Science.gov

Sample records for mechanistic feature-scale profile

  1. Feature Scale Simulations of Deposition Processes

    NASA Astrophysics Data System (ADS)

    Moroz, Paul; Moroz, Daniel J.

    2015-09-01

    Deposition processes, together with etching, planarization, and implantation, represent the basis of materials processing. Requirements for the accuracy of processing are becoming ever more stringent and thus the role of numerical simulations grows. The feature scale simulator FPS3D allows detailed simulation of simultaneous deposition, etching, and implantation processes. In this report, we emphasize FPD3D's capability to simulate deposition. We simulate and analyze the deposition of copper seed layer films into high-aspect-ratio features, examining the profile conformity and feature-filling quality of the deposited copper layers and their dependence on the energy and angular distributions of incoming fluxes of species. A number of cases were analyzed, including the following: isotropic flow of Cu, directional flow of Cu, isotropic flow of Cu together with ions, and directional flow of Cu together with ions. It was found that directional flow of Cu together with ions has significant advantages over other options, allowing efficient Cu seed layer deposition even for small high-aspect-ratio features. We also discuss detailed structure of deposited layers such as agglomeration into islands with specific orientation and film roughness.

  2. Microfluidic Mobility Shift Profiling of Lysine Acetyltransferases Enables Screening and Mechanistic Analysis of Cellular Acetylation Inhibitors.

    PubMed

    Sorum, Alexander W; Shrimp, Jonathan H; Roberts, Allison M; Montgomery, David C; Tiwari, Neil K; Lal-Nag, Madhu; Simeonov, Anton; Jadhav, Ajit; Meier, Jordan L

    2016-03-18

    Lysine acetyltransferases (KATs) are critical regulators of signaling in many diseases, including cancer. A major challenge in establishing the targetable functions of KATs in disease is a lack of well-characterized, cell-active KAT inhibitors. To confront this challenge, here we report a microfluidic mobility shift platform for the discovery and characterization of small molecule KAT inhibitors. Novel fluorescent peptide substrates were developed for four well-known KAT enzymes (p300, Crebbp, Morf, and Gcn5). Enzyme-catalyzed acetylation alters the electrophoretic mobility of these peptides in a microfluidic chip, allowing facile and direct monitoring of KAT activity. A pilot screen was used to demonstrate the utility of microfluidic mobility shift profiling to identify known and novel modulators of KAT activity. Real-time kinetic monitoring of KAT activity revealed that garcinol, a natural product KAT inhibitor used in cellular studies, exhibits time-dependent and detergent-sensitive inhibition, consistent with an aggregation-based mechanism. In contrast, the cell-permeable bisubstrate inhibitor Tat-CoA exhibited potent and time-independent KAT inhibition, highlighting its potential utility as a cellular inhibitor of KAT activity. These studies define microfluidic mobility shift profiling as a powerful platform for the discovery and characterization of small molecule inhibitors of KAT activity, and provide mechanistic insights potentially important for the application of KAT inhibitors in cellular contexts. PMID:26428393

  3. Dicycloplatin, a novel platinum analog in chemotherapy: synthesis of chinese pre-clinical and clinical profile and emerging mechanistic studies.

    PubMed

    Yu, Jing Jie; Yang, Xuqing; Song, Qinhua; Mueller, Michael D; Remick, Scot C

    2014-01-01

    Dicycloplatin (DCP) has better solubility and stability than both cisplatin and carboplatin. Pre-clinical and phase I studies demonstrated significant antitumor activity and fewer adverse events than carboplatin. Phase II clinical trials in advanced non-small cell lung cancer found efficacy and safety of DCP-plus-paclitaxel comparable to carboplatin-plus-paclitaxel but better tolerability. This article summarizes and reviews pre-clinical and clinical data for dicycloplatin from the Chinese medical literature. We also report on new mechanistic findings in our laboratory in West Virginia, USA. Patient blood samples were collected for DCP-prototype determination by liquid chromatography mass spectrometry (LC-MS/MS). Molecular studies of ovarian cancer cells treated with DCP or cisplatin were carried out for gene-signature profiling using immunoblotting. Pharmacokinetic mass-spectrometry showed different spectrum profiles of DCP and carboplatin in plasma. Plasma concentration of DCP prototype was 17.1 μg/ml 2h after administration, with a peak concentration of 26.9 μg/ml at 0.5 h. Immunoblotting showed DCP-induced activation of DNA damage pathways, including double-phosphorylated checkpoint kinase 2 (CHK2) and breast cancer 1 (BRCA1) and triple-phosphorylated p53, compared to controls. Cisplatin produced a similar profile, with increased p53 protein. DCP and cisplatin activate DNA-damage response through similar pathways. DCP may be more soluble and stable, and better-tolerated. PMID:24403501

  4. Bioinforrnatics of Gene Expression Profiling Data Provide Mechanistic Understanding of Acute Ozone-Induced Lung injury

    EPA Science Inventory

    Acute ozone-induced pulmonary injury and inflammation are well characterized. A few studies have used gene expression profiling to determine the types of changes induced by ozone; however the mechanisms or the pathways involved are less well understood. We presumed that robust bi...

  5. Mechanistic modeling of the vertical soil organic matter profile in terrestrial ecosystems

    NASA Astrophysics Data System (ADS)

    Braakhekke, Maarten; Beer, Christian; Hoosbeek, Marcel; Reichstein, Markus; Kruijt, Bart; Wutzler, Thomas; Kattge, Jens; Schrumpf, Marion; Kabat, Pavel

    2010-05-01

    Modelling and measuring studies of soil organic carbon have traditionally focused on the 30 cm of the soil. In the recent past however, interest in the vertical distribution of soil carbon has increased due to 1) estimates suggesting that the deep soil globally stores a large amount of carbon, and 2) increasing evidence that soil carbon stabilization is be controlled by different processes at different depths that are likely to respond varyingly to future global changes, possibly leading to release of previously stabilized carbon. Therefore the ‘bucket' approach employed in traditional soil carbon models is not sufficient to adequately predict future soil carbon dynamics on long time scales. Furthermore, aggregation of soil temperature and moisture response of the whole profile may lead to biased results on short time scales as well. Hence, a more vertically explicit representation is needed, but development and parameterization of such models is hindered by lack of understanding of the processes involved in SOM profile development. Our study aims to answer the following questions: 1) what are the key driving processes that determine the vertical profile of soil organic matter and their comparative strength? and 2) can we improve soil carbon cycle models by accounting for the vertical SOM profile? In this scope we have developed SOMPROF, a new soil carbon model that dynamically simulates the vertical profile of the SOM fraction in the mineral soil, as well as the storage of organic matter in organic surface horizons L, F and H. The model includes two mechanisms of vertical organic matter transport: 1) diffusion, representing bioturbation (mixing of the soil matrix by soil biota), and 2) advection, representing downward movement with infiltrating water. Furthermore organic matter may be input directly at depth by root turnover. The model includes 5 organic carbon pools that differ with respect to their transport behavior and decomposability. The model has been

  6. Metabolic Model-Based Integration of Microbiome Taxonomic and Metabolomic Profiles Elucidates Mechanistic Links between Ecological and Metabolic Variation

    PubMed Central

    Noecker, Cecilia; Eng, Alexander; Srinivasan, Sujatha; Theriot, Casey M.; Young, Vincent B.; Jansson, Janet K.; Fredricks, David N.; Borenstein, Elhanan

    2016-01-01

    Multiple molecular assays now enable high-throughput profiling of the ecology, metabolic capacity, and activity of the human microbiome. However, to date, analyses of such multi-omic data typically focus on statistical associations, often ignoring extensive prior knowledge of the mechanisms linking these various facets of the microbiome. Here, we introduce a comprehensive framework to systematically link variation in metabolomic data with community composition by utilizing taxonomic, genomic, and metabolic information. Specifically, we integrate available and inferred genomic data, metabolic network modeling, and a method for predicting community-wide metabolite turnover to estimate the biosynthetic and degradation potential of a given community. Our framework then compares variation in predicted metabolic potential with variation in measured metabolites’ abundances to evaluate whether community composition can explain observed shifts in the community metabolome, and to identify key taxa and genes contributing to the shifts. Focusing on two independent vaginal microbiome data sets, each pairing 16S community profiling with large-scale metabolomics, we demonstrate that our framework successfully recapitulates observed variation in 37% of metabolites. Well-predicted metabolite variation tends to result from disease-associated metabolism. We further identify several disease-enriched species that contribute significantly to these predictions. Interestingly, our analysis also detects metabolites for which the predicted variation negatively correlates with the measured variation, suggesting environmental control points of community metabolism. Applying this framework to gut microbiome data sets reveals similar trends, including prediction of bile acid metabolite shifts. This framework is an important first step toward a system-level multi-omic integration and an improved mechanistic understanding of the microbiome activity and dynamics in health and disease. IMPORTANCE

  7. Mechanistic validation.

    PubMed

    Hartung, Thomas; Hoffmann, Sebastian; Stephens, Martin

    2013-01-01

    Validation of new approaches in regulatory toxicology is commonly defined as the independent assessment of the reproducibility and relevance (the scientific basis and predictive capacity) of a test for a particular purpose. In large ring trials, the emphasis to date has been mainly on reproducibility and predictive capacity (comparison to the traditional test) with less attention given to the scientific or mechanistic basis. Assessing predictive capacity is difficult for novel approaches (which are based on mechanism), such as pathways of toxicity or the complex networks within the organism (systems toxicology). This is highly relevant for implementing Toxicology for the 21st Century, either by high-throughput testing in the ToxCast/Tox21 project or omics-based testing in the Human Toxome Project. This article explores the mostly neglected assessment of a test's scientific basis, which moves mechanism and causality to the foreground when validating/qualifying tests. Such mechanistic validation faces the problem of establishing causality in complex systems. However, pragmatic adaptations of the Bradford Hill criteria, as well as bioinformatic tools, are emerging. As critical infrastructures of the organism are perturbed by a toxic mechanism we argue that by focusing on the target of toxicity and its vulnerability, in addition to the way it is perturbed, we can anchor the identification of the mechanism and its verification. PMID:23665802

  8. Transcriptional Profiling of Dibenzo[def,p]chrysene-induced Spleen Atrophy Provides Mechanistic Insights into its Immunotoxicity in MutaMouse.

