research is recommended using high-quality randomized controlled trials.

Evaluating progressive-rendering algorithms in appearance design tasks.

Science.gov (United States)

Jiawei Ou; Karlik, Ondrej; Křivánek, Jaroslav; Pellacini, Fabio

2013-01-01

Progressive rendering is becoming a popular alternative to precomputational approaches to appearance design. However, progressive algorithms create images exhibiting visual artifacts at early stages. A user study investigated these artifacts' effects on user performance in appearance design tasks. Novice and expert subjects performed lighting and material editing tasks with four algorithms: random path tracing, quasirandom path tracing, progressive photon mapping, and virtual-point-light rendering. Both the novices and experts strongly preferred path tracing to progressive photon mapping and virtual-point-light rendering. None of the participants preferred random path tracing to quasirandom path tracing or vice versa; the same situation held between progressive photon mapping and virtual-point-light rendering. The user workflow didn’t differ significantly with the four algorithms. The Web Extras include a video showing how four progressive-rendering algorithms converged (at http://youtu.be/ck-Gevl1e9s), the source code used, and other supplementary materials.

Progression and Regression of Hepatic Lesions in a Mouse Model of NASH Induced by Dietary Intervention and Its Implications in Pharmacotherapy

Directory of Open Access Journals (Sweden)

Zhi-Ming Ding

2018-05-01

Full Text Available Understanding of the temporal changes of hepatic lesions in the progression and regression of non-alcoholic steatohepatitis (NASH is vital to elucidation of the pathogenesis of NASH, and critical to the development of a strategy for NASH pharmacotherapy. There are challenges in studying hepatic lesion progression and regression in NASH patients due to the slow development of NASH in humans, one being the requirement for multiple biopsies during the longitudinal follow-up. Here we studied lesion progression and regression in the diet-induced animal model of NASH by application or removal of the pathogenic diet for multiple time periods. Male C57BL/6 mice fed Western diet developed progressive hepatic steatosis/macrovesicular vacuolation, inflammation, and hepatocyte degeneration, as well as perisinusoidal fibrosis and occasionally portal fibrosis as early as 2 months after initiation of the Western diet. In the same period, the mice exhibited elevated ALT (alanine aminotransferase and AST (aspartate aminotransferase enzyme activities, CK18 (cytokeratin−18, PIIINP (N-terminal propeptide of type III collagen, and TIMP-1 (tissue inhibitor of metalloproteinase−1. Hepatic steatosis diminished rapidly when the Western diet was replaced by normal rodent chow diet and hepatic inflammation and hepatocyte degeneration were also reduced. Interestingly, perisinusoidal fibrosis and portal fibrosis regressed 8 months after chow diet replacement. To understand pharmacotherapy for NASH, mice with established NASH hepatic lesions were treated with either FXR agonist obeticholic acid (Ocaliva, or CCR2/5 antagonist Cenicriviroc. Similar to the diet replacement, metabolic modulator Ocaliva markedly reduced steatosis/macrovesicular vacuolation, hepatic inflammation, and hepatocyte degeneration effectively, but exhibited no significant effect on liver fibrosis. Anti-inflammation drug Cenicriviroc, on the other hand, markedly decreased inflammation and hepatocyte

Tristetraprolin: A novel target of diallyl disulfide that inhibits the progression of breast cancer.

Science.gov (United States)

Xiong, Ting; Liu, Xiao-Wang; Huang, Xue-Long; Xu, Xiong-Feng; Xie, Wei-Quan; Zhang, Su-Jun; Tu, Jian

2018-05-01

Diallyl disulfide (DADS), a volatile component of garlic oil, has various biological properties, including antioxidant, antiangiogenic and anticancer effects. The present study aimed to explore novel targets of DADS that may slow or stop the progression of breast cancer. First, xenograft tumor models were created by subcutaneously injecting MCF-7 and MDA-MB-231 breast cancer cells into nude mice. Subsequently, western blot analysis was performed to investigate the expression of tristetraprolin (TTP), urokinase-type plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP-9) in the xenograft tumors, and cell cultures. Tablet cloning, Transwell and wound healing assays revealed that DADS treatment significantly inhibited the proliferation, invasion and migration of breast cancer cells. In addition, DADS treatment led to significant downregulation of uPA and MMP-9 protein expression, but significantly upregulated TTP expression in vivo and in vitro . Knocking down TTP expression using small interfering RNA reversed the aforementioned effects of DADS, which suggests TTP is a key target of DADS in inhibiting the progression of breast cancer.

Regression of Nonalcoholic Fatty Liver Disease with Zinc and Selenium Co-supplementation after Disease Progression in Rats.

Science.gov (United States)

Shidfar, Farzad; Faghihi, Amirhosein; Amiri, Hamid Lorvand; Mousavi, Seyedeh Neda

2018-01-01

Studies have shown that zinc and selenium deficiency is common in nonalcoholic fatty liver disease (NAFLD). However, the effects of zinc and selenium co-supplementation before and/or after disease progression on NAFLD are not clear enough. The aim of this study was to compare the effects of zinc and selenium co-supplementation before and/or after disease progression on NAFLD prognosis. Forty male Sprague-Dawley rats (197±4 g) were randomly assigned to 4 dietary groups: normal-fat diet (NFD; receiving 9% of calories as fat), high-fat diet (HFD; receiving 82% of calories as fat), supplementation before disease progression (S+HFD), and supplementation after disease progression (HFD+S). The diets were implemented over a 20-week period in all the groups. Biochemical and histologic parameters were compared between the 4 groups, and between-group comparisons were also carried out. There were significant differences in the average food dietary intake (P<0.001), weight (P<0.001), fasting blood sugar (P=0.005), triglyceride (P<0.001), total cholesterol (P<0.001), low-density lipoprotein cholesterol (P=0.002), high-density lipoprotein cholesterol (P=0.001), alanine aminotransferase (P<0.001), and aspartate aminotransferase (P<0.001) between the 4 dietary groups. Serum triglyceride and total cholesterol were significantly lower in the HFD+S Group than in the S+HFD Group (P<0.001 and P=0.003, respectively). Fat accumulation was significantly reduced in the HFD+S Group (P<0.001). Zinc and selenium co-supplementation after disease progression improved biochemical and histologic parameters in an experimental model of NAFLD.

Mineral cycling in soil and litter arthropod food chains. Annual progress report, February 1, 1983-January 31, 1984

International Nuclear Information System (INIS)

Crossley, D.A. Jr.

1983-01-01

This annual report describes progress in research on the influence of soil fauna on the general process of terrestrial decomposition. The major goal is to investigate the regulation of decomposition by soil arthropods. Methods have included radioactive tracer measurements of food chain dynamics, rates of nutrient or mineral element flow during decomposition, and simulation modeling. This year's report describes significant progress in defining the influence of soil arthropods in stimulating microbial immobilization of nutrients. Preliminary efforts to define the importance of the soil-litter macroarthropods are also reported

Study of progressive depigmentation of dog′s muzzle

Directory of Open Access Journals (Sweden)

Shah K

1991-01-01

Full Text Available A new animal model is developed using dog′s muzzle to demonstrate progressive depigmen-tation after birth. Dog′s muzzle is heavily pigmented with pigment melanin and looks black in colour. Progressive depigmentation was observed two months after birth in a pup born with a depigmented mucous membrane of the mouth and lips. This resembles the vitiligo of humans.

Allopurinol Against Progression of Chronic Kidney Disease.

Science.gov (United States)

Golmohammadi, Sima; Almasi, Afshin; Manouchehri, M; Omrani, Hamid Reza; Zandkarimi, Mohammad Reza

2017-07-01

Hyperuricemia is common in approximately 50% of patients with kidney failure due to decreased uric acid excretion, and it has been recently known as an independent factor in the progression of renal insufficiency. Allopurinol inhibits the production of uric acid. The aim of this study was to evaluate the effect of allopurinol on chronic kidney disease progression. In a clinical trial, patients with stages 3 and 4 of chronic kidney disease were divided into two groups to receive allopurinol, 100 mg, daily and placebo for 12 months. Patients' kidney function and serum uric acid levels were assessed at baseline and 3, 6, and 12 months after initial administration. Subgroups of patients with severe and mild glomerular filtration rate (GFR) impairment (GFR, 15 mL/min/1.73 m2 to 30 mL/min/1.73 m2 and 30 mL/min/1.73 m2 to 60 mL/min/1.73 m2, respectively), were compared between the groups. Serum uric acid levels decreased significantly during after 12 months of allopurinol administration (P = .004). In patients with severe GFR impairment, serum creatinine levels did not decrease significantly and there was no significant increase in GFR, but in those with mild GFR impairment, serum creatinine levels decreased and GFR increase significantly (P kidney disease progression and could be administered with other effective medications for controlling the kidney disease.

