WorldWideScience

Sample records for modeling significant progress

  1. Significance and Progress of Bionics

    Institute of Scientific and Technical Information of China (English)

    Yongxiang Lu

    2004-01-01

    The four topics are described including the driving force and source of the scientific and technological creation, the definition and history of the bionics, the important significance of bionics in the development of the human beings, and the leading edge and progress of bionics. The appetency of human for the creation is the essential motivity of the innovation in science and technology. Nature and society are the objects for us to cognize and serve, meanwhile, the best teachers for us to learn from them. It is only 5 million years for human's development, but evolution of life has over 3.5 billion years history. Although, copying the creation from the human being is important, however, it has much more potential and opportunity in imitating the nature, and more possibility to promote the ability of original innovation. The significance and progress of bionics are summarized, in this paper, and the leading edges of bionics, in the near future, are forecasted.

  2. Inhibition of tumor progression during allergic airway inflammation in a murine model: significant role of TGF-β.

    Science.gov (United States)

    Tirado-Rodriguez, Belen; Baay-Guzman, Guillermina; Hernandez-Pando, Rogelio; Antonio-Andres, Gabriela; Vega, Mario I; Rocha-Zavaleta, Leticia; Bonifaz, Laura C; Huerta-Yepez, Sara

    2015-09-01

    TGF-β is an important mediator of pulmonary allergic inflammation, and it has been recently reported to be a potential inhibitor of lung tumor progression. The correlation between cancer and allergic inflammatory diseases remains controversial. Thus, the aim of the present study was to evaluate the effects of pulmonary allergic inflammation and in particular the role of TGF-β on cancer progression. Cancer cells were implanted in a BALB/c mice model of allergic airway inflammation, and tumor growth was measured. Apoptosis was evaluated by TUNEL assay, and TGF-β was measured by ELISA. Expression of proliferating cell nuclear antigen, TGF-β, TGF-β receptors I and II, phospho-Smad2 and phospho-Smad4 was evaluated by immunohistochemistry and quantified using digital pathology. The effect of a TGF-β activity inhibitor and recombinant TGF-β on tumor growth was analyzed. The effect of exogenous TGF-β on cell proliferation and apoptosis was evaluated in vitro. Mice with allergic airway inflammation exhibited decreased tumor volumes due to cell proliferation inhibition and increased apoptosis. TGF-β was increased in the sera and tumor tissues of allergic mice. TGF-β activity inhibition increased tumor progression in allergic mice by enhancing proliferation and decreasing apoptosis of tumor cells. The administration of TGF-β resulted in reduced tumor growth. This study is the first to establish an inverse relationship between allergic airway inflammation and tumor progression. This effect appears to be mediated by TGF-β, which is overexpressed in tumor cells during pulmonary allergic inflammation. This study indicates that TGF-β is a potential target for antitumor therapy.

  3. Prevention of progression in monoclonal gammopathy of undetermined significance.

    Science.gov (United States)

    Rajkumar, S Vincent

    2009-09-15

    Monoclonal gammopathy of undetermined significance (MGUS) is a common premalignant plasma cell proliferative disorder with a lifelong risk of progression to multiple myeloma. Because myeloma is an incurable malignancy, strategies to delay or prevent progression in high-risk patients are of considerable importance.

  4. Prevention of Progression in Monoclonal Gammopathy of Undetermined Significance

    Science.gov (United States)

    Rajkumar, S. Vincent

    2009-01-01

    Summary Monoclonal gammopathy of undetermined significance (MGUS) is a common premalignant plasma cell proliferative disorder with a lifelong risk of progression to multiple myeloma. Since myeloma is an incurable malignancy, strategies to delay or prevent progression in high-risk patients are of considerable importance. PMID:19737944

  5. Glenohumeral arthritis after Latarjet procedure: Progression and it's clinical significance.

    Science.gov (United States)

    Kee, Young Moon; Kim, Hwan Jin; Kim, Jung Youn; Rhee, Yong Girl

    2017-09-01

    The risk factors of glenohumeral arthritis after the Latarjet procedure remain relatively unexplored. The purposes of this study are to evaluate the clinical significance of glenohumeral arthritis after the Latarjet procedure, and to investigate risk factors associated with arthritis progression. We evaluated 110 patients (110 shoulders) who underwent the Latarjet procedure for recurrent anterior shoulder instability. Patients had a mean age of 23.8 years (range, 14-52 years) at the time of the operation, and the mean duration of follow-up was 31 months (range, 24-111 months). At the last follow-up, the mean Visual Analog Scale (VAS), Rowe and University of California at Los Angeles (UCLA) scores significantly improved from 3.1, 36.5 and 23.6 points preoperatively to 1.6, 87.6 and 32.6 points (all P Latarjet procedure was in 20 shoulders (18.2%). At the final, overall prevalence of arthritis was 23.6% (26 shoulders). The non-arthritis group showed significantly better functional outcomes (VAS score: 0.9, Rowe Score: 89.3, UCLA score: 33.5) than the arthritis group (2.1, 84.9, 29.2; all P Latarjet procedure yielded satisfactory functional outcomes with low recurrent rate at mid-term follow-up. Development or progression of arthritis was observed in 18.2% of patients, postoperatively. Glenohumeral arthritis after the Latarjet procedure had an adverse effect on clinical outcome. Generalized laxity and lateral overhang should be considered as risk factors of progression to glenohumeral arthritis after the Latarjet procedure. Copyright © 2017 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.

  6. NSFC Funded Project Made Significant Progress in Quantum Dynamics

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    Prof.Zhang Donghui,Prof.Yang Xueming and colleagues in Dalian Institute of Chemical Physics, CAS published on Science in July,2011 an article "Experimental and Theoretical Differential Cross Sections for a Four-atom Reaction;HD+OH→H_2O+D",summarizing results of a research project funded by NSFC.This is a significant progress made by Chinese scientists in chemical reaction dynamics. Differential cross sections(DCSs) of chemical reactions characterize the effective target area of the

  7. Revisiting multiple models of progression of β-cell loss of function in type 1 diabetes: Significance for prevention and cure.

    Science.gov (United States)

    Li, Xia; Cheng, Jin; Zhou, Zhiguang

    2016-07-01

    Type 1 diabetes (T1D) results from a chronic autoimmune process that leads to β-cell destruction and exogenous insulin dependence. The natural history of T1D proposed by Eisenbarth suggested six relatively independent stages over the course of the entire disease process, which was considered to be linear and chronic. Based on this classical theory, immunotherapies aim to prevent or reverse all these periods of β-cell loss. Over the past 30 years, much novel information about the pathogenesis of T1D proved that there are complex metabolic changes occurring throughout the entire disease process. Therefore, new possible models for the natural history of the disease have been proposed; these models, in turn, may help facilitate fresh avenues for the prevention and cure of T1D. Herein, we briefly review recent findings in this field of research, with the aim of providing a better theoretical basis for clinical practice. © 2016 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

  8. Differential action of glycoprotein hormones: significance in cancer progression.

    Science.gov (United States)

    Govindaraj, Vijayakumar; Arya, Swathy V; Rao, A J

    2014-02-01

    Growth of multicellular organisms depends on maintenance of proper balance between proliferation and differentiation. Any disturbance in this balance in animal cells can lead to cancer. Experimental evidence is provided to conclude with special reference to the action of follicle-stimulating hormone (FSH) on Sertoli cells, and luteinizing hormone (LH) on Leydig cells that these hormones exert a differential action on their target cells, i.e., stimulate proliferation when the cells are in an undifferentiated state which is the situation with cancer cells and promote only functional parameters when the cell are fully differentiated. Hormones and growth factors play a key role in cell proliferation, differentiation, and apoptosis. There is a growing body of evidence that various tumors express some hormones at high levels as well as their cognate receptors indicating the possibility of a role in progression of cancer. Hormones such as LH, FSH, and thyroid-stimulating hormone have been reported to stimulate cell proliferation and act as tumor promoter in a variety of hormone-dependent cancers including gonads, lung, thyroid, uterus, breast, prostate, etc. This review summarizes evidence to conclude that these hormones are produced by some cancer tissues to promote their own growth. Also an attempt is made to explain the significance of the differential action of hormones in progression of cancer with special reference to prostate cancer.

  9. Progress in Initiator Modeling

    Energy Technology Data Exchange (ETDEWEB)

    Hrousis, C A; Christensen, J S

    2009-05-04

    There is great interest in applying magnetohydrodynamic (MHD) simulation techniques to the designs of electrical high explosive (HE) initiators, for the purpose of better understanding a design's sensitivities, optimizing its performance, and/or predicting its useful lifetime. Two MHD-capable LLNL codes, CALE and ALE3D, are being used to simulate the process of ohmic heating, vaporization, and plasma formation in the bridge of an initiator, be it an exploding bridgewire (EBW), exploding bridgefoil (EBF) or slapper type initiator. The initiation of the HE is simulated using Tarver Ignition & Growth reactive flow models. 1-D, 2-D and 3-D models have been constructed and studied. The models provide some intuitive explanation of the initiation process and are useful for evaluating the potential impact of identified aging mechanisms (such as the growth of intermetallic compounds or powder sintering). The end product of this work is a simulation capability for evaluating margin in proposed, modified or aged initiation system designs.

  10. Significant Progress in Petroleum Geology and Exploration of China

    Institute of Scientific and Technical Information of China (English)

    Hu Jianyi; Dou Lirong

    1994-01-01

    @@ Since the mid 80s, great progress has been achieved in petroleum exploration in China,supported by the advance in petroleum geology. New frontiers, new areas and new sequences have been opened for exploration, so the petroleum petential continuously increases.

  11. Significant Progress in Pilot Test of Polymer Flooding in Daqing Oilfield

    Institute of Scientific and Technical Information of China (English)

    Liu Heng; Fu Dewu

    1994-01-01

    @@ Daqing oilfields have been developed with water injection for over thirty years. Currently,the pilot tests of polymer flooding for enhanced oil recovery are being conducted and significant progress has been made.

  12. Identification of the potential risk factors for monoclonal gammopathy of undetermined significance of progression.

    Science.gov (United States)

    Li, Rong; Du, Juan; Hou, Jian

    2015-01-01

    Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell disorder. The etiology of MGUS progression remains unclear and is a current topic of investigation. This review summarizes the essential features of MGUS and the potential risk factors for MGUS of progression. Many clinical studies have been conducted to identify the critical risk markers that play important roles in progression. Some clinical variables, such as immunophenotypic markers and cytogenetic changes, have been recognized as potential risk factors. In this review, we discuss novel insights from recent studies of potential risk factors, and we propose future directions for clinical management and additional studies.

  13. Cancer progression modeling using static sample data.

    Science.gov (United States)

    Sun, Yijun; Yao, Jin; Nowak, Norma J; Goodison, Steve

    2014-01-01

    As molecular profiling data continues to accumulate, the design of integrative computational analyses that can provide insights into the dynamic aspects of cancer progression becomes feasible. Here, we present a novel computational method for the construction of cancer progression models based on the analysis of static tumor samples. We demonstrate the reliability of the method with simulated data, and describe the application to breast cancer data. Our findings support a linear, branching model for breast cancer progression. An interactive model facilitates the identification of key molecular events in the advance of disease to malignancy.

  14. The significance of dynamin 2 expression for prostate cancer progression, prognostication, and therapeutic targeting.

    Science.gov (United States)

    Xu, Bin; Teng, Liang Hong; Silva, Sabrina Daniela da; Bijian, Krikor; Al Bashir, Samir; Jie, Su; Dolph, Michael; Alaoui-Jamali, Moulay A; Bismar, Tarek A

    2014-02-01

    Dynamin 2 (Dyn2) is essential for intracellular vesicle formation and trafficking, cytokinesis, and receptor endocytosis. In this study, we investigated the implication of Dyn2 as a prognostic marker and therapeutic target for progressive prostate cancer (PCA). We evaluated Dyn2 protein expression by immunohistochemistry in two cohorts: men with localized PCA treated by retropubic radical prostatectomy (n = 226), and men with advanced/castrate-resistant PCA (CRPC) treated by transurethral resection of prostate (TURP) (n = 253). The role of Dyn2 in cell invasiveness was assessed by in vitro and in vivo experiments using androgen-responsive and refractory PCA preclinical models. Dyn2 expression was significantly increased across advanced stages of PCA compared to benign prostate tissue (P size and lymph node metastases in vivo. In isolated PCA cells, Dyn2 was found to regulate focal adhesion turnover, which is critical for cell migration; this mechanism requires full Dyn2 compared to mutants deficient in GTPase activity. In conclusion, Dyn2 overexpression is associated with neoplastic prostate epithelium and is associated with poor prognosis. Inhibition of Dyn2 prevents cell invasiveness in androgen-responsive and -refractory PCA models, supporting the potential benefit of Dyn2 to serve as a therapeutic target for advanced PCA.

  15. NSFC Funded Project Made Significant Progress in Intelligent Nanomaterial and Device

    Institute of Scientific and Technical Information of China (English)

    2012-01-01

    Smart and intelligent nanomaterials are currently in sharp focus in materials research as their proper- ties are increasingly becoming more understood. Professor Wei Chen and his colleagues from Suzhou Insti tute of Nano Teeh 〉. Nano-Bionics, CAS, have made significant progress in carbon nanotube/graphene based bio-inspired actuators.

  16. Progressive Damage Modeling of Notched Composites

    Science.gov (United States)

    Aitharaju, Venkat; Aashat, Satvir; Kia, Hamid; Satyanarayana, Arunkumar; Bogert, Philip

    2016-01-01

    There is an increased interest in using non-crimp fabric reinforced composites for primary and secondary structural weight savings in high performance automobile applications. However, one of the main challenges in implementing these composites is the lack of understanding of damage progression under a wide variety of loading conditions for general configurations. Towards that end, researchers at GM and NASA are developing new damage models to predict accurately the progressive failure of these composites. In this investigation, the developed progressive failure analysis model was applied to study damage progression in center-notched and open-hole tension specimens for various laminate schemes. The results of a detailed study with respect to the effect of element size on the analysis outcome are presented.

  17. Modelling vocal anatomy's significant effect on speech

    NARCIS (Netherlands)

    de Boer, B.

    2010-01-01

    This paper investigates the effect of larynx position on the articulatory abilities of a humanlike vocal tract. Previous work has investigated models that were built to resemble the anatomy of existing species or fossil ancestors. This has led to conflicting conclusions about the relation between

  18. Progress With Nonhuman Animal Models of Addiction.

    Science.gov (United States)

    Crabbe, John C

    2016-09-01

    Nonhuman animals have been major contributors to the science of the genetics of addiction. Given the explosion of interest in genetics, it is fair to ask, are we making reasonable progress toward our goals with animal models? I will argue that our goals are changing and that overall progress has been steady and seems likely to continue apace. Genetics tools have developed almost incredibly rapidly, enabling both more reductionist and more synthetic or integrative approaches. I believe that these approaches to making progress have been unbalanced in biomedical science, favoring reductionism, particularly in animal genetics. I argue that substantial, novel progress is also likely to come in the other direction, toward synthesis and abstraction. Another area in which future progress with genetic animal models seems poised to contribute more is the reconciliation of human and animal phenotypes, or consilience. The inherent power of the genetic animal models could be more profitably exploited. In the end, animal research has continued to provide novel insights about how genes influence individual differences in addiction risk and consequences. The rules of the genetics game are changing so fast that it is hard to remember how comparatively little we knew even a generation ago. Rather than worry about whether we have been wasting time and resources asking the questions we have been, we should look to the future and see if we can come up with some new ones. The valuable findings from the past will endure, and the sidetracks will be forgotten.

  19. Modeling cancer progression via pathway dependencies.

    Directory of Open Access Journals (Sweden)

    Elena J Edelman

    2008-02-01

    Full Text Available Cancer is a heterogeneous disease often requiring a complexity of alterations to drive a normal cell to a malignancy and ultimately to a metastatic state. Certain genetic perturbations have been implicated for initiation and progression. However, to a great extent, underlying mechanisms often remain elusive. These genetic perturbations are most likely reflected by the altered expression of sets of genes or pathways, rather than individual genes, thus creating a need for models of deregulation of pathways to help provide an understanding of the mechanisms of tumorigenesis. We introduce an integrative hierarchical analysis of tumor progression that discovers which a priori defined pathways are relevant either throughout or in particular steps of progression. Pathway interaction networks are inferred for these relevant pathways over the steps in progression. This is followed by the refinement of the relevant pathways to those genes most differentially expressed in particular disease stages. The final analysis infers a gene interaction network for these refined pathways. We apply this approach to model progression in prostate cancer and melanoma, resulting in a deeper understanding of the mechanisms of tumorigenesis. Our analysis supports previous findings for the deregulation of several pathways involved in cell cycle control and proliferation in both cancer types. A novel finding of our analysis is a connection between ErbB4 and primary prostate cancer.

  20. Recent progress on countercurrent chromatography modeling

    OpenAIRE

    Wang, Fengkang; Ito, Yoichiro; Wei, Yun

    2014-01-01

    As countercurrent chromatography is becoming an established method in chromatography for many kinds of products, it is becoming increasingly important to model the process and to be able to predict the peaks for a given process. The CCC industries are looking for rapid methods to analyze the processes of countercurrent chromatography and select suitable solvent system. In this paper, recent progress is reviewed in the development and demonstration of several types of models of countercurrent ...

  1. Corticortophin releasing factor 2 receptor agonist treatment significantly slows disease progression in mdx mice

    Directory of Open Access Journals (Sweden)

    Stevens Paula J

    2007-07-01

    Full Text Available Abstract Background Duchenne muscular dystrophy results from mutation of the dystrophin gene, causing skeletal and cardiac muscle loss of function. The mdx mouse model of Duchenne muscular dystrophy is widely utilized to evaluate the potential of therapeutic regimens to modulate the loss of skeletal muscle function associated with dystrophin mutation. Importantly, progressive loss of diaphragm function is the most consistent striated muscle effect observed in the mdx mouse model, which is the same as in patients suffering from Duchenne muscular dystrophy. Methods Using the mdx mouse model, we have evaluated the effect that corticotrophin releasing factor 2 receptor (CRF2R agonist treatment has on diaphragm function, morphology and gene expression. Results We have observed that treatment with the potent CRF2R-selective agonist PG-873637 prevents the progressive loss of diaphragm specific force observed during aging of mdx mice. In addition, the combination of PG-873637 with glucocorticoids not only prevents the loss of diaphragm specific force over time, but also results in recovery of specific force. Pathological analysis of CRF2R agonist-treated diaphragm muscle demonstrates that treatment reduces fibrosis, immune cell infiltration, and muscle architectural disruption. Gene expression analysis of CRF2R-treated diaphragm muscle showed multiple gene expression changes including globally decreased immune cell-related gene expression, decreased extracellular matrix gene expression, increased metabolism-related gene expression, and, surprisingly, modulation of circadian rhythm gene expression. Conclusion Together, these data demonstrate that CRF2R activation can prevent the progressive degeneration of diaphragm muscle associated with dystrophin gene mutation.

  2. A prediction model for progressive disease in systemic sclerosis

    Science.gov (United States)

    Meijs, Jessica; Schouffoer, Anne A; Ajmone Marsan, Nina; Stijnen, Theo; Putter, Hein; Ninaber, Maarten K; Huizinga, Tom W J; de Vries-Bouwstra, Jeska K

    2015-01-01

    Objective To develop a model that assesses the risk for progressive disease in patients with systemic sclerosis (SSc) over the short term, in order to guide clinical management. Methods Baseline characteristics and 1 year follow-up results of 163 patients with SSc referred to a multidisciplinary healthcare programme were evaluated. Progressive disease was defined as: death, ≥10% decrease in forced vital capacity, ≥15% decrease in diffusing capacity for carbon monoxide, ≥10% decrease in body weight, ≥30% decrease in estimated-glomerular filtration rate, ≥30% increase in modified Rodnan Skin Score (with Δ≥5) or ≥0.25 increase in Scleroderma Health Assessment Questionnaire. The number of patients with progressive disease was determined. Univariable and multivariable logistic regression analyses were used to assess the probability of progressive disease for each individual patient. Performance of the prediction model was evaluated using a calibration plot and area under the receiver operating characteristic curve. Results 63 patients had progressive disease, including 8 patients who died ≤18 months after first evaluation. Multivariable analysis showed that friction rubs, proximal muscular weakness and decreased maximum oxygen uptake as % predicted, adjusted for age, gender and use of immunosuppressive therapy at baseline, were significantly associated with progressive disease. Using the prediction model, the predicted chance for progressive disease increased from a pretest chance of 37% to 67–89%. Conclusions Using the prediction model, the chance for progressive disease for individual patients could be doubled. Friction rubs, proximal muscular weakness and maximum oxygen uptake as % predicted were identified as relevant parameters. PMID:26688749

  3. Aberrant expression of zinc transporter ZIP4 (SLC39A4) significantly contributes to human pancreatic cancer pathogenesis and progression.

    Science.gov (United States)

    Li, Min; Zhang, Yuqing; Liu, Zijuan; Bharadwaj, Uddalak; Wang, Hao; Wang, Xinwen; Zhang, Sheng; Liuzzi, Juan P; Chang, Shou-Mei; Cousins, Robert J; Fisher, William E; Brunicardi, F Charles; Logsdon, Craig D; Chen, Changyi; Yao, Qizhi

    2007-11-20

    Zinc is an essential trace element and catalytic/structural component used by many metalloenzymes and transcription factors. Recent studies indicate a possible correlation of zinc levels with the cancer risk; however, the exact role of zinc and zinc transporters in cancer progression is unknown. We have observed that a zinc transporter, ZIP4 (SLC39A4), was substantially overexpressed in 16 of 17 (94%) clinical pancreatic adenocarcinoma specimens compared with the surrounding normal tissues, and ZIP4 mRNA expression was significantly higher in human pancreatic cancer cells than human pancreatic ductal epithelium (HPDE) cells. This indicates that aberrant ZIP4 up-regulation may contribute to the pancreatic cancer pathogenesis and progression. We studied the effects of ZIP4 overexpression in pancreatic cancer cell proliferation in vitro and pancreatic cancer progression in vivo. We found that forced expression of ZIP4 increased intracellular zinc levels, increased cell proliferation by 2-fold in vitro, and significantly increased tumor volume by 13-fold in the nude mice model with s.c. xenograft compared with the control cells. In the orthotopic nude mice model, overexpression of ZIP4 not only increased the primary tumor weight (7.2-fold), it also increased the peritoneal dissemination and ascites incidence. Moreover, increased cell proliferation and higher zinc content were also observed in the tumor tissues that overexpressed ZIP4. These data reveal an important outcome of aberrant ZIP4 expression in contributing to pancreatic cancer pathogenesis and progression. It may suggest a therapeutic strategy whereby ZIP4 is targeted to control pancreatic cancer growth.

  4. Recent progress on the Random Conductance Model

    CERN Document Server

    Biskup, Marek

    2011-01-01

    Recent progress on the understanding of the Random Conductance Model is reviewed and commented. A particular emphasis is on the results on the scaling limit of the random walk among random conductances for almost every realization of the environment, observations on the behavior of the effective resistance as well as the scaling limit of certain models of gradient fields with non-convex interactions. The text is an expanded version of the lecture notes for a course delivered at the 2011 Cornell Summer School on Probability.

  5. Progression of Diabetic Capillary Occlusion: A Model.

    Directory of Open Access Journals (Sweden)

    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.

  6. Progress and significance in research on the early Middle Cambrian Kaili Biota, Guizhou Province,China

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Important progress in research on the Kaili Biota has been made recently. Many interesting components from Chengjiang Biota and Burgess Shale Biota have been discovered, e.g. Microdictyon of lobopodia; Ottoia, Palaeoscolex of worms; Naraoia, Marrella of Trilobitioidea, Mollisonia, anamalocarids and other non-trilobite arthropods; and new sorts of echinoder-mas, macroalage fossils and so on. Recent work on the Kaili Biota has resulted in the following developments: (i) an increase in the number of animal genera, up to more than 100 genera in total, so that the Kaili Biota has become the third most diverse of the Burgess Shale-type Biota after the Burgess Shale and Chengjiang Biotas; and (ii) the most noteworthy fossils in the Kaili Biota are echinoderms, non-trilobite arthropods and soft-bodied medusiform fossils, especially the most diverse echinoderms. The progress provides envidence for the biodiversity of marine organisms presented after the "Cambrian Explosion" and serves as a link between the earlist Cambrian Chengjiang Biota and late early Middle Cambrian Burgess Shale Biota. It is of great significance in the reconstruction of the Cambrian palaeoplate, palaeongeography and in research on taphonomy.

  7. [Research Progress of circRNA and Its Significance in Forensic Science].

    Science.gov (United States)

    Zhang, Ya-qi; Shao, Cheng-chen; Li, Cheng-tao; Zhao, Zi-qin; Xie, Jian-hui

    2016-04-01

    RNA has received more attention in the field of forensic medicine and the development of the new biological markers based on RNA shows great significance in the analysis of complex cases. circular RNA (circRNA) is a kind of non-coding RNA which is widely reported recently. Although the regulatory mechanisms of generation and expression are not fully clear, the existing research indicates that circRNA has important biological functions. CircRNA has a cell-type-specific expression with great stability and a high expression level, which makes it meaningful in forensic applications potentially. In this paper, the research progress, the generation and regulation of circRNA as well as its biological characteristics and functions are summarized, which will provide references for related studies and forensic applications.

  8. Maspin expression and its clinicopathological significance in tumorigenesis and progression of gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Meng-Chun Wang; Yan-Min Yang; Xiao-Han Li; Fang Dong; Yan Li

    2004-01-01

    AIM: To investigate maspin expression in tumorigenesis and progression of gastric cancer and to explore its relevant molecular mechanisms.METHODS: Formalin-fixed and paraffin-embedded tissues from normal mucosa (n=182), dysplasia (n=69), cancer (n=113) of the stomach were studied for maspin expression by immunohistochemistry. Microvessel density (MVD) in gastric cancer was labeled using anti-CD34 antibody. Maspin expression was compared with clinical parameters and MVD of tumors. Caspase-3 expression was also detected in gastric carcinoma by immunohistochemistry. The relationship between Caspase-3 and maspin expression was concerned as well.RESULTS: The positive rates of maspin expression were 79.8%(145/182), 75.4%(52/69) and 50.4%(57/113) in normal mucosa, dysplasia and cancer of the stomach,respectively. Cancer less frequently expressed maspin than normal mucosa and dysplasia (P<0.05). Maspin expression showed a significantly negative association with invasive depth, metastasis, Lauren's and Nakamura's classification (P<0.05), but not with tumor size, Borrmann's classification,growth pattern or TNM staging (P>0.05). The positive rate of Caspase-3 was significantly lower in gastric cancer than in normal gastric mucosa (P<0.05,32.7% vs 50.4%). It was noteworthy that maspin expression was negatively correlated with MVD, but positively correlated with expression of Caspase-3 in gastric cancer (P<0.05).CONCLUSION: Down-regulated maspin expression is a late molecular event in gastric carcinogenesis. Reduced expression of maspin contributes to progression of gastric cancer probably by inhibiting cell adhesion, enhancing cell mobility,decreasing cell apoptosis and facilitating angiogenesis.Additionally altered expression of maspin underlies the molecular mechanism of differentiation of gastric cancer and supports the different histogenetic pathways of intestinal and diffuse gastric cancers. Maspin expression can be considered as an effective and objective

  9. 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.

  10. Progress in Modeling and Simulation of Batteries

    Energy Technology Data Exchange (ETDEWEB)

    Turner, John A [ORNL

    2016-01-01

    Modeling and simulation of batteries, in conjunction with theory and experiment, are important research tools that offer opportunities for advancement of technologies that are critical to electric motors. The development of data from the application of these tools can provide the basis for managerial and technical decision-making. Together, these will continue to transform batteries for electric vehicles. This collection of nine papers presents the modeling and simulation of batteries and the continuing contribution being made to this impressive progress, including topics that cover: * Thermal behavior and characteristics * Battery management system design and analysis * Moderately high-fidelity 3D capabilities * Optimization Techniques and Durability As electric vehicles continue to gain interest from manufacturers and consumers alike, improvements in economy and affordability, as well as adoption of alternative fuel sources to meet government mandates are driving battery research and development. Progress in modeling and simulation will continue to contribute to battery improvements that deliver increased power, energy storage, and durability to further enhance the appeal of electric vehicles.

  11. Significant uncertainty in global scale hydrological modeling from precipitation data errors

    NARCIS (Netherlands)

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

    2015-01-01

    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

  12. Significant uncertainty in global scale hydrological modeling from precipitation data erros

    NARCIS (Netherlands)

    Sperna Weiland, F.; Vrugt, J.A.; Beek, van P.H.; Weerts, A.H.; Bierkens, M.F.P.

    2015-01-01

    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

  13. 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.

  14. A significant decrease in diagnosis of primary progressive multiple sclerosis: A cohort study.

    Science.gov (United States)

    Westerlind, Helga; Stawiarz, Leszek; Fink, Katharina; Hillert, Jan; Manouchehrinia, Ali

    2016-07-01

    Several reports indicate changes to prevalence, incidence, female-to-male ratio in multiple sclerosis. Diagnostic criteria, course definitions and clinical management of the disease have also undergone change during the recent decades. To investigate temporal trends in the diagnosis of primary progressive multiple sclerosis (PPMS) in Sweden. Through the Swedish MS registry we investigated the proportion of PPMS diagnosis in birth, diagnosis and age period cohorts using Poisson regression. A total of 16,915 patients were categorised into six birth-cohorts from 1946 to 1975 and seven date-of-diagnosis-cohorts from 1980 to 2014. We observed a decrease in the uncorrected analysis of diagnosis of PPMS from 19.2% to 2.2% and an average decrease of 23% (p decrease per diagnosis-cohort was seen. In the age-specific diagnosis period cohorts the same decreasing trend of PPMS diagnosis was observed in almost all groups. The diagnosis of PPMS has significantly decreased in Sweden specifically after introduction of disease-modifying treatments. Such decrease can have severe impacts on the future research on PPMS. Our data also suggest that the current trend to emphasise presence or absence of inflammatory activity is already reflected in clinical practice. © The Author(s), 2016.

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

    Science.gov (United States)

    Lee, Chung; Kim, So Young; Kim, Nayoung K. D.; Chang, Mun Young; Rhee, Jihye; Park, Mi-Hyun; Koo, Soo Kyung; Kim, Min Young; Han, Jin Hee; Oh, Seung-ha; Park, Woong-Yang; Choi, Byung Yoon

    2016-01-01

    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. PMID:27792758

  16. Inferring tree causal models of cancer progression with probability raising.

    Directory of Open Access Journals (Sweden)

    Loes Olde Loohuis

    Full Text Available Existing techniques to reconstruct tree models of progression for accumulative processes, such as cancer, seek to estimate causation by combining correlation and a frequentist notion of temporal priority. In this paper, we define a novel theoretical framework called CAPRESE (CAncer PRogression Extraction with Single Edges to reconstruct such models based on the notion of probabilistic causation defined by Suppes. We consider a general reconstruction setting complicated by the presence of noise in the data due to biological variation, as well as experimental or measurement errors. To improve tolerance to noise we define and use a shrinkage-like estimator. We prove the correctness of our algorithm by showing asymptotic convergence to the correct tree under mild constraints on the level of noise. Moreover, on synthetic data, we show that our approach outperforms the state-of-the-art, that it is efficient even with a relatively small number of samples and that its performance quickly converges to its asymptote as the number of samples increases. For real cancer datasets obtained with different technologies, we highlight biologically significant differences in the progressions inferred with respect to other competing techniques and we also show how to validate conjectured biological relations with progression models.

  17. Clinical Significance of Optic Disc Progression by Topographic Change Analysis Maps in Glaucoma: An 8-Year Follow-Up Study

    Directory of Open Access Journals (Sweden)

    D. Kourkoutas

    2014-01-01

    Full Text Available Aim. To investigate the ability of Heidelberg Retina Tomograph (HRT3 Topographic Change Analysis (TCA map to predict the subsequent development of clinical change, in patients with glaucoma. Materials. 61 eyes of 61 patients, which, from a retrospective review were defined as stable on optic nerve head (ONH stereophotographs and visual field (VF, were enrolled in a prospective study. Eyes were classified as TCA-stable or TCA-progressed based on the TCA map. All patients underwent HRT3, VF, and ONH stereophotography at 9–12 months intervals. Clinical glaucoma progression was determined by masked assessment of ONH stereophotographs and VF Guided Progression Analysis. Results. The median (IQR total HRT follow-up period was 8.1 (7.3, 9.1 years, which included a median retrospective and prospective follow-up time of 3.9 (3.1, 5.0 and 4.0 (3.5, 4.7 years, respectively. In the TCA-stable eyes, VF and/or photographic progression occurred in 5/13 (38.4% eyes compared to 11/48 (22.9% of the TCA-progressed eyes. There was no statistically significant association between TCA progression and clinically relevant (photographic and/or VF progression (hazard ratio, 1.18; P=0.762. The observed median time to clinical progression from enrollment was significantly shorter in the TCA-progressed group compared to the TCA-stable group (P=0.04. Conclusion. Our results indicate that the commercially available TCA progression criteria do not adequately predict subsequent photographic and/or VF progression.

  18. 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.

  19. Substantial Progress Yet Significant Opportunity for Improvement in Stroke Care in China.

    Science.gov (United States)

    Li, Zixiao; Wang, Chunjuan; Zhao, Xingquan; Liu, Liping; Wang, Chunxue; Li, Hao; Shen, Haipeng; Liang, Li; Bettger, Janet; Yang, Qing; Wang, David; Wang, Anxin; Pan, Yuesong; Jiang, Yong; Yang, Xiaomeng; Zhang, Changqing; Fonarow, Gregg C; Schwamm, Lee H; Hu, Bo; Peterson, Eric D; Xian, Ying; Wang, Yilong; Wang, Yongjun

    2016-11-01

    Stroke is a leading cause of death in China. Yet the adherence to guideline-recommended ischemic stroke performance metrics in the past decade has been previously shown to be suboptimal. Since then, several nationwide stroke quality management initiatives have been conducted in China. We sought to determine whether adherence had improved since then. Data were obtained from the 2 phases of China National Stroke Registries, which included 131 hospitals (12 173 patients with acute ischemic stroke) in China National Stroke Registries phase 1 from 2007 to 2008 versus 219 hospitals (19 604 patients) in China National Stroke Registries phase 2 from 2012 to 2013. Multiple regression models were developed to evaluate the difference in adherence to performance measure between the 2 study periods. The overall quality of care has improved over time, as reflected by the higher composite score of 0.76 in 2012 to 2013 versus 0.63 in 2007 to 2008. Nine of 13 individual performance metrics improved. However, there were no significant improvements in the rates of intravenous thrombolytic therapy and anticoagulation for atrial fibrillation. After multivariate analysis, there remained a significant 1.17-fold (95% confidence interval, 1.14-1.21) increase in the odds of delivering evidence-based performance metrics in the more recent time periods versus older data. The performance metrics with the most significantly increased odds included stroke education, dysphagia screening, smoking cessation, and antithrombotics at discharge. Adherence to stroke performance metrics has increased over time, but significant opportunities remain for further improvement. Continuous stroke quality improvement program should be developed as a national priority in China. © 2016 American Heart Association, Inc.

  20. Progress towards a Venus reference cloud model

    Science.gov (United States)

    Wilson, Colin; Ignatiev, Nikolay; Marcq, Emmanuel

    Venus is completely enveloped by clouds. The main cloud layers stretch from altitudes of 48 - 75 km, with additional tenuous hazes found at altitudes 30 - 100 km. Clouds play a crucial role in governing atmospheric circulation, chemistry and climate on all planets, but particularly so on Venus due to the optical thickness of the atmosphere. The European Space Agency’s Venus Express (VEx) satellite has carried out a wealth of observations of Venus clouds since its arrival at Venus in April 2006. Many VEx observations are relevant to cloud science - from imagers and spectrometers to solar, stellar and radio occultation - each covering different altitude ranges, spectral ranges and atmospheric constituents. We have formed an International Team at the International Space Science Institute to bring together scientists from each of the relevant Venus Express investigation teams as well as from previous missions, as well as those developing computational and analytical models of clouds and hazes. The aims of the project are (1) to create self-consistent reference cloud/haze models which capture not only a mean cloud structure but also its main modes of variability; and (2) to bring together modelers and observers, to reach an understanding of clouds and hazes on Venus which matches all observables and is physically consistent. Our approach is to first to assemble an averaged cloud profile for low latitudes, showing how cloud number abundances and other observables vary as a function of altitude, consistent with all available observations. In a second step, we will expand this work to produce a reference cloud profile which varies with latitude and local solar time, as well as optical thickness of the cloud. We will present our status in progressing towards this goal. We acknowledge the support of the International Space Science Institute of Berne, Switzerland, in hosting our Team’s meetings.

  1. Flood Progression Modelling and Impact Analysis

    DEFF Research Database (Denmark)

    Mioc, Darka; Anton, François; Nickerson, B.

    People living in the lower valley of the St. John River, New Brunswick, Canada, frequently experience flooding when the river overflows its banks during spring ice melt and rain. To better prepare the population of New Brunswick for extreme flooding, we developed a new flood prediction model...... that computes floodplain polygons before the flood occurs. This allows emergency managers to access the impact of the flood before it occurs and make the early decisions for evacuation of the population and flood rescue. This research shows that the use of GIS and LiDAR technologies combined with hydrological...... modelling can significantly improve the decision making and visualization of flood impact needed for emergency planning and flood rescue. Furthermore, the 3D GIS application we developed for modelling flooded buildings and infrastructure provides a better platform for modelling and visualizing flood...

  2. Progress in the genetics of polygenic brain disorders: significant new challenges for neurobiology.

    Science.gov (United States)

    McCarroll, Steven A; Hyman, Steven E

    2013-10-30

    Advances in genome analysis, accompanied by the assembly of large patient cohorts, are making possible successful genetic analyses of polygenic brain disorders. If the resulting molecular clues, previously hidden in the genomes of affected individuals, are to yield useful information about pathogenesis and inform the discovery of new treatments, neurobiology will have to rise to many difficult challenges. Here we review the underlying logic of the genetic investigations, describe in more detail progress in schizophrenia and autism, and outline the challenges for neurobiology that lie ahead. We argue that technologies at the disposal of neuroscience are adequately advanced to begin to study the biology of common and devastating polygenic disorders.

  3. 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.

  4. Effect of statins, smoking and obesity on progression of monoclonal gammopathy of undetermined significance: a case-control study.

    Science.gov (United States)

    Thompson, Michael A; Kyle, Robert A; Melton, L Joseph; Plevak, Matthew F; Rajkumar, S Vincent

    2004-05-01

    Interleukin-6 (IL-6) and C-reactive protein (CRP, a surrogate marker for IL-6) are important in monoclonal gammopathy of undetermined significance (MGUS) and myeloma. Smoking and obesity may elevate CRP levels, while statins decrease CRP levels. A case-control study in 200 MGUS patients found that statin use, smoking history and obesity do not affect MGUS progression.

  5. Establishing the colitis-associated cancer progression mouse models.

    Science.gov (United States)

    Zheng, Haiming; Lu, Zhanjun; Wang, Ruhua; Chen, Niwei; Zheng, Ping

    2016-12-01

    Inflammatory bowel disease (IBD) has been reported as an important inducer of colorectal cancer (CRC). The most malignant IBD-associated CRC type has been highlighted as colitis-associated cancer (CAC). However, lack of CAC cases and difficulties of the long follow-up research have challenged researchers in molecular mechanism probing. Here, we established pre-CAC mouse models (dextran sulfate sodium [DSS] group and azoxymethane [AOM] group) and CAC mouse model (DSS/AOM group) to mimic human CAC development through singly or combinational treatment with DSS and AOM followed by disease activity index analysis. We found that these CAC mice showed much more severe disease phenotype, including serious diarrhea, body weight loss, rectal prolapse and bleeding, bloody stool, tumor burden, and bad survival. By detecting expression patterns of several therapeutic targets-Apc, p53, Kras, and TNF-α-in these mouse models through western blot, histology analysis, qRT-PCR, and ELISA methods, we found that the oncogene Kras expression remained unchanged, while the tumor suppressors-Apc and p53 expression were both significantly downregulated with malignancy progression from pre-CAC to CAC, and TNF-α level was elevated the most in CAC mice blood which is of potential clinical use. These data indicated the successful establishment of CAC development mouse models, which mimics human CAC well both in disease phenotype and molecular level, and highlighted the promoting role of inflammation in CAC progression. This useful tool will facilitate the further study in CAC molecular mechanism.

  6. Overexpression of centromere protein H is significantly associated with breast cancer progression and overall patient survival

    Institute of Scientific and Technical Information of China (English)

    Wen-Ting Liao; Yan Feng; Men-Lin Li; Guang-Lin Liu; Man-Zhi Li; Mu-Sheng Zeng; Li-Bing Song

    2011-01-01

    Breast cancer is one of the leading causes of cancer death worldwide.This study aimed to analyze the expression of centromere protein H (CENP-H) in breast cancer and to correlate it with clinicopathologic data,including patient survival.Using reverse transcription-polymerase chain reaction and Westem blotting to detect the expression of CENP-H in normal mammary epithelial cells,immortalized mammary epithelial cell lines,and breast cancer cell lines,we observed that the mRNA and protein levels of CENP-H were higher in breast cancer cell lines and in immortalized mammary epithelial cells than in normal mammary epithelial cells.We next examined CENP-H expression in 307 paraffin-embedded archived samples of clinicopathologically characterized breast cancer using immunohistochemistry,and detected high CENP-H expression in 134 (43.6%) samples.Statistical analysis showed that CENP-H expression was related with clinical stage (P = 0.001),T classification (P = 0.032),N classification (P =0.018),and Ki-67 (P<0.001).Patients with high CENP-H expression had short overall survival.Multivariate analysis showed that CENP-H expression was an independent prognostic indicator for patient survival.Our results suggest that CENP-H protein is a valuable marker of breast cancer progression and prognosis.

  7. Progress in Significant Soil Science Fields of China over the Last Three Decades: A Review

    Institute of Scientific and Technical Information of China (English)

    ZHAO Qi-Guo; HE Ji-Zheng; YAN Xiao-Yuan; ZHANG Bin; ZHANG Gan-Lin; CAI Zu-Cong

    2011-01-01

    Due to continuous decreases in arable land area and continuous population increases, Chinese soil scientists face great challenges in meeting food demands, mitigating adverse environmental impacts, and sustaining or enhancing soil productivity under intensive agriculture.With the aim of promoting the application of soil science knowledge, this paper reviews the achievements of Chinese scientists in soil resource use and management, soil fertility, global change mitigation and soil biology over the last 30 years.During this period, soil resource science has provided essential support for the use and exploitation of Chinese soil resources, and has itself developed through introduction of new theories such as Soil Taxonomy and new technologies such us remote sensing.Soil fertility science has contributed to the alleviation and elimination of impeding physical and chemical factors that constrain availability of essential nutrients and water in soils, the understanding of nutrient cycling in agroecosystems, and the increase in nutrient use efficiency for sustainable crop production.Chinese soil scientists have contributed to the understanding of the cropland's role in global change, particularly to the understanding of methane and nitrous oxide emission from rice fields and the effect of elevated carbon dioxide and ozone on rice-wheat system.Soil biology research has progressed in biological N fixation, distribution of fauna in Chinese soils, and bioremediation of polluted soils.A new generation of soil scientists has arisen in the last three decades.The gaps between research and application in these soil science fields are also discussed.

  8. 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.'

  9. Cardio-eigenoscopy: significance of this new method in prognosis of risks of fatal arrhythmia progression in AMI patients

    Directory of Open Access Journals (Sweden)

    Dmitry V. Issakevich

    2013-05-01

    Full Text Available The aim of the study was to evaluate the significance of cardioeigenoscopy method for the prognosis of risks of fatal arrhythmia (the primary and secondary VF progression in AMI individuals.The study was performed with the use of the PC-assisted hemodynamic analyzer Cardiocode. The cardio-eigenoscopy was developed as a methodology that is capable of presenting all ECG changes in the basis of eigenvectors of a covariance matrix of ECG amplitudes and providing an analysis of a spectrum of eigenvalues. The ECG analysis software is implemented as a real-time monitoring of a set of parameters that makes possible to evaluate the therapy effectiveness. The cardio-eigenoscopy method is capable of assessing the risk of progression of fatal arrhythmia events in MI patients. The major markers of the possible progression of fatal arrhythmia were identified. The cardioeigenoscopy provided the maximum expressibility of an ECG curve at any specified EVE values.

  10. Enforcement actions: Significant actions resolved individual actions. Semiannual progress report, January 1996--June 1996

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-08-01

    This document summarizes significant enforcement actions that have been resolved during the period of January-June 1996. The report includes copies of Orders and Notices of Violations sent by the Nuclear Regulatory Commission to individuals with respect to the enforcement actions.

  11. Oil cracking to gases: Kinetic modeling and geological significance

    Institute of Scientific and Technical Information of China (English)

    TIAN Hui; WANG Zhaoming; XIAO Zhongyao; LI Xianqing; XIAO Xianming

    2006-01-01

    ATriassic oil sample from LN14 of Tarim Basin was pyrolyzed using the sealed gold tubes at 200-620℃ under a constant pressure of 50 MPa.The gaseous and residual soluble hydrocarbons were analyzed. The results show that the cracking of oil to gas can be divided into two distinct stages: the primary generation of total C1-5 gases from liquid oil characterized by the dominance of C2-5 hydrocarbons and the secondary or further cracking of C2-5gases to methane and carbon-rich matters leading to the progressive dryness of gases. Based on the experimental data, the kinetic parameters were determined for the primary generation and secondary cracking of oil cracking gases and extrapolated to geological conditions to predict the thermal stability and cracking extent of crude oil. Finally, an evolution model for the thermal destruction of crude oil was proposed and its implications to the migration and accumulation of oil cracking gases were discussed.

  12. Enforcement actions: Significant actions resolved material licensees. Semiannual progress report, July--December 1996

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-04-01

    This compilation summarizes significant enforcement actions that have been resolved during the period and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to material 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.

  13. Enforcement actions: Significant actions resolved individual actions. Semiannual progress report, January 1997--June 1997

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-09-01

    This compilation summarizes significant enforcement actions that have been resolved during the period (January - June 1997) and includes copies of Orders and Notices of Violation sent by the Nuclear Regulatory Commission to individuals 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. The Commission believes this information may be useful to licensees in making employment decisions.

  14. Enforcement actions: Significant actions resolved individuals actions. Semiannual progress report, July--December 1996

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-04-01

    This compilation summarizes significant enforcement actions that have been resolved during the period (July - December 1996) and includes copies of Orders and Notices of Violation sent by the Nuclear Regulatory Commission to individuals 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. The Commission believes this information may be useful to licensees in making employment decisions.

  15. Enforcement actions: Significant actions resolved; Quarterly progress report, October--December 1993: Volume 12, No. 4

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1994-03-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (October - December 1993) 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.

  16. Enforcement actions: Significant actions resolved reactor licensees. Semiannual progress report, July 1996--December 1996

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-04-01

    This compilation summarizes significant enforcement actions that have been resolved during the period (July-December 1996) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to reactor 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.

  17. Enforcement actions: Significant actions resolved material licensees. Quarterly progress report, April 1995--June 1995

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-08-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (April-June 1995) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to material 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.

  18. Enforcement actions: Significant actions resolved. Quarterly progress report, April--June 1993: Volume 12, No. 2

    Energy Technology Data Exchange (ETDEWEB)

    1993-09-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (April--June 1993) 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.

  19. Significance of decreased serum interleukin-10 levels in the progression of cerebral infarction.

    Science.gov (United States)

    Diao, Zeng-Yan; Wang, Cui-Lan; Qi, Hong-Shun; Jia, Guo-Yong; Yan, Chuan-Zhu

    2016-05-01

    Anti-inflammatory cytokine and its serological detection may have an important role in the process of cardiovascular and cerebrovascular diseases. We investigated whether serum interleukin-10 (IL-10) is associated with cerebral infarction or not in the general population. Identified comprehensive searching was performed covering PubMed, EMBASE, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, China BioMedicine, and China National Knowledge Infrastructure databases. Two reviewers extracted data and assessed studies independently. Information was extracted separately and classed into Asians and Caucasians. Summary standardized mean differences (SMDs) with 95 % confidence intervals (CI) were used with the utilization of Z test. Nine studies ranged from 2003 to 2014 were collected for meta-analysis. Results identified a negative association between serum IL-10 levels and cerebral infarction (SMD = 1.80, 95 % CI 0.79-2.81, P IL-10 level may be the main risk factor for cerebral infarction in India (SMD = 1.44, 95 % CI 1.13-1.75, P IL-10 levels were negatively correlated with cerebral infarction in Asians (SMD = 2.52, 95 % CI 0.47-4.57, P = 0.016), while not in Caucasians (P > 0.05). The lower serum IL-10 concentration was significantly associated with an increased likelihood of cerebral infarction in this meta-analysis. More prospective studies should be conducted to provide stronger evidence justifying the use of IL-10 as new biomarker to identify a predisposition toward cerebral infarction.

  20. Parameter and Process Significance in Mechanistic Modeling of Cellulose Hydrolysis

    Science.gov (United States)

    Rotter, B.; Barry, A.; Gerhard, J.; Small, J.; Tahar, B.

    2005-12-01

    The rate of cellulose hydrolysis, and of associated microbial processes, is important in determining the stability of landfills and their potential impact on the environment, as well as associated time scales. To permit further exploration in this field, a process-based model of cellulose hydrolysis was developed. The model, which is relevant to both landfill and anaerobic digesters, includes a novel approach to biomass transfer between a cellulose-bound biofilm and biomass in the surrounding liquid. Model results highlight the significance of the bacterial colonization of cellulose particles by attachment through contact in solution. Simulations revealed that enhanced colonization, and therefore cellulose degradation, was associated with reduced cellulose particle size, higher biomass populations in solution, and increased cellulose-binding ability of the biomass. A sensitivity analysis of the system parameters revealed different sensitivities to model parameters for a typical landfill scenario versus that for an anaerobic digester. The results indicate that relative surface area of cellulose and proximity of hydrolyzing bacteria are key factors determining the cellulose degradation rate.

  1. The solubilities of significant organic compounds in HLW tanks upernate solutions - FY 1997 progress report

    Energy Technology Data Exchange (ETDEWEB)

    Barney, G.S.

    1997-09-16

    ). Solubilities of all the organic salts, except for glycolate, decrease with increasing sodium hydroxide and sodium nitrate concentration because of the common ion effect of Na+. Sodium glycolate solubility increased with increasing hydroxide concentration. The complex waste solutions had sodium ion concentrations 3.4 to 7. 0 molar higher than unsaturated solutions. This caused a significant lowering of the solubilities of the organic sodium salts due to the common ion effect of sodium. Results of EDTA adsorption measurements show that EDTA or EDTA-metal complexes can be adsorbed onto hydrous metal oxides (that make up the sludge layers in the tanks) under conditions simulating the high-level waste tanks. The extent of adsorption is not large and depends on the concentration of hydroxide in the waste solutions. Higher hydroxide concentrations lower adsorption of EDTA. Adsorption also depends on the type of metal hydrous oxide present. Adsorption data for Fe(III), Cr(III), and NI(IV) hydrous oxides show that chromium(III) hydrous oxide adsorbs EDTA most effectively.

  2. 幼猪脊柱侧凸模型中椎体与椎间盘楔形变的进展规律及其意义%Progression of vertebral and disc wedging in immature porcine scoliosis model and its significance

    Institute of Scientific and Technical Information of China (English)

    钱邦平; 郑欣; 邱勇; 孙旭; 朱泽章; 王斌; 俞扬; 吴涛

    2013-01-01

    Objectives: To investigate the evolution of the disc and vertebral wedging under unilateral tethering in porcine scoliosis model and its significance. Methods: Seven female pigs underwent posterior asymetric tethering surgery. All pigs underwent serial postero-anterior X-ray films at 4-week intervals to document progression of the deformity. The disc and vertebral wedging in the curve was measured by Cobb's method. The wedging angle of 5 vertebrae and 4 discs which included apex and 2 ending vertebrae as well as discs between these vertefirae were analyzed. The wedging angle of every disc and vertebra in whole major curve was measured, and the proportion to the Cobb angle was calculated (wedging percentage) respectively. Results: The wedging angle of the vertebra in the apical area increased over time. The wedging angle of the apical vertebra and disc was found larger than that of the adjacent vertebrae. Immediately after operation, the wedging of intervertebral discs contributed to the scoliosis completely. However, the contribution of the vertebral wedging to the scoliosis increased over time. The wedging of the vertebra contributed largely (71.5%) to the scoliosis at 8 weeks postoperatively. Conclusions: The relative contributions of vertebral and disc wedging to the Cobb angle vary over time under asymmetric tethering. To obtain a reliable scoliosis animal model, adequate tethering period is required to get prominent vertebral wedging.%目的:探讨幼猪脊柱侧凸模型中椎体和椎间盘楔形变随拴系固定时间变化的规律及其意义.方法:对7只后路不对称性拴系造模成功的侧凸幼猪在术后即刻、4周、8周分别进行全脊柱后前位X线片检查,应用Cobb法测量侧凸范围内每个椎体和椎间盘的楔变角,分析顶椎及其上、下各两个椎体和相应的4个椎间盘的楔变角在拴系时期内变化的规律,并计算不同时期内所有椎体楔变角之和与所有椎间盘楔变角之和分别占整

  3. Endogenizing technological progress: The MESEMET model

    NARCIS (Netherlands)

    P.A.G. van Bergeijk (Peter); G.H.A. van Hagen; R.A. de Mooij (Ruud); J. van Sinderen (Jarig)

    1997-01-01

    textabstractThis paper endogenizes technology and human capital formation in the MESEM model that was developed by van Sinderen (Economic Modelling, 1993, 13, 285-300). Tax allowances for private R&D expenditures and public expenditures on both education and R& D are effective instruments to stimula

  4. Teaching physical activities to students with significant disabilities using video modeling.

    Science.gov (United States)

    Cannella-Malone, Helen I; Mizrachi, Sharona V; Sabielny, Linsey M; Jimenez, Eliseo D

    2013-06-01

    The objective of this study was to examine the effectiveness of video modeling on teaching physical activities to three adolescents with significant disabilities. The study implemented a multiple baseline across six physical activities (three per student): jumping rope, scooter board with cones, ladder drill (i.e., feet going in and out), ladder design (i.e., multiple steps), shuttle run, and disc ride. Additional prompt procedures (i.e., verbal, gestural, visual cues, and modeling) were implemented within the study. After the students mastered the physical activities, we tested to see if they would link the skills together (i.e., complete an obstacle course). All three students made progress learning the physical activities, but only one learned them with video modeling alone (i.e., without error correction). Video modeling can be an effective tool for teaching students with significant disabilities various physical activities, though additional prompting procedures may be needed.

  5. Prognosis Research Strategy (PROGRESS 3: prognostic model research.

    Directory of Open Access Journals (Sweden)

    Ewout W Steyerberg

    Full Text Available Prognostic models are abundant in the medical literature yet their use in practice seems limited. In this article, the third in the PROGRESS series, the authors review how such models are developed and validated, and then address how prognostic models are assessed for their impact on practice and patient outcomes, illustrating these ideas with examples.

  6. New models of neoplastic progression in Barrett's oesophagus

    NARCIS (Netherlands)

    Pavlov, Kirill; Maley, Carlo C.

    2010-01-01

    Research in Barrett's oesophagus, and neoplastic progression to OAC (oesophageal adenocarcinoma), is hobbled by the lack of good pre-clinical models that capture the evolutionary dynamics of Barrett's cell populations. Current models trade off tractability for realism. Computational models are perha

  7. Is flow velocity a significant parameter in flood damage modelling?

    Directory of Open Access Journals (Sweden)

    H. Kreibich

    2009-10-01

    Full Text Available Flow velocity is generally presumed to influence flood damage. However, this influence is hardly quantified and virtually no damage models take it into account. Therefore, the influences of flow velocity, water depth and combinations of these two impact parameters on various types of flood damage were investigated in five communities affected by the Elbe catchment flood in Germany in 2002. 2-D hydraulic models with high to medium spatial resolutions were used to calculate the impact parameters at the sites in which damage occurred. A significant influence of flow velocity on structural damage, particularly on roads, could be shown in contrast to a minor influence on monetary losses and business interruption. Forecasts of structural damage to road infrastructure should be based on flow velocity alone. The energy head is suggested as a suitable flood impact parameter for reliable forecasting of structural damage to residential buildings above a critical impact level of 2 m of energy head or water depth. However, general consideration of flow velocity in flood damage modelling, particularly for estimating monetary loss, cannot be recommended.

  8. Progress in Global Multicompartmental Modelling of DDT

    Science.gov (United States)

    Stemmler, I.; Lammel, G.

    2009-04-01

    Dichlorophenyltrichloroethane, DDT, and its major metabolite dichlorophenyldichloroethylene, DDE, are long-lived in the environment (persistent) and circulate since the 1950s. They accumulate along food chains, cause detrimental effects in marine and terrestrial wild life, and pose a hazard for human health. DDT was widely used as an insecticide in the past and is still in use in a number of tropical countries to combat vector borne diseases like malaria and typhus. It is a multicompartmental substance with only a small mass fraction residing in air. A global multicompartment chemistry transport model (MPI-MCTM; Semeena et al., 2006) is used to study the environmental distribution and fate of dichlorodiphenyltrichloroethane (DDT). For the first time a horizontally and vertically resolved global model was used to perform a long-term simulation of DDT and DDE. The model is based on general circulation models for the ocean (MPIOM; Marsland et al., 2003) and atmosphere (ECHAM5). In addition, an oceanic biogeochemistry model (HAMOCC5.1; Maier-Reimer et al., 2005 ) and a microphysical aerosol model (HAM; Stier et al., 2005 ) are included. Multicompartmental substances are cycling in atmosphere (3 phases), ocean (3 phases), top soil (3 phases), and vegetation surfaces. The model was run for 40 years forced with historical agricultural application data of 1950-1990. The model results show that the global environmental contamination started to decrease in air, soil and vegetation after the applications peaked in 1965-70. In some regions, however, the DDT mass had not yet reached a maximum in 1990 and was still accumulating mass until the end of the simulation. Modelled DDT and DDE concentrations in atmosphere, ocean and soil are evaluated by comparison with observational data. The evaluation of the model results indicate that degradation of DDE in air was underestimated. Also for DDT, the discrepancies between model results and observations are related to uncertainties of

  9. Significance of peak height velocity as a predictive factor for curve progression in patients with idiopathic scoliosis

    Science.gov (United States)

    2015-01-01

    progression in patients with IS. Conclusions These findings indicate that 31.5 degrees of spinal curvature when patients are at PHV is a significant predictive indicator for progression of the curve to a magnitude requiring surgery. We suggest that the curve-progression risk assessment in patients with IS should include PHV, along with measures of skeletal and non-skeletal maturities. PMID:25815057

  10. Significant correlation between expression level of HSP gp96 and progression of hepatitis B virus induced diseases

    Institute of Scientific and Technical Information of China (English)

    Xiao-Dong Zhu; Cheng-Lin Li; Zhen-Wei Lang; George F Gao; Po Tien

    2004-01-01

    AIM: Gp96, also known as Grp94, is a member of heat shock protein (HSP) family and binds repertoires of peptides thereof eliciting peptide-specific T cell immune responses.It predominantly locates inside the endoplasmic reticulum (ER) with some cell surface expression in certain cancerous cells. Previous studies have shown that gp96 expression level was up-regulated in tumor cells, including hepatocellular carcinoma (HCC). However, relationship between the extent of gp96 expression and disease progression especially HBV-induced chronic infection, cirrhosis and hepatocellular carcinoma, has not been addressed before. As primary HCC can be induced and progressed from chronic hepatitis B virus (HBV) infection and HBV-induced cirrhosis, we designed an immunohistochemical experiment to test the correlation between gp96 expression level and HBV-induced disease progression, from chronic HBV infection, cirrhosis to HCC.METHODS: We chose liver samples from different patients of hepatitis B virus induced diseases, including chronic hepatitis B (77 patients), cirrhosis (27 patients) and primary HCC (30 patients), to test the expression level of gp96 in different affected groups. Formalin-fixed, and paraffinembedded liver tissues taken from these patients were immuno-stained by using an anti-gp96 monoclonal antibody for the expression level of gp96 protein in the sections. In addition, Western blotting of whole cell lysates derived from established human embryonic liver cell lines and several human HCC cell lines (Huh7, HepG2, SSMC-7721) was compared with the expression of gp96.RESULTS: We found that the extent of elevated gp96expression was significantly correlated with the disease progression, and was the highest in HCC patients, lowest in chronic HBV infection and was that of the cirrhosis in the middle.CONCLUSION: Increased expression of gp96 might be used as a diagnostic or prognostic bio-marker for the HBV infection and HBV-induced diseases.