    PubMed

    Chepelev, Nikolai L; Long, Alexandra S; Williams, Andrew; Kuo, Byron; Gagné, Rémi; Kennedy, Dean A; Phillips, David H; Arlt, Volker M; White, Paul A; Yauk, Carole L

    2016-01-01

    Dibenzo[def,p]chrysene (DBC) is the most carcinogenic polycyclic aromatic hydrocarbon (PAH) examined to date. We investigated the immunotoxicity of DBC, manifested as spleen atrophy, following acute exposure of adult MutaMouse males by oral gavage. Mice were exposed to 0, 2.0, 6.2, or 20.0 mg DBC /kg-bw per day, for 3 days. Genotoxic endpoints (DBC-DNA adducts and lacZ mutant frequency in spleen and bone marrow, and red blood cell micronucleus frequency) and global gene expression changes were measured. All of the genotoxicity measures increased in a dose-dependent manner in spleen and bone marrow. Gene expression analysis showed that DBC activates p53 signaling pathways related to cellular growth and proliferation, which was evident even at the low dose. Strikingly, the expression profiles of DBC exposed mouse spleens were highly inversely correlated with the expression profiles of the only published toxicogenomics dataset of enlarged mouse spleen. This analysis suggested a central role for Bnip3l, a pro-apoptotic protein involved in negative regulation of erythroid maturation. RT-PCR confirmed expression changes in several genes related to apoptosis, iron metabolism, and aryl hydrocarbon receptor signaling that are regulated in the opposite direction during spleen atrophy versus benzo[a]pyrene-mediated splenomegaly. In addition, benchmark dose modeling of toxicogenomics data yielded toxicity estimates that are very close to traditional toxicity endpoints. This work illustrates the power of toxicogenomics to reveal rich mechanistic information for immunotoxic compounds and its ability to provide information that is quantitatively similar to that derived from standard toxicity methods in health risk assessment. PMID:26496743

  9. Feature Scale Simulation of PECVD of SiO2 in SiH4/N2O Mixture

    NASA Astrophysics Data System (ADS)

    Liu, Xuan; Ge, Jie; Yang, Yi; Song, Yixu; Ren, Tianling

    2014-04-01

    In this paper, to simulate the process of PECVD (plasma enhanced chemical vapor deposition) of SiO2, the plasma chemistry and plasma density of SiH4/N2O mixture have been studied with an inductive coupled plasma model, and the level set methodology has been used to obtain the feature scale variation during the process. In this simulation, the goal is to fill a trench. We studied how ion sputtering and chamber pressure affect the feature scale model. After the simulation, we found that the trench will close up at the top after a few steps, and if we add the ion sputtering into the surface reactions, the trench top will close up a little later. When the chamber pressure is improved, the plasma density will increase, so the trench top will close up earlier. In semiconductor device manufacture, people can control the trench's feature scale through adjusting these two parameters.

  10. Profiles.

    ERIC Educational Resources Information Center

    School Arts, 1979

    1979-01-01

    Profiles seven Black, Native American, and Chicano artists and art teachers: Hale A. Woodruff, Allan Houser, Luis Jimenez, Betrand D. Phillips, James E. Pate, I, and Fernando Navarro. This article is part of a theme issue on multicultural art. (SJL)

  11. Mechanistic investigations of shuttle glow

    NASA Technical Reports Server (NTRS)

    Caledonia, G. E.; Holtzclaw, K. W.; Krech, R. H.; Sonnenfroh, D. M.; Leone, A.; Blumberg, W. A. M.

    1993-01-01

    A series of laboratory measurements have been performed in order to provide a mechanistic interpretation for the visible shuttle glow. These studies involved interactions of an 8 km/s oxygen atom beam with both contaminant dosed surfaces and gaseous targets. We conclude that visible shuttle glow arises from surface mediated O + NO recombination via a Langmuir-Hinshelwood mechanism and that the gas-phase exchange reaction O + N2 - NO + N provides a viable source of precursor NO above surfaces oriented in the ram direction.

  12. Mechanistic investigations of shuttle glow

    SciTech Connect

    Caledonia, G.E.; Holtzclaw, K.W.; Krech, R.H.; Sonnenfroh, D.M. ); Leone, A. ); Blumber, W.A.M. )

    1993-03-01

    A series of laboratory measurements have been performed in order to provide a mechanistic interpretation for the visible shuttle glow. These studies involved interactions in an 8 km/s oxygen atom beam with both contaminant dosed surfaces and gaseous targets. The authors conclude that visible shuttle glow arises from surface mediated O + NO recombination via a Langmuir-Hinshelwood mechanism and that the gas-phase exchange reaction O + N[sub 2] [r arrow] NO + N provides a viable source of precursor NO above surfaces oriented in the ram direction. 35 refs., 4 figs.

  13. Assessment of Borderline Personality Features in Population Samples: Is the Personality Assessment Inventory-Borderline Features Scale Measurement Invariant across Sex and Age?

    ERIC Educational Resources Information Center

    De Moor, Marleen H. M.; Distel, Marijn A.; Trull, Timothy J.; Boomsma, Dorret I.

    2009-01-01

    Borderline personality disorder (BPD) is more often diagnosed in women than in men, and symptoms tend to decline with age. Using a large community sample, the authors investigated whether sex and age differences in four main features of BPD, measured with the "Personality Assessment Inventory-Borderline Features" scale (PAI-BOR; Morey, 1991), are…

  14. Food for Thought ... Mechanistic Validation

    PubMed Central

    Hartung, Thomas; Hoffmann, Sebastian; Stephens, Martin

    2013-01-01

    Summary Validation of new approaches in regulatory toxicology is commonly defined as the independent assessment of the reproducibility and relevance (the scientific basis and predictive capacity) of a test for a particular purpose. In large ring trials, the emphasis to date has been mainly on reproducibility and predictive capacity (comparison to the traditional test) with less attention given to the scientific or mechanistic basis. Assessing predictive capacity is difficult for novel approaches (which are based on mechanism), such as pathways of toxicity or the complex networks within the organism (systems toxicology). This is highly relevant for implementing Toxicology for the 21st Century, either by high-throughput testing in the ToxCast/ Tox21 project or omics-based testing in the Human Toxome Project. This article explores the mostly neglected assessment of a test's scientific basis, which moves mechanism and causality to the foreground when validating/qualifying tests. Such mechanistic validation faces the problem of establishing causality in complex systems. However, pragmatic adaptations of the Bradford Hill criteria, as well as bioinformatic tools, are emerging. As critical infrastructures of the organism are perturbed by a toxic mechanism we argue that by focusing on the target of toxicity and its vulnerability, in addition to the way it is perturbed, we can anchor the identification of the mechanism and its verification. PMID:23665802

  15. HTGR Mechanistic Source Terms White Paper

    SciTech Connect

    Wayne Moe

    2010-07-01

    The primary purposes of this white paper are: (1) to describe the proposed approach for developing event specific mechanistic source terms for HTGR design and licensing, (2) to describe the technology development programs required to validate the design methods used to predict these mechanistic source terms and (3) to obtain agreement from the NRC that, subject to appropriate validation through the technology development program, the approach for developing event specific mechanistic source terms is acceptable

  16. Natural selection and mechanistic regularity.

    PubMed

    DesAutels, Lane

    2016-06-01

    In this article, I address the question of whether natural selection operates regularly enough to qualify as a mechanism of the sort characterized by Machamer, Darden, and Craver (2000). Contrary to an influential critique by Skipper and Millstein (2005), I argue that natural selection can be seen to be regular enough to qualify as an MDC mechanism just fine-as long as we pay careful attention to some important distinctions regarding mechanistic regularity and abstraction. Specifically, I suggest that when we distinguish between process vs. product regularity, mechanism-internal vs. mechanism-external sources of irregularity, and abstract vs. concrete regularity, we can see that natural selection is only irregular in senses that are unthreatening to its status as an MDC mechanism. PMID:26921876

  17. Rational and Mechanistic Perspectives on Reinforcement Learning

    ERIC Educational Resources Information Center

    Chater, Nick

    2009-01-01

    This special issue describes important recent developments in applying reinforcement learning models to capture neural and cognitive function. But reinforcement learning, as a theoretical framework, can apply at two very different levels of description: "mechanistic" and "rational." Reinforcement learning is often viewed in mechanistic terms--as…

  18. Data graphs and mechanistic explanation.

    PubMed

    Burnston, Daniel C

    2016-06-01

    It is a widespread assumption in philosophy of science that representations of data are not explanatory-that they are mere stepping stones towards an explanation, such as a representation of a mechanism. I draw on instances of representational and explanatory practice from mammalian chronobiology to suggest that this assumption is unsustainable. In many instances, biologists employ representations of data in explanatory ways that are not reducible to constraints on or evidence for representations of mechanisms. Data graphs are used to represent relationships between quantities across conditions, and often these representations are necessary for explaining particular aspects of the phenomena under study. The benefit of the analysis is two-fold. First, it provides a more accurate account of explanatory practice in broadly mechanistic investigation in biology. Second, it suggests that there is not an explanatorily "fundamental" type of representation in biology. Rather, the practice of explanation consists in the construction of different types of representations and their employment for distinct explanatory purposes. PMID:26871740

  19. Negative mechanistic reasoning in medical intervention assessment.

    PubMed

    Jerkert, Jesper

    2015-12-01

    Traditionally, mechanistic reasoning has been assigned a negligible role in standard EBM (evidence-based medicine) literature, although some recent authors have argued for an upgrade. Even so, the mechanistic reasoning that has received attention has almost exclusively been positive--both in an epistemic sense of claiming that there is a mechanistic chain and in a health-related sense of there being claimed benefits for the patient. Negative mechanistic reasoning has been neglected, both in the epistemic and in the health-related sense. I distinguish three main types of negative mechanistic reasoning and subsume them under a new definition of mechanistic reasoning in the context of assessing medical interventions. This definition is wider than a previous suggestion in the literature. Each negative type corresponds to a range of evidential strengths, and it is argued that there are differences with respect to typical evidential strengths. The variety of negative mechanistic reasoning should be acknowledged in EBM, and it presents a serious challenge to proponents of so-called medical hierarchies of evidence. PMID:26597869

  20. MECHANISTIC INDICATORS OF CHILDHOOD ASTHMA (MICA)

    EPA Science Inventory

    The US Environmental Protection Agency (EPA) is interested in the interplay of environmental and genetic factors on the development and exacerbation of asthma. The Mechanistic Indicators of Childhood Asthma (MICA) study will use exposure measurements and markers of environmental ...

  1. Submarine Glacial Geomorphology of the Continental Shelf East of the Antarctic Peninsula: Variable Feature-Scales and Overprinting Patterns

    NASA Astrophysics Data System (ADS)

    Campo, Jennifer; Wellner, Julia; Lavoie, Caroline; Domack, Eugene; Yoo, Kyu-Cheul

    2015-04-01

    profiles across each of these sets of features, we highlight that only two sets are actually mega-scale glacial lineations. The other two are actually sets of sub parallel iceberg furrows that are interpreted to have come from calving at a nearby grounding line. Additional crosscutting flow patterns are observed in the area of the Seal Nunataks, between the Larsen A and B embayments. Flow indicators are oriented directly offshore (~E-W), parallel to the Nunataks; this flow pattern is interpreted to be from LGM time. Additional flow indicators go from the Nunataks to the northeast, into the Larsen A embayment; however, a similar flow pattern is not observed on the south side of the Seal Nunataks. This pattern is interpreted as more recent flow and thus reorganization of the flow pattern as the grounding line retreated.

  2. Mechanistic models in computational social science

    NASA Astrophysics Data System (ADS)

    Holme, Petter; Liljeros, Fredrik

    2015-09-01

    Quantitative social science is not only about regression analysis or, in general, data inference. Computer simulations of social mechanisms have an over 60 years long history. They have been used for many different purposes—to test scenarios, to test the consistency of descriptive theories (proof-of-concept models), to explore emergent phenomena, for forecasting, etc. In this essay, we sketch these historical developments, the role of mechanistic models in the social sciences and the influences from the natural and formal sciences. We argue that mechanistic computational models form a natural common ground for social and natural sciences, and look forward to possible future information flow across the social-natural divide.

  3. Testing mechanistic models of growth in insects.

    PubMed

    Maino, James L; Kearney, Michael R

    2015-11-22

    Insects are typified by their small size, large numbers, impressive reproductive output and rapid growth. However, insect growth is not simply rapid; rather, insects follow a qualitatively distinct trajectory to many other animals. Here we present a mechanistic growth model for insects and show that increasing specific assimilation during the growth phase can explain the near-exponential growth trajectory of insects. The presented model is tested against growth data on 50 insects, and compared against other mechanistic growth models. Unlike the other mechanistic models, our growth model predicts energy reserves per biomass to increase with age, which implies a higher production efficiency and energy density of biomass in later instars. These predictions are tested against data compiled from the literature whereby it is confirmed that insects increase their production efficiency (by 24 percentage points) and energy density (by 4 J mg(-1)) between hatching and the attainment of full size. The model suggests that insects achieve greater production efficiencies and enhanced growth rates by increasing specific assimilation and increasing energy reserves per biomass, which are less costly to maintain than structural biomass. Our findings illustrate how the explanatory and predictive power of mechanistic growth models comes from their grounding in underlying biological processes. PMID:26609084

  4. Mechanistic Indicators of Childhood Asthma (MICA) Study

    EPA Science Inventory

    The Mechanistic Indicators of Childhood Asthma (MICA) Study has been designed to incorporate state-of-the-art technologies to examine the physiological and environmental factors that interact to increase the risk of asthmatic responses. MICA is primarily a clinically-bases obser...