Enforcement actions: Significant actions resolved: Quarterly progress report, July--September 1988

International Nuclear Information System (INIS)

1988-12-01

This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (July--September 1988) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

Enforcement actions: Significant actions resolved: Quarterly progress report, October--December 1988

International Nuclear Information System (INIS)

1989-02-01

This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (October--December 1988) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

Enforcement actions: Significant actions resolved: Quarterly progress report, April-June 1987

International Nuclear Information System (INIS)

1987-08-01

This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (April-June 1987) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

Enforcement actions: Significant actions resolved: Quarterly progress report, April--June 1988

International Nuclear Information System (INIS)

1988-08-01

This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (April--June 1988) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

Enforcement actions: Significant actions resolved: Quarterly progress report, July-September 1987

International Nuclear Information System (INIS)

1987-12-01

This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (July-September 1987) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

Enforcement actions: Significant actions resolved: Quarterly progress report, January-March 1988

International Nuclear Information System (INIS)

1988-06-01

This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (January-March 1988) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

Progressive Impairment of Lactate-based Gluconeogenesis in the Huntington's Disease Mouse Model R6/2.

Science.gov (United States)

Nielsen, Signe Marie Borch; Hasholt, Lis; Nørremølle, Anne; Josefsen, Knud

2015-04-20

Huntington's disease (HD) is a neurodegenerative illness, where selective neuronal loss in the brain caused by expression of mutant huntingtin protein leads to motor dysfunction and cognitive decline in addition to peripheral metabolic changes. In this study we confirm our previous observation of impairment of lactate-based hepatic gluconeogenesis in the transgenic HD mouse model R6/2 and determine that the defect manifests very early and progresses in severity with disease development, indicating a potential to explore this defect in a biomarker context. Moreover, R6/2 animals displayed lower blood glucose levels during prolonged fasting compared to wild type animals.

EGovernment Stage Model: Evaluating the Rate of Web Development Progress of Government Websites in Saudi Arabia

OpenAIRE

Osama Alfarraj; Steve Drew; Rayed Abdullah AlGhamdi

2011-01-01

This paper contributes to the issue of eGovernment implementation in Saudi Arabia by discussing the current situation of ministry websites. It evaluates the rate of web development progress of vital government websites in Saudi Arabia using the eGovernment stage model. In 2010, Saudi Arabia ranked 58th in the world and 4th in the Gulf region in eGovernment readiness according to United Nations reports. In particular, Saudi Arabia has ranked 75th worldwide for its online service index and its ...

Presentation on the Modeling and Educational Demonstrations Laboratory Curriculum Materials Center (MEDL-CMC): A Working Model and Progress Report

Science.gov (United States)

Glesener, G. B.; Vican, L.

2015-12-01

Physical analog models and demonstrations can be effective educational tools for helping instructors teach abstract concepts in the Earth, planetary, and space sciences. Reducing the learning challenges for students using physical analog models and demonstrations, however, can often increase instructors' workload and budget because the cost and time needed to produce and maintain such curriculum materials is substantial. First, this presentation describes a working model for the Modeling and Educational Demonstrations Laboratory Curriculum Materials Center (MEDL-CMC) to support instructors' use of physical analog models and demonstrations in the science classroom. The working model is based on a combination of instructional resource models developed by the Association of College & Research Libraries and by the Physics Instructional Resource Association. The MEDL-CMC aims to make the curriculum materials available for all science courses and outreach programs within the institution where the MEDL-CMC resides. The sustainability and value of the MEDL-CMC comes from its ability to provide and maintain a variety of physical analog models and demonstrations in a wide range of science disciplines. Second, the presentation then reports on the development, progress, and future of the MEDL-CMC at the University of California Los Angeles (UCLA). Development of the UCLA MEDL-CMC was funded by a grant from UCLA's Office of Instructional Development and is supported by the Department of Earth, Planetary, and Space Sciences. Other UCLA science departments have recently shown interest in the UCLA MEDL-CMC services, and therefore, preparations are currently underway to increase our capacity for providing interdepartmental service. The presentation concludes with recommendations and suggestions for other institutions that wish to start their own MEDL-CMC in order to increase educational effectiveness and decrease instructor workload. We welcome an interuniversity collaboration to

High resolution molecular and histological analysis of renal disease progression in ZSF1 fa/faCP rats, a model of type 2 diabetic nephropathy.

Science.gov (United States)

Dower, Ken; Zhao, Shanrong; Schlerman, Franklin J; Savary, Leigh; Campanholle, Gabriela; Johnson, Bryce G; Xi, Li; Nguyen, Vuong; Zhan, Yutian; Lech, Matthew P; Wang, Ju; Nie, Qing; Karsdal, Morten A; Genovese, Federica; Boucher, Germaine; Brown, Thomas P; Zhang, Baohong; Homer, Bruce L; Martinez, Robert V

2017-01-01

ZSF1 rats exhibit spontaneous nephropathy secondary to obesity, hypertension, and diabetes, and have gained interest as a model system with potentially high translational value to progressive human disease. To thoroughly characterize this model, and to better understand how closely it recapitulates human disease, we performed a high resolution longitudinal analysis of renal disease progression in ZSF1 rats spanning from early disease to end stage renal disease. Analyses included metabolic endpoints, renal histology and ultrastructure, evaluation of a urinary biomarker of fibrosis, and transcriptome analysis of glomerular-enriched tissue over the course of disease. Our findings support the translational value of the ZSF1 rat model, and are provided here to assist researchers in the determination of the model's suitability for testing a particular mechanism of interest, the design of therapeutic intervention studies, and the identification of new targets and biomarkers for type 2 diabetic nephropathy.

Curcumin Based Drug Screening for Inhibitors of NF kappa B in a Cell Model of Prostate Cancer Progression

Science.gov (United States)

2008-02-01

identify new and structurally diverse chemical analogs of the polyphenolic phytochemical Curcumin from the Indian herb Curcuma longa (family...AD_________________ Award Number: W81XWH-07-1-0081 TITLE: Curcumin Based Drug Screening for... Curcumin Based Drug Screening for Inhibitors of NF kappa B in a Cell Model of Prostate Cancer Progression 5b. GRANT NUMBER W81XWH-07-1-0081 5c

A review of the progress with statistical models of passive component reliability

Energy Technology Data Exchange (ETDEWEB)

Lydell, Bengt O. Y. [Sigma-Phase Inc., Vail (United States)

2017-03-15

During the past 25 years, in the context of probabilistic safety assessment, efforts have been directed towards establishment of comprehensive pipe failure event databases as a foundation for exploratory research to better understand how to effectively organize a piping reliability analysis task. The focused pipe failure database development efforts have progressed well with the development of piping reliability analysis frameworks that utilize the full body of service experience data, fracture mechanics analysis insights, expert elicitation results that are rolled into an integrated and risk-informed approach to the estimation of piping reliability parameters with full recognition of the embedded uncertainties. The discussion in this paper builds on a major collection of operating experience data (more than 11,000 pipe failure records) and the associated lessons learned from data analysis and data applications spanning three decades. The piping reliability analysis lessons learned have been obtained from the derivation of pipe leak and rupture frequencies for corrosion resistant piping in a raw water environment, loss-of-coolant-accident frequencies given degradation mitigation, high-energy pipe break analysis, moderate-energy pipe break analysis, and numerous plant-specific applications of a statistical piping reliability model framework. Conclusions are presented regarding the feasibility of determining and incorporating aging effects into probabilistic safety assessment models.

A Review of the Progress with Statistical Models of Passive Component Reliability

Directory of Open Access Journals (Sweden)

Bengt O.Y. Lydell

2017-03-01

Full Text Available During the past 25 years, in the context of probabilistic safety assessment, efforts have been directed towards establishment of comprehensive pipe failure event databases as a foundation for exploratory research to better understand how to effectively organize a piping reliability analysis task. The focused pipe failure database development efforts have progressed well with the development of piping reliability analysis frameworks that utilize the full body of service experience data, fracture mechanics analysis insights, expert elicitation results that are rolled into an integrated and risk-informed approach to the estimation of piping reliability parameters with full recognition of the embedded uncertainties. The discussion in this paper builds on a major collection of operating experience data (more than 11,000 pipe failure records and the associated lessons learned from data analysis and data applications spanning three decades. The piping reliability analysis lessons learned have been obtained from the derivation of pipe leak and rupture frequencies for corrosion resistant piping in a raw water environment, loss-of-coolant-accident frequencies given degradation mitigation, high-energy pipe break analysis, moderate-energy pipe break analysis, and numerous plant-specific applications of a statistical piping reliability model framework. Conclusions are presented regarding the feasibility of determining and incorporating aging effects into probabilistic safety assessment models.

A review of the progress with statistical models of passive component reliability

International Nuclear Information System (INIS)

Lydell, Bengt O. Y.