  11. SOME PROGRESS IN THE LATTICE BOLTMANN MODEL

    Institute of Scientific and Technical Information of China (English)

    FENG SHI-DE; TSUTAHARA MICHIHISA; JI ZHONG-ZHEN

    2001-01-01

    A lattice Boltzmann equation model has been developed by using the equilibrium distribution function of the Maxwell-Boltzmann-like form, which is third order in fluid velocity uα. The criteria of energy conservation between the macroscopic physical quantities and the microscopic particles are introduced into the model, thus the thermal hydrodynamic equations containing the effect of buoyancy force can be recovered in terms of the Taylor and ChapmanEnskog asymptotic expansion methods. The two-dimensional thermal convection phenomena in a square cavity and between two concentric cylinders have been calculated by implementing a heat flux boundary condition. Both numerical results are in good agreement with the conventional numerical results.

  12. State-space size considerations for disease-progression models.

    Science.gov (United States)

    Regnier, Eva D; Shechter, Steven M

    2013-09-30

    Markov models of disease progression are widely used to model transitions in patients' health state over time. Usually, patients' health status may be classified according to a set of ordered health states. Modelers lump together similar health states into a finite and usually small, number of health states that form the basis of a Markov chain disease-progression model. This increases the number of observations used to estimate each parameter in the transition probability matrix. However, lumping together observably distinct health states also obscures distinctions among them and may reduce the predictive power of the model. Moreover, as we demonstrate, precision in estimating the model parameters does not necessarily improve as the number of states in the model declines. This paper explores the tradeoff between lumping error introduced by grouping distinct health states and sampling error that arises when there are insufficient patient data to precisely estimate the transition probability matrix. Copyright © 2013 John Wiley & Sons, Ltd.

  13. Gear Windage Modeling Progress - Experimental Validation Status

    Science.gov (United States)

    Kunz, Rob; Handschuh, Robert F.

    2008-01-01

    In the Subsonics Rotary Wing (SRW) Project being funded for propulsion work at NASA Glenn Research Center, performance of the propulsion system is of high importance. In current rotorcraft drive systems many gearing components operate at high rotational speed (pitch line velocity > 24000 ft/ min). In our testing of high speed helical gear trains at NASA Glenn we have found that the work done on the air - oil mist within the gearbox can become a significant part of the power loss of the system. This loss mechanism is referred to as windage. The effort described in this presentation is to try to understand the variables that affect windage, develop a good experimental data base to validate, the analytical project being conducted at Penn State University by Dr. Rob Kunz under a NASA SRW NRA. The presentation provides an update to the status of these efforts.

  14. Progress in studying scintillator proportionality: Phenomenological model

    Energy Technology Data Exchange (ETDEWEB)

    Bizarri, Gregory; Cherepy, Nerine; Choong, Woon-Seng; Hull, Giulia; Moses, William; Payne, Sephen; Singh, Jai; Valentine, John; Vasilev, Andrey; Williams, Richard

    2009-04-30

    We present a model to describe the origin of non-proportional dependence of scintillator light yield on the energy of an ionizing particle. The non-proportionality is discussed in terms of energy relaxation channels and their linear and non-linear dependences on the deposited energy. In this approach, the scintillation response is described as a function of the deposited energy deposition and the kinetic rates of each relaxation channel. This mathematical framework allows both a qualitative interpretation and a quantitative fitting representation of scintillation non-proportionality response as function of kinetic rates. This method was successfully applied to thallium doped sodium iodide measured with SLYNCI, a new facility using the Compton coincidence technique. Finally, attention is given to the physical meaning of the dominant relaxation channels, and to the potential causes responsible for the scintillation non-proportionality. We find that thallium doped sodium iodide behaves as if non-proportionality is due to competition between radiative recombinations and non-radiative Auger processes.

  15. Capabilities and accessibility: a model for progress

    Directory of Open Access Journals (Sweden)

    Nick Tyler

    2011-11-01

    Full Text Available Accessibility is seen to be a core issue which relates directly to the quality of life: if a person cannot reach and use a facility then they cannot take advantage of the benefits that the facility is seeking to provide. In some cases this is about being able to take part in an activity for enjoyment, but in some it is a question of the exercise of human rights – access to healthcare, education, voting and other citizens’ rights. This paper argues that such an equitable accessibility approach requires understanding of the relationships between the capabilities that a person has and the capabilities required of them by society in order to achieve the accessibility they seek. The Capabilities Model, which has been developed at UCL is an attempt to understand this relationship and the paper sets out an approach to quantifying the capabilities in a way that allows designers and implementers of environmental construction and operation to have a more robust approach to their decisions about providing accessibility.

  16. RECENT PROGRESS IN NONLINEAR EDDY-VISCOSITY TURBULENCE MODELING

    Institute of Scientific and Technical Information of China (English)

    符松; 郭阳; 钱炜祺; 王辰

    2003-01-01

    This article presents recent progresses in turbulence modeling in the Unit for Turbulence Simulation in the Department of Engineering Mechanics at Tsinghua University. The main contents include: compact Non-Linear Eddy-Viscosity Model (NLEVM) based on the second-moment closure, near-wall low-Re non-linear eddy-viscosity model and curvature sensitive turbulence model.The models have been validated in a wide range of complex flow test cases and the calculated results show that the present models exhibited overall good performance.

  17. Progressive IRP Models for Power Resources Including EPP

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  19. Multiresolution wavelet-ANN model for significant wave height forecasting.

    Digital Repository Service at National Institute of Oceanography (India)

    Deka, P.C.; Mandal, S.; Prahlada, R.

    Hybrid wavelet artificial neural network (WLNN) has been applied in the present study to forecast significant wave heights (Hs). Here Discrete Wavelet Transformation is used to preprocess the time series data (Hs) prior to Artificial Neural Network...

  20. Clinical significance of SOX9 in human non-small cell lung cancer progression and overall patient survival

    Directory of Open Access Journals (Sweden)

    Zhou Chun-Hui

    2012-03-01

    Full Text Available Abstract Background Sex determining region Y (SRY-related high mobility groupbox 9 (SOX9 is an important transcription factor required for development, which regulates the expression of target genes in the associated pathway. The aim of this study was to describe the expression of SOX9 in human non-small cell lung cancer (NSCLC and to investigate the association between SOX9 expression and progression of NSCLC. Methods SOX9 protein and mRNA expression in normal human pneumonocytes, lung cancer cell lines, and eight pairs of matched lung cancer tissues and their adjacent normal lung tissues were detected by Western blotting and real-time reverse transcription-polymerase chain reaction (RT-PCR. Immunohistochemistry was used to determine SOX9 protein expression in 142 cases of histologically characterized NSCLC. Statistical analyses were applied to test for prognostic and diagnostic associations. Results SOX9 in lung cancer cell lines was upregulated at both mRNA and protein levels, and SOX9 mRNA and protein were also elevated in NSCLC tissues compared with levels in corresponding adjacent non-cancerous lung tissues. Immunohistochemical analysis demonstrated a high expression of SOX9 in 74/142 (52.1% paraffin-embedded archival lung cancer biopsies. Statistical analysis indicated that upregulation of SOX9 was significantly correlated with the histological stage of NSCLC (P = 0.017 and that patients with a high SOX9 level exhibited a shorter survival time (P Conclusions This work shows that SOX9 may serve as a novel and prognostic marker for NSCLC, and play a role during the development and progression of the disease.

  1. 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.

  2. Scalar Dark Matter Models with Significant Internal Bremsstrahlung

    CERN Document Server

    Giacchino, Federica; Tytgat, Michel H G

    2013-01-01

    There has been interest recently on particle physics models that may give rise to sharp gamma ray spectral features from dark matter annihilation. Because dark matter is supposed to be electrically neutral, it is challenging to build weakly interacting massive particle models that may accommodate both a large cross section into gamma rays at, say, the Galactic center, and the right dark matter abundance. In this work, we consider the gamma ray signatures of a class of scalar dark matter models that interact with Standard Model dominantly through heavy vector-like fermions (the vector-like portal). We focus on a real scalar singlet S annihilating into lepton-antilepton pairs. Because this two-body final-state annihilation channel is d-wave suppressed in the chiral limit, we show that virtual internal bremsstrahlung emission of a gamma ray gives a large correction, both today and at the time of freeze-out. For the sake of comparison, we confront this scenario to the familiar case of a Majorana singlet annihilat...

  3. Finite element modeling of a progressively expanding shape memory stent.

    Science.gov (United States)

    Thériault, Philippe; Terriault, Patrick; Brailovski, Vladimir; Gallo, Richard

    2006-01-01

    Cardiovascular stents are small cylindrical devices introduced in stenosed arteries to reopen the lumen and restore blood flow. However, this treatment presents complications, including restenosis, which is the reclosing of the artery's diameter after the insertion of a stent. The structure of the prosthesis penetrates into and injures the walls of the patient's artery. There then follows a proliferation of cells and the formation of scar tissue around the injury, similar to the scarring of other organic tissues. This reaction to the trauma subjects the artery to close. The proposed solution is to develop a Nitinol stent with a progressive expansion device made of polyethylene, allowing smooth and gradual contact between the stent and the artery's wall by creep effect. The purpose of this paper is to describe the technology and methodology for the numerical study of this kind of stent through the finite element method. ANSYS 8.0 software is used to perform the analysis. The Nitinol is modeled with a superelastic law and the polyethylene with a yield hardening law. A first simulation determines the final geometry of the stent laser cut from a small tube. A second simulation examines the behavior of the prosthesis during surgery and over the 4 weeks following the operation. The results demonstrate that a compromise can be reached between a limited expansion prior the inflation of the expandable balloon and a significant expansion by creep of the polymer rings.

  4. Using animal models to determine the significance of complement activation in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Loeffler David A

    2004-10-01

    Full Text Available Abstract Complement inflammation is a major inflammatory mechanism whose function is to promote the removal of microorganisms and the processing of immune complexes. Numerous studies have provided evidence for an increase in this process in areas of pathology in the Alzheimer's disease (AD brain. Because complement activation proteins have been demonstrated in vitro to exert both neuroprotective and neurotoxic effects, the significance of this process in the development and progression of AD is unclear. Studies in animal models of AD, in which brain complement activation can be experimentally altered, should be of value for clarifying this issue. However, surprisingly little is known about complement activation in the transgenic animal models that are popular for studying this disorder. An optimal animal model for studying the significance of complement activation on Alzheimer's – related neuropathology should have complete complement activation associated with senile plaques, neurofibrillary tangles (if present, and dystrophic neurites. Other desirable features include both classical and alternative pathway activation, increased neuronal synthesis of native complement proteins, and evidence for an increase in complement activation prior to the development of extensive pathology. In order to determine the suitability of different animal models for studying the role of complement activation in AD, the extent of complement activation and its association with neuropathology in these models must be understood.

  5. gems: An R Package for Simulating from Disease Progression Models

    Directory of Open Access Journals (Sweden)

    Nello Blaser

    2015-03-01

    Full Text Available Mathematical models of disease progression predict disease outcomes and are useful epidemiological tools for planners and evaluators of health interventions. The R package gems is a tool that simulates disease progression in patients and predicts the effect of different interventions on patient outcome. Disease progression is represented by a series of events (e.g., diagnosis, treatment and death, displayed in a directed acyclic graph. The vertices correspond to disease states and the directed edges represent events. The package gems allows simulations based on a generalized multistate model that can be described by a directed acyclic graph with continuous transition-specific hazard functions. The user can specify an arbitrary hazard function and its parameters. The model includes parameter uncertainty, does not need to be a Markov model, and may take the history of previous events into account. Applications are not limited to the medical field and extend to other areas where multistate simulation is of interest. We provide a technical explanation of the multistate models used by gems, explain the functions of gems and their arguments, and show a sample application.

  6. The significance of genetics in pathophysiologic models of premature birth.

    Science.gov (United States)

    Uberos, Jose

    2017-05-31

    Prematurity is a major health problem in all countries, especially in certain ethic groups and increasing recurrence imply the influence of genetic factors. Published genetic polymorphisms are identified in relation to the 4 pathophysiological models of prematurity described: Chorioamniotic-decidual inflammation, premature contraction pathway, decidual haemorrhage and susceptibility to environmental toxins. 240 articles are identified, 52 articles are excluded because they are not original, not written in English or duplicated. From them 125 articles were included in qualitative analysis This review aims to update recent knowledge about genes associated with premature birth.

  7. 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.

  8. A simple model of scientific progress - with examples

    CERN Document Server

    Scorzato, Luigi

    2016-01-01

    One of the main goals of scientific research is to provide a description of the empirical data which is as accurate and comprehensive as possible, while relying on as few and simple assumptions as possible. In this paper, I propose a definition of the notion of "few and simple assumptions" that is not affected by known problems. This leads to the introduction of a simple model of scientific progress that is based only on empirical accuracy and conciseness. An essential point in this task is the understanding of the role played by "measurability" in the formulation of a scientific theory. This is the key to prevent artificially concise formulations. The model is confronted here with many possible objections and with challenging cases of real progress. Although I cannot exclude that the model might have some limitations, it includes all the cases of genuine progress examined here, and no spurious one. In this model, I stress the role of the "state of the art", which is the collection of all the theories that ar...

  9. 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

  10. Accuracy of pitch matching significantly improved by live voice model.

    Science.gov (United States)

    Granot, Roni Y; Israel-Kolatt, Rona; Gilboa, Avi; Kolatt, Tsafrir

    2013-05-01

    Singing is, undoubtedly, the most fundamental expression of our musical capacity, yet an estimated 10-15% of Western population sings "out-of-tune (OOT)." Previous research in children and adults suggests, albeit inconsistently, that imitating a human voice can improve pitch matching. In the present study, we focus on the potentially beneficial effects of the human voice and especially the live human voice. Eighteen participants varying in their singing abilities were required to imitate in singing a set of nine ascending and descending intervals presented to them in five different randomized blocked conditions: live piano, recorded piano, live voice using optimal voice production, recorded voice using optimal voice production, and recorded voice using artificial forced voice production. Pitch and interval matching in singing were much more accurate when participants repeated sung intervals as compared with intervals played to them on the piano. The advantage of the vocal over the piano stimuli was robust and emerged clearly regardless of whether piano tones were played live and in full view or were presented via recording. Live vocal stimuli elicited higher accuracy than recorded vocal stimuli, especially when the recorded vocal stimuli were produced in a forced vocal production. Remarkably, even those who would be considered OOT singers on the basis of their performance when repeating piano tones were able to pitch match live vocal sounds, with deviations well within the range of what is considered accurate singing (M=46.0, standard deviation=39.2 cents). In fact, those participants who were most OOT gained the most from the live voice model. Results are discussed in light of the dual auditory-motor encoding of pitch analogous to that found in speech. Copyright © 2013 The Voice Foundation. Published by Mosby, Inc. All rights reserved.

  11. Progress on Analytical Modeling of Coherent Electron Cooling

    Energy Technology Data Exchange (ETDEWEB)

    Wang, G.; Blaskiewicz, M.; Litvinenko, V.; Webb, S.

    2010-05-23

    We report recent progresses on analytical studies of Coherent Electron Cooling. The phase space electron beam distribution obtained from the 1D FEL amplifier is applied to an infinite electron plasma model and the electron density evolution inside the kicker is derived. We also investigate the velocity modulation in the modulator and obtain a closed form solution for the current density evolution for infinite homogeneous electron plasma.

  12. Model-theoretical foundation of action and progression

    Institute of Scientific and Technical Information of China (English)

    田启家; 史忠植

    1997-01-01

    Action is one of the most important concepts in computer science, and situation calculus is the standard formalism for representing and reasoning about actions and their effects. Situation calculus essentially could be presented in a logic framework. Based on the framework LR, such a logic framework is given. Minimal action theory is proposed and studied from the point of view of model theory. By theorems of mathematical logic, some results about the definability about the progression in minimal action theory are obtained.

  13. Computational algebraic geometry for statistical modeling FY09Q2 progress.

    Energy Technology Data Exchange (ETDEWEB)

    Thompson, David C.; Rojas, Joseph Maurice; Pebay, Philippe Pierre

    2009-03-01

    This is a progress report on polynomial system solving for statistical modeling. This is a progress report on polynomial system solving for statistical modeling. This quarter we have developed our first model of shock response data and an algorithm for identifying the chamber cone containing a polynomial system in n variables with n+k terms within polynomial time - a significant improvement over previous algorithms, all having exponential worst-case complexity. We have implemented and verified the chamber cone algorithm for n+3 and are working to extend the implementation to handle arbitrary k. Later sections of this report explain chamber cones in more detail; the next section provides an overview of the project and how the current progress fits into it.

  14. Reliability-based design optimization with progressive surrogate models

    Science.gov (United States)

    Kanakasabai, Pugazhendhi; Dhingra, Anoop K.

    2014-12-01

    Reliability-based design optimization (RBDO) has traditionally been solved as a nested (bilevel) optimization problem, which is a computationally expensive approach. Unilevel and decoupled approaches for solving the RBDO problem have also been suggested in the past to improve the computational efficiency. However, these approaches also require a large number of response evaluations during optimization. To alleviate the computational burden, surrogate models have been used for reliability evaluation. These approaches involve construction of surrogate models for the reliability computation at each point visited by the optimizer in the design variable space. In this article, a novel approach to solving the RBDO problem is proposed based on a progressive sensitivity surrogate model. The sensitivity surrogate models are built in the design variable space outside the optimization loop using the kriging method or the moving least squares (MLS) method based on sample points generated from low-discrepancy sampling (LDS) to estimate the most probable point of failure (MPP). During the iterative deterministic optimization, the MPP is estimated from the surrogate model for each design point visited by the optimizer. The surrogate sensitivity model is also progressively updated for each new iteration of deterministic optimization by adding new points and their responses. Four example problems are presented showing the relative merits of the kriging and MLS approaches and the overall accuracy and improved efficiency of the proposed approach.

  15. Significance of peak height velocity as a predictive factor for curve progression in patients with idiopathic scoliosis

    OpenAIRE

    Chazono, Masaaki; Tanaka, Takaaki; Marumo, Keishi; Kono, Katsuki; Suzuki, Nobumasa

    2015-01-01

    Background Much attention has been paid to peak height velocity (PHV) as a possible predictor of curve progression in patients with idiopathic scoliosis (IS). The aim of this study was to analyze the relationship between the magnitude of the Cobb angle at PHV and scoliosis progression, defined as having surgery prior to skeletal maturity in female patients with IS. Methods A retrospective review identified 56 skeletally immature female IS patients who were followed until maturity. The mean ag...

  16. Modelling Hydrological Consequences of Climate Change-Progress and Challenges

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    The simulation of hydrological consequences of climate change has received increasing attention from the hydrology and land-surface modelling communities. There have been many studies of climate-change effects on hydrology and water resources which usually consist of three steps: (1) use of general circulation models (GCMs) to provide future global climate scenarios under the effect of increasing greenhouse gases,(2) use of downscaling techniques (both nested regional climate models, RCMs, and statistical methods)for "downscaling" the GCM output to the scales compatible with hydrological models, and (3) use of hydrologic models to simulate the effects of climate change on hydrological regimes at various scales.Great progress has been achieved in all three steps during the past few years, however, large uncertainties still exist in every stage of such study. This paper first reviews the present achievements in this field and then discusses the challenges for future studies of the hydrological impacts of climate change.

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

    Science.gov (United States)

    Van Kampen, Jackalina M; Baranowski, David C; Robertson, Harold A; Shaw, Christopher A; Kay, Denis G

    2015-01-01

    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 olfactory bulb, then

  18. Sequential Molecular and Cellular Events during Neoplastic Progression: A Mouse Syngeneic Ovarian Cancer Model

    Directory of Open Access Journals (Sweden)

    Paul C. Roberts

    2005-10-01

    Full Text Available Studies performed to identify early events of ovarian cancer and to establish molecular markers to support early detection and development of chemopreventive regimens have been hindered by a lack of adequate cell models. Taking advantage of the spontaneous transformation of mouse ovarian surface epithelial (MDSE cells in culture, we isolated and characterized distinct transitional stages of ovarian cancer as the cells progressed from a premalignant nontumorigenic phenotype to a highly aggressive malignant phenotype. Transitional stages were concurrent with progressive increases in proliferation, anchorage-independent growth capacity, in vivo tumor formation, and aneuploidy. During neoplastic progression, our ovarian cancer model underwent distinct remodeling of the actin cytoskeleton and focal adhesion complexes, concomitant with downregulation and/or aberrant subcellular localization of two tumor-suppressor proteins Ecadherin and connexin-43. In addition, we demonstrate that epigenetic silencing of E-cadherin through promoter methylation is associated with neoplastic progression of our ovarian cancer model. These results establish critical interactions between cellular cytoskeletal remodeling and epigenetic silencing events in the progression of ovarian cancer. Thus, our MDSE model provides an excellent tool to identify both cellularand molecular changes in the early and late stages of ovarian cancer, to evaluate their regulation, and to determine their significance in an immunocompetent in vivo environment.

  19. Modeling and Predicting AD Progression by Regression Analysis of Sequential Clinical Data

    KAUST Repository

    Xie, Qing

    2016-02-23

    Alzheimer\\'s Disease (AD) is currently attracting much attention in elders\\' care. As the increasing availability of massive clinical diagnosis data, especially the medical images of brain scan, it is highly significant to precisely identify and predict the potential AD\\'s progression based on the knowledge in the diagnosis data. In this paper, we follow a novel sequential learning framework to model the disease progression for AD patients\\' care. Different from the conventional approaches using only initial or static diagnosis data to model the disease progression for different durations, we design a score-involved approach and make use of the sequential diagnosis information in different disease stages to jointly simulate the disease progression. The actual clinical scores are utilized in progress to make the prediction more pertinent and reliable. We examined our approach by extensive experiments on the clinical data provided by the Alzheimer\\'s Disease Neuroimaging Initiative (ADNI). The results indicate that the proposed approach is more effective to simulate and predict the disease progression compared with the existing methods.

  20. 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.

  1. The complex model of risk and progression of AMD estimation

    Directory of Open Access Journals (Sweden)

    V. S. Akopyan

    2014-07-01

    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.

  2. A novel homologous model for noninvasive monitoring of endometriosis progression.

    Science.gov (United States)

    Ferrero, Hortensia; Buigues, Anna; Martínez, Jessica; Simón, Carlos; Pellicer, Antonio; Gómez, Raúl

    2017-02-01

    To date, several groups have generated homologous models of endometriosis through the implantation of endometrial tissue fluorescently labeled by green fluorescent protein (GFP) or tissue from luciferase-expressing transgenic mice into recipient animals, enabling noninvasive monitoring of lesion signal. These models present an advantage over endpoint models, but some limitations persist; use of transgenic mice is laborious and expensive, and GFP presents poor tissue penetration due to the relatively short emission wavelength. For this reason, a homologous mouse model of endometriosis that allows in vivo monitoring of generated lesions over time and mimics human lesions in recipient mice would be most desirable. In this regard, using C57BL/6 and B6N-Tyrc-Brd/BrdCrCrl mice, we optimized a decidualization protocol to obtain large volumes of decidual endometrium and mimic human lesions. Subsequently, to obtain a more robust and reliable noninvasive monitoring of lesions, we used the fluorescent reporter mCherry, which presents deeper tissue penetration and higher photostability, showing that endometrial tissue was properly labeled with 1 × 108 PFU/mL mCherry adenoviral vectors. mCherry-labeled endometriotic tissue was implanted in recipient mice, generating lesions that displayed characteristics typical of human endometriotic lesions, such as epithelial cells forming glands, local inflammation, collagen deposits, and new vessel formation. In vivo monitoring demonstrated that subcutaneous implantation on ventral abdomen of recipient mice provided the most intense and reliable signal for noninvasive lesion monitoring over a period of at least 20 days. This homologous model improves upon previously reported models of endometriosis and provides opportunities to study mechanism underlying endometriotic lesion growth and progression. We created a cost-effective but accurate homologous mouse model of endometriosis that allows the study of growth and progression of

  3. Monte Carlo autofluorescence modeling of cervical intraepithelial neoplasm progression

    Science.gov (United States)

    Chu, S. C.; Chiang, H. K.; Wu, C. E.; He, S. Y.; Wang, D. Y.

    2006-02-01

    Monte Carlo fluorescence model has been developed to estimate the autofluorescent spectra associated with the progression of the Exo-Cervical Intraepithelial Neoplasm (CIN). We used double integrating spheres system and a tunable light source system, 380 to 600 nm, to measure the reflection and transmission spectra of a 50 μm thick tissue, and used Inverse Adding-Doubling (IAD) method to estimate the absorption (μa) and scattering (μs) coefficients. Human cervical tissue samples were sliced vertically (longitudinal) by the frozen section method. The results show that the absorption and scattering coefficients of cervical neoplasia are 2~3 times higher than normal tissues. We applied Monte Carlo method to estimate photon distribution and fluorescence emission in the tissue. By combining the intrinsic fluorescence information (collagen, NADH, and FAD), the anatomical information of the epithelium, CIN, stroma layers, and the fluorescence escape function, the autofluorescence spectra of CIN at different development stages were obtained.We have observed that the progression of the CIN results in gradually decreasing of the autofluorescence intensity of collagen peak intensity. In addition, the existence of the CIN layer formeda barrier that blocks the autofluorescence escaping from the stroma layer due to the strong extinction(scattering and absorption) of the CIN layer. To our knowledge, this is the first study measuring the CIN optical properties in the visible range; it also successfully demonstrates the fluorescence model forestimating autofluorescence spectra of cervical tissue associated with the progression of the CIN tissue;this model is very important in assisting the CIN diagnosis and treatment in clinical medicine.

  4. Modelling progressive autonomic failure in MSA: where are we now?

    Science.gov (United States)

    Stemberger, Sylvia; Wenning, Gregor K

    2011-05-01

    Multiple system atrophy (MSA) is a fatal late-onset α-synucleinopathy that presents with features of ataxia, Parkinsonism, and pyramidal dysfunction in any combination. Over the last decade, efforts have been made to develop preclinical MSA testbeds for novel interventional strategies. The main focus has been on murine analogues of MSA-linked motor features and their underlying brainstem, cerebellar and basal ganglia pathology. Although progressive autonomic failure (AF) is a prominent clinical feature of patients with MSA, reflecting a disruption of both central and peripheral autonomic networks controlling cardiovascular, respiratory, urogenital, gastrointestinal and sudomotor functions, attempts of modelling this aspect of the human disease have been limited. However, emerging evidence suggests that AF-like features may occur in transgenic MSA models reflecting α-synucleinopathy lesions in distributed autonomic networks. Further research is needed to fully characterize both autonomic and motor features in optimized preclinical MSA models.

  5. 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.

  6. PUMA promotes apoptosis of hematopoietic progenitors driving leukemic progression in a mouse model of myelodysplasia.

    Science.gov (United States)

    Guirguis, A A; Slape, C I; Failla, L M; Saw, J; Tremblay, C S; Powell, D R; Rossello, F; Wei, A; Strasser, A; Curtis, D J

    2016-06-01

    Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis with resultant cytopenias. Increased apoptosis and aberrantly functioning progenitors are thought to contribute to this phenotype. As is the case for other malignancies, overcoming apoptosis is believed to be important in progression toward acute myeloid leukemia (AML). Using the NUP98-HOXD13 (NHD13) transgenic mouse model of MDS, we previously reported that overexpression of the anti-apoptotic protein BCL2, blocked apoptosis and improved cytopenias, paradoxically, delaying leukemic progression. To further understand this surprising result, we examined the role of p53 and its pro-apoptotic effectors, PUMA and NOXA in NHD13 mice. The absence of p53 or PUMA but not NOXA reduced apoptosis and expanded the numbers of MDS-repopulating cells. Despite a similar effect on apoptosis and cell numbers, the absence of p53 and PUMA had diametrically opposed effects on progression to AML: absence of p53 accelerated leukemic progression, while absence of PUMA significantly delayed progression. This may be explained in part by differences in cellular responses to DNA damage. The absence of p53 led to higher levels of γ-H2AX (indicative of persistent DNA lesions) while PUMA-deficient NHD13 progenitors resolved DNA lesions in a manner comparable to wild-type cells. These results suggest that targeting PUMA may improve the cytopenias of MDS without a detrimental effect on leukemic progression thus warranting further investigation.

  7. Significado das metaloproteinases na progressão da doença periodontal = Significance of metalloproteinases in the progression of the periodontal disease

    Directory of Open Access Journals (Sweden)

    Seabra, Flávio Roberto Guerra

    2014-01-01

    Full Text Available Objetivos: avaliar a expressão imunohistoquímica das metaloproteinases da matriz (MMP -1, -2 e -9 na progressão da doença periodontal. Materiais e métodos: treze biópsias gengivais com diagnóstico clínico de gengivite e 13 com periodontite foram processadas pelo método de imunohistoquímica. A marcação das MMPs foi feita de acordo com a intensidade, tanto no epitélio quanto no tecido conjuntivo, em: ausente (-, que foi atribuída a pontuação 0; fraca (+, pontuação 1; e marcação forte (++, pontuação 2. Resultados: na gengivite, a MMP-1 foi significativamente mais expressa do que as outras MMPs, tanto no epitélio (p=0,0008 como no tecido conjuntivo (p=0,0049. Na periodontite, tanto a MMP-1 quanto a MMP-9 foram significativamente expressas no epitélio (p<0,0001 e no tecido conjuntivo (p=0,0002. MMP-1 e MMP- 9 apresentaram maior expressão na periodontite do que na gengivite, sendo a MMP-1 no tecido conjuntivo (p=0,03 e MMP-9 no epitélio (p=0,003 e no tecido conjuntivo (p=0,04. Conclusão: Os resultados indicam que a MMP-1 tem papel importante na degradação do tecido conjuntivo e na perda óssea e a MMP-9, que foi mais expressa em periodontite, pode ter algum papel na progressão da gengivite para periodontite, atuando na reabsorção óssea

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

    Directory of Open Access Journals (Sweden)

    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

  9. The lag time in initiating clinical testing of new drugs in combination with radiation therapy, a significant barrier to progress?

    Science.gov (United States)

    Blumenfeld, P; Pfeffer, R M; Symon, Z; Den, R B; Dicker, A P; Raben, D; Lawrence, Y R

    2014-01-01

    Background: The clinical development of new drugs with radiation appears to be limited. We hypothesised that phase I clinical trials with radiation therapy (RT) are initiated too late into a new drug's lifetime, impeding the ability to complete RT–drug development programmes before patent expiration. Methods: We identified novel drug–radiation phase I combination trials performed between 1980 and 2012 within the PubMed and ClinicalTrials.gov databases. Data gathered for each drug included: date the initial phase I trial with/without RT was opened/published, date of the published positive phase III trials, and patent expiration dates. Lag time was defined as the interval between opening of the phase I trial without RT and the opening of the phase I with RT. Linear regression was used to model how the lag time has changed over time. Results: The median lag time was 6 years. The initial phase I trial with RT was typically published 2 years after the first published positive phase III trial and 11 years before patent expiration. Using a best-fit linear model, lag time decreased from 10 years for phase I trials published in 1990 to 5 years in 2005 (slope significantly non-zero, P<0.001). Conclusions: Clinical drug development with RT commences late in the life cycle of anti-cancer agents. Taking into account the additional time required for late-phase clinical trials, the delay in initiating clinical testing of drug–RT combinations discourages drug companies from further pursuing RT-based development. Encouragingly, lag time appears to be decreasing. Further reduction in lag time may accelerate RT-based drug development, potentially improving patient outcomes. PMID:25117813

  10. Alzheimer's disease: a mathematical model for onset and progression

    CERN Document Server

    Bertsch, Michiel; Marcello, Norina; Tesi, Maria Carla; Tosin, Andrea

    2015-01-01

    In this paper we propose a mathematical model for the onset and progression of Alzheimer's disease based on transport and diffusion equations. We regard brain neurons as a continuous medium, and structure them by their degree of malfunctioning. 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. We model these two processes by a system of Smoluchowski equations for the amyloid concentration, coupled to a kinetic-type transport equation for the distribution function of the degree of malfunctioning of neurons. The second equation contains an integral term describing the random onset of the disease as a jump process localized in particularly sensitive areas of the brain. Even though we deliberately neglect many aspects of the complexity of the brain and the disease, numerical simulations are in good qualitative agreement with clinical...

  11. The Clinical Significance of Uric Acid and Complement Activation in the Progression of IgA Nephropathy

    Directory of Open Access Journals (Sweden)

    Yasar Caliskan

    2016-02-01

    Full Text Available Background/Aims: The aim of this study is to investigate the utility of clinical [age, gender, mean arterial pressure (MAP] and laboratory parameters [eGFR, hemoglobin (Hgb, serum levels of creatinine, uric acid, albumin, proteinuria, hematuria] and also histopathological lesions (Oxford classification parameters, crescents, intensity and pattern of staining for C3, C1Q, IgA, IgG, IgM as progression markers in patients with IgA Nephropathy (IgAN. Methods: A total of 111 IgAN patients with a follow-up period >1 year or who reached kidney failure [GFR category G5 chronic kidney disease (CKD] Results: Mean follow-up period was 33±29 months. Thirty-seven (33.3% patients progressed to kidney failure and 4 (3.6% patients developed eGFR decline ≥50% from the baseline after a median of 23 and 65 months, respectively. In multivariate Cox regression analysis, baseline levels of Hgb (HR:0.782, 95% CI 0.559-0.973, p=0.037, serum uric acid (HR:1.293, 95% CI 1.023-1.621, p=0.046, eGFR (HR:0.966, 95% CI 0.947-0.984, p=0.004 and intensity of C3 staining (HR:1.550, 95% CI 1.198-1.976, p=0.049 predicted primary endpoint. Serum uric acid level was associated independently with T score (β=0.303, p=0.005 in patients with eGFR>30 ml/min/m2. Conclusions: Hyperuricemia and the deposition of C3 are independent risk factors for IgAN progression.

  12. Models and correlations of the DEBRIS Late-Phase Melt Progression Model

    Energy Technology Data Exchange (ETDEWEB)

    Schmidt, R.C.; Gasser, R.D. [Sandia National Labs., Albuquerque, NM (United States). Reactor Safety Experiments Dept.

    1997-09-01

    The DEBRIS Late Phase Melt Progression Model is an assembly of models, embodied in a computer code, which is designed to treat late-phase melt progression in dry rubble (or debris) regions that can form as a consequence of a severe core uncover accident in a commercial light water nuclear reactor. The approach is fully two-dimensional, and incorporates a porous medium modeling framework together with conservation and constitutive relationships to simulate the time-dependent evolution of such regions as various physical processes act upon the materials. The objective of the code is to accurately model these processes so that the late-phase melt progression that would occur in different hypothetical severe nuclear reactor accidents can be better understood and characterized. In this report the models and correlations incorporated and used within the current version of DEBRIS are described. These include the global conservation equations solved, heat transfer and fission heating models, melting and refreezing models (including material interactions), liquid and solid relocation models, gas flow and pressure field models, and the temperature and compositionally dependent material properties employed. The specific models described here have been used in the experiment design analysis of the Phebus FPT-4 debris-bed fission-product release experiment. An earlier DEBRIS code version was used to analyze the MP-1 and MP-2 late-phase melt progression experiments conducted at Sandia National Laboratories for the US Nuclear Regulatory Commission.

  13. NUMERICAL MODELLING OF PROGRESSIVE FAILURE IN PARTICULATE COMPOSITES LIKE SANDSTONE

    Institute of Scientific and Technical Information of China (English)

    1999-01-01

    The beam-particle model is presented for analyzing the progressive failure of particulate composites such as sandstone and concrete. In the model, the medium is schematized as an assembly of particles which are linked through a network of brittle-breaking beam elements. The mechanical behaviour of particle elements is governed by the distinct element method and finite element method. The propagation of the cracking process in particulate composites is mimicked by removing the beam element from the mesh as soon as the stress in the beam exceeds the strength assigned to that particular beam. The new model can be utilized at a meso-scale and in different loading conditions. Two physical experiments are performed to verify the numerical results. The crack patterns and load-displacement response obtained with the proposed numerical model are in good agreement with the experimental results. Moreover, the influence of heterogeneity on crack patterns is also discussed and the correlation existing between the fracture evolution and the loads imposed on the specimen is characterized by fractal dimensions.

  14. Comparisons of model simulations of climate variability with data, Task 2. [Progress report

    Energy Technology Data Exchange (ETDEWEB)

    1990-12-31

    Significant progress has been made in our investigations aimed at diagnosing low frequency variations of climate in General Circulation Models. We have analyzed three versions of the Oregon State University General Circulation Model (OSU GCM). These are: (1) the Slab Model in which the ocean is treated as a static heat reservoir of fixed depth, (2) the coupled upper ocean-atmosphere model in which the ocean dynamics are calculated in two layers of variable depths representing the mixed layers and the thermocline; this model is referred to OSU2 in the following discussion, and (3) the coupled full ocean-atmosphere model in which the ocean is represented by six layers of variable depth; this model is referred to as OSU6 GCM in the discussion.

  15. 2D model for melt progression through rods and debris

    Energy Technology Data Exchange (ETDEWEB)

    Fichot, F. [IPSN/DRS, CEA Cadarache, St. Paul-lez-Durance (France)

    2001-07-01

    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)

  16. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management

    NARCIS (Netherlands)

    R. Kyle (Robert); B.G.M. Durie (Brian); S.V. Rajkumar (Vincent); O. Landgren; J. Bladé (Joan); G. Merlini; N. Kröger; H. Einsele (Hermann); D. Vesole (David); M.A. Dimopoulos (Meletios); J.F. San Miguel (Jesús Fernando); H. Avet-Loiseau; R. Hajek (Roman); W. Chen (Wei); K.C. Anderson (Kenneth Carl); H. Ludwig (Heinz); P. Sonneveld (Pieter); S. Pavlovsky; A. Palumbo (Antonio); P.G. Richardson; B. Barlogie (Bart); P. Greipp (Philip); R. Vescio (Robert); I. Turesson; J. Westin (Johan); M. Boccadoro (Mario)

    2010-01-01

    textabstractMonoclonal gammopathy of undetermined significance (MGUS) was identified in 3.2% of 21 463 residents of Olmsted County, Minnesota, 50 years of age or older. The risk of progression to multiple myeloma, Waldenstrom's macroglobulinemia, AL amyloidosis or a lymphoproliferative disorder is a

  17. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management

    NARCIS (Netherlands)

    R. Kyle (Robert); B.G.M. Durie (Brian); S.V. Rajkumar (Vincent); O. Landgren; J. Bladé (Joan); G. Merlini; N. Kröger; H. Einsele (Hermann); D. Vesole (David); M.A. Dimopoulos (Meletios); J.F. San Miguel (Jesús Fernando); H. Avet-Loiseau; R. Hajek (Roman); W. Chen (Wei); K.C. Anderson (Kenneth Carl); H. Ludwig (Heinz); P. Sonneveld (Pieter); S. Pavlovsky; A. Palumbo (Antonio); P.G. Richardson; B. Barlogie (Bart); P. Greipp (Philip); R. Vescio (Robert); I. Turesson; J. Westin (Johan); M. Boccadoro (Mario)

    2010-01-01

    textabstractMonoclonal gammopathy of undetermined significance (MGUS) was identified in 3.2% of 21 463 residents of Olmsted County, Minnesota, 50 years of age or older. The risk of progression to multiple myeloma, Waldenstrom's macroglobulinemia, AL amyloidosis or a lymphoproliferative disorder is a

  18. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management

    NARCIS (Netherlands)

    R. Kyle (Robert); B.G.M. Durie (Brian); S.V. Rajkumar (Vincent); O. Landgren; J. Bladé (Joan); G. Merlini; N. Kröger; H. Einsele (Hermann); D. Vesole (David); M.A. Dimopoulos (Meletios); J.F. San Miguel (Jesús Fernando); H. Avet-Loiseau; R. Hajek (Roman); W. Chen (Wei); K.C. Anderson (Kenneth Carl); H. Ludwig (Heinz); P. Sonneveld (Pieter); S. Pavlovsky; A. Palumbo (Antonio); P.G. Richardson; B. Barlogie (Bart); P. Greipp (Philip); R. Vescio (Robert); I. Turesson; J. Westin (Johan); M. Boccadoro (Mario)

    2010-01-01

    textabstractMonoclonal gammopathy of undetermined significance (MGUS) was identified in 3.2% of 21 463 residents of Olmsted County, Minnesota, 50 years of age or older. The risk of progression to multiple myeloma, Waldenstrom's macroglobulinemia, AL amyloidosis or a lymphoproliferative disorder is

  19. Modelling the Progression of Male Swimmers’ Performances through Adolescence

    Directory of Open Access Journals (Sweden)

    Shilo J. Dormehl

    2016-01-01

    Full Text Available Insufficient data on adolescent athletes is contributing to the challenges facing youth athletic development and accurate talent identification. The purpose of this study was to model the progression of male sub-elite swimmers’ performances during adolescence. The performances of 446 males (12–19 year olds competing in seven individual events (50, 100, 200 m freestyle, 100 m backstroke, breaststroke, butterfly, 200 m individual medley over an eight-year period at an annual international schools swimming championship, run under FINA regulations were collected. Quadratic functions for each event were determined using mixed linear models. Thresholds of peak performance were achieved between the ages of 18.5 ± 0.1 (50 m freestyle and 200 m individual medley and 19.8 ± 0.1 (100 m butterfly years. The slowest rate of improvement was observed in the 200 m individual medley (20.7% and the highest in the 100 m butterfly (26.2%. Butterfly does however appear to be one of the last strokes in which males specialise. The models may be useful as talent identification tools, as they predict the age at which an average sub-elite swimmer could potentially peak. The expected rate of improvement could serve as a tool in which to monitor and evaluate benchmarks.

  20. Progress in Finite Element Modeling of the Lower Extremities

    Science.gov (United States)

    2015-06-01

    as well as have a vision for the future. Modeling the human body is a challenging endeavor due to its geometric complexity, numerous interacting ...efforts and documents some major improvements to the lower leg model with a vision of the future in mind . We also introduce significant details regarding...variability matters in the context of predicting injury is an open research question. These challenges and the unknowns introduce numerous practical

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

    Directory of Open Access Journals (Sweden)

    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

  2. EXPRESSION OF MASPIN AND KAI1 AND THEIR CLINICOPATHOLOGICAL SIGNIFICANCE IN CARCINOGENESIS AND PROGRESSION OF GASTRIC CANCER

    Institute of Scientific and Technical Information of China (English)

    Hua-chuan Zheng; Meng-chun Wang; Jin-yi Li; Xue-fei Yang; Jin-min Sun; Yan Xin

    2004-01-01

    Objective To investigate the roles of maspin and kail expression in tumorigenesis and progression of gastric cancer.Methods Maspin and kail expressions were detected in normal gastric mucosa (n = 182), gastric dysplasia (n = 69), and gastric cancer (n = 113) by immunohisto-chemistry. Their expressions were compared with clinicopathological parameters of tumors. Relationship between maspin and kai1 expression was also concerned in gastric cancer.Results The positive rates ofmaspin expression were 79.8% (145/182), 75.4% (52/69), and 50.4% (57/113) in normal gastric mucosa, gastric dysplasia, and gastric cancer, while those of kail expression were 81.9% (149/182), 65.2% (49/69),and 58.4% (66/113) in corresponding tissues respectively. Gastric cancer less frequently expressed maspin than the normal gastric mucosa and gastric dysplasia (P < 0.05), while dysplasia and cancer showed less frequent expression of kail than normal mucosa (P < 0.05). Maspin expression showed negative association with invasive depth, metastasis, Lauren's and histological classifications (P < 0.05), but not with tumor size, Borrmann's classification, growth pattern or TNM staging (P > 0.05). Kail expression was negatively correlated with invasive depth, metastasis, growth pattern, Lauren's and histological classifications (P < 0.05), but not with tumor size, Borrmann's classification or TNM staging (P > 0.05). Maspin and kail were collaboratively expressed in gastric cancer (P < 0.05).Conclusions Down-regulated expressions of maspin and kail play an important role in gastric carcinogenesis. Abnormal expression of maspin and kail might have inhibitory effects on invasion and metastasis of gastric cancer and act as an effective and objective marker to indicate the pathobiological behaviors of gastric cancer.

  3. Natalizumab Significantly Improves Cognitive Impairment over Three Years in MS: Pattern of Disability Progression and Preliminary MRI Findings.

    Directory of Open Access Journals (Sweden)

    Flavia Mattioli

    Full Text Available Previous studies reported that Multiple Sclerosis (MS patients treated with natalizumab for one or two years exhibit a significant reduction in relapse rate and in cognitive impairment, but the long term effects on cognitive performance are unknown. This study aimed to evaluate the effects of natalizumab on cognitive impairment in a cohort of 24 consecutive patients with relapsing remitting MS treated for 3 years. The neuropsychological tests, as well as relapse number and EDSS, were assessed at baseline and yearly for three years. The impact on cortical atrophy was also considered in a subgroup of them, and are thus to be considered as preliminary. Results showed a significant reduction in the number of impaired neuropsychological tests after three years, a significant decrease in annualized relapse rate at each time points compared to baseline and a stable EDSS. In the neuropsychological assessment, a significant improvement in memory, attention and executive function test scores was detected. Preliminary MRI data show that, while GM volume did not change at 3 years, a significantly greater parahippocampal and prefrontal gray matter density was noticed, the former correlating with neuropsychological improvement in a memory test. This study showed that therapy with Natalizumab is helpful in improving cognitive performance, and is likely to have a protective role on grey matter, over a three years follow-up.

  4. Prognostic significance of genetic polymorphisms in disease progression and survival in prostate cancer after androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    Tsung-Yi Huang

    2015-06-01

    Full Text Available It is believed that androgens and their receptors regulate normal prostate growth and mediate prostate cancer development. Androgen deprivation therapy is the most commonly used treatment for advanced prostate cancer. Although the therapy is initially effective, progression of the disease to castration-resistant prostate cancer is almost inevitable, leading to treatment failure. Despite the existence of current clinical parameters, new biomarkers are urgently needed to improve the prognosis. Some molecules and DNA-based genetic biomarkers are under investigation as potential prognostic factors. The advancement in molecular cytogenetic research, such as genome-wide association for single-nucleotide polymorphisms, has made possible the detection of genetic mutations. In this study, a literature search from August 1985 to April 2013 was performed through the PubMed database using the keywords “genetic polymorphisms”, “prostate cancer” and “androgen deprivation therapy”. The results revealed that several genome-wide association studies (such as rs16901979, rs7931342, HSD17B4, rs6162 in the CYP17A1, rs4243229 and rs7201637 in the HSD17B2, rs1062577 in the ESR1, SLCO1B3, SLCO2B1, rs2939244 in the ARRDC3, rs9508016 in the FLT1, rs6504145 in the SKAP1, rs7830611 in the FBXO32, rs9508016 in the FLT1, rs12529 in the AKR1C3, rs16934641 in the BNC2, rs3763763 in the TACC2, rs2051778 in the ALPK1, and rs3763763 in the TACC2, AR, ESR1, and ESR2 and single-nucleotide polymorphisms in important pathways (such as androgen signal, biosynthesis, metabolism, androgen receptor binding site, response element, androgen receptor CAG repeat polymorphism length, and estrogen receptor-binding sites involved in prostate cancer occurrence and mechanism could serve as candidate biomarkers for the early detection of castration-resistant prostate cancer after androgen deprivation therapy. Additional investigations are required to decipher precisely the gene

  5. Enforcement actions: Significant actions resolved. Volume 14, No. 2, Part 1: Individual actions. Quarterly progress report, April--June 1995

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-09-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (April--June 1995) and includes copies of Orders sent by the Nuclear Regulatory Commission to individuals 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. The Commission believes this information may be useful to licensees in making employment decisions.

  6. Enforcement actions: Significant actions resolved -- individual actions. Semiannual progress report, July--December 1997; Volume 16, Number 2, Part 1

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1998-04-01

    This compilation summarizes significant enforcement actions that have been resolved during the period (July--December 1997) and includes copies of Orders and Notices of Violation sent by the Nuclear Regulatory Commission to individuals 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. The Commission believes this information may be useful to licensees in making employment decisions.

  7. Enforcement actions: Significant actions resolved, material licensees. Semiannual progress report, July--December 1997; Volume 16, Number 2, Part 3

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1998-04-01

    This compilation summarizes significant enforcement actions that have been resolved during the period (July--December 1997) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to material 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.

  8. Enforcement actions: Significant actions resolved material licensees (non-medical). Quarterly progress report, October 1994--December 1994

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-02-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (October - December 1994) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to material licensees (non-medical) 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.

  9. Enforcement actions: Significant actions resolved reactor licensees. Quarterly progress report, October--December 1994, Volume 13, No. 4, Part 1

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-02-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (October--December 1994) and includes copies of letters Notices, and Orders sent by the Nuclear Regulatory Commission to reactor 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.

  10. Enforcement actions: Significant actions resolved medical licensees. Quarterly progress report, January 1995--March 1995. Volume 14, No. 1, Part 2

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-05-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (January-March 1995) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to medical 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.

  11. Enforcement actions: Significant actions resolved, reactor licensees. Semiannual progress report, July--December 1997; Volume 16, Number 2, Part 2

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1998-04-01

    This compilation summarizes significant enforcement actions that have been resolved during the period (July--December 1997) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to reactor 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.

  12. Enforcement actions: Significant actions resolved reactor licensees. Volume 14, No. 2, Part 2, Quarterly progress report, April--June 1995

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-08-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (April--June 1995) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to reactor 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.

  13. Enforcement actions: Significant actions resolved, reactor licensees. Semiannual progress report, January--June 1997; Volume 16, Number 1, Part 2

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-09-01

    This compilation summarizes significant enforcement actions that have been resolved during the period (January--June 1997) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to reactor 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.

  14. Progress and Current Challenges in Modeling Large RNAs.

    Science.gov (United States)

    Somarowthu, Srinivas

    2016-02-27

    Recent breakthroughs in next-generation sequencing technologies have led to the discovery of several classes of non-coding RNAs (ncRNAs). It is now apparent that RNA molecules are not only just carriers of genetic information but also key players in many cellular processes. While there has been a rapid increase in the number of ncRNA sequences deposited in various databases over the past decade, the biological functions of these ncRNAs are largely not well understood. Similar to proteins, RNA molecules carry out a function by forming specific three-dimensional structures. Understanding the function of a particular RNA therefore requires a detailed knowledge of its structure. However, determining experimental structures of RNA is extremely challenging. In fact, RNA-only structures represent just 1% of the total structures deposited in the PDB. Thus, computational methods that predict three-dimensional RNA structures are in high demand. Computational models can provide valuable insights into structure-function relationships in ncRNAs and can aid in the development of functional hypotheses and experimental designs. In recent years, a set of diverse RNA structure prediction tools have become available, which differ in computational time, input data and accuracy. This review discusses the recent progress and challenges in RNA structure prediction methods.

  15. Chronic Progressive Neurodegeneration in a transgenic mouse model of Prion disease

    Directory of Open Access Journals (Sweden)

    Nina Fainstein

    2016-11-01

    Full Text Available Neurodegenerative diseases present pathologically with progressive structural destruction of neurons and accumulation of mis-folded proteins specific for each condition leading to brain atrophy and functional disability. Many animal models exert deposition of pathogenic protein without accompanying neurodegeneration pattern. The lack of a comprehensive model hinders the efforts to develop treatment. We performed longitudinal quantification of cellular, neuronal and synaptic density, as well as of neurogenesis in brains of mice, mimicking for genetic Creutzfeldt-Jacob disease as compared to age matched wild type mice. Mice exhibited a neurodegenerative process indicated by progressive reduction in cortical neurons and synapses, starting at age of 4-6 months, in accordance with neurologic disability. This was accompanied by significant decrease in subventricular/subependymal zone neurogenesis. Although increased hippocampal neurogenesis was detected in mice, a neurodegenerative process of CA1 and CA3 regions associated with impaired hippocampal-dependent memory function was observed. In conclusion, mice exhibit pathological neurodegeneration concomitant with progressive neurological disease, indicating these mice can serve as a model for neurodegenerative diseases.

  16. Significance of stromal-1 and stromal-2 signatures and biologic prognostic model in diffuse large B-cell lymphoma

    Science.gov (United States)

    Abdou, Asmaa Gaber; Asaad, Nancy; Kandil, Mona; Shabaan, Mohammed; Shams, Asmaa

    2017-01-01

    Objective : Diffuse Large B Cell Lymphoma (DLBCL) is a heterogeneous group of tumors with different biological and clinical characteristics that have diverse clinical outcomes and response to therapy. Stromal-1 signature of tumor microenvironment of DLBCL represents extracellular matrix deposition and histiocytic infiltrate, whereas stromal-2 represents angiogenesis that could affect tumor progression. Methods : The aim of the present study is to assess the significance of stromal-1 signature using SPARC-1 and stromal-2 signature using CD31 expression and then finally to construct biologic prognostic model (BPM) in 60 cases of DLBCL via immunohistochemistry. Results : Microvessel density (PBPM showed that 42 cases (70%) were of low biologic score (0–1) and 18 cases (30%) were of high biologic score (2–3). Low BPM cases showed less probability for splenic involvement (P=0.04) and a higher rate of complete response to therapy compared with high score cases (P=0.08). Conclusions : The DLBCL microenvironment could modulate tumor progression behavior since angiogenesis and SPARC positive stromal cells promote dissemination by association with spleen involvement and capsular invasion. Biologic prognostic models, including modified BPM, which considered cell origin of DLBCL and stromal signature pathways, could determine DLBCL progression and response to therapy. PMID:28607806

  17. Validating and optimizing the effects of model progression in simulation-based inquiry learning

    NARCIS (Netherlands)

    Mulder, Y.G.; Lazonder, A.W.; Jong, de T.; Anjewierden, A.A.; Bollen, L.

    2012-01-01

    Model progression denotes the organization of the inquiry learning process in successive phases of increasing complexity. This study investigated the effectiveness of model progression in general, and explored the added value of either broadening or narrowing students’ possibilities to change model

  18. Multi-state relative survival modelling of colorectal cancer progression and mortality.

    Science.gov (United States)

    Gilard-Pioc, Séverine; Abrahamowicz, Michal; Mahboubi, Amel; Bouvier, Anne-Marie; Dejardin, Olivier; Huszti, Ella; Binquet, Christine; Quantin, Catherine

    2015-06-01

    Accurate identification of factors associated with progression of colorectal cancer remains a challenge. In particular, it is unclear which statistical methods are most suitable to separate the effects of putative prognostic factors on cancer progression vs cancer-specific and other cause mortality. To address these challenges, we analyzed 10 year follow-up data for patients who underwent curative surgery for colorectal cancer in 1985-2000. Separate analyses were performed in two French cancer registries. Results of three multivariable models were compared: Cox model with recurrence as a time-dependent variable, and two multi-state models, which separated prognostic factor effects on recurrence vs death, with or without recurrence. Conventional multi-state model analyzed all-cause mortality while new relative survival multi-state model focused on cancer-specific mortality. Among the 2517 and 2677 patients in the two registries, about 50% died without a recurrence, and 28% had a recurrence, of whom almost 90% died. In both multi-state models men had significantly increased risk of cancer recurrence in both registries (HR=0.79; 95% CI: 0.68-0.92 and HR=0.83; 95% CI: 0.71-0.96). However, the two multi-state models identified different prognostic factors for mortality without recurrence. In contrast to the conventional model, in the relative survival analyses gender had no independent association with cancer-specific mortality whereas patients diagnosed with stage III cancer had significantly higher risks in both registries (HR=1.67; 95% CI: 1.27-2.22 and HR=2.38; 95% CI: 1.29-3.27). In conclusion, relative survival multi-state model revealed that different factors may be associated with cancer recurrence vs cancer-specific mortality either after or without a recurrence.

  19. Testing Markovianity in the three-state progressive model via future-past association.

    Science.gov (United States)

    Rodríguez-Girondo, Mar; de Uña-Álvarez, Jacobo

    2012-03-01

    The three-state progressive model is a special multi-state model with important applications in Survival Analysis. It provides a suitable representation of the individual's history when an intermediate event (with a possible influence on the survival prognosis) is experienced before the main event of interest. Estimation of transition probabilities in this and other multi-state models is usually performed through the Aalen-Johansen estimator. However, Aalen-Johansen may be biased when the underlying process is not Markov. In this paper, we provide a new approach for testing Markovianity in the three-state progressive model. The new method is based on measuring the future-past association along time. This results in a deep inspection of the process that often reveals a non-Markovian behaviour with different trends in the association measure. A test of significance for zero future-past association at each time point is introduced, and a significance trace is proposed accordingly. The finite sample performance of the test is investigated through simulations. We illustrate the new method through real data analysis. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

    Science.gov (United States)

    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.

  1. The progress and promise of zebrafish as a model to study mast cells.

    Science.gov (United States)

    Prykhozhij, Sergey V; Berman, Jason N

    2014-09-01

    Immunological and hematological research using the zebrafish (Danio rerio) has significantly advanced our understanding of blood lineage ontology, cellular functions and mechanisms, and provided opportunities for disease modeling. Mast cells are an immunological cell type involved in innate and adaptive immune systems, hypersensitivity reactions and cancer progression. The application of zebrafish to study mast cell biology exploits the developmental and imaging opportunities inherent in this model system to enable detailed genetic and molecular studies of this lineage outside of traditional mammalian models. In this review, we first place the importance of mast cell research in zebrafish into the context of comparative studies of mast cells in other fish species and highlight its advantages due to superior experimental tractability and direct visualization in transparent embryos. We discuss current and future tools for mast cell research in zebrafish and the notable results of using zebrafish for understanding mast cell fate determination and our development of a systemic mastocytosis model.