  5. Exploring Organic Mechanistic Puzzles with Molecular Modeling

    ERIC Educational Resources Information Center

    Horowitz, Gail; Schwartz, Gary

    2004-01-01

    The molecular modeling was used to reinforce more general skills such as deducing and drawing reaction mechanisms, analyzing reaction kinetics and thermodynamics and drawing reaction coordinate energy diagrams. This modeling was done through the design of mechanistic puzzles, involving reactions not familiar to the students.

  6. Mechanistic fracture criteria for the failure of human cortical bone

    SciTech Connect

    Nalla, Ravi K.; Kinney, John H.; Ritchie, Robert O.

    2002-12-13

    A mechanistic understanding of fracture in human bone is critical to predicting fracture risk associated with age and disease. Despite extensive work, a mechanistic framework for describing how the underlying microstructure affects the failure mode in bone is lacking.

  7. Mechanistic analysis of challenge-response experiments.

    PubMed

    Shotwell, M S; Drake, K J; Sidorov, V Y; Wikswo, J P

    2013-09-01

    We present an application of mechanistic modeling and nonlinear longitudinal regression in the context of biomedical response-to-challenge experiments, a field where these methods are underutilized. In this type of experiment, a system is studied by imposing an experimental challenge, and then observing its response. The combination of mechanistic modeling and nonlinear longitudinal regression has brought new insight, and revealed an unexpected opportunity for optimal design. Specifically, the mechanistic aspect of our approach enables the optimal design of experimental challenge characteristics (e.g., intensity, duration). This article lays some groundwork for this approach. We consider a series of experiments wherein an isolated rabbit heart is challenged with intermittent anoxia. The heart responds to the challenge onset, and recovers when the challenge ends. The mean response is modeled by a system of differential equations that describe a candidate mechanism for cardiac response to anoxia challenge. The cardiac system behaves more variably when challenged than when at rest. Hence, observations arising from this experiment exhibit complex heteroscedasticity and sharp changes in central tendency. We present evidence that an asymptotic statistical inference strategy may fail to adequately account for statistical uncertainty. Two alternative methods are critiqued qualitatively (i.e., for utility in the current context), and quantitatively using an innovative Monte-Carlo method. We conclude with a discussion of the exciting opportunities in optimal design of response-to-challenge experiments. PMID:23859366

  8. Mechanistic facility safety and source term analysis

    SciTech Connect

    PLYS, M.G.

    1999-06-09

    A PC-based computer program was created for facility safety and source term analysis at Hanford The program has been successfully applied to mechanistic prediction of source terms from chemical reactions in underground storage tanks, hydrogen combustion in double contained receiver tanks, and proccss evaluation including the potential for runaway reactions in spent nuclear fuel processing. Model features include user-defined facility room, flow path geometry, and heat conductors, user-defined non-ideal vapor and aerosol species, pressure- and density-driven gas flows, aerosol transport and deposition, and structure to accommodate facility-specific source terms. Example applications are presented here.

  9. Mechanistic studies of carbon monoxide reduction

    SciTech Connect

    Geoffroy, G.L.

    1990-06-12

    The progress made during the current grant period (1 January 1988--1 April 1990) in three different areas of research is summarized. The research areas are: (1) oxidatively-induced double carbonylation reactions to form {alpha}-ketoacyl complexes and studies of the reactivity of the resulting compounds, (2) mechanistic studies of the carbonylation of nitroaromatics to form isocyanates, carbamates, and ureas, and (3) studies of the formation and reactivity of unusual metallacycles and alkylidene ligands supported on binuclear iron carbonyl fragments. 18 refs., 5 figs., 1 tab.

  10. Composite Nanomechanics: A Mechanistic Properties Prediction

    NASA Technical Reports Server (NTRS)

    Chamis, Christos C.; Handler, Louis M.; Manderscheid, Jane M.

    2007-01-01

    A unique mechanistic theory is described to predict the properties of nanocomposites. The theory is based on composite micromechanics with progressive substructuring down to a nanoscale slice of a nanofiber where all the governing equations are formulated. These equations hav e been programmed in a computer code. That computer code is used to predict 25 properties of a mononanofiber laminate. The results are pr esented graphically and discussed with respect to their practical sig nificance. Most of the results show smooth distributions. Results for matrix-dependent properties show bimodal through-the-thickness distr ibution with discontinuous changes from mode to mode.

  11. Composite Nanomechanics: A Mechanistic Properties Prediction

    NASA Technical Reports Server (NTRS)

    Chamis, Christos C.; Handler, Louis M.; Manderscheid, Jane M.

    2007-01-01

    A unique mechanistic theory is described to predict the properties of nanocomposites. The theory is based on composite micromechanics with progressive substructuring down to a nanoscale slice of a nanofiber where all the governing equations are formulated. These equations have been programmed in a computer code. That computer code is used to predict 25 properties of a mononanofiber laminate. The results are presented graphically and discussed with respect to their practical significance. Most of the results show smooth distributions. Results for matrix-dependent properties show bimodal through-the-thickness distribution with discontinuous changes from mode to mode.

  12. LDRD final report : on the development of hybrid level-set/particle methods for modeling surface evolution during feature-scale etching and deposition processes.

    SciTech Connect

    McBride, Cory L.; Schmidt, Rodney Cannon; Musson, Lawrence Cale

    2005-01-01

    Two methods for creating a hybrid level-set (LS)/particle method for modeling surface evolution during feature-scale etching and deposition processes are developed and tested. The first method supplements the LS method by introducing Lagrangian marker points in regions of high curvature. Once both the particle set and the LS function are advanced in time, minimization of certain objective functions adjusts the LS function so that its zero contour is in closer alignment with the particle locations. It was found that the objective-minimization problem was unexpectedly difficult to solve, and even when a solution could be found, the acquisition of it proved more costly than simply expanding the basis set of the LS function. The second method explored is a novel explicit marker-particle method that we have named the grid point particle (GPP) approach. Although not a LS method, the GPP approach has strong procedural similarities to certain aspects of the LS approach. A key aspect of the method is a surface rediscretization procedure--applied at each time step and based on a global background mesh--that maintains a representation of the surface while naturally adding and subtracting surface discretization points as the surface evolves in time. This method was coded in 2-D, and tested on a variety of surface evolution problems by using it in the ChISELS computer code. Results shown for 2-D problems illustrate the effectiveness of the method and highlight some notable advantages in accuracy over the LS method. Generalizing the method to 3D is discussed but not implemented.

  13. Appropriateness of mechanistic and non-mechanistic models for the application of ultrafiltration to mixed waste

    SciTech Connect

    Foust, Henry; Ghosehajra, Malay

    2007-07-01

    This study asks two questions: (1) How appropriate is the use of a basic filtration equation to the application of ultrafiltration of mixed waste, and (2) How appropriate are non-parametric models for permeate rates (volumes)? To answer these questions, mechanistic and non-mechanistic approaches are developed for permeate rates and volumes associated with an ultrafiltration/mixed waste system in dia-filtration mode. The mechanistic approach is based on a filtration equation which states that t/V vs. V is a linear relationship. The coefficients associated with this linear regression are composed of physical/chemical parameters of the system and based the mass balance equation associated with the membrane and associated developing cake layer. For several sets of data, a high correlation is shown that supports the assertion that t/V vs. V is a linear relationship. It is also shown that non-mechanistic approaches, i.e., the use of regression models to are not appropriate. One models considered is Q(p) = a*ln(Cb)+b. Regression models are inappropriate because the scale-up from a bench scale (pilot scale) study to full-scale for permeate rates (volumes) is not simply the ratio of the two membrane surface areas. (authors)

  14. Reaction Coordinates and Mechanistic Hypothesis Tests.

    PubMed

    Peters, Baron

    2016-05-27

    Reaction coordinates are integral to several classic rate theories that can (a) predict kinetic trends across conditions and homologous reactions, (b) extract activation parameters with a clear physical interpretation from experimental rates, and (c) enable efficient calculations of free energy barriers and rates. New trajectory-based rare events methods can provide rates directly from dynamical trajectories without a reaction coordinate. Trajectory-based frameworks can also generate ideal (but abstract) reaction coordinates such as committors and eigenfunctions of the master equation. However, rates and mechanistic insights obtained from trajectory-based methods and abstract coordinates are not readily generalized across simulation conditions or reaction families. We discuss methods for identifying physically meaningful reaction coordinates, including committor analysis, variational transition state theory, Kramers-Langer-Berezhkovskii-Szabo theory, and statistical inference methods that can use path sampling data to screen, mix, and optimize thousands of trial coordinates. Special focus is given to likelihood maximization and inertial likelihood maximization approaches. PMID:27090846

  15. Reaction Coordinates and Mechanistic Hypothesis Tests

    NASA Astrophysics Data System (ADS)

    Peters, Baron

    2016-05-01

    Reaction coordinates are integral to several classic rate theories that can (a) predict kinetic trends across conditions and homologous reactions, (b) extract activation parameters with a clear physical interpretation from experimental rates, and (c) enable efficient calculations of free energy barriers and rates. New trajectory-based rare events methods can provide rates directly from dynamical trajectories without a reaction coordinate. Trajectory-based frameworks can also generate ideal (but abstract) reaction coordinates such as committors and eigenfunctions of the master equation. However, rates and mechanistic insights obtained from trajectory-based methods and abstract coordinates are not readily generalized across simulation conditions or reaction families. We discuss methods for identifying physically meaningful reaction coordinates, including committor analysis, variational transition state theory, Kramers-Langer-Berezhkovskii-Szabo theory, and statistical inference methods that can use path sampling data to screen, mix, and optimize thousands of trial coordinates. Special focus is given to likelihood maximization and inertial likelihood maximization approaches.

  16. Development of a mechanistic model for forced convection subcooled boiling

    NASA Astrophysics Data System (ADS)

    Shaver, Dillon R.