2017-01-01

During the past 25 years, in the context of probabilistic safety assessment, efforts have been directed towards establishment of comprehensive pipe failure event databases as a foundation for exploratory research to better understand how to effectively organize a piping reliability analysis task. The focused pipe failure database development efforts have progressed well with the development of piping reliability analysis frameworks that utilize the full body of service experience data, fracture mechanics analysis insights, expert elicitation results that are rolled into an integrated and risk-informed approach to the estimation of piping reliability parameters with full recognition of the embedded uncertainties. The discussion in this paper builds on a major collection of operating experience data (more than 11,000 pipe failure records) and the associated lessons learned from data analysis and data applications spanning three decades. The piping reliability analysis lessons learned have been obtained from the derivation of pipe leak and rupture frequencies for corrosion resistant piping in a raw water environment, loss-of-coolant-accident frequencies given degradation mitigation, high-energy pipe break analysis, moderate-energy pipe break analysis, and numerous plant-specific applications of a statistical piping reliability model framework. Conclusions are presented regarding the feasibility of determining and incorporating aging effects into probabilistic safety assessment models

Modeling carbon dioxide sequestration in saline aquifers: Significance of elevated pressures and salinities

International Nuclear Information System (INIS)

Allen, D.E.; Strazisar, B.R.; Soong, Y.; Hedges, S.W.

2005-01-01

The ultimate capacity of saline formations to sequester carbon dioxide by solubility and mineral trapping must be determined by simulating sequestration with geochemical models. These models, however, are only as reliable as the data and reaction scheme on which they are based. Several models have been used to make estimates of carbon dioxide solubility and mineral formation as a function of pressure and fluid composition. Intercomparison of modeling results indicates that failure to adjust all equilibrium constants to account for elevated carbon dioxide pressures results in significant errors in both solubility and mineral formation estimates. Absence of experimental data at high carbon dioxide pressures and high salinities make verification of model results difficult. Results indicate standalone solubility models that do not take mineral reactions into account will underestimate the total capacity of aquifers to sequester carbon dioxide in the long term through enhanced solubility and mineral trapping mechanisms. Overall, it is difficult to confidently predict the ultimate sequestration capacity of deep saline aquifers using geochemical models. (author)

Early and progressive impairment of spinal blood flow-glucose metabolism coupling in motor neuron degeneration of ALS model mice.

Science.gov (United States)

Miyazaki, Kazunori; Masamoto, Kazuto; Morimoto, Nobutoshi; Kurata, Tomoko; Mimoto, Takahumi; Obata, Takayuki; Kanno, Iwao; Abe, Koji

2012-03-01

The exact mechanism of selective motor neuron death in amyotrophic lateral sclerosis (ALS) remains still unclear. In the present study, we performed in vivo capillary imaging, directly measured spinal blood flow (SBF) and glucose metabolism, and analyzed whether if a possible flow-metabolism coupling is disturbed in motor neuron degeneration of ALS model mice. In vivo capillary imaging showed progressive decrease of capillary diameter, capillary density, and red blood cell speed during the disease course. Spinal blood flow was progressively decreased in the anterior gray matter (GM) from presymptomatic stage to 0.80-fold of wild-type (WT) mice, 0.61 at early-symptomatic, and 0.49 at end stage of the disease. Local spinal glucose utilization (LSGU) was transiently increased to 1.19-fold in anterior GM at presymptomatic stage, which in turn progressively decreased to 0.84 and 0.60 at early-symptomatic and end stage of the disease. The LSGU/SBF ratio representing flow-metabolism uncoupling (FMU) preceded the sequential pathological changes in the spinal cord of ALS mice and was preferentially found in the affected region of ALS. The present study suggests that this early and progressive FMU could profoundly involve in the whole disease process as a vascular factor of ALS pathology, and could also be a potential target for therapeutic intervention of ALS.

Pivotal roles of Kupffer cells in the progression and regression of DDC-induced chronic cholangiopathy.

Science.gov (United States)

Jemail, Leila; Miyao, Masashi; Kotani, Hirokazu; Kawai, Chihiro; Minami, Hirozo; Abiru, Hitoshi; Tamaki, Keiji

2018-04-23

Kupffer cells (KCs) are key players in maintaining tissue homeostasis and are involved in various liver diseases. However, the roles of KCs in the pathogenesis of cholangiopathy are largely unknown. We aimed to investigate the precise roles of KCs in both the progression and regression phases of the 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced cholangiopathy model. In the early phase of DDC-induced cholangiopathy, the number of KCs significantly increased over time. Moreover, KCs were associated with abnormal phenotypic changes in other liver cells, such as hepatocytes, biliary epithelial cells, liver sinusoidal endothelial cells, and hepatic stellate cells. In contrast, KC depletion by clodronate administration suppressed the progression of the disease, and maintained the phenotypes of other cells. In the regression phase, the numbers of KCs significantly decreased, and the cells redifferentiated to their quiescent state. In contrast, KC depletion delayed the recovery of cells by maintaining other liver cells in an active state. These findings suggest that KCs play detrimental roles in the progression phase; however, they are beneficial in the regression phase by mediating interactions between other liver cells. Our data provide new insights into the roles of KCs in the pathogenesis of cholangiopathy.

USP22 regulates oncogenic signaling pathways to drive lethal cancer progression.

Science.gov (United States)

Schrecengost, Randy S; Dean, Jeffry L; Goodwin, Jonathan F; Schiewer, Matthew J; Urban, Mark W; Stanek, Timothy J; Sussman, Robyn T; Hicks, Jessica L; Birbe, Ruth C; Draganova-Tacheva, Rossitza A; Visakorpi, Tapio; DeMarzo, Angelo M; McMahon, Steven B; Knudsen, Karen E

2014-01-01

Increasing evidence links deregulation of the ubiquitin-specific proteases 22 (USP22) deubitiquitylase to cancer development and progression in a select group of tumor types, but its specificity and underlying mechanisms of action are not well defined. Here we show that USP22 is a critical promoter of lethal tumor phenotypes that acts by modulating nuclear receptor and oncogenic signaling. In multiple xenograft models of human cancer, modeling of tumor-associated USP22 deregulation demonstrated that USP22 controls androgen receptor accumulation and signaling, and that it enhances expression of critical target genes coregulated by androgen receptor and MYC. USP22 not only reprogrammed androgen receptor function, but was sufficient to induce the transition to therapeutic resistance. Notably, in vivo depletion experiments revealed that USP22 is critical to maintain phenotypes associated with end-stage disease. This was a significant finding given clinical evidence that USP22 is highly deregulated in tumors, which have achieved therapeutic resistance. Taken together, our findings define USP22 as a critical effector of tumor progression, which drives lethal phenotypes, rationalizing this enzyme as an appealing therapeutic target to treat advanced disease.

Influence of Distal Resistance and Proximal Stiffness on Hemodynamics and RV Afterload in Progression and Treatments of Pulmonary Hypertension: A Computational Study with Validation Using Animal Models

Directory of Open Access Journals (Sweden)

Zhenbi Su

2013-01-01

Full Text Available We develop a simple computational model based on measurements from a hypoxic neonatal calf model of pulmonary hypertension (PH to investigate the interplay between vascular and ventricular measures in the setting of progressive PH. Model parameters were obtained directly from in vivo and ex vivo measurements of neonatal calves. Seventeen sets of model-predicted impedance and mean pulmonary arterial pressure (mPAP show good agreement with the animal measurements, thereby validating the model. Next, we considered a predictive model in which three parameters, PVR, elastic modulus (EM, and arterial thickness, were varied singly from one simulation to the next to study their individual roles in PH progression. Finally, we used the model to predict the individual impacts of clinical (vasodilatory and theoretical (compliance increasing PH treatments on improving pulmonary hemodynamics. Our model (1 displayed excellent patient-specific agreement with measured global pulmonary parameters; (2 quantified relationships between PVR and mean pressure and PVS and pulse pressure, as well as studiying the right ventricular (RV afterload, which could be measured as a hydraulic load calculated from spectral analysis of pulmonary artery pressure and flow waves; (3 qualitatively confirmed the derangement of vascular wall shear stress in progressive PH; and (4 established that decreasing proximal vascular stiffness through a theoretical treatment of reversing proximal vascular remodeling could decrease RV afterload.

Progressively consolidating historical visual explorations for new discoveries

Science.gov (United States)

Zhao, Kaiyu; Ward, Matthew O.; Rundensteiner, Elke A.; Higgins, Huong N.