  2. Significance of radiation models in investigating the flow phenomena around a Jovian entry body

    Science.gov (United States)

    Tiwari, S. N.; Subramanian, S. V.

    1978-01-01

    Formulation is presented to demonstrate the significance of a simplified radiation model in investigating the flow-phenomena in the viscous radiating shock layer of a Jovian entry body. For this, a nongray absorption model for hydrogen-helium gas is developed which consists of 30 steps over the spectral range of 0-20 eV. By employing this model results were obtained for temperature, pressure, density, and radiative flux in the shock layer and along the body surface. These are compared with results of two sophisticated radiative transport models available in the literature. Use of the present radiation model results in significant reduction in computational time. Results of this model are found to be in general agreement with results of other models. It is concluded that use of the present model is justified in investigating the flow phenomena around a Jovian entry body because it is relatively simple, computationally fast, and yields fairly accurate results.

  3. Progressive collapse analysis using updated models for alternate path analysis after a blast

    Science.gov (United States)

    Eskew, Edward; Jang, Shinae; Bertolaccini, Kelly

    2016-04-01

    Progressive collapse is of rising importance within the structural engineering community due to several recent cases. The alternate path method is a design technique to determine the ability of a structure to sustain the loss of a critical element, or elements, and still resist progressive collapse. However, the alternate path method only considers the removal of the critical elements. In the event of a blast, significant damage may occur to nearby members not included in the alternate path design scenarios. To achieve an accurate assessment of the current condition of the structure after a blast or other extreme event, it may be necessary to reduce the strength or remove additional elements beyond the critical members designated in the alternate path design method. In this paper, a rapid model updating technique utilizing vibration measurements is used to update the structural model to represent the real-time condition of the structure after a blast occurs. Based upon the updated model, damaged elements will either have their strength reduced, or will be removed from the simulation. The alternate path analysis will then be performed, but only utilizing the updated structural model instead of numerous scenarios. After the analysis, the simulated response from the analysis will be compared to failure conditions to determine the buildings post-event condition. This method has the ability to incorporate damage to noncritical members into the analysis. This paper will utilize numerical simulations based upon a unified facilities criteria (UFC) example structure subjected to an equivalent blast to validate the methodology.

  4. Progress in Inertial Fusion Energy Modelling at DENIM

    Energy Technology Data Exchange (ETDEWEB)

    Velarde, G; Cabellos, O; Caturla, M J; Florido, R; Gil, J M; Leon, P T; Mancini, R; Marian, J; Martel, P; Martinez-Val, J M; Minguez, E; Mota, F; Ogando, F; Perlado, J M; Piera, M; Reyes, S; Rodriguez, R; Rubiano, J G; Salvador, M; Sanz, J; Sauvan, P; Velarde, M; Velarde, P

    2004-11-17

    New results of the jet driven ignition target are presented, both with direct and indirect drive. This target is based on the conical guided target used in fast ignition, but use only one laser pulse. The ignition of the target is started by the impact of a jet produced in the guiding cone, instead of using charged particles generated by a other high power laser. We have shown that a laser or X-ray pulse could be used to produce a high velocity jet of several hundred of km/s by an accumulative effect, and we use these ideas to design this new kind of targets. In order to increase the efficiency of the process, we scan in the simulations different materials, cone profiles and laser intensities. ANALOP is a code developed to calculate opacities for hot plasmas, using analytical potentials including density and temperature effects. It has been recently updated to include the radiative transport into the rate equations by mean of the escape factors, and in parallel a line transport code which solve self-consistently the rate equation and radiative transfer equation in 1D planar geometry has been also developed. We have developed a comprehensive methodology to compute uncertainties on activation calculations. First we developed a sensitivity-uncertainty analysis method, providing the uncertainties of the different inventory responses functions due to the uncertainty of each of the reaction cross sections separately. Lately, we have developed and proved the excellent behaviour of a Monte Carlo-based methodology in assessing the synergetic/global effect of the complete set of cross-sections uncertainties on calculated radiological quantities. The methods have been applied to the activation analysis of the National Ignition Facility (NIF) and different IFE concepts (HYLIFE and Sombrero). Research on multiscale modeling of radiation damage in metals will be presented in comparison with ''ad hoc'' experiments. Research on SiC composite is being pursued at

  5. Quasi-degenerate Neutrino mass models and their significance: A model independent investigation

    CERN Document Server

    Roy, S

    2016-01-01

    The prediction of possible ordering of neutrino masses relies mostly on the model selected. Alienating the $\\mu-\\tau$ interchange symmetry from discrete flavour symmetry based models, turns the neutrino mass matrix less predictive. But this inspires one to seek the answer from other phenomenological frameworks. We need a proper parametrization of the neutrino mass matrices concerning individual hierarchies. In the present work, we attempt to study the six different cases of Quasi-degenerate (QDN) neutrino models. The related mass matrices, $m_{LL}^{\

  6. The Spillover Effect of Technological Progress Based on Two Sector Model: An Empirical Study of Chinese Manufacturing Sector

    Directory of Open Access Journals (Sweden)

    Sun Xiao-hua

    2014-04-01

    Full Text Available As the technology has the nature of public good, industrial technology innovation activities have positive externalities on related sectors. Two-sector model is built to identify and calculate the spillover effects of technological progress. Specifically, the industry is divided into two sectors, and technological progress in one sector is added to the production function of the other to research the relationship between technological progress in one sector and output growth of the other. Panel data constituted by time-series from 2000 to 2007 and cross-section data of 31 provinces in Chinese manufacturing sectors is used for empirical testing. The conclusion is drawn that there are very significant spillover effects from the technological progress in equipment manufacturing sector on non-equipment manufacturing sector. The estimated results of different divisions prove that the production efficiency of equipment manufacturing sector and equipment updating speed of non-equipment manufacturing sector influence the spillover effects.

  7. Toward the virtual stomach: progress in multiscale modeling of gastric electrophysiology and motility.

    Science.gov (United States)

    Du, Peng; O'Grady, Gregory; Gao, Jerry; Sathar, Shameer; Cheng, Leo K

    2013-01-01

    Experimental progress in investigating normal and disordered gastric motility is increasingly being complimented by sophisticated multiscale modeling studies. Mathematical modeling has become a valuable tool in this effort, as there is an ever-increasing need to gain an integrative and quantitative understanding of how physiological mechanisms achieve coordinated functions across multiple biophysical scales. These interdisciplinary efforts have been particularly notable in the area of gastric electrophysiology, where they are beginning to yield a comprehensive and integrated in silico organ modeling framework, or 'virtual stomach'. At the cellular level, a number of biophysically based mathematical cell models have been developed, and these are now being applied in areas including investigations of gastric electrical pacemaker mechanisms, smooth muscle electrophysiology, and electromechanical coupling. At the tissue level, micro-structural models are being creatively developed and employed to investigate clinically significant questions, such as the functional effects of ICC degradation on gastrointestinal (GI) electrical activation. At the organ level, high-resolution electrical mapping and modeling studies are combined to provide improved insights into normal and dysrhythmic gastric electrical activation. These efforts are also enabling detailed forward and inverse modeling studies at the 'whole body' level, with implications for diagnostic techniques for gastric dysrhythmias. These recent advances, together with several others highlighted in this review, collectively demonstrate a powerful trend toward applying mathematical models to effectively investigate structure-function relationships and overcome multiscale challenges in basic and clinical GI research.

  8. A Bit Progress on Word—Based Language Model

    Institute of Scientific and Technical Information of China (English)

    陈勇; 陈国评

    2003-01-01

    A good language model is essential to a postprocessing algorithm for recognition systems. In the past, researchers have pre-sented various language models, such as character based language models, word based language model, syntactical rules :language mod-el, hybrid models, etc. The word N-gram model is by far an effective and efficient model, but one has to address the problem of data sparseness in establishing the model. Katz and Kneser et al. respectively presented effective remedies to solve this challenging prob-lem. In this study, we proposed an improvement to their methods by incorporating Chinese language-specific information or Chinese word class information into the system.

  9. The Significance of the Bystander Effect: Modeling, Experiments, and More Modeling

    Energy Technology Data Exchange (ETDEWEB)

    Brenner, David J.

    2009-07-22

    Non-targeted (bystander) effects of ionizing radiation are caused by intercellular signaling; they include production of DNA damage and alterations in cell fate (i.e. apoptosis, differentiation, senescence or proliferation). Biophysical models capable of quantifying these effects may improve cancer risk estimation at radiation doses below the epidemiological detection threshold. Understanding the spatial patterns of bystander responses is important, because it provides estimates of how many bystander cells are affected per irradiated cell. In a first approach to modeling of bystander spatial effects in a three-dimensional artificial tissue, we assumed the following: (1) The bystander phenomenon results from signaling molecules (S) that rapidly propagate from irradiated cells and decrease in concentration (exponentially in the case of planar symmetry) as distance increases. (2) These signals can convert cells to a long-lived epigenetically activated state, e.g. a state of oxidative stress; cells in this state are more prone to DNA damage and behavior alterations than normal and therefore exhibit an increased response (R) for many end points (e.g. apoptosis, differentiation, micronucleation). These assumptions were implemented by a mathematical formalism and computational algorithms. The model adequately described data on bystander responses in the 3D system using a small number of adjustable parameters. Mathematical models of radiation carcinogenesis are important for understanding mechanisms and for interpreting or extrapolating risk. There are two classes of such models: (1) long-term formalisms that track pre-malignant cell numbers throughout an entire lifetime but treat initial radiation dose-response simplistically and (2) short-term formalisms that provide a detailed initial dose-response even for complicated radiation protocols, but address its modulation during the subsequent cancer latency period only indirectly. We argue that integrating short- and long

  10. Animal Models of Diabetic Neuropathy: Progress Since 1960s

    Directory of Open Access Journals (Sweden)

    Md. Shahidul Islam

    2013-01-01

    Full Text Available Diabetic or peripheral diabetic neuropathy (PDN is one of the major complications among some other diabetic complications such as diabetic nephropathy, diabetic retinopathy, and diabetic cardiomyopathy. The use of animal models in the research of diabetes and diabetic complications is very common when rats and mice are most commonly used for many reasons. A numbers of animal models of diabetic and PDN have been developed in the last several decades such as streptozotocin-induced diabetic rat models, conventional or genetically modified or high-fat diet-fed C57BL/Ks (db/db mice models, streptozotocin-induced C57BL6/J and ddY mice models, Chinese hamster neuropathic model, rhesus monkey PDN model, spontaneously diabetic WBN/Kob rat model, L-fucose-induced neropathic rat model, partial sciatic nerve ligated rat model, nonobese diabetic (NOD mice model, spontaneously induced Ins2 Akita mice model, leptin-deficient (ob/ob mice model, Otsuka Long-Evans Tokushima Fatty (OLETF rat model, surgically-induced neuropathic model, and genetically modified Spontaneously Diabetic Torii (SDT rat model, none of which are without limitations. An animal model of diabetic or PDN should mimic the all major pathogeneses of human diabetic neuropathy. Hence, this review comparatively evaluates the animal models of diabetic and PDN which are developed since 1960s with their advantages and disadvantages to help diabetic research groups in order to more accurately choose an appropriate model to meet their specific research objectives.

  11. Modeling Progressive Damage Using Local Displacement Discontinuities Within the FEAMAC Multiscale Modeling Framework

    Science.gov (United States)

    Ranatunga, Vipul; Bednarcyk, Brett A.; Arnold, Steven M.

    2010-01-01

    A method for performing progressive damage modeling in composite materials and structures based on continuum level interfacial displacement discontinuities is presented. The proposed method enables the exponential evolution of the interfacial compliance, resulting in unloading of the tractions at the interface after delamination or failure occurs. In this paper, the proposed continuum displacement discontinuity model has been used to simulate failure within both isotropic and orthotropic materials efficiently and to explore the possibility of predicting the crack path, therein. Simulation results obtained from Mode-I and Mode-II fracture compare the proposed approach with the cohesive element approach and Virtual Crack Closure Techniques (VCCT) available within the ABAQUS (ABAQUS, Inc.) finite element software. Furthermore, an eccentrically loaded 3-point bend test has been simulated with the displacement discontinuity model, and the resulting crack path prediction has been compared with a prediction based on the extended finite element model (XFEM) approach.

  12. Advanced Modeling, Simulation and Analysis (AMSA) Capability Roadmap Progress Review

    Science.gov (United States)

    Antonsson, Erik; Gombosi, Tamas

    2005-01-01

    Contents include the following: NASA capability roadmap activity. Advanced modeling, simulation, and analysis overview. Scientific modeling and simulation. Operations modeling. Multi-special sensing (UV-gamma). System integration. M and S Environments and Infrastructure.

  13. Model-based Prognostics with Concurrent Damage Progression Processes

    Data.gov (United States)

    National Aeronautics and Space Administration — Model-based prognostics approaches rely on physics-based models that describe the behavior of systems and their components. These models must account for the several...

  14. 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

  15. Novel submicronized rebamipide liquid with moderate viscosity: significant effects on oral mucositis in animal models.

    Science.gov (United States)

    Nakashima, Takako; Sako, Nobutomo; Matsuda, Takakuni; Uematsu, Naoya; Sakurai, Kazushi; Ishida, Tatsuhiro

    2014-01-01

    This study aimed at developing a novel rebamipide liquid for an effective treatment of oral mucositis. The healing effects of a variety of liquids comprising submicronized rebamipide crystals were investigated using a rat cauterization-induced oral ulcer model. Whereas 2% rebamipide liquid comprising micro-crystals did not exhibit significant curative effect, 2% rebamipide liquids comprising submicronized crystals with moderate viscosities exhibited healing effects following intra-oral administration. The 2% and 4% optimized rebamipide liquids showed significant healing effects in the rat oral ulcer model (prebamipide liquid significantly reduced the percent area of ulcerated injury (prebamipide liquid with moderate viscosity following intra-oral administration showed better both healing effect in the rat oral ulcer model and preventive effect in the rat irradiation-induced glossitis model.

  16. 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.

  17. 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.

    Science.gov (United States)

    Kim, Yee Suk; Lee, Sungin; Zong, Nansu; Kahng, Jimin

    2017-06-01

    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 (P<0.001), while no significant association was identified for other genotypes in terms of genotype and clinical progress. There was a significant association between clearance and good prognosis (P<0.001). Persistent infection was higher in patients aged ≥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%; P<0.001). In the LDA analysis, using symmetric Dirichlet priors α=0.1 and β=0.01, and clusters (k)=5 or 10 provided the most meaningful groupings. Statistical and LDA analyses produced consistent results regarding the association between persistent infection of HPV-16, old age and long infection period with a clinical progression of CIN2 or worse

  18. Bcl-2 promotes malignant progression in a PDGF-B-dependent murine model of oligodendroglioma.

    Science.gov (United States)

    Doucette, Tiffany; Yang, Yuhui; Zhang, Wei; Fuller, Gregory N; Suki, Dima; Fults, Daniel W; Rao, Ganesh

    2011-11-01

    A significant subset of gliomas arises after activation of the proproliferative platelet-derived growth factor (PDGF) pathway. The progression of low-grade gliomas to more malignant tumors may be due to oncogenic cellular programs combining with those suppressing apoptosis. Antiapoptotic genes are overexpressed in a variety of cancers, and the antiapoptotic gene, BCL2, is associated with treatment resistance and tumor recurrence in gliomas. However, the impact of antiapoptotic gene expression to tumor formation and progression is unclear. We overexpressed Bcl-2 in a PDGFB-dependent mouse model of oligodendroglioma, a common glioma subtype, to assess its effect in vivo. We hypothesized that the antiapoptotic effect would complement the proproliferative effect of PDGFB to promote tumor formation and progression to anaplastic oligodendroglioma (AO). Here, we show that coexpression of PDGFB and Bcl-2 results in a higher overall tumor formation rate compared to PDGFB alone. Coexpression of PDGFB and Bcl-2 promotes progression to AO with prominent foci of necrosis, a feature of high-grade gliomas. Median tumor latency was shorter in mice injected with PDGFB and Bcl-2 compared to those injected with PDGFB alone. Although independent expression of Bcl-2 was insufficient to induce tumors, suppression of apoptosis (detected by cleaved caspase-3 expression) was more pronounced in AOs induced by PDGFB and Bcl-2 compared to those induced by PDGFB alone. Tumor cell proliferation (detected by phosphohistone H3 activity) was also more robust in high-grade tumors induced by PDGFB and Bcl-2. Our results indicate that suppressed apoptosis enhances oligodendroglioma formation and engenders a more malignant phenotype.

  19. Steady progression of osteoarthritic features in the canine groove model

    NARCIS (Netherlands)

    Marijnissen, A.C.A.; Roermund, P.M. van; Verzijl, N.; Tekoppele, J.M.; Bijlsma, J.W.J.; Lafeber, F.P.J.G.

    2002-01-01

    Objective: Recently we described a canine model of osteoarthritis (OA), the groove model with features of OA at 10 weeks after induction, identical to those seen in the canine anterior cruciate ligament transection (ACLT) model. This new model depends on cartilage damage accompanied by transient int

  20. Steady progression of osteoarthritic features in the canine groove model

    NARCIS (Netherlands)

    Marijnissen, A.C.A.; Roermund, P.M. van; Verzijl, N.; Tekoppele, J.M.; Bijlsma, J.W.J.; Lafeber, F.P.J.G.

    2002-01-01

    Objective: Recently we described a canine model of osteoarthritis (OA), the groove model with features of OA at 10 weeks after induction, identical to those seen in the canine anterior cruciate ligament transection (ACLT) model. This new model depends on cartilage damage accompanied by transient int

  1. A Bayesian Network Approach to Modeling Learning Progressions and Task Performance. CRESST Report 776

    Science.gov (United States)

    West, Patti; Rutstein, Daisy Wise; Mislevy, Robert J.; Liu, Junhui; Choi, Younyoung; Levy, Roy; Crawford, Aaron; DiCerbo, Kristen E.; Chappel, Kristina; Behrens, John T.

    2010-01-01

    A major issue in the study of learning progressions (LPs) is linking student performance on assessment tasks to the progressions. This report describes the challenges faced in making this linkage using Bayesian networks to model LPs in the field of computer networking. The ideas are illustrated with exemplar Bayesian networks built on Cisco…

  2. Progress in Hadronic Physics Modelling in Geant4

    Energy Technology Data Exchange (ETDEWEB)

    Apostolakis, John; /CERN; Folger, Gunter; /CERN; Grichine, Vladimir; /CERN; Heikkinen, Aatos; /Helsinki Inst. of Phys.; Howard, Alexander; /CERN; Ivanchenko, Vladimir; /CERN; Kaitaniemi, Pekka; /Helsinki Inst. of Phys.; Koi, Tatsumi; /SLAC; Kosov, Mikhail; /CERN /Moscow, ITEP; Quesada, Jose Manuel; /Seville U.; Ribon, Alberto; /CERN; Uzhinsky, Vladimir; /CERN; Wright, Dennis; /SLAC

    2011-11-28

    Geant4 offers a set of models to simulate hadronic showers in calorimeters. Recent improvements to several models relevant to the modelling of hadronic showers are discussed. These include improved cross sections, a revision of the FTF model, the addition of quasi-elastic scattering to the QGS model, and enhancements in the nuclear precompound and de-excitation models. The validation of physics models against thin target experiments has been extended especially in the energy region 10 GeV and below. Examples of new validation results are shown.

  3. A decade of progress in observing and modelling Antarctic subglacial water systems.

    Science.gov (United States)

    Fricker, Helen A; Siegfried, Matthew R; Carter, Sasha P; Scambos, Ted A

    2016-01-28

    In the decade since the discovery of active Antarctic subglacial water systems by detection of subtle surface displacements, much progress has been made in our understanding of these dynamic systems. Here, we present some of the key results of observations derived from ICESat laser altimetry, CryoSat-2 radar altimetry, Operation IceBridge airborne laser altimetry, satellite image differencing and ground-based continuous Global Positioning System (GPS) experiments deployed in hydrologically active regions. These observations provide us with an increased understanding of various lake systems in Antarctica: Whillans/Mercer Ice Streams, Crane Glacier, Recovery Ice Stream, Byrd Glacier and eastern Wilkes Land. In several cases, subglacial water systems are shown to control ice flux through the glacier system. For some lake systems, we have been able to construct more than a decade of continuous lake activity, revealing internal variability on time scales ranging from days to years. This variability indicates that continuous, accurate time series of altimetry data are critical to understanding these systems. On Whillans Ice Stream, our results from a 5-year continuous GPS record demonstrate that subglacial lake flood events significantly change the regional ice dynamics. We also show how models for subglacial water flow have evolved since the availability of observations of lake volume change, from regional-scale models of water routeing to process models of channels carved into the subglacial sediment instead of the overlying ice. We show that progress in understanding the processes governing lake drainage now allows us to create simulated lake volume time series that reproduce time series from satellite observations. This transformational decade in Antarctic subglacial water research has moved us significantly closer to understanding the processes of water transfer sufficiently for inclusion in continental-scale ice-sheet models.

  4. An Improved Syngeneic Orthotopic Murine Model of Human Breast Cancer Progression

    Science.gov (United States)

    Rashid, Omar M.; Nagahashi, Masayuki; Ramachandran, Suburamaniam; Dumur, Catherine; Schaum, Julia; Yamada, Akimitsu; Terracina, Krista P.; Milstien, Sheldon; Spiegel, Sarah; Takabe, Kazuaki

    2014-01-01

    Purpose Breast cancer drug development costs nearly $610 million and 37 months in preclinical mouse model trials with minimal success rates. Despite these inefficiencies, there are still no consensus breast cancer preclinical models. Methods Murine mammary adenocarcinoma 4T1-luc2 cells were implanted subcutaneous (SQ) or orthotopically percutaneous injection in the area of the nipple (OP), or surgically into the chest 2nd mammary fat pad under direct vision (ODV) in Balb/c immunocompetent mice. Tumor progression was followed by in vivo bioluminescence and direct measurements, pathology and survival determined, and tumor gene expression analyzed by genome-wide microarrays. Results ODV produced less variable sized tumors and was a reliable method of implantation. ODV implantation into the chest 2nd mammary pad rather than into the abdominal 4th mammary pad, the most common implantation site, better mimicked human breast cancer progression pattern, which correlated with bioluminescent tumor burden and survival. Compared to SQ, ODV produced tumors that differentially expressed genes whose interaction networks are of importance in cancer research. qPCR validation of 10 specific target genes of interest in ongoing clinical trials demonstrated significant differences in expression. Conclusions ODV implantation into the chest 2nd mammary pad provides the most reliable model that mimics human breast cancer compared from subcutaneous implantation that produces tumors with different genome expression profiles of clinical significance. Increased understanding of the limitations of the different preclinical models in use will help guide new investigations and may improve the efficiency of breast cancer drug development. PMID:25200444

  5. Innovation in Academic Progression: Progress of the New Mexico Nursing Education Consortium Model.

    Science.gov (United States)

    Landen, Jenny; Evans-Prior, Diane; Dakin, Becky; Liesveld, Judy

    The Institute of Medicine (IOM) challenged nursing education programs to increase the proportion of nurses with a baccalaureate degree in nursing to 80 percent by 2020. All 18 state-funded prelicensure nursing programs in New Mexico joined forces to create the New Mexico Nursing Education Consortium (NMNEC). NMNEC is a model of collaboration with a statewide common curriculum that provides seamless transferability for students between schools while offering the BSN on community college campuses. Over three years, university partnerships with community colleges increased prelicensure BSN seats by 77 percent. This article describes the NMNEC model, challenges and opportunities associated with implementation, current program outcomes, and factors that have contributed to NMNEC's success. Also discussed are future steps for sustainability and growth as NMNEC continues in its commitment to meeting the IOM challenge.

  6. Developing a Learning Progression for Number Sense Based on the Rule Space Model in China

    Science.gov (United States)

    Chen, Fu; Yan, Yue; Xin, Tao

    2017-01-01

    The current study focuses on developing the learning progression of number sense for primary school students, and it applies a cognitive diagnostic model, the rule space model, to data analysis. The rule space model analysis firstly extracted nine cognitive attributes and their hierarchy model from the analysis of previous research and the…

  7. Clinical progress and its significance in current apical surgery%根尖手术的临床进展和意义

    Institute of Scientific and Technical Information of China (English)

    王霄

    2012-01-01

    Enormous progress has been made and the success of treatment has been improved in apical surgery by using the surgical microscopy, ultrasound equipment, and new materials in recent years. The purpose of this article is to review the clinical progress and significance in current concepts, operating equipments, surgical techniques, root-end filling materials, and the application of the guide tissue regeneration in apical surgery.%近来,口腔显微镜、超声器械和新材料等应用于根管外科领域,给根尖手术带来了巨大的变化,提高了手术的成功率.本文就当前的根尖手术现状、手术器械、手术技术、根尖倒充填材料和引导组织再生术在根尖手术中的应用等临床进展和意义作一综述.

  8. A comparative study of two prediction models for brain tumor progression

    Science.gov (United States)

    Zhou, Deqi; Tran, Loc; Wang, Jihong; Li, Jiang

    2015-03-01

    MR diffusion tensor imaging (DTI) technique together with traditional T1 or T2 weighted MRI scans supplies rich information sources for brain cancer diagnoses. These images form large-scale, high-dimensional data sets. Due to the fact that significant correlations exist among these images, we assume low-dimensional geometry data structures (manifolds) are embedded in the high-dimensional space. Those manifolds might be hidden from radiologists because it is challenging for human experts to interpret high-dimensional data. Identification of the manifold is a critical step for successfully analyzing multimodal MR images. We have developed various manifold learning algorithms (Tran et al. 2011; Tran et al. 2013) for medical image analysis. This paper presents a comparative study of an incremental manifold learning scheme (Tran. et al. 2013) versus the deep learning model (Hinton et al. 2006) in the application of brain tumor progression prediction. The incremental manifold learning is a variant of manifold learning algorithm to handle large-scale datasets in which a representative subset of original data is sampled first to construct a manifold skeleton and remaining data points are then inserted into the skeleton by following their local geometry. The incremental manifold learning algorithm aims at mitigating the computational burden associated with traditional manifold learning methods for large-scale datasets. Deep learning is a recently developed multilayer perceptron model that has achieved start-of-the-art performances in many applications. A recent technique named "Dropout" can further boost the deep model by preventing weight coadaptation to avoid over-fitting (Hinton et al. 2012). We applied the two models on multiple MRI scans from four brain tumor patients to predict tumor progression and compared the performances of the two models in terms of average prediction accuracy, sensitivity, specificity and precision. The quantitative performance metrics were

  9. Non-conventional modeling of extreme significant wave height through random sets

    Institute of Scientific and Technical Information of China (English)

    ZHANG Yi; LAM Jasmine Siu Lee

    2014-01-01

    The analysis and design of offshore structures necessitates the consideration of wave loads. Realistic model-ing of wave loads is particularly important to ensure reliable performance of these structures. Among the available methods for the modeling of the extreme significant wave height on a statistical basis, the peak over threshold method has attracted most attention. This method employs Poisson process to character-ize time-varying properties in the parameters of an extreme value distribution. In this paper, the peak over threshold method is reviewed and extended to account for subjectivity in the modeling. The freedom in selecting the threshold and the time span to separate extremes from the original time series data is incorpo-rated as imprecision in the model. This leads to an extension from random variables to random sets in the probabilistic model for the extreme significant wave height. The extended model is also applied to different periods of the sampled data to evaluate the significance of the climatic conditions on the uncertainties of the parameters.

  10. Multiple Damage Progression Paths in Model-based Prognostics

    Data.gov (United States)

    National Aeronautics and Space Administration — Model-based prognostics approaches employ do- main knowledge about a system, its components, and how they fail through the use of physics-based models. Compo- nent...

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    Ramirez, Grisela

    2016-01-01

    Abstract 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. PMID:27699209

  13. Progress in modeling of fluid flows in crystal growth processes

    Institute of Scientific and Technical Information of China (English)

    Qisheng Chen; Yanni Jiang; Junyi Yan; Ming Qin

    2008-01-01

    Modeling of fluid flows in crystal growth processes has become an important research area in theoretical and applied mechanics.Most crystal growth processes involve fluid flows,such as flows in the melt,solution or vapor.Theoretical modeling has played an important role in developing technologies used for growing semiconductor crystals for high performance electronic and optoelectronic devices.The application of devices requires large diameter crystals with a high degree of crystallographic perfection,low defect density and uniform dopant distribution.In this article,the flow models developed in modeling of the crystal growth processes such as Czochralski,ammono-thermal and physical vapor transport methods are reviewed.In the Czochralski growth modeling,the flow models for thermocapillary flow,turbulent flow and MHD flow have been developed.In the ammonothermal growth modeling,the buoyancy and porous media flow models have been developed based on a single-domain and continuum approach for the composite fluid-porous layer systems.In the physical vapor transport growth modeling,the Stefan flow model has been proposed based on the flow-kinetics theory for the vapor growth.In addition,perspectives for future studies on crystal growth modeling are proposed.

  14. Beethoven, a mouse model for dominant, progressive hearing loss DFNA36.

    Science.gov (United States)

    Vreugde, Sarah; Erven, Alexandra; Kros, Corné J; Marcotti, Walter; Fuchs, Helmut; Kurima, Kiyoto; Wilcox, Edward R; Friedman, Thomas B; Griffith, Andrew J; Balling, Rudi; Hrabé De Angelis, Martin; Avraham, Karen B; Steel, Karen P

    2002-03-01

    Despite recent progress in identifying genes underlying deafness, there are still relatively few mouse models of specific forms of human deafness. Here we describe the phenotype of the Beethoven (Bth) mouse mutant and a missense mutation in Tmc1 (transmembrane cochlear-expressed gene 1). Progressive hearing loss (DFNA36) and profound congenital deafness (DFNB7/B11) are caused by dominant and recessive mutations of the human ortholog, TMC1 (ref. 1), for which Bth and deafness (dn) are mouse models, respectively.

  15. Research progress on animal models of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Wen DONG

    2015-08-01

    Full Text Available Alzheimer's disease (AD is a degenerative disease of the central nervous system, and its pathogenesis is complex. Animal models play an important role in study on pathogenesis and treatment of AD. This paper summarized methods of building models, observation on animal models and evaluation index in recent years, so as to provide related evidence for basic and clinical research in future. DOI: 10.3969/j.issn.1672-6731.2015.08.003

  16. Recent progress in battery models for hybrid wind power systems

    Energy Technology Data Exchange (ETDEWEB)

    Manwell, J.F.; McGowan, J.G.; Baring-Gould, I.; Stein, W. [Univ. of Massachusetts, Amherst, MA (United States)

    1995-12-31

    This paper summarizes the latest University of Massachusetts work on the analytical modeling and experimental testing of battery component models for hybrid power systems. An extension of the Kinetic Battery Model (KiBaM), developed at the University of Massachusetts is presented. The original model was based on a combination of phenomenological and physical considerations. As described in this paper, the modified KiBaM can now model the sharp increase in voltage near the end of charging, and the sharp drop in voltage when the battery is nearly empty. This model may readily be coupled with a DC load or charging source (such as a DC wind turbine or photovoltaic panels) to determine the corresponding DC bus voltage. For example, it is now an integral part of the DC bus section of the University of Massachusetts HYBRID simulation models. The paper describes the development of the extensions to the KiBaM model and the method of determining the constants from test data. On the experimental/applications side, it includes an illustration of how the constants are obtained from representative data (using a specially developed testing apparatus), and an example of how the model can be used.

  17. A new model to estimate significant wave heights with ERS-1/2 scatterometer data

    Institute of Scientific and Technical Information of China (English)

    GUO Jie; HE Yijun; William Perrie; SHEN Hui; CHU Xiaoqing

    2009-01-01

    A new model is proposed to estimate the significant wave heights with ERS-1/2 scatterometer data. The results show that the relationship between wave parameters and radar backscattering cross section is similar to that between wind and the radar backscattering cross section. Therefore, the relationship between significant wave height and the radar backscattering cross section is established with a neural network algorithm, which is, if the average wave period is ≤7s, the root mean square of significant wave height retrieved from ERS-1/2 data is 0.51 m, or 0.72 m if it is >7s otherwise.

  18. Significance of exchanging SSURGO and STATSGO data when modeling hydrology in diverse physiographic terranes

    Science.gov (United States)

    Williamson, Tanja N.; Taylor, Charles J.; Newson, Jeremy K.

    2013-01-01

    The Water Availability Tool for Environmental Resources (WATER) is a TOPMODEL-based hydrologic model that depends on spatially accurate soils data to function in diverse terranes. In Kentucky, this includes mountainous regions, karstic plateau, and alluvial plains. Soils data are critical because they quantify the space to store water, as well as how water moves through the soil to the stream during storm events. We compared how the model performs using two different sources of soils data--Soil Survey Geographic Database (SSURGO) and State Soil Geographic Database laboratory data (STATSGO)--for 21 basins ranging in size from 17 to 1564 km2. Model results were consistently better when SSURGO data were used, likely due to the higher field capacity, porosity, and available-water holding capacity, which cause the model to store more soil-water in the landscape and improve streamflow estimates for both low- and high-flow conditions. In addition, there were significant differences in the conductivity multiplier and scaling parameter values that describe how water moves vertically and laterally, respectively, as quantified by TOPMODEL. We also evaluated whether partitioning areas that drain to streams via sinkholes in karstic basins as separate hydrologic modeling units (HMUs) improved model performance. There were significant differences between HMUs in properties that control soil-water storage in the model, although the effect of partitioning these HMUs on streamflow simulation was inconclusive.

  19. 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.

  20. Strategies for Testing Statistical and Practical Significance in Detecting DIF with Logistic Regression Models

    Science.gov (United States)

    Fidalgo, Angel M.; Alavi, Seyed Mohammad; Amirian, Seyed Mohammad Reza

    2014-01-01

    This study examines three controversial aspects in differential item functioning (DIF) detection by logistic regression (LR) models: first, the relative effectiveness of different analytical strategies for detecting DIF; second, the suitability of the Wald statistic for determining the statistical significance of the parameters of interest; and…

  1. Images as drivers of progress in cardiac computational modelling.

    Science.gov (United States)

    Lamata, Pablo; Casero, Ramón; Carapella, Valentina; Niederer, Steve A; Bishop, Martin J; Schneider, Jürgen E; Kohl, Peter; Grau, Vicente

    2014-08-01

    Computational models have become a fundamental tool in cardiac research. Models are evolving to cover multiple scales and physical mechanisms. They are moving towards mechanistic descriptions of personalised structure and function, including effects of natural variability. These developments are underpinned to a large extent by advances in imaging technologies. This article reviews how novel imaging technologies, or the innovative use and extension of established ones, integrate with computational models and drive novel insights into cardiac biophysics. In terms of structural characterization, we discuss how imaging is allowing a wide range of scales to be considered, from cellular levels to whole organs. We analyse how the evolution from structural to functional imaging is opening new avenues for computational models, and in this respect we review methods for measurement of electrical activity, mechanics and flow. Finally, we consider ways in which combined imaging and modelling research is likely to continue advancing cardiac research, and identify some of the main challenges that remain to be solved.

  2. Damage progression from impact in layered glass modeled with peridynamics

    Science.gov (United States)

    Bobaru, Florin; Ha, Youn; Hu, Wenke

    2012-12-01

    Dynamic fracture in brittle materials has been difficult to model and predict. Interfaces, such as those present in multi-layered glass systems, further complicate this problem. In this paper we use a simplified peridynamic model of a multi-layer glass system to simulate damage evolution under impact with a high-velocity projectile. The simulation results are compared with results from recently published experiments. Many of the damage morphologies reported in the experiments are captured by the peridynamic results. Some finer details seen in experiments and not replicated by the computational model due to limitations in available computational resources that limited the spatial resolution of the model, and to the simple contact conditions between the layers instead of the polyurethane bonding used in the experiments. The peridynamic model uncovers a fascinating time-evolution of damage and the dynamic interaction between the stress waves, propagating cracks, interfaces, and bending deformations, in three-dimensions.

  3. On the significance of the Nash-Sutcliffe efficiency measure for event-based flood models

    Science.gov (United States)

    Moussa, Roger

    2010-05-01

    When modelling flood events, the important challenge that awaits the modeller is first to choose a rainfall-runoff model, then to calibrate a set of parameters that can accurately simulate a number of flood events and related hydrograph shapes, and finally to evaluate the model performance separately on each event using multi-criteria functions. This study analyses the significance of the Nash-Sutcliffe efficiency (NSE) and proposes a new method to assess the performance of flood event models (see Moussa, 2010, "When monstrosity can be beautiful while normality can be ugly : assessing the performance of event-based-flood-models", Hydrological Science Journal, in press). We focus on the specific cases of events difficult to model and characterized by low NSE values, which we call "monsters". The properties of the NSE were analysed as a function of the calculated hydrograph shape and of the benchmark reference model. As application case, a multi-criteria analysis method to assess the model performance on each event is proposed and applied on the Gardon d'Anduze catchment. This paper discusses first the significance of the well-known Nash-Sutcliffe efficiency (NSE) criteria function when calculated separately on flood events. The NSE is a convenient and normalized measure of model performance, but does not provide a reliable basis for comparing the results of different case studies. We show that simulated hydrographs with low or negative values of NSE, called "monsters", can be due solely to a simple lag translation or a homothetic ratio of the observed hydrograph which reproduces the dynamic of the hydrograph, with acceptable errors on other criteria. In the opposite, results show that simulations with a NSE close to 1 can become "monsters" and give very low values (even negative) of the criteria function G, if the average observed discharged used as a benchmark reference model in the NSE is modified. This paper argues that the definition of an appropriate benchmark

  4. The East model: recent results and new progresses

    CERN Document Server

    Faggionato, Alessandra; Roberto, Cyril; Toninelli, Cristina

    2012-01-01

    The East model is a particular one dimensional interacting particle system in which certain transitions are forbidden according to some constraints depending on the configuration of the system. As such it has received particular attention in the physics literature as a special case of a more general class of systems referred to as kinetically constrained models, which play a key role in explaining some features of the dynamics of glasses. In this paper we give an extensive overview of recent rigorous results concerning the equilibrium and non-equilibrium dynamics of the East model together with some new improvements.

  5. Geant4 and beyond: recent progress in precision physics modeling

    CERN Document Server

    Batic, Matej; Han, Min Cheol; Hauf, Steffen; Hoff, Gabriela; Kim, Chan Hyeong; Kim, Han Sung; Kim, Sung Hun; Kuster, Markus; Pia, Maria Grazia; Saracco, Paolo; Weidenspointner, Georg

    2014-01-01

    This extended abstract briefly summarizes ongoing research activity on the evaluation and experimental validation of physics methods for photon and electron transport. The analysis includes physics models currently implemented in Geant4 as well as modeling methods used in other Monte Carlo codes, or not yet considered in general purpose Monte Carlo simulation systems. The validation of simulation models is performed with the support of rigorous statistical methods, which involve goodness-of-fit tests followed by categorical analysis. All results are quantitative, and are fully documented.

  6. Progress towards understanding heterotypic interactions in multi-culture models of breast cancer.

    Science.gov (United States)

    Regier, Mary C; Alarid, Elaine T; Beebe, David J

    2016-06-13

    Microenvironments in primary tumors and metastases include multiple cell types whose dynamic and reciprocal interactions are central to progression of the disease. However, the literature involving breast cancer studied in vitro is dominated by cancer cells in mono-culture or co-cultured with one other cell type. For in vitro studies of breast cancer the inclusion of multiple cell types has led to models that are more representative of in vivo behaviors and functions as compared to more traditional monoculture. Here, we review foundational co-culture techniques and their adaptation to multi-culture (including three or more cell types). Additionally, while macroscale methods involving conditioned media, direct contact, and indirect interactions have been informative, we examined many advances that have been made more recently using microscale systems with increased control over cellular and structural complexity. Throughout this discussion we consider the benefits and limitations of current multi-culture methods and the significant results they have produced.

  7. A Single Dopamine Pathway Underlies Progressive Locomotor Deficits in a Drosophila Model of Parkinson Disease

    Directory of Open Access Journals (Sweden)

    Thomas Riemensperger

    2013-11-01

    Full Text Available Expression of the human Parkinson-disease-associated protein α-synuclein in all Drosophila neurons induces progressive locomotor deficits. Here, we identify a group of 15 dopaminergic neurons per hemisphere in the anterior medial region of the brain whose disruption correlates with climbing impairments in this model. These neurons selectively innervate the horizontal β and β′ lobes of the mushroom bodies, and their connections to the Kenyon cells are markedly reduced when they express α-synuclein. Using selective mushroom body drivers, we show that blocking or overstimulating neuronal activity in the β′ lobe, but not the β or γ lobes, significantly inhibits negative geotaxis behavior. This suggests that modulation of the mushroom body β′ lobes by this dopaminergic pathway is specifically required for an efficient control of startle-induced locomotion in flies.

  8. Global gene expression profile progression in Gaucher disease mouse models

    Directory of Open Access Journals (Sweden)

    Zhang Wujuan

    2011-01-01

    Full Text Available Abstract Background Gaucher disease is caused by defective glucocerebrosidase activity and the consequent accumulation of glucosylceramide. The pathogenic pathways resulting from lipid laden macrophages (Gaucher cells in visceral organs and their abnormal functions are obscure. Results To elucidate this pathogenic pathway, developmental global gene expression analyses were conducted in distinct Gba1 point-mutated mice (V394L/V394L and D409 V/null. About 0.9 to 3% of genes had altered expression patterns (≥ ± 1.8 fold change, representing several categories, but particularly macrophage activation and immune response genes. Time course analyses (12 to 28 wk of INFγ-regulated pro-inflammatory (13 and IL-4-regulated anti-inflammatory (11 cytokine/mediator networks showed tissue differential profiles in the lung and liver of the Gba1 mutant mice, implying that the lipid-storage macrophages were not functionally inert. The time course alterations of the INFγ and IL-4 pathways were similar, but varied in degree in these tissues and with the Gba1 mutation. Conclusions Biochemical and pathological analyses demonstrated direct relationships between the degree of tissue glucosylceramides and the gene expression profile alterations. These analyses implicate IFNγ-regulated pro-inflammatory and IL-4-regulated anti-inflammatory networks in differential disease progression with implications for understanding the Gaucher disease course and pathophysiology.

  9. Animal Models of Diabetic Neuropathy: Progress Since 1960s

    OpenAIRE

    Md. Shahidul Islam

    2013-01-01

    Diabetic or peripheral diabetic neuropathy (PDN) is one of the major complications among some other diabetic complications such as diabetic nephropathy, diabetic retinopathy, and diabetic cardiomyopathy. The use of animal models in the research of diabetes and diabetic complications is very common when rats and mice are most commonly used for many reasons. A numbers of animal models of diabetic and PDN have been developed in the last several decades such as streptozotocin-induced diabetic rat...

  10. Progress in and prospects for fluvial flood modelling.

    Science.gov (United States)

    Wheater, H S

    2002-07-15

    Recent floods in the UK have raised public and political awareness of flood risk. There is an increasing recognition that flood management and land-use planning are linked, and that decision-support modelling tools are required to address issues of climate and land-use change for integrated catchment management. In this paper, the scientific context for fluvial flood modelling is discussed, current modelling capability is considered and research challenges are identified. Priorities include (i) appropriate representation of spatial precipitation, including scenarios of climate change; (ii) development of a national capability for continuous hydrological simulation of ungauged catchments; (iii) improved scientific understanding of impacts of agricultural land-use and land-management change, and the development of new modelling approaches to represent those impacts; (iv) improved representation of urban flooding, at both local and catchment scale; (v) appropriate parametrizations for hydraulic simulation of in-channel and flood-plain flows, assimilating available ground observations and remotely sensed data; and (vi) a flexible decision-support modelling framework, incorporating developments in computing, data availability, data assimilation and uncertainty analysis.

  11. 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

  12. A multicontinuum progressive damage model for composite materials motivated by the kinetic theory of fracture

    Science.gov (United States)

    Schumacher, Shane Christian

    2002-01-01

    A conventional composite material for structural applications is composed of stiff reinforcing fibers embedded in a relatively soft polymer matrix, e.g. glass fibers in an epoxy matrix. Although composites have numerous advantages over traditional materials, the presence of two vastly different constituent materials has confounded analysts trying to predict failure. The inability to accurately predict the inelastic response of polymer based composites along with their ultimate failure is a significant barrier to their introduction to new applications. Polymer based composite materials also tend to exhibit rate and time dependent failure characteristics. Lack of knowledge about the rate dependent response and progressive failure of composite structures has led to the current practice of designing these structures with static properties. However, high strain rate mechanical properties can vary greatly from the static properties. The objective of this research is to develop a finite element based failure analysis tool for composite materials that incorporates strain rate hardening effects in the material failure model. The analysis method, referred to as multicontinuum theory (MCT) retains the identity of individual constituents by treating them as separate but linked continua. Retaining the constituent identities allows one to extract continuum phase averaged stress/strain fields for the constituents in a routine structural analysis. Time dependent failure is incorporated in MCT by introducing a continuum damage model into MCT. In addition to modeling time and rate dependent failure, the damage model is capable of capturing the nonlinear stress-strain response observed in composite materials.

  13. The EST Model for Predicting Progressive Damage and Failure of Open Hole Bending Specimens

    Science.gov (United States)

    Joseph, Ashith P. K.; Waas, Anthony M.; Pineda, Evan J.

    2016-01-01

    Progressive damage and failure in open hole composite laminate coupons subjected to flexural loading is modeled using Enhanced Schapery Theory (EST). Previous studies have demonstrated that EST can accurately predict the strength of open hole coupons under remote tensile and compressive loading states. This homogenized modeling approach uses single composite shell elements to represent the entire laminate in the thickness direction and significantly reduces computational cost. Therefore, when delaminations are not of concern or are active in the post-peak regime, the version of EST presented here is a good engineering tool for predicting deformation response. Standard coupon level tests provides all the input data needed for the model and they are interpreted in conjunction with finite element (FE) based simulations. Open hole bending test results of three different IM7/8552 carbon fiber composite layups agree well with EST predictions. The model is able to accurately capture the curvature change and deformation localization in the specimen at and during the post catastrophic load drop event.

  14. Progress in microscopic direct reaction modeling of nucleon induced reactions

    Energy Technology Data Exchange (ETDEWEB)

    Dupuis, M.; Bauge, E.; Hilaire, S.; Lechaftois, F.; Peru, S.; Pillet, N.; Robin, C. [CEA, DAM, DIF, Arpajon (France)

    2015-12-15

    A microscopic nuclear reaction model is applied to neutron elastic and direct inelastic scatterings, and pre-equilibrium reaction. The JLM folding model is used with nuclear structure information calculated within the quasi-particle random phase approximation implemented with the Gogny D1S interaction. The folding model for direct inelastic scattering is extended to include rearrangement corrections stemming from both isoscalar and isovector density variations occurring during a transition. The quality of the predicted (n,n), (n,n{sup '}), (n,xn) and (n,n{sup '}γ) cross sections, as well as the generality of the present microscopic approach, shows that it is a powerful tool that can help improving nuclear reactions data quality. Short- and long-term perspectives are drawn to extend the present approach to more systems, to include missing reactions mechanisms, and to consistently treat both structure and reaction problems. (orig.)

  15. Modeling NSCLC Progression: Recent Advances and Opportunities Available

    OpenAIRE

    Suleiman, Ahmed Abbas; Nogova, Lucia; Fuhr, Uwe, 1960-

    2013-01-01

    Non-small cell lung cancer (NSCLC) is one of the leading causes of death around the world with an estimated 5-year relative survival rate of 16% at diagnosis. Development of drugs treating NSCLC is not easy, and the success rate for an anticancer treatment to pass through the whole clinical development process is as low as 5%. Modeling and simulation lend themselves as tools which can potentially streamline drug development. A critical component of the models developed is a description of how...

  16. 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; Guelcher, Scott A

    2017-01-01

    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 vs. 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 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 that recapitulate the physical and cellular properties of the tissue microenvironment for investigating mechanisms of disease progression and for screening drugs.

  17. Reprogramming of human cancer cells to pluripotency for models of cancer progression

    Science.gov (United States)

    Kim, Jungsun; Zaret, Kenneth S

    2015-01-01

    The ability to study live cells as they progress through the stages of cancer provides the opportunity to discover dynamic networks underlying pathology, markers of early stages, and ways to assess therapeutics. Genetically engineered animal models of cancer, where it is possible to study the consequences of temporal-specific induction of oncogenes or deletion of tumor suppressors, have yielded major insights into cancer progression. Yet differences exist between animal and human cancers, such as in markers of progression and response to therapeutics. Thus, there is a need for human cell models of cancer progression. Most human cell models of cancer are based on tumor cell lines and xenografts of primary tumor cells that resemble the advanced tumor state, from which the cells were derived, and thus do not recapitulate disease progression. Yet a subset of cancer types have been reprogrammed to pluripotency or near-pluripotency by blastocyst injection, by somatic cell nuclear transfer and by induced pluripotent stem cell (iPS) technology. The reprogrammed cancer cells show that pluripotency can transiently dominate over the cancer phenotype. Diverse studies show that reprogrammed cancer cells can, in some cases, exhibit early-stage phenotypes reflective of only partial expression of the cancer genome. In one case, reprogrammed human pancreatic cancer cells have been shown to recapitulate stages of cancer progression, from early to late stages, thus providing a model for studying pancreatic cancer development in human cells where previously such could only be discerned from mouse models. We discuss these findings, the challenges in developing such models and their current limitations, and ways that iPS reprogramming may be enhanced to develop human cell models of cancer progression. PMID:25712212

  18. The Naval Ocean Vertical Aerosol Model : Progress Report

    NARCIS (Netherlands)

    Leeuw, G. de; Gathman, S.G.; Davidson, K.L.; Jensen, D.R.

    1990-01-01

    The Naval Oceanic Vertical Aerosol Model (NOVAM) has been formulated to estimate the vertical structure of the optical and infrared extinction coefficients in the marine atmospheric boundary layer (MABL). NOVAM was designed to predict the non-uniform and non-logarithmic extinction profiles which are

  19. Modeling sheet-flow sand transport under progressive surface waves

    NARCIS (Netherlands)

    Kranenburg, W.M.

    2013-01-01

    In the near-shore zone, energetic sea waves generate sheet-flow sand transport. In present day coastal models, wave-induced sheet-flow sand transport rates are usually predicted with semi-empirical transport formulas, based on extensive research on this phenomenon in oscillatory flow tunnels. Howeve

  20. Field significance of performance measures in the context of regional climate model evaluation. Part 2: precipitation

    Science.gov (United States)

    Ivanov, Martin; Warrach-Sagi, Kirsten; Wulfmeyer, Volker

    2017-02-01

    A new approach for rigorous spatial analysis of the downscaling performance of regional climate model (RCM) simulations is introduced. It is based on a multiple comparison of the local tests at the grid cells and is also known as `field' or `global' significance. The block length for the local resampling tests is precisely determined to adequately account for the time series structure. New performance measures for estimating the added value of downscaled data relative to the large-scale forcing fields are developed. The methodology is exemplarily applied to a standard EURO-CORDEX hindcast simulation with the Weather Research and Forecasting (WRF) model coupled with the land surface model NOAH at 0.11 ∘ grid resolution. Daily precipitation climatology for the 1990-2009 period is analysed for Germany for winter and summer in comparison with high-resolution gridded observations from the German Weather Service. The field significance test controls the proportion of falsely rejected local tests in a meaningful way and is robust to spatial dependence. Hence, the spatial patterns of the statistically significant local tests are also meaningful. We interpret them from a process-oriented perspective. While the downscaled precipitation distributions are statistically indistinguishable from the observed ones in most regions in summer, the biases of some distribution characteristics are significant over large areas in winter. WRF-NOAH generates appropriate stationary fine-scale climate features in the daily precipitation field over regions of complex topography in both seasons and appropriate transient fine-scale features almost everywhere in summer. As the added value of global climate model (GCM)-driven simulations cannot be smaller than this perfect-boundary estimate, this work demonstrates in a rigorous manner the clear additional value of dynamical downscaling over global climate simulations. The evaluation methodology has a broad spectrum of applicability as it is

  1. Progress in Geant4 Electromagnetic Physics Modelling and Validation

    Science.gov (United States)

    Apostolakis, J.; Asai, M.; Bagulya, A.; Brown, J. M. C.; Burkhardt, H.; Chikuma, N.; Cortes-Giraldo, M. A.; Elles, S.; Grichine, V.; Guatelli, S.; Incerti, S.; Ivanchenko, V. N.; Jacquemier, J.; Kadri, O.; Maire, M.; Pandola, L.; Sawkey, D.; Toshito, T.; Urban, L.; Yamashita, T.

    2015-12-01

    In this work we report on recent improvements in the electromagnetic (EM) physics models of Geant4 and new validations of EM physics. Improvements have been made in models of the photoelectric effect, Compton scattering, gamma conversion to electron and muon pairs, fluctuations of energy loss, multiple scattering, synchrotron radiation, and high energy positron annihilation. The results of these developments are included in the new Geant4 version 10.1 and in patches to previous versions 9.6 and 10.0 that are planned to be used for production for run-2 at LHC. The Geant4 validation suite for EM physics has been extended and new validation results are shown in this work. In particular, the effect of gamma-nuclear interactions on EM shower shape at LHC energies is discussed.

  2. Progress in Geant4 Electromagnetic Physics Modelling and Validation

    CERN Document Server

    Apostolakis, J; Bagulya, A; Brown, J M C; Burkhardt, H; Chikuma, N; Cortes-Giraldo, M A; Elles, S; Grichine, V; Guatelli, S; Incerti, S; Ivanchenko, V N; Jacquemier, J; Kadri, O; Maire, M; Pandola, L; Sawkey, D; Toshito, T; Urban, L; Yamashita, T

    2015-01-01

    In this work we report on recent improvements in the electromagnetic (EM) physics models of Geant4 and new validations of EM physics. Improvements have been made in models of the photoelectric effect, Compton scattering, gamma conversion to electron and muon pairs, fluctuations of energy loss, multiple scattering, synchrotron radiation, and high energy positron annihilation. The results of these developments are included in the new Geant4 version 10.1 and in patches to previous versions 9.6 and 10.0 that are planned to be used for production for run-2 at LHC. The Geant4 validation suite for EM physics has been extended and new validation results are shown in this work. In particular, the effect of gamma-nuclear interactions on EM shower shape at LHC energies is discussed.

  3. Progress in Geant4 Electromagnetic Physics Modelling and Validation

    CERN Document Server

    Apostolakis, J; Bagulya, A; Brown, J M C; Burkhardt, H; Chikuma, N; Cortes-Giraldo, M A; Elles, S; Grichine, V; Guatelli, S; Incerti, S; Ivanchenko, V N; Jacquemier, J; Kadri, O; Maire, M; Pandola, L; Sawkey, D; Toshito, T; Urban, L; Yamashita, T

    2015-01-01

    In this work we report on recent improvements in the electromagnetic (EM) physics models of Geant4 and new validations of EM physics. Improvements have been made in models of the photoelectric effect, Compton scattering, gamma conversion to electron and muon pairs, fluctuations of energy loss, multiple scattering, synchrotron radiation, and high energy positron annihilation. The results of these developments are included in the new Geant4 version 10.1 and in patches to previous versions 9.6 and 10.0 that are planned to be used for production for run-2 at LHC. The Geant4 validation suite for EM physics has been extended and new validation results are shown in this work. In particular, the effect of gamma-nuclear interactions on EM shower shape at LHC energies is discussed.

  4. Preface: International Reference Ionosphere - Progress in Ionospheric Modelling

    Science.gov (United States)

    Bilitza Dieter; Reinisch, Bodo

    2010-01-01

    The international reference ionosphere (lRI) is the internationally recommended empirical model for the specification of ionospheric parameters supported by the Committee on Space Research (COSPAR) and the International Union of Radio Science (URSI) and recognized by the International Standardization Organization (ISO). IRI is being continually improved by a team of international experts as new data become available and better models are being developed. This issue chronicles the latest phase of model updates as reported during two IRI-related meetings. The first was a special session during the Scientific Assembly of the Committee of Space Research (COSPAR) in Montreal, Canada in July 2008 and the second was an IRI Task Force Activity at the US Air Force Academy in Colorado Springs in May 2009. This work led to several improvements and additions of the model which will be included in the next version, IRI-201O. The issue is divided into three sections focusing on the improvements made in the topside ionosphere, the F-peak, and the lower ionosphere, respectively. This issue would not have been possible without the reviewing efforts of many individuals. Each paper was reviewed by two referees. We thankfully acknowledge the contribution to this issue made by the following reviewers: Jacob Adeniyi, David Altadill, Eduardo Araujo, Feza Arikan, Dieter Bilitza, Jilijana Cander, Bela Fejer, Tamara Gulyaeva, Manuel Hermindez-Pajares, Ivan Kutiev, John MacDougal, Leo McNamara, Bruno Nava, Olivier Obrou, Elijah Oyeyemi, Vadym Paznukhov, Bodo Reinisch, John Retterer, Phil Richards, Gary Sales, J.H. Sastri, Ludger Scherliess, Iwona Stanislavska, Stamir Stankov, Shin-Yi Su, Manlian Zhang, Y ongliang Zhang, and Irina Zakharenkova. We are grateful to Peggy Ann Shea for her final review and guidance as the editor-in-chief for special issues of Advances in Space Research. We thank the authors for their timely submission and their quick response to the reviewer comments and humbly

  5. Progress towards quantum simulating the classical O(2) Model

    Science.gov (United States)

    2014-12-01

    Hilbert space spanned by the eigenstates |n〉 of the “angular momentum” operator L = −i∂/∂θ with all positive and negative integer eigenvalues n. The...Ua = Ub = W are very large and positive , the on-site Hilbert space can then be restricted to the states satisfying nx = 2 at each site. All the other...gauge theory, to physical models potentially implementable on optical lattices and evolving at physical time. Using the tensor renormalization -group

  6. Theory, Modeling and Simulation: Research progress report 1994--1995

    Energy Technology Data Exchange (ETDEWEB)

    Garrett, B.C.; Dixon, D.A.; Dunning, T.H.

    1997-01-01

    The Pacific Northwest National Laboratory (PNNL) has established the Environmental Molecular Sciences Laboratory (EMSL). In April 1994, construction began on the new EMSL, a collaborative research facility devoted to advancing the understanding of environmental molecular science. Research in the Theory, Modeling, and Simulation (TM and S) program will play a critical role in understanding molecular processes important in restoring DOE`s research, development, and production sites, including understanding the migration and reactions of contaminants in soils and ground water, developing processes for isolation and processing of pollutants, developing improved materials for waste storage, understanding the enzymatic reactions involved in the biodegradation of contaminants, and understanding the interaction of hazardous chemicals with living organisms. The research objectives of the TM and S program are fivefold: to apply available electronic structure and dynamics techniques to study fundamental molecular processes involved in the chemistry of natural and contaminated systems; to extend current electronic structure and dynamics techniques to treat molecular systems of future importance and to develop new techniques for addressing problems that are computationally intractable at present; to apply available molecular modeling techniques to simulate molecular processes occurring in the multi-species, multi-phase systems characteristic of natural and polluted environments; to extend current molecular modeling techniques to treat ever more complex molecular systems and to improve the reliability and accuracy of such simulations; and to develop technologies for advanced parallel architectural computer systems. Research highlights of 82 projects are given.