    The focus of this work is on the formulation, implementation, and testing of a mechanistic model of subcooled boiling. Subcooled boiling is the process of vapor generation on a heated wall when the bulk liquid temperature is still below saturation. This is part of a larger effort by the US DoE's CASL project to apply advanced computational tools to the simulation of light water reactors. To support this effort, the formulation of the dispersed field model is described and a complete model of interfacial forces is formulated. The model has been implemented in the NPHASE-CMFD computer code with a K-epsilon model of turbulence. The interfacial force models are built on extensive work by other authors, and include novel formulations of the turbulent dispersion and lift forces. The complete model of interfacial forces is compared to experiments for adiabatic bubbly flows, including both steady-state and unsteady conditions. The same model is then applied to a transient gas/liquid flow in a complex geometry of fuel channels in a sodium fast reactor. Building on the foundation of the interfacial force model, a mechanistic model of forced-convection subcooled boiling is proposed. This model uses the heat flux partitioning concept and accounts for condensation of bubbles attached to the wall. This allows the model to capture the enhanced heat transfer associated with boiling before the point of net generation of vapor, a phenomenon consistent with existing experimental observations. The model is compared to four different experiments encompassing flows of light water, heavy water, and R12 at different pressures, in cylindrical channels, an internally heated annulus, and a rectangular channel. The experimental data includes axial and radial profiles of both liquid temperature and vapor volume fraction, and the agreement can be considered quite good. The complete model is then applied to simulations of subcooled boiling in nuclear reactor subchannels consistent with the

  17. Somatodendritic dopamine release: recent mechanistic insights.

    PubMed

    Rice, Margaret E; Patel, Jyoti C

    2015-07-01

    Dopamine (DA) is a key transmitter in motor, reward and cogitative pathways, with DA dysfunction implicated in disorders including Parkinson's disease and addiction. Located in midbrain, DA neurons of the substantia nigra pars compacta project via the medial forebrain bundle to the dorsal striatum (caudate putamen), and DA neurons in the adjacent ventral tegmental area project to the ventral striatum (nucleus accumbens) and prefrontal cortex. In addition to classical vesicular release from axons, midbrain DA neurons exhibit DA release from their cell bodies and dendrites. Somatodendritic DA release leads to activation of D2 DA autoreceptors on DA neurons that inhibit their firing via G-protein-coupled inwardly rectifying K(+) channels. This helps determine patterns of DA signalling at distant axonal release sites. Somatodendritically released DA also acts via volume transmission to extrasynaptic receptors that modulate local transmitter release and neuronal activity in the midbrain. Thus, somatodendritic release is a pivotal intrinsic feature of DA neurons that must be well defined in order to fully understand the physiology and pathophysiology of DA pathways. Here, we review recent mechanistic aspects of somatodendritic DA release, with particular emphasis on the Ca(2+) dependence of release and the potential role of exocytotic proteins. PMID:26009764

  18. Mechanistically based mapping of human cardiac fibrillation

    PubMed Central

    Zaman, Junaid A. B.

    2016-01-01

    Abstract The mechanisms underpinning human cardiac fibrillation remain elusive. In his 1913 paper ‘On dynamic equilibrium in the heart’, Mines proposed that an activation wave front could propagate repeatedly in a circle, initiated by a stimulus in the vulnerable period. While the dynamics of activation and recovery are central to cardiac fibrillation, these physiological data are rarely used in clinical mapping. Fibrillation is a rapid irregular rhythm with spatiotemporal disorder resulting from two fundamental mechanisms – sources in preferred cardiac regions or spatially diffuse self‐sustaining activity, i.e. with no preferred source. On close inspection, however, this debate may also reflect mapping technique. Fibrillation is initiated from triggers by regional dispersion in repolarization, slow conduction and wavebreak, then sustained by non‐uniform interactions of these mechanisms. Notably, optical mapping of action potentials in atrial fibrillation (AF) show spiral wave sources (rotors) in nearly all studies including humans, while most traditional electrogram analyses of AF do not. Techniques may diverge in fibrillation because electrograms summate non‐coherent waves within an undefined field whereas optical maps define waves with a visually defined field. Also fibrillation operates at the limits of activation and recovery, which are well represented by action potentials while fibrillatory electrograms poorly represent repolarization. We conclude by suggesting areas for study that may be used, until such time as optical mapping is clinically feasible, to improve mechanistic understanding and therapy of human cardiac fibrillation. PMID:26607671

  19. Mechanistic chemical perspective of hydrogen sulfide signaling.

    PubMed

    Nagy, Péter

    2015-01-01

    Hydrogen sulfide is now a well-appreciated master regulator in a diverse array of physiological processes. However, as a consequence of the rapid growth of the area, sulfide biology suffers from an increasing number of controversial observations and interpretations. A better understanding of the underlying molecular pathways of sulfide's actions is key to reconcile controversial issues, which calls for rigorous chemical/biochemical investigations. Protein sulfhydration and coordination/redox chemical interactions of sulfide with heme proteins are the two most extensively studied pathways in sulfide biochemistry. These pathways are important mediators of protein functions, generate bioactive sulfide metabolites, contribute to sulfide storage/trafficking and carry antioxidant functions. In addition, inorganic polysulfides, which are oxidative sulfide metabolites, are increasingly recognized as important players in sulfide biology. This chapter provides an overview of our mechanistic perspective on the reactions that govern (i) sulfide's bioavailability (including the delicate enzyme machineries that orchestrate sulfide production and consumption and the roles of the large sulfide-storing pools as biological buffers), (ii) biological significance and mechanisms of persulfide formation (including the reduction of disulfides, condensation with sulfenic acids, oxidation of thiols with polysulfides and radical-mediated pathways), (iii) coordination and redox chemical interactions of sulfide with heme proteins (including cytochrome c oxidase, hemoglobins, myoglobins and peroxidases), and (iv) the chemistry of polysulfides. PMID:25725513

  20. Structural and mechanistic insights on nitrate reductases.

    PubMed

    Coelho, Catarina; Romão, Maria João

    2015-12-01

    Nitrate reductases (NR) belong to the DMSO reductase family of Mo-containing enzymes and perform key roles in the metabolism of the nitrogen cycle, reducing nitrate to nitrite. Due to variable cell location, structure and function, they have been divided into periplasmic (Nap), cytoplasmic, and membrane-bound (Nar) nitrate reductases. The first crystal structure obtained for a NR was that of the monomeric NapA from Desulfovibrio desulfuricans in 1999. Since then several new crystal structures were solved providing novel insights that led to the revision of the commonly accepted reaction mechanism for periplasmic nitrate reductases. The two crystal structures available for the NarGHI protein are from the same organism (Escherichia coli) and the combination with electrochemical and spectroscopic studies also lead to the proposal of a reaction mechanism for this group of enzymes. Here we present an overview on the current advances in structural and functional aspects of bacterial nitrate reductases, focusing on the mechanistic implications drawn from the crystallographic data. PMID:26362109

  1. Mechanistically based mapping of human cardiac fibrillation.

    PubMed

    Narayan, Sanjiv M; Zaman, Junaid A B

    2016-05-01

    The mechanisms underpinning human cardiac fibrillation remain elusive. In his 1913 paper 'On dynamic equilibrium in the heart', Mines proposed that an activation wave front could propagate repeatedly in a circle, initiated by a stimulus in the vulnerable period. While the dynamics of activation and recovery are central to cardiac fibrillation, these physiological data are rarely used in clinical mapping. Fibrillation is a rapid irregular rhythm with spatiotemporal disorder resulting from two fundamental mechanisms - sources in preferred cardiac regions or spatially diffuse self-sustaining activity, i.e. with no preferred source. On close inspection, however, this debate may also reflect mapping technique. Fibrillation is initiated from triggers by regional dispersion in repolarization, slow conduction and wavebreak, then sustained by non-uniform interactions of these mechanisms. Notably, optical mapping of action potentials in atrial fibrillation (AF) show spiral wave sources (rotors) in nearly all studies including humans, while most traditional electrogram analyses of AF do not. Techniques may diverge in fibrillation because electrograms summate non-coherent waves within an undefined field whereas optical maps define waves with a visually defined field. Also fibrillation operates at the limits of activation and recovery, which are well represented by action potentials while fibrillatory electrograms poorly represent repolarization. We conclude by suggesting areas for study that may be used, until such time as optical mapping is clinically feasible, to improve mechanistic understanding and therapy of human cardiac fibrillation. PMID:26607671

  2. Black tea polyphenols: a mechanistic treatise.

    PubMed

    Butt, M S; Imran, A; Sharif, M K; Ahmad, Rabia Shabir; Xiao, Hang; Imran, M; Rsool, H A

    2014-01-01

    Dietary interventions are among the emerging trends to curtail physiological malfunctioning like cancer, diabetes, cardiac complications, etc. The essence of phytonutrients has developed the concept of nutraceuticals at the junction of diet health linkages. In this context, theaflavin & thearubigins are the oxidized derivatives of black tea catechins during fermentation having nutraceutical potential owing to esterification of hydroxyl ring with digallate esters. Theaflavin may influence activation of transcription factors such as NFnB or AP-1 that ultimately hinder the formation of nitric oxide expression gene. Likewise, black tea contains a unique amino acid theanine acts as neurotransmitter owing to its ability to cross the blood-brain barrier. Moreover, it boasts immunity by enhancing the disease-fighting ability of gamma delta T cells. Theaflavin & thearubigins act as safeguard against oxidative stress thereby effective in the cardiac functioning. The mechanistic approach of these antioxidants is likely to be associated with inhibition of redox sensitive transcription factors & pro-oxidant enzymes such as xanthine oxidase or nitric oxide synthase. However, their involvement in antioxidative enzyme induction as in glutathione-S-transferases is also well documented. They act as curative agent against numerous pathological disorders by disrupting the electron chain thus inhibiting the progression of certain ailments. Black tea polyphenols established themselves as strong antioxidants due to their standard one-electron potential, and their vitality is dependent on the concentration of polyphenols and pH for their inclusive execution. Present review is an attempt to enrich the readers regarding the health promoting aspects of black tea polyphenols. Concomitantly, it needs core attention of researchers for the exploitations of black tea flavanols as an important dietary constituent for the vulnerable segment. PMID:24499118

  3. Predictive toxicodynamics: Empirical/mechanistic approaches.

    PubMed

    Frazier, J M

    1997-10-01

    A major objective of the toxicological sciences is to predict the in vivo toxicological consequences of human exposure to pure chemicals, complex mixtures and commercial formulations. Historically, the experimental approach to this goal has been to investigate toxicological processes in whole animal models and extrapolate the results obtained to predict human risk using various extrapolation procedures (high-dose/low-dose extrapolation, interspecies extrapolation and route-to-route extrapolation). Can in vitro methods be more widely employed in quantitative risk assessment? One major limitation to the broader application of in vitro toxicity testing methods is the lack of validated techniques for the extrapolation of in vitro-derived toxicodynamic data to the in vivo situation. The objective of this paper is to describe some approaches to the development of techniques to extrapolate in vitro toxicity testing data to predict in vivo toxicological responses. An empirical approach within the context of a mechanistic framework is explored. The basic hypothesis is that the in vivo response can be constructed from a cellular toxicity factor that accounts for the cellular response and a toxicodynamic factor that relates toxicological events at the cellular level to the observable in vivo responses. A predictive paradigm to describe the in vivo acute target organ toxicity (hepatotoxicity) of a model chemical (cadmium) is discussed. The cellular toxicity factor is derived from in vitro toxicity testing studies using isolated rat hepatocytes. The toxicodynamic factor is derived through Biologically-Based Response (BBR) modelling techniques to predict target organ toxicity markers (i.e. plasma hepatic enzyme levels as markers for acute hepatotoxicity). The ultimate goal is to develop validated extrapolation procedures that can be applied to predicting target organ toxicity quantitatively in human populations based on in vitro toxicity studies using human cellular models. PMID

  4. Mechanistic Insights into Homogeneous and Heterogeneous Asymmetric Iron Catalysis

    NASA Astrophysics Data System (ADS)

    Sonnenberg, Jessica

    Our group has been focused on replacing toxic and expensive precious metal catalysts with iron for the synthesis of enantiopure compounds for industrial applications. During an investigation into the mechanism of asymmetric transfer hydrogenation with our first generation iron-(P-N-N-P) catalysts we found substantial evidence for zero-valent iron nanoparticles coated in chiral ligand acting as the active site. Extensive experimental and computational experiments were undertaken which included NMR, DFT, reaction profile analysis, substoichiometric poisoning, electron microscope imaging, XPS and multiphasic analysis, all of which supported the fact that NPs were the active species in catalysis. Reversibility of this asymmetric reaction on the nanoparticle surface was then probed using oxidative kinetic resolution of racemic alcohols, yielding modest enantiopurity and high turnover frequencies (TOF) for a range of aromatic alcohols. Efficient dehydrogenation of ammonia-borane for hydrogen evolution and the formation of B-N oligomers was also shown using the NP system, yielding highly active systems, with a maximum TOF of 3.66 H2/s-1 . We have also begun to focus on the development of iron catalysts for asymmetric direct hydrogenation of ketones using hydrogen gas. New chiral iron-(P-N-P) catalysts were developed and shown to be quite active and selective for a wide range of substrates. Mechanistic investigations primarily using NMR and DFT indicated that a highly active trans-dihydride species was being formed during catalyst activation. Lastly, a new library of chiral P-N-P and P-NH-P ligands were developed, as well as their corresponding iron complexes, some of which show promise for the development of future generations of active asymmetric direct hydrogenation catalysts.