2013-12-01

A significant task within data mining is to identify data models of interest. While facilitating the exploration tasks, most visualization systems do not make use of all the data models that are generated during the exploration. In this paper, we introduce a system that allows the user to gain insights from the data space progressively by forming data models and consolidating the generated models on the fly. Each model can be a a computationally extracted or user-defined subset that contains a certain degree of interest and might lead to some discoveries. When the user generates more and more data models, the degree of interest of some portion of some models will either grow (indicating higher occurrence) or will fluctuate or decrease (corresponding to lower occurrence). Our system maintains a collection of such models and accumulates the interestingness of each model into a consolidated model. In order to consolidate the models, the system summarizes the associations between the models in the collection and identifies support (models reinforce each other), complementary (models complement each other), and overlap of the models. The accumulated interestingness keeps track of historical exploration and helps the user summarize their findings which can lead to new discoveries. This mechanism for integrating results from multiple models can be applied to a wide range of decision support systems. We demonstrate our system in a case study involving the financial status of US companies.

Trends and progress in system identification

CERN Document Server

Eykhoff, Pieter

1981-01-01

Trends and Progress in System Identification is a three-part book that focuses on model considerations, identification methods, and experimental conditions involved in system identification. Organized into 10 chapters, this book begins with a discussion of model method in system identification, citing four examples differing on the nature of the models involved, the nature of the fields, and their goals. Subsequent chapters describe the most important aspects of model theory; the """"classical"""" methods and time series estimation; application of least squares and related techniques for the e

Microscopic and macroscopic models for the onset and progression of Alzheimer's disease

Science.gov (United States)

Bertsch, Michiel; Franchi, Bruno; Carla Tesi, Maria; Tosin, Andrea

2017-10-01

In the first part of this paper we review a mathematical model for the onset and progression of Alzheimer’s disease (AD) that was developed in subsequent steps over several years. The model is meant to describe the evolution of AD in vivo. In Achdou et al (2013 J. Math. Biol. 67 1369-92) we treated the problem at a microscopic scale, where the typical length scale is a multiple of the size of the soma of a single neuron. Subsequently, in Bertsch et al (2017 Math. Med. Biol. 34 193-214) we concentrated on the macroscopic scale, where brain neurons are regarded as a continuous medium, structured by their degree of malfunctioning. In the second part of the paper we consider the relation between the microscopic and the macroscopic models. In particular we show under which assumptions the kinetic transport equation, which in the macroscopic model governs the evolution of the probability measure for the degree of malfunctioning of neurons, can be derived from a particle-based setting. The models are based on aggregation and diffusion equations for β-Amyloid (Aβ from now on), a protein fragment that healthy brains regularly produce and eliminate. In case of dementia Aβ monomers are no longer properly washed out and begin to coalesce forming eventually plaques. Two different mechanisms are assumed to be relevant for the temporal evolution of the disease: (i) diffusion and agglomeration of soluble polymers of amyloid, produced by damaged neurons; (ii) neuron-to-neuron prion-like transmission. In the microscopic model we consider mechanism (i), modelling it by a system of Smoluchowski equations for the amyloid concentration (describing the agglomeration phenomenon), with the addition of a diffusion term as well as of a source term on the neuronal membrane. At the macroscopic level instead we model processes (i) and (ii) by a system of Smoluchowski equations for the amyloid concentration, coupled to a kinetic-type transport equation for the distribution function of the

The Ignition Physics Campaign on NIF: Status and Progress

International Nuclear Information System (INIS)

Edwards, M. J.

2016-01-01

We have made significant progress in ICF implosion performance on NIF since the 2011 IFSA. Employing a 3-shock, high adiabat CH (“High-Foot”) design, total neutron yields have increased 10-fold to 6.3 x10 15 (a yield of ∼ 17 kJ, which is greater than the energy invested in the DT fuel ∼ 12kJ). At that level, the yield from alpha self-heating is essentially equivalent to the compression yield, indicating that we are close to the alpha self-heating regime. Low adiabat, 4-shock High Density Carbon (HDC) capsules have been imploded in conventional gas-filled hohlraums, and employing a 6 ns, 2-shock pulse, HDC capsules were imploded in near-vacuum hohlraums with overall coupling ∼ 98%. Both the 4- and 2-shock HDC capsules had very low mix and high yield over simulated performance. Rugby holraums have demonstrated uniform x-ray drive with minimal Cross Beam Energy Transfer (CBET), and we have made good progress in measuring and modelling growth of ablation front hydro instabilities. (paper)

A review on primary progressive aphasia

Directory of Open Access Journals (Sweden)

Gabriel C Léger

2007-01-01

Full Text Available Gabriel C Léger1,2, Nancy Johnson31Neurology Service, Hôtel-Dieu du Centre Hospitalier de l’Univertité de Montréal, Montréal, Québec, Canada; 2Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada; 3Cognitive Neurology and Alzheimer’s Disease Center, Department of Psychiatry and Behavioral Science, Northwestern University Feinberg School of Medicine, Chicago, IL, USAAbstract: Primary progressive aphasia (PPA is a neurodegenerative disease of insidious onset presenting with progressive isolated loss of language function, without significant impairment in other cognitive domains. Current diagnostic criteria require the language dysfunction to remain isolated for at least two years, and to remain the salient feature as the disease progresses, usually to involve other domains such as behavior, executive functions, and judgment. Although PPA in its early stages can usually be differentiated from probable Alzheimer’s disease (PRAD and the behavioral variant of frontotemporal lobar degeneration by the absence of significant changes in memory and behavior, and the preservation of activities daily living, progression of the disease often leads to deficits more consistent with the latter. Underlying etiologies remain heterogeneous: the neuropathological characteristics associated with frontotemporal lobar degeneration, cortocobasal degeneration, and motor neuron disease are usually found. There is a strong genetic susceptibility with affliction of first-degree relatives with similar disease in up to 40 to 50% in some series. Pathogenic mutations in genes coding for the proteins tau and progranulin have been isolated. These are leading to a better understanding of the neuropathological mechanisms and hopefully targeted disease-modifying therapy. Current therapy is limited to improving mood symptoms and targeting behavior changes as they develop. Referral to specialized centers where speech therapy, counseling, and education

Relationship between visual field progression and baseline refraction in primary open-angle glaucoma.

Science.gov (United States)

Naito, Tomoko; Yoshikawa, Keiji; Mizoue, Shiro; Nanno, Mami; Kimura, Tairo; Suzumura, Hirotaka; Umeda, Yuzo; Shiraga, Fumio

2016-01-01

To analyze the relationship between visual field (VF) progression and baseline refraction in Japanese patients with primary open-angle glaucoma (POAG) including normal-tension glaucoma. In this retrospective study, the subjects were patients with POAG who had undergone VF tests at least ten times with a Humphrey Field Analyzer (Swedish interactive thresholding algorithm standard, Central 30-2 program). VF progression was defined as a significantly negative value of mean deviation (MD) slope at the final VF test. Multivariate logistic regression models were applied to detect an association between MD slope deterioration and baseline refraction. A total of 156 eyes of 156 patients were included in this analysis. Significant deterioration of MD slope was observed in 70 eyes of 70 patients (44.9%), whereas no significant deterioration was evident in 86 eyes of 86 patients (55.1%). The eyes with VF progression had significantly higher baseline refraction compared to those without apparent VF progression (-1.9±3.8 diopter [D] vs -3.5±3.4 D, P=0.0048) (mean ± standard deviation). When subject eyes were classified into four groups by the level of baseline refraction applying spherical equivalent (SE): no myopia (SE > -1D), mild myopia (-1D ≥ SE > -3D), moderate myopia (-3D ≥ SE > -6D), and severe myopia (-6D ≥ SE), the Cochran-Armitage trend analysis showed a decreasing trend in the proportion of MD slope deterioration with increasing severity of myopia (P=0.0002). The multivariate analysis revealed that baseline refraction (P=0.0108, odds ratio [OR]: 1.13, 95% confidence interval [CI]: 1.03-1.25) and intraocular pressure reduction rate (P=0.0150, OR: 0.97, 95% CI: 0.94-0.99) had a significant association with MD slope deterioration. In the current analysis of Japanese patients with POAG, baseline refraction was a factor significantly associated with MD slope deterioration as well as intraocular pressure reduction rate. When baseline refraction was classified into

Impacts of fresh lime juice and peel on atherosclerosis progression in an animal model

Directory of Open Access Journals (Sweden)

Maryam Boshtam

2013-11-01

Full Text Available BACKGROUND: The main protective role of antioxidants in the progression of atherosclerosis has been shown in some studies. Therefore, this project evaluated the effects of Citrus aurantifolia (Christm juice and peel on antioxidant activity and atherosclerosis progression in rabbits receiving a hypercholesterolemic diet. METHODS: Forty white New Zealand male rabbits were randomly allocated to four groups. All groups were on hypercholesterolemic diet for two months. While the first group was considered as the hypercholesterolemic control, groups 2 and 3 (intervention groups received 5 ml/day lime juice and 1 g/day dried lime peel powder, respectively. Group 4 was fed a normal diet (normal control. Before and after the study, weight was measured and a fasting blood specimen was taken from the rabbits. Serum lipids analyses and antioxidant activity evaluations were then performed. The rabbits’ aorta and coronary arteries were separated and the presence of fatty streaks was studied. RESULTS: Comparing to the hypercholesterolemic control group (-25.2 ± 7.0, only the plasma total antioxidant capacity change was significantly more in rabbits supplemented with lime juice (16.3 ± 14.7 and peel (8.6 ± 7.1 (P = 0.008. The presence of fatty streaks in coronary arteries and aorta of the intervention groups [juice (0.2 ± 0.01; peel (0.0 ± 0.00] was significantly decreased compared to the hypercholesterolemic control group (1.2 ± 0.4 (P < 0.001. CONCLUSION: Based on our findings, Citrus aurantifolia peel and juice increase plasma antioxidant capacity in rabbits, and can thus prevent or decelerate the process of atherogenesis. However, lime peel is more effective than lime juice.   Keywords: Animal, Atherosclerosis, Atherogenic Diet, Fatty Streak, Intervention, Lime    Normal 0 false false false EN-US X-NONE AR-SA

Risk of progression in macula-on rhegmatogenous retinal detachment.