  7. Progress Towards an LES Wall Model Including Unresolved Roughness

    Science.gov (United States)

    Craft, Kyle; Redman, Andrew; Aikens, Kurt

    2015-11-01

    Wall models used in large eddy simulations (LES) are often based on theories for hydraulically smooth walls. While this is reasonable for many applications, there are also many where the impact of surface roughness is important. A previously developed wall model has been used primarily for jet engine aeroacoustics. However, jet simulations have not accurately captured thick initial shear layers found in some experimental data. This may partly be due to nozzle wall roughness used in the experiments to promote turbulent boundary layers. As a result, the wall model is extended to include the effects of unresolved wall roughness through appropriate alterations to the log-law. The methodology is tested for incompressible flat plate boundary layers with different surface roughness. Correct trends are noted for the impact of surface roughness on the velocity profile. However, velocity deficit profiles and the Reynolds stresses do not collapse as well as expected. Possible reasons for the discrepancies as well as future work will be presented. This work used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation grant number ACI-1053575. Computational resources on TACC Stampede were provided under XSEDE allocation ENG150001.

  8. Theoretical models for coronary vascular biomechanics: Progress & challenges

    Science.gov (United States)

    Waters, Sarah L.; Alastruey, Jordi; Beard, Daniel A.; Bovendeerd, Peter H.M.; Davies, Peter F.; Jayaraman, Girija; Jensen, Oliver E.; Lee, Jack; Parker, Kim H.; Popel, Aleksander S.; Secomb, Timothy W.; Siebes, Maria; Sherwin, Spencer J.; Shipley, Rebecca J.; Smith, Nicolas P.; van de Vosse, Frans N.

    2013-01-01

    A key aim of the cardiac Physiome Project is to develop theoretical models to simulate the functional behaviour of the heart under physiological and pathophysiological conditions. Heart function is critically dependent on the delivery of an adequate blood supply to the myocardium via the coronary vasculature. Key to this critical function of the coronary vasculature is system dynamics that emerge via the interactions of the numerous constituent components at a range of spatial and temporal scales. Here, we focus on several components for which theoretical approaches can be applied, including vascular structure and mechanics, blood flow and mass transport, flow regulation, angiogenesis and vascular remodelling, and vascular cellular mechanics. For each component, we summarise the current state of the art in model development, and discuss areas requiring further research. We highlight the major challenges associated with integrating the component models to develop a computational tool that can ultimately be used to simulate the responses of the coronary vascular system to changing demands and to diseases and therapies. PMID:21040741

  9. Does Statistical Significance Help to Evaluate Predictive Performance of Competing Models?

    Directory of Open Access Journals (Sweden)

    Levent Bulut

    2016-04-01

    Full Text Available In Monte Carlo experiment with simulated data, we show that as a point forecast criterion, the Clark and West's (2006 unconditional test of mean squared prediction errors does not reflect the relative performance of a superior model over a relatively weaker one. The simulation results show that even though the mean squared prediction errors of a constructed superior model is far below a weaker alternative, the Clark- West test does not reflect this in their test statistics. Therefore, studies that use this statistic in testing the predictive accuracy of alternative exchange rate models, stock return predictability, inflation forecasting, and unemployment forecasting should not weight too much on the magnitude of the statistically significant Clark-West tests statistics.

  10. A background error covariance model of significant wave height employing Monte Carlo simulation

    Institute of Scientific and Technical Information of China (English)

    GUO Yanyou; HOU Yijun; ZHANG Chunmei; YANG Jie

    2012-01-01

    The quality of background error statistics is one of the key components for successful assimilation of observations in a numerical model.The background error covariance(BEC)of ocean waves is generally estimated under an assumption that it is stationary over a period of time and uniform over a domain.However,error statistics are in fact functions of the physical processes governing the meteorological situation and vary with the wave condition.In this paper,we simulated the BEC of the significant wave height(SWH)employing Monte Carlo methods.An interesting result is that the BEC varies consistently with the mean wave direction(MWD).In the model domain,the BEC of the SWH decreases significantly when the MWD changes abruptly.A new BEC model of the SWH based on the correlation between the BEC and MWD was then developed.A case study of regional data assimilation was performed,where the SWH observations of buoy 22001 were used to assess the SWH hindcast.The results show that the new BEC model benefits wave prediction and allows reasonable approximations of anisotropy and inhomogeneous errors.

  11. Modeling Methodology of Progressive Collapse by the Example of Real High-Rise Buildings

    OpenAIRE

    Mariya Barabash

    2014-01-01

    The purpose of the research was to find out several ways to design real buildings with protective measures against progressive collapse. There are no uniform guidelines for choosing the type of finite element able to provide the necessary accuracy of the calculation model taking into account all the main factors affecting the strength and stability of the building. Therefore it is required to develop numerical methods for calculation on progressive collapse of buildings bearing structural ele...

  12. A large scale survey reveals that chromosomal copy-number alterations significantly affect gene modules involved in cancer initiation and progression

    Directory of Open Access Journals (Sweden)

    Cigudosa Juan C

    2011-05-01

    Full Text Available Abstract Background Recent observations point towards the existence of a large number of neighborhoods composed of functionally-related gene modules that lie together in the genome. This local component in the distribution of the functionality across chromosomes is probably affecting the own chromosomal architecture by limiting the possibilities in which genes can be arranged and distributed across the genome. As a direct consequence of this fact it is therefore presumable that diseases such as cancer, harboring DNA copy number alterations (CNAs, will have a symptomatology strongly dependent on modules of functionally-related genes rather than on a unique "important" gene. Methods We carried out a systematic analysis of more than 140,000 observations of CNAs in cancers and searched by enrichments in gene functional modules associated to high frequencies of loss or gains. Results The analysis of CNAs in cancers clearly demonstrates the existence of a significant pattern of loss of gene modules functionally related to cancer initiation and progression along with the amplification of modules of genes related to unspecific defense against xenobiotics (probably chemotherapeutical agents. With the extension of this analysis to an Array-CGH dataset (glioblastomas from The Cancer Genome Atlas we demonstrate the validity of this approach to investigate the functional impact of CNAs. Conclusions The presented results indicate promising clinical and therapeutic implications. Our findings also directly point out to the necessity of adopting a function-centric, rather a gene-centric, view in the understanding of phenotypes or diseases harboring CNAs.

  13. Modeling corticosteroid effects in a rat model of rheumatoid arthritis I: mechanistic disease progression model for the time course of collagen-induced arthritis in Lewis rats.

    Science.gov (United States)

    Earp, Justin C; Dubois, Debra C; Molano, Diana S; Pyszczynski, Nancy A; Keller, Craig E; Almon, Richard R; Jusko, William J

    2008-08-01

    A mechanism-based model was developed to describe the time course of arthritis progression in the rat. Arthritis was induced in male Lewis rats with type II porcine collagen into the base of the tail. Disease progression was monitored by paw swelling, bone mineral density (BMD), body weights, plasma corticosterone (CST) concentrations, and tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and glucocorticoid receptor (GR) mRNA expression in paw tissue. Bone mineral density was determined by PIXImus II dual energy X-ray densitometry. Plasma CST was assayed by high-performance liquid chromatography. Cytokine and GR mRNA were determined by quantitative real-time polymerase chain reaction. Disease progression models were constructed from transduction and indirect response models and applied using S-ADAPT software. A delay in the onset of increased paw TNF-alpha and IL-6 mRNA concentrations was successfully characterized by simple transduction. This rise was closely followed by an up-regulation of GR mRNA and CST concentrations. Paw swelling and body weight responses peaked approximately 21 days after induction, whereas bone mineral density changes were greatest at 23 days after induction. After peak response, the time course in IL-1beta, IL-6 mRNA, and paw edema slowly declined toward a disease steady state. Model parameters indicate TNF-alpha and IL-1beta mRNA most significantly induce paw edema, whereas IL-6 mRNA exerted the most influence on BMD. The model for bone mineral density captures rates of turnover of cancellous and cortical bone and the fraction of each in the different regions analyzed. This small systems model integrates and quantitates multiple factors contributing to arthritis in rats.

  14. Sexual Recruitment in Zostera marina: Progress toward a Predictive Model.

    Science.gov (United States)

    Furman, Bradley T; Peterson, Bradley J

    2015-01-01

    Ecophysiological stress and physical disturbance are capable of structuring meadows through a combination of direct biomass removal and recruitment limitation; however, predicting these effects at landscape scales has rarely been successful. To model environmental influence on sexual recruitment in perennial Zostera marina, we selected a sub-tidal, light-replete study site with seasonal extremes in temperature and wave energy. During an 8-year observation period, areal coverage increased from 4.8 to 42.7%. Gains were stepwise in pattern, attributable to annual recruitment of patches followed by centrifugal growth and coalescence. Recruitment varied from 13 to 4,894 patches per year. Using a multiple linear regression approach, we examined the association between patch appearance and relative wave energy, atmospheric condition and water temperature. Two models were developed, one appropriate for the dispersal of naked seeds, and another for rafted flowers. Results indicated that both modes of sexual recruitment varied as functions of wind, temperature, rainfall and wave energy, with a regime shift in wind-wave energy corresponding to periods of rapid colonization within our site. Temporal correlations between sexual recruitment and time-lagged climatic summaries highlighted floral induction, seed bank and small patch development as periods of vulnerability. Given global losses in seagrass coverage, regions of recovery and re-colonization will become increasingly important. Lacking landscape-scale process models for seagrass recruitment, temporally explicit statistical approaches presented here could be used to forecast colonization trajectories and to provide managers with real-time estimates of future meadow performance; i.e., when to expect a good year in terms of seagrass expansion. To facilitate use as forecasting tools, we did not use statistical composites or normalized variables as our predictors. This study, therefore, represents a first step toward linking

  15. Sexual Recruitment in Zostera marina: Progress toward a Predictive Model.

    Directory of Open Access Journals (Sweden)

    Bradley T Furman

    Full Text Available Ecophysiological stress and physical disturbance are capable of structuring meadows through a combination of direct biomass removal and recruitment limitation; however, predicting these effects at landscape scales has rarely been successful. To model environmental influence on sexual recruitment in perennial Zostera marina, we selected a sub-tidal, light-replete study site with seasonal extremes in temperature and wave energy. During an 8-year observation period, areal coverage increased from 4.8 to 42.7%. Gains were stepwise in pattern, attributable to annual recruitment of patches followed by centrifugal growth and coalescence. Recruitment varied from 13 to 4,894 patches per year. Using a multiple linear regression approach, we examined the association between patch appearance and relative wave energy, atmospheric condition and water temperature. Two models were developed, one appropriate for the dispersal of naked seeds, and another for rafted flowers. Results indicated that both modes of sexual recruitment varied as functions of wind, temperature, rainfall and wave energy, with a regime shift in wind-wave energy corresponding to periods of rapid colonization within our site. Temporal correlations between sexual recruitment and time-lagged climatic summaries highlighted floral induction, seed bank and small patch development as periods of vulnerability. Given global losses in seagrass coverage, regions of recovery and re-colonization will become increasingly important. Lacking landscape-scale process models for seagrass recruitment, temporally explicit statistical approaches presented here could be used to forecast colonization trajectories and to provide managers with real-time estimates of future meadow performance; i.e., when to expect a good year in terms of seagrass expansion. To facilitate use as forecasting tools, we did not use statistical composites or normalized variables as our predictors. This study, therefore, represents a first

  16. Underpotential deposition of metals - Progress and prospects in modelling

    Indian Academy of Sciences (India)

    V Sudha; M V Sangaranarayanan

    2005-05-01

    Underpotential deposition (UPD) of metals is analysed from the perspective of phenomenological and statistical thermodynamic considerations; the parameters influencing the UPD shift have been quantitatively indicated using a general formalism. The manner in which the macroscopic properties pertaining to the depositing ions and solvent dipoles and the nature of the metallic substrate influence the UPD process are highlighted; earlier correlations of the UPD shift with the work function differences are rationalised. Anion-induced phase transitions which manifest as sharp peaks in experimental cyclic voltammograms are discussed using statistical thermodynamic models.

  17. Decreased expression of Kallmann syndrome 1 sequence gene (KAL1) contributes to oral squamous cell carcinoma progression and significantly correlates with poorly differentiated grade.

    Science.gov (United States)

    Liu, Jiannan; Cao, Wei; Chen, Wantao; Xu, Liqun; Zhang, Chenping

    2015-02-01

    Kallmann syndrome 1 sequence gene (KAL1) protein is an extracellular matrix associated protein which plays vital roles in neurons development and cell migration. However, its biological functions and clinical implications have yet not been revealed in oral carcinogenesis. The objective of the study was to evaluate the role of KAL1 in oral cancer and determine clinical significance of KAL1 in oral squamous cell carcinomas (OSCCs). The expression pattern of KAL1 was examined in a testing cohort including OSCCs (n = 42) and paired adjacent tissues (PATs) (n = 14) by real-time PCR. The result was further validated in a validating cohort of OSCCs (n = 32). Correlation between clinicopathological parameters and KAL1 mRNA levels was analyzed by Kruskal-Wallis test. In vitro, the effects of KAL1 ablation through siRNA-mediated knockdown on the proliferation of OSCC cells were determined by CCK-8, BrdU, and colonies formation assays, respectively. In addition, cell cycle distribution was further evaluated by cytometry. We observed that remarkably decreased expression of KAL1 mRNA in two independent cohorts (P = 0.0002 and P = 0.033, respectively). Furthermore, downregulated KAL1 mRNA was significantly associated with worse pathological grade (P = 0.013 and P = 0.035, respectively). Upon KAL1 silencing, the proliferation and colonies formation potentials of OSCC cells were notably promoted by accelerating G1 to M phase transition. These data indicated that KAL1 plays a potential suppressive role on OSCC initiation and progression, and KAL1 gene may serve as an adjuvant biomarker for the identification of pathological grade. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Activation of vasopressin neurons leads to phenotype progression in a mouse model for familial neurohypophysial diabetes insipidus.

    Science.gov (United States)

    Hiroi, Maiko; Morishita, Yoshiaki; Hayashi, Masayuki; Ozaki, Nobuaki; Sugimura, Yoshihisa; Nagasaki, Hiroshi; Shiota, Akira; Oiso, Yutaka; Arima, Hiroshi

    2010-02-01

    Familial neurohypophysial diabetes insipidus (FNDI) is a rare disease that is inherited in an autosomal dominant manner. In a previous study, we made a mouse model for FNDI, which showed progressive polyuria accompanied by inclusion bodies in the arginine vasopressin (AVP) neurons formed by aggregates in the endoplasmic reticulum. The present study was conducted to determine whether the activities of AVP neurons are related to the phenotype progression in the FNDI model. In the first experiment, female heterozygous mice were administered either desmopressin (dDAVP) or a vehicle (control) subcutaneously with osmotic minipumps for 30 days. The dDAVP treatment significantly decreased the urine volume, AVP mRNA expression, and inclusion bodies in the AVP neurons. Urine volume in the dDAVP group remained significantly less than the control for 14 days even after the minipumps were removed. In the second experiment, the males were fed either a 0.2% Na or 2.0% Na diet for 6 mo. Urine AVP excretion was significantly increased in the 2.0% Na group compared with the 0.2% Na group for the first 2 mo but gradually decreased thereafter. Throughout the experiments, urine volume increased progressively in the 2.0% Na group but not in the 0.2% Na group. Immunohistochemical analyses revealed that inclusion bodies in the AVP cells had significantly increased in the 2.0% Na compared with the 0.2% Na group. These data demonstrated that activation of AVP neurons could accelerate the aggregate formation as well as the progression of the polyuria in the FNDI model mice.

  19. Progressing towards a Model of Intrinsic Inclusion in a Mainstream Primary School: A SENCo's Experience

    Science.gov (United States)

    Fisher, Helen

    2012-01-01

    This article explores a Special Educational Needs Coordinator's experience of progressing from a "mainstream + SEN" approach to inclusion, defined as an extrinsically inclusive model, and perhaps more closely aligned to integration, towards a model of intrinsic inclusiveness. A three-tiered reading/spelling programme was implemented, using a…

  20. Recent progress in plasma modelling at INFN-LNS

    Energy Technology Data Exchange (ETDEWEB)

    Neri, L., E-mail: neri@lns.infn.it; Castro, G.; Mascali, D.; Celona, L.; Gammino, S. [INFN-Laboratori Nazionali del Sud, Via S. Sofia 62, 95125 Catania (Italy); Torrisi, G. [INFN-Laboratori Nazionali del Sud, Via S. Sofia 62, 95125 Catania (Italy); Università Mediterranea di Reggio Calabria, Via Graziella, 89100 Reggio Calabria (Italy); Galatà, A. [INFN-Laboratori Nazionali di Legnaro, Viale dell’Università 2, 35020 Legnaro, Padova (Italy)

    2016-02-15

    At Istituto Nazionale di Fisica Nucleare - Laboratori Nazionali del Sud (INFN-LNS), the development of intense ion and proton sources has been supported by a great deal of work on the modelling of microwave generated plasmas for many years. First, a stationary version of the particle-in-cell code was developed for plasma modelling starting from an iterative strategy adopted for the space charge dominated beam transport simulations. Electromagnetic properties of the plasma and full-waves simulations are now affordable for non-homogenous and non-isotropic magnetized plasma via “cold” approximation. The effects of Coulomb collisions on plasma particles dynamics was implemented with the Langevin formalism, instead of simply applying the Spitzer 90° collisions through a Monte Carlo technique. A wide database of different cross sections related to reactions occurring in a hydrogen plasma was implemented. The next step consists of merging such a variety of approaches for retrieving an “as-a-whole” picture of plasma dynamics in ion sources. The preliminary results will be summarized in the paper for a microwave discharge ion source designed for intense and high quality proton beams production, proton source for European Spallation Source project. Even if the realization of a predictive software including the complete processes involved in plasma formation is still rather far, a better comprehension of the source behavior is possible and so the simulations may support the optimization phase.

  1. Recent progress in plasma modelling at INFN-LNS

    Science.gov (United States)

    Neri, L.; Castro, G.; Torrisi, G.; Galatà, A.; Mascali, D.; Celona, L.; Gammino, S.

    2016-02-01

    At Istituto Nazionale di Fisica Nucleare - Laboratori Nazionali del Sud (INFN-LNS), the development of intense ion and proton sources has been supported by a great deal of work on the modelling of microwave generated plasmas for many years. First, a stationary version of the particle-in-cell code was developed for plasma modelling starting from an iterative strategy adopted for the space charge dominated beam transport simulations. Electromagnetic properties of the plasma and full-waves simulations are now affordable for non-homogenous and non-isotropic magnetized plasma via "cold" approximation. The effects of Coulomb collisions on plasma particles dynamics was implemented with the Langevin formalism, instead of simply applying the Spitzer 90° collisions through a Monte Carlo technique. A wide database of different cross sections related to reactions occurring in a hydrogen plasma was implemented. The next step consists of merging such a variety of approaches for retrieving an "as-a-whole" picture of plasma dynamics in ion sources. The preliminary results will be summarized in the paper for a microwave discharge ion source designed for intense and high quality proton beams production, proton source for European Spallation Source project. Even if the realization of a predictive software including the complete processes involved in plasma formation is still rather far, a better comprehension of the source behavior is possible and so the simulations may support the optimization phase.

  2. Classical Cepheid pulsation models --- VI. The Hertzsprung progression

    Science.gov (United States)

    Bono, G.; Marconi, M.; Stellingwerf, R. F.

    2000-08-01

    We present the results of an extensive theoretical investigation on the pulsation behavior of Bump Cepheids. We constructed several sequences of full amplitude, nonlinear, convective models by adopting a chemical composition typical of Large Magellanic Cloud (LMC) Cepheids (Y=0.25, Z=0.008) and stellar masses ranging from M/M⊙ =6.55 to 7.45. We find that theoretical light and velocity curves reproduce the HP, and indeed close to the blue edge the bump is located along the descending branch, toward longer periods it crosses at first the luminosity/velocity maximum and then it appears along the rising branch. In particular, we find that the predicted period at the HP center is PHP = 11.24∓0.46 d and that such a value is in very good agreement with the empirical value estimated by adopting the Fourier parameters of LMC Cepheid light curves i.e. PHP = 11.2 ∓ 0.8 d (Welch et al. 1997). Moreover, light and velocity amplitudes present a "double-peaked" distribution which is in good qualitative agreement with observational evidence on Bump Cepheids. It turns out that both the skewness and the acuteness typically show a well-defined minimum at the HP center and the periods range from PHP = 10.73 ∓ 0.97 d to PHP = 11.29 ∓ 0.53 d which are in good agreement with empirical estimates. We also find that the models at the HP center are located within the resonance region but not on the 2:1 resonance line (P2/P0 = 0.5), and indeed the P2/P0 ratios roughly range from 0.51 (cool models) to 0.52 (hot models). Interestingly enough, the predicted Bump Cepheid masses, based on a Mass-Luminosity (ML) relation which neglects the convective core overshooting, are in good agreement with the empirical masses of Galactic Cepheids estimated by adopting the Baade-Wesselink method (Gieren 1989). As a matter of fact, the observed mass at the HP center -P ≍ 11.2 d- is 6.9 ∓ 0.9 M⊙, while the predicted mass is 7.0 ∓ 0.45 M⊙. Even by accounting for the metallicity difference

  3. Expression and clinical significance of the Kv3.4 potassium channel subunit in the development and progression of head and neck squamous cell carcinomas.

    Science.gov (United States)

    Menéndez, Sofía Tirados; Rodrigo, Juan P; Allonca, Eva; García-Carracedo, Darío; Alvarez-Alija, Gustavo; Casado-Zapico, Sara; Fresno, Manuel F; Rodríguez, Carmen; Suárez, Carlos; García-Pedrero, Juana M

    2010-08-01

    The concept of ion channels as membrane therapeutic targets and diagnostic/prognostic biomarkers has attracted growing attention. We therefore investigated the expression pattern and clinical significance of the Kv3.4 potassium channel subunit during the development and progression of head and neck squamous cell carcinomas (HNSCCs). KCNC4 mRNA levels were determined by real-time RT-PCR in both HNSCC tissue specimens and derived cell lines. Kv3.4 protein expression was evaluated by immunohistochemistry in paraffin-embedded tissue specimens from 84 patients with laryngeal/pharyngeal squamous cell carcinomas and 67 patients with laryngeal dysplasias. Molecular alterations were correlated with clinicopathological parameters and patient outcome. Increased KCNC4 mRNA levels were found in 15 (54%) of 28 tumours, compared to the corresponding normal epithelia and varied mRNA levels were detected in 12 HNSCC-derived cell lines analysed. Increased Kv3.4 protein expression was observed in 34 (40%) of 84 carcinomas and also at early stages of HNSCC tumourigenesis. Thus, 35 (52%) of 67 laryngeal lesions displayed Kv3.4-positive staining in the dysplastic areas, whereas both stromal cells and normal adjacent epithelia exhibited negligible expression. No significant correlations were found between Kv3.4-positive expression in HNSCC and clinical data; however, Kv3.4 expression tended to diminish in advanced-stage tumours. Interestingly, patients carrying Kv3.4-positive dysplasias experienced a significantly higher laryngeal cancer incidence than did those with negative lesions (p = 0.0209). In addition, functional studies using HNSCC cells revealed that inhibition of Kv3.4 expression by siRNA leads to the inhibition of cell proliferation via selective cell cycle arrest at the G2/M phase without affecting apoptosis. Collectively, these data demonstrate for the first time that Kv3.4 expression is frequently increased during HNSCC tumourigenesis and correlated significantly with a

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

    Directory of Open Access Journals (Sweden)

    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.

  5. 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.

  6. 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

    Two micromechanical, representative unit cell type models of fiber reinforced composite (FRC) are applied to simulate explicitly onset and accumulation of scattered local damage in the form of interface debonding. The first model is based on the analytical, multipole expansion type solution...... 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....

  7. On the computational assessment of white matter hyperintensity progression: difficulties in method selection and bias field correction performance on images with significant white matter pathology

    Energy Technology Data Exchange (ETDEWEB)

    Valdes Hernandez, Maria del C.; Gonzalez-Castro, Victor; Wang, Xin; Doubal, Fergus; Munoz Maniega, Susana; Wardlaw, Joanna M. [Centre for Clinical Brian Sciences, Department of Neuroimaging Sciences, Edinburgh (United Kingdom); Ghandour, Dina T. [University of Edinburgh, College of Medicine and Veterinary Medicine, Edinburgh (United Kingdom); Armitage, Paul A. [University of Sheffield, Department of Cardiovascular Sciences, Sheffield (United Kingdom)

    2016-05-15

    Subtle inhomogeneities in the scanner's magnetic fields (B{sub 0} and B{sub 1}) alter the intensity levels of the structural magnetic resonance imaging (MRI) affecting the volumetric assessment of WMH changes. Here, we investigate the influence that (1) correcting the images for the B{sub 1} inhomogeneities (i.e. bias field correction (BFC)) and (2) selection of the WMH change assessment method can have on longitudinal analyses of WMH progression and discuss possible solutions. We used brain structural MRI from 46 mild stroke patients scanned at stroke onset and 3 years later. We tested three BFC approaches: FSL-FAST, N4 and exponentially entropy-driven homomorphic unsharp masking (E{sup 2}D-HUM) and analysed their effect on the measured WMH change. Separately, we tested two methods to assess WMH changes: measuring WMH volumes independently at both time points semi-automatically (MCMxxxVI) and subtracting intensity-normalised FLAIR images at both time points following image gamma correction. We then combined the BFC with the computational method that performed best across the whole sample to assess WMH changes. Analysis of the difference in the variance-to-mean intensity ratio in normal tissue between BFC and uncorrected images and visual inspection showed that all BFC methods altered the WMH appearance and distribution, but FSL-FAST in general performed more consistently across the sample and MRI modalities. The WMH volume change over 3 years obtained with MCMxxxVI with vs. without FSL-FAST BFC did not significantly differ (medians(IQR)(with BFC) = 3.2(6.3) vs. 2.9(7.4)ml (without BFC), p = 0.5), but both differed significantly from the WMH volume change obtained from subtracting post-processed FLAIR images (without BFC)(7.6(8.2)ml, p < 0.001). This latter method considerably inflated the WMH volume change as subtle WMH at baseline that became more intense at follow-up were counted as increase in the volumetric change. Measurement of WMH volume change remains

  8. Therapeutic AAV9-mediated suppression of mutant SOD1 slows disease progression and extends survival in models of inherited ALS.

    Science.gov (United States)

    Foust, Kevin D; Salazar, Desirée L; Likhite, Shibi; Ferraiuolo, Laura; Ditsworth, Dara; Ilieva, Hristelina; Meyer, Kathrin; Schmelzer, Leah; Braun, Lyndsey; Cleveland, Don W; Kaspar, Brian K

    2013-12-01

    Mutations in superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (ALS) resulting in progressive motor neuron death through one or more acquired toxicities. Involvement of wild-type SOD1 has been linked to sporadic ALS, as misfolded SOD1 has been reported in affected tissues of sporadic patients and toxicity of astrocytes derived from sporadic ALS patients to motor neurons has been reported to be reduced by lowering the synthesis of SOD1. We now report slowed disease onset and progression in two mouse models following therapeutic delivery using a single peripheral injection of an adeno-associated virus serotype 9 (AAV9) encoding an shRNA to reduce the synthesis of ALS-causing human SOD1 mutants. Delivery to young mice that develop aggressive, fatal paralysis extended survival by delaying both disease onset and slowing progression. In a later-onset model, AAV9 delivery after onset markedly slowed disease progression and significantly extended survival. Moreover, AAV9 delivered intrathecally to nonhuman primates is demonstrated to yield robust SOD1 suppression in motor neurons and glia throughout the spinal cord and therefore, setting the stage for AAV9-mediated therapy in human clinical trials.

  9. Impact of changes in metabolic control on progression to photocoagulation for clinically significant macular oedema:a 20 year study of type 1 diabetes

    DEFF Research Database (Denmark)

    Sander, B.; Larsen, M.; Andersen, Elisabeth Wreford;

    2013-01-01

    Center from 1988 to 2008, using the endpoint referral to first photocoagulation treatment for clinically significant diabetic macular oedema. The analysis included 1,878 patients (median observation, 8 years). Changes were defined as the inter-visit change; in the case of an event the last event...... model. A recent decrease of ≥0.5 percentage points or an increase in HbA1c of >0.5 percentage points per 6 months was associated with HRs of 3.04 and 1.28, respectively, compared with lesser changes in HbA1c. Conclusions/interpretation In this study, large recent...

  10. Estimating successive cancer risks in Lynch Syndrome families using a progressive three-state model.

    Science.gov (United States)

    Choi, Yun-Hee; Briollais, Laurent; Green, Jane; Parfrey, Patrick; Kopciuk, Karen

    2014-02-20

    Lynch Syndrome (LS) families harbor mutated mismatch repair genes,which predispose them to specific types of cancer. Because individuals within LS families can experience multiple cancers over their lifetime, we developed a progressive three-state model to estimate the disease risk from a healthy (state 0) to a first cancer (state 1) and then to a second cancer (state 2). Ascertainment correction of the likelihood was made to adjust for complex sampling designs with carrier probabilities for family members with missing genotype information estimated using their family's observed genotype and phenotype information in a one-step expectation-maximization algorithm. A sandwich variance estimator was employed to overcome possible model misspecification. The main objective of this paper is to estimate the disease risk (penetrance) for age at a second cancer after someone has experienced a first cancer that is also associated with a mutated gene. Simulation study results indicate that our approach generally provides unbiased risk estimates and low root mean squared errors across different family study designs, proportions of missing genotypes, and risk heterogeneities. An application to 12 large LS families from Newfoundland demonstrates that the risk for a second cancer was substantial and that the age at a first colorectal cancer significantly impacted the age at any LS subsequent cancer. This study provides new insights for developing more effective management of mutation carriers in LS families by providing more accurate multiple cancer risk estimates.

  11. 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 climate between early and late spring phenophases, as well as between leaf 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.

  12. 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

  13. Significant glial alterations in response to iron loading in a novel organotypic hippocampal slice culture model

    Science.gov (United States)

    Healy, Sinead; McMahon, Jill; Owens, Peter; FitzGerald, Una

    2016-01-01

    Aberrant iron deposition in the brain is associated with neurodegenerative disorders including Multiple Sclerosis, Alzheimer’s disease and Parkinson’s disease. To study the collective response to iron loading, we have used hippocampal organotypic slices as a platform to develop a novel ex vivo model of iron accumulation. We demonstrated differential uptake and toxicity of iron after 12 h exposure to 10 μM ferrous ammonium sulphate, ferric citrate or ferrocene. Having established the supremacy of ferrocene in this model, the cultures were then loaded with 0.1–100 μM ferrocene for 12 h. One μM ferrocene exposure produced the maximal 1.6-fold increase in iron compared with vehicle. This was accompanied by a 1.4-fold increase in ferritin transcripts and mild toxicity. Using dual-immunohistochemistry, we detected ferritin in oligodendrocytes, microglia, but rarely in astrocytes and never in neurons in iron-loaded slice cultures. Moreover, iron loading led to a 15% loss of olig2-positive cells and a 16% increase in number and greater activation of microglia compared with vehicle. However, there was no appreciable effect of iron loading on astrocytes. In what we believe is a significant advance on traditional mono- or dual-cultures, our novel ex vivo slice-culture model allows characterization of the collective response of brain cells to iron-loading. PMID:27808258

  14. A Parallelized Pumpless Artificial Placenta System Significantly Prolonged Survival Time in a Preterm Lamb Model.

    Science.gov (United States)

    Miura, Yuichiro; Matsuda, Tadashi; Usuda, Haruo; Watanabe, Shimpei; Kitanishi, Ryuta; Saito, Masatoshi; Hanita, Takushi; Kobayashi, Yoshiyasu

    2016-05-01

    An artificial placenta (AP) is an arterio-venous extracorporeal life support system that is connected to the fetal circulation via the umbilical vasculature. Previously, we published an article describing a pumpless AP system with a small priming volume. We subsequently developed a parallelized system, hypothesizing that the reduced circuit resistance conveyed by this modification would enable healthy fetal survival time to be prolonged. We conducted experiments using a premature lamb model to test this hypothesis. As a result, the fetal survival period was significantly prolonged (60.4 ± 3.8 vs. 18.2 ± 3.2 h, P < 0.01), and circuit resistance and minimal blood lactate levels were significantly lower in the parallel circuit group, compared with our previous single circuit group. Fetal physiological parameters remained stable until the conclusion of the experiments. In summary, parallelization of the AP system was associated with reduced circuit resistance and lactate levels and allowed preterm lamb fetuses to survive for a significantly longer period when compared with previous studies.

  15. 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.

  16. Phasic firing in vasopressin cells: understanding its functional significance through computational models.

    Directory of Open Access Journals (Sweden)

    Duncan J MacGregor

    Full Text Available Vasopressin neurons, responding to input generated by osmotic pressure, use an intrinsic mechanism to shift from slow irregular firing to a distinct phasic pattern, consisting of long bursts and silences lasting tens of seconds. With increased input, bursts lengthen, eventually shifting to continuous firing. The phasic activity remains asynchronous across the cells and is not reflected in the population output signal. Here we have used a computational vasopressin neuron model to investigate the functional significance of the phasic firing pattern. We generated a concise model of the synaptic input driven spike firing mechanism that gives a close quantitative match to vasopressin neuron spike activity recorded in vivo, tested against endogenous activity and experimental interventions. The integrate-and-fire based model provides a simple physiological explanation of the phasic firing mechanism involving an activity-dependent slow depolarising afterpotential (DAP generated by a calcium-inactivated potassium leak current. This is modulated by the slower, opposing, action of activity-dependent dendritic dynorphin release, which inactivates the DAP, the opposing effects generating successive periods of bursting and silence. Model cells are not spontaneously active, but fire when perturbed by random perturbations mimicking synaptic input. We constructed one population of such phasic neurons, and another population of similar cells but which lacked the ability to fire phasically. We then studied how these two populations differed in the way that they encoded changes in afferent inputs. By comparison with the non-phasic population, the phasic population responds linearly to increases in tonic synaptic input. Non-phasic cells respond to transient elevations in synaptic input in a way that strongly depends on background activity levels, phasic cells in a way that is independent of background levels, and show a similar strong linearization of the response

  17. The omega-3 fatty acid eicosapentaenoic acid accelerates disease progression in a model of amyotrophic lateral sclerosis.

    Directory of Open Access Journals (Sweden)

    Ping K Yip

    Full Text Available Amyotrophic lateral sclerosis (ALS is a progressive fatal neurodegenerative disease characterised by loss of motor neurons that currently has no cure. Omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA, have many health benefits including neuroprotective and myoprotective potential. We tested the hypothesis that a high level of dietary EPA could exert beneficial effects in ALS. The dietary exposure to EPA (300 mg/kg/day in a well-established mouse model of ALS expressing the G93A superoxide dismutase 1 (SOD1 mutation was initiated at a pre-symptomatic or symptomatic stage, and the disease progression was monitored until the end stage. Daily dietary EPA exposure initiated at the disease onset did not significantly alter disease presentation and progression. In contrast, EPA treatment initiated at the pre-symptomatic stage induced a significantly shorter lifespan. In a separate group of animals sacrificed before the end stage, the tissue analysis showed that the vacuolisation detected in G93A-SOD1 mice was significantly increased by exposure to EPA. Although EPA did not alter motor neurone loss, EPA reversed the significant increase in activated microglia and the astrocytic activation seen in G93A-SOD1 mice. The microglia in the spinal cord of G93A-SOD1 mice treated with EPA showed a significant increase in 4-hydroxy-2-hexenal, a highly toxic aldehydic oxidation product of omega-3 fatty acids. These data show that dietary EPA supplementation in ALS has the potential to worsen the condition and accelerate the disease progression. This suggests that great caution should be exerted when considering dietary omega-3 fatty acid supplements in ALS patients.

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

    Directory of Open Access Journals (Sweden)

    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

  19. Progress in the Development and Application of Climate Ocean Models and Ocean-Atmosphere Coupled Models in China

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    A review is presented about the development and application of climate ocean models and oceanatmosphere coupled models developed in China as well as 8 review of climate variability and climate change studies performed with these models.While the history of model development is briefly reviewed,emphasis has been put on the achievements made in the last five years.Advances in model development are described along with a summary on scientific issues addressed by using these models.The focus of the review is the climate ocean models and the associated coupled models,including both global and regional models,developed at the Institute of Atmospheric Physics,Chinese Academy of Sciences.The progress of either coupled model development made by other institutions or climate modeling using internationally developed models also is reviewed.

  20. Research Progress of J Wave Syndromes and Its Clinical Significance%J波综合征及其临床意义研究进展

    Institute of Scientific and Technical Information of China (English)

    沈雁岩

    2012-01-01

    J wave refers to a dome or hump wave on electrocardiogram which drifts off the baseline and is formed from an elevation of the QRS-ST junction( J point), amplitude≥0. 1mV, period≥0.2ms. J wave syndromes was defined in researches in the past few years,referring to a series of collective clinical syndromes characterized by J wave on electrocardiogram, with the same ionic mechanism,the tendency of ventricular tachycardia-ventricular fibrillation-sudden cardiac death and combining with or without organic heart disease. Certain types of J wave syndromes have become new high-risk warning index of malignant ventricular arrhythmia and sudden cardiac death. So here is to make a review on the important research progresses of J wave syndromes in mechanism of ion flow and cell electrophysiology, genetic basis, clinical significance of classification and syndrome types and treatment in recent years.%摘要:J波指心电图QRS波结束和ST段起始的结合点(J点)抬高,振幅≥0.1 mV,时程≥20 ms,向上圆顶样或驼峰样偏离基线的波.近年来的研究中将与心电图J波有关,具备相同离子流机制,具有室性心动过速-心室颤动-心脏性猝死的倾向,合并或不合并器质性心脏病的临床综合征统称为J波综合征,认为其某些类型成为恶性室性心律失常心脏性猝死高危预警的新指标.现就近年来J波综合征在离子流和细胞电生理机制、遗传学基础、分类分型与临床意义以及治疗方面的重要进展进行综述.

  1. A systematic experimental investigation of significant parameters affecting model tire hydroplaning

    Science.gov (United States)

    Wray, G. A.; Ehrlich, I. R.

    1973-01-01

    The results of a comprehensive parametric study of model and small pneumatic tires operating on a wet surface are presented. Hydroplaning inception (spin down) and rolling restoration (spin up) are discussed. Conclusions indicate that hydroplaning inception occurs at a speed significantly higher than the rolling restoration speed. Hydroplaning speed increases considerably with tread depth, surface roughness and tire inflation pressure of footprint pressure, and only moderately with increased load. Water film thickness affects spin down speed only slightly. Spin down speed varies inversely as approximately the one-sixth power of film thickness. Empirical equations relating tire inflation pressure, normal load, tire diameter and water film thickness have been generated for various tire tread and surface configurations.

  2. Computer modeling of gastric parietal cell: significance of canalicular space, gland lumen, and variable canalicular [K+].

    Science.gov (United States)

    Crothers, James M; Forte, John G; Machen, Terry E

    2016-05-01

    A computer model, constructed for evaluation of integrated functioning of cellular components involved in acid secretion by the gastric parietal cell, has provided new interpretations of older experimental evidence, showing the functional significance of a canalicular space separated from a mucosal bath by a gland lumen and also shedding light on basolateral Cl(-) transport. The model shows 1) changes in levels of parietal cell secretion (with stimulation or H-K-ATPase inhibitors) result mainly from changes in electrochemical driving forces for apical K(+) and Cl(-) efflux, as canalicular [K(+)] ([K(+)]can) increases or decreases with changes in apical H(+)/K(+) exchange rate; 2) H-K-ATPase inhibition in frog gastric mucosa would increase [K(+)]can similarly with low or high mucosal [K(+)], depolarizing apical membrane voltage similarly, so electrogenic H(+) pumping is not indicated by inhibition causing similar increase in transepithelial potential difference (Vt) with 4 and 80 mM mucosal K(+); 3) decreased H(+) secretion during strongly mucosal-positive voltage clamping is consistent with an electroneutral H-K-ATPase being inhibited by greatly decreased [K(+)]can (Michaelis-Menten mechanism); 4) slow initial change ("long time-constant transient") in current or Vt with clamping of Vt or current involves slow change in [K(+)]can; 5) the Na(+)-K(+)-2Cl(-) symporter (NKCC) is likely to have a significant role in Cl(-) influx, despite evidence that it is not necessary for acid secretion; and 6) relative contributions of Cl(-)/HCO3 (-) exchanger (AE2) and NKCC to Cl(-) influx would differ greatly between resting and stimulated states, possibly explaining reported differences in physiological characteristics of stimulated open-circuit Cl(-) secretion (≈H(+)) and resting short-circuit Cl(-) secretion (>H(+)).

  3. Are We There Yet? Using Rubrics to Support Progress toward Proficiency and Model Formative Assessment

    Science.gov (United States)

    Kinne, Lenore J.; Hasenbank, Jon F.; Coffey, David

    2014-01-01

    Classroom assessment, especially formative assessment, is one of the most challenging areas for new teachers, so it is imperative that teacher educators model effective classroom assessment practices. This article describes the use of rubrics in formative assessment, to support candidates in their progress toward mastery of course outcomes and to…

  4. SUCCESS AND PROGRESS IN HIGHER-EDUCATION : A STRUCTURAL MODEL OF STUDYING

    NARCIS (Netherlands)

    MINNAERT, A; JANSSEN, PJ

    1992-01-01

    In Belgium, the success rates of freshmen in higher education are relatively low. To understand this phenomenon a structural model for indiviaual differences in study success and progress is suggested. Starting from the theory that studying is the integration of thinking and learning on the basis of

  5. 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

  6. STATISTICAL INFERENCE OF WEIBULL DISTRIBUTION FOR TAMPERED FAILURE RATE MODEL IN PROGRESSIVE STRESS ACCELERATED LIFE TESTING

    Institute of Scientific and Technical Information of China (English)

    WANG Ronghua; FEI Heliang

    2004-01-01

    In this note, the tampered failure rate model is generalized from the step-stress accelerated life testing setting to the progressive stress accelerated life testing for the first time. For the parametric setting where the scale parameter satisfying the equation of the inverse power law is Weibull, maximum likelihood estimation is investigated.

  7. 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

  8. 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.

  9. Significant Features Found in Simulated Tropical Climates Using a Cloud Resolving Model

    Science.gov (United States)

    Shie, C.-L.; Tao, W.-K.; Simpson, J.; Sui, C.-H.

    2000-01-01

    Cloud resolving model (CRM) has widely been used in recent years for simulations involving studies of radiative-convective systems and their role in determining the tropical regional climate. The growing popularity of CRMs usage can be credited for their inclusion of crucial and realistic features such like explicit cloud-scale dynamics, sophisticated microphysical processes, and explicit radiative-convective interaction. For example, by using a two-dimensional cloud model with radiative-convective interaction process, found a QBO-like (quasibiennial oscillation) oscillation of mean zonal wind that affected the convective system. Accordingly, the model-generated rain band corresponding to convective activity propagated in the direction of the low-level zonal mean winds; however, the precipitation became "localized" (limited within a small portion of the domain) as zonal mean winds were removed. Two other CRM simulations by S94 and Grabowski et al. (1996, hereafter G96), respectively that produced distinctive quasi-equilibrium ("climate") states on both tropical water and energy, i.e., a cold/dry state in S94 and a warm/wet state in G96, have later been investigated by T99. They found that the pattern of the imposed large-scale horizontal wind and the magnitude of the imposed surface fluxes were the two crucial mechanisms in determining the tropical climate states. The warm/wet climate was found associated with prescribed strong surface winds, or with maintained strong vertical wind shears that well-organized convective systems prevailed. On the other hand, the cold/dry climate was produced due to imposed weak surface winds and weak wind shears throughout a vertically mixing process by convection. In this study, considered as a sequel of T99, the model simulations to be presented are generally similar to those of T99 (where a detailed model setup can be found), except for a more detailed discussion along with few more simulated experiments. There are twelve major

  10. 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

  11. 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

  12. Significance tests to determine the direction of effects in linear regression models.

    Science.gov (United States)

    Wiedermann, Wolfgang; Hagmann, Michael; von Eye, Alexander

    2015-02-01

    Previous studies have discussed asymmetric interpretations of the Pearson correlation coefficient and have shown that higher moments can be used to decide on the direction of dependence in the bivariate linear regression setting. The current study extends this approach by illustrating that the third moment of regression residuals may also be used to derive conclusions concerning the direction of effects. Assuming non-normally distributed variables, it is shown that the distribution of residuals of the correctly specified regression model (e.g., Y is regressed on X) is more symmetric than the distribution of residuals of the competing model (i.e., X is regressed on Y). Based on this result, 4 one-sample tests are discussed which can be used to decide which variable is more likely to be the response and which one is more likely to be the explanatory variable. A fifth significance test is proposed based on the differences of skewness estimates, which leads to a more direct test of a hypothesis that is compatible with direction of dependence. A Monte Carlo simulation study was performed to examine the behaviour of the procedures under various degrees of associations, sample sizes, and distributional properties of the underlying population. An empirical example is given which illustrates the application of the tests in practice.

  13. [The significance of activities in the Imperial Orthodox Palestine Society for progression of medicine in the Middle East (to the 130th anniversary of foundation)].

    Science.gov (United States)

    Gorelova, L Ye; Afanasiyeva, Ye A

    2012-01-01

    The article deals with the history of foundation of the Imperial Orthodox Palestine Society in Jerusalem and its input into progression of medicine in the Middle east. The medical activity of Russian physicians in medical institutions of the Society is reflected too.

  14. Progress in the Development of an Integrated Modeling Tool to Support DIII-D and EAST

    Science.gov (United States)

    Ren, Q.; Lao, L. L.; Chu, M. S.; St. John, H. E.; Abla, G.; Collier, A.; Prater, R.; Park, J. M.; Li, G.; Guo, W.; Pan, C.; Srinivasan, R.; Worrall, M.

    2009-11-01

    Recent progress in the development of the IMFIT Integrated modeling tool is presented. The goal of IMFIT is to develop a modern and efficient integrated modeling platform to support DIII-D and EAST research, including the capability to simulate the behavior of tokamak discharges. Recent progress includes user-friendly and Python-based GUIs with multi-links to equilibrium, transport, and stability codes to facilitate modeling and analysis, and EFIT F90 upgrade with dynamic memory allocation and MPI option to support multiple devices and grid sizes. Through the GUI, straightforward analysis for kinetic EFIT reconstruction is made available. Ongoing developments include design of efficient algorithms to support interactions among physics modules such as EFIT/ONETWO/TGLF coupling for scenario development and transport flux analysis and EFIT/PEST3/TORAY coupling for modeling of tearing mode stability. Details will be presented.

  15. Computing supersonic non-premixed turbulent combustion by an SMLD flamelet progress variable model

    CERN Document Server

    Coclite, A; Gurtner, M; De Palma, P; Haidnd, O J; Pascazio, G

    2015-01-01

    This paper describes the numerical simulation of the NASA Langley Research Center supersonic H2 -Air combustion chamber performed using two approaches to model the presumed probability density function (PDF) in the flamelet progress variable (FPV) framework. The first one is a standard FPV model, built presuming the functional shape of the PDFs of the mixture fraction, Z, and of the progress parameter, {\\Lambda}. In order to enhance the prediction capabilities of such a model in high-speed reacting flows, a second approach is proposed employing the statistically most likely distribution (SMLD) techcnique to presume the joint PDF of Z and {\\Lambda}, without any assumption about their behaviour. The standard and FPV-SMLD models have been developed using the low Mach number assumption. In both cases, the temperature is evaluated by solving the total-energy conservation equation, providing a more suitable approach for the simulation of supersonic combustion. By comparison with experimental data, the proposed SMLD...

  16. Time-dependent loss of mitochondrial function precedes progressive histologic cartilage degeneration in a rabbit meniscal destabilization model.

    Science.gov (United States)

    Goetz, Jessica E; Coleman, Mitchell C; Fredericks, Douglas C; Petersen, Emily; Martin, James A; McKinley, Todd O; Tochigi, Yuki

    2017-03-01

    The goals of this work were to characterize progression of osteoarthritic cartilage degeneration in a rabbit medial meniscus destabilization (MMD) model and then to use the model to identify pre-histologic disruptions in chondrocyte metabolism under chronically elevated joint contact stresses in vivo. To characterize PTOA progression, 24 rabbits received either MMD or sham surgery. Limb loading was analyzed preoperatively and at regular postoperative intervals using a Tekscan pressure-sensitive walkway. Animals were euthanized 8 (n = 8 MMD; n = 8 sham) or 26 weeks (n = 8 MMD) postoperatively for histological cartilage evaluation by an objective, semi-automated Mankin scoring routine. To examine pre-histologic pathology, MMD was performed on an additional 20 rabbits, euthanized 1 (n = 9) or 4 weeks (n = 10) postoperatively. Chondrocytes were harvested fresh for measurement of mitochondrial function, an intracellular indicator of pathology after mechanical injury. Both MMD and sham surgery caused slight decreases in limb loading which returned to preoperative levels after 2 weeks. Histologically apparent cartilage damage progressed from 8 to 26 weeks after MMD. Changes in chondrocyte respiration were variable at 1 week, but by 4 weeks postoperatively chondrocyte mitochondrial function was significantly reduced. Many human injuries that lead to PTOA are relatively mild, and the cell-level mechanisms leading to disease remain unclear. We have documented PTOA progression in an animal model of subtle joint injury under continued use, and demonstrated that this model provides a realistic environment for investigation of multi-stage cellular pathology that develops prior to overt tissue degeneration and which could be targeted for disease modifying treatments. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:590-599, 2017.

  17. Development of the PCAD Model to Assess Biological Significance of Acoustic Disturbance

    Science.gov (United States)

    2014-09-30

    Tyack, and J. Harwood. 2014. Using short-term measures of behaviour to estimate long-term fitness of southern elephant seals. Marine Ecology Progress...Rules for Categorizing Species’ Extinction Risk to Help Develop Quantitative Listing Criteria for the US Endangered Species Act. Conservation...Schwarz, S. E. Simmons, L. Thomas, P. Tyack, and J. Harwood. 2014. Using short-term measures of behaviour to estimate long-term fitness of southern

  18. Applying the Rule Space Model to Develop a Learning Progression for Thermochemistry

    Science.gov (United States)

    Chen, Fu; Zhang, Shanshan; Guo, Yanfang; Xin, Tao

    2016-11-01

    We used the Rule Space Model, a cognitive diagnostic model, to measure the learning progression for thermochemistry for senior high school students. We extracted five attributes and proposed their hierarchical relationships to model the construct of thermochemistry at four levels using a hypothesized learning progression. For this study, we developed 24 test items addressing the attributes of exothermic and endothermic reactions, chemical bonds and heat quantity change, reaction heat and enthalpy, thermochemical equations, and Hess's law. The test was administered to a sample base of 694 senior high school students taught in 3 schools across 2 cities. Results based on the Rule Space Model analysis indicated that (1) the test items developed by the Rule Space Model were of high psychometric quality for good analysis of difficulties, discriminations, reliabilities, and validities; (2) the Rule Space Model analysis classified the students into seven different attribute mastery patterns; and (3) the initial hypothesized learning progression was modified by the attribute mastery patterns and the learning paths to be more precise and detailed.

  19. 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.

  20. Forkhead box A3 attenuated the progression of fibrosis in a rat model of biliary atresia.

    Science.gov (United States)

    Dong, Rui; Yang, Yifan; Shen, Zhen; Zheng, Chao; Jin, Zhu; Huang, Yanlei; Zhang, Zhien; Zheng, Shan; Chen, Gong

    2017-03-30

    Biliary atresia is a rare, devastating disease of infants where a fibroinflammatory process destroys the bile ducts, leading to fibrosis and biliary cirrhosis, and death if untreated. The cause and pathogenesis remain largely unknown. We tried to investigate factors involved in biliary atresia, especially forkhead box A3 (Foxa3), which might exert a role in the treatment of liver disease. We used RNA sequencing to sequence the whole transcriptomes of livers from six biliary atresia and six choledochal cysts patients. Then, we employed a rat disease model by bile duct ligation (BDL) and adenovirus transduction to address the function of Foxa3 in biliary atresia. We found that tight junction, adherence junction, cell cycle, apoptosis, chemokine singling, VEGF and MAPK signaling pathways were enriched in biliary atresia livers. We showed that Foxa3 expression was notably decreased in liver samples from biliary atresia patients. More importantly, we found that its lower expression predicted a poorer overall survival of biliary atresia patients. Rats that received BDL surgery and Foxa3 expression adenovirus resulted in a significant decrease in the deposition of collagen, and expression of profibrotic cytokines (transforming growth factor-β and connective tissue growth factor) and fibrosis markers (α-smooth muscle actin, collagen I and collagen III), as compared with rats that received BDL surgery and control adenovirus. Our data suggested a protection role for Foxa3 during the progression of liver fibrosis in biliary atresia, and thereby supported increasing Foxa3 as a targeted treatment strategy.

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

    Directory of Open Access Journals (Sweden)

    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.

  2. Development of PIN and Prostate Adenocarcinoma Cell Lines: A Model System for Multistage Tumor Progression

    Directory of Open Access Journals (Sweden)

    Colin R. Soares

    2002-01-01

    Full Text Available Existing prostate cancer cell lines have been derived from late stages of human prostate cancer. In this paper, we present two cell lines generated from prostatic intraepithelial neoplasia (PIN, the precursor lesion for prostate adenocarcinoma. Pr-111 and Pr-117 were established from PIN lesions that developed in the C3(1/Tag transgenic model of prostate cancer. Pr-111 and Pr-117 cells express simian virus 40 large T antigen (SV40 Tag and are immortalized in culture, distinguishing them from normal prostate cells. The growth rates of these two cell lines are quite different; with Pr-111 cells growing much more slowly (doubling time approximately 40 hours compared to Pr-117 cells (doubling time approximately 22 hours, and also show significantly different growth rates in different media. Both prostate cell lines express cytokeratin and androgen receptor (AR with Pr-111 cells demonstrating androgen-dependent growth and Pr-117 cells exhibiting androgen-responsive growth characteristics. Athymic nude mice injected with Pr-111 cells either do not develop tumors or develop tumors after a long latency period of 14 weeks. Pr-117 cells, however, develop tumors by 3 to 6 weeks, suggesting that Pr-117 cells represent a later stage of tumor progression. These two novel cell lines will be useful for studying early stages of prostate tumor development and androgen responsiveness.

  3. Pharmacological kynurenine 3-monooxygenase enzyme inhibition significantly reduces neuropathic pain in a rat model.

    Science.gov (United States)

    Rojewska, Ewelina; Piotrowska, Anna; Makuch, Wioletta; Przewlocka, Barbara; Mika, Joanna

    2016-03-01

    Recent studies have highlighted the involvement of the kynurenine pathway in the pathology of neurodegenerative diseases, but the role of this system in neuropathic pain requires further extensive research. Therefore, the aim of our study was to examine the role of kynurenine 3-monooxygenase (Kmo), an enzyme that is important in this pathway, in a rat model of neuropathy after chronic constriction injury (CCI) to the sciatic nerve. For the first time, we demonstrated that the injury-induced increase in the Kmo mRNA levels in the spinal cord and the dorsal root ganglia (DRG) was reduced by chronic administration of the microglial inhibitor minocycline and that this effect paralleled a decrease in the intensity of neuropathy. Further, minocycline administration alleviated the lipopolysaccharide (LPS)-induced upregulation of Kmo mRNA expression in microglial cell cultures. Moreover, we demonstrated that not only indirect inhibition of Kmo using minocycline but also direct inhibition using Kmo inhibitors (Ro61-6048 and JM6) decreased neuropathic pain intensity on the third and the seventh days after CCI. Chronic Ro61-6048 administration diminished the protein levels of IBA-1, IL-6, IL-1beta and NOS2 in the spinal cord and/or the DRG. Both Kmo inhibitors potentiated the analgesic properties of morphine. In summary, our data suggest that in neuropathic pain model, inhibiting Kmo function significantly reduces pain symptoms and enhances the effectiveness of morphine. The results of our studies show that the kynurenine pathway is an important mediator of neuropathic pain pathology and indicate that Kmo represents a novel pharmacological target for the treatment of neuropathy.

  4. Cyclosporin A significantly improves preeclampsia signs and suppresses inflammation in a rat model.

    Science.gov (United States)

    Hu, Bihui; Yang, Jinying; Huang, Qian; Bao, Junjie; Brennecke, Shaun Patrick; Liu, Huishu

    2016-05-01

    Preeclampsia is associated with an increased inflammatory response. Immune suppression might be an effective treatment. The aim of this study was to examine whether Cyclosporin A (CsA), an immunosuppressant, improves clinical characteristics of preeclampsia and suppresses inflammation in a lipopolysaccharide (LPS) induced preeclampsia rat model. Pregnant rats were randomly divided into 4 groups: group 1 (PE) rats each received LPS via tail vein on gestational day (GD) 14; group 2 (PE+CsA5) rats were pretreated with LPS (1.0 μg/kg) on GD 14 and were then treated with CsA (5mg/kg, ip) on GDs 16, 17 and 18; group 3 (PE+CsA10) rats were pretreated with LPS (1.0 μg/kg) on GD 14 and were then treated with CsA (10mg/kg, ip) on GDs 16, 17 and 18; group 4 (pregnant control, PC) rats were treated with the vehicle (saline) used for groups 1, 2 and 3. Systolic blood pressure, urinary albumin, biometric parameters and the levels of serum cytokines were measured on day 20. CsA treatment significantly reduced LPS-induced systolic blood pressure and the mean 24-h urinary albumin excretion. Pro-inflammatory cytokines IL-6, IL-17, IFN-γ and TNF-α were increased in the LPS treatment group but were reduced in (LPS+CsA) group (PCyclosporine A improved preeclampsia signs and attenuated inflammatory responses in the LPS induced preeclampsia rat model which suggests that immunosuppressant might be an alternative management option for preeclampsia. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Prostate cancer risk and DNA damage: translational significance of selenium supplementation in a canine model.

    Science.gov (United States)

    Waters, David J; Shen, Shuren; Glickman, Lawrence T; Cooley, Dawn M; Bostwick, David G; Qian, Junqi; Combs, Gerald F; Morris, J Steven

    2005-07-01

    Daily supplementation with the essential trace mineral selenium significantly reduced prostate cancer risk in men in the Nutritional Prevention of Cancer Trial. However, the optimal intake of selenium for prostate cancer prevention is unknown. We hypothesized that selenium significantly regulates the extent of genotoxic damage within the aging prostate and that the relationship between dietary selenium intake and DNA damage is non-linear, i.e. more selenium is not necessarily better. To test this hypothesis, we conducted a randomized feeding trial in which 49 elderly beagle dogs (physiologically equivalent to 62-69-year-old men) received nutritionally adequate or supranutritional levels of selenium for 7 months, in order to mimic the range of dietary selenium intake of men in the United States. Our results demonstrate an intriguing U-shaped dose-response relationship between selenium status (toenail selenium concentration) and the extent of DNA damage (alkaline Comet assay) within the prostate. Further, we demonstrate that the concentration of selenium that minimizes DNA damage in the aging dog prostate remarkably parallels the selenium concentration in men that minimizes prostate cancer risk. By studying elderly dogs, the only non-human animal model of spontaneous prostate cancer, we have established a new approach to bridge the gap between laboratory and human studies that can be used to select the appropriate dose of anticancer agents for large-scale human cancer prevention trials. From the U-shaped dose-response, it follows that not all men will necessarily benefit from increasing their selenium intake and that measurement of baseline nutrient status should be required for all individuals in prevention trials to avoid oversupplementation.