  5. MECHANISTIC DOSIMETRY MODELS OF NANOMATERIAL DEPOSITION IN THE RESPIRATORY TRACT

    EPA Science Inventory

    Accurate health risk assessments of inhalation exposure to nanomaterials will require dosimetry models that account for interspecies differences in dose delivered to the respiratory tract. Mechanistic models offer the advantage to interspecies extrapolation that physicochemica...

  6. Application of Mechanistic Toxicology Data to Ecological Risk Assessments

    EPA Science Inventory

    The ongoing evolution of knowledge and tools in the areas of molecular biology, bioinformatics, and systems biology holds significant promise for reducing uncertainties associated with ecological risk assessment. As our understanding of the mechanistic basis of responses of organ...

  7. Bridging paradigms: hybrid mechanistic-discriminative predictive models.

    PubMed

    Doyle, Orla M; Tsaneva-Atansaova, Krasimira; Harte, James; Tiffin, Paul A; Tino, Peter; Díaz-Zuccarini, Vanessa

    2013-03-01

    Many disease processes are extremely complex and characterized by multiple stochastic processes interacting simultaneously. Current analytical approaches have included mechanistic models and machine learning (ML), which are often treated as orthogonal viewpoints. However, to facilitate truly personalized medicine, new perspectives may be required. This paper reviews the use of both mechanistic models and ML in healthcare as well as emerging hybrid methods, which are an exciting and promising approach for biologically based, yet data-driven advanced intelligent systems. PMID:23392334

  8. MECHANISTIC STUDIES OF IMPROVED FOAM EOR PROCESSES

    SciTech Connect

    William R. Rossen

    2003-03-31

    . We find that such behavior is consistent with earlier models of foam viscosity in tubes, and a modified model for the low-quality regime can account for this behavior. It is not yet clear why this new regime appears in some cases and not in others. Simple modeling suggests that the answer may have to do with the sensitivity of gas trapping to pressure gradient. Research on Task 3 continued to focus on foam generation at limited pressure gradient in sandpacks. We investigated the effects of permeability, surfactant concentration and liquid injection rates on foam generation. In addition, a careful review of published studies showed that repeated snap-off is not a plausible mechanism of foam generation in homogeneous porous media beyond the stage of initial drainage from a fully liquid-saturated state. Snap-off has been the focus of much research on foam generation and is incorporated into most mechanistic foam simulators. This finding should force a reconsideration of its role in foam generation and properties in porous media.

  9. From formamide to purine: an energetically viable mechanistic reaction pathway.

    PubMed

    Wang, Jing; Gu, Jiande; Nguyen, Minh Tho; Springsteen, Greg; Leszczynski, Jerzy

    2013-02-28

    A step-by-step mechanistic pathway following the transformation of formamide to purine through a five-membered ring intermediate has been explored by density functional theory computations. The highlight of the mechanistic route detailed here is that the proposed pathway represents the simplest reaction pathway. All necessary reactants are generated from a single starting compound, formamide, through energetically viable reactions. Several important reaction steps are involved in this mechanistic route: formylation-dehydration, Leuckart reduction, five- and six-membered ring-closure, and deamination. On the basis of the study of noncatalytic pathways, catalytic water has been found to provide energetically viable step-by-step mechanistic pathways. Among these reaction steps, five-member ring-closure is the rate-determining step. The energy barrier (ca. 42 kcal/mol) of this rate-control step is somewhat lower than the rate-determining step (ca. 44 kcal/mol) for a pyrimidine-based pathway reported previously. The mechanistic pathway reported herein is less energetically demanding than for previously proposed routes to adenine. PMID:23347082

  10. Explanation and inference: mechanistic and functional explanations guide property generalization

    PubMed Central

    Lombrozo, Tania; Gwynne, Nicholas Z.

    2014-01-01

    The ability to generalize from the known to the unknown is central to learning and inference. Two experiments explore the relationship between how a property is explained and how that property is generalized to novel species and artifacts. The experiments contrast the consequences of explaining a property mechanistically, by appeal to parts and processes, with the consequences of explaining the property functionally, by appeal to functions and goals. The findings suggest that properties that are explained functionally are more likely to be generalized on the basis of shared functions, with a weaker relationship between mechanistic explanations and generalization on the basis of shared parts and processes. The influence of explanation type on generalization holds even though all participants are provided with the same mechanistic and functional information, and whether an explanation type is freely generated (Experiment 1), experimentally provided (Experiment 2), or experimentally induced (Experiment 2). The experiments also demonstrate that explanations and generalizations of a particular type (mechanistic or functional) can be experimentally induced by providing sample explanations of that type, with a comparable effect when the sample explanations come from the same domain or from a different domains. These results suggest that explanations serve as a guide to generalization, and contribute to a growing body of work supporting the value of distinguishing mechanistic and functional explanations. PMID:25309384

  11. Mechanistic Study of Manganese-Substituted Glycerol Dehydrogenase Using a Kinetic and Thermodynamic Analysis

    PubMed Central

    Fang, Baishan; Niu, Jin; Ren, Hong; Guo, Yingxia; Wang, Shizhen

    2014-01-01

    Mechanistic insights regarding the activity enhancement of dehydrogenase by metal ion substitution were investigated by a simple method using a kinetic and thermodynamic analysis. By profiling the binding energy of both the substrate and product, the metal ion's role in catalysis enhancement was revealed. Glycerol dehydrogenase (GDH) from Klebsiella pneumoniae sp., which demonstrated an improvement in activity by the substitution of a zinc ion with a manganese ion, was used as a model for the mechanistic study of metal ion substitution. A kinetic model based on an ordered Bi-Bi mechanism was proposed considering the noncompetitive product inhibition of dihydroxyacetone (DHA) and the competitive product inhibition of NADH. By obtaining preliminary kinetic parameters of substrate and product inhibition, the number of estimated parameters was reduced from 10 to 4 for a nonlinear regression-based kinetic parameter estimation. The simulated values of time-concentration curves fit the experimental values well, with an average relative error of 11.5% and 12.7% for Mn-GDH and GDH, respectively. A comparison of the binding energy of enzyme ternary complex for Mn-GDH and GDH derived from kinetic parameters indicated that metal ion substitution accelerated the release of dioxyacetone. The metal ion's role in catalysis enhancement was explicated. PMID:24896258

  12. Mechanistic Models of Friction Stir Welding

    NASA Technical Reports Server (NTRS)

    Stewart, Michael B.

    1998-01-01

    showed that the balance of moments through the weld plug was not possible under steady state conditions and realistic temperature profiles. This led to some consideration of a quasi-steady oscillating process. Later when force measurements became available some models were modified and new ones were proposed.

  13. Mechanistically Consistent Reduced Models of Synthetic Gene Networks

    PubMed Central

    Mier-y-Terán-Romero, Luis; Silber, Mary; Hatzimanikatis, Vassily

    2013-01-01

    Designing genetic networks with desired functionalities requires an accurate mathematical framework that accounts for the essential mechanistic details of the system. Here, we formulate a time-delay model of protein translation and mRNA degradation by systematically reducing a detailed mechanistic model that explicitly accounts for the ribosomal dynamics and the cleaving of mRNA by endonucleases. We exploit various technical and conceptual advantages that our time-delay model offers over the mechanistic model to probe the behavior of a self-repressing gene over wide regions of parameter space. We show that a heuristic time-delay model of protein synthesis of a commonly used form yields a notably different prediction for the parameter region where sustained oscillations occur. This suggests that such heuristics can lead to erroneous results. The functional forms that arise from our systematic reduction can be used for every system that involves transcription and translation and they could replace the commonly used heuristic time-delay models for these processes. The results from our analysis have important implications for the design of synthetic gene networks and stress that such design must be guided by a combination of heuristic models and mechanistic models that include all relevant details of the process. PMID:23663853

  14. Bridging Mechanistic and Phenomenological Models of Complex Biological Systems

    PubMed Central

    Transtrum, Mark K.; Qiu, Peng

    2016-01-01

    The inherent complexity of biological systems gives rise to complicated mechanistic models with a large number of parameters. On the other hand, the collective behavior of these systems can often be characterized by a relatively small number of phenomenological parameters. We use the Manifold Boundary Approximation Method (MBAM) as a tool for deriving simple phenomenological models from complicated mechanistic models. The resulting models are not black boxes, but remain expressed in terms of the microscopic parameters. In this way, we explicitly connect the macroscopic and microscopic descriptions, characterize the equivalence class of distinct systems exhibiting the same range of collective behavior, and identify the combinations of components that function as tunable control knobs for the behavior. We demonstrate the procedure for adaptation behavior exhibited by the EGFR pathway. From a 48 parameter mechanistic model, the system can be effectively described by a single adaptation parameter τ characterizing the ratio of time scales for the initial response and recovery time of the system which can in turn be expressed as a combination of microscopic reaction rates, Michaelis-Menten constants, and biochemical concentrations. The situation is not unlike modeling in physics in which microscopically complex processes can often be renormalized into simple phenomenological models with only a few effective parameters. The proposed method additionally provides a mechanistic explanation for non-universal features of the behavior. PMID:27187545

  15. THYROID FOLLICULAR CELL CARCINOGENESIS: MECHANISTIC AND SCIENCE POLICY CONSIDERATIONS

    EPA Science Inventory

    EPA's Guidelines for Carcinogen Risk Assessment call for use of mechanistic and other relevant information in making choices about the models to be used in extrapolating hazard estimates from high to low exposures. The Forum report on thyroid neoplasia proposes that, under clearl...

  16. DEVELOPMENT AND VALIDATION OF A MECHANISTIC GROUND SPRAYER MODEL

    EPA Science Inventory

    In the last ten years the Spray Drift Task Force (SDTF), U.S. Environmental Protection Agency (EPA), USDA Agricultural Research Service, and USDA Forest Service cooperated in the refinement and evaluation of a mechanistically-based aerial spray model (contained within AGDISP and ...

  17. MECHANISTIC AND SOURCE UNDERSTANDING OF PCDD/F FORMATION

    EPA Science Inventory

    The paper discusses mechanistic and source understanding of polychlorinated dibenzo-p-dioxin and dibenzofuran (PCDD/F) formation. (NOTE: Considerable research effort has been expended over the last 15-plus years to understand how combustion sources result in formation of PCDDs/F...

  18. MECHANISTIC-BASED DISINFECTION AND DISINFECTION BYPRODUCT MODELS

    EPA Science Inventory

    We propose developing a mechanistic-based numerical model for chlorine decay and regulated DBP (THM and HAA) formation derived from (free) chlorination; the model framework will allow future modifications for other DBPs and chloramination. Predicted chlorine residual and DBP r...

  19. Does Mechanistic Thinking Improve Student Success in Organic Chemistry?

    ERIC Educational Resources Information Center

    Grove, Nathaniel P.; Cooper, Melanie M.; Cox, Elizabeth L.