Science.gov (United States)

Callizo, Josep; Pfeiffer, Sebastian; Lahme, Eva; van Oterendorp, Christian; Khattab, Mohammed; Bemme, Sebastian; Kulanga, Miroslav; Hoerauf, Hans; Feltgen, Nicolas

2017-08-01

To identify factors that may lead to a rapid progression in macula-on rhegmatogenous retinal detachment (RRD), in particular, those that may lead to macular involvement. Observational, prospective, single-center study. Patients referred for surgery due to primary rhegmatogenous retinal detachment with the macula on between 2009 and 2013 were included. Relevant factors analyzed included age, time delay until surgery, lens status, myopia, the detachment's location and configuration as well as number, size and type of retinal breaks. Eyes underwent optical coherence tomography to detect macular detachment. A multivariate analysis was performed to investigate the effect of several factors in the progression of retinal detachment. A total of 116 eyes of 116 patients were included. Mean time delay between admission and surgery was 1.8 ± 1.4 days. Progression was observed in 19.8% of the eyes. Of those, 47.8% presented macular detachment. Ten of the 11 (90.9%) eyes presenting progression involving the macula also exhibited a bullous configuration, which was the only parameter that correlated significantly with detachment progression in patients with (p = 0.0036) and without (p = 0.0014) macular involvement. For the first time in a prospective trial, a bullous configuration was found to be a highly significant predictor for progression in macula-on detachments. Our data support prompt surgery in patients diagnosed with bullous macula-on RRD.

Role for transforming growth factor-beta1 in alport renal disease progression.

Science.gov (United States)

Sayers, R; Kalluri, R; Rodgers, K D; Shield, C F; Meehan, D T; Cosgrove, D

1999-11-01

Alport syndrome results from mutations in either the alpha3(IV), alpha4(IV), or alpha5(IV) collagen genes. The disease is characterized by a progressive glomerulonephritis usually associated with a high-frequency sensorineural hearing loss. A mouse model for an autosomal form of Alport syndrome [collagen alpha3(IV) knockout] was produced and characterized. In this study, the model was exploited to demonstrate a potential role for transforming growth factor-beta1 (TGF-beta1) in Alport renal disease pathogenesis. Kidneys from normal and Alport mice, taken at different stages during the course of renal disease progression, were analyzed by Northern blot, in situ hybridization, and immunohistology for expression of TGF-beta1 and components of the extracellular matrix. Normal and Alport human kidney was examined for TGF-beta1 expression using RNase protection. The mRNAs encoding TGF-beta1 (in both mouse and human), entactin, fibronectin, and the collagen alpha1(IV) and alpha2(IV) chains were significantly induced in total kidney as a function of Alport renal disease progression. The induction of these specific mRNAs was observed in the glomerular podocytes of animals with advanced disease. Type IV collagen, laminin-1, and fibronectin were markedly elevated in the tubulointerstitium at 10 weeks, but not at 6 weeks, suggesting that elevated expression of specific mRNAs on Northern blots reflects events associated with tubulointerstitial fibrosis. The concomitant accumulation of mRNAs encoding TGF-beta1 and extracellular matrix components in the podocytes of diseased kidneys may reflect key events in Alport renal disease progression. These data suggest a role for TGF-beta1 in both glomerular and tubulointerstitial damage associated with Alport syndrome.

DA-1229, a dipeptidyl peptidase IV inhibitor, protects against renal injury by preventing podocyte damage in an animal model of progressive renal injury.

Science.gov (United States)

Eun Lee, Jee; Kim, Jung Eun; Lee, Mi Hwa; Song, Hye Kyoung; Ghee, Jung Yeon; Kang, Young Sun; Min, Hye Sook; Kim, Hyun Wook; Cha, Jin Joo; Han, Jee Young; Han, Sang Youb; Cha, Dae Ryong

2016-05-01

Although dipeptidyl peptidase IV (DPPIV) inhibitors are known to have renoprotective effects, the mechanism underlying these effects has remained elusive. Here we investigated the effects of DA-1229, a novel DPPIV inhibitor, in two animal models of renal injury including db/db mice and the adriamycin nephropathy rodent model of chronic renal disease characterized by podocyte injury. For both models, DA-1229 was administered at 300 mg/kg/day. DPPIV activity in the kidney was significantly higher in diabetic mice compared with their nondiabetic controls. Although DA-1229 did not affect glycemic control or insulin resistance, DA-1229 did improve lipid profiles, albuminuria and renal fibrosis. Moreover, DA-1229 treatment resulted in decreased urinary excretion of nephrin, decreased circulating and kidney DPPIV activity, and decreased macrophage infiltration in the kidney. In adriamycin-treated mice, DPPIV activity in the kidney and urinary nephrin loss were both increased, whereas glucagon-like peptide-1 concentrations were unchanged. Moreover, DA-1229 treatment significantly improved proteinuria, renal fibrosis and inflammation associated with decreased urinary nephrin loss, and kidney DPP4 activity. In cultured podocytes, DA-1229 restored the high glucose/angiotensin II-induced increase of DPPIV activity and preserved the nephrin levels in podocytes. These findings suggest that activation of DPPIV in the kidney has a role in the progression of renal disease, and that DA-1229 may exert its renoprotective effects by preventing podocyte injury.

Shifting closeness: interpersonal effects of personal goal progress.

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Fitzsimons, Gráinne M; Fishbach, Ayelet

2010-04-01

In this article, we examine how the shifting motivational priority of personal goals affects relationship closeness. We hypothesize that people will draw closer to significant others who are instrumental (vs. noninstrumental) for a goal that has not been progressing well-a goal that is thus high in motivational priority. Once the goal has progressed successfully, we predict that people will cease to draw closer to instrumental others. Five studies support these predictions by showing that the impact of goal progress on reduced preference for instrumental others (Experiment 1) depends on the framing of progress as partial attainment (vs. greater commitment, Experiment 2) and the intention to balance across goals (vs. focus on one goal; Experiments 3-4). We find that moving away from instrumental others post progress is functional, in that it allows for drawing closer to those who are instrumental for alternative goals (Experiment 5).

SIRT6 knockout cells resist apoptosis initiation but not progression: a computational method to evaluate the progression of apoptosis.

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Domanskyi, Sergii; Nicholatos, Justin W; Schilling, Joshua E; Privman, Vladimir; Libert, Sergiy

2017-11-01

Apoptosis is essential for numerous processes, such as development, resistance to infections, and suppression of tumorigenesis. Here, we investigate the influence of the nutrient sensing and longevity-assuring enzyme SIRT6 on the dynamics of apoptosis triggered by serum starvation. Specifically, we characterize the progression of apoptosis in wild type and SIRT6 deficient mouse embryonic fibroblasts using time-lapse flow cytometry and computational modelling based on rate-equations and cell distribution analysis. We find that SIRT6 deficient cells resist apoptosis by delaying its initiation. Interestingly, once apoptosis is initiated, the rate of its progression is higher in SIRT6 null cells compared to identically cultured wild type cells. However, SIRT6 null cells succumb to apoptosis more slowly, not only in response to nutrient deprivation but also in response to other stresses. Our data suggest that SIRT6 plays a role in several distinct steps of apoptosis. Overall, we demonstrate the utility of our computational model to describe stages of apoptosis progression and the integrity of the cellular membrane. Such measurements will be useful in a broad range of biological applications.

En Face Spectral-Domain Optical Coherence Tomography for the Monitoring of Lesion Area Progression in Stargardt Disease.