  6. Kernel density surface modelling as a means to identify significant concentrations of vulnerable marine ecosystem indicators.

    Directory of Open Access Journals (Sweden)

    Ellen Kenchington

    Full Text Available The United Nations General Assembly Resolution 61/105, concerning sustainable fisheries in the marine ecosystem, calls for the protection of vulnerable marine ecosystems (VME from destructive fishing practices. Subsequently, the Food and Agriculture Organization (FAO produced guidelines for identification of VME indicator species/taxa to assist in the implementation of the resolution, but recommended the development of case-specific operational definitions for their application. We applied kernel density estimation (KDE to research vessel trawl survey data from inside the fishing footprint of the Northwest Atlantic Fisheries Organization (NAFO Regulatory Area in the high seas of the northwest Atlantic to create biomass density surfaces for four VME indicator taxa: large-sized sponges, sea pens, small and large gorgonian corals. These VME indicator taxa were identified previously by NAFO using the fragility, life history characteristics and structural complexity criteria presented by FAO, along with an evaluation of their recovery trajectories. KDE, a non-parametric neighbour-based smoothing function, has been used previously in ecology to identify hotspots, that is, areas of relatively high biomass/abundance. We present a novel approach of examining relative changes in area under polygons created from encircling successive biomass categories on the KDE surface to identify "significant concentrations" of biomass, which we equate to VMEs. This allows identification of the VMEs from the broader distribution of the species in the study area. We provide independent assessments of the VMEs so identified using underwater images, benthic sampling with other gear types (dredges, cores, and/or published species distribution models of probability of occurrence, as available. For each VME indicator taxon we provide a brief review of their ecological function which will be important in future assessments of significant adverse impact on these habitats here

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

    DEFF Research Database (Denmark)

    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 publishe...

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

    DEFF Research Database (Denmark)

    Ramin, Elham; Sin, Gürkan; Mikkelsen, Peter Steen;

    2014-01-01

    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...... 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...

  9. Modeling Methodology of Progressive Collapse by the Example of Real High-Rise Buildings

    Directory of Open Access Journals (Sweden)

    Mariya Barabash

    2014-12-01

    Full Text Available The purpose of the research was to find out several ways to design real buildings with protective measures against progressive collapse. There are no uniform guidelines for choosing the type of finite element able to provide the necessary accuracy of the calculation model taking into account all the main factors affecting the strength and stability of the building. Therefore it is required to develop numerical methods for calculation on progressive collapse of buildings bearing structural elements in case of emergency. In addition, our task was to present a methodology that allows checking the stability of the building agains progressive collapse. By the technique nonlinear analysis on special (emergency regulations combination of loads and impacts is performed, including permanent and long-term regulatory burden and the impact of hypothetical local fractures bearing structures. This study was carried out on the high rise apartment complex with underground parking. In the empirical part of the study the main concern was to find out the reasons of progressive collapse of structures, taking into account stepwise assembly, building inspection performed rollover. Also the existing building retail and office complex “Gulliver” with public facilities and parking is considered, where computation was made on the progressive collapse of the upper slab technical floor. The calculation was carried out on plates or emergency landing helicopter crash on the floor slab. Analysis of the results leads to the following conclusions. To assess the real vitality of the building in an emergency situation, and resistance to progressive collapse it is recommended to count design taking into account physical and geometric nonlinearity and process modeling lifecycle.

  10. 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.

  11. Folic acid supplementation promotes mammary tumor progression in a rat model.

    Science.gov (United States)

    Deghan Manshadi, Shaidah; Ishiguro, Lisa; Sohn, Kyoung-Jin; Medline, Alan; Renlund, Richard; Croxford, Ruth; Kim, Young-In

    2014-01-01

    Folic acid supplementation may prevent the development of cancer in normal tissues but may promote the progression of established (pre)neoplastic lesions. However, whether or not folic acid supplementation can promote the progression of established (pre)neoplastic mammary lesions is unknown. This is a critically important issue because breast cancer patients and survivors in North America are likely exposed to high levels of folic acid owing to folic acid fortification and widespread supplemental use after cancer diagnosis. We investigated whether folic acid supplementation can promote the progression of established mammary tumors. Female Sprague-Dawley rats were placed on a control diet and mammary tumors were initiated with 7,12-dimethylbenza[a]anthracene at puberty. When the sentinel tumor reached a predefined size, rats were randomized to receive a diet containing the control, 2.5x, 4x, or 5x supplemental levels of folic acid for up to 12 weeks. The sentinel mammary tumor growth was monitored weekly. At necropsy, the sentinel and all other mammary tumors were analyzed histologically. The effect of folic acid supplementation on the expression of proteins involved in proliferation, apoptosis, and mammary tumorigenesis was determined in representative sentinel adenocarcinomas. Although no clear dose-response relationship was observed, folic acid supplementation significantly promoted the progression of the sentinel mammary tumors and was associated with significantly higher sentinel mammary tumor weight and volume compared with the control diet. Furthermore, folic acid supplementation was associated with significantly higher weight and volume of all mammary tumors. The most significant and consistent mammary tumor-promoting effect was observed with the 2.5x supplemental level of folic acid. Folic acid supplementation was also associated with an increased expression of BAX, PARP, and HER2. Our data suggest that folic acid supplementation may promote the progression

  12. 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.

  13. High-fat diet induces significant metabolic disorders in a mouse model of polycystic ovary syndrome.

    Science.gov (United States)

    Lai, Hao; Jia, Xiao; Yu, Qiuxiao; Zhang, Chenglu; Qiao, Jie; Guan, Youfei; Kang, Jihong

    2014-11-01

    Polycystic ovary syndrome (PCOS) is the most common female endocrinopathy associated with both reproductive and metabolic disorders. Dehydroepiandrosterone (DHEA) is currently used to induce a PCOS mouse model. High-fat diet (HFD) has been shown to cause obesity and infertility in female mice. The possible effect of an HFD on the phenotype of DHEA-induced PCOS mice is unknown. The aim of the present study was to investigate both reproductive and metabolic features of DHEA-induced PCOS mice fed a normal chow or a 60% HFD. Prepubertal C57BL/6 mice (age 25 days) on the normal chow or an HFD were injected (s.c.) daily with the vehicle sesame oil or DHEA for 20 consecutive days. At the end of the experiment, both reproductive and metabolic characteristics were assessed. Our data show that an HFD did not affect the reproductive phenotype of DHEA-treated mice. The treatment of HFD, however, caused significant metabolic alterations in DHEA-treated mice, including obesity, glucose intolerance, dyslipidemia, and pronounced liver steatosis. These findings suggest that HFD induces distinct metabolic features in DHEA-induced PCOS mice. The combined DHEA and HFD treatment may thus serve as a means of studying the mechanisms involved in metabolic derangements of this syndrome, particularly in the high prevalence of hepatic steatosis in women with PCOS.

  14. 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

  15. Progress in marine ecosystem modelling and the “unreasonable effectiveness of mathematics”

    Science.gov (United States)

    Anderson, Thomas R.

    2010-04-01

    Modelling methodology, it is argued, is primarily about providing explanations of data which, if sufficiently convincing, provide a basis for prediction and forecasting. Models allow us to synthesise our knowledge and explore its ramifications, leading to insight and discovery. As such, modelling is invaluable to the progress of marine science, the development and implementation of ever more complex models moving in tandem with our expanding knowledge base. It is possible to argue, however, that mathematics can be "unreasonably effective" at describing phenomena, particularly for complex models where there are often many free parameters to tune against limited data. Errors become difficult to pinpoint and correct, and creativity may be stifled as models become entrenched within the prevailing paradigm. Indiscriminately adding layer upon layer of complexity in models may therefore be counter productive, particularly if prediction of future scenarios such as changing climate is the ultimate goal. The inclusion of additional complexity in models is nevertheless desirable, where relevant and practicable. New modelling approaches that are coming to the fore likely hold the key to future progress such as targeting complexity in key species and trophic levels, adaptive parameterisations and the representation of physiological trade-offs, providing the potential to simulate emergent community structure.

  16. Mucin (Muc expression during pancreatic cancer progression in spontaneous mouse model: potential implications for diagnosis and therapy

    Directory of Open Access Journals (Sweden)

    Rachagani Satyanarayana

    2012-10-01

    Full Text Available Abstract Background Pancreatic cancer (PC is a lethal malignancy primarily driven by activated Kras mutations and characterized by the deregulation of several genes including mucins. Previous studies on mucins have identified their significant role in both benign and malignant human diseases including PC progression and metastasis. However, the initiation of MUC expression during PC remains unknown because of lack of early stage tumor tissues from PC patients. Methods In the present study, we have evaluated stage specific expression patterns of mucins during mouse PC progression in (KrasG12D;Pdx1-Cre (KC murine PC model from pancreatic intraepithelial neoplasia (PanIN to pancreatic ductal adenocarcinoma (PDAC by immunohistochemistry and quantitative real-time PCR. Results In agreement with previous studies on human PC, we observed a progressive increase in the expression of mucins particularly Muc1, Muc4 and Muc5AC in the pancreas of KC (as early as PanIN I mice with advancement of PanIN lesions and PDAC both at mRNA and protein levels. Additionally, mucin expression correlated with the increased expression of inflammatory cytokines IFN-γ (p CXCL1 (p CXCL2 (p  Conclusions Our study reinforces the potential utility of the KC murine model for determining the functional role of mucins in PC pathogenesis by crossing KC mice with corresponding mucin knockout mice and evaluating mucin based diagnostic and therapeutic approaches for lethal PC.

  17. Progressive brain damage, synaptic reorganization and NMDA activation in a model of epileptogenic cortical dysplasia.

    Directory of Open Access Journals (Sweden)

    Francesca Colciaghi

    Full Text Available Whether severe epilepsy could be a progressive disorder remains as yet unresolved. We previously demonstrated in a rat model of acquired focal cortical dysplasia, the methylazoxymethanol/pilocarpine - MAM/pilocarpine - rats, that the occurrence of status epilepticus (SE and subsequent seizures fostered a pathologic process capable of modifying the morphology of cortical pyramidal neurons and NMDA receptor expression/localization. We have here extended our analysis by evaluating neocortical and hippocampal changes in MAM/pilocarpine rats at different epilepsy stages, from few days after onset up to six months of chronic epilepsy. Our findings indicate that the process triggered by SE and subsequent seizures in the malformed brain i is steadily progressive, deeply altering neocortical and hippocampal morphology, with atrophy of neocortex and CA regions and progressive increase of granule cell layer dispersion; ii changes dramatically the fine morphology of neurons in neocortex and hippocampus, by increasing cell size and decreasing both dendrite arborization and spine density; iii induces reorganization of glutamatergic and GABAergic networks in both neocortex and hippocampus, favoring excitatory vs inhibitory input; iv activates NMDA regulatory subunits. Taken together, our data indicate that, at least in experimental models of brain malformations, severe seizure activity, i.e., SE plus recurrent seizures, may lead to a widespread, steadily progressive architectural, neuronal and synaptic reorganization in the brain. They also suggest the mechanistic relevance of glutamate/NMDA hyper-activation in the seizure-related brain pathologic plasticity.

  18. 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.

  19. Significance of model credibility in estimating climate projection distributions for regional hydroclimatological risk assessments

    Science.gov (United States)

    Brekke, L.D.; Dettinger, M.D.; Maurer, E.P.; Anderson, M.

    2008-01-01

    Ensembles of historical climate simulations and climate projections from the World Climate Research Programme's (WCRP's) Coupled Model Intercomparison Project phase 3 (CMIP3) multi-model dataset were investigated to determine how model credibility affects apparent relative scenario likelihoods in regional risk assessments. Methods were developed and applied in a Northern California case study. An ensemble of 59 twentieth century climate simulations from 17 WCRP CMIP3 models was analyzed to evaluate relative model credibility associated with a 75-member projection ensemble from the same 17 models. Credibility was assessed based on how models realistically reproduced selected statistics of historical climate relevant to California climatology. Metrics of this credibility were used to derive relative model weights leading to weight-threshold culling of models contributing to the projection ensemble. Density functions were then estimated for two projected quantities (temperature and precipitation), with and without considering credibility-based ensemble reductions. An analysis for Northern California showed that, while some models seem more capable at recreating limited aspects twentieth century climate, the overall tendency is for comparable model performance when several credibility measures are combined. Use of these metrics to decide which models to include in density function development led to local adjustments to function shapes, but led to limited affect on breadth and central tendency, which were found to be more influenced by 'completeness' of the original ensemble in terms of models and emissions pathways. ?? 2007 Springer Science+Business Media B.V.

  20. More Use of Peritoneal Dialysis Gives Significant Savings: A Systematic Review and Health Economic Decision Model

    Science.gov (United States)

    Pike, Eva; Hamidi, Vida; Ringerike, Tove; Wisloff, Torbjorn; Klemp, Marianne

    2017-01-01

    Background Patients with end-stage renal disease (ESRD) are in need of renal replacement therapy as dialysis and/or transplantation. The prevalence of ESRD and, thus, the need for dialysis are constantly growing. The dialysis modalities are either peritoneal performed at home or hemodialysis (HD) performed in-center (hospital or satellite) or home. We examined effectiveness and cost-effectiveness of HD performed at different locations (hospital, satellite, and home) and peritoneal dialysis (PD) at home in the Norwegian setting. Methods We conducted a systematic review for patients above 18 years with end-stage renal failure requiring dialysis in several databases and performed several meta-analyses of existing literature. Mortality and major complications that required were our main clinical outcomes. The quality of the evidence for each outcome was evaluated using GRADE. Cost-effectiveness was assessed by developing a probabilistic Markov model. The analysis was carried out from a societal perspective, and effects were expressed in quality-adjusted life-years. Uncertainties in the base-case parameter values were explored with a probabilistic sensitivity analysis. Scenario analyses were conducted by increasing the proportion of patients receiving PD with a corresponding reduction in HD patients in-center both for Norway and Europian Union. We assumed an annual growth rate of 4% in the number of dialysis patients, and a relative distribution between PD and HD in-center of 30% and 70%, respectively. Results From a societal perspective and over a 5-year time horizon, PD was the most cost-effective dialysis alternative. We found no significant difference in mortality between peritoneal and HD modalities. Our scenario analyses showed that a shift toward more patients on PD (as a first choice) with a corresponding reduction in HD in-center gave a saving over a 5-year period of 32 and 10,623 million EURO, respectively, for Norway and the European Union. Conclusions PD was

  1. Significant impacts of irrigation water sources and methods on modeling irrigation effects in the ACME Land Model

    Energy Technology Data Exchange (ETDEWEB)

    Leng, Guoyong; Leung, Lai-Yung; Huang, Maoyi

    2017-07-01

    An irrigation module that considers both irrigation water sources and irrigation methods has been incorporated into the ACME Land Model (ALM). Global numerical experiments were conducted to evaluate the impacts of irrigation water sources and irrigation methods on the simulated irrigation effects. All simulations shared the same irrigation soil moisture target constrained by a global census dataset of irrigation amounts. Irrigation has large impacts on terrestrial water balances especially in regions with extensive irrigation. Such effects depend on the irrigation water sources: surface-water-fed irrigation leads to decreases in runoff and water table depth, while groundwater-fed irrigation increases water table depth, with positive or negative effects on runoff depending on the pumping intensity. Irrigation effects also depend significantly on the irrigation methods. Flood irrigation applies water in large volumes within short durations, resulting in much larger impacts on runoff and water table depth than drip and sprinkler irrigations. Differentiating the irrigation water sources and methods is important not only for representing the distinct pathways of how irrigation influences the terrestrial water balances, but also for estimating irrigation water use efficiency. Specifically, groundwater pumping has lower irrigation water use efficiency due to enhanced recharge rates. Different irrigation methods also affect water use efficiency, with drip irrigation the most efficient followed by sprinkler and flood irrigation. Our results highlight the importance of explicitly accounting for irrigation sources and irrigation methods, which are the least understood and constrained aspects in modeling irrigation water demand, water scarcity and irrigation effects in Earth System Models.

  2. Strength evolution law of cracked rock based on localized progressive damage model

    Institute of Scientific and Technical Information of China (English)

    ZHANG Ping; LI Xi-bing; LI Ning

    2008-01-01

    In the light of the localized progressive damage model, the evolution law of cohesive and frictional strength with irreversible strains was determined. Then, the location and the extent of the excavation disturbed zone in one deep rock engineering were predicted by using the strength evolution law. The theoretical result is close to the result of in-situ test. The strength evolution law excels the elastic-perfectly plastic model and elasto-brittte plastic model in which the cohesive and frictional strength are mobilized simultaneously. The results obtained indicate that the essential failure mechanism of the cracked rock can be described by the cohesion weakening and friction strengthening evolution law.

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

    Directory of Open Access Journals (Sweden)

    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.

  4. An estrogen-induced endometrial hyperplasia mouse model recapitulating human disease progression and genetic aberrations.

    Science.gov (United States)

    Yang, Chieh-Hsiang; Almomen, Aliyah; Wee, Yin Shen; Jarboe, Elke A; Peterson, C Matthew; Janát-Amsbury, Margit M

    2015-07-01

    Endometrial hyperplasia (EH) is a condition originating from uterine endometrial glands undergoing disordered proliferation including the risk to progress to endometrial adenocarcinoma. In recent years, a steady increase in EH cases among younger women of reproductive age accentuates the demand of therapeutic alternatives, which emphasizes that an improved disease model for therapeutic agents evaluation is concurrently desired. Here, a new hormone-induced EH mouse model was developed using a subcutaneous estradiol (E2)-sustained releasing pellet, which elevates the serum E2 level in mice, closely mimicking the effect known as estrogen dominance with underlying, pathological E2 levels in patients. The onset and progression of EH generated within this model recapitulate a clinically relevant, pathological transformation, beginning with disordered proliferation developing to simple EH, advancing to atypical EH, and then progressing to precancerous stages, all following a chronologic manner. Although a general increase in nuclear progesterone receptor (PR) expression occurred after E2 expression, a total loss in PR was noted in some endometrial glands as disease advanced to simple EH. Furthermore, estrogen receptor (ER) expression in the nucleus of endometrial cells was reduced in disordered proliferation and increased when EH progressed to atypical EH and precancerous stages. This EH model also resembles other pathological patterns found in human disease such as leukocytic infiltration, genetic aberrations in β-catenin, and joint phosphatase and tensin homolog/paired box gene 2 (PTEN/PAX2) silencing. In summary, this new and comprehensively characterized EH model is cost-effective, easily reproducible, and may serve as a tool for preclinical testing of therapeutic agents and facilitate further investigation of EH.

  5. Predicting recurrence and progression of non-muscle-invasive bladder cancer in Korean patients: a comparison of the EORTC and CUETO models.

    Science.gov (United States)

    Choi, Se Young; Ryu, Jae Hyung; Chang, In Ho; Kim, Tae-Hyoung; Myung, Soon Chul; Moon, Young Tae; Kim, Kyung Do; Kim, Jin Wook

    2014-10-01

    This study aimed to confirm the utility of the European Organization for Research and Treatment of Cancer (EORTC) and the Spanish Urological Club for Oncological Treatment (CUETO) scoring systems and to determine which model is preferred as a prognostic model in Korean patients with non-muscle-invasive bladder cancer. Between 1985 and 2011, 531 patients who were treated by transurethral resection of bladder cancer were retrospectively analyzed by use of the EORTC and CUETO models. Statistically, we performed Kaplan-Meier survival analysis; calculated Harrell's concordance index, receiver operating characteristic (ROC) curve, and cutoff values; and performed univariate and multivariate Cox proportional hazards regression analyses. For risk of recurrence, with the use of the EORTC model, all groups had statistically significant differences except between the group with a score of 0 and the group with a score of 1-4. With the use of the CUETO model, all groups differed significantly. For risk of progression, with the use of the EORTC model, significant differences were observed between all groups except between the group with a score of 2-6 and the group with a score of 7-13. With the use of the CUETO model, a significant difference was observed between the group with a score of 0 and the other groups. The concordance index of the EORTC and CUETO models was 0.759 and 0.836 for recurrence and 0.704 and 0.745 for progression, respectively. The area under the ROC curve for the EORTC and CUETO models was 0.832 and 0.894 for recurrence and 0.722 and 0.724 for progression, respectively. Both scoring systems, especially the CUETO model, showed value in predicting recurrence and progression in Korean patients, which will help in individualizing treatment and follow-up schedules.

  6. Timing of progression from Chlamydia trachomatis infection to pelvic inflammatory disease: a mathematical modelling study

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    Herzog Sereina A

    2012-08-01

    Full Text Available Abstract Background Pelvic inflammatory disease (PID results from the ascending spread of microorganisms from the vagina and endocervix to the upper genital tract. PID can lead to infertility, ectopic pregnancy and chronic pelvic pain. The timing of development of PID after the sexually transmitted bacterial infection Chlamydia trachomatis (chlamydia might affect the impact of screening interventions, but is currently unknown. This study investigates three hypothetical processes for the timing of progression: at the start, at the end, or throughout the duration of chlamydia infection. Methods We develop a compartmental model that describes the trial structure of a published randomised controlled trial (RCT and allows each of the three processes to be examined using the same model structure. The RCT estimated the effect of a single chlamydia screening test on the cumulative incidence of PID up to one year later. The fraction of chlamydia infected women who progress to PID is obtained for each hypothetical process by the maximum likelihood method using the results of the RCT. Results The predicted cumulative incidence of PID cases from all causes after one year depends on the fraction of chlamydia infected women that progresses to PID and on the type of progression. Progression at a constant rate from a chlamydia infection to PID or at the end of the infection was compatible with the findings of the RCT. The corresponding estimated fraction of chlamydia infected women that develops PID is 10% (95% confidence interval 7-13% in both processes. Conclusions The findings of this study suggest that clinical PID can occur throughout the course of a chlamydia infection, which will leave a window of opportunity for screening to prevent PID.

  7. Policy Decisions for a Price Dependent Demand Rate Inventory Model with Progressive Payments Scheme

    OpenAIRE

    Rajat Kumar; Mukesh Kumar

    2012-01-01

    Problem statement: In this proposed research, we developed an inventory model to formulate an optimal ordering policies for supplier who offers progressive permissible delay periods to the retailer to settle his/her account. We assumed that the annual demand rate as a decreasing function of price with constant rate of deterioration and time-varying holding cost. Shortages in inventory are allowed which is completely backlogged. Approach: The main objective of this study to frame an inventory ...

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

    OpenAIRE

    Milad, Mohammed R.; Quirk, Gregory J

    2012-01-01

    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 neuroscien...

  9. 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

  10. [The natural history of cervical intraepithelial neoplasia I and the clinical significance of p16(INK4a) protein as a marker of progression in cervical intraepithelial neoplasia I].

    Science.gov (United States)

    Wang, Rongmin; Li, Xuejie; Qian, Min; Niu, Jianghua; You, Zhixue

    2015-03-01

    To describe the natural history of cervical intraepithelial neoplasia (CIN) I and the biologic factors associated with the progression of CIN I and to analyze the predictive values of p16(INK4a) protein for the progression of CIN I. From August 2010 to July 2013, 104 patients referred for abnormal cytology [≤ low-grade squamous intraepithelial lesion (LSIL); including negative for intraepithelial lesion or malignancy (NILM), atypical squamous cells of undetermined significance (ASCUS), LSIL] and high-risk (HR) HPV positive, and were diagnosed CIN I by colposcopy-assisted biopsy and followed at 1-year intervals in the First Affiliated Hospital of Nanjing Medical University. In order to analyze the relationship between the progression of CIN I with clinical biologic factors, including patient age, cervical cytology before colposcopy, loads of HR HPV, HPV L1 capsid protein, p16(INK4a) protein, χ(2) tests was used to compare the different frequencies of factors in groups of progressed and persisted/regressed CIN I, then five factors with progressed CIN I were processed into binary logistic regression analysis. (1) In the first year of follow-up, among 104 patients (including 15 cases NILM, 78 cases ASCUS, 11 cases LSIL), 52 cases of them were NILM and HR HPV negative, 30 cases were negative for intraepithelial lesion, 10 cases were CIN I, 5 cases were CIN II and 7 cases were CIN III. In total, 82 cases (78.8%, 82/104) cases had regressed, 10 cases (9.6%, 10/104) persisted, 12 cases (11.5%, 12/104) progressed [including 5 cases (4.8% , 5/104) progressed to CIN II, 7 cases (6.7% , 7/104) progressed to CIN III, none progressed to invasive cancer]. (2) All patients, 88 cases of them accepted immunohistochemical detection the expression of p16(INK4a) protein. The result shown that 30 cases (34%, 30/88) were positive and 58 cases (66%, 58/88) were negative. And 94 cases accepted immunocytochemical detection the expression of HPV L1 capsid protein, 49 cases (52% , 49

  11. Cancer progression mediated by horizontal gene transfer in an in vivo model.

    Directory of Open Access Journals (Sweden)

    Catalina Trejo-Becerril

    Full Text Available It is known that cancer progresses by vertical gene transfer, but this paradigm ignores that DNA circulates in higher organisms and that it is biologically active upon its uptake by recipient cells. Here we confirm previous observations on the ability of cell-free DNA to induce in vitro cell transformation and tumorigenesis by treating NIH3T3 recipient murine cells with serum of colon cancer patients and supernatant of SW480 human cancer cells. Cell transformation and tumorigenesis of recipient cells did not occur if serum and supernatants were depleted of DNA. It is also demonstrated that horizontal cancer progression mediated by circulating DNA occurs via its uptake by recipient cells in an in vivo model where immunocompetent rats subjected to colon carcinogenesis with 1,2-dimethylhydrazine had increased rate of colonic tumors when injected in the dorsum with human SW480 colon carcinoma cells as a source of circulating oncogenic DNA, which could be offset by treating these animals with DNAse I and proteases. Though the contribution of biologically active molecules other than DNA for this phenomenon to occur cannot be ruled out, our results support the fact that cancer cells emit into the circulation biologically active DNA to foster tumor progression. Further exploration of the horizontal tumor progression phenomenon mediated by circulating DNA is clearly needed to determine whether its manipulation could have a role in cancer therapy.

  12. IVUS-based FSI models for human coronary plaque progression study: components, correlation and predictive analysis.

    Science.gov (United States)

    Wang, Liang; Wu, Zheyang; Yang, Chun; Zheng, Jie; Bach, Richard; Muccigrosso, David; Billiar, Kristen; Maehara, Akiko; Mintz, Gary S; Tang, Dalin

    2015-01-01

    Atherosclerotic plaque progression is believed to be associated with mechanical stress conditions. Patient follow-up in vivo intravascular ultrasound coronary plaque data were acquired to construct fluid-structure interaction (FSI) models with cyclic bending to obtain flow wall shear stress (WSS), plaque wall stress (PWS) and strain (PWSn) data and investigate correlations between plaque progression measured by wall thickness increase (WTI), cap thickness increase (CTI), lipid depth increase (LDI) and risk factors including wall thickness (WT), WSS, PWS, and PWSn. Quarter average values (n = 178-1016) of morphological and mechanical factors from all slices were obtained for analysis. A predictive method was introduced to assess prediction accuracy of risk factors and identify the optimal predictor(s) for plaque progression. A combination of WT and PWS was identified as the best predictor for plaque progression measured by WTI. Plaque WT had best overall correlation with WTI (r = -0.7363, p WTI: (r = -0.3208, p < 1E-10); cap thickness: (r = 0.4541, p < 1E-10); CTI: (r = -0.1719, p = 0.0190); LD: (r = -0.2206, p < 1E-10); LDI: r = 0.1775, p < 0.0001). WSS had mixed correlation results.

  13. Cancer Progression Mediated by Horizontal Gene Transfer in an In Vivo Model

    Science.gov (United States)

    Trejo-Becerril, Catalina; Pérez-Cárdenas, Enrique; Taja-Chayeb, Lucía; Anker, Philippe; Herrera-Goepfert, Roberto; Medina-Velázquez, Luis A.; Hidalgo-Miranda, Alfredo; Pérez-Montiel, Delia; Chávez-Blanco, Alma; Cruz-Velázquez, Judith; Díaz-Chávez, José; Gaxiola, Miguel; Dueñas-González, Alfonso

    2012-01-01

    It is known that cancer progresses by vertical gene transfer, but this paradigm ignores that DNA circulates in higher organisms and that it is biologically active upon its uptake by recipient cells. Here we confirm previous observations on the ability of cell-free DNA to induce in vitro cell transformation and tumorigenesis by treating NIH3T3 recipient murine cells with serum of colon cancer patients and supernatant of SW480 human cancer cells. Cell transformation and tumorigenesis of recipient cells did not occur if serum and supernatants were depleted of DNA. It is also demonstrated that horizontal cancer progression mediated by circulating DNA occurs via its uptake by recipient cells in an in vivo model where immunocompetent rats subjected to colon carcinogenesis with 1,2-dimethylhydrazine had increased rate of colonic tumors when injected in the dorsum with human SW480 colon carcinoma cells as a source of circulating oncogenic DNA, which could be offset by treating these animals with DNAse I and proteases. Though the contribution of biologically active molecules other than DNA for this phenomenon to occur cannot be ruled out, our results support the fact that cancer cells emit into the circulation biologically active DNA to foster tumor progression. Further exploration of the horizontal tumor progression phenomenon mediated by circulating DNA is clearly needed to determine whether its manipulation could have a role in cancer therapy. PMID:23285175

  14. CLINICAL-SIGNIFICANCE OF INTERLEUKIN-6 MEASUREMENT IN EARLY RHEUMATOID-ARTHRITIS - RELATION WITH LABORATORY AND CLINICAL-VARIABLES AND RADIOLOGICAL PROGRESSION IN A 3 YEAR PROSPECTIVE-STUDY

    NARCIS (Netherlands)

    VANLEEUWEN, MA; WESTRA, J; LIMBURG, PC; VANRIEL, PLCM; VANRIJSWIJK, MH

    1995-01-01

    Objective-To evaluate the clinical significance of interleukin-6 (IL-6) measurements in relation to laboratory and clinical measures of disease activity and radiological progression in early rheumatoid arthritis (RA). Methods-A Irrespective study was performed in 51 patients with early RA during the

  15. Progress toward the Determination of Complete Vertex Operators for The IIB Matrix Model

    CERN Document Server

    Kitazawa, Y; Saito, O; Kitazawa, Yoshihisa; Mizoguchi, Shun'ya; Saito, Osamu

    2006-01-01

    We report on progress in determining the complete form of vertex operators for the IIB matrix model. The exact expressions are obtained for those emitting massless IIB supergravity fields up to sixth order in the light-cone superfield, in which the conjugate gravitino and conjugate two-form vertex operators are newly determined. We also provide a consistency check by computing the kinematical factor of a four-point graviton amplitude in a D-instanton background. We conjecture that the low-energy effective action of the IIB matrix model at large N is given by tree-level supergravity coupled to the vertex operators.

  16. User-defined Material Model for Thermo-mechanical Progressive Failure Analysis

    Science.gov (United States)

    Knight, Norman F., Jr.

    2008-01-01

    Previously a user-defined material model for orthotropic bimodulus materials was developed for linear and nonlinear stress analysis of composite structures using either shell or solid finite elements within a nonlinear finite element analysis tool. Extensions of this user-defined material model to thermo-mechanical progressive failure analysis are described, and the required input data are documented. The extensions include providing for temperature-dependent material properties, archival of the elastic strains, and a thermal strain calculation for materials exhibiting a stress-free temperature.

  17. Innovations in individual feature history management - The significance of feature-based temporal model

    Science.gov (United States)

    Choi, J.; Seong, J.C.; Kim, B.; Usery, E.L.

    2008-01-01

    A feature relies on three dimensions (space, theme, and time) for its representation. Even though spatiotemporal models have been proposed, they have principally focused on the spatial changes of a feature. In this paper, a feature-based temporal model is proposed to represent the changes of both space and theme independently. The proposed model modifies the ISO's temporal schema and adds new explicit temporal relationship structure that stores temporal topological relationship with the ISO's temporal primitives of a feature in order to keep track feature history. The explicit temporal relationship can enhance query performance on feature history by removing topological comparison during query process. Further, a prototype system has been developed to test a proposed feature-based temporal model by querying land parcel history in Athens, Georgia. The result of temporal query on individual feature history shows the efficiency of the explicit temporal relationship structure. ?? Springer Science+Business Media, LLC 2007.

  18. Significance of hydrological model choice and land use changes when doing climate change impact assessment

    Science.gov (United States)

    Bjørnholt Karlsson, Ida; Obel Sonnenborg, Torben; Refsgaard, Jens Christian; Høgh Jensen, Karsten

    2014-05-01

    Uncertainty in impact studies arises both from Global Climate Models (GCM), emission projections, statistical downscaling, Regional Climate Models (RCM), hydrological models and calibration techniques (Refsgaard et al. 2013). Some of these uncertainties have been evaluated several times in the literature; however few studies have investigated the effect of hydrological model choice on the assessment results (Boorman & Sefton 1997; Jiang et al. 2007; Bastola et al. 2011). These studies have found that model choice results in large differences, up to 70%, in the predicted discharge changes depending on the climate input. The objective of the study is to investigate the impact of climate change on hydrology of the Odense catchment, Denmark both in response to (a) different climate projections (GCM-RCM combinations); (b) different hydrological models and (c) different land use scenarios. This includes: 1. Separation of the climate model signal; the hydrological model signal and the land use signal 2. How do the different hydrological components react under different climate and land use conditions for the different models 3. What land use scenario seems to provide the best adaptation for the challenges of the different future climate change scenarios from a hydrological perspective? Four climate models from the ENSEMBLES project (Hewitt & Griggs 2004): ECHAM5 - HIRHAM5, ECHAM5 - RCA3, ARPEGE - RM5.1 and HadCM3 - HadRM3 are used, assessing the climate change impact in three periods: 1991-2010 (present), 2041-2060 (near future) and 2081-2100 (far future). The four climate models are used in combination with three hydrological models with different conceptual layout: NAM, SWAT and MIKE SHE. Bastola, S., C. Murphy and J. Sweeney (2011). "The role of hydrological modelling uncertainties in climate change impact assessments of Irish river catchments." Advances in Water Resources 34: 562-576. Boorman, D. B. and C. E. M. Sefton (1997). "Recognising the uncertainty in the

  19. Kinetics of disease progression and host response in a rat model of bubonic plague.

    Science.gov (United States)

    Sebbane, Florent; Gardner, Donald; Long, Daniel; Gowen, Brian B; Hinnebusch, B Joseph

    2005-05-01

    Plague, caused by the gram-negative bacterium Yersinia pestis, primarily affects rodents but is also an important zoonotic disease of humans. Bubonic plague in humans follows transmission by infected fleas and is characterized by an acute, necrotizing lymphadenitis in the regional lymph nodes that drain the intradermal flea bite site. Septicemia rapidly follows with spread to spleen, liver, and other organs. We developed a model of bubonic plague using the inbred Brown Norway strain of Rattus norvegicus to characterize the progression and kinetics of infection and the host immune response after intradermal inoculation of Y. pestis. The clinical signs and pathology in the rat closely resembled descriptions of human bubonic plague. The bacteriology; histopathology; host cellular response in infected lymph nodes, blood, and spleen; and serum cytokine levels were analyzed at various times after infection to determine the kinetics and route of disease progression and to evaluate hypothesized Y. pestis pathogenic mechanisms. Understanding disease progression in this rat infection model should facilitate further investigations into the molecular pathogenesis of bubonic plague and the immune response to Y. pestis at different stages of the disease.

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

    Science.gov (United States)

    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.

  1. Three-dimensional cultures modeling premalignant progression of human breast epithelial cells: role of cysteine cathepsins

    Science.gov (United States)

    Mullins, Stefanie R.; Sameni, Mansoureh; Blum, Galia; Bogyo, Matthew; Sloane, Bonnie F.; Moin, Kamiar

    2013-01-01

    The expression of the cysteine protease cathepsin B is increased in early stages of human breast cancer. To assess the potential role of cathepsin B in premalignant progression of breast epithelial cells, we employed a 3D reconstituted basement membrane overlay culture model of MCF10A human breast epithelial cells and isogenic variants that replicate the in vivo phenotypes of hyperplasia (MCF10AneoT) and atypical hyperplasia (MCF10AT1). MCF10A cells developed into polarized acinar structures with central lumens. In contrast, MCF10AneoT and MCF10AT1 cells form larger structures in which the lumens are filled with cells. CA074Me, a cell-permeable inhibitor selective for the cysteine cathepsins B and L, reduced proliferation and increased apoptosis of MCF10A, MCF10AneoT and MCF10AT1 cells in 3D culture. We detected active cysteine cathepsins in the isogenic MCF10 variants in 3D culture with GB111, a cell-permeable activity-based probe, and established differential inhibition of cathepsin B in our 3D cultures. We conclude that cathepsin B promotes proliferation and premalignant progression of breast epithelial cells. These findings are consistent with studies by others showing that deletion of cathepsin B in the transgenic MMTV-PyMT mice, a murine model that is predisposed to development of mammary cancer, reduces malignant progression. PMID:23667900

  2. Humanized mouse model of ovarian cancer recapitulates patient solid tumor progression, ascites formation, and metastasis.

    Directory of Open Access Journals (Sweden)

    Richard B Bankert

    Full Text Available Ovarian cancer is the most common cause of death from gynecological cancer. Understanding the biology of this disease, particularly how tumor-associated lymphocytes and fibroblasts contribute to the progression and metastasis of the tumor, has been impeded by the lack of a suitable tumor xenograft model. We report a simple and reproducible system in which the tumor and tumor stroma are successfully engrafted into NOD-scid IL2Rγ(null (NSG mice. This is achieved by injecting tumor cell aggregates derived from fresh ovarian tumor biopsy tissues (including tumor cells, and tumor-associated lymphocytes and fibroblasts i.p. into NSG mice. Tumor progression in these mice closely parallels many of the events that are observed in ovarian cancer patients. Tumors establish in the omentum, ovaries, liver, spleen, uterus, and pancreas. Tumor growth is initially very slow and progressive within the peritoneal cavity with an ultimate development of tumor ascites, spontaneous metastasis to the lung, increasing serum and ascites levels of CA125, and the retention of tumor-associated human fibroblasts and lymphocytes that remain functional and responsive to cytokines for prolonged periods. With this model one will be able to determine how fibroblasts and lymphocytes within the tumor microenvironment may contribute to tumor growth and metastasis, and will make it possible to evaluate the efficacy of therapies that are designed to target these cells in the tumor stroma.

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

    Directory of Open Access Journals (Sweden)

    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.

  4. Significance of uncertainties derived from settling tank model structure and parameters on predicting WWTP performance - A global sensitivity analysis study

    DEFF Research Database (Denmark)

    Ramin, Elham; Sin, Gürkan; Mikkelsen, Peter Steen

    2011-01-01

    Uncertainty derived from one of the process models – such as one-dimensional secondary settling tank (SST) models – can impact the output of the other process models, e.g., biokinetic (ASM1), as well as the integrated wastewater treatment plant (WWTP) models. The model structure and parameter...... uncertainty of settler models can therefore propagate, and add to the uncertainties in prediction of any plant performance criteria. Here we present an assessment of the relative significance of secondary settling model performance in WWTP simulations. We perform a global sensitivity analysis (GSA) based....... The outcome of this study contributes to a better understanding of uncertainty in WWTPs, and explicitly demonstrates the significance of secondary settling processes that are crucial elements of model prediction under dry and wet-weather loading conditions....

  5. Numerical modelling of the effect of weathering on the progressive failure of underground limestone mines

    CERN Document Server

    Ghabezloo, Siavash

    2008-01-01

    The observations show that the collapse of underground limestone mines results from a progressive failure due to gradual weathering of the rockmass. The following stages can be considered for the limestone weathering and degradation process in underground mines: condensation of the water on the roof of the gallery, infiltration of water in the porous rock, migration of the air CO2 molecules in the rock pore water by convection and molecular diffusion, dissolution of limestone by CO2 rich water and consequently, reduction of the strength properties of rock. Considering this process, a set of equations governing different hydrochemo-mechanical aspects of the weathering phenomenon and progressive failure occurring in these mines is presented. Then the feasibility of numerical modelling of this process is studied and a simple example of application is presented.

  6. Significantly improved HIV inhibitor efficacy prediction employing proteochemometric models generated from antivirogram data.

    Directory of Open Access Journals (Sweden)

    Gerard J P van Westen

    Full Text Available Infection with HIV cannot currently be cured; however it can be controlled by combination treatment with multiple anti-retroviral drugs. Given different viral genotypes for virtually each individual patient, the question now arises which drug combination to use to achieve effective treatment. With the availability of viral genotypic data and clinical phenotypic data, it has become possible to create computational models able to predict an optimal treatment regimen for an individual patient. Current models are based only on sequence data derived from viral genotyping; chemical similarity of drugs is not considered. To explore the added value of chemical similarity inclusion we applied proteochemometric models, combining chemical and protein target properties in a single bioactivity model. Our dataset was a large scale clinical database of genotypic and phenotypic information (in total ca. 300,000 drug-mutant bioactivity data points, 4 (NNRTI, 8 (NRTI or 9 (PI drugs, and 10,700 (NNRTI 10,500 (NRTI or 27,000 (PI mutants. Our models achieved a prediction error below 0.5 Log Fold Change. Moreover, when directly compared with previously published sequence data, derived models PCM performed better in resistance classification and prediction of Log Fold Change (0.76 log units versus 0.91. Furthermore, we were able to successfully confirm both known and identify previously unpublished, resistance-conferring mutations of HIV Reverse Transcriptase (e.g. K102Y, T216M and HIV Protease (e.g. Q18N, N88G from our dataset. Finally, we applied our models prospectively to the public HIV resistance database from Stanford University obtaining a correct resistance prediction rate of 84% on the full set (compared to 80% in previous work on a high quality subset. We conclude that proteochemometric models are able to accurately predict the phenotypic resistance based on genotypic data even for novel mutants and mixtures. Furthermore, we add an applicability domain to

  7. Numerical investigation of high-pressure combustion in rocket engines using Flamelet/Progress-variable models

    CERN Document Server

    Coclite, A; De Palma, P; Pascazio, G

    2015-01-01

    The present paper deals with the numerical study of high pressure LOx/H2 or LOx/hydrocarbon combustion for propulsion systems. The present research effort is driven by the continued interest in achieving low cost, reliable access to space and more recently, by the renewed interest in hypersonic transportation systems capable of reducing time-to-destination. Moreover, combustion at high pressure has been assumed as a key issue to achieve better propulsive performance and lower environmental impact, as long as the replacement of hydrogen with a hydrocarbon, to reduce the costs related to ground operations and increase flexibility. The current work provides a model for the numerical simulation of high- pressure turbulent combustion employing detailed chemistry description, embedded in a RANS equations solver with a Low Reynolds number k-omega turbulence model. The model used to study such a combustion phenomenon is an extension of the standard flamelet-progress-variable (FPV) turbulent combustion model combined ...

  8. 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.

  9. Modeling of III-nitride light-emitting diodes: progress, problems, and perspectives

    Science.gov (United States)

    Karpov, Sergey Yu.

    2011-02-01

    Recent progress in III-nitride LED modeling is reviewed with the focus on physical models that provide a better understanding of such hot issues, as factors limiting the internal quantum efficiency of light emission and high-current efficiency droop, polarization doping in graded-composition III-nitride alloys and its utilization in LEDs, current crowding in LED dice and its impact on the light extraction efficiency, and optimal light conversion in white LED lamps. Specific features of III-nitride materials, their impact on the LED operation, and models accounting for these features are considered. Insufficient understanding of transport mechanisms of non-equilibrium electrons and holes and their localization in InGaN inhomogeneous active regions are discussed along with other still unsolved problems. Influence of technological factors on LED heterostructures and their operation is argued in the context of further model developments.

  10. Modelling the spatial-temporal progression of the 2009 A/H1N1 influenza pandemic in Chile.

    Science.gov (United States)

    Bürger, Raimund; Chowell, Gerardo; Mulet, Pep; Villada, Luis M

    2016-02-01

    A spatial-temporal transmission model of 2009 A/H1N1 pandemic influenza across Chile, a country that spans a large latitudinal range, is developed to characterize the spatial variation in peak timing of that pandemic as a function of local transmission rates, spatial connectivity assumptions for Chilean regions, and the putative location of introduction of the novel virus into the country. Specifically, a metapopulation SEIR (susceptible-exposed-infected-removed) compartmental model that tracks the transmission dynamics of influenza in 15 Chilean regions is calibrated. The model incorporates population mobility among neighboring regions and indirect mobility to and from other regions via the metropolitan central region ('hub region'). The stability of the disease-free equilibrium of this model is analyzed and compared with the corresponding stability in each region, concluding that stability may occur even with some regions having basic reproduction numbers above 1. The transmission model is used along with epidemiological data to explore potential factors that could have driven the spatial-temporal progression of the pandemic. Simulations and sensitivity analyses indicate that this relatively simple model is sufficient to characterize the south-north gradient in peak timing observed during the pandemic, and suggest that south Chile observed the initial spread of the pandemic virus, which is in line with a retrospective epidemiological study. The 'hub region' in our model significantly enhanced population mixing in a short time scale.

  11. 75 FR 29587 - Notice of Availability of Revised Model Proposed No Significant Hazards Consideration...

    Science.gov (United States)

    2010-05-26

    ... of Nuclear Reactor Regulation, U.S. Nuclear Regulatory Commission, Washington, DC, 20555-0001... Processes Branch, Division of Policy and Rulemaking, Office of Nuclear Reactor Regulation. Revised Model... with the confidence in the ability of the fission product barriers (i.e., fuel cladding,...

  12. Significant Term List Based Metadata Conceptual Mining Model for Effective Text Clustering

    Directory of Open Access Journals (Sweden)

    J. Janet

    2012-01-01

    Full Text Available As the engineering world are growing fast, the usage of data for the day to day activity of the engineering industry also growing rapidly. In order to handle and to find the hidden knowledge from huge data storage, data mining is very helpful right now. Text mining, network mining, multimedia mining, trend analysis are few applications of data mining. In text mining, there are variety of methods are proposed by many researchers, even though high precision, better recall are still is a critical issues. In this study, text mining is focused and conceptual mining model is applied for improved clustering in the text mining. The proposed work is termed as Meta data Conceptual Mining Model (MCMM, is validated with few world leading technical digital library data sets such as IEEE, ACM and Scopus. The performance derived as precision, recall are described in terms of Entropy, F-Measure which are calculated and compared with existing term based model and concept based mining model.

  13. Significance of Kinetics for Sorption on Inorganic Colloids: Modeling and Data Interpretation Issues

    Science.gov (United States)

    Painter, S.; Cvetkovic, V.; Pickett, D.; Turner, D.

    2001-12-01

    Irreversible or slowly reversible attachment to inorganic colloids is a process that may enhance radionuclide transport in the environment. An understanding of sorption kinetics is critical in evaluating this process. A two-site kinetic model for sorption on inorganic colloids is developed and used to evaluate laboratory data. This model was developed as an alternative to the equilibrium colloid sorption model employed by the U.S. Department of Energy (DOE) in their performance assessment for the proposed repository for high-level nuclear waste at Yucca Mountain, Nevada. The model quantifies linear first-order sorption on two types of hypothetical sites (fast and slow) characterized by two pairs of rates (forward and reverse). We use the model to explore data requirements for long-term predictive calculations and to evaluate laboratory kinetic sorption data of Lu et al. Five batch sorption data sets are considered with Pu(V) as the tracer and montmorillonite, hematite, silica, and smectite as colloids. Using asymptotic results applicable on the 240 hour time-scale of the experiments, a robust estimation procedure is developed for the fast-site partitioning coefficient and the slow forward rate. The estimated range for the partition coefficient is 1.1-76 L/g; the range for the slow forward rate is 0.0017-0.02 L/h. Comparison of one-site and two-site sorption interpretations reveals the difficulty in discriminating between the two models for montmorillonite and to a lesser extent for hematite. For silica and smectite the two-site model clearly provides a better representation of the data as compared with a single site model. Kinetic data for silica are available for different colloid concentrations (0.2 g/L and 1.0 g/L). For the range of experimental conditions considered, the forward rate appears to be independent of the colloid concentration. The slow reverse rate cannot be estimated on the time scale of the experiments; we estimate the detection limits for the

  14. An Ecological-Transactional Model of Significant Risk Factors for Child Psychopathology in Outer Mongolia

    Science.gov (United States)

    Kohrt, Holbrook E.; Kohrt, Brandon A.; Waldman, Irwin; Saltzman, Kasey; Carrion, Victor G.

    2004-01-01

    The present study examined significant risk factors, including child maltreatment, for child psychopathology in a cross-cultural setting. Ninety-nine Mongolian boys, ages 3-10 years, were assessed. Primary caregivers (PCG) completed structured interviews including the Emory Combined Rating Scale (ECRS) and the Mood and Feelings Questionnaire…

  15. Magnitude, modeling and significance of swelling and shrinkage processes in clay soils.

    NARCIS (Netherlands)

    Bronswijk, J.J.B.

    1991-01-01

    The dynamic process of swelling and shrinkage in clay soils has significant practical consequences, such as the rapid transport of water and solutes via shrinkage cracks to the subsoil, and the destruction of buildings and roads on clay soils. In order to develop measuring methods and computer simul

  16. 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

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

    Energy Technology Data Exchange (ETDEWEB)

    Brodin, N. Patrik, E-mail: nils.patrik.brodin@rh.dk [Radiation Medicine Research Center, Department of Radiation Oncology, Rigshospitalet, Copenhagen (Denmark); Niels Bohr Institute, University of Copenhagen, Copenhagen (Denmark); Vogelius, Ivan R. [Radiation Medicine Research Center, Department of Radiation Oncology, Rigshospitalet, Copenhagen (Denmark); Björk-Eriksson, Thomas [Department of Oncology, Skåne University Hospital and Lund University, Lund (Sweden); Munck af Rosenschöld, Per [Radiation Medicine Research Center, Department of Radiation Oncology, Rigshospitalet, Copenhagen (Denmark); Niels Bohr Institute, University of Copenhagen, Copenhagen (Denmark); Bentzen, Søren M. [Radiation Medicine Research Center, Department of Radiation Oncology, Rigshospitalet, Copenhagen (Denmark); Department of Human Oncology, University of Wisconsin Medical School, Madison, Wisconsin (United States)

    2013-10-01

    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.

  18. Significance of different animal species in experimental models for in vivo investigations of hematopoiesis

    Directory of Open Access Journals (Sweden)

    Kovačević-Filipović Milica

    2004-01-01

    Full Text Available Numerous discoveries in medicine are results of experiments on different animal species. The most frequently used animals in hematopoiesis investigations are laboratory mice and rats, but so-called big animals, such as pigs, sheep, cats, dogs, and monkeys, evolution-wise closer to humans have a place in experimental hematology as well. The specific problematics of a certain animal specie can lead to fundamental knowledge on certain aspects of the process of hematopoiesis end the biology of stem cells in hematopoiesis. Furthermore, comparative investigations of certain phenomena in different species help in the recognition of the general rules in the living world. In the area f preclinicalinvesti- gations, animal models are an inevitable step in studies of transplantation biology of stem cells in hematopoiesis, as well as in studies of biologically active molecules which have an effect on the hematopoietic system. Knowledge acquired on animal models is applied in both human and veterinary medicine.

  19. Recent advances in mechanical characterisation of biofilm and their significance for material modelling.

    Science.gov (United States)

    Böl, Markus; Ehret, Alexander E; Bolea Albero, Antonio; Hellriegel, Jan; Krull, Rainer

    2013-06-01

    In recent years, the advances in microbiology show that biofilms are structurally complex, dynamic and adaptable systems including attributes of multicellular organisms and miscellaneous ecosystems. One may distinguish between beneficial and harmful biofilms appearing in daily life as well as various industrial processes. In order to advance the growth of the former or prevent the latter type of biofilm, a detailed understanding of its properties is indispensable. Besides microbiological aspects, this concerns the determination of mechanical characteristics, which provides the basis for material modelling. In the present paper the existing experimental methods that have been proposed since the 1980s are reviewed and critically discussed with respect to their usefulness and applicability to develop numerical modelling approaches.

  20. Development of the PCAD Model to Assess Biological Significance of Acoustic Disturbance

    Science.gov (United States)

    2015-09-30

    mother-calf separation as a function of body mass index ( BMI ) and proportion lipid in blubber. We have also quantified the relationship between those...the approach. This is best accomplished by selecting species that are as similar as possible to target species and are also extremely well-studied...We identified northern elephant seals and Atlantic bottlenose dolphins as the best species to parameterize the PCAD model. These species represent

  1. Significance of genetic information in risk assessment and individual classification using silicosis as a case model

    Energy Technology Data Exchange (ETDEWEB)

    McCanlies, E.; Landsittel, D.P.; Yucesoy, B.; Vallyathan, V.; Luster, M.L.; Sharp, D.S. [NIOSH, Morgantown, WV (United States)

    2002-06-01

    Over the last decade the role of genetic data in epidemiological research has expanded considerably. The authors recently published a case-control study that evaluated the interaction between silica exposure and minor variants in the genes coding for interleukin-1alpha. (IL-1alpha), interleukin-1 receptor antagonist (IL-1RA) and tumor necrosis factor alpha (TNFalpha) as risk factors associated with silicosis, a fibrotic lung disease. In contrast, this report uses data generated from these studies to illustrate the utility of genetic information for the purposes of risk assessment and clinical prediction. Specifically, this study addresses how, given a known exposure, genetic information affects the characterization of risk groups. Relative operating characteristic (ROC) curves were then used to determine the impact of genetic information on individual classification. Logistic regression modeling procedures were used to estimate the predicted probability of developing silicosis. This probability was then used to construct predicted risk deciles, first for a model with occupational exposure only and then for a model containing occupational exposure and genetic main effects and interactions. The results indicate that genetic information plays a valuable role in effectively characterizing risk groups and mechanisms of disease operating in a substantial proportion of the population. However, in the case of fibrotic lung disease caused by silica exposure, information about the presence or absence of the minor variants of IL-1alpha, IL-1RA and TNFalpha is unlikely to be a useful tool for individual classification.

  2. 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

  3. 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

  4. In vivo non-invasive serial monitoring of FDG-PET progression and regression in a rabbit model of atherosclerosis.

    Science.gov (United States)

    Worthley, Stephen G; Zhang, Zhuang Y; Machac, Josef; Helft, Gérard; Tang, Cheuk; Liew, Gary Y H; Zaman, Azfar G; Worthley, Matthew I; Fayad, Zahi A; Buchsbaum, Monte S; Fuster, Valentin; Badimon, Juan J

    2009-03-01

    We investigated the ability of fluorodeoxyglucose positron emission tomography (FDG PET) imaging to serially monitor macrophage content in a rabbit model of atherosclerosis. Atherosclerosis was induced in rabbits (n = 8) by a combination of atherogenic diet and balloon denudation of the aorta. At the end of nine months, the rabbits were randomized to a further six months of the same atherogenic diet (progression group) or normal diet (regression group). In vivo uptake of FDG by the thoracic aorta was measured using aortic uptake-to-blood radioactivity ratios at the start and end of the randomized period. A significant increase in FDG uptake of the progression group after continued cholesterol feeding (aortic uptake-to-blood radioactivity: 0.57 +/- 0.02 to 0.68 +/- 0.02, P = 0.001), and a corresponding fall in FDG uptake of the regression group after returning to a normal chow diet (aortic uptake-to-blood radioactivity ratios: 0.67 +/- 0.02 to 0.53 +/- 0.02, P < 0.0001). FDG PET can quantify in vivo macrophage content and serially monitor changes in FDG activity in this rabbit model.

  5. 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.

  6. The recent progress in proteochemometric modelling: focusing on target descriptors, cross-term descriptors and application scope.

    Science.gov (United States)

    Qiu, Tianyi; Qiu, Jingxuan; Feng, Jun; Wu, Dingfeng; Yang, Yiyan; Tang, Kailin; Cao, Zhiwei; Zhu, Ruixin

    2017-01-01

    As an extension of the conventional quantitative structure activity relationship models, proteochemometric (PCM) modelling is a computational method that can predict the bioactivity relations between multiple ligands and multiple targets. Traditional PCM modelling includes three essential elements: descriptors (including target descriptors, ligand descriptors and cross-term descriptors), bioactivity data and appropriate learning functions that link the descriptors to the bioactivity data. Since its appearance, PCM modelling has developed rapidly over the past decade by taking advantage of the progress of different descriptors and machine learning techniques, along with the increasing amounts of available bioactivity data. Specifically, the new emerging target descriptors and cross-term descriptors not only significantly increased the performance of PCM modelling but also expanded its application scope from traditional protein-ligand interaction to more abundant interactions, including protein-peptide, protein-DNA and even protein-protein interactions. In this review, target descriptors and cross-term descriptors, as well as the corresponding application scope, are intensively summarized. Additionally, we look forward to seeing PCM modelling extend into new application scopes, such as Target-Catalyst-Ligand systems, with the further development of descriptors, machine learning techniques and increasing amounts of available bioactivity data. © The Author 2016. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  7. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer.

    Science.gov (United States)

    Saloman, Jami L; Albers, Kathryn M; Li, Dongjun; Hartman, Douglas J; Crawford, Howard C; Muha, Emily A; Rhim, Andrew D; Davis, Brian M

    2016-03-15

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro- and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations.

  8. Policy Decisions for a Price Dependent Demand Rate Inventory Model with Progressive Payments Scheme

    Directory of Open Access Journals (Sweden)

    Rajat Kumar

    2012-01-01

    Full Text Available Problem statement: In this proposed research, we developed an inventory model to formulate an optimal ordering policies for supplier who offers progressive permissible delay periods to the retailer to settle his/her account. We assumed that the annual demand rate as a decreasing function of price with constant rate of deterioration and time-varying holding cost. Shortages in inventory are allowed which is completely backlogged. Approach: The main objective of this study to frame an inventory model in real life situations. In this study, we introduced a new idea of trade credits, namely, the supplier charges the retailer progressive interest rates if the retailer prolongs its unpaid balance. By offering progressive interest rates to the retailers, a supplier, can secure competitive market advantage over the competitors and possibly improve market share profit. This study has two main purposes, first the mathematical model of an inventory system are establish under the above conditions and second demonstrate that the optimal solution not only exists but also feasible. We developed theoretical results to obtain the optimal replenishment interval by examine the explicit condition. An algorithm is given to find the flow of optimal ordering policy. Results: The results is illustrated with the help of numerical example using Mathematica software and the optimal solution of the problem is Z (p, T1 = 76.8586 at (p, T1 = (0.952656, 0.128844. Conclusion: We proposed an algorithm to find the optimal ordering policy. A numerical study has been performed to observe the sensitivity of the effect of demand parameter changes.