    2012-01-01

    The use of the curved-arrow notation to depict electron flow during mechanistic processes is one of the most important representational conventions in the organic chemistry curriculum. Our previous research documented a disturbing trend: when asked to predict the products of a series of reactions, many students do not spontaneously engage in…

  20. Bridging Mechanistic and Phenomenological Models of Complex Biological Systems.

    PubMed

    Transtrum, Mark K; Qiu, Peng

    2016-05-01

    The inherent complexity of biological systems gives rise to complicated mechanistic models with a large number of parameters. On the other hand, the collective behavior of these systems can often be characterized by a relatively small number of phenomenological parameters. We use the Manifold Boundary Approximation Method (MBAM) as a tool for deriving simple phenomenological models from complicated mechanistic models. The resulting models are not black boxes, but remain expressed in terms of the microscopic parameters. In this way, we explicitly connect the macroscopic and microscopic descriptions, characterize the equivalence class of distinct systems exhibiting the same range of collective behavior, and identify the combinations of components that function as tunable control knobs for the behavior. We demonstrate the procedure for adaptation behavior exhibited by the EGFR pathway. From a 48 parameter mechanistic model, the system can be effectively described by a single adaptation parameter τ characterizing the ratio of time scales for the initial response and recovery time of the system which can in turn be expressed as a combination of microscopic reaction rates, Michaelis-Menten constants, and biochemical concentrations. The situation is not unlike modeling in physics in which microscopically complex processes can often be renormalized into simple phenomenological models with only a few effective parameters. The proposed method additionally provides a mechanistic explanation for non-universal features of the behavior. PMID:27187545

  1. Rearrangements of Allylic Sulfinates to Sulfones: A Mechanistic Study

    ERIC Educational Resources Information Center

    Ball, David B.; Mollard, Paul; Voigtritter, Karl R.; Ball, Jenelle L.

    2010-01-01

    Most current organic chemistry textbooks are organized by functional groups and those of us who teach organic chemistry use functional-group organization in our courses but ask students to learn organic chemistry from a mechanistic approach. To enrich and extend the chemical understanding and knowledge of pericyclic-type reactions for chemistry…

  2. Mechanistic investigation of a hemostatic keratin biomaterial

    NASA Astrophysics Data System (ADS)

    Rahmany, Maria Bahawdory

    biomaterial surfaces. While other groups have discussed keratin's capacity to specifically adhere cells, this work was the first to utilize function blocking antibodies to deduce the specific receptors involved in mediating the cell-keratin interaction. To explore keratin's role in the second arm of coagulation, the clotting cascade, we followed the kinetic behavior of fibrin generation in the presence and absence of keratin. Confirmed with samples of plasma and a purified system of fibrinogen and thrombin, we observed an increased rate of fibrin polymerization in the presence of keratin proteins. The final goal of this project was to utilize a Chinese hamster ovary cell line to more specifically explore integrin-mediated cell interactions with keratin biomaterials in a controlled, biologically relevant system. Together, this work provides key details regarding keratin's hemostatic characteristics, providing the foundations for further development and optimizing of the material's unique characteristics for use as a hemostatic agent. More broadly, application of the CHO cell model could provide a useful tool for developing a receptor-ligand profile for keratin biomaterials.

  3. Antimalarial benzoheterocyclic 4-aminoquinolines: Structure-activity relationship, in vivo evaluation, mechanistic and bioactivation studies.

    PubMed

    Ongarora, Dennis S B; Strydom, Natasha; Wicht, Kathryn; Njoroge, Mathew; Wiesner, Lubbe; Egan, Timothy J; Wittlin, Sergio; Jurva, Ulrik; Masimirembwa, Collen M; Chibale, Kelly

    2015-09-01

    A novel class of benzoheterocyclic analogues of amodiaquine designed to avoid toxic reactive metabolite formation was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant) and NF54 (sensitive) strains of the malaria parasite Plasmodium falciparum. Structure-activity relationship studies led to the identification of highly promising analogues, the most potent of which had IC50s in the nanomolar range against both strains. The compounds further demonstrated good in vitro microsomal metabolic stability while those subjected to in vivo pharmacokinetic studies had desirable pharmacokinetic profiles. In vivo antimalarial efficacy in Plasmodium berghei infected mice was evaluated for four compounds, all of which showed good activity following oral administration. In particular, compound 19 completely cured treated mice at a low multiple dose of 4×10mg/kg. Mechanistic and bioactivation studies suggest hemozoin formation inhibition and a low likelihood of forming quinone-imine reactive metabolites, respectively. PMID:26264839

  4. A framework for recognizing mechanistic reasoning in student scientific inquiry

    NASA Astrophysics Data System (ADS)

    Russ, Rosemary S.

    A central ambition of science education reform is to help students develop abilities for scientific inquiry. Education research is thus rightly focused on defining what constitutes "inquiry" and developing tools for assessing it. There has been progress with respect to particular aspects of inquiry, namely student abilities for controlled experimentation and scientific argumentation. However, we suggest that in addition to these frameworks for assessing the structure of inquiry we need frameworks for analyzing the substance of that inquiry. In this work we draw attention to and evaluate the substance of student mechanistic reasoning. Both within the history and philosophy of science and within science education research, scientific inquiry is characterized in part as understanding the causal mechanisms that underlie natural phenomena. The challenge for science education, however, is that there has not been the same progress with respect to making explicit what constitutes mechanistic reasoning as there has been in making explicit other aspects of inquiry. This dissertation attempts to address this challenge. We adapt an account of mechanism in professional research science to develop a framework for reliably recognizing mechanistic reasoning in student discourse. The coding scheme articulates seven specific aspects of mechanistic reasoning and can be used to systematically analyze narrative data for patterns in student thinking. It provides a tool for detecting quality reasoning that may be overlooked by more traditional assessments. We apply the mechanism coding scheme to video and written data from a range of student inquiries, from large group discussions among first grade students to the individual problem solving of graduate students. While the primary result of this work is the coding scheme itself and the finding that it provides a reliable means of analyzing transcript data for evidence of mechanistic thinking, the rich descriptions we develop in each case

  5. Mechanistic model for catalytic recombination during aerobraking maneuvers

    NASA Technical Reports Server (NTRS)

    Willey, Ronald J.

    1989-01-01

    Several mechanistic models are developed to predict recombination coefficients for use in heat shield design for reusable surface insulation (RSI) on aerobraking vehicles such as space shuttles. The models are applied over a temperature range of 300 to 1800 K and a stagnation pressure range of 0 to 3,000 Pa. A four parameter model in temperature was found to work best; however, several models (including those with atom concentrations at the surface) were also investigated. Mechanistic models developed with atom concentration terms may be applicable when sufficient data becomes available. The requirement is shown for recombination experiments in the 300 to 1000 K and 1500 to 1850 K temperature range, with deliberate concentration variations.

  6. Answering evolutionary questions: A guide for mechanistic biologists.

    PubMed

    Masel, Joanna; Promislow, Daniel E L

    2016-07-01

    The questions and methods of molecular biology and evolutionary biology are clearly distinct, yet a unified approach can lead to deep insights. Unfortunately, attempts to unify these approaches are fraught with pitfalls. In this informal series of questions and answers, we offer the mechanistically oriented biologist a set of steps to come up with evolutionarily reasonable and meaningful hypotheses. We emphasize the critical power and importance of carefully constructed null hypotheses, and we illustrate our ideas with examples representing a range of topics, from the biology of aging, to protein structure, to speciation, and more. We also stress the importance of mathematics as the lingua franca for biologists of all stripes, and encourage mechanistic biologists to seek out quantitative collaborators to build explicit mathematical models, making their assumptions explicit, and their logic clear and testable. Biologists in all realms of inquiry stand to gain from strong bridges between our disciplines. PMID:27151396

  7. Underreliance on mechanistic models: Comment on Ferguson (2015).

    PubMed

    Tryon, Warren W

    2016-09-01

    Ferguson (see record ) proposed that our overreliance on mechanistic models is responsible for the public's negative view of psychology. On the contrary, I claim that our explanations do not actually explain because they lack mechanism information and that is why the public has a negative view of psychology. Some of the mechanism information required to move from interpretations to explanations can be found in parallel distributed processing connectionist neural network models of psychology and behavior. (PsycINFO Database Record PMID:27571530

  8. Mechanistic model and analysis of doxorubicin release from liposomal formulations.

    PubMed

    Fugit, Kyle D; Xiang, Tian-Xiang; Choi, Du H; Kangarlou, Sogol; Csuhai, Eva; Bummer, Paul M; Anderson, Bradley D

    2015-11-10

    Reliable and predictive models of drug release kinetics in vitro and in vivo are still lacking for liposomal formulations. Developing robust, predictive release models requires systematic, quantitative characterization of these complex drug delivery systems with respect to the physicochemical properties governing the driving force for release. These models must also incorporate changes in release due to the dissolution media and methods employed to monitor release. This paper demonstrates the successful development and application of a mathematical mechanistic model capable of predicting doxorubicin (DXR) release kinetics from liposomal formulations resembling the FDA-approved nanoformulation DOXIL® using dynamic dialysis. The model accounts for DXR equilibria (e.g. self-association, precipitation, ionization), the change in intravesicular pH due to ammonia release, and dialysis membrane transport of DXR. The model was tested using a Box-Behnken experimental design in which release conditions including extravesicular pH, ammonia concentration in the release medium, and the dilution of the formulation (i.e. suspension concentration) were varied. Mechanistic model predictions agreed with observed DXR release up to 19h. The predictions were similar to a computer fit of the release data using an empirical model often employed for analyzing data generated from this type of experimental design. Unlike the empirical model, the mechanistic model was also able to provide reasonable predictions of release outside the tested design space. These results illustrate the usefulness of mechanistic modeling to predict drug release from liposomal formulations in vitro and its potential for future development of in vitro - in vivo correlations for complex nanoformulations. PMID:26310713

  9. Millifluidics for Chemical Synthesis and Time-resolved Mechanistic Studies

    PubMed Central

    Krishna, Katla Sai; Biswas, Sanchita; Navin, Chelliah V.; Yamane, Dawit G.; Miller, Jeffrey T.; Kumar, Challa S.S.R.

    2013-01-01

    Procedures utilizing millifluidic devices for chemical synthesis and time-resolved mechanistic studies are described by taking three examples. In the first, synthesis of ultra-small copper nanoclusters is described. The second example provides their utility for investigating time resolved kinetics of chemical reactions by analyzing gold nanoparticle formation using in situ X-ray absorption spectroscopy. The final example demonstrates continuous flow catalysis of reactions inside millifluidic channel coated with nanostructured catalyst. PMID:24327099

  10. Millifluidics for chemical synthesis and time-resolved mechanistic studies.

    PubMed

    Krishna, Katla Sai; Biswas, Sanchita; Navin, Chelliah V; Yamane, Dawit G; Miller, Jeffrey T; Kumar, Challa S S R

    2013-01-01

    Procedures utilizing millifluidic devices for chemical synthesis and time-resolved mechanistic studies are described by taking three examples. In the first, synthesis of ultra-small copper nanoclusters is described. The second example provides their utility for investigating time resolved kinetics of chemical reactions by analyzing gold nanoparticle formation using in situ X-ray absorption spectroscopy. The final example demonstrates continuous flow catalysis of reactions inside millifluidic channel coated with nanostructured catalyst. PMID:24327099

  11. Home range analysis using a mechanistic home range model

    SciTech Connect

    Moorcroft, P.R. . Dept. of Ecology and Evolutionary Biology); Lewis, M.A. . Dept. of Mathematics) Crabtree, R.L. . Dept. of Fish and Wildlife Resources)

    1999-07-01

    The traditional models used to characterize animal home ranges have no mechanistic basis underlying their descriptions of space use, and as a result, the analysis of animal home ranges has primarily been a descriptive endeavor. In this paper, the authors characterize coyote (Canis latrans) home range patterns using partial differential equations for expected space use that are formally derived from underlying descriptions of individual movement behavior. To the authors' knowledge, this is the first time that mechanistic models have been used to characterize animal home ranges. The results provide empirical support for a model formulation of movement response to scent marks, and suggest that having relocation data for individuals in adjacent groups is necessary to capture the spatial arrangement of home range boundaries. The authors then show how the model fits can be used to obtain predictions for individual movement and scent marking behavior and to predict changes in home range patterns. More generally, the findings illustrate how mechanistic models permit the development of a predictive theory for the relationship between movement behavior and animal spatial distribution.