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Melillo, Paolo; Testa, Francesco; Rossi, Settimio; Di Iorio, Valentina; Orrico, Ada; Auricchio, Alberto; Simonelli, Francesca

2016-07-01

We investigated the progression of Stargardt disease (STGD1) over a multiyear follow-up by evaluating the macular lesion area as computed by an automatic algorithm from spectral-domain optical coherence tomography (SD-OCT). We reviewed medical records of STGD1 patients, with a clinical and molecular diagnosis of STGD1 at a single institution, who underwent best-corrected visual acuity (BCVA), fundus photography, SD-OCT, full-field electroretinography, and, when available, fundus autofluorescence (FAF). Regression models were fitted on the selected clinical parameters; in particular, on the macular lesion area computed by SD-OCT, to evaluate the disease progression over a multiyear follow-up. The comparison between SD-OCT and FAF, available for 22 patients, showed that macular lesion area, assessed by SD-OCT, significantly correlated with the area of absent FAF (P disease, showing a significant progression over the follow-up. Our findings suggest that the evaluation of macular lesion area by en face SD-OCT, together with FAF, could drive the choice of the most amenable candidates and the most suitable area to be treated in gene therapy clinical trials.

Geodynamic Effects of Ocean Tides: Progress and Problems

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Richard, Ray

1999-01-01

Satellite altimetry, particularly Topex/Poseidon, has markedly improved our knowledge of global tides, thereby allowing significant progress on some longstanding problems in geodynamics. This paper reviews some of that progress. Emphasis is given to global-scale problems, particularly those falling within the mandate of the new IERS Special Bureau for Tides: angular momentum, gravitational field, geocenter motion. For this discussion I use primarily the new ocean tide solutions GOT99.2, CSR4.0, and TPXO.4 (for which G. Egbert has computed inverse-theoretic error estimates), and I concentrate on new results in angular momentum and gravity and their solid-earth implications. One example is a new estimate of the effective tidal Q at the M_2 frequency, based on combining these ocean models with tidal estimates from satellite laser ranging. Three especially intractable problems are also addressed: (1) determining long-period tides in the Arctic [large unknown effect on the inertia tensor, particularly for Mf]; (2) determining the global psi_l tide [large unknown effect on interpretations of gravimetry for the near-diurnal free wobble]; and (3) determining radiational tides [large unknown temporal variations at important frequencies]. Problems (2) and (3) are related.

Small scale tests on the progressive retreat of soil slopes

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Voulgari, Chrysoula; Utili, Stefano; Castellanza, Riccardo

2015-04-01

In this paper, the influence due to the presence of cracks on the morphologic evolution of natural cliffs subject to progressive retreat induced by weathering is investigated through small scale laboratory tests. Weathering turns hard rocks into soft rocks that maintain the structure of the intact rocks, but are characterised by higher void ratios and reduced bond strengths; soft rocks are transformed into granular soils generally called residual soils. A number of landslides develop in slopes due to weathering which results in the progressive retrogression of the slope face and the further degradation within the weathering zone. Cracks, that are widely present, can be a result of weathering and they can cause a significant decrease in their stability, as they provide preferential flow channels which increase the soil permeability and decrease the soil strength. The geological models employed until now are mainly empirical. Several researchers have tried to study the stability of slopes through experimental procedures. Centrifuge modelling is widely used to investigate the failure of slopes. Small scale tests are also an important approach, in order to study the behaviour of a slope under certain conditions, such as the existence of water, as they allow the observation of the infiltration processes, the movement of the weathering front, deformation and failure. However, the deformation response of a slope subject to weathering is not yet thoroughly clarified. In this work, a set of experiments were conducted to investigate weathering induced successive landslides. Weathering was applied to the slope model by wetting the slope crest through a rainfall simulator device. The moisture content of the soil during the tests was monitored by soil moisture sensors that were buried inside the slope model. High resolution cameras were recording the behaviour of the slope model. GeoPIV was used to analyse the frames and obtain the deformations of the slope model during the

SIGNIFICANCE OF LABORATORY PARAMETERS IN PROGNOSIS OF OUTCOMES OF ACUTE MYOCARDIAL INFARCTION

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I. E. Belaya

2017-01-01

Full Text Available The study objective is to validate a mathematical model for prognosis of progression of the acute period of myocardial infarction.Materials and methods. We examined 135 patients with acute Q-wave myocardial infarction of the left ventricle aged between 34 and 88 years (mean age 66, standard deviation 12 years, among them 64 women and 71 men. For prognosis of the outcome of the acute period of myocardial infarction we used an approach based on intellectual data analysis (data mining in combination with mathematical methods based on decision trees.Results. Using decision tree algorithms, we singled out laboratory parameters (attributes which were subsequently used as input. Adequacy of classification of these attributes was determined by a contingency table. Accuracy of the obtained calculation results was 95.56 % demonstrating good agreement between the model and observed data. In a decision tree visualization, the most significant 8 laboratory parameters were determined. Significance of NO2  metabolite was 24.9 %, triglycerides – 16.7 %, urea – 14.8 %, erythrocytes – 11.2 %, alanine aminotransferase – 9.4 %, very low density lipoproteins – 9.4 %, creatinine – 8.5 %, prothrombin index – 5.1 %. In the Rules tab, only rules 4 and 9 can be used with confidence, because their confidence level approaches 100 %, and effect cost for the fact of death was 33.59 % and 32.03 %, respectively.Conclusion. Using a decision tree algorithm, we determined prognostically significant factors for progression of acute myocardial infarction. The following set of parameters predicts unfavorable outcome (death with 95.56 % accuracy: NO2  < level 22.755 mmol/l, triglycerides ≥ 1.565 mmol/l, erythrocytes < 4.91 M/uL, alanine aminotransferase < 1.23 mmol/l, urea < 7.05 mmol/l, very low-density lipoproteins < 0.965 mmol/l, creatinine ≥ 91.55 µmol/l, NO2 level ≥ 22.755 mmol/l predicts a favorable outcome with 95.56 % accuracy. 

Towards local progression estimation of pulmonary emphysema using CT.

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Staring, M; Bakker, M E; Stolk, J; Shamonin, D P; Reiber, J H C; Stoel, B C

2014-02-01

Whole lung densitometry on chest CT images is an accepted method for measuring tissue destruction in patients with pulmonary emphysema in clinical trials. Progression measurement is required for evaluation of change in health condition and the effect of drug treatment. Information about the location of emphysema progression within the lung may be important for the correct interpretation of drug efficacy, or for determining a treatment plan. The purpose of this study is therefore to develop and validate methods that enable the local measurement of lung density changes, which requires proper modeling of the effect of respiration on density. Four methods, all based on registration of baseline and follow-up chest CT scans, are compared. The first naïve method subtracts registered images. The second employs the so-called dry sponge model, where volume correction is performed using the determinant of the Jacobian of the transformation. The third and the fourth introduce a novel adaptation of the dry sponge model that circumvents its constant-mass assumption, which is shown to be invalid. The latter two methods require a third CT scan at a different inspiration level to estimate the patient-specific density-volume slope, where one method employs a global and the other a local slope. The methods were validated on CT scans of a phantom mimicking the lung, where mass and volume could be controlled. In addition, validation was performed on data of 21 patients with pulmonary emphysema. The image registration method was optimized leaving a registration error below half the slice increment (median 1.0 mm). The phantom study showed that the locally adapted slope model most accurately measured local progression. The systematic error in estimating progression, as measured on the phantom data, was below 2 gr/l for a 70 ml (6%) volume difference, and 5 gr/l for a 210 ml (19%) difference, if volume correction was applied. On the patient data an underlying linearity assumption

Work, Health, Music: The enduring Rusyn model of a good life amid changing socioeconomic contexts of progress

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K. M. Cantin

2013-11-01

Full Text Available Rusyns in Eastern and Central Europe have experience with two predominant models of “progress”: the Soviet-style communist and the neoliberal.  Proponents of each system promised to better the lives of all but did not take into account what “better” meant to local populations, including Rusyns.  Increasingly, European governmental and nongovernmental organizations are redefining notions of progress and development to accord with values of sustainability and a capability approach (CA to well-being.  Giovanola (2005 and Robeyns (2005 have argued that scholars of the CA need to better develop concepts of “personhood” and “human flourishing”, and to better explain the importance of social group membership and norms to living a valued life.  The emerging anthropological focus on well-being, emphasizing culturally specific definitions of what happiness and a good life mean, can provide these conceptualizations.  As a case in point, I use freelist and interview data obtained from residents in the Prešov Region of Slovakia and the Zakarpattia Oblast of Ukraine along with Rusyn cultural narratives drawn from poems, folktales, plays, songs, interviews, and speeches to identify prevalent models of “personhood” and “a good life”. I discuss how these narratives intersect and diverge with discourses of happiness and progress along with the implications for Rusyns' ability to flourish. 