  9. Enforcement actions: Significant actions resolved individual actions. Volume 14, Nos. 3 and 4, Part 1. Semiannual progress report, July--December 1995

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-02-01

    This compilation summarizes significant enforcement actions that have been resolved during the period (July - December 1995) and includes copies of Orders and Notices of Violation sent by the Nuclear Regulatory Commission to individuals 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. The Commission believes this information may be useful to licensees in making employment decisions.

  10. In Vitro Co-Culture Models of Breast Cancer Metastatic Progression towards Bone

    Directory of Open Access Journals (Sweden)

    Chiara Arrigoni

    2016-08-01

    Full Text Available Advanced breast cancer frequently metastasizes to bone through a multistep process involving the detachment of cells from the primary tumor, their intravasation into the bloodstream, adhesion to the endothelium and extravasation into the bone, culminating with the establishment of a vicious cycle causing extensive bone lysis. In recent years, the crosstalk between tumor cells and secondary organs microenvironment is gaining much attention, being indicated as a crucial aspect in all metastatic steps. To investigate the complex interrelation between the tumor and the microenvironment, both in vitro and in vivo models have been exploited. In vitro models have some advantages over in vivo, mainly the possibility to thoroughly dissect in controlled conditions and with only human cells the cellular and molecular mechanisms underlying the metastatic progression. In this article we will review the main results deriving from in vitro co-culture models, describing mechanisms activated in the crosstalk between breast cancer and bone cells which drive the different metastatic steps.

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

    CERN Document Server

    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.

  12. In Vitro Co-Culture Models of Breast Cancer Metastatic Progression towards Bone

    Science.gov (United States)

    Arrigoni, Chiara; Bersini, Simone; Gilardi, Mara; Moretti, Matteo

    2016-01-01

    Advanced breast cancer frequently metastasizes to bone through a multistep process involving the detachment of cells from the primary tumor, their intravasation into the bloodstream, adhesion to the endothelium and extravasation into the bone, culminating with the establishment of a vicious cycle causing extensive bone lysis. In recent years, the crosstalk between tumor cells and secondary organs microenvironment is gaining much attention, being indicated as a crucial aspect in all metastatic steps. To investigate the complex interrelation between the tumor and the microenvironment, both in vitro and in vivo models have been exploited. In vitro models have some advantages over in vivo, mainly the possibility to thoroughly dissect in controlled conditions and with only human cells the cellular and molecular mechanisms underlying the metastatic progression. In this article we will review the main results deriving from in vitro co-culture models, describing mechanisms activated in the crosstalk between breast cancer and bone cells which drive the different metastatic steps. PMID:27571063

  13. Load redistribution rules for progressive failure in shallow landslides: Threshold mechanical models

    Science.gov (United States)

    Fan, Linfeng; Lehmann, Peter; Or, Dani

    2017-01-01

    Rainfall-induced landslides are often preceded by progressive failures that culminate in abrupt mass release. Local failure progression is captured by a landslide hydro-mechanical triggering model that represents the soil mantle as interacting columns linked by tensile and compressive mechanical "bonds." Mechanical bonds may fail at a prescribed threshold leaving a modeling challenge of how to redistribute their load to neighboring intact soil columns. We employed an elastic spring-block model to analytically derive redistribution rules defined by the stiffness ratio of compressive to tensile bonds. These linear-elastic rules were generalized to real soil using measurable Young's modulus and Poisson's ratio. Results indicate that "local" failure characteristics of ductile-like soils (e.g., clay) are reproduced by low stiffness ratios, whereas "global" failure of brittle sandy soils corresponds to large stiffness ratios. Systematic analyses yield guidelines for selecting load redistribution rules for failure of geological materials and mass-movement phenomena represented by discrete threshold-mechanics.

  14. Role of Compaction Ratio in the Mathematical Model of Progressive Collapse

    OpenAIRE

    Beck, Charles M.

    2008-01-01

    We derive a mathematical model of progressive collapse and examine role of compaction. Contrary to a previous result by Ba\\v{z}ant and Verdure, J. Engr. Mech. ASCE 133 (2006) 308, we find that compaction slows down the avalanche by effectively increasing the resistive force. We compare currently available estimates of the resistive force, that of Ba\\v{z}ant and Verdure (2006) corrected for compaction for World Trade Center (WTC) 2, and of Beck, www.arxiv.org:physics/0609105, for WTC 1 and 2. ...

  15. Progression model tissue microarray (TMA) for the study of uterine carcinomas.

    Science.gov (United States)

    Arafa, Mohammad; Boniver, Jacques; Delvenne, Philippe

    2010-01-01

    Cervical and endometrial uterine carcinomas are heterogeneous groups of cancers, which are preceded by preneoplastic lesions. More accurate tools are needed to improve the diagnosis and to define markers which may be relevant for the diagnosis, prediction of disease progression and therapeutic response.High throughput technologies for testing and validating molecular targets in cancer lesions and in their precursors are presently available. Among them, the tissue microarray (TMA) presents the advantage of a morphological control of the analyzed tissue fragment. In this article, we review the different aspects of the TMA technology with a special consideration to a uterine carcinogenesis model.

  16. Fear extinction as a model for translational neuroscience: ten years of progress.

    Science.gov (United States)

    Milad, Mohammed R; Quirk, Gregory J

    2012-01-01

    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 a high degree of coordination between rodent and human researchers examining fear extinction. Here we review the major advances and highlight new approaches to understanding and exploiting fear extinction. Research in fear extinction could serve as a model for translational research in other areas of behavioral neuroscience.

  17. Breast cancer-associated metastasis is significantly increased in a model of autoimmune arthritis

    Science.gov (United States)

    Das Roy, Lopamudra; Pathangey, Latha B; Tinder, Teresa L; Schettini, Jorge L; Gruber, Helen E; Mukherjee, Pinku

    2009-01-01

    Introduction Sites of chronic inflammation are often associated with the establishment and growth of various malignancies including breast cancer. A common inflammatory condition in humans is autoimmune arthritis (AA) that causes inflammation and deformity of the joints. Other systemic effects associated with arthritis include increased cellular infiltration and inflammation of the lungs. Several studies have reported statistically significant risk ratios between AA and breast cancer. Despite this knowledge, available for a decade, it has never been questioned if the site of chronic inflammation linked to AA creates a milieu that attracts tumor cells to home and grow in the inflamed bones and lungs which are frequent sites of breast cancer metastasis. Methods To determine if chronic inflammation induced by autoimmune arthritis contributes to increased breast cancer-associated metastasis, we generated mammary gland tumors in SKG mice that were genetically prone to develop AA. Two breast cancer cell lines, one highly metastatic (4T1) and the other non-metastatic (TUBO) were used to generate the tumors in the mammary fat pad. Lung and bone metastasis and the associated inflammatory milieu were evaluated in the arthritic versus the non-arthritic mice. Results We report a three-fold increase in lung metastasis and a significant increase in the incidence of bone metastasis in the pro-arthritic and arthritic mice compared to non-arthritic control mice. We also report that the metastatic breast cancer cells augment the severity of arthritis resulting in a vicious cycle that increases both bone destruction and metastasis. Enhanced neutrophilic and granulocytic infiltration in lungs and bone of the pro-arthritic and arthritic mice and subsequent increase in circulating levels of proinflammatory cytokines, such as macrophage colony stimulating factor (M-CSF), interleukin-17 (IL-17), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and tumor necrosis factor

  18. Support for significant evolutions of the user data model in ROOT files

    Energy Technology Data Exchange (ETDEWEB)

    Canal, Ph; Russo, P [Fermilab, Batavia, IL (United States); Brun, R; Janyst, L [CERN, Geneva (Switzerland); Fine, V; Lauret, J, E-mail: pcanal@fnal.go [Brookhaven National Laboratory, Upton, NY (United States)

    2010-04-01

    One of the main strengths of ROOT input and output (I/O) is its inherent support for schema evolution. Two distinct modes are supported, one manual via a hand coded streamer function and one fully automatic via the ROOT StreamerInfo. One draw back of the streamer functions is that they are not usable by TTree objects in split mode. Until now, the user could not customize the automatic schema evolution mechanism and the only mechanism to go beyond the default rules was to revert to using the streamer function. In ROOT 5.22/00, we introduced a new mechanism which allows user provided extensions of the automatic schema evolution that can be used in object-wise, member-wise and split modes. This paper will describe the many possibilities ranging from the simple assignment of transient members to the complex reorganization of the user's object model.

  19. Trait impressions as overgeneralized responses to adaptively significant facial qualities: evidence from connectionist modeling.

    Science.gov (United States)

    Zebrowitz, Leslie A; Fellous, Jean-Marc; Mignault, Alain; Andreoletti, Carrie

    2003-01-01

    Connectionist modeling experiments tested anomalous-face and baby-face overgeneralization hypotheses proposed to explain consensual trait impressions of faces. Activation of a neural network unit trained to respond to anomalous faces predicted impressions of normal adult faces varying in attractiveness as well as several elderly stereotypes. Activation of a neural network unit trained to respond to babies' faces predicted impressions of adults varying in babyfaceness as well as 1 elderly stereotype. Thus, similarities of normal adult faces to anomalous faces or babies' faces contribute to impressions of them quite apart from knowledge of overlapping social stereotypes. The evolutionary importance of appropriate responses to unfit individuals or babies is presumed to produce a strong response preparedness that is overgeneralized to faces resembling the unfit or babies.

  20. Mouse models of lipodystrophy and their significance in understanding fat regulation.

    Science.gov (United States)

    Rochford, Justin J

    2014-01-01

    Adipose tissue plays a critical role in human metabolic health. This is most dramatically illustrated by the severe metabolic disease that occurs in syndromes of lipodystrophy where individuals fail to develop or maintain appropriate adipose tissue mass. The most severe form of this disorder is congenital generalized lipodystrophy (CGL). Individuals with CGL have a striking paucity of adipose tissue and typically display severe metabolic disease with insulin resistance and dyslipidemia. Understanding of the metabolic consequences of lipodystrophies and their underlying molecular mechanisms will provide new information regarding the development and function of human adipose tissue. Mouse models of these conditions offer key resources to investigate this in vivo. Adipocyte dysfunction is believed to underlie the development of metabolic disease in obesity. Hence, understanding how one might beneficially manipulate adipose tissue by studying genes whose disruption causes lipodystrophy is likely to suggest novel means to improve metabolic health in common obesity.

  1. Support for significant evolutions of the user data model in ROOT files

    Energy Technology Data Exchange (ETDEWEB)

    Canal, P.; /Fermilab; Brun, R.; /CERN; Fine, V.; /Brookhaven; Janyst, L.; /CERN; Lauret, J.; /Brookhaven; Russo, P.; /Fermilab

    2010-01-01

    One of the main strengths of ROOT input and output (I/O) is its inherent support for schema evolution. Two distinct modes are supported, one manual via a hand coded streamer function and one fully automatic via the ROOT StreamerInfo. One draw back of the streamer functions is that they are not usable by TTree objects in split mode. Until now, the user could not customize the automatic schema evolution mechanism and the only mechanism to go beyond the default rules was to revert to using the streamer function. In ROOT 5.22/00, we introduced a new mechanism which allows user provided extensions of the automatic schema evolution that can be used in object-wise, member-wise and split modes. This paper will describe the many possibilities ranging from the simple assignment of transient members to the complex reorganization of the user's object model.

  2. Genetic Risk Score Modelling for Disease Progression in New-Onset Type 1 Diabetes Patients

    DEFF Research Database (Denmark)

    Brorsson, Caroline A.; Nielsen, Lotte B.; Andersen, Marie Louise;

    2016-01-01

    1 diabetes (T1D). As gene expression may represent an intermediate phenotype between genetic variation and disease, we hypothesized that genes within T1D loci which are expressed in islets and transcriptionally regulated by proinflammatory cytokines would be the best predictors of disease...... progression. Two-thirds of 46 GWAS candidate genes examined were expressed in human islets, and 11 of these significantly changed expression levels following exposure to proinflammatory cytokines (IL-1β + IFNγ + TNFα) for 48 h. Using the GWAS single nucleotide polymorphisms (SNPs) from each locus, we...

  3. Appraisement on Contributive Ratio of Scientific and Technical Progresses in Milk Productive Enterprises by Model C2GS2

    Institute of Scientific and Technical Information of China (English)

    SUN Futian; SUN Liqun; YANG Guanglin

    2008-01-01

    Scientific and technical progress has been the driving forces of enterprises development. Milk productive enterprises are developing faster and growing better. It is very important to measure the contributive ratio of scientific and technical progress in milk productive enterprises. And the appraisement could help to develop milk productive enterprises. The model C2GS2 was established to appraise the contributive ratio of scientific and technical progress in milk productive enterprises in the research. And the appraisement on the contributive ratio of scientific and technical progress in milk productive enterprises was made by the model. In the results of appraisement, science and technology play a main role in milk productive enterprises. It is shown that our milk productive enterprises are developed by scientific and technical progress while not by input of productive factors.

  4. Preconditioning Provides Neuroprotection in Models of CNS Disease: Paradigms and Clinical Significance

    Science.gov (United States)

    Stetler, R. Anne; Leak, Rehana K.; Gan, Yu; Li, Peiying; Hu, Xiaoming; Jing, Zheng; Chen, Jun; Zigmond, Michael J.; Gao, Yanqin

    2014-01-01

    Preconditioning is a phenomenon in which brief episodes of a sublethal insult induce robust protection against subsequent lethal injuries. Preconditioning has been observed in multiple organisms and can occur in the brain as well as other tissues. Extensive animal studies suggest that the brain can be preconditioned to resist acute injuries, such as ischemic stroke, neonatal hypoxia/ischemia, trauma, and agents that are used in models of neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease. Effective preconditioning stimuli are numerous and diverse, ranging from transient ischemia, hypoxia, hyperbaric oxygen, hypothermia and hyperthermia, to exposure to neurotoxins and pharmacological agents. The phenomenon of “cross-tolerance,” in which a sublethal stress protects against a different type of injury, suggests that different preconditioning stimuli may confer protection against a wide range of injuries. Research conducted over the past few decades indicates that brain preconditioning is complex, involving multiple effectors such as metabolic inhibition, activation of extra- and intracellular defense mechanisms, a shift in the neuronal excitatory/inhibitory balance, and reduction in inflammatory sequelae. An improved understanding of brain preconditioning should help us identify innovative therapeutic strategies that prevent or at least reduce neuronal damage in susceptible patients. In this review, we focus on the experimental evidence of preconditioning in the brain and systematically survey the models used to develop paradigms for neuroprotection, and then discuss the clinical potential of brain preconditioning. In a subsequent components of this two-part series, we will discuss the cellular and molecular events that are likely to underlie these phenomena. PMID:24389580

  5. Label-free detection of tumor markers in a colon carcinoma tumor progression model by confocal Raman microspectroscopy

    Science.gov (United States)

    Scalfi-Happ, Claudia; Rück, Angelika; Udart, Martin; Hauser, Carmen; Dürr, Christine; Kriebel, Martin

    2013-06-01

    Living colon carcinoma cells were investigated by confocal Raman microspectroscopy. An in vitro model of tumor progression was established. Evaluation of data sets by cluster analysis reveals that lipid bodies might be a valuable diagnostic parameter for early carcinogenesis.

  6. Patients infected with CRF07_BC have significantly lower viral loads than patients with HIV-1 subtype B: mechanism and impact on disease progression.

    Directory of Open Access Journals (Sweden)

    Szu-Wei Huang

    Full Text Available The circulating recombinant form (CRF 07_BC is the most prevalent HIV-1 strain among injection drug users (IDUs in Taiwan. It contains a 7 amino-acid deletion in its p6gag. We conducted a cohort study to compare viral loads and CD4 cell count changes between patients infected with subtype B and CRF07_BC and to elucidate its mechanism. Twenty-one patients infected with CRF07_BC and 59 patients with subtype B were selected from a cohort of 667 HIV-1/AIDS patients whom have been followed up for 3 years. Generalized estimated equation was used to analyze their clinical data and the results showed that patients infected with CRF07_BC had significantly lower viral loads (about 58,000 copies per ml less than patients with subtype B infection (p = 0.002. The replicative capacity of nine CRF07_BC and four subtype B isolates were compared and the results showed that the former had significantly lower replicative capacity than the latter although all of them were CCR5- tropic and non-syncytium inducing viruses. An HIV-1-NL4-3 mutant virus which contains a 7 amino-acid deletion in p6gag (designated as 7d virus was generated and its live cycle was investigated. The results showed that 7d virus had significantly lower replication capacity, poorer protease-mediated processing and viral proteins production. Electron microscopic examination of cells infected with wild-type or 7d virus demonstrated that the 7d virus had poorer and slower viral maturation processes: more viruses attached to the cell membrane and higher proportion of immature virions outside the cells. The interaction between p6gag and Alix protein was less efficient in cells infected with 7d virus. In conclusion, patients infected with CRF07_BC had significantly lower viral loads than patients infected with subtype B and it may due to the deletion of 7 amino acids which overlaps with Alix protein-binding domain of the p6gag.

  7. Enforcement actions: Significant actions resolved material licensees (non-medical). Volume 14, No. 1, Part 3, Quarterly progress report, January--March 1995

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-05-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (January--March 1995) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to Material Licensees (non-Medical) 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.

  8. Enforcement actions: Significant actions resolved, reactor licensees. Semiannual progress report, July--December 1995. Volume 14, Numbers 3 and 4, Part 2

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-02-01

    This compilation summarizes significant enforcement actions that have been resolved during the period (July--December 1995) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to reactor 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.

  9. Enforcement actions: Significant actions resolved, material licensees. Semiannual progress report, July--December 1995: Volume 14, Numbers 3 and 4, Part 3

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-02-01

    This compilation summarizes significant enforcement actions that have been resolved during the period (July--December 1995) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to material 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.

  10. Thermophysical modeling of asteroids from WISE thermal infrared data - Significance of the shape model and the pole orientation uncertainties

    CERN Document Server

    Hanuš, Josef; Ďurech, Josef; Alí-Lagoa, Victor

    2015-01-01

    In the analysis of thermal infrared data of asteroids by means of thermophysical models (TPMs) it is a common practice to neglect the uncertainty of the shape model and the rotational state, which are taken as an input for the model. Here, we present a novel method of investigating the importance of the shape model and the pole orientation uncertainties in the thermophysical modeling - the varied shape TPM (VS-TPM). Our method uses optical photometric data to generate various shape models that map the uncertainty in the shape and the rotational state. The TPM procedure is then run for all these shape models. We apply the implementation of the classical TPM as well as our VS-TPM to the convex shape models of several asteroids together with their thermal infrared data acquired by the NASA's Wide-field Infrared Survey Explorer (WISE) and compare the results. These show that the uncertainties of the shape model and the pole orientation can be very important (e.g., for the determination of the thermal inertia) and...

  11. Progress in Modeling Global Atmospheric CO2 Fluxes and Transport: Results from Simulations with Diurnal Fluxes

    Science.gov (United States)

    Collatz, G. James; Kawa, R.

    2007-01-01

    Progress in better determining CO2 sources and sinks will almost certainly rely on utilization of more extensive and intensive CO2 and related observations including those from satellite remote sensing. Use of advanced data requires improved modeling and analysis capability. Under NASA Carbon Cycle Science support we seek to develop and integrate improved formulations for 1) atmospheric transport, 2) terrestrial uptake and release, 3) biomass and 4) fossil fuel burning, and 5) observational data analysis including inverse calculations. The transport modeling is based on meteorological data assimilation analysis from the Goddard Modeling and Assimilation Office. Use of assimilated met data enables model comparison to CO2 and other observations across a wide range of scales of variability. In this presentation we focus on the short end of the temporal variability spectrum: hourly to synoptic to seasonal. Using CO2 fluxes at varying temporal resolution from the SIB 2 and CASA biosphere models, we examine the model's ability to simulate CO2 variability in comparison to observations at different times, locations, and altitudes. We find that the model can resolve much of the variability in the observations, although there are limits imposed by vertical resolution of boundary layer processes. The influence of key process representations is inferred. The high degree of fidelity in these simulations leads us to anticipate incorporation of realtime, highly resolved observations into a multiscale carbon cycle analysis system that will begin to bridge the gap between top-down and bottom-up flux estimation, which is a primary focus of NACP.

  12. Significant progression of load on the musculoskeletal system with extremely high loads, with rapid weekly weight gains, using the Anatoly Gravitational System, in a 10-week training period

    Directory of Open Access Journals (Sweden)

    Burke DT

    2013-10-01

    Full Text Available David T Burke,1 David Tran,1 Di Cui,1 Daniel P Burke,2 Samir Al-Adawi,3 Atsu SS Dorvlo41Emory University Medical School, Atlanta, GA, USA; 2Georgia College and State University, GA, USA; 3Department of Behavioral Medicine, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman; 4Department of Mathematics and Statistics, College of Science, Sultan Qaboos University, Muscat, OmanAbstract: In an age of increasing numbers of lifestyle diseases and plasticity of longevity, exercise and weight training have been increasingly recognized as both preventing and mitigating the severity of many illnesses. This study was designed to determine whether significant weight-lifting gains could be realized through the Anatoly Gravitational System. Specifically, this study sought to determine whether this once-weekly weight-training system could result in significant weekly strength gains during a 10-week training period. A total of 50 participants, ranging in age from 17 to 67 years, completed at least 10 weekly 30-minute training sessions. The results suggest participants could, on average, double their weight-lifting capacity within 10 sessions. This preliminary study, which would require further scrutiny, suggests the Anatoly Gravitational System provides a rather unique opportunity to load the musculoskeletal system with extremely high loads, with rapid weekly weight gains, using only short weekly training sessions. More studies are warranted to scrutinize these findings.Keywords: Anatoly Gravitational System, weight training, musculoskeletal system

  13. Developing and upgrading of solar system thermal energy storage simulation models. Technical progress report, March 1, 1978-August 31, 1978

    Energy Technology Data Exchange (ETDEWEB)

    Kuhn, J K; von Fuchs, G F; Warren, A W; Zob, A P

    1979-07-01

    The objective of the program are: 1) collect, standardize, and link existing TES models from the literature and other STO contractors; 2) correlate TES models with available TES component test data; 3) develop streamlined versions of validated TES component models; and 4) provide DOE and industry with a competent solar TES simulation tool. Progress during the reporting period was concerned primarily with the first and second objectives. A rock bed model was evolved and analytical results were correlated with component test data, and water tank model development was continued in detail. Progress is detailed. (WHK)

  14. Towards the Significance of Decision Aid in Building Information Modeling (BIM Software Selection Process

    Directory of Open Access Journals (Sweden)

    Omar Mohd Faizal

    2014-01-01

    Full Text Available Building Information Modeling (BIM has been considered as a solution in construction industry to numerous problems such as delays, increased lead in times and increased costs. This is due to the concept and characteristic of BIM that will reshaped the way construction project teams work together to increase productivity and improve the final project outcomes (cost, time, quality, safety, functionality, maintainability, etc.. As a result, the construction industry has witnesses numerous of BIM software available in market. Each of this software has offers different function, features. Furthermore, the adoption of BIM required high investment on software, hardware and also training expenses. Thus, there is indentified that there is a need of decision aid for appropriated BIM software selection that fulfill the project needs. However, research indicates that there is limited study attempt to guide decision in BIM software selection problem. Thus, this paper highlight the importance of decision making and support for BIM software selection as it is vital to increase productivity, construction project throughout building lifecycle.

  15. Progressive mitochondrial protein lysine acetylation and heart failure in a model of Friedreich's ataxia cardiomyopathy.

    Science.gov (United States)

    Stram, Amanda R; Wagner, Gregory R; Fogler, Brian D; Pride, P Melanie; Hirschey, Matthew D; Payne, R Mark

    2017-01-01

    The childhood heart disease of Friedreich's Ataxia (FRDA) is characterized by hypertrophy and failure. It is caused by loss of frataxin (FXN), a mitochondrial protein involved in energy homeostasis. FRDA model hearts have increased mitochondrial protein acetylation and impaired sirtuin 3 (SIRT3) deacetylase activity. Protein acetylation is an important regulator of cardiac metabolism and loss of SIRT3 increases susceptibility of the heart to stress-induced cardiac hypertrophy and ischemic injury. The underlying pathophysiology of heart failure in FRDA is unclear. The purpose of this study was to examine in detail the physiologic and acetylation changes of the heart that occur over time in a model of FRDA heart failure. We predicted that increased mitochondrial protein acetylation would be associated with a decrease in heart function in a model of FRDA. A conditional mouse model of FRDA cardiomyopathy with ablation of FXN (FXN KO) in the heart was compared to healthy controls at postnatal days 30, 45 and 65. We evaluated hearts using echocardiography, cardiac catheterization, histology, protein acetylation and expression. Acetylation was temporally progressive and paralleled evolution of heart failure in the FXN KO model. Increased acetylation preceded detectable abnormalities in cardiac function and progressed rapidly with age in the FXN KO mouse. Acetylation was also associated with cardiac fibrosis, mitochondrial damage, impaired fat metabolism, and diastolic and systolic dysfunction leading to heart failure. There was a strong inverse correlation between level of protein acetylation and heart function. These results demonstrate a close relationship between mitochondrial protein acetylation, physiologic dysfunction and metabolic disruption in FRDA hypertrophic cardiomyopathy and suggest that abnormal acetylation contributes to the pathophysiology of heart disease in FRDA. Mitochondrial protein acetylation may represent a therapeutic target for early intervention.

  16. A longitudinal model for disease progression was developed and applied to multiple sclerosis

    Science.gov (United States)

    Lawton, Michael; Tilling, Kate; Robertson, Neil; Tremlett, Helen; Zhu, Feng; Harding, Katharine; Oger, Joel; Ben-Shlomo, Yoav

    2015-01-01

    Objectives To develop a model of disease progression using multiple sclerosis (MS) as an exemplar. Study Design and Settings Two observational cohorts, the University of Wales MS (UoWMS), UK (1976), and British Columbia MS (BCMS) database, Canada (1980), with longitudinal disability data [the Expanded Disability Status Scale (EDSS)] were used; individuals potentially eligible for MS disease-modifying drugs treatments, but who were unexposed, were selected. Multilevel modeling was used to estimate the EDSS trajectory over time in one data set and validated in the other; challenges addressed included the choice and function of time axis, complex observation-level variation, adjustments for MS relapses, and autocorrelation. Results The best-fitting model for the UoWMS cohort (404 individuals, and 2,290 EDSS observations) included a nonlinear function of time since onset. Measurement error decreased over time and ad hoc methods reduced autocorrelation and the effect of relapse. Replication within the BCMS cohort (978 individuals and 7,335 EDSS observations) led to a model with similar time (years) coefficients, time [0.22 (95% confidence interval {CI}: 0.19, 0.26), 0.16 (95% CI: 0.10, 0.22)] and log time [−0.13 (95% CI: −0.39, 0.14), −0.15 (95% CI: −0.70, 0.40)] for BCMS and UoWMS, respectively. Conclusion It is possible to develop robust models of disability progression for chronic disease. However, explicit validation is important given the complex methodological challenges faced. PMID:26071892

  17. Thermal Injury Model in the Rabbit Ear with Quantifiable Burn Progression and Hypertrophic Scar.

    Science.gov (United States)

    Friedrich, Emily E; Niknam-Bienia, Solmaz; Xie, Ping; Jia, Sheng-Xian; Hong, Seok Jong; Mustoe, Thomas A; Galiano, Robert D

    2017-04-01

    Hypertrophic scar is a major clinical outcome of deep-partial thickness to full thickness thermal burn injury. Appropriate animal models are a limitation to burn research due to the lack of, or access to, animal models which address the endpoint of hypertrophic scar. Lower species, such as rodents, heal mainly by contracture, which limits the duration of study. Higher species, such as pigs, heal more similarly to humans, but are associated with high cost, long duration for scar development, challenges in quantifying scar hypertrophy, and poor manageability. Here we present a quantifiable deep-partial thickness burn model in the rabbit ear. Burns were created using a dry-heated brass rod for 10 s and 20 s at 90°C. At the time of eschar excision on day 3, excisional wounds were made on the contralateral ear for comparison. Burn wound progression, in which the wound size expands over time is a major distinction between excisional and thermal injuries, was quantified at 1 h and 3 d after the injuries using calibrated photographs and histology and the size of the wounds was found to be unchanged from the initial wound size at 1 h, but 10% in the 20 s burn wounds at 3 d. A quantifiable hypertrophic scar, measured by histology as the scar elevation index, was present in both 20 s burn wounds and excisional wounds at day 35. ImageJ measurements revealed that the 20 s burn wound scars were 22% larger than the excisional wound scars and the 20 s burn scar area measurements from histology were 26% greater than in the excisional wound scar. The ability to measure both burn progression and scar hypertrophy over a 35-day time frame suits this model to screening early intervention burn wound therapeutics or scar treatments in a burn-specific scar model. This article is protected by copyright. All rights reserved.

  18. Effects of insulin on human pancreatic cancer progression modeled in vitro.

    Science.gov (United States)

    Chan, Michelle T; Lim, Gareth E; Skovsø, Søs; Yang, Yu Hsuan Carol; Albrecht, Tobias; Alejandro, Emilyn U; Hoesli, Corinne A; Piret, James M; Warnock, Garth L; Johnson, James D

    2014-11-06

    Pancreatic adenocarcinoma is one of the most lethal cancers, yet it remains understudied and poorly understood. Hyperinsulinemia has been reported to be a risk factor of pancreatic cancer, and the rapid rise of hyperinsulinemia associated with obesity and type 2 diabetes foreshadows a rise in cancer incidence. However, the actions of insulin at the various stages of pancreatic cancer progression remain poorly defined. Here, we examined the effects of a range of insulin doses on signalling, proliferation and survival in three human cell models meant to represent three stages in pancreatic cancer progression: primary pancreatic duct cells, the HPDE immortalized pancreatic ductal cell line, and the PANC1 metastatic pancreatic cancer cell line. Cells were treated with a range of insulin doses, and their proliferation/viability were tracked via live cell imaging and XTT assays. Signal transduction was assessed through the AKT and ERK signalling pathways via immunoblotting. Inhibitors of AKT and ERK signalling were used to determine the relative contribution of these pathways to the survival of each cell model. While all three cell types responded to insulin, as indicated by phosphorylation of AKT and ERK, we found that there were stark differences in insulin-dependent proliferation, cell viability and cell survival among the cell types. High concentrations of insulin increased PANC1 and HPDE cell number, but did not alter primary duct cell proliferation in vitro. Cell survival was enhanced by insulin in both primary duct cells and HPDE cells. Moreover, we found that primary cells were more dependent on AKT signalling, while HPDE cells and PANC1 cells were more dependent on RAF/ERK signalling. Our data suggest that excessive insulin signalling may contribute to proliferation and survival in human immortalized pancreatic ductal cells and metastatic pancreatic cancer cells, but not in normal adult human pancreatic ductal cells. These data suggest that signalling pathways

  19. Fault-related fold styles and progressions in fold-thrust belts: Insights from sandbox modeling

    Science.gov (United States)

    Yan, Dan-Ping; Xu, Yan-Bo; Dong, Zhou-Bin; Qiu, Liang; Zhang, Sen; Wells, Michael

    2016-03-01

    Fault-related folds of variable structural styles and assemblages commonly coexist in orogenic belts with competent-incompetent interlayered sequences. Despite their commonality, the kinematic evolution of these structural styles and assemblages are often loosely constrained because multiple solutions exist in their structural progression during tectonic restoration. We use a sandbox modeling instrument with a particle image velocimetry monitor to test four designed sandbox models with multilayer competent-incompetent materials. Test results reveal that decollement folds initiate along selected incompetent layers with decreasing velocity difference and constant vorticity difference between the hanging wall and footwall of the initial fault tips. The decollement folds are progressively converted to fault-propagation folds and fault-bend folds through development of fault ramps breaking across competent layers and are followed by propagation into fault flats within an upper incompetent layer. Thick-skinned thrust is produced by initiating a decollement fault within the metamorphic basement. Progressive thrusting and uplifting of the thick-skinned thrust trigger initiation of the uppermost incompetent decollement with formation of a decollement fold and subsequent converting to fault-propagation and fault-bend folds, which combine together to form imbricate thrust. Breakouts at the base of the early formed fault ramps along the lowest incompetent layers, which may correspond to basement-cover contacts, domes the upmost decollement and imbricate thrusts to form passive roof duplexes and constitute the thin-skinned thrust belt. Structural styles and assemblages in each of tectonic stages are similar to that in the representative orogenic belts in the South China, Southern Appalachians, and Alpine orogenic belts.

  20. Myriocin significantly increases the mortality of a non-mammalian model host during Candida pathogenesis.

    Directory of Open Access Journals (Sweden)

    Nadja Rodrigues de Melo

    Full Text Available Candida albicans is a major human pathogen whose treatment is challenging due to antifungal drug toxicity, drug resistance and paucity of antifungal agents available. Myrocin (MYR inhibits sphingosine synthesis, a precursor of sphingolipids, an important cell membrane and signaling molecule component. MYR also has dual immune suppressive and antifungal properties, potentially modulating mammalian immunity and simultaneously reducing fungal infection risk. Wax moth (Galleria mellonella larvae, alternatives to mice, were used to establish if MYR suppressed insect immunity and increased survival of C. albicans-infected insects. MYR effects were studied in vivo and in vitro, and compared alone and combined with those of approved antifungal drugs, fluconazole (FLC and amphotericin B (AMPH. Insect immune defenses failed to inhibit C. albicans with high mortalities. In insects pretreated with the drug followed by C. albicans inoculation, MYR+C. albicans significantly increased mortality to 93% from 67% with C. albicans alone 48 h post-infection whilst AMPH+C. albicans and FLC+C. albicans only showed 26% and 0% mortalities, respectively. MYR combinations with other antifungal drugs in vivo also enhanced larval mortalities, contrasting the synergistic antifungal effect of the MYR+AMPH combination in vitro. MYR treatment influenced immunity and stress management gene expression during C. albicans pathogenesis, modulating transcripts putatively associated with signal transduction/regulation of cytokines, I-kappaB kinase/NF-kappaB cascade, G-protein coupled receptor and inflammation. In contrast, all stress management gene expression was down-regulated in FLC and AMPH pretreated C. albicans-infected insects. Results are discussed with their implications for clinical use of MYR to treat sphingolipid-associated disorders.

  1. 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.

  2. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  4. Progressive failure analysis of composite structure based on micro- and macro-mechanics models

    Institute of Scientific and Technical Information of China (English)

    孙志刚; 阮绍明; 陈磊; 宋迎东

    2015-01-01

    Based on parameter design language, a program of progressive failure analysis in composite structures is proposed. In this program, the relationship between macro- and micro-mechanics is established and the macro stress distribution of the composite structure is calculated by commercial finite element software. According to the macro-stress, the damaged point is found and the micro-stress distribution of representative volume element is calculated by finite-volume direct averaging micromechanics (FVDAM). Compared with the results calculated by failure criterion based on macro-stress field (the maximum stress criteria and Hashin criteria) and micro-stress field (Huang model), it is proven that the failure analysis based on macro- and micro-mechanics model is feasible and efficient.

  5. Stochastic modeling of progressive breakdown in ultrathin SiO2 films

    Science.gov (United States)

    Miranda, E.; Cester, A.; Paccagnella, A.

    2003-12-01

    The breakdown dynamics of ultrathin SiO2 films in metal-oxide-semiconductor structures has been investigated. We show that the progressive increase of the leakage current that flows through the oxide when subjected to constant electrical stress can be modeled by the stochastic logistic differential equation. This approach relies on a time scale separation in which a deterministic term provides the S-shaped growth trajectory while a second term of the equation deals with the noisy behavior. Because of the inherent mean reverting property of the simulation process, the proposed model is also able to cover cases in which sudden upward and downward changes of the system's conductance are registered.

  6. Catastrophic shifts and lethal thresholds in a propagating front model of unstable tumor progression

    Science.gov (United States)

    Amor, Daniel R.; Solé, Ricard V.

    2014-08-01

    Unstable dynamics characterizes the evolution of most solid tumors. Because of an increased failure of maintaining genome integrity, a cumulative increase in the levels of gene mutation and loss is observed. Previous work suggests that instability thresholds to cancer progression exist, defining phase transition phenomena separating tumor-winning scenarios from tumor extinction or coexistence phases. Here we present an integral equation approach to the quasispecies dynamics of unstable cancer. The model exhibits two main phases, characterized by either the success or failure of cancer tissue. Moreover, the model predicts that tumor failure can be due to either a reduced selective advantage over healthy cells or excessive instability. We also derive an approximate, analytical solution that predicts the front speed of aggressive tumor populations on the instability space.

  7. Catastrophic shifts and lethal thresholds in a propagating front model of unstable tumour progression

    CERN Document Server

    Amor, Daniel R

    2014-01-01

    Unstable dynamics characterizes the evolution of most solid tumors. Because of an increased failure of maintaining genome integrity, a cumulative increase in the levels of gene mutation and loss is observed. Previous work suggests that instability thresholds to cancer progression exist, defining phase transition phenomena separating tumor-winning scenarios from tumor extinction or coexistence phases. Here we present an integral equation approach to the quasispecies dynamics of unstable cancer. The model exhibits two main phases, characterized by either the success or failure of cancer tissue. Moreover, the model predicts that tumor failure can be due to either a reduced selective advantage over healthy cells or excessive instability. We also derive an approximate, analytical solution that predicts the front speed of aggressive tumor populations on the instability space.

  8. A Multiscale Progressive Failure Modeling Methodology for Composites that Includes Fiber Strength Stochastics

    Science.gov (United States)

    Ricks, Trenton M.; Lacy, Thomas E., Jr.; Bednarcyk, Brett A.; Arnold, Steven M.; Hutchins, John W.

    2014-01-01

    A multiscale modeling methodology was developed for continuous fiber composites that incorporates a statistical distribution of fiber strengths into coupled multiscale micromechanics/finite element (FE) analyses. A modified two-parameter Weibull cumulative distribution function, which accounts for the effect of fiber length on the probability of failure, was used to characterize the statistical distribution of fiber strengths. A parametric study using the NASA Micromechanics Analysis Code with the Generalized Method of Cells (MAC/GMC) was performed to assess the effect of variable fiber strengths on local composite failure within a repeating unit cell (RUC) and subsequent global failure. The NASA code FEAMAC and the ABAQUS finite element solver were used to analyze the progressive failure of a unidirectional SCS-6/TIMETAL 21S metal matrix composite tensile dogbone specimen at 650 degC. Multiscale progressive failure analyses were performed to quantify the effect of spatially varying fiber strengths on the RUC-averaged and global stress-strain responses and failure. The ultimate composite strengths and distribution of failure locations (predominately within the gage section) reasonably matched the experimentally observed failure behavior. The predicted composite failure behavior suggests that use of macroscale models that exploit global geometric symmetries are inappropriate for cases where the actual distribution of local fiber strengths displays no such symmetries. This issue has not received much attention in the literature. Moreover, the model discretization at a specific length scale can have a profound effect on the computational costs associated with multiscale simulations.models that yield accurate yet tractable results.

  9. A Bayesian model for censored positive count data in evaluating breast cancer progression.

    Science.gov (United States)

    Yeh, Hung-Wen; Jiang, Yu; Garrard, Lili; Lei, Yang; Gajewski, Byron

    2013-01-01

    Basic science researchers transplant human cancer tissues from patients with ductal carcinoma in situ (DCIS) to animals and observe the progression of the disease. Successful transplants show invasion of human tissues across mammary ducts in animal fat pads and cause DCIS-like lesions in one or more ducts. In this work, we consider data from a recent publication of breast cancer research where positive counts of affected ducts may be subject to censoring. We fit the data with zero-truncated Poisson (ZTP) models with an informative prior of gamma. Due to the zero-truncation and right censoring, posterior distributions may not be conventional gamma and are estimated through Markov chain Monte Carlo and grid approximation. For each of the two cell lines, we fit a model with group-specific parameters for DCIS subtypes classified by the cell surface biomarkers, and another model with a homogeneous parameter across groups. Models are compared by the Deviance Information Criterion (DIC). For the chosen prior parameter values, Bayes estimates are comparative to the maximum likelihood estimates, and the DIC favors the simpler model in both cell lines.

  10. Micromechanics Modeling of Composites Subjected to Multiaxial Progressive Damage in the Constituents

    Science.gov (United States)

    Bednarcyk, Brett A.; Aboudi, Jacob; Amold, Steven M.

    2010-01-01

    The high-fidelity generalized method of cells composite micromechanics model is extended to include constituent-scale progressive damage via a proposed damage model. The damage model assumes that all material nonlinearity is due to damage in the form of reduced stiffness, and it uses six scalar damage variables (three for tension and three for compression) to track the damage. Damage strains are introduced that account for interaction among the strain components and that also allow the development of the damage evolution equations based on the constituent material uniaxial stress strain response. Local final-failure criteria are also proposed based on mode-specific strain energy release rates and total dissipated strain energy. The coupled micromechanics-damage model described herein is applied to a unidirectional E-glass/epoxy composite and a proprietary polymer matrix composite. Results illustrate the capability of the coupled model to capture the vastly different character of the monolithic (neat) resin matrix and the composite in response to far-field tension, compression, and shear loading.

  11. Differential expression proteomics of human colorectal cancer based on a syngeneic cellular model for the progression of adenoma to carcinoma.

    Science.gov (United States)

    Roth, Udo; Razawi, Hanieh; Hommer, Julia; Engelmann, Katja; Schwientek, Tilo; Müller, Stefan; Baldus, Stephan E; Patsos, Georgios; Corfield, Anthony P; Paraskeva, Christos; Hanisch, Franz-Georg

    2010-01-01

    This is the first differential expression proteomics study on a human syngeneic cellular in vitro progression model of the colorectal adenoma-to-carcinoma sequence, the anchorage-dependent non-tumorigenic adenoma derived cell line AA/C1 and the derived anchorage-independent and tumorigenic carcinoma cell line AA/C1/SB10C. The study is based on quantitative 2-DE and is complemented by Western blot validation. Excluding redundancies due to proteolysis and post-translational modified isoforms of over 2000 protein spots, 13 proteins were revealed as regulated with statistical variance being within the 95th confidence level and were identified by peptide mass fingerprinting in MALDI MS. Progression-associated proteins belong to the functional complexes of anaerobic glycolysis/gluconeogenesis, steroid biosynthesis, prostaglandin biosynthesis, the regulation and maintenance of the cytoskeleton, protein biosynthesis and degradation, the regulation of apoptosis or other functions. Partial but significant overlap was revealed with previous proteomics and transcriptomics studies in colorectal carcinoma. Among upregulated proteins we identified 3-HMG-CoA synthase, protein phosphatase 1, prostaglandin E synthase 2, villin 1, annexin A1, triosephosphate isomerase, phosphoserine aminotransferase 1, fumarylacetoacetate hydrolase and pyrroline-5-carboxylate reductase 1 (PYCR1), while glucose-regulated protein 78, cathepsin D, lamin A/C and quinolate phosphoribosyltransferase were downregulated.

  12. Casodex treatment induces hypoxia-related gene expression in the LNCaP prostate cancer progression model

    Directory of Open Access Journals (Sweden)

    Gopalakrishnan Velliyur K

    2005-03-01

    Full Text Available Abstract Background The changes in gene expression profile as prostate cancer progresses from an androgen-dependent disease to an androgen-independent disease are still largely unknown. Methods We examined the gene expression profile in the LNCaP prostate cancer progression model during chronic treatment with Casodex using cDNA microarrays consisting of 2305 randomly chosen genes. Results Our studies revealed a representative collection of genes whose expression was differentially regulated in LNCaP cells upon treatment with Casodex. A set of 15 genes were shown to be highly expressed in Casodex-treated LNCaP cells compared to the reference sample. This set of highly expressed genes represents a signature collection unique to prostate cancer since their expression was significantly greater than that of the collective pool of ten cancer cell lines of the reference sample. The highly expressed signature collection included the hypoxia-related genes membrane metallo-endopeptidase (MME, cyclin G2, and Bcl2/adenovirus E1B 19 kDa (BNIP3. Given the roles of these genes in angiogenesis, cell cycle regulation, and apoptosis, we further analyzed their expression and concluded that these genes may be involved in the molecular changes that lead to androgen-independence in prostate cancer. Conclusion Our data indicate that one of the mechanisms of Casodex action in prostate cancer cells is induction of hypoxic gene expression.

  13. Efficacy of dietary antioxidants combined with a chemotherapeutic agent on human colon cancer progression in a fluorescent orthotopic mouse model.

    Science.gov (United States)

    Ma, Huaiyu; Das, Tapas; Pereira, Suzette; Yang, Zhijian; Zhao, Ming; Mukerji, Pradip; Hoffman, Robert M

    2009-07-01

    We report here the efficacy of dietary antioxidants in combination with chemotherapy on tumor growth in the orthotopic COLO-205-green fluorescent protein (GFP) human colon cancer mouse model. The orthotopically-transplanted nude mice used for the study were randomly divided into 5 groups (A-E) after surgical orthotopic implantation (SOI) of tumor tissue. The following diets were given: Diet A, modified AIN-93M mature rodent diet with 4% fish oil; Diet B, modified AIN-93M which contains added antioxidants vitamin A, vitamin E, and selenium at levels present in the standard AIN-93M diet; Diet C, Diet A without added antioxidants vitamin A, vitamin E, or selenium; Diet D, Diet A with 5 times the amount of added antioxidants vitamin A, vitamin E, and selenium present in Diet B. Cisplatin, 7 mg/kg, was administered intraperitoneally on day 16 after SOI. Throughout the course of treatment, noninvasive whole-body imaging, based on the GFP expression of the tumor, permitted visualization of tumor progression. At sacrifice, the mean tumor weights showed significant statistical differences in all of the treated groups compared to the negative control (no cisplatin treatment) (p cisplatin efficacy by high-dose antioxidants in combination with fish oil for colon cancer progression and suggests the design of clinical trials for this regimen.

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

    Directory of Open Access Journals (Sweden)

    Fumiaki Sato

    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.

  15. Weighted Feature Significance: A Simple, Interpretable Model of Compound Toxicity Based on the Statistical Enrichment of Structural Features

    OpenAIRE

    Huang, Ruili; Southall, Noel; Xia, Menghang; Cho, Ming-Hsuang; Jadhav, Ajit; Nguyen, Dac-Trung; Inglese, James; Tice, Raymond R.; Austin, Christopher P.

    2009-01-01

    In support of the U.S. Tox21 program, we have developed a simple and chemically intuitive model we call weighted feature significance (WFS) to predict the toxicological activity of compounds, based on the statistical enrichment of structural features in toxic compounds. We trained and tested the model on the following: (1) data from quantitative high–throughput screening cytotoxicity and caspase activation assays conducted at the National Institutes of Health Chemical Genomics Center, (2) dat...

  16. 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.

  17. 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

  18. Transgenic Monkey Model of the Polyglutamine Diseases Recapitulating Progressive Neurological Symptoms

    Science.gov (United States)

    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

  19. Progressive Consent and Specimen Accrual Models to Address Sustainability: A Decade's Experience at an Oregon Biorepository.

    Science.gov (United States)

    Ost, John A; Newton, Paul W; Neilson, Duncan R; Cioffi, Joseph A; Wackym, P Ashley; Perkins, R Serene

    2017-02-01

    The Legacy Biorepository is a College of American Pathologists-accredited biorepository operating within a seven-hospital healthcare system, with a decade's experience in specimen accrual, storage, and distribution. While standardization of our practices through accreditation remains a priority, we along with others face challenges with regard to sustainability. Purposeful changes in our consent process, which we term "progressive consent," are expected to improve sustainability and operational flexibility while increasing our scientific impact. Until 2015, informed consent was performed primarily by biorepository staff at an estimated time of 1 hour per case. After a process improvement exercise, we successfully changed our informed consent process to a modified front-door model, with use of material and data for research as an opt-in or opt-out selection on the institutional patient informed consent form provided to surgery patients in the healthcare system. Successful implementation of this change required the engagement and participation of multiple stakeholders in healthcare system leadership, hospital administration, research, legal, regulatory, and patient care levels. A modified front-door consent enabled us to collect an additional 38 specimens in the first two quarters of 2016, with a time commitment of 15.75 hours, a time savings per specimen increasing in Q2 over Q1. We estimate a potential savings of 43 hours in 2016. This progressive model allowed us to maintain our frozen sample collection while increasing the availability of paraffin-embedded tissue and bodily fluids. Augmenting our tissue collection added little expense per case (approximately half that of each frozen tissue aliquot) and increased the range of biospecimens collected. Biorepository financial sustainability is a critical issue. Thorough evaluation and modification of existing procedures and collection models, as well as cost recovery initiatives, can translate into savings

  20. Chronic administration of ethanol leaf extract of Moringa oleifera Lam. (Moringaceae) may compromise glycaemic efficacy of Sitagliptin with no significant effect in retinopathy in a diabetic rat model.

    Science.gov (United States)

    Olurishe, Comfort; Kwanashie, Helen; Zezi, Abdulkadiri; Danjuma, Nuhu; Mohammed, Bisalla

    2016-12-24

    Moringa oleifera Lam. (Moringaceae) has gained awareness for its antidiabetic effect, and is used as alternative therapy or concurrently with orthodox medicines such as sitagliptin in diabetes mellitus. This is without ascertaining the possibility of drug-herb interactions, which could either lead to enhanced antidiabetic efficacy, increased toxicity, or compromised glycaemic control with negative consequence in diabetic retinopathy. To investigate the effect, of sitagliptin (50mg/kg), Moringa oleifera (300mg/kg) leaf extract, and a combination of both on glycaemic control parameters, lenticular opacity and changes in retinal microvasculature in alloxan (150mg/kg i.p) induced diabetic rat model. Seven groups of eight rats per group were used, with groups I, II and VII as normal (NC), diabetic (DC) and post-prandial controls (PPC). Groups III to VI were diabetic rats on sitagliptin (III), M. oleifera (IV), sitagliptin and M. oleifera (SM) (V), for 42 days with 2 weeks delayed treatment in a post-prandial hyperglycaemic group (PPSM) (VI). Glycaemic control parameters, insulin levels, body weights, and effects of retinal microvasculature on lenticular opacity/morphology were investigated. A significant decrease in fasting blood glucose (FBG) levels was displayed in SM group from day 14(60%) (poleifera showed a progressive decrease in anti-hyperglycaemic effect of sitagliptin, and although it delayed the onset of lenticular opacity (i.e. cataract-like changes) it did not prevent the progression nor ameliorated pathologic lesions in the retina. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  1. Longitudinal deformation models, spatial regularizations and learning strategies to quantify Alzheimer's disease progression.

    Science.gov (United States)

    Fiot, Jean-Baptiste; Raguet, Hugo; Risser, Laurent; Cohen, Laurent D; Fripp, Jurgen; Vialard, François-Xavier

    2014-01-01

    In the context of Alzheimer's disease, two challenging issues are (1) the characterization of local hippocampal shape changes specific to disease progression and (2) the identification of mild-cognitive impairment patients likely to convert. In the literature, (1) is usually solved first to detect areas potentially related to the disease. These areas are then considered as an input to solve (2). As an alternative to this sequential strategy, we investigate the use of a classification model using logistic regression to address both issues (1) and (2) simultaneously. The classification of the patients therefore does not require any a priori definition of the most representative hippocampal areas potentially related to the disease, as they are automatically detected. We first quantify deformations of patients' hippocampi between two time points using the large deformations by diffeomorphisms framework and transport these deformations to a common template. Since the deformations are expected to be spatially structured, we perform classification combining logistic loss and spatial regularization techniques, which have not been explored so far in this context, as far as we know. The main contribution of this paper is the comparison of regularization techniques enforcing the coefficient maps to be spatially smooth (Sobolev), piecewise constant (total variation) or sparse (fused LASSO) with standard regularization techniques which do not take into account the spatial structure (LASSO, ridge and ElasticNet). On a dataset of 103 patients out of ADNI, the techniques using spatial regularizations lead to the best classification rates. They also find coherent areas related to the disease progression.

  2. Progress in rapid climate changes and their modeling study in millennial and centennial scales

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Rapid climate change at millennial and centennial scales is one of the most important aspects in paleoclimate study.It has been found that rapid climate change at millennial and centennial scales is a global phenomenon during both the glacial age and the Holocene with amplitudes typical of geological or astronomical time-scales.Simulations of glacial and Holocene climate changes have demonstrated the response of the climate system to the changes of earth orbital parameter and the importance of variations in feedbacks of ocean,vegetation,icecap and greenhouse gases.Modeling experiments suggest that the Atlantic thermohaline circulation was sensitive to the fresh water input into the North Atlantic and was closely related to the rapid climate changes during the last glacial age and the Holocene.Adopting the Earth-system models of inter mediate complexity (EMICs),CLIMBER-2,the response of East Asian climate change to Dansgaard/Oeschger and Heinrich events during the typical last glacial period (60 ka B.P.-20 ka B.P.) and impacts of ice on the Tibetan plateau on Holocene climate change were stimulated,studied and revealed.Further progress of paleoclimate modeling depends on developing finer-grid models and reconstructing more reliable boundary conditions.More attention should be paid on the study of mechanisms of abrupt climatic changes as well as regional climate changes in the background of global climate change.

  3. Microfluidic culture models to study the hydrodynamics of tumor progression and therapeutic response.

    Science.gov (United States)

    Buchanan, Cara; Rylander, Marissa Nichole

    2013-08-01

    The integration of tissue engineering strategies with microfluidic technologies has enabled the design of in vitro microfluidic culture models that better adapt to morphological changes in tissue structure and function over time. These biomimetic microfluidic scaffolds accurately mimic native 3D microenvironments, as well as permit precise and simultaneous control of chemical gradients, hydrodynamic stresses, and cellular niches within the system. The recent application of microfluidic in vitro culture models to cancer research offers enormous potential to aid in the development of improved therapeutic strategies by supporting the investigation of tumor angiogenesis and metastasis under physiologically relevant flow conditions. The intrinsic material properties and fluid mechanics of microfluidic culture models enable high-throughput anti-cancer drug screening, permit well-defined and controllable input parameters to monitor tumor cell response to various hydrodynamic conditions or treatment modalities, as well as provide a platform for elucidating fundamental mechanisms of tumor physiology. This review highlights recent developments and future applications of microfluidic culture models to study tumor progression and therapeutic targeting under conditions of hydrodynamic stress relevant to the complex tumor microenvironment.

  4. Multidisciplinary model-based-engineering for laser weapon systems: recent progress

    Science.gov (United States)

    Coy, Steve; Panthaki, Malcolm

    2013-09-01

    We are working to develop a comprehensive, integrated software framework and toolset to support model-based engineering (MBE) of laser weapons systems. MBE has been identified by the Office of the Director, Defense Science and Engineering as one of four potentially "game-changing" technologies that could bring about revolutionary advances across the entire DoD research and development and procurement cycle. To be effective, however, MBE requires robust underlying modeling and simulation technologies capable of modeling all the pertinent systems, subsystems, components, effects, and interactions at any level of fidelity that may be required in order to support crucial design decisions at any point in the system development lifecycle. Very often the greatest technical challenges are posed by systems involving interactions that cut across two or more distinct scientific or engineering domains; even in cases where there are excellent tools available for modeling each individual domain, generally none of these domain-specific tools can be used to model the cross-domain interactions. In the case of laser weapons systems R&D these tools need to be able to support modeling of systems involving combined interactions among structures, thermal, and optical effects, including both ray optics and wave optics, controls, atmospheric effects, target interaction, computational fluid dynamics, and spatiotemporal interactions between lasing light and the laser gain medium. To address this problem we are working to extend Comet™, to add the addition modeling and simulation capabilities required for this particular application area. In this paper we will describe our progress to date.

  5. Rock avalanches: significance and progress (Invited)

    Science.gov (United States)

    Davies, T. R.

    2013-12-01

    1. The probability distribution of landslide volumes follows a power-law indicating that large rock avalanches dominate the terrestrial sediment supply from mountains, and that their source area morphologies dominate mountain topography. 2. Large rock slope failures (~ 106 m3 or greater) often mobilise into rock avalanches, which can travel extraordinarily long distances with devastating effect. This hypermobility has been the subject of many investigations; we have demonstrated that it can be explained quantitatively and accurately by considering the energetics of the intense rock fragmentation that always occurs during motion of a large rock mass. 3. Study of rock avalanche debris psd shows that the energy used in creating new rock surface area during fragmentation is not lost to surface energy, but is recycled generating a high-frequency elastic energy field that reduces the frictional resistance to motion during runout. 4. Rock avalanches that deposit on glaciers can eventually form large terminal moraines that have no connection with any climatic event; unless these are identified as rock-avalanche-influenced they can confuse palaeoclimatic inferences drawn from moraine ages. Rock-avalanche-derived fines, however, can be identified in moraine debris up to ten thousand years old by the characteristic micron-scale agglomerates that form during intense fragmentation, and which are absent from purely climatically-induced moraines; there is thus a strong case for re-examining existing palaeoclimatic databases to eliminate potentially rock-avalanche-influenced moraine ages. 5. Rock avalanches (especially coseismic ones) are a serious hazard, being very destructive in their own right; they also block river valleys, forming landslide dams and potentially devastating dambreak floods, and subsequent severe decade-scale aggradation of downstream fans and floodplains. Rock avalanches falling into lakes or fiords can cause catastrophic tsunami that pose a serious risk to waterside developments. Lake tsunami risk assessments can be derived from submarine landslide deposits. 6. Delineating hazard zones for these phenomena depends entirely on identifying the sites of future coseismic slope failures; in some cases this appears possible by identifying precursory coseismic displacements accumulated during previous earthquakes.

  6. 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

  7. Monoclonal gammopathy of undetermined significance

    National Research Council Canada - National Science Library

    Kyle, Robert A; Vincent Rajkumar, S

    2006-01-01

    Summary Significant advances have been made in our understanding of the natural history, pathogenesis, mechanisms of progression and prognosis of monoclonal gammopathy of undetermined significance (MGUS...

  8. PROGRESSIVE FRAGMENT MODELING OF FAILURE WAVE IN CERAMICS UNDER PLANAR IMPACT LOADING

    Institute of Scientific and Technical Information of China (English)

    YAO Guo-wen; LIU Zhan-fang; HUANG Pei-yan

    2006-01-01

    Polycrystalline ceramics have heterogeneous meso-structures which result in high singularity in stress distribution. Based on this, a progressive fragment model was proposed which describes the failure wave formation and propagation in shocked ceramics.The governing equation of the failure wave was characterized by inelastic bulk strain with material damage and fracture. And the inelastic bulk strain consists of dilatant strain from nucleation and expansion of microcracks and condensed strain from collapse of original pores. Numerical simulation of the free surface velocity was performed in good agreement with planar impact experiments on 92.93% aluminas at China Academy of Engineering Physics. And the longitudinal, lateral and shear stress histories upon the arrival of the failure wave were predicted, which present the diminished shear strength and lost spall strength in the failed layer.

  9. [Geothermal system temperature-depth database and model for data analysis]. 5. quarterly technical progress report

    Energy Technology Data Exchange (ETDEWEB)

    Blackwell, D.D.