  12. Mechanistic profiling of the siRNA delivery dynamics of lipid-polymer hybrid nanoparticles.

    PubMed

    Colombo, Stefano; Cun, Dongmei; Remaut, Katrien; Bunker, Matt; Zhang, Jianxin; Martin-Bertelsen, Birte; Yaghmur, Anan; Braeckmans, Kevin; Nielsen, Hanne M; Foged, Camilla

    2015-03-10

    Understanding the delivery dynamics of nucleic acid nanocarriers is fundamental to improve their design for therapeutic applications. We investigated the carrier structure-function relationship of lipid-polymer hybrid nanoparticles (LPNs) consisting of poly(DL-lactic-co-glycolic acid) (PLGA) nanocarriers modified with the cationic lipid dioleoyltrimethyl-ammoniumpropane (DOTAP). A library of siRNA-loaded LPNs was prepared by systematically varying the nitrogen-to-phosphate (N/P) ratio. Atomic force microscopy (AFM) and cryo-transmission electron microscopy (cryo-TEM) combined with small angle X-ray scattering (SAXS) and confocal laser scanning microscopy (CLSM) studies suggested that the siRNA-loaded LPNs are characterized by a core-shell structure consisting of a PLGA matrix core coated with lamellar DOTAP structures with siRNA localized both in the core and in the shell. Release studies in buffer and serum-containing medium combined with in vitro gene silencing and quantification of intracellular siRNA suggested that this self-assembling core-shell structure influences the siRNA release kinetics and the delivery dynamics. A main delivery mechanism appears to be mediated via the release of transfection-competent siRNA-DOTAP lipoplexes from the LPNs. Based on these results, we suggest a model for the nanostructural characteristics of the LPNs, in which the siRNA is organized in lamellar superficial assemblies and/or as complexes entrapped in the polymeric matrix. PMID:25540904

  13. Explaining the atypical reaction profiles of heme enzymes with a novel mechanistic hypothesis and kinetic treatment.

    PubMed

    Manoj, Kelath Murali; Baburaj, Arun; Ephraim, Binoy; Pappachan, Febin; Maviliparambathu, Pravitha Parapurathu; Vijayan, Umesh K; Narayanan, Sivaprasad Valiyaveettil; Periasamy, Kalaiselvi; George, Ebi Ashley; Mathew, Lazar T

    2010-01-01

    Many heme enzymes show remarkable versatility and atypical kinetics. The fungal extracellular enzyme chloroperoxidase (CPO) characterizes a variety of one and two electron redox reactions in the presence of hydroperoxides. A structural counterpart, found in mammalian microsomal cytochrome P450 (CYP), uses molecular oxygen plus NADPH for the oxidative metabolism (predominantly hydroxylation) of substrate in conjunction with a redox partner enzyme, cytochrome P450 reductase. In this study, we employ the two above-mentioned heme-thiolate proteins to probe the reaction kinetics and mechanism of heme enzymes. Hitherto, a substrate inhibition model based upon non-productive binding of substrate (two-site model) was used to account for the inhibition of reaction at higher substrate concentrations for the CYP reaction systems. Herein, the observation of substrate inhibition is shown for both peroxide and final substrate in CPO catalyzed peroxidations. Further, analogy is drawn in the "steady state kinetics" of CPO and CYP reaction systems. New experimental observations and analyses indicate that a scheme of competing reactions (involving primary product with enzyme or other reaction components/intermediates) is relevant in such complex reaction mixtures. The presence of non-selective reactive intermediate(s) affords alternate reaction routes at various substrate/product concentrations, thereby leading to a lowered detectable concentration of "the product of interest" in the reaction milieu. Occam's razor favors the new hypothesis. With the new hypothesis as foundation, a new biphasic treatment to analyze the kinetics is put forth. We also introduce a key concept of "substrate concentration at maximum observed rate". The new treatment affords a more acceptable fit for observable experimental kinetic data of heme redox enzymes. PMID:20498847

  14. Explaining the Atypical Reaction Profiles of Heme Enzymes with a Novel Mechanistic Hypothesis and Kinetic Treatment

    PubMed Central

    Manoj, Kelath Murali; Baburaj, Arun; Ephraim, Binoy; Pappachan, Febin; Maviliparambathu, Pravitha Parapurathu; Vijayan, Umesh K.; Narayanan, Sivaprasad Valiyaveettil; Periasamy, Kalaiselvi; George, Ebi Ashley; Mathew, Lazar T.

    2010-01-01

    Many heme enzymes show remarkable versatility and atypical kinetics. The fungal extracellular enzyme chloroperoxidase (CPO) characterizes a variety of one and two electron redox reactions in the presence of hydroperoxides. A structural counterpart, found in mammalian microsomal cytochrome P450 (CYP), uses molecular oxygen plus NADPH for the oxidative metabolism (predominantly hydroxylation) of substrate in conjunction with a redox partner enzyme, cytochrome P450 reductase. In this study, we employ the two above-mentioned heme-thiolate proteins to probe the reaction kinetics and mechanism of heme enzymes. Hitherto, a substrate inhibition model based upon non-productive binding of substrate (two-site model) was used to account for the inhibition of reaction at higher substrate concentrations for the CYP reaction systems. Herein, the observation of substrate inhibition is shown for both peroxide and final substrate in CPO catalyzed peroxidations. Further, analogy is drawn in the “steady state kinetics” of CPO and CYP reaction systems. New experimental observations and analyses indicate that a scheme of competing reactions (involving primary product with enzyme or other reaction components/intermediates) is relevant in such complex reaction mixtures. The presence of non-selective reactive intermediate(s) affords alternate reaction routes at various substrate/product concentrations, thereby leading to a lowered detectable concentration of “the product of interest” in the reaction milieu. Occam's razor favors the new hypothesis. With the new hypothesis as foundation, a new biphasic treatment to analyze the kinetics is put forth. We also introduce a key concept of “substrate concentration at maximum observed rate”. The new treatment affords a more acceptable fit for observable experimental kinetic data of heme redox enzymes. PMID:20498847

  15. Mechanistic modeling of ion-exchange process chromatography of charge variants of monoclonal antibody products.

    PubMed

    Kumar, Vijesh; Leweke, Samuel; von Lieres, Eric; Rathore, Anurag S

    2015-12-24

    Ion-exchange chromatography (IEX) is universally accepted as the optimal method for achieving process scale separation of charge variants of a monoclonal antibody (mAb) therapeutic. These variants are closely related to the product and a baseline separation is rarely achieved. The general practice is to fractionate the eluate from the IEX column, analyze the fractions and then pool the desired fractions to obtain the targeted composition of variants. This is, however, a very cumbersome and time consuming exercise. A mechanistic model that is capable of simulating the peak profile will be a much more elegant and effective way to make a decision on the pooling strategy. This paper proposes a mechanistic model, based on the general rate model, to predict elution peak profile for separation of the main product from its variants. The proposed approach uses inverse fit of process scale chromatogram for estimation of model parameters using the initial values that are obtained from theoretical correlations. The packed bed column has been modeled along with the chromatographic system consisting of the mixer, tubing and detectors as a series of dispersed plug flow and continuous stirred tank reactors. The model uses loading ranges starting at 25% to a maximum of 70% of the loading capacity and hence is applicable to process scale separations. Langmuir model has been extended to include the effects of salt concentration and temperature on the model parameters. The extended Langmuir model that has been proposed uses one less parameter than the SMA model and this results in a significant ease of estimating the model parameters from inverse fitting. The proposed model has been validated with experimental data and has been shown to successfully predict peak profile for a range of load capacities (15-28mg/mL), gradient lengths (10-30CV), bed heights (6-20cm), and for three different resins with good accuracy (as measured by estimation of residuals). The model has been also

  16. Recurrent Glioblastomas Reveal Molecular Subtypes Associated with Mechanistic Implications of Drug-Resistance

    PubMed Central

    Park, Chul-Kee; Jung, Shin; Park, Eun Sung; Lee, Ju-Seog; Kim, Se-Hyuk; Woo, Hyun Goo

    2015-01-01

    Previously, transcriptomic profiling studies have shown distinct molecular subtypes of glioblastomas. It has also been suggested that the recurrence of glioblastomas could be achieved by transcriptomic reprograming of tumors, however, their characteristics are not yet fully understood. Here, to gain the mechanistic insights on the molecular phenotypes of recurrent glioblastomas, gene expression profiling was performed on the 43 cases of glioblastomas including 15 paired primary and recurrent cases. Unsupervised clustering analyses revealed two subtypes of G1 and G2, which were characterized by proliferation and neuron-like gene expression traits, respectively. While the primary tumors were classified as G1 subtype, the recurrent glioblastomas showed two distinct expression types. Compared to paired primary tumors, the recurrent tumors in G1 subtype did not show expression alteration. By contrast, the recurrent tumors in G2 subtype showed expression changes from proliferation type to neuron-like one. We also observed the expression of stemness-related genes in G1 recurrent tumors and the altered expression of DNA-repair genes (i.e., AURK, HOX, MGMT, and MSH6) in the G2 recurrent tumors, which might be responsible for the acquisition of drug resistance mechanism during tumor recurrence in a subtype-specific manner. We suggest that recurrent glioblastomas may choose two different strategies for transcriptomic reprograming to escape the chemotherapeutic treatment during tumor recurrence. Our results might be helpful to determine personalized therapeutic strategy against heterogeneous glioma recurrence. PMID:26466313

  17. Systematic interpolation method predicts protein chromatographic elution from batch isotherm data without a detailed mechanistic isotherm model.