Using Markov Chains to predict the natural progression of diabetic retinopathy

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Priyanka Srikanth

2015-02-01

Full Text Available AIM: To study the natural progression of diabetic retinopathy in patients with type 2 diabetes. METHODS: This was an observational study of 153 cases with type 2 diabetes from 2010 to 2013. The state of patient was noted at end of each year and transition matrices were developed to model movement between years. Patients who progressed to severe non-proliferative diabetic retinopathy (NPDR were treated. Markov Chains and Chi-square test were used for statistical analysis. RESULTS: We modelled the transition of 153 patients from NPDR to blindness on an annual basis. At the end of year 3, we compared results from the Markov model versus actual data. The results from Chi-square test confirmed that there was statistically no significant difference (P=0.70 which provided assurance that the model was robust to estimate mean sojourn times. The key finding was that a patient entering the system in mild NPDR state is expected to stay in that state for 5y followed by 1.07y in moderate NPDR, be in the severe NPDR state for 1.33y before moving into PDR for roughly 8y. It is therefore expected that such a patient entering the model in a state of mild NPDR will enter blindness after 15.29y. CONCLUSION: Patients stay for long time periods in mild NPDR before transitioning into moderate NPDR. However, they move rapidly from moderate NPDR to proliferative diabetic retinopathy (PDR and stay in that state for long periods before transitioning into blindness.

Using Markov chains to predict the natural progression of diabetic retinopathy

Institute of Scientific and Technical Information of China (English)

Priyanka; Srikanth

2015-01-01

AIM: To study the natural progression of diabetic retinopathy in patients with type 2 diabetes.METHODS: This was an observational study of 153 cases with type 2 diabetes from 2010 to 2013. The state of patient was noted at end of each year and transition matrices were developed to model movement between years. Patients who progressed to severe non-proliferative diabetic retinopathy(NPDR) were treated.Markov Chains and Chi-square test were used for statistical analysis.RESULTS: We modelled the transition of 153 patients from NPDR to blindness on an annual basis. At the end of year 3, we compared results from the Markov model versus actual data. The results from Chi-square test confirmed that there was statistically no significant difference(P =0.70) which provided assurance that the model was robust to estimate mean sojourn times. The key finding was that a patient entering the system in mild NPDR state is expected to stay in that state for 5y followed by 1.07 y in moderate NPDR, be in the severe NPDR state for 1.33 y before moving into PDR for roughly8 y. It is therefore expected that such a patient entering the model in a state of mild NPDR will enter blindness after 15.29 y.CONCLUSION: Patients stay for long time periods in mild NPDR before transitioning into moderate NPDR.However, they move rapidly from moderate NPDR to proliferative diabetic retinopathy(PDR) and stay in that state for long periods before transitioning into blindness.

A Progressive Damage Model for unidirectional Fibre Reinforced Composites with Application to Impact and Penetration Simulation

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Kerschbaum, M.; Hopmann, C.

2016-06-01

The computationally efficient simulation of the progressive damage behaviour of continuous fibre reinforced plastics is still a challenging task with currently available computer aided engineering methods. This paper presents an original approach for an energy based continuum damage model which accounts for stress-/strain nonlinearities, transverse and shear stress interaction phenomena, quasi-plastic shear strain components, strain rate effects, regularised damage evolution and consideration of load reversal effects. The physically based modelling approach enables experimental determination of all parameters on ply level to avoid expensive inverse analysis procedures. The modelling strategy, implementation and verification of this model using commercially available explicit finite element software are detailed. The model is then applied to simulate the impact and penetration of carbon fibre reinforced cross-ply specimens with variation of the impact speed. The simulation results show that the presented approach enables a good representation of the force-/displacement curves and especially well agreement with the experimentally observed fracture patterns. In addition, the mesh dependency of the results were assessed for one impact case showing only very little change of the simulation results which emphasises the general applicability of the presented method.

Effect of Single-Sex Education on Progress in GCSE

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Malacova, Eva

2007-01-01

Multilevel modeling was carried out on national value-added data to study the effects of single-sex education on the progress of pupils from 2002 Key Stage 3 to 2004 GCSE. The analysis suggests that pupils in a selective environment achieve higher progress in single-sex schools; however, the advantage of single-sex schooling seems to decrease with…

Expression and significance of HIF-1α and VEGF in rats with diabetic retinopathy

Institute of Scientific and Technical Information of China (English)

Hong-Tao Yan; Guan-Fang Su

2014-01-01

Objective:To investigate the expression of hypoxia inducible factor-1α(HIF-1α) and vascular endothelial growth factor(VEGF) in diabetic retinopathy(DR) rats and its effect on theDR occurrence and development.Methods:A total of120SD rats were randomly divided into trial group and control group with60 in each.STZi.p. was used in the trial group to establish theDM model, citrate buffer salt of same amount was usedi.p. to the control group.1,3 and6 months after injection, respective20 rats were sacrificed in each group to observe expression ofHIF-1α andVEGF in the rat retina tissue at different time points.Results:Expression ofHIF-1α andVEGF were negative in the control group; expression ofHIF-1α andVEGF protein in retinal tissue were weak after1 month ofDR mold formation.It showed progressive enhancement along with the progression in different organizations, differences between groups were significant (P<0.05).Conclusions:Expressions ofHIF-1α andVEGF were correlated with disease progression in early diabetic retinopathy.Retinal oxygen can induce over-expression ofHIF-1α andVEGF.It shows thatHIF-1α andVEGF play an important role in the pathogenesis ofDR.

Subjective cognitive concerns and neuropsychiatric predictors of progression to the early clinical stages of Alzheimer disease.

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Donovan, Nancy J; Amariglio, Rebecca E; Zoller, Amy S; Rudel, Rebecca K; Gomez-Isla, Teresa; Blacker, Deborah; Hyman, Bradley T; Locascio, Joseph J; Johnson, Keith A; Sperling, Reisa A; Marshall, Gad A; Rentz, Dorene M

2014-12-01

To examine neuropsychiatric and neuropsychological predictors of progression from normal to early clinical stages of Alzheimer disease (AD). From a total sample of 559 older adults from the Massachusetts Alzheimer's Disease Research Center longitudinal cohort, 454 were included in the primary analysis: 283 with clinically normal cognition (CN), 115 with mild cognitive impairment (MCI), and 56 with subjective cognitive concerns (SCC) but no objective impairment, a proposed transitional group between CN and MCI. Two latent cognitive factors (memory-semantic, attention-executive) and two neuropsychiatric factors (affective, psychotic) were derived from the Alzheimer's Disease Centers' Uniform Data Set neuropsychological battery and Neuropsychiatric Inventory brief questionnaire. Factors were analyzed as predictors of time to progression to a worse diagnosis using a Cox proportional hazards regression model with backward elimination. Covariates included baseline diagnosis, gender, age, education, prior depression, antidepressant medication, symptom duration, and interaction terms. Higher/better memory-semantic factor score predicted lower hazard of progression (hazard ratio [HR] = 0.4 for 1 standard deviation [SD] increase, p factor score predicted higher hazard (HR = 1.3 for one SD increase, p = 0.01). No other predictors were significant in adjusted analyses. Using diagnosis as a sole predictor of transition to MCI, the SCC diagnosis carried a fourfold risk of progression compared with CN (HR = 4.1, p factors as significant predictors of more rapid progression from normal to early stages of cognitive decline and highlight the subgroup of cognitively normal elderly with SCC as those with elevated risk of progression to MCI. Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

Scalar Potential Model progress

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Hodge, John

2007-04-01

Because observations of galaxies and clusters have been found inconsistent with General Relativity (GR), the focus of effort in developing a Scalar Potential Model (SPM) has been on the examination of galaxies and clusters. The SPM has been found to be consistent with cluster cellular structure, the flow of IGM from spiral galaxies to elliptical galaxies, intergalactic redshift without an expanding universe, discrete redshift, rotation curve (RC) data without dark matter, asymmetric RCs, galaxy central mass, galaxy central velocity dispersion, and the Pioneer Anomaly. In addition, the SPM suggests a model of past expansion, past contraction, and current expansion of the universe. GR corresponds to the SPM in the limit in which a flat and static scalar potential field replaces the Sources and Sinks such as between clusters and on the solar system scale which is small relative to the distance to a Source. The papers may be viewed at http://web.infoave.net/˜scjh/ .