    1998-04-25

    During this first quarter of the second year of the contract activity has involved several different tasks. The author has continued to work on three tasks most intensively during this quarter: the task of implementing the data base for geothermal system temperature-depth, the maintenance of the WWW site with the heat flow and gradient data base, and finally the development of a modeling capability for analysis of the geothermal system exploration data. The author has completed the task of developing a data base template for geothermal system temperature-depth data that can be used in conjunction with the regional data base that he had already developed and is now implementing it. Progress is described.

  10. Progress of Time-dependent Transport Simulations Using GYRO and Neoclassical Models Within FACETS

    Science.gov (United States)

    Vadlamani, S.; Pankin, A. Y.; Kruger, S.; Carlsson, J.; Cary, J.; Pletzer, A.; Candy, J.; Collier, A.; Fahey, M.

    2009-05-01

    Progress on the integration of the turbulent transport code GYRO and the neoclassical codes such as NCLASS into the FACETS (Framework Application for Core-Edge Transport Simulations) framework through the use of a multi-language Fortran/C/C++ friendly FMCFM (Framework for Modernization and Componentization of Fusion Modules) interface is presented. The FMCFM framework provides a common interface to varying fusion transport modules and libraries such as those in the National Transport Code Collaboration (NTCC) module library [1]. The interlanguage wrapper code is automatically generated. First results of coupled GYRO-NCLASS-FACETS simulations using realistic initial profiles and particle/heat sources are presented. [1] A. H. Kritz et al. Comp. Phys. Communications 164 ,108 (2004) [2] See A. Pankin's et al. presentation on transport models in FACETS (Sherwood 2009)

  11. Effects of Vitamin D Supplementation during the Induction and Progression of Osteoarthritis in a Rat Model

    Directory of Open Access Journals (Sweden)

    E. C. Castillo

    2012-01-01

    Full Text Available Epidemiological studies correlate low levels of vitamin D with the osteoarthritis (OA progression. Cytokines and metalloproteases play a major role in OA promoting the inflammation and degradation of the cartilage and can be induced through the Toll-like receptor (TLR pathway. The aim of this study was to evaluate the protective effect of vitamin D supplementation on the development of osteoarthritis (OA through examining the genetic regulation of TLRs, cytokines, and metalloproteases in chondrocytes as well as the wideness of cartilage in rats with OA. Our results demonstrate that the signaling through TLR-4 is a proinflammatory mechanism in osteoarthritis that drives the upregulation of MMP-3, IL-1β, and TNF-α gene expression, leading to cartilage degradation and inflammation. Vitamin D supplementation had a protective effect during the onset but not during the chronic stage of OA in the rat model.

  12. Introduction to special issue on animal models of neuropsychiatric disorders and substance use disorders: Progress and gaps.

    Science.gov (United States)

    Smith, Mark A; Evans, Suzette M

    2017-04-01

    This is an introduction to the special issue, "Animal Models of Neuropsychiatric Disorders and Substance Use Disorders: Progress and Gaps." This issue presents 6 original research reports describing the use of mice and rats to model neurodevelopmental disorders, depressive disorders, anxiety disorders, and substance use disorders. Collectively, these studies demonstrate the progress of the field and the gaps and challenges that remain. They also illustrate the range of conditions that are informed by animal models and identify the clinical populations that stand to benefit from their use in preclinical research. (PsycINFO Database Record

  13. Experimental and theoretical modelling of sand-water-object interaction under nonlinear progressive waves

    Science.gov (United States)

    Testik, Firat Yener

    An experimental and theoretical study has been conducted to obtain a fundamental understanding of the dynamics of the sand, water and a solid object interaction as progressive gravity waves impinge on a sloping beach. Aside from obvious scientific interest, this exceedingly complex physical problem is important for naval applications, related to the behavior of disk/cylindrical shaped objects (mines) in the coastal waters. To address this problem, it was divided into a set of simpler basic problems. To begin, nonlinear progressive waves were investigated experimentally in a wave tank for the case of a rigid (impermeable) sloping bottom. Parameterizations for wave characteristics were proposed and compared with the experiments. In parallel, a numerical wave tank model (NWT) was calibrated using experimental data from a single run, and wave field in the wave tank was simulated numerically for the selected experiments. Subsequently, a layer of sand was placed on the slope and bottom topography evolution processes (ripple and sandbar dynamics, bottom topography relaxation under variable wave forcing, etc.) were investigated experimentally. Models for those processes were developed and verified by experimental measurements. Flow over a circular cylinder placed horizontally on a plane wall was also studied. The far-flow field of the cylinder placed in the wave tank was investigated experimentally and numerical results from the NWT simulations were compared with the experimental data. In the mean time, the near-flow velocity/vorticity field around a short cylinder under steady and oscillatory flow was studied in a towing tank. Horseshoe vortex formation and periodic shedding were documented and explained. With the understanding gained through the aforementioned studies, dynamics and burial/scour around the bottom objects in the wave tank were studied. Possible scenarios on the behavior of the disk-shaped objects were identified and explained. Scour around 3D cylindrical

  14. 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 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.

  15. 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.

  16. The Progress of Induced Pluripotent Stem Cells as Models of Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Ji-feng Kang

    2016-01-01

    Full Text Available In recent years, induced pluripotent stem cells (iPSCs were widely used for investigating the mechanisms of Parkinson’s disease (PD. Somatic cells from patients with SNCA (α-synuclein, LRRK2 (leucine-rich repeat kinase 2, PINK1 (PTEN induced putative kinase 1, Parkin mutations, and at-risk individuals carrying GBA (β-glucocerebrosidase mutations have been successfully induced to iPSCs and subsequently differentiated into dopaminergic (DA neurons. Importantly, some PD-related cell phenotypes, including α-synuclein aggregation, mitophagy, damaged mitochondrial DNA, and mitochondrial dysfunction, have been described in these iPSCs models, which further investigated the pathogenesis of PD. In 2007, Takahashi et al. and Vodyanik et al. generated iPSCs from human somatic cells for the first time. Since then, patients derived iPSCs were applied for disease modeling, drug discovery and screening, autologous cell replacement therapy, and other biological applications. iPSC research has now become a hot topic in a wide range of fields. This review summarizes the recent progress of PD patients derived iPSC models in pathogenic mechanism investigation and potential clinical applications, especially their promising strategy in pharmacological study and DA neurons transplantation therapy. However, the challenges of iPSC transplantation still exist, and it has a long way to go before it can be used in clinical application.

  17. 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 thermal and moisture management of electronic enclosures are fields of high interest in recent years. It is now generally accepted that the protection of electronic devices is dependent on avoiding critical levels of relative humidity (typically 60–90%) during operations. Leveraging the devel......The thermal and moisture management of electronic enclosures are fields of high interest in recent years. It is now generally accepted that the protection of electronic devices is dependent on avoiding critical levels of relative humidity (typically 60–90%) during operations. Leveraging...... 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...... equivalent RC-circuit models for concentration of water vapor and temperature in the electronic enclosure. After reducing the potential parameter-value space for the critical features using the RC-approach, the optimization strategy uses simpler 2D CFD models of temperature and moisture transport to further...

  18. Loss of HCN1 enhances disease progression in mouse models of CNG channel-linked retinitis pigmentosa and achromatopsia.

    Science.gov (United States)

    Schön, Christian; Asteriti, Sabrina; Koch, Susanne; Sothilingam, Vithiyanjali; Garcia Garrido, Marina; Tanimoto, Naoyuki; Herms, Jochen; Seeliger, Mathias W; Cangiano, Lorenzo; Biel, Martin; Michalakis, Stylianos

    2016-03-15

    Most inherited blinding diseases are characterized by compromised retinal function and progressive degeneration of photoreceptors. However, the factors that affect the life span of photoreceptors in such degenerative retinal diseases are rather poorly understood. Here, we explore the role of hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) in this context. HCN1 is known to adjust retinal function under mesopic conditions, and although it is expressed at high levels in rod and cone photoreceptor inner segments, no association with any retinal disorder has yet been found. We investigated the effects of an additional genetic deletion of HCN1 on the function and survival of photoreceptors in a mouse model of CNGB1-linked retinitis pigmentosa (RP). We found that the absence of HCN1 in Cngb1 knockout (KO) mice exacerbated photoreceptor degeneration. The deleterious effect was reduced by expression of HCN1 using a viral vector. Moreover, pharmacological inhibition of HCN1 also enhanced rod degeneration in Cngb1 KO mice. Patch-clamp recordings revealed that the membrane potentials of Cngb1 KO and Cngb1/Hcn1 double-KO rods were both significantly depolarized. We also found evidence for altered calcium homeostasis and increased activation of the protease calpain in Cngb1/Hcn1 double-KO mice. Finally, the deletion of HCN1 also exacerbated degeneration of cone photoreceptors in a mouse model of CNGA3-linked achromatopsia. Our results identify HCN1 as a major modifier of photoreceptor degeneration and suggest that pharmacological inhibition of HCN channels may enhance disease progression in RP and achromatopsia patients. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  19. Differential Progressive Remodeling of Coronary and Cerebral Arteries and Arterioles in an Aortic Coarctation Model of Hypertension

    Directory of Open Access Journals (Sweden)

    Heather N. Hayenga

    2012-11-01

    Full Text Available OBJECTIVES: Effects of hypertension on arteries and arterioles often manifest first as a thickened wall, with associated changes in passive material properties (e.g., stiffness or function (e.g., cellular phenotype, synthesis and removal rates, and vasomotor responsiveness. Less is known, however, regarding the relative evolution of such changes in vessels from different vascular beds.METHODS: We used an aortic coarctation model of hypertension in the mini-pig to elucidate spatiotemporal changes in geometry and wall composition (including layer-specific thicknesses as well as presence of collagen, elastin, smooth muscle, endothelial, macrophage, and hematopoietic cells in three different arterial beds, specifically aortic, cerebral, and coronary, and vasodilator function in two different arteriolar beds, the cerebral and coronary.RESULTS: Marked geometric and structural changes occurred in the thoracic aorta and left anterior descending coronary artery within 2 weeks of the establishment of hypertension and continued to increase over the 8-week study period. In contrast, no significant changes were observed in the middle cerebral arteries from the same animals. Consistent with these differential findings at the arterial level, we also found a diminished nitric oxide-mediated dilation to adenosine at 8 weeks of hypertension in coronary arterioles, but not cerebral arterioles.CONCLUSION: These findings, coupled with the observation that temporal changes in wall constituents and the presence of macrophages differed significantly between the thoracic aorta and coronary arteries, confirm a strong differential progressive remodeling within different vascular beds. Taken together, these results suggest a spatiotemporal progression of vascular remodeling, beginning first in large elastic arteries and delayed in distal vessels.

  20. Prognostic significance of the 2004 WHO/ISUP classification for prediction of recurrence, progression, and cancer-specific mortality of non-muscle-invasive urothelial tumors of the urinary bladder: a clinicopathologic study of 1,515 cases.

    Science.gov (United States)

    Pan, Chin-Chen; Chang, Yen-Hwa; Chen, Kuang-Kuo; Yu, Hui-Jung; Sun, Chih-Hao; Ho, Donald M T

    2010-05-01

    To verify prognostic significance of the 2004 World Health Organization (WHO)/International Society of Urological Pathology (ISUP) grading systems, we retrospectively studied the tumors of 1,515 patients who underwent transurethral resection of primary non-muscle-invasive urothelial tumors (pTa, 1,006 patients; pT1, 509 patients) confined to the bladder. Cases were classified according to the 2004 WHO/ISUP systems as 212 cases of papillary urothelial neoplasm of low malignant potential (PUNLMP), 706 low-grade papillary urothelial carcinomas (LPUCs), and 597 high-grade papillary urothelial carcinomas (HPUCs). PUNLMP showed the statistically significantly lowest recurrence cumulative incidence compared with the other tumor types. There were significant differences and trends for higher progression and cancer-specific mortality cumulative incidence in the following order: PUNLMP, LPUC, pTa HPUC, and pT1 HPUC. No differences of progression and cancer-specific mortality cumulative incidence were found between pTa and pT1 LPUC. Our study validates the usefulness of the 2004 WHO/ISUP system to classify urothelial tumors into prognostically distinct categories that would contribute to the design of therapeutic and monitoring strategies for patients with non-muscle-invasive bladder urothelial tumors.

  1. A more robust model of the biodiesel reaction, allowing identification of process conditions for significantly enhanced rate and water tolerance.

    Science.gov (United States)

    Eze, Valentine C; Phan, Anh N; Harvey, Adam P

    2014-03-01

    A more robust kinetic model of base-catalysed transesterification than the conventional reaction scheme has been developed. All the relevant reactions in the base-catalysed transesterification of rapeseed oil (RSO) to fatty acid methyl ester (FAME) were investigated experimentally, and validated numerically in a model implemented using MATLAB. It was found that including the saponification of RSO and FAME side reactions and hydroxide-methoxide equilibrium data explained various effects that are not captured by simpler conventional models. Both the experiment and modelling showed that the "biodiesel reaction" can reach the desired level of conversion (>95%) in less than 2min. Given the right set of conditions, the transesterification can reach over 95% conversion, before the saponification losses become significant. This means that the reaction must be performed in a reactor exhibiting good mixing and good control of residence time, and the reaction mixture must be quenched rapidly as it leaves the reactor.

  2. Krüppel-like Factor 4 Inhibits Tumorigenic Progression and Metastasis in a Mouse Model of Breast Cancer

    Directory of Open Access Journals (Sweden)

    Jennifer L Yori

    2011-07-01

    Full Text Available Krüppel-like factor 4 (KLF4 is a zinc finger transcription factor that functions as an oncogene or tumor suppressor in a highly tissue-specific cell-dependent manner. However, its precise role in breast cancer and metastasis remains unclear. Here, we show that transient adenoviral expression of KLF4 in the 4T1 orthotopic mammary cancer model significantly attenuated primary tumor growth as well as micrometastases to the lungs and liver. These results can be attributed, in part, to decreased proliferation and increased apoptosis. Further supporting a tumor-suppressive role for KLF4 in the breast, we found that KLF4 expression is lost in a mouse model of HER2/NEU/ERBB2-positive breast cancer. To determine whether enforced KLF4 expression could alter tumor latency in these mice, we used a doxycycline-inducible expression model in the context of the MMTV-Neu transgene. Surprisingly, tumors that developed in this model also lost KLF4 expression, suggesting negative selection for sustained expression. We have previously reported that KLF4 inhibits epithelial-to-mesenchymal transition (EMT, a preliminary step in metastatic progression. Overexpression of KLF4 in 4T1 cells led to a significant reduction in the expression of Snail, a key mediator of EMT and metastasis. Conversely, KLF4 silencing increased Snail expression in the nontransformed MCF-10A cell line. Collectively, these data demonstrate the first functional, in vivo evidence for KLF4 as a tumor suppressor in breast cancer cells. Furthermore, our findings suggest an inhibitory role for KLF4 during breast cancer metastases that functions, in part, through repression of Snail.

  3. Generalized Models: An Application to Identify Environmental Variables That Significantly Affect the Abundance of Three Tree Species

    Directory of Open Access Journals (Sweden)

    Pablo Antúnez

    2017-02-01

    Full Text Available In defining the environmental preferences of plant species, statistical models are part of the essential tools in the field of modern ecology. However, conventional linear models require compliance with some parametric assumptions and if these requirements are not met, imply a serious limitation of the applied model. In this study, the effectiveness of linear and nonlinear generalized models was examined to identify the unitary effect of the principal environmental variables on the abundance of three tree species growing in the natural temperate forests of Oaxaca, Mexico. The covariates that showed a significant effect on the distribution of tree species were the maximum and minimum temperatures and the precipitation during specific periods. Results suggest that the generalized models, particularly smoothed models, were able to detect the increase or decrease of the abundance against changes in an environmental variable; they also revealed the inflection of the regression. In addition, these models allow partial characterization of the realized niche of a given species according to some specific variables, regardless of the type of relationship.

  4. [The production of mouse model of slowly progressive diabetes mellitus and the preventive effect of low molecular weight chitosan on the progression of the diabetes mellitus].

    Science.gov (United States)

    Ito, Mikio

    2013-01-01

    The aim of our study was to produce a new diabetic model by a single i.p. injection of various doses of streptozotocin (STZ) to 8-week-old male Institute of Cancer Research (ICR) mice. When STZ was i.p. injected at doses rainging from 75 to 200 mg/kg, in the group injected 200 mg/kg STZ, the non-fasting serum glucose levels markedly rose from 1 week after STZ administration and the high glucose levels were maintained for 9 weeks. The serum glucose levels in the group administered 100 mg/kg STZ were within a normal range at 1 week after STZ administration, but thereafter continued to increase gradually till 9 weeks. In contrast with the serum glucose levels, a marked reduction in the percentage of the relative numbers of β-cells in the islets of pancreas from 1 week in mice injected 200 mg/kg STZ was observed. On the other hand, in 100 mg/kg STZ mice, the number of β-cells was almost normal percentage at 1 week and then continued to gradually decrease as the time went on throughout 24-week-observation. These results indicate that only the 100 mg/kg STZ injection produces slowly progressive diabetes mellitus in mice. Low molecular weight (LMW) chitosan (chitosan lactate, average of molecular weight: 20000) was administered as drinking water from prediabetic stage (from 2 weeks after 100 mg/kg STZ injection). The 0.2% or 0.8% LMW chitosan administration prevented the progression of 100 mg/kg STZ-induced slowly progressive diabetes mellitus. The mechanisms, which LMW chitosan is effective in this model may be discussed on β-cells.

  5. 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

  6. Longitudinal deformation models, spatial regularizations and learning strategies to quantify Alzheimer's disease progression

    Directory of Open Access Journals (Sweden)

    Jean-Baptiste Fiot

    2014-01-01

    Full Text Available In the context of Alzheimer's disease, two challenging issues are (1 the characterization of local hippocampal shape changes specific to disease progression and (2 the identification of mild-cognitive impairment patients likely to convert. In the literature, (1 is usually solved first to detect areas potentially related to the disease. These areas are then considered as an input to solve (2. As an alternative to this sequential strategy, we investigate the use of a classification model using logistic regression to address both issues (1 and (2 simultaneously. The classification of the patients therefore does not require any a priori definition of the most representative hippocampal areas potentially related to the disease, as they are automatically detected. We first quantify deformations of patients' hippocampi between two time points using the large deformations by diffeomorphisms framework and transport these deformations to a common template. Since the deformations are expected to be spatially structured, we perform classification combining logistic loss and spatial regularization techniques, which have not been explored so far in this context, as far as we know. The main contribution of this paper is the comparison of regularization techniques enforcing the coefficient maps to be spatially smooth (Sobolev, piecewise constant (total variation or sparse (fused LASSO with standard regularization techniques which do not take into account the spatial structure (LASSO, ridge and ElasticNet. On a dataset of 103 patients out of ADNI, the techniques using spatial regularizations lead to the best classification rates. They also find coherent areas related to the disease progression.

  7. 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...... particle conversion patterns. The improved model will impact the simulation capabilities of biomass fired boilers in the areas of thermal conditions, NOx formation and particle deposition behaviour.......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...

  8. A multistate model to evaluate COPD progression integrating drugs consumption data and hospital databases

    Directory of Open Access Journals (Sweden)

    Nicola Bartolomeo

    2015-06-01

    Full Text Available Background The increase in costs related to the diagnosis and treatment of chronic-degenerative diseases requires a better knowledge of the true care pathway of patients. The study objective was to explore, using multi-state modeling, how analyses of drug prescriptions and data obtained from hospital discharge sheets can be used in combination to build a model of patients health care pathway in a non experimental setting. The model was applied to Chronic Obstructive Pulmonary Disease (COPD. Methods Based on the GOLD guidelines, access to hospitalization for COPD and prescription pharmaceuticals were awarded to seven transients states theoretically progressive. The intensity of transition were estimated with the non-parametric method proposed by Aalen and Johansen for multi-state Markov models non-homogeneous in time. Results The COPD patients included in the study are 111190. Patients admitted with a diagnosis of non acute COPD had a growing probability over time of needing prescriptions for inhaled corticosteroids (ICS or the set combination of long-acting beta-agonists (LABA and ICS; they also had a rising probability of an exacerbation. The use of ICS alone or in combination with LABA delays a hospital admission for acute respiratory failure by about 6 months, as compared to short-acting beta-agonists or anticholinergics. Conclusion The probabilities of a transition and their distribution in relation to time, sex, age and clinical status can be a helpful tool for those operating in the health care sector, who are called upon to carry out decisions from the standpoints of both efficacious clinical management and an efficient use of resources.

  9. Reviewing progress in PJM's capacity market structure via the new reliability pricing model

    Energy Technology Data Exchange (ETDEWEB)

    Sener, Adil Caner; Kimball, Stefan

    2007-12-15

    The Reliability Pricing Model introduces significant changes to the capacity market structure of PJM. The main feature of the RPM design is a downward-sloping demand curve, which replaces the highly volatile vertical demand curve. The authors review the latest RPM structure, results of the auctions, and the future course of the implementation process. (author)

  10. Role of Compaction Ratio in the Mathematical Model of Progressive Collapse

    CERN Document Server

    Beck, Charles M

    2008-01-01

    We derive a mathematical model of progressive collapse and examine role of compaction. Contrary to a previous result by Ba\\v{z}ant and Verdure, J. Engr. Mech. ASCE 133 (2006) 308, we find that compaction slows down the avalanche by effectively increasing the resistive force. We compare currently available estimates of the resistive force, that of Ba\\v{z}ant and Verdure (2006) corrected for compaction for World Trade Center (WTC) 2, and of Beck, www.arxiv.org:physics/0609105, for WTC 1 and 2. We concentrate on a damage wave propagating through the building before the avalanche that figures in both models: an implicit heat wave that reduces the resistive force of the building by 60% in Ba\\v{z}ant and Verdure (2006), or a wave of massive destruction that reduces the resistive force by 75% in Beck (2006). We show that the avalanche cannot supply the energy to the heat wave as this increases the resistive force by two orders of magnitude. We thus reaffirm the conclusion of Beck (2006) that the avalanche is initiat...

  11. Modeling invasive breast cancer: growth factors propel progression of HER2-positive premalignant lesions.

    Science.gov (United States)

    Pradeep, C-R; Zeisel, A; Köstler, W J; Lauriola, M; Jacob-Hirsch, J; Haibe-Kains, B; Amariglio, N; Ben-Chetrit, N; Emde, A; Solomonov, I; Neufeld, G; Piccart, M; Sagi, I; Sotiriou, C; Rechavi, G; Domany, E; Desmedt, C; Yarden, Y

    2012-08-01

    The HER2/neu oncogene encodes a receptor-like tyrosine kinase whose overexpression in breast cancer predicts poor prognosis and resistance to conventional therapies. However, the mechanisms underlying aggressiveness of HER2 (human epidermal growth factor receptor 2)-overexpressing tumors remain incompletely understood. Because it assists epidermal growth factor (EGF) and neuregulin receptors, we overexpressed HER2 in MCF10A mammary cells and applied growth factors. HER2-overexpressing cells grown in extracellular matrix formed filled spheroids, which protruded outgrowths upon growth factor stimulation. Our transcriptome analyses imply a two-hit model for invasive growth: HER2-induced proliferation and evasion from anoikis generate filled structures, which are morphologically and transcriptionally analogous to preinvasive patients' lesions. In the second hit, EGF escalates signaling and transcriptional responses leading to invasive growth. Consistent with clinical relevance, a gene expression signature based on the HER2/EGF-activated transcriptional program can predict poorer prognosis of a subgroup of HER2-overexpressing patients. In conclusion, the integration of a three-dimensional cellular model and clinical data attributes progression of HER2-overexpressing lesions to EGF-like growth factors acting in the context of the tumor's microenvironment.

  12. The photon dose calculation algorithm used in breast radiotherapy has significant impact on the parameters of radiobiological models.

    Science.gov (United States)

    Petillion, Saskia; Swinnen, Ans; Defraene, Gilles; Verhoeven, Karolien; Weltens, Caroline; Van den Heuvel, Frank

    2014-07-08

    The comparison of the pencil beam dose calculation algorithm with modified Batho heterogeneity correction (PBC-MB) and the analytical anisotropic algorithm (AAA) and the mutual comparison of advanced dose calculation algorithms used in breast radiotherapy have focused on the differences between the physical dose distributions. Studies on the radiobiological impact of the algorithm (both on the tumor control and the moderate breast fibrosis prediction) are lacking. We, therefore, investigated the radiobiological impact of the dose calculation algorithm in whole breast radiotherapy. The clinical dose distributions of 30 breast cancer patients, calculated with PBC-MB, were recalculated with fixed monitor units using more advanced algorithms: AAA and Acuros XB. For the latter, both dose reporting modes were used (i.e., dose-to-medium and dose-to-water). Next, the tumor control probability (TCP) and the normal tissue complication probability (NTCP) of each dose distribution were calculated with the Poisson model and with the relative seriality model, respectively. The endpoint for the NTCP calculation was moderate breast fibrosis five years post treatment. The differences were checked for significance with the paired t-test. The more advanced algorithms predicted a significantly lower TCP and NTCP of moderate breast fibrosis then found during the corresponding clinical follow-up study based on PBC calculations. The differences varied between 1% and 2.1% for the TCP and between 2.9% and 5.5% for the NTCP of moderate breast fibrosis. The significant differences were eliminated by determination of algorithm-specific model parameters using least square fitting. Application of the new parameters on a second group of 30 breast cancer patients proved their appropriateness. In this study, we assessed the impact of the dose calculation algorithms used in whole breast radiotherapy on the parameters of the radiobiological models. The radiobiological impact was eliminated by

  13. Serum NX-DCP as a New Noninvasive Model to Predict Significant Liver Fibrosis in Chronic Hepatitis C.

    Science.gov (United States)

    Saito, Masaya; Yano, Yoshihiko; Hirano, Hirotaka; Momose, Kenji; Yoshida, Masaru; Azuma, Takeshi

    2015-02-01

    Finding a noninvasive method to predict liver fibrosis using inexpensive and easy-to-use markers is important. We aimed to clarify whether NX-des-γ-carboxyprothrombin (NX-DCP) could become a new noninvasive model to predict liver fibrosis in hepatitis C virus (HCV) related liver disease. We performed a prospective cohort study on a consecutive group of 101 patients who underwent liver biopsy for HCV-related liver disease at Kobe University Hospital. Laboratory measurements were performed on the same day as the biopsy. Factors associated with significant fibrosis (F3-4) were assessed by multivariate analyses. A comparison of predictive ability between multivariate factors and abovementioned noninvasive models was also performed. Increase in serum NX-DCP was significantly related to increase in fibrosis stage (P = 0.006). Moreover, NX-DCP was a multivariate factor associated with the presence of significant fibrosis F 3-4 (median 21 of F0-2 group vs. median 22 of F3-4 group with P = 0.002). The AUC of NX-DCP showed no significant differences compared with those of the AST-to-platelet ratio index (APRI), modified-APRI, the Göteborg University Cirrhosis Index (GUCI), the Lok index, the Hui score, cirrhosis discriminating score (CDS) and the Pohl score (P > 0.05). NX-DCP correlated positively with fibrosis stage and could discriminate well between HCV-related patients with or without significant fibrosis. Moreover, NX-DCP had a similar predictive ability to the abovementioned models, and thereby could be a new noninvasive prediction tool for fibrosis.

  14. Axl tyrosine kinase protects against tubulo-interstitial apoptosis and progression of renal failure in a murine model of chronic kidney disease and hyperphosphataemia.

    Directory of Open Access Journals (Sweden)

    Gareth D Hyde

    Full Text Available Chronic kidney disease (CKD is defined as the progressive loss of renal function often involving glomerular, tubulo-interstitial and vascular pathology. CKD is associated with vascular calcification; the extent of which predicts morbidity and mortality. However, the molecular regulation of these events and the progression of chronic kidney disease are not fully elucidated. To investigate the function of Axl receptor tyrosine kinase in CKD we performed a sub-total nephrectomy and fed high phosphate (1% diet to Axl+/+ and Axl-/- mice. Plasma Gas6 (Axl' ligand, renal Axl expression and downstream Akt signalling were all significantly up-regulated in Axl+/+ mice following renal mass reduction and high phosphate diet, compared to age-matched controls. Axl-/- mice had significantly enhanced uraemia, reduced bodyweight and significantly reduced survival following sub-total nephrectomy and high phosphate diet compared to Axl+/+ mice; only 45% of Axl-/- mice survived to 14 weeks post-surgery compared to 87% of Axl+/+ mice. Histological analysis of kidney remnants revealed no effect of loss of Axl on glomerular hypertrophy, calcification or renal sclerosis but identified significantly increased tubulo-interstitial apoptosis in Axl-/- mice. Vascular calcification was not induced in Axl+/+ or Axl-/- mice in the time frame we were able to examine. In conclusion, we identify the up-regulation of Gas6/Axl signalling as a protective mechanism which reduces tubulo-interstitial apoptosis and slows progression to end-stage renal failure in the murine nephrectomy and high phosphate diet model of CKD.

  15. Axl tyrosine kinase protects against tubulo-interstitial apoptosis and progression of renal failure in a murine model of chronic kidney disease and hyperphosphataemia.

    Science.gov (United States)

    Hyde, Gareth D; Taylor, Rebecca F; Ashton, Nick; Borland, Samantha J; Wu, Hon Sing Geoffrey; Gilmore, Andrew P; Canfield, Ann E

    2014-01-01

    Chronic kidney disease (CKD) is defined as the progressive loss of renal function often involving glomerular, tubulo-interstitial and vascular pathology. CKD is associated with vascular calcification; the extent of which predicts morbidity and mortality. However, the molecular regulation of these events and the progression of chronic kidney disease are not fully elucidated. To investigate the function of Axl receptor tyrosine kinase in CKD we performed a sub-total nephrectomy and fed high phosphate (1%) diet to Axl+/+ and Axl-/- mice. Plasma Gas6 (Axl' ligand), renal Axl expression and downstream Akt signalling were all significantly up-regulated in Axl+/+ mice following renal mass reduction and high phosphate diet, compared to age-matched controls. Axl-/- mice had significantly enhanced uraemia, reduced bodyweight and significantly reduced survival following sub-total nephrectomy and high phosphate diet compared to Axl+/+ mice; only 45% of Axl-/- mice survived to 14 weeks post-surgery compared to 87% of Axl+/+ mice. Histological analysis of kidney remnants revealed no effect of loss of Axl on glomerular hypertrophy, calcification or renal sclerosis but identified significantly increased tubulo-interstitial apoptosis in Axl-/- mice. Vascular calcification was not induced in Axl+/+ or Axl-/- mice in the time frame we were able to examine. In conclusion, we identify the up-regulation of Gas6/Axl signalling as a protective mechanism which reduces tubulo-interstitial apoptosis and slows progression to end-stage renal failure in the murine nephrectomy and high phosphate diet model of CKD.

  16. Animal model for progressive resistance exercise: a detailed description of model and its implications for basic research in exercise

    OpenAIRE

    Cassilhas, Ricardo Cardoso [UNIFESP; Reis,Ismair Teodoro; Venâncio, Daniel; Fernandes, Jansen [UNIFESP; Tufik,Sérgio; de Mello, Marco Túlio

    2013-01-01

    The Several animal models have been proposed for resistance training. In addition, the results of these studies have been highly variable. Some of the studies have used negative reinforcement, electric shock or food deprivation to motivate the learning of the task. Features such as conditioning through electric shock may undermine the significance of the results or even prevent the model from being successfully executed. Due to these reasons, in this study we propose to use an adaptation of t...

  17. An innovative approach to the formation of a progressive taxation probabilistic model on personal incomes

    National Research Council Canada - National Science Library

    Kalinina Olga

    2016-01-01

      This article suggests a mathematical justification of the possibility of transition to progressive taxation on personal incomes, allowing socially redistribute the tax burden between different groups...

  18. 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.

  19. Progress towards a more predictive model for hohlraum radiation drive and symmetry

    Science.gov (United States)

    Jones, O. S.; Suter, L. J.; Scott, H. A.; Barrios, M. A.; Farmer, W. A.; Hansen, S. B.; Liedahl, D. A.; Mauche, C. W.; Moore, A. S.; Rosen, M. D.; Salmonson, J. D.; Strozzi, D. J.; Thomas, C. A.; Turnbull, D. P.

    2017-05-01

    For several years, we have been calculating the radiation drive in laser-heated gold hohlraums using flux-limited heat transport with a limiter of 0.15, tabulated values of local thermodynamic equilibrium gold opacity, and an approximate model for not in a local thermodynamic equilibrium (NLTE) gold emissivity (DCA_2010). This model has been successful in predicting the radiation drive in vacuum hohlraums, but for gas-filled hohlraums used to drive capsule implosions, the model consistently predicts too much drive and capsule bang times earlier than measured. In this work, we introduce a new model that brings the calculated bang time into better agreement with the measured bang time. The new model employs (1) a numerical grid that is fully converged in space, energy, and time, (2) a modified approximate NLTE model that includes more physics and is in better agreement with more detailed offline emissivity models, and (3) a reduced flux limiter value of 0.03. We applied this model to gas-filled hohlraum experiments using high density carbon and plastic ablator capsules that had hohlraum He fill gas densities ranging from 0.06 to 1.6 mg/cc and hohlraum diameters of 5.75 or 6.72 mm. The new model predicts bang times to within ±100 ps for most experiments with low to intermediate fill densities (up to 0.85 mg/cc). This model predicts higher temperatures in the plasma than the old model and also predicts that at higher gas fill densities, a significant amount of inner beam laser energy escapes the hohlraum through the opposite laser entrance hole.

  20. Progression of liver cirrhosis to HCC: an application of hidden Markov model

    Directory of Open Access Journals (Sweden)

    Serio Gabriella

    2011-04-01

    Full Text Available Abstract Background Health service databases of administrative type can be a useful tool for the study of progression of a disease, but the data reported in such sources could be affected by misclassifications of some patients' real disease states at the time. Aim of this work was to estimate the transition probabilities through the different degenerative phases of liver cirrhosis using health service databases. Methods We employed a hidden Markov model to determine the transition probabilities between two states, and of misclassification. The covariates inserted in the model were sex, age, the presence of comorbidities correlated with alcohol abuse, the presence of diagnosis codes indicating hepatitis C virus infection, and the Charlson Index. The analysis was conducted in patients presumed to have suffered the onset of cirrhosis in 2000, observing the disease evolution and, if applicable, death up to the end of the year 2006. Results The incidence of hepatocellular carcinoma (HCC in cirrhotic patients was 1.5% per year. The probability of developing HCC is higher in males (OR = 2.217 and patients over 65 (OR = 1.547; over 65-year-olds have a greater probability of death both while still suffering from cirrhosis (OR = 2.379 and if they have developed HCC (OR = 1.410. A more severe casemix affects the transition from HCC to death (OR = 1.714. The probability of misclassifying subjects with HCC as exclusively affected by liver cirrhosis is 14.08%. Conclusions The hidden Markov model allowing for misclassification is well suited to analyses of health service databases, since it is able to capture bias due to the fact that the quality and accuracy of the available information are not always optimal. The probability of evolution of a cirrhotic subject to HCC depends on sex and age class, while hepatitis C virus infection and comorbidities correlated with alcohol abuse do not seem to have an influence.

  1. Recent progress and review of Physics Dynamics Coupling in geophysical models

    CERN Document Server

    Gross, Markus; Rasch, Philip J; Caldwell, Peter M; Williamson, David L; Klocke, Daniel; Jablonowski, Christiane; Thatcher, Diana R; Wood, Nigel; Cullen, Mike; Beare, Bob; Willett, Martin; Lemarié, Florian; Blayo, Eric; Malardel, Sylvie; Termonia, Piet; Gassmann, Almut; Lauritzen, Peter H; Johansen, Hans; Zarzycki, Colin M; Sakaguchi, Koichi; Leung, Ruby

    2016-01-01

    Geophysical models of the atmosphere and ocean invariably involve parameterizations. These represent two distinct areas: a) Subgrid processes which the model cannot (yet) resolve, due to its discrete resolution, and b) sources in the equation, due to radiation for example. Hence coupling between these physics parameterizations and the resolved fluid dynamics and also between the dynamics of the different fluids in the system (air and water) is necessary. This coupling is an important aspect of geophysical models. However, often model development is strictly segregated into either physics or dynamics. Hence, this area has many more unanswered questions than in-depth understanding. Furthermore, recent developments in the design of dynamical cores (e.g. significant increase of resolution, move to non-hydrostatic equation sets etc), extended process physics (e.g. prognostic micro physics, 3D turbulence, non-vertical radiation etc) and predicted future changes of the computational infrastructure (e.g. Exascale wit...

  2. Protective Effect of Perindopril on Tumor Progression and Angiogenesis in Animal Model of Breast Cancer.

    Science.gov (United States)

    Patel, Snehal S; Nakka, Surender

    2017-01-01

    Studies have shown that the renin angiotensin system via angiogenesis is involved in tumor development. Therefore, objective of the present study was to examine the effect of perindopril on tumor growth and angiogenesis in animal models of breast cancer. In the present study, the effect of perindopril on tumor development of mammary gland cancer induced by 7,12-dimethylbenz[a]anthracene, mouse tumor xenograft and corneal micropocket model has been investigated. Anti-angiogenic effect by chick yolk sac membrane assay has also been studied. In the present study, it has been found that perindopril produced a significant inhibition of tumor growth, in DMBA induced breast cancer. Treatment also produced significant suppression of cancer biomarkers such as lactate dehydrogenase, gamma glutamyl transferase and inflammatory markers such as C-reactive protein, erythrocyte sedimentation rate. Histopathological analysis also showed that perindopril was able to inhibit tumor development by the inhibition of hyperplastic lesions. Perindopril produced significant inhibition of tumor growth, in a mouse xenograft model and caused inhibition of neovascularization in the corneal micropocket model. In chick yolk sac membrane assay, perindopril showed inhibition of vascular growth and reduced blood vessel formation. Therefore, perindopril is widely used in clinical practice, may represent a neo-adjuvant therapy for treatment of breast cancer. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  3. Progress and prospects for genetic modification of nonhuman primate models in biomedical research.

    Science.gov (United States)

    Chan, Anthony W S

    2013-01-01

    The growing interest of modeling human diseases using genetically modified (transgenic) nonhuman primates (NHPs) is a direct result of NHPs (rhesus macaque, etc.) close relation to humans. NHPs share similar developmental paths with humans in their anatomy, physiology, genetics, and neural functions; and in their cognition, emotion, and social behavior. The NHP model within biomedical research has played an important role in the development of vaccines, assisted reproductive technologies, and new therapies for many diseases. Biomedical research has not been the primary role of NHPs. They have mainly been used for safety evaluation and pharmacokinetics studies, rather than determining therapeutic efficacy. The development of the first transgenic rhesus macaque (2001) revolutionized the role of NHP models in biomedicine. Development of the transgenic NHP model of Huntington's disease (2008), with distinctive clinical features, further suggested the uniqueness of the model system; and the potential role of the NHP model for human genetic disorders. Modeling human genetic diseases using NHPs will continue to thrive because of the latest advances in molecular, genetic, and embryo technologies. NHPs rising role in biomedical research, specifically pre-clinical studies, is foreseeable. The path toward the development of transgenic NHPs and the prospect of transgenic NHPs in their new role in future biomedicine needs to be reviewed. This article will focus on the advancement of transgenic NHPs in the past decade, including transgenic technologies and disease modeling. It will outline new technologies that may have significant impact in future NHP modeling and will conclude with a discussion of the future prospects of the transgenic NHP model.

  4. Association of Immunosuppression with DR6 Expression during the Development and Progression of Spontaneous Ovarian Cancer in Laying Hen Model.

    Science.gov (United States)

    McNeal, Sa'Rah; Bitterman, Pincas; Bahr, Janice M; Edassery, Seby L; Abramowicz, Jacques S; Basu, Sanjib; Barua, Animesh

    2016-01-01

    Ovarian cancer (OVCA) mainly disseminates in the peritoneal cavity. Immune functions are important to prevent OVCA progression and recurrence. The mechanism of immunosuppression, a hallmark of tumor progression, is not well understood. The goal of this study was to determine the immune system's responses and its suppression during OVCA development and progression in hens. Frequencies of CD8+ T cells and IgY-containing cells and expression of immunosuppressors including IRG1 and DR6 in OVCA at early and late stages in hens were examined. Frequencies of stromal but not the intratumoral CD+8 T cells and IgY-containing cells increased significantly (P < 0.01) during OVCA development and progression. Tumor progression was associated with increased expression of IRG1 and DR6 and decreased infiltration of immune cells into the tumor. Frequency of stromal but not intratumoral immune cells increases during OVCA development and progression. Tumor-induced IRG1 and DR6 may prevent immune cells from invading the tumor.

  5. MAMM (Methane and other greenhouse gases in the Arctic - Measurements, process studies and Modelling) progress report

    Science.gov (United States)

    Nisbet, E. G.; Pyle, J. A.

    2012-12-01

    MAMM consortium (led by JA Pyle, Univ. Cambridge, with partners from Univ. East Anglia; Univ. Manchester; Royal Holloway, Univ. of London; NERC Centre for Ecology and Hydrology). The UK MAMM project (Methane and other greenhouse gases in the Arctic - Measurements, process studies and Modelling) is designed to improve quantitative knowledge of Arctic methane and other greenhouse gases from various sources (e.g. wetlands, natural gas, clathrates), to determine magnitudes and spatial distributions, and to develop process understanding (e.g. dependence of fluxes on temperature). In Arctic Finland, Sweden, Norway and Spitsbergen, intensive low-level aircraft campaigns (flights in spring, summer, autumn 2012 and 2013, with the UK FAAM BAe146 aircraft) are designed to measure concentrations of CH4 and other gases across the Arctic by time and location, with in situ sampling for δ13CCH4 at selected sites on land (Zeppelin, Pallas, Alert) and Keeling-plot diel determination of wetland source signatures. High altitude flights sampled stratosphere-troposphere exchange in the Arctic to assess the impact of the polar vortex on methane isotope budgets. Methane column profiles are measured by combining ground based eddy covariance and chamber measurements with aircraft measurements, using a landscape-scale box model approach and flying up and downwind of source regions. Airborne remote sensing is being used to retrieve CH4 columns for comparison with in-situ profiles and testing of hyperspectral retrieval methods from satellite platforms. Longer-term time series measurements are also being established in Kjølnes, northern Norway, for a range of greenhouse and related species via continuous or flask/bag sampling. Modelling studies are in progress to assess the overall Arctic influence on the global methane budget, including detailed back-trajectory analysis of the measurements, especially the isotopic data, to identify sources of methane by location, type (e.g. gasfield, wetland

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

    LENUS (Irish Health Repository)

    Donatello, Simona

    2011-01-01

    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.

  7. 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.

  8. Loss of ovarian function in the VCD mouse-model of menopause leads to insulin resistance and a rapid progression into the metabolic syndrome.

    Science.gov (United States)

    Romero-Aleshire, Melissa J; Diamond-Stanic, Maggie K; Hasty, Alyssa H; Hoyer, Patricia B; Brooks, Heddwen L

    2009-09-01

    Factors comprising the metabolic syndrome occur with increased incidence in postmenopausal women. To investigate the effects of ovarian failure on the progression of the metabolic syndrome, female B(6)C(3)F(1) mice were treated with 4-vinylcyclohexene diepoxide (VCD) and fed a high-fat (HF) diet for 16 wk. VCD destroys preantral follicles, causing early ovarian failure and is a well-characterized model for the gradual onset of menopause. After 12 wk on a HF diet, VCD-treated mice had developed an impaired glucose tolerance, whereas cycling controls were unaffected [12 wk AUC HF mice 13,455 +/- 643 vs. HF/VCD 17,378 +/- 1140 mg/dl/min, P diet, VCD-treated mice had significantly higher fasting insulin levels (HF 5.4 +/- 1.3 vs. HF/VCD 10.1 +/- 1.4 ng/ml, P diet (HF 56.2 +/- 16.7 vs. HF/VCD 113.1 +/- 19.6 mg/dl x microU/ml, P diet gained more weight than mice on a standard diet, and weight gain in HF/VCD mice was significantly increased compared with HF cycling controls. Interestingly, even without a HF diet, progression into VCD-induced menopause caused a significant increase in cholesterol and free fatty acids. Furthermore, in mice fed a standard diet (6% fat), insulin resistance developed 4 mo after VCD-induced ovarian failure. Insulin resistance following ovarian failure (menopause) was prevented by estrogen replacement. Studies here demonstrate that ovarian failure (menopause) accelerates progression into the metabolic syndrome and that estrogen replacement prevents the onset of insulin resistance in VCD-treated mice. Thus, the VCD model of menopause provides a physiologically relevant means of studying how sex hormones influence the progression of the metabolic syndrome.

  9. Nested arithmetic progressions of oscillatory phases in Olsen's enzyme reaction model.

    Science.gov (United States)

    Gallas, Marcia R; Gallas, Jason A C

    2015-06-01

    We report some regular organizations of stability phases discovered among self-sustained oscillations of a biochemical oscillator. The signature of such organizations is a nested arithmetic progression in the number of spikes of consecutive windows of periodic oscillations. In one of them, there is a main progression of windows whose consecutive number of spikes differs by one unit. Such windows are separated by a secondary progression of smaller windows whose number of spikes differs by two units. Another more complex progression involves a fan-like nested alternation of stability phases whose number of spikes seems to grow indefinitely and to accumulate methodically in cycles. Arithmetic progressions exist abundantly in several control parameter planes and can be observed by tuning just one among several possible rate constants governing the enzyme reaction.

  10. The Y-Box Binding Protein 1 Suppresses Alzheimer's Disease Progression in Two Animal Models.

    Directory of Open Access Journals (Sweden)

    N V Bobkova

    Full Text Available The Y-box binding protein 1 (YB-1 is a member of the family of DNA- and RNA binding proteins. It is involved in a wide variety of DNA/RNA-dependent events including cell proliferation and differentiation, stress response, and malignant cell transformation. Previously, YB-1 was detected in neurons of the neocortex and hippocampus, but its precise role in the brain remains undefined. Here we show that subchronic intranasal injections of recombinant YB-1, as well as its fragment YB-11-219, suppress impairment of spatial memory in olfactory bulbectomized (OBX mice with Alzheimer's type degeneration and improve learning in transgenic 5XFAD mice used as a model of cerebral amyloidosis. YB-1-treated OBX and 5XFAD mice showed a decreased level of brain β-amyloid. In OBX animals, an improved morphological state of neurons was revealed in the neocortex and hippocampus; in 5XFAD mice, a delay in amyloid plaque progression was observed. Intranasally administered YB-1 penetrated into the brain and could enter neurons. In vitro co-incubation of YB-1 with monomeric β-amyloid (1-42 inhibited formation of β-amyloid fibrils, as confirmed by electron microscopy. This suggests that YB-1 interaction with β-amyloid prevents formation of filaments that are responsible for neurotoxicity and neuronal death. Our data are the first evidence for a potential therapeutic benefit of YB-1 for treatment of Alzheimer's disease.

  11. Durability Modeling of Environmental Barrier Coating (EBC Using Finite Element Based Progressive Failure Analysis

    Directory of Open Access Journals (Sweden)

    Ali Abdul-Aziz

    2014-01-01

    Full Text Available The necessity for a protecting guard for the popular ceramic matrix composites (CMCs is getting a lot of attention from engine manufacturers and aerospace companies. The CMC has a weight advantage over standard metallic materials and more performance benefits. However, these materials undergo degradation that typically includes coating interface oxidation as opposed to moisture induced matrix which is generally seen at a higher temperature. Additionally, other factors such as residual stresses, coating process related flaws, and casting conditions may influence the degradation of their mechanical properties. These durability considerations are being addressed by introducing highly specialized form of environmental barrier coating (EBC that is being developed and explored in particular for high temperature applications greater than 1100°C. As a result, a novel computational simulation approach is presented to predict life for EBC/CMC specimen using the finite element method augmented with progressive failure analysis (PFA that included durability, damage tracking, and material degradation model. The life assessment is carried out using both micromechanics and macromechanics properties. The macromechanics properties yielded a more conservative life for the CMC specimen as compared to that obtained from the micromechanics with fiber and matrix properties as input.

  12. A growth model for primary cancer (II). New rules, progress curves and morphology transitions

    Science.gov (United States)

    Jr, S. C. Ferreira; Martins, M. L.; Vilela, M. J.

    1999-10-01

    In the present paper we extend the analysis of another model recently proposed to simulate the growth of carcinoma “in situ”, which includes cell proliferation, motility and death, as well as chemotactic interactions among cells. The tumour patterns generated by two distinct growth rules are characterised by its gyration radius, surface roughness, total number of cancer cells, and number of cells on tumour periphery. Our results indicate that very distinct morphological patterns follow Gompertz growth curves and their gyration radii increase linearly in time and scale, in the asymptotic limit, as a square root of the total number of tumour cells. In contrast, these distinct tumour patterns exhibit different scaling laws for their surfaces. Thus, some biological features of malignant behaviour seem to influence particularly the structure of the tumour border, while its gyration radius and progress curve are described by more robust functions. Finally, for both rules used, morphology transitions as well as a transient behaviour up to the onset of the phase of rapid growth in the Gompertz curves are observed.

  13. Hypertension accelerates the progression of Alzheimer-like pathology in a mouse model of the disease.

    Science.gov (United States)

    Cifuentes, Diana; Poittevin, Marine; Dere, Ekrem; Broquères-You, Dong; Bonnin, Philippe; Benessiano, Joëlle; Pocard, Marc; Mariani, Jean; Kubis, Nathalie; Merkulova-Rainon, Tatyana; Lévy, Bernard I

    2015-01-01

    Cerebrovascular impairment is frequent in patients with Alzheimer disease and is believed to influence clinical manifestation and severity of the disease. Cardiovascular risk factors, especially hypertension, have been associated with higher risk of developing Alzheimer disease. To investigate the mechanisms underlying the hypertension, Alzheimer disease cross talk, we established a mouse model of dual pathology by infusing hypertensive doses of angiotensin II into transgenic APPPS1 mice overexpressing mutated human amyloid precursor and presenilin 1 proteins. At 4.5 months, at the early stage of disease progression, only hypertensive APPPS1 mice presented impairment of temporal order memory performance in the episodic-like memory task. This cognitive deficit was associated with an increased number of cortical amyloid deposits (223±5 versus 207±5 plaques/mm(2); PHypertensive APPPS1 mice presented several cerebrovascular alterations, including a 25% reduction in cerebral microvessel density and a 30% to 40% increase in cerebral vascular amyloid deposits, as well as a decrease in vascular endothelial growth factor A expression in the brain, compared with normotensive APPPS1 mice. Moreover, the brain levels of nitric oxide synthase 1 and 3 and the nitrite/nitrate levels were reduced in hypertensive APPPS1 mice (by 49%, 34%, and 33%, respectively, compared with wild-type mice; Phypertension accelerates the development of Alzheimer disease-related structural and functional alterations, partially through cerebral vasculature impairment and reduced nitric oxide production.

  14. Insulin-like growth factor-binding protein 2-driven glioma progression is prevented by blocking a clinically significant integrin, integrin-linked kinase, and NF-κB network

    Science.gov (United States)

    Holmes, Kristen M.; Annala, Matti; Chua, Corrine Y. X.; Dunlap, Sarah M.; Liu, Yuexin; Hugen, Niek; Moore, Lynette M.; Cogdell, David; Hu, Limei; Nykter, Matti; Hess, Kenneth; Fuller, Gregory N.; Zhang, Wei

    2012-01-01

    Insulin-like growth factor-binding protein 2 (IGFBP2) is increasingly recognized as a glioma oncogene, emerging as a target for therapeutic intervention. In this study, we used an integrative approach to characterizing the IGFBP2 network, combining transcriptional profiling of human glioma with validation in glial cells and the replication-competent ASLV long terminal repeat with a splice acceptor/tv-a glioma mouse system. We demonstrated that IGFBP2 expression is closely linked to genes in the integrin and integrin-linked kinase (ILK) pathways and that these genes are associated with prognosis. We further showed that IGFBP2 activates integrin β1 and downstream invasion pathways, requires ILK to induce cell motility, and activates NF-κB. Most significantly, the IGFBP2/integrin/ILK/NF-κB network functions as a physiologically active signaling pathway in vivo by driving glioma progression; interfering with any point in the pathway markedly inhibits progression. The results of this study reveal a signaling pathway that is both targetable and highly relevant to improving the survival of glioma patients. PMID:22345562

  15. Nanoparticle-based sorting of circulating tumor cells by epithelial antigen expression during disease progression in an animal model.

    Science.gov (United States)

    Muhanna, Nidal; Mepham, Adam; Mohamadi, Reza M; Chan, Harley; Khan, Tahsin; Akens, Margarete; Besant, Justin D; Irish, Jonathan; Kelley, Shana O

    2015-10-01

    Circulating tumor cells (CTCs) can be used as markers for the detection, characterization, and targeted therapeutic management of cancer. We recently developed a nanoparticle-mediated approach for capture and sorting of CTCs based on their specific epithelial phenotype. In the current study, we investigate the phenotypic transition of tumor cells in an animal model and show the correlation of this transition with tumor progression. VX2 tumor cells were injected into rabbits, and CTCs were evaluated during tumor progression and correlated with computerized tomography (CT) measurements of tumor volume. The results showed a dramatic increase of CTCs during the four weeks of tumor growth. Following resection, CTC levels dropped but then rebounded, likely due to lymph node metastases. Additionally, CTCs showed a marked loss of the epithelial cell adhesion molecule (EpCAM) relative to precursor cells. In conclusion, the device accurately traces disease progression and CTC phenotypic shift in an animal model. The detection of circulating tumor cells (CTCs) has been used to predict disease prognosis. In this study, the authors developed a nanoparticle-mediated platform based on microfluidics to analyze the differential expressions of epithelial cell adhesion molecule (EpCAM) on CTCs in an animal model. It was found that the loss of EpCAM correlated with disease progression. Hence, the use of this platform may be further applied in other cancer models in the future. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. A model for microbial phosphorus cycling in bioturbated marine sediments: Significance for phosphorus burial in the early Paleozoic

    Science.gov (United States)

    Dale, Andrew W.; Boyle, Richard A.; Lenton, Timothy M.; Ingall, Ellery D.; Wallmann, Klaus

    2016-09-01

    A diagenetic model is used to simulate the diagenesis and burial of particulate organic carbon (Corg) and phosphorus (P) in marine sediments underlying anoxic versus oxic bottom waters. The latter are physically mixed by animals moving through the surface sediment (bioturbation) and ventilated by burrowing, tube-dwelling organisms (bioirrigation). The model is constrained using an empirical database including burial ratios of Corg with respect to organic P (Corg:Porg) and total reactive P (Corg:Preac), burial efficiencies of Corg and Porg, and inorganic carbon-to-phosphorus regeneration ratios. If Porg is preferentially mineralized relative to Corg during aerobic respiration, as many previous studies suggest, then the simulated Porg pool is found to be completely depleted. A modified model that incorporates the redox-dependent microbial synthesis of polyphosphates and Porg (termed the microbial P pump) allows preferential mineralization of the bulk Porg pool relative to Corg during both aerobic and anaerobic respiration and is consistent with the database. Results with this model show that P burial is strongly enhanced in sediments hosting fauna. Animals mix highly labile Porg away from the aerobic sediment layers where mineralization rates are highest, thereby mitigating diffusive PO43- fluxes to the bottom water. They also expand the redox niche where microbial P uptake occurs. The model was applied to a hypothetical shelf setting in the early Paleozoic; a time of the first radiation of benthic fauna. Results show that even shallow bioturbation at that time may have had a significant impact on P burial. Our model provides support for a recent study that proposed that faunal radiation in ocean sediments led to enhanced P burial and, possibly, a stabilization of atmospheric O2 levels. The results also help to explain Corg:Porg ratios in the geological record and the persistence of Porg in ancient marine sediments.

  17. A negative correlation between human carotid atherosclerotic plaque progression and plaque wall stress: in vivo MRI-based 2D/3D FSI models.

    Science.gov (United States)

    Tang, Dalin; Yang, Chun; Mondal, Sayan; Liu, Fei; Canton, Gador; Hatsukami, Thomas S; Yuan, Chun

    2008-01-01

    It is well accepted that atherosclerosis initiation and progression correlate positively with low and oscillating flow wall shear stresses (FSS). However, this mechanism cannot explain why advanced plaques continue to grow under elevated FSS conditions. In vivo magnetic resonance imaging (MRI)-based 2D/3D multi-component models with fluid-structure interactions (FSI, 3D only) for human carotid atherosclerotic plaques were introduced to quantify correlations between plaque progression measured by wall thickness increase (WTI) and plaque wall (structure) stress (PWS) conditions. A histologically validated multi-contrast MRI protocol was used to acquire multi-year in vivo MRI images. Our results using 2D models (200-700 data points/patient) indicated that 18 out of 21 patients studied showed significant negative correlation between WTI and PWS at time 2 (T2). The 95% confidence interval for the Pearson correlation coefficient is (-0.443,-0.246), p<0.0001. Our 3D FSI model supported the 2D correlation results and further indicated that combining both plaque structure stress and flow shear stress gave better approximation results (PWS, T2: R(2)=0.279; FSS, T1: R(2)=0.276; combining both: R(2)=0.637). These pilot studies suggest that both lower PWS and lower FSS may contribute to continued plaque progression and should be taken into consideration in future investigations of diseases related to atherosclerosis.

  18. An automated nowcasting model of significant instability events in the flight terminal area of Rio de Janeiro, Brazil

    Science.gov (United States)

    Borges França, Gutemberg; Valdonel de Almeida, Manoel; Rosette, Alessana C.

    2016-05-01

    This paper presents a novel model, based on neural network techniques, to produce short-term and local-specific forecasts of significant instability for flights in the terminal area of Galeão Airport, Rio de Janeiro, Brazil. Twelve years of data were used for neural network training/validation and test. Data are originally from four sources: (1) hourly meteorological observations from surface meteorological stations at five airports distributed around the study area; (2) atmospheric profiles collected twice a day at the meteorological station at Galeão Airport; (3) rain rate data collected from a network of 29 rain gauges in the study area; and (4) lightning data regularly collected by national detection networks. An investigation was undertaken regarding the capability of a neural network to produce early warning signs - or as a nowcasting tool - for significant instability events in the study area. The automated nowcasting model was tested using results from five categorical statistics, indicated in parentheses in forecasts of the first, second, and third hours, respectively, namely proportion correct (0.99, 0.97, and 0.94), BIAS (1.10, 1.42, and 2.31), the probability of detection (0.79, 0.78, and 0.67), false-alarm ratio (0.28, 0.45, and 0.73), and threat score (0.61, 0.47, and 0.25). Possible sources of error related to the test procedure are presented and discussed. The test showed that the proposed model (or neural network) can grab the physical content inside the data set, and its performance is quite encouraging for the first and second hours to nowcast significant instability events in the study area.

  19. Monitoring stroke progression: in vivo imaging of cortical perfusion, blood-brain barrier permeability and cellular damage in the rat photothrombosis model.