Regression of Nonalcoholic Fatty Liver Disease with Zinc and Selenium Co-supplementation after Disease Progression in Rats

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Farzad Shidfar

2018-01-01

Full Text Available Background: Studies have shown that zinc and selenium deficiency is common in nonalcoholic fatty liver disease (NAFLD. However, the effects of zinc and selenium co-supplementation before and/or after disease progression on NAFLD are not clear enough. The aim of this study was to compare the effects of zinc and selenium co-supplementation before and/or after disease progression on NAFLD prognosis. Methods: Forty male Sprague–Dawley rats (197±4 g were randomly assigned to 4 dietary groups: normal-fat diet (NFD; receiving 9% of calories as fat, high-fat diet (HFD; receiving 82% of calories as fat, supplementation before disease progression (S+HFD, and supplementation after disease progression (HFD+S. The diets were implemented over a 20-week period in all the groups. Biochemical and histologic parameters were compared between the 4 groups, and between-group comparisons were also carried out. Results: There were significant differences in the average food dietary intake (P<0.001, weight (P<0.001, fasting blood sugar (P=0.005, triglyceride (P<0.001, total cholesterol (P<0.001, low-density lipoprotein cholesterol (P=0.002, high-density lipoprotein cholesterol (P=0.001, alanine aminotransferase (P<0.001, and aspartate aminotransferase (P<0.001 between the 4 dietary groups. Serum triglyceride and total cholesterol were significantly lower in the HFD+S Group than in the S+HFD Group (P<0.001 and P=0.003, respectively. Fat accumulation was significantly reduced in the HFD+S Group (P<0.001. Conclusion: Zinc and selenium co-supplementation after disease progression improved biochemical and histologic parameters in an experimental model of NAFLD.

[Progress in stem cells and regenerative medicine].

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Wang, Libin; Zhu, He; Hao, Jie; Zhou, Qi

2015-06-01

Stem cells have the ability to differentiate into all types of cells in the body and therefore have great application potential in regenerative medicine, in vitro disease modelling and drug screening. In recent years, stem cell technology has made great progress, and induced pluripotent stem cell technology revolutionizes the whole stem cell field. At the same time, stem cell research in our country has also achieved great progress and becomes an indispensable power in the worldwide stem cell research field. This review mainly focuses on the research progress in stem cells and regenerative medicine in our country since the advent of induced pluripotent stem cell technology, including induced pluripotent stem cells, transdifferentiation, haploid stem cells, and new gene editing tools.

Clinical progress of human papillomavirus genotypes and their persistent infection in subjects with atypical squamous cells of undetermined significance cytology: Statistical and latent Dirichlet allocation analysis

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Kim, Yee Suk; Lee, Sungin; Zong, Nansu; Kahng, Jimin

2017-01-01

The present study aimed to investigate differences in prognosis based on human papillomavirus (HPV) infection, persistent infection and genotype variations for patients exhibiting atypical squamous cells of undetermined significance (ASCUS) in their initial Papanicolaou (PAP) test results. A latent Dirichlet allocation (LDA)-based tool was developed that may offer a facilitated means of communication to be employed during patient-doctor consultations. The present study assessed 491 patients (139 HPV-positive and 352 HPV-negative cases) with a PAP test result of ASCUS with a follow-up period ≥2 years. Patients underwent PAP and HPV DNA chip tests between January 2006 and January 2009. The HPV-positive subjects were followed up with at least 2 instances of PAP and HPV DNA chip tests. The most common genotypes observed were HPV-16 (25.9%, 36/139), HPV-52 (14.4%, 20/139), HPV-58 (13.7%, 19/139), HPV-56 (11.5%, 16/139), HPV-51 (9.4%, 13/139) and HPV-18 (8.6%, 12/139). A total of 33.3% (12/36) patients positive for HPV-16 had cervical intraepithelial neoplasia (CIN)2 or a worse result, which was significantly higher than the prevalence of CIN2 of 1.8% (8/455) in patients negative for HPV-16 (Paged ≥51 years (38.7%) than in those aged ≤50 years (20.4%; P=0.036). Progression from persistent infection to CIN2 or worse (19/34, 55.9%) was higher than clearance (0/105, 0.0%; Page and long infection period with a clinical progression of CIN2 or worse. Therefore, LDA results may be presented as explanatory evidence during time-constrained patient-doctor consultations in order to deliver information regarding the patient's status. PMID:28587376

Murine nephrotoxic nephritis as a model of chronic kidney disease

DEFF Research Database (Denmark)

Ougaard, M. K.E.; Kvist, P. H.; Jensen, H. E.

2018-01-01

Using the nonaccelerated murine nephrotoxic nephritis (NTN) as a model of chronic kidney disease (CKD) could provide an easily inducible model that enables a rapid test of treatments. Originally, the NTN model was developed as an acute model of glomerulonephritis, but in this study we evaluate...... progressive mesangial expansion and significant renal fibrosis within three weeks suggesting CKD development. CD1 and C57BL/6 females showed a similar disease progression, but female mice seemed more susceptible to NTS compared to male mice. The presence of albuminuria, GFR decline, mesangial expansion...

Inhibition of prostate cancer osteoblastic progression with VEGF121/rGel, a single agent targeting osteoblasts, osteoclasts, and tumor neovasculature.

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Mohamedali, Khalid A; Li, Zhi Gang; Starbuck, Michael W; Wan, Xinhai; Yang, Jun; Kim, Sehoon; Zhang, Wendy; Rosenblum, Michael G; Navone, Nora M

2011-04-15

A hallmark of prostate cancer (PCa) progression is the development of osteoblastic bone metastases, which respond poorly to available therapies. We previously reported that VEGF(121)/rGel targets osteoclast precursors and tumor neovasculature. Here we tested the hypothesis that targeting nontumor cells expressing these receptors can inhibit tumor progression in a clinically relevant model of osteoblastic PCa. Cells from MDA PCa 118b, a PCa xenograft obtained from a bone metastasis in a patient with castrate-resistant PCa, were injected into the femurs of mice. Osteoblastic progression was monitored following systemic administration of VEGF(121)/rGel. VEGF(121)/rGel was cytotoxic in vitro to osteoblast precursor cells. This cytotoxicity was specific as VEGF(121)/rGel internalization into osteoblasts was VEGF(121) receptor driven. Furthermore, VEGF(121)/rGel significantly inhibited PCa-induced bone formation in a mouse calvaria culture assay. In vivo, VEGF(121)/rGel significantly inhibited the osteoblastic progression of PCa cells in the femurs of nude mice. Microcomputed tomographic analysis revealed that VEGF(121)/rGel restored the bone volume fraction of tumor-bearing femurs to values similar to those of the contralateral (non-tumor-bearing) femurs. VEGF(121)/rGel significantly reduced the number of tumor-associated osteoclasts but did not change the numbers of peritumoral osteoblasts. Importantly, VEGF(121)/rGel-treated mice had significantly less tumor burden than control mice. Our results thus indicate that VEGF(121)/rGel inhibits osteoblastic tumor progression by targeting angiogenesis, osteoclastogenesis, and bone formation. Targeting VEGF receptor (VEGFR)-1- or VEGFR-2-expressing cells is effective in controlling the osteoblastic progression of PCa in bone. These findings provide the basis for an effective multitargeted approach for metastatic PCa. ©2011 AACR.

Inhibition of prostate cancer osteoblastic progression with VEGF121/rGel, a single agent targeting osteoblasts, osteoclasts, and tumor neovasculature

Science.gov (United States)

Mohamedali, Khalid A.; Li, Zhi Gang; Starbuck, Michael W.; Wan, Xinhai; Yang, Jun; Kim, Sehoon; Zhang, Wendy; Rosenblum, Michael G.; Navone, Nora M.

2011-01-01

Purpose A hallmark of prostate cancer (PCa) progression is the development of osteoblastic bone metastases, which respond poorly to available therapies. We previously reported that VEGF121/rGel targets osteoclast precursors and tumor neovasculature. Here we tested the hypothesis that targeting non-tumor cells expressing these receptors can inhibit tumor progression in a clinically relevant model of osteoblastic PCa. Experimental Design Cells from MDA PCa 118b, a PCa xenograft obtained from a bone metastasis in a patient with castrate-resistant PCa, were injected into the femurs of mice. Osteoblastic progression was monitored following systemic administration of VEGF121/rGel. Results VEGF121/rGel was cytotoxic in vitro to osteoblast precursor cells. This cytotoxicity was specific as VEGF121/rGel internalization into osteoblasts was VEGF121 receptor driven. Furthermore, VEGF121/rGel significantly inhibited PCa-induced bone formation in a mouse calvaria culture assay. In vivo, VEGF121/rGel significantly inhibited the osteoblastic progression of PCa cells in the femurs of nude mice. Microcomputed tomography analysis revealed that VEGF121/rGel restored the bone volume fraction of tumor-bearing femurs to values similar to those of the contralateral (non–tumor bearing) femurs. VEGF121/rGel significantly reduced the number of tumor-associated osteoclasts but did not change the numbers of peritumoral osteoblasts. Importantly, VEGF121/rGel-treated mice had significantly less tumor burden than control mice. Our results thus indicate that VEGF121/rGel inhibits osteoblastic tumor progression by targeting angiogenesis, osteoclastogenesis, and bone formation. Conclusions Targeting VEGFR-1 – or VEGFR-2–expressing cells is effective in controlling the osteoblastic progression of PCa in bone. These findings provide the basis for an effective multitargeted approach for metastatic PCa. PMID:21343372