    Science.gov (United States)

    Schoknecht, Karl; Prager, Ofer; Vazana, Udi; Kamintsky, Lyn; Harhausen, Denise; Zille, Marietta; Figge, Lena; Chassidim, Yoash; Schellenberger, Eyk; Kovács, Richard; Heinemann, Uwe; Friedman, Alon

    2014-11-01

    Focal cerebral ischemia is among the main causes of death and disability worldwide. The ischemic core often progresses, invading the peri-ischemic brain; however, assessing the propensity of the peri-ischemic brain to undergo secondary damage, understanding the underlying mechanisms, and adjusting treatment accordingly remain clinically unmet challenges. A significant hallmark of the peri-ischemic brain is dysfunction of the blood-brain barrier (BBB), yet the role of disturbed vascular permeability in stroke progression is unclear. Here we describe a longitudinal in vivo fluorescence imaging approach for the evaluation of cortical perfusion, BBB dysfunction, free radical formation and cellular injury using the photothrombosis vascular occlusion model in male Sprague Dawley rats. Blood-brain barrier dysfunction propagated within the peri-ischemic brain in the first hours after photothrombosis and was associated with free radical formation and cellular injury. Inhibiting free radical signaling significantly reduced progressive cellular damage after photothrombosis, with no significant effect on blood flow and BBB permeability. Our approach allows a dynamic follow-up of cellular events and their response to therapeutics in the acutely injured cerebral cortex.

  20. Using perimetric data to estimate ganglion cell loss for detecting progression of glaucoma: a comparison of models.

    Science.gov (United States)

    Price, Derek A; Swanson, William H; Horner, Douglas G

    2017-07-01

    Models relating perimetric sensitivities to ganglion cell numbers have been proposed for combining structural and functional measures from patients with glaucoma. Here we compared seven models for ability to differentiate progressing and stable patients, testing the hypothesis that the model incorporating local spatial scale would have the best performance. The models were compared for the United Kingdom Glaucoma Treatment Study (UKGTS) data for the right eyes of 489 patients recently diagnosed with glaucoma. The SITA 24-2 program was utilised for perimetry and Stratus OCT fast scanning protocol for thickness of circumpapillary retinal nerve fibre layer (RNFL). The first analysis defined progression in terms of decline in RNFL thickness. The highest and lowest quintiles (22 subjects per group) were identified for change in thickness of inferior temporal (IT), superior temporal (ST), and global RNFL (μm year(-1) ); a two-way anova was used to look for differences between the models in ability to discriminate the two quintiles. The second analysis defined a 'progression group' as those who were flagged by the UKGTS criteria as having progressive loss in perimetric sensitivity, and a 'no progression' group as those with rate of change in Mean Deviation (MD) closest to 0 dB year(-1) (87 subjects per group). The third analysis characterised variability of retinal ganglion cell (RGC) models for the two groups in the second analysis, using the standard deviation of residuals from linear regression of ganglion cell number over time to compute Coefficient of Variation (CoV). The first analysis produced a negative result because the three anovas found no effect of model or interaction of model and group (F6,294 0.08). There was an effect of group only for the anova with the ST sector (F6,294 = 12.2, p models. The third analysis found that even when variability in MD was low, the CoV was so large that test-retest variation could include 100% loss of ganglion cells. Two very

  1. Progress of clinical practice on the management of burn-associated pain: Lessons from animal models.

    Science.gov (United States)

    McIntyre, Matthew K; Clifford, John L; Maani, Christopher V; Burmeister, David M

    2016-09-01

    Opioid-based analgesics provide the mainstay for attenuating burn pain, but they have a myriad of side effects including respiratory depression, nausea, impaired gastrointestinal motility, sedation, dependence, physiologic tolerance, and opioid-induced hyperalgesia. To test and develop novel analgesics, validated burn-relevant animal models of pain are indispensable. Herein we review such animal models, which are mostly limited to rodent models of burn-induced, inflammatory, and neuropathic pain. The latter two are pain syndromes that provide insight into the pain caused by systemic pro-inflammatory cytokines and direct injury to nerves (e.g., after severe burn), respectively. To date, no single animal model optimally mimics the complex pathophysiology and pain that a human burn patient experiences. No currently available burn-pain model examines effects of pharmacological intervention on wound healing. As cornerstones of pain and wound healing, pro-inflammatory mediators may be utilized for insight into both processes. Moreover, common clinical concerns such as systemic inflammatory response syndrome and multiple organ dysfunction remain unaddressed. For development of analgesics, these aberrations can significantly alter the potential efficacy and/or adverse effects of a prescribed analgesic following burn trauma. We therefore suggest that a multi-model strategy would be the most clinically relevant when evaluating novel analgesics for use in burn patients.

  2. Combination of telmisartan with sildenafil ameliorate progression of diabetic nephropathy in streptozotocin-induced diabetic model.

    Science.gov (United States)

    El-Mahdy, Nageh Ahmed; El-Sayad, Magda El-Sayed; El-Kadem, Aya Hassan

    2016-07-01

    Diabetic nephropathy (DN) is a leading cause of end-stage renal disease in the world. Several signaling pathways are involved in the pathogenesis of DN including elevation in level of angiotensin II, formation of advanced glycation end products (AGE), activation of protein kinase c (PKC), and lipid accumulation. These pathways activate one another mutually leading to oxidative stress, increasing expression of transforming growth factor beta-1(TGF-β 1) and release of interleukins and adhesion molecules, so the aim of this study is to interrupt more than pathogenic pathway to ameliorate the progression of DN. In the present study, white male rats (N=48) were divided into six groups (8 rats each), the first two groups served as normal control and a control vehicle group while the remaining four groups were rendered diabetic by a single intraperitoneal injection of Streptozotocin (STZ) and being left for 4 weeks to develop DN. Thereafter, the rats were divided into DN group, DN group receiving Telmisartan or Sildenafil or Telmisartan Sildenafil combination. After the specified treatment period, urine samples were collected (using metabolic cages) to measure proteinuria, animals were then euthanized, blood and tissue samples were collected for measurement of Blood glucose,BUN, S.Cr, LDL, NO, TGF-β1, IL-1β, AGEPs, and SOD. The combination therapy showed significant decrease in BUN, S.Cr,LDL, TGF-β1, IL-1β, Proteinuria and AGEPs and significant increase in SOD and NO. The findings showed that combination therapy was able to ameliorate DN and that the effects were superior to the single drugs alone.

  3. Pomalidomide shows significant therapeutic activity against CNS lymphoma with a major impact on the tumor microenvironment in murine models.

    Science.gov (United States)

    Li, Zhimin; Qiu, Yushi; Personett, David; Huang, Peng; Edenfield, Brandy; Katz, Jason; Babusis, Darius; Tang, Yang; Shirely, Michael A; Moghaddam, Mehran F; Copland, John A; Tun, Han W

    2013-01-01

    Primary CNS lymphoma carries a poor prognosis. Novel therapeutic agents are urgently needed. Pomalidomide (POM) is a novel immunomodulatory drug with anti-lymphoma activity. CNS pharmacokinetic analysis was performed in rats to assess the CNS penetration of POM. Preclinical evaluation of POM was performed in two murine models to assess its therapeutic activity against CNS lymphoma. The impact of POM on the CNS lymphoma immune microenvironment was evaluated by immunohistochemistry and immunofluorescence. In vitro cell culture experiments were carried out to further investigate the impact of POM on the biology of macrophages. POM crosses the blood brain barrier with CNS penetration of ~ 39%. Preclinical evaluations showed that it had significant therapeutic activity against CNS lymphoma with significant reduction in tumor growth rate and prolongation of survival, that it had a major impact on the tumor microenvironment with an increase in macrophages and natural killer cells, and that it decreased M2-polarized tumor-associated macrophages and increased M1-polarized macrophages when macrophages were evaluated based on polarization status. In vitro studies using various macrophage models showed that POM converted the polarization status of IL4-stimulated macrophages from M2 to M1, that M2 to M1 conversion by POM in the polarization status of lymphoma-associated macrophages is dependent on the presence of NK cells, that POM induced M2 to M1 conversion in the polarization of macrophages by inactivating STAT6 signaling and activating STAT1 signaling, and that POM functionally increased the phagocytic activity of macrophages. Based on our findings, POM is a promising therapeutic agent for CNS lymphoma with excellent CNS penetration, significant preclinical therapeutic activity, and a major impact on the tumor microenvironment. It can induce significant biological changes in tumor-associated macrophages, which likely play a major role in its therapeutic activity against CNS

  4. Progressive refining of spatial and temporal resolutions in a hydrological model: how far should we go?

    Science.gov (United States)

    de Lavenne, Alban; Ficchi, Andrea; Goullet, Julien

    2017-04-01

    significantly improved at refined resolutions for events with convective trends. Indeed, a synergy between spatial and temporal resolutions is obtained when refining both of them at the same time. These encouraging results suggest that in a flood forecasting context, in particular for fast response catchments subject to intense events, a significant increase of model performance can be expected by refining both resolutions. References de Lavenne, A.; Thirel, G.; Andréassian, V.; Perrin, C. & Ramos, M.-H. (2016), 'Spatial variability of the parameters of a semi-distributed hydrological model', PIAHS 373, 87-94. Goullet, J. (2016) 'A la recherche des résolutions spatiales et temporelles caractéristiques du comportement hydrologique d'un bassin versant', Master's thesis, UPMC, Paris.

  5. Blockade of gap junction hemichannel suppresses disease progression in mouse models of amyotrophic lateral sclerosis and Alzheimer's disease.

    Science.gov (United States)

    Takeuchi, Hideyuki; Mizoguchi, Hiroyuki; Doi, Yukiko; Jin, Shijie; Noda, Mariko; Liang, Jianfeng; Li, Hua; Zhou, Yan; Mori, Rarami; Yasuoka, Satoko; Li, Endong; Parajuli, Bijay; Kawanokuchi, Jun; Sonobe, Yoshifumi; Sato, Jun; Yamanaka, Koji; Sobue, Gen; Mizuno, Tetsuya; Suzumura, Akio

    2011-01-01

    Glutamate released by activated microglia induces excitotoxic neuronal death, which likely contributes to non-cell autonomous neuronal death in neurodegenerative diseases, including amyotrophic lateral sclerosis and Alzheimer's disease. Although both blockade of glutamate receptors and inhibition of microglial activation are the therapeutic candidates for these neurodegenerative diseases, glutamate receptor blockers also perturbed physiological and essential glutamate signals, and inhibitors of microglial activation suppressed both neurotoxic/neuroprotective roles of microglia and hardly affected disease progression. We previously demonstrated that activated microglia release a large amount of glutamate specifically through gap junction hemichannel. Hence, blockade of gap junction hemichannel may be potentially beneficial in treatment of neurodegenerative diseases. In this study, we generated a novel blood-brain barrier permeable gap junction hemichannel blocker based on glycyrrhetinic acid. We found that pharmacologic blockade of gap junction hemichannel inhibited excessive glutamate release from activated microglia in vitro and in vivo without producing notable toxicity. Blocking gap junction hemichannel significantly suppressed neuronal loss of the spinal cord and extended survival in transgenic mice carrying human superoxide dismutase 1 with G93A or G37R mutation as an amyotrophic lateral sclerosis mouse model. Moreover, blockade of gap junction hemichannel also significantly improved memory impairments without altering amyloid β deposition in double transgenic mice expressing human amyloid precursor protein with K595N and M596L mutations and presenilin 1 with A264E mutation as an Alzheimer's disease mouse model. Our results suggest that gap junction hemichannel blockers may represent a new therapeutic strategy to target neurotoxic microglia specifically and prevent microglia-mediated neuronal death in various neurodegenerative diseases.

  6. Blockade of gap junction hemichannel suppresses disease progression in mouse models of amyotrophic lateral sclerosis and Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Hideyuki Takeuchi

    Full Text Available BACKGROUND: Glutamate released by activated microglia induces excitotoxic neuronal death, which likely contributes to non-cell autonomous neuronal death in neurodegenerative diseases, including amyotrophic lateral sclerosis and Alzheimer's disease. Although both blockade of glutamate receptors and inhibition of microglial activation are the therapeutic candidates for these neurodegenerative diseases, glutamate receptor blockers also perturbed physiological and essential glutamate signals, and inhibitors of microglial activation suppressed both neurotoxic/neuroprotective roles of microglia and hardly affected disease progression. We previously demonstrated that activated microglia release a large amount of glutamate specifically through gap junction hemichannel. Hence, blockade of gap junction hemichannel may be potentially beneficial in treatment of neurodegenerative diseases. METHODS AND FINDINGS: In this study, we generated a novel blood-brain barrier permeable gap junction hemichannel blocker based on glycyrrhetinic acid. We found that pharmacologic blockade of gap junction hemichannel inhibited excessive glutamate release from activated microglia in vitro and in vivo without producing notable toxicity. Blocking gap junction hemichannel significantly suppressed neuronal loss of the spinal cord and extended survival in transgenic mice carrying human superoxide dismutase 1 with G93A or G37R mutation as an amyotrophic lateral sclerosis mouse model. Moreover, blockade of gap junction hemichannel also significantly improved memory impairments without altering amyloid β deposition in double transgenic mice expressing human amyloid precursor protein with K595N and M596L mutations and presenilin 1 with A264E mutation as an Alzheimer's disease mouse model. CONCLUSIONS: Our results suggest that gap junction hemichannel blockers may represent a new therapeutic strategy to target neurotoxic microglia specifically and prevent microglia-mediated neuronal

  7. Progression to multi-scale models and the application to food system intervention strategies.

    Science.gov (United States)

    Gröhn, Yrjö T

    2015-02-01

    The aim of this article is to discuss how the systems science approach can be used to optimize intervention strategies in food animal systems. It advocates the idea that the challenges of maintaining a safe food supply are best addressed by integrating modeling and mathematics with biological studies critical to formulation of public policy to address these challenges. Much information on the biology and epidemiology of food animal systems has been characterized through single-discipline methods, but until now this information has not been thoroughly utilized in a fully integrated manner. The examples are drawn from our current research. The first, explained in depth, uses clinical mastitis to introduce the concept of dynamic programming to optimize management decisions in dairy cows (also introducing the curse of dimensionality problem). In the second example, a compartmental epidemic model for Johne's disease with different intervention strategies is optimized. The goal of the optimization strategy depends on whether there is a relationship between Johne's and Crohn's disease. If so, optimization is based on eradication of infection; if not, it is based on the cow's performance only (i.e., economic optimization, similar to the mastitis example). The third example focuses on food safety to introduce risk assessment using Listeria monocytogenes and Salmonella Typhimurium. The last example, practical interventions to effectively manage antibiotic resistance in beef and dairy cattle systems, introduces meta-population modeling that accounts for bacterial growth not only in the host (cow), but also in the cow's feed, drinking water and the housing environment. Each example stresses the need to progress toward multi-scale modeling. The article ends with examples of multi-scale systems, from food supply systems to Johne's disease. Reducing the consequences of foodborne illnesses (i.e., minimizing disease occurrence and associated costs) can only occur through an

  8. Progress in modeling polarization optical components for the Daniel K. Inouye Solar Telescope

    Science.gov (United States)

    Sueoka, Stacey Ritsuyo; Harrington, David M.

    2016-07-01

    The DKIST will have a suite of first-light polarimetric instrumentation requiring precise calibration of a complex articulated optical path. The optics are subject to large thermal loads caused by the 300Watts of collected solar irradiance across the 5 arc minute field of view. The calibration process requires stable optics to generate known polarization states. We present modeling of several optical, thermal and mechanical effects of the calibration optics, the first transmissive optical elements in the light path, because they absorb substantial heat. Previous studies showed significant angle of incidence effects from the f/13 converging beam and the 5 arc minute field of view, but were only modeled at a single nominal temperature. New thermal and polarization modeling of these calibration retarders shows heating causes significant stability limitations both in time and with field caused by the bulk temperature rise along with depth and radial thermal gradients. Modeling efforts include varying coating and material absorption, Mueller matrix stability estimates and mitigation efforts.

  9. Forward-looking infrared imaging predicts ultimate burn depth in a porcine vertical injury progression model.

    Science.gov (United States)

    Miccio, Joseph; Parikh, Shruti; Marinaro, Xavier; Prasad, Atulya; McClain, Steven; Singer, Adam J; Clark, Richard A F

    2016-03-01

    relevant criterion standard, temperature minima at 2 days after burn was found to be the most sensitive and specific test. FLIR imaging is a fast and simple tool that has been shown to predict burn wound outcome in a porcine vertical injury progression model. Data showed that more severe burn wounds get cooler between 1 and 2 days after burn. We found four analytic methods of FLIR images that were predictive of burn progression at 1 and 2 days after burn; however, temperature minima 2 days after burn appeared to be the best predictive test for injury progression to a full-thickness burn. Although these results must be validated in clinical studies, FLIR imaging has the potential to aid clinicians in assessing burn severity and thereby assisting in burn wound management. Copyright © 2015 Elsevier Ltd and ISBI. All rights reserved.

  10. 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

  11. Comparison of resistance training progression models on maximal strength in sub-elite adolescent rugby union players.

    Science.gov (United States)

    Harries, Simon K; Lubans, David R; Callister, Robin

    2016-02-01

    To determine changes in maximal strength between two different resistance training progression models, linear (LP) and daily undulating (DUP), over a 12-week resistance training programme in sub-elite adolescent rugby union players. The study used a quasi-experimental study design. Following baseline assessments, participants from Squad 1 were randomised to either LP or DUP; participants from Squad 2 formed a non-randomised comparison group (CON). Participants were 26 sub-elite adolescent rugby union players who were assessed at baseline and after 12 weeks. Outcomes included 5 repetition maximum (RM) box squat and bench press, height, body weight, skeletal muscle mass, percentage body fat and maturation status. Participants in both the LP and DUP groups significantly increased their squat and bench press strength from baseline to 12 weeks. There were no significant differences between groups for squat and bench press increases after 12 weeks (p>0.05). No significant increases in squat or bench press strength were observed after 12 weeks in the CON group. Increases in lower body strength were large in the LP group (ES: 1.64) and very large in the DUP group (ES: 2.33). Upper body strength changes were small in both groups (LP, ES: 0.57; DUP, ES: 0.31). Twelve weeks of LP or DUP resistance training are both effective at increasing maximal lower and upper body strength in adolescent rugby athletes. Additionally, twice weekly frequency of resistance training in adolescent rugby athletes with greater than 6-months resistance training experience is sufficient to elicit substantial increases in maximal strength. Copyright © 2015 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

  12. The combined use of Building Information Modelling (BIM) and Unmanned Aerial Vehicle (UAV) technologies for the 3D illustration of the progress of works in infrastructure construction projects

    Science.gov (United States)

    Vacanas, Yiannis; Themistocleous, Kyriacos; Agapiou, Athos; Hadjimitsis, Diofantos

    2016-08-01

    Building Information Modelling (BIM) technology is already part of the construction industry and is considered by professionals as a very useful tool for all phases of a construction project. BIM technology, with the particularly useful 3D illustrations which it provides, can be used to illustrate and monitor the progress of works effectively through the entire lifetime of the project. Unmanned Aerial Vehicles (UAVs) have undergone significant advances in equipment capabilities and now have the capacity to acquire high resolution imagery from different angles in a cost effective and efficient manner. By using photogrammetry, characteristics such as distances, areas, volumes, elevations, object sizes, and object shape can be determined within overlapping areas. This paper explores the combined use of BIM and UAV technologies in order to achieve efficient and accurate as-built data collection and 3D illustrations of the works progress during an infrastructure construction project.

  13. Progress in model development to quantify High Explosive Violent Response (HEVR) to mechancial insult

    Energy Technology Data Exchange (ETDEWEB)

    Reaugh, J E

    2008-07-29

    explosive near the trajectory of the impactor. The damage is manifest as surface area through the creation of cracks and fragments, and also as porosity through the separation of crack faces and isolation of the fragments. Open porosity permits a flame to spread easily and so ignite the surface area that was created. The surface area itself leads to in increase in the mass-burning rate. As the kinetic energy and power of the insult increases, the degree of damage and the volume of damage both increase. Upon a localized ignition, the flame spreads to envelop the damaged volume, and the pressure rises at an accelerated rate until neither mechanical strength nor inertial confinement can successfully contain the pressure. The confining structure begins to expand. This reduces the pressure and may even extinguish the flame. Both the mass of explosive involved and the rate at which the gas is produced contribute to each of several different measures of violence. Such measures include damage to the confinement, the velocity and fragment size distributions from what was the confinement, and air blast. Figure 1 illustrates the interaction of the various phenomena described above. Our model comprises several interacting elements. The production of damage, the ignition criterion, the mass rate of burning (reaction rate), the equations of state and constitutive models of the solid explosive reactant (unburned) and gas products, flame propagation in damaged reactant, and the progressive failure of the confinement are all elements of the model. The model is intended for implementation in a general-purpose simulation program (hydrocode) that solves the partial differential equations for the conservation of mass, momentum, and energy in conjunction with equations of state and strength.

  14. Hydrothermal Fe cycling and deep ocean organic carbon scavenging: Model-based evidence for significant POC supply to seafloor sediments

    Science.gov (United States)

    German, C. R.; Legendre, L. L.; Sander, S. G.; Niquil, N.; Luther, G. W.; Bharati, L.; Han, X.; Le Bris, N.

    2015-06-01

    Submarine hydrothermal venting has recently been identified to have the potential to impact ocean biogeochemistry at the global scale. This is the case because processes active in hydrothermal plumes are so vigorous that the residence time of the ocean, with respect to cycling through hydrothermal plumes, is comparable to that of deep ocean mixing caused by thermohaline circulation. Recently, it has been argued that seafloor venting may provide a significant source of bio-essential Fe to the oceans as the result of a close coupling between Fe and organic carbon in hydrothermal plumes. But a complementary question remains to be addressed: does this same intimate Fe-Corg association in hydrothermal plumes cause any related impact to the global C cycle? To address this, SCOR-InterRidge Working Group 135 developed a modeling approach to synthesize site-specific field data from the East Pacific Rise 9°50‧ N hydrothermal field, where the range of requisite data sets is most complete, and combine those inputs with global estimates for dissolved Fe inputs from venting to the oceans to establish a coherent model with which to investigate hydrothermal Corg cycling. The results place new constraints on submarine Fe vent fluxes worldwide, including an indication that the majority of Fe supplied to hydrothermal plumes should come from entrainment of diffuse flow. While this same entrainment is not predicted to enhance the supply of dissolved organic carbon to hydrothermal plumes by more than ∼10% over background values, what the model does indicate is that scavenging of carbon in association with Fe-rich hydrothermal plume particles should play a significant role in the delivery of particulate organic carbon to deep ocean sediments, worldwide.

  15. Changes of High Mobility Group box 1 in Serum of Pig Acute Hepatic Failure Model and Significance

    Institute of Scientific and Technical Information of China (English)

    Fan ZHANG; Yongwen HE; Zhongping DUAN

    2008-01-01

    The role of the high mobility group box 1 (HMGB-1) in acute hepatic failure and the ef- fect of artificial liver support system treatment on HMGB-1 level were investigated. Pig models of acute hepatic failure were induced by D-galactosamine and randomly divided into two groups with or without artificial liver support system treatment. Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels were detected by the enzyme linked immunosorbent assay (ELISA), the expression of HMGB-1 by Western blot, and serum levels of HMGB-1, liver function and hepatic pathology were observed after artificial liver support system treatment. The levels of TNF-α and IL-1β were increased and reached the peak at 24th h in the acute hepatic failure group, then quickly decreased. The serum level of HMGB-1 was increased at 24th h in the acute hepatic failure group and reached the peak at 48th h, then kept a stable high level. Significant liver injury appeared at 24th h and was continuously getting worse in the pig models of acute hepatic failure. In contrast, the liver injury was significantly alleviated and serum level of HMGB-1 was significantly decreased in the group treated with artificial liver support system (P<0.05). It was suggested that HMGB-1 may participate in the inflammatory response and liver injury in the late stage of the acute liver failure. Artificial liver support system treatment can reduce serum HMGB-1 level and relieve liver pathological damage.

  16. Dopamine Transporter Neuroimaging as an Enrichment Biomarker in Early Parkinson's Disease Clinical Trials: A Disease Progression Modeling Analysis.

    Science.gov (United States)

    Conrado, Daniela J; Nicholas, Timothy; Tsai, Kuenhi; Macha, Sreeraj; Sinha, Vikram; Stone, Julie; Corrigan, Brian; Bani, Massimo; Muglia, Pierandrea; Watson, Ian A; Kern, Volker D; Sheveleva, Elena; Marek, Kenneth; Stephenson, Diane T; Romero, Klaus

    2017-07-27

    Given the recognition that disease-modifying therapies should focus on earlier Parkinson's disease stages, trial enrollment based purely on clinical criteria poses significant challenges. The goal herein was to determine the utility of dopamine transporter neuroimaging as an enrichment biomarker in early motor Parkinson's disease clinical trials. Patient-level longitudinal data of 672 subjects with early-stage Parkinson's disease in the Parkinson's Progression Markers Initiative (PPMI) observational study and the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) clinical trial were utilized in a linear mixed-effects model analysis. The rate of worsening in the motor scores between subjects with or without a scan without evidence of dopamine transporter deficit was different both statistically and clinically. The average difference in the change from baseline of motor scores at 24 months between biomarker statuses was -3.16 (90% confidence interval [CI] = -0.96 to -5.42) points. Dopamine transporter imaging could identify subjects with a steeper worsening of the motor scores, allowing trial enrichment and 24% reduction of sample size. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  17. Roflumilast enhances the renal protective effects of retinoids in an HIV-1 transgenic mouse model of rapidly progressive renal failure.

    Science.gov (United States)

    Zhong, Yifei; Wu, Yingwei; Liu, Ruijie; Deng, Yueyi; Mallipattu, Sandeep K; Klotman, Paul E; Chuang, Peter Y; He, John C

    2012-05-01

    Retinoic acid decreases proteinuria and glomerulosclerosis in several animal models of kidney disease by protecting podocytes from injury. Our recent in vitro studies suggest that all-trans retinoic acid induces podocyte differentiation by activating the retinoic acid receptor-α (RARα)/cAMP/PKA/CREB pathway. When used in combination with all-trans retinoic acid, an inhibitor of phosphodiesterase 4 further enhanced podocyte differentiation by increasing intracellular cAMP. Additionally, we found that Am580, a specific RARα agonist, has similar renal protective effects as all-trans retinoic acid in a rederived colony of HIV-1 transgenic mice with rapidly progressive renal failure (HIV-Tg) that mimics human HIV-associated nephropathy. Treatment with either the inhibitor of phosphodiesterase 4, roflumilast, or Am580 significantly reduced proteinuria, attenuated kidney injury, and improved podocyte differentiation in these HIV-Tg mice. Additional renal protective effects were found when roflumilast was combined with Am580. Consistent with the in vitro data, glomeruli from HIV-Tg mice treated with both Am580 and roflumilast had more active phosphorylated CREB than with either agent alone. Thus, phosphodiesterase 4 inhibitors could be used in combination with RARα agonists to provide additional renal protection.

  18. Measurement and apportionment of radon source terms for modeling indoor environments. Final progress report, March 1990--August 1992

    Energy Technology Data Exchange (ETDEWEB)

    Harley, N.H.

    1992-12-31

    During the present 2 1/2 year contract period, we have made significant Progress in modeling the source apportionment of indoor {sup 222}Rn and in {sup 222}Rn decay product dosimetry. Two additional areas were worked on which we believe are useful for the DOE Radon research Program. One involved an analysis of the research house data, grouping the hourly house {sup 222}Rn measurements into 2 day, 7 day and 90 day intervals to simulate the response of passive monitors. Another area requiring some attention resulted in a publication of 3 years of our indoor/outdoor measurements in a high-rise apartment. Little interest has been evinced in apartment measurements yet 20% of the US population lives in multiple-family dwellings, not in contact with the ground. These data together with a summary of all other published data on apartments showed that apartments have only about 50% greater {sup 222}Rn concentration than the measured outdoor {sup 222}Rn. Apartment dwellers generally represent a low risk group regarding {sup 222}Rn exposure. The following sections describe the main projects in some detail.

  19. A review and synthesis of late Pleistocene extinction modeling: progress delayed by mismatches between ecological realism, interpretation, and methodological transparency.

    Science.gov (United States)

    Yule, Jeffrey V; Fournier, Robert J; Jensen, Christopher X J; Yang, Jinyan

    2014-06-01

    Late Pleistocene extinctions occurred globally over a period of about 50,000 years, primarily affecting mammals of > or = 44 kg body mass (i.e., megafauna) first in Australia, continuing in Eurasia and, finally, in the Americas. Polarized debate about the cause(s) of the extinctions centers on the role of climate change and anthropogenic factors (especially hunting). Since the late 1960s, investigators have developed mathematical models to simulate the ecological interactions that might have contributed to the extinctions. Here, we provide an overview of the various methodologies used and conclusions reached in the modeling literature, addressing both the strengths and weaknesses of modeling as an explanatory tool. Although late Pleistocene extinction models now provide a solid foundation for viable future work, we conclude, first, that single models offer less compelling support for their respective explanatory hypotheses than many realize; second, that disparities in methodology (both in terms of model parameterization and design) prevent meaningful comparison between models and, more generally, progress from model to model in increasing our understanding of these extinctions; and third, that recent models have been presented and possibly developed without sufficient regard for the transparency of design that facilitates scientific progress.

  20. A Weibull multi-state model for the dependence of progression-free survival and overall survival.

    Science.gov (United States)

    Li, Yimei; Zhang, Qiang

    2015-07-30

    In oncology clinical trials, overall survival, time to progression, and progression-free survival are three commonly used endpoints. Empirical correlations among them have been published for different cancers, but statistical models describing the dependence structures are limited. Recently, Fleischer et al. proposed a statistical model that is mathematically tractable and shows some flexibility to describe the dependencies in a realistic way, based on the assumption of exponential distributions. This paper aims to extend their model to the more flexible Weibull distribution. We derived theoretical correlations among different survival outcomes, as well as the distribution of overall survival induced by the model. Model parameters were estimated by the maximum likelihood method and the goodness of fit was assessed by plotting estimated versus observed survival curves for overall survival. We applied the method to three cancer clinical trials. In the non-small-cell lung cancer trial, both the exponential and the Weibull models provided an adequate fit to the data, and the estimated correlations were very similar under both models. In the prostate cancer trial and the laryngeal cancer trial, the Weibull model exhibited advantages over the exponential model and yielded larger estimated correlations. Simulations suggested that the proposed Weibull model is robust for data generated from a range of distributions.

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

    African Journals Online (AJOL)

    in HIV infected individuals that as a consequence of HIV infection, selective depletion ... a marker of HIV progression in the absence of any defense mechanism 115 ..... dynamics and the hyperactivation theory of AIDS pathogenesis, Mathemat-.

  2. A dual acting compound releasing nitric oxide (NO) and ibuprofen, NCX 320, shows significant therapeutic effects in a mouse model of muscular dystrophy.

    Science.gov (United States)

    Sciorati, Clara; Miglietta, Daniela; Buono, Roberta; Pisa, Viviana; Cattaneo, Dario; Azzoni, Emanuele; Brunelli, Silvia; Clementi, Emilio

    2011-09-01

    A resolutive therapy for muscular dystrophies, a heterogeneous group of genetic diseases leading to muscular degeneration and in the severe forms to death, is still lacking. Since inflammation and defects in nitric oxide generation are recognized key pathogenic events in muscular dystrophy, we have analysed the effects of a derivative of ibuprofen, NCX 320, belonging to the class of cyclooxygenase inhibiting nitric oxide donator (CINOD), in the α-sarcoglycan null mice, a severe mouse model of dystrophy. NCX 320 was administered daily in the diet for 8months starting 1month from weaning. Muscle functional recovery was evaluated by free wheel and treadmill tests at 8months. Serum creatine kinase activity, as well as the number of diaphragm inflammatory infiltrates and necrotic fibres, was measured as indexes of skeletal muscle damage. Muscle regeneration was evaluated in diaphragm and tibialis anterior muscles, measuring the numbers of centronucleated fibres and of myogenic precursor cells. NCX 320 mitigated muscle damage, reducing significantly serum creatine kinase activity, the number of necrotic fibres and inflammatory infiltrates. Moreover, NCX 320 stimulated muscle regeneration increasing significantly the number of myogenic precursor cells and regenerating fibres. All these effects concurred in inducing a significant improvement of muscle function, as assessed by both free wheel and treadmill tests. These results describe the properties of a new compound incorporating nitric oxide donation together with anti-inflammatory properties, showing that it is effective in slowing muscle dystrophy progression long term. Of importance, this new compound deserves specific attention for its potential in the therapy of muscular dystrophy given that ibuprofen is well tolerated in paediatric patients and with a profile of safety that makes it suitable for chronic treatment such as the one required in muscular dystrophies.

  3. Impaired osteoclast homeostasis in the cystatin B-deficient mouse model of progressive myoclonus epilepsy

    Directory of Open Access Journals (Sweden)

    Otto Manninen

    2015-12-01

    Full Text Available Progressive myoclonus epilepsy of Unverricht–Lundborg type (EPM1 is an autosomal recessively inherited disorder characterized by incapacitating stimulus-sensitive myoclonus and tonic-clonic epileptic seizures with onset at the age of 6 to 16 years. EPM1 patients also exhibit a range of skeletal changes, e.g., thickened frontal cranial bone, arachnodactyly and scoliosis. Mutations in the gene encoding cystatin B (CSTB underlie EPM1. CSTB is an inhibitor of cysteine cathepsins, including cathepsin K, a key enzyme in bone resorption by osteoclasts. CSTB has previously been shown to protect osteoclasts from experimentally induced apoptosis and to modulate bone resorption in vitro. Nevertheless, its physiological function in bone and the cause of the bone changes in patients remain unknown. Here we used the CSTB-deficient mouse (Cstb−/− model of EPM1 to evaluate the contribution of defective CSTB protein function on bone pathology and osteoclast differentiation and function. Micro-computed tomography of hind limbs revealed thicker trabeculae and elevated bone mineral density in the trabecular bone of Cstb−/− mice. Histology from Cstb−/− mouse bones showed lower osteoclast count and thinner growth plates in long bones. Bone marrow-derived osteoclast cultures revealed lower osteoclast number and size in the Cstb−/− group. Cstb−/− osteoclasts formed less and smaller resorption pits in an in vitro assay. This impaired resorptive capacity was likely due to a decrease in osteoclast numbers and size. These data imply that the skeletal changes in Cstb−/− mice and in EPM1 patients are a result of CSTB deficiency leading to impaired osteoclast formation and consequently compromised resorptive capacity. These results suggest that the role of CSTB in osteoclast homeostasis and modulation of bone metabolism extends beyond cathepsin K regulation.

  4. In vivo MRI characterization of progressive cardiac dysfunction in the mdx mouse model of muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Daniel J Stuckey

    Full Text Available AIMS: The mdx mouse has proven to be useful in understanding the cardiomyopathy that frequently occurs in muscular dystrophy patients. Here we employed a comprehensive array of clinically relevant in vivo MRI techniques to identify early markers of cardiac dysfunction and follow disease progression in the hearts of mdx mice. METHODS AND RESULTS: Serial measurements of cardiac morphology and function were made in the same group of mdx mice and controls (housed in a non-SPF facility using MRI at 1, 3, 6, 9 and 12 months after birth. Left ventricular (LV and right ventricular (RV systolic and diastolic function, response to dobutamine stress and myocardial fibrosis were assessed. RV dysfunction preceded LV dysfunction, with RV end systolic volumes increased and RV ejection fractions reduced at 3 months of age. LV ejection fractions were reduced at 12 months, compared with controls. An abnormal response to dobutamine stress was identified in the RV of mdx mice as early as 1 month. Late-gadolinium-enhanced MRI identified increased levels of myocardial fibrosis in 6, 9 and 12-month-old mdx mice, the extent of fibrosis correlating with the degree of cardiac remodeling and hypertrophy. CONCLUSIONS: MRI could identify cardiac abnormalities in the RV of mdx mice as young as 1 month, and detected myocardial fibrosis at 6 months. We believe these to be the earliest MRI measurements of cardiac function reported for any mice, and the first use of late-gadolinium-enhancement in a mouse model of congenital cardiomyopathy. These techniques offer a sensitive and clinically relevant in vivo method for assessment of cardiomyopathy caused by muscular dystrophy and other diseases.

  5. Progressive alterations of hippocampal CA3-CA1 synapses in an animal model of depression.

    Science.gov (United States)

    Qiao, Hui; An, Shu-Cheng; Ren, Wei; Ma, Xin-Ming

    2014-12-15

    Major depressive disorder is the most prevalent psychiatric condition, but the cellular and molecular mechanisms underlying this disorder are largely unknown, although multiple hypotheses have been proposed. The aim of this study was to characterize the progressive alteration of neuronal plasticity in the male rat hippocampus during depression induced by chronic unpredictable mild stress (CUMS), an established animal model of depression. The data in the hippocampus were collected on days 7, 14 and 21 after the onset of three-week CUMS. When analyzed on day 21, three-week CUMS induced typically depressive-like behaviors, impaired LTP induction, and decreased basal synaptic transmission at hippocampal CA3-CA1 synapses recorded in vivo, which was accompanied by decreased density of dendritic spines in CA1 and CA3 pyramidal neurons. The levels of both Kalirin-7 and brain-derived neurotrophic factor (BDNF) in the hippocampus were decreased at the same time. On day 14 (middle phase), some depressive-like behaviors were observed, which was accompanied by depressed basal synaptic transmission and enhanced LTP induction at the CA3-CA1 synapses. However, BDNF expression was decreased without alteration of Kalirin7 expression in comparison with no-stress control. Depressed basal synaptic transmission occurred in the middle phase of CUMS may contribute to decreased expression of BDNF. On day 7, depressive-like behaviors were not observed, and LTP induction, spine density, Kalirin-7 and BDNF expression were not altered by CUMS in comparison with no-stress control. These results showed that the functional changes at CA3-CA1synapses occurred earlier than the structural alteration during three-week CUMS as a strategy of neural adaptation, and rats required three weeks to develop depressive-like behaviors during CUMS. Our results suggest an important role of Kalirin-7 in CUMS-mediated alterations in spine density, synaptic function and overall depressive-like behaviors on day 21.

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

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    Osama Alfarraj

    2011-09-01

    Full Text Available 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 components compared to the neighbouring Gulf country of Bahrain, which was ranked 8th for the same index. While this is still modest in relation to the Saudi government’s expectation concerning its vision for eGovernment implementation for 2010, and the results achieved by the neighbouring Gulf countries such as Bahrain and the United Arab Emirates on the eGovernment index, the Saudi government has endeavoured to meet the public needs concerning eGovernment and carry out the implementation of eGovernment properly. Governments may heed the importance of actively launching official government websites – the focus of this study – as the main portals for delivering their online services to all the different categories of eGovernment (including G2C, G2B, and G2G. However, certain Saudi ministries have not given due attention to this vital issue. This is evidenced by the fact that some of their websites are not fully developed or do not yet exist, which clearly impedes that particular ministry from appropriately delivering eServices.

  7. Caffeine alleviates progressive motor deficits in a transgenic mouse model of spinocerebellar ataxia.

    Science.gov (United States)

    Gonçalves, Nélio; Simões, Ana T; Prediger, Rui D; Hirai, Hirokazu; Cunha, Rodrigo A; Pereira de Almeida, Luís

    2017-03-01

    Machado-Joseph disease (MJD) is a neurodegenerative spinocerebellar ataxia (SCA) associated with an expanded polyglutamine tract within ataxin-3 for which there is currently no available therapy. We previously showed that caffeine, a nonselective adenosine receptor antagonist, delays the appearance of striatal damage resulting from expression of full-length mutant ataxin-3. Here we investigated the ability of caffeine to alleviate behavioral deficits and cerebellar neuropathology in transgenic mice with a severe ataxia resulting from expression of a truncated fragment of polyglutamine-expanded ataxin-3 in Purkinje cells. Control and transgenic c57Bl6 mice expressing in the mouse cerebella a truncated form of human ataxin-3 with 69 glutamine repeats were allowed to freely drink water or caffeinated water (1g/L). Treatments began at 7 weeks of age, when motor and ataxic phenotype emerges in MJD mice, and lasted up to 20 weeks. Mice were tested in a panel of locomotor behavioral paradigms, namely rotarod, beam balance and walking, pole, and water maze cued-platform version tests, and then sacrificed for cerebellar histology. Caffeine consumption attenuated the progressive loss of general and fine-tuned motor function, balance, and grip strength, in parallel with preservation of cerebellar morphology through decreasing the loss of Purkinje neurons and the thinning of the molecular layer in different folia. Caffeine also rescued the putative striatal-dependent executive and cognitive deficiencies in MJD mice. Our findings provide the first in vivo demonstration that caffeine intake alleviates behavioral disabilities in a severely impaired animal model of SCA. Ann Neurol 2017;81:407-418. © 2016 American Neurological Association.

  8. Thioredoxin-1 protects against neutrophilic inflammation and emphysema progression in a mouse model of chronic obstructive pulmonary disease exacerbation.

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    Naoya Tanabe

    Full Text Available BACKGROUND: Exacerbations of chronic obstructive pulmonary disease (COPD are characterized by acute enhancement of airway neutrophilic inflammation under oxidative stress and can be involved in emphysema progression. However, pharmacotherapy against the neutrophilic inflammation and emphysema progression associated with exacerbation has not been established. Thioredoxin-1 has anti-oxidative and anti-inflammatory properties and it can ameliorate neutrophilic inflammation through anti-chemotactic effects and prevent cigarette smoke (CS-induced emphysema. We aimed to determine whether thioredoxin-1 can suppress neutrophilic inflammation and emphysema progression in a mouse model of COPD exacerbation and if so, to reveal the underlying mechanisms. RESULTS: Mice were exposed to CS and then challenged with polyinosine-polycytidylic acid [poly(I:C], an agonist for virus-induced innate immunity. Airway neutrophilic inflammation, oxidative stress and lung apoptosis were enhanced in smoke-sensitive C57Bl/6, but not in smoke-resistant NZW mice. Exposure to CS and poly(I:C challenge accelerated emphysema progression in C57Bl/6 mice. Thioredoxin-1 suppressed neutrophilic inflammation and emphysema progression. Poly(I:C caused early neutrophilic inflammation through keratinocyte-derived chemokine and granulocyte-macrophage colony-stimulating factor (GM-CSF release in the lung exposed to CS. Late neutrophilic inflammation was caused by persistent GM-CSF release, which thioredoxin-1 ameliorated. Thioredoxin-1 enhanced pulmonary mRNA expression of MAP kinase phosphatase 1 (MKP-1, and the suppressive effects of thioredoxin-1 on prolonged GM-CSF release and late neutrophilic inflammation disappeared by inhibiting MKP-1. CONCLUSION: Using a mouse model of COPD exacerbation, we demonstrated that thioredoxin-1 ameliorated neutrophilic inflammation by suppressing GM-CSF release, which prevented emphysema progression. Our findings deepen understanding of the mechanisms

  9. Modeling plant, microorganisms, and mineral surface competition for soil nitrogen and phosphorus: Competition representations and ecological significance

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    Zhu, Q.; Riley, W. J.; Chambers, J. Q.; Tang, J.

    2014-12-01

    It is widely accepted that terrestrial ecosystem carbon dynamics are strongly coupled and controlled by soil nutrients status. Nutrient availability serves as an indicator of aboveground carbon productivity and ecosystem stability, especially when soils are infertile. In these conditions, plants have to outcompete microorganism and mineral surfaces to acquire nutrients required for photosynthesis, respiration, seed production, defense, etc. It is usually hypothesized that microbes are short-term winners but long-term losers in nutrient competition. Microbes quickly trap available soil nitrogen and phosphorous, thereby preventing nutrient inaccessibility through hydrological leaching and mineral surface adsorption. Over longer temporal scales, nutrients are released into the soil and become available for plant uptake. Despite its ecological significance, nutrient competition is either absent or over-simplified (e.g., assuming all consumers are equally competitive) in terrestrial biogeochemistry models. Here, we aim to test the representation of different competitive strategies and to investigate their ecological consequences with a newly developed biogeochemical model structure. The new model includes three major soil nutrients (ammonia, nitrate, and phosphate) and multiple consumers (plants, microbes, mineral surfaces, nitrifiers, and denitrifiers). We analyze predicted soil carbon, nitrogen, and phosphorus dynamics with three different competitive strategies: (1) plants compete poorly against microorganisms; (2) all consumers are equally competitive; and (3) an explicit Equilibrium Chemical Approximation (ECA; Tang and Riley (2013)) treatment. We find that very different ecosystem states are predicted when assuming different competitive structures, and that the ECA approach provides the best match with a large suite of observational constraints from tropical experimental and transect studies. We conclude that terrestrial biogeochemical models should represent a

  10. Modeling the significance of including C redistribution when determining changes in net carbon storage along a cultivated toposequence

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    Chirinda, Ngonidzashe; Olesen, Jørgen E.; Heckrath, Goswin; Paradelo Pérez, Marcos; Taghizadeh-Toosi, Arezoo

    2016-04-01

    Globally, soil carbon (C) reserves are second only to those in the ocean, and accounts for a significant C reservoir. In the case of arable soils, the quantity of stored C is influenced by various factors (e.g. management practices). Currently, the topography related influences on in-field soil C dynamics remain largely unknown. However, topography is known to influence a multiplicity of factors that regulate C input, storage and redistribution. To understand the patterns and untangle the complexity of soil C dynamics in arable landscapes, our study was conducted with soils from shoulderslope and footslope positions on a 7.1 ha winter wheat field in western Denmark. We first collected soil samples from shoulderslope and footslope positions with various depth intervals down to 100 cm and analyzed them for physical and chemical properties including texture and soil organic C contents. In-situ carbon dioxide (CO2) concentrations were measured at different soil profile depths at both positions for a year. Soil moisture content and temperature at 5 and 40 cm depth was measured continuously. Additionally, surface soil CO2 fluxes at shoulderslope and footslope positions were measured. We then used measurement data collected from the two landscape positions to calibrate the one-dimensional mechanistic model SOILCO2 module of the HYDRUS-1D software package and obtained soil CO2 fluxes from soil profile at two landscape positions. Furthermore, we tested whether the inclusion of vertical and lateral soil C movement improved the modeling of C dynamics in cultivated landscapes. For that, soil profile CO2 fluxes were compared with those obtained using a simple process-based soil whole profile C model, C-TOOL, which was modified to include vertical and lateral movement of C on landscape. Our results highlight the need to consider vertical and lateral soil C movement in the modeling of C dynamics in cultivated landscapes, for better qualification of net carbon storage.

  11. Reactive oxygen species, DNA damage, and error-prone repair: a model for genomic instability with progression in myeloid leukemia?

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    Rassool, Feyruz V; Gaymes, Terry J; Omidvar, Nader; Brady, Nicola; Beurlet, Stephanie; Pla, Marika; Reboul, Murielle; Lea, Nicholas; Chomienne, Christine; Thomas, Nicholas S B; Mufti, Ghulam J; Padua, Rose Ann

    2007-09-15

    Myelodysplastic syndromes (MDS) comprise a heterogeneous group of disorders characterized by ineffective hematopoiesis, with an increased propensity to develop acute myelogenous leukemia (AML). The molecular basis for MDS progression is unknown, but a key element in MDS disease progression is loss of chromosomal material (genomic instability). Using our two-step mouse model for myeloid leukemic disease progression involving overexpression of human mutant NRAS and BCL2 genes, we show that there is a stepwise increase in the frequency of DNA damage leading to an increased frequency of error-prone repair of double-strand breaks (DSB) by nonhomologous end-joining. There is a concomitant increase in reactive oxygen species (ROS) in these transgenic mice with disease progression. Importantly, RAC1, an essential component of the ROS-producing NADPH oxidase, is downstream of RAS, and we show that ROS production in NRAS/BCL2 mice is in part dependent on RAC1 activity. DNA damage and error-prone repair can be decreased or reversed in vivo by N-acetyl cysteine antioxidant treatment. Our data link gene abnormalities to constitutive DNA damage and increased DSB repair errors in vivo and provide a mechanism for an increase in the error rate of DNA repair with MDS disease progression. These data suggest treatment strategies that target RAS/RAC pathways and ROS production in human MDS/AML.

  12. Epigenetic modifications, chromatin distribution and TP53 transcription in a model of breast cancer progression.

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    Santos, Gilson C; da Silva, Ana P A; Feldman, Lucas; Ventura, Grasiella M; Vassetzky, Yegor; de Moura Gallo, Claudia V

    2015-04-01

    In the present paper we aimed to characterize epigenetic aspects and analyze TP53 transcription in the 21 T series, composed of breast cell lines: non-cancerous H16N2; Atypical Ductal Hyperplasia 21PT; Ductal Carcinoma in situ 21NT and Invasive Metastatic Carcinoma 21MT1. We detected a global genomic hypomethylation in 21NT and 21MT1. The histone modification markers analysis showed an important global decrease of the active chromatin mark H4Ac in 21MT1 relative to the other cell lines while the repressive mark H3K9Me3 were not significantly altered. The mRNA levels of DNA methylation and histone modification key enzymes are consistent with the observed genomic hypomethylation and histone hypoacetylation. The expression of DNMT3A/B increased at the initial stages of oncogenesis and the expression of DNMT1 and HAT1 decreased at the advanced stages of breast cancer. Using a confocal immunofluorescent assay, we observed that H4Ac was mostly located at the periphery and the repressive mark H3K9Me3, at the center of 21NT and 21MT1 cells nuclei. TP53 P1 promoter was found to be in an open chromatin state, with a relatively high enrichment of H4Ac and similar TP53 transcription levels in all 21 T cell lines. In conclusion, we observed epigenetic alterations (global genome hypomethylation, global hypoacetylation and accumulation of pericentric heterochromatin) in metastatic breast cancer cells of the 21 T series. These alterations may act at later stages of breast cancer progression and may not affect TP53 transcription at the P1 promoter.

  13. Oncogene interactions are required for glioma development and progression as revealed by a tissue specific transgenic mouse model

    Institute of Scientific and Technical Information of China (English)

    Lynette M. Moore; Kristen M. Holmes; Gregory N. Fuller; Wei Zhang

    2011-01-01

    The aggressive and invasive nature of brain tumors has hampered progress in the design and implementation of efficacious therapies. The recent success of targeted therapies in other tumor types makes this an attractive area for research yet complicating matters is the ability of brain tumors to circumvent the targeted pathways to develop drug resistance. Effective therapies will likely need to target more than one signaling pathway or target multiple nodes within a given pathway. Key to identifying these targets is the elucidation of the driver and passenger molecules within these pathways. Animal models provide a useful tool with many advantages in the study of these pathways. These models provide a means to dissect the critical components of tumorigenesis, as well as serve as agents for preclinical testing. This review focuses on the use of the RCAS/tv-a mouse model of brain tumors and describes their unique ability to provide insight into the role of oncogene cooperation in tumor development and progression.

  14. Role of the lung in the progression of multiple organ dysfunction syndrome in ageing rat model

    Institute of Scientific and Technical Information of China (English)

    WANG Xue-ping; ZHU Qing-lei; XUE Qiao; LI Yang; QIAN Xiao-shun; WANG Zhong-liang; WANG Shi-wen

    2012-01-01

    Background Multiple organ dysfunction syndrome in the elderly (MODSE) is a problem with high mortality in the critical care of elderly patients.The pathogenesis of MODSE remains elusive.This study aimed to establish rat models of MODSE and to investigate the pathogenetic mechanism responsible for the development of MODSE in the rat models.Methods Twenty-four-month old rats (elderly) received intravenous injection of lipopolysaccharide (LPS) to induce rat model of MODSE.In the model,we observed the physical responses,biochemical indices changes,histopathological features of vital organs,including lung,liver,heart,and kidney.We also investigated the sequence of individual organ dysfunction and changes of proinflammatory factors.Three-month-old rats.serving as young rat controls,received parallel procedures.Besides,normal saline injection was also performed on elderly and young control rats.Results All rats displayed different degree of physical response after LPS injection,preceded by deterioration of respiratory status.At 6 hours,lung injury was observed,which started eariier than other organ injury that was observed in about 24 hours.Furthermore,all vital organ injury was more severe in elderiy rats than in young rats at the same time points.After LPS injection,pulmonary alveolar macrophages apoptosis rate increased obviously,and was more significant in elderly rats ((43.4±8.4)%) than in young rats ((24.2±3.0)%).LPS injection also enhanced tumor necrosis factor α (TNF-α) concentration significantly in these organs.Its peak concentration appeared at 6 hours in lung tissue and at 24 hours in other organs after LPS injection.TNF-α level was higher in elderly rats than in young rats at the same time points.The increase was most significant in lung tissue.After intravenous administration of LPS.toll-like receptor 4(TLR4) expression in lung tissue was upregulated markedly,and peaked at 6 hours.In contrast,upregulation of TLR4expression in liver peaked at 24

  15. Optical polarization tractography revealed significant fiber disarray in skeletal muscles of a mouse model for Duchenne muscular dystrophy.

    Science.gov (United States)

    Wang, Y; Zhang, K; Wasala, N B; Duan, D; Yao, G

    2015-02-01

    Optical polarization tractography (OPT) was recently developed to visualize tissue fiber architecture with cellular-level resolution and accuracy. In this study, we explored the feasibility of using OPT to study muscle disease in the mdx4cv mouse model of Duchenne muscular dystrophy. The freshly dissected tibialis anterior muscles of mdx4cv and normal mice were imaged. A "fiber disarray index" (FDI) was developed to quantify the myofiber disorganization. In necrotic muscle regions of the mdx4cv mice, the FDI was significantly elevated and can be used to segment the 3D necrotic regions for assessing the overall muscle damage. These results demonstrated the OPT's capability for imaging microscopic fiber alternations in muscle research.

  16. Ovine pulmonary adenocarcinoma as an animal model of progressive lung cancer and the impact of nutritional selenium supply.

    Science.gov (United States)

    Humann-Ziehank, Esther; Wolf, Petra; Renko, Kostja; Schomburg, Lutz; Ludwig Bruegmann, Michael; Andreae, Arnim; Brauer, Carsten; Ganter, Martin

    2011-01-01

    Jaagsiekte sheep retrovirus (JSRV) is known to induce ovine pulmonary adenocarcinoma (OPA). Several studies have suggested an influence of selenium (Se) status on cancer progression. Thus, combining OPA with a defined Se supply might serve as a suitable animal model to study the impact of Se on lung cancer progression. 16 naturally JSRV-infected sheep were divided into 2 treatment groups receiving (a) CT) was performed repeatedly and evaluated using a CT-OPA-score system. Liver biopsies were taken three-monthly, blood samples were collected biweekly to study treatment effects on Se concentrations and glutathione peroxidase (GPx) activity. Cell pellets from bronchoalveolar lavage fluid (BALF) were tested for JSRV by PCR to approve the infection. To date, four animals of the ongoing study have been euthanised. Autopsy and histopathology were performed and correlated to CT analysis. JSRV was detected in BALF cell pellets. Progression of lung tumours was monitored successfully by repeated CT examinations, enabling the detection of even small nodules or increased lung density. Histopathology revealed bronchioloalveolar adenocarcinoma in lung areas suspicious to be OPA from CT evaluation. Score-based analysis of CT images for quantifying tumour progression proved as a valuable tool. Se concentration and GPx activity increased in liver and serum of group b and verified the efficiency of different feeding regime. In conclusion, OPA along with CT, autopsy/histopathology, trace element and enzyme activity analysis provide a suitable large animal model to examine the impact of Se supply on lung tumourigenesis.

  17. Attenuation of Rhes activity significantly delays the appearance of behavioral symptoms in a mouse model of Huntington's disease.

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    Brandon A Baiamonte

    Full Text Available Huntington's disease (HD is a neuropsychiatric disorder characterized by choreiform movement of the limbs, cognitive disability, psychosis and dementia. It is invariably associated with an abnormally long CAG expansion within the IT15 gene on human chromosome 4. Although the mutant huntingtin protein is ubiquitously expressed in HD patients, cellular degeneration occurs predominantly in neurons within the corpus striatum and cerebral cortex. The Ras homolog Rhes is expressed very selectively in the precise brain areas affected by HD. Recent in vitro work suggests that Rhes may be a co-factor with mutant huntingtin in cell death. The objective of the present study was to examine whether the inhibition of Rhes would attenuate or delay the symptoms of HD in vivo. We used a transgenic mouse model of HD crossed with Rhes knockout mice to show that the behavioral symptoms of HD are regulated by Rhes. HD(+/Rhes(-/- mice showed significantly delayed expression of HD-like symptoms in this in vivo model. Drugs that block or inhibit the actions of Rhes may be useful as the first treatments for HD.

  18. Progress towards a more predictive model for hohlraum radiation drive and symmetry

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    Jones, Ogden

    2016-10-01

    The high flux model (HFM) was first developed to match emission levels observed from Au spheres illuminated symmetrically at the UR-LLE OMEGA laser. It utilizes a modern non-LTE atomic physics model and an electron thermal flux limiter of 0.15 or a non-local electron transport model. Shortly thereafter, the HFM was also found to better match the radiation drive observed through the laser entrance hole of laser-heated vacuum hohlraums on the NIF. Subsequent capsule implosion experiments driven by hohlraums filled with 1-1.6 mg/cc of He, having case-to-capsule ratios of 2.6, and pulse lengths 15-20 ns have been characterized by relatively large amounts of laser backscatter losses (up to 18% of the input laser energy). They have also utilized cross beam energy transfer (CBET) to transfer power to the lasers depositing energy near the hohlraum waist. When the HFM is applied to these experiments, the hohlraum x-ray drive is over-predicted by 20-30% during peak laser power, and the drive symmetry cannot be matched without making ad hoc corrections. More recent experiments using hohlraum fills from 0-0.6 mg/cc He, case-to-capsule ratios 3-4, and pulse lengths 6-10 ns have little or no CBET or backscatter and are in better agreement with calculations using the HFM, although discrepancies remain. Uncertainties remaining in the computational models of emissivity, laser absorption, heat transport, etc. used in our hydrodynamic codes can significantly affect predictions. In this work we test various physically-plausible adjustments or alternatives to these models in order to find a more predictive model for radiation drive in the regime with little or no backscatter or CBET. We utilize measurements of the radiation drive, shape and trajectory of the imploding shell, shape of the stagnated hot spot, and bang time in capsule implosions and spectroscopic measurements of the hohlraum plasma conditions to compare against high resolution hydrodynamic calculations using the various

  19. Filtrate of Phellinus linteus Broth Culture Reduces Infarct Size Significantly in a Rat Model of Permanent Focal Cerebral Ischemia.

    Science.gov (United States)

    Suzuki, Sakiko; Kawamata, Takakazu; Okada, Yoshikazu; Kobayashi, Tomonori; Nakamura, Tomoyuki; Hori, Tomokatsu

    2011-01-01

    Phellinus linteus, a natural growing mushroom, has been known to exhibit anti-tumor, anti-inflammatory, anti-allergic and anti-oxidant effects. Aiming to exploit the neuroprotective effects of P. linteus, we evaluated its effects on infarct volume reduction in a rat model of focal cerebral ischemia. Male Sprague-Dawley rats were subjected to right middle cerebral artery occlusion. Filtrate of P. linteus broth culture (various doses), fractionated filtrate (based on molecular weight) or control medium was administered