    PubMed

    Creasy, Arch; Barker, Gregory; Yao, Yan; Carta, Giorgio

    2015-09-01

    Predicting protein elution for overloaded ion exchange columns requires models capable of describing protein binding over broad ranges of protein and salt concentrations. Although approximate mechanistic models are available, they do not always have the accuracy needed for precise predictions. The aim of this work is to develop a method to predict protein chromatographic behavior from batch isotherm data without relying on a mechanistic model. The method uses a systematic empirical interpolation (EI) scheme coupled with a lumped kinetic model with rate parameters determined from HETP measurements for non-binding conditions, to numerically predict the column behavior. For two experimental systems considered in this work, predictions based on the EI scheme are in excellent agreement with experimental elution profiles under highly overloaded conditions without using any adjustable parameters. A qualitative study of the sensitivity of predicting protein elution profiles to the precision, granularity, and extent of the batch adsorption data shows that the EI scheme is relatively insensitive to the properties of the dataset used, requiring only that the experimental ranges of protein and salt concentrations overlap those under which the protein actually elutes from the column and possess a ± 10% measurement precision. PMID:26015091

  18. In Silico, Experimental, Mechanistic Model for Extended-Release Felodipine Disposition Exhibiting Complex Absorption and a Highly Variable Food Interaction

    PubMed Central

    Kim, Sean H. J.; Jackson, Andre J.; Hunt, C. Anthony

    2014-01-01

    The objective of this study was to develop and explore new, in silico experimental methods for deciphering complex, highly variable absorption and food interaction pharmacokinetics observed for a modified-release drug product. Toward that aim, we constructed an executable software analog of study participants to whom product was administered orally. The analog is an object- and agent-oriented, discrete event system, which consists of grid spaces and event mechanisms that map abstractly to different physiological features and processes. Analog mechanisms were made sufficiently complicated to achieve prespecified similarity criteria. An equation-based gastrointestinal transit model with nonlinear mixed effects analysis provided a standard for comparison. Subject-specific parameterizations enabled each executed analog’s plasma profile to mimic features of the corresponding six individual pairs of subject plasma profiles. All achieved prespecified, quantitative similarity criteria, and outperformed the gastrointestinal transit model estimations. We observed important subject-specific interactions within the simulation and mechanistic differences between the two models. We hypothesize that mechanisms, events, and their causes occurring during simulations had counterparts within the food interaction study: they are working, evolvable, concrete theories of dynamic interactions occurring within individual subjects. The approach presented provides new, experimental strategies for unraveling the mechanistic basis of complex pharmacological interactions and observed variability. PMID:25268237

  19. [Mechanistic examination of organometallic electron transfer reactions: Annual report, 1989

    SciTech Connect

    Not Available

    1989-12-31

    Our mechanistic examination of electron transfer reactions between organometallic complexes has required data from our stopped-flow infrared spectrophotometer that was constructed in the first year. Our research on organometallic electron transfer reaction mechanisms was recognized by an invitation to the Symposium on Organometallic Reaction Mechanisms at the National ACS meeting in Miami. We have obtained a reasonable understanding of the electron transfer reactions between metal cations and anions and between metal carbonyl anions and metal carbonyl dimers. In addition we have begun to obtain data on the outer sphere electron transfer between metal carbonyl anions and coordination complexes and on reactions involving cluster anions.

  20. (Mechanistic examination of organometallic electron transfer reactions: Annual report, 1989)

    SciTech Connect

    Not Available

    1989-01-01

    Our mechanistic examination of electron transfer reactions between organometallic complexes has required data from our stopped-flow infrared spectrophotometer that was constructed in the first year. Our research on organometallic electron transfer reaction mechanisms was recognized by an invitation to the Symposium on Organometallic Reaction Mechanisms at the National ACS meeting in Miami. We have obtained a reasonable understanding of the electron transfer reactions between metal cations and anions and between metal carbonyl anions and metal carbonyl dimers. In addition we have begun to obtain data on the outer sphere electron transfer between metal carbonyl anions and coordination complexes and on reactions involving cluster anions.

  1. Mechanistic systems modeling to guide drug discovery and development

    PubMed Central

    Schmidt, Brian J.; Papin, Jason A.; Musante, Cynthia J.

    2013-01-01

    A crucial question that must be addressed in the drug development process is whether the proposed therapeutic target will yield the desired effect in the clinical population. Pharmaceutical and biotechnology companies place a large investment on research and development, long before confirmatory data are available from human trials. Basic science has greatly expanded the computable knowledge of disease processes, both through the generation of large omics data sets and a compendium of studies assessing cellular and systemic responses to physiologic and pathophysiologic stimuli. Given inherent uncertainties in drug development, mechanistic systems models can better inform target selection and the decision process for advancing compounds through preclinical and clinical research. PMID:22999913

  2. Discerning mechanistically rewired biological pathways by cumulative interaction heterogeneity statistics

    PubMed Central

    Cotton, Travis B.; Nguyen, Hien H.; Said, Joseph I.; Ouyang, Zhengyu; Zhang, Jinfa; Song, Mingzhou

    2015-01-01

    Changes in response of a biological pathway could be a consequence of either pathway rewiring, changed input, or a combination of both. Most pathway analysis methods are not designed for mechanistic rewiring such as regulatory element variations. This limits our understanding of biological pathway evolution. Here we present a Q-method to discern whether changed pathway response is caused by mechanistic rewiring of pathways due to evolution. The main innovation is a cumulative pathway interaction heterogeneity statistic accounting for rewiring-specific effects on the rate of change of each molecular variable across conditions. The Q-method remarkably outperformed differential-correlation based approaches on data from diverse biological processes. Strikingly, it also worked well in differentiating rewired chaotic systems, whose dynamics are notoriously difficult to predict. Applying the Q-method on transcriptome data of four yeasts, we show that pathway interaction heterogeneity for known metabolic and signaling pathways is indeed a predictor of interspecies genetic rewiring due to unbalanced TATA box-containing genes among the yeasts. The demonstrated effectiveness of the Q-method paves the way to understanding network evolution at the resolution of functional biological pathways. PMID:25921728

  3. Trichloroethylene: Mechanistic, Epidemiologic and Other Supporting Evidence of Carcinogenic Hazard

    PubMed Central

    Rusyn, Ivan; Chiu, Weihsueh A.; Lash, Lawrence H.; Kromhout, Hans; Hansen, Johnni; Guyton, Kathryn Z.

    2013-01-01

    The chlorinated solvent trichloroethylene (TCE) is a ubiquitous environmental pollutant. The carcinogenic hazard of TCE was the subject of a 2012 evaluation by a Working Group of the International Agency for Research on Cancer (IARC). Information on exposures, relevant data from epidemiologic studies, bioassays in experimental animals, and toxicity and mechanism of action studies was used to conclude that TCE is carcinogenic to humans (Group 1). This article summarizes the key evidence forming the scientific bases for the IARC classification. Exposure to TCE from environmental sources (including from hazardous waste sites and contaminated water) is common throughout the world. While workplace use of TCE has been declining, occupational exposures remain of concern, especially in developing countries. Strongest human evidence is from studies of occupational TCE exposure and kidney cancer. Positive, although less consistent, associations were reported for liver cancer and non-Hodgkin's lymphoma. TCE is carcinogenic at multiple sites in multiple species and strains of experimental animals. The mechanistic evidence includes extensive data on the toxicokinetics and genotoxicity of TCE and its metabolites. Together, available evidence provided a cohesive database supporting the human cancer hazard of TCE, particularly in the kidney. For other target sites of carcinogenicity, mechanistic and other data were found to be more limited. Important sources of susceptibility to TCE toxicity and carcinogenicity were also reviewed by the Working Group. In all, consideration of the multiple evidence streams presented herein informed the IARC conclusions regarding the carcinogenicity of TCE. PMID:23973663

  4. Mechanistic study of a diazo dye degradation by Soybean Peroxidase

    PubMed Central

    2013-01-01

    Background Enzyme based remediation of wastewater is emerging as a novel, efficient and environmentally-friendlier approach. However, studies showing detailed mechanisms of enzyme mediated degradation of organic pollutants are not widely published. Results The present report describes a detailed study on the use of Soybean Peroxidase to efficiently degrade Trypan Blue, a diazo dye. In addition to examining various parameters that can affect the dye degradation ability of the enzyme, such as enzyme and H2O2 concentration, reaction pH and temperature, we carried out a detailed mechanistic study of Trypan Blue degradation. HPLC-DAD and LC-MS/MS studies were carried out to confirm dye degradation and analyze the intermediate metabolites and develop a detailed mechanistic dye degradation pathway. Conclusion We report that Soybean peroxidase causes Trypan Blue degradation via symmetrical azo bond cleavage and subsequent radical-initiated ring opening of the metabolites. Interestingly, our results also show that no high molecular weight polymers were produced during the peroxidase-H2O2 mediated degradation of the phenolic Trypan Blue. PMID:23711110

  5. Surgery for malignant gliomas: mechanistic reasoning and slippery statistics.

    PubMed

    Mitchell, Patrick; Ellison, David W; Mendelow, A David

    2005-07-01

    Current surgical treatment of malignant gliomas largely depends on mechanistic reasoning and data collected in non-randomised studies. Technological advance has enabled more accurate resection of tumours and preservation of eloquent brain areas but ethical considerations have restricted randomised trials on the efficacy of surgery to one small trial that found a 3 month survival advantage for patients over age 65 years who received surgery and interim analysis of a larger trial. There is an argument for surgery as a palliative measure in patients with symptoms caused by mechanisms that are surgically remediable. Whether there is any survival advantage from surgery in patients other than those with immediately life-threatening, surgically remediable complications, such as raised intracranial pressure, is unclear. The available data show that if such an advantage does exist, it is modest at best. Adjuvant treatments given surgically are being studied. Chemotherapy wafers are the most prominent of the adjuvant treatments but the evidence available is insufficient to recommend their use in routine practice. In this review we examine the prevailing mechanistic model and observational data; we assess how these are applied and the priorities they indicate for future research. PMID:15963444

  6. From data patterns to mechanistic models in acute critical illness.

    PubMed

    Aerts, Jean-Marie; Haddad, Wassim M; An, Gary; Vodovotz, Yoram

    2014-08-01

    The complexity of the physiologic and inflammatory response in acute critical illness has stymied the accurate diagnosis and development of therapies. The Society for Complex Acute Illness was formed a decade ago with the goal of leveraging multiple complex systems approaches to address this unmet need. Two main paths of development have characterized the society's approach: (i) data pattern analysis, either defining the diagnostic/prognostic utility of complexity metrics of physiologic signals or multivariate analyses of molecular and genetic data and (ii) mechanistic mathematical and computational modeling, all being performed with an explicit translational goal. Here, we summarize the progress to date on each of these approaches, along with pitfalls inherent in the use of each approach alone. We suggest that the next decade holds the potential to merge these approaches, connecting patient diagnosis to treatment via mechanism-based dynamical system modeling and feedback control and allowing extrapolation from physiologic signals to biomarkers to novel drug candidates. As a predicate example, we focus on the role of data-driven and mechanistic models in neuroscience and the impact that merging these modeling approaches can have on general anesthesia. PMID:24768566

  7. Discerning mechanistically rewired biological pathways by cumulative interaction heterogeneity statistics.

    PubMed

    Cotton, Travis B; Nguyen, Hien H; Said, Joseph I; Ouyang, Zhengyu; Zhang, Jinfa; Song, Mingzhou

    2015-01-01

    Changes in response of a biological pathway could be a consequence of either pathway rewiring, changed input, or a combination of both. Most pathway analysis methods are not designed for mechanistic rewiring such as regulatory element variations. This limits our understanding of biological pathway evolution. Here we present a Q-method to discern whether changed pathway response is caused by mechanistic rewiring of pathways due to evolution. The main innovation is a cumulative pathway interaction heterogeneity statistic accounting for rewiring-specific effects on the rate of change of each molecular variable across conditions. The Q-method remarkably outperformed differential-correlation based approaches on data from diverse biological processes. Strikingly, it also worked well in differentiating rewired chaotic systems, whose dynamics are notoriously difficult to predict. Applying the Q-method on transcriptome data of four yeasts, we show that pathway interaction heterogeneity for known metabolic and signaling pathways is indeed a predictor of interspecies genetic rewiring due to unbalanced TATA box-containing genes among the yeasts. The demonstrated effectiveness of the Q-method paves the way to understanding network evolution at the resolution of functional biological pathways. PMID:25921728

  8. A mechanistic PK/PD model for two anti-IL13 antibodies explains the difference in total IL-13 accumulation observed in clinical studies.

    PubMed

    Tiwari, Abhinav; Kasaian, Marion; Heatherington, Anne C; Jones, Hannah M; Hua, Fei

    2016-07-01

    IMA-638 and IMA-026 are humanized IgG1 monoclonal antibodies (mAbs) that target non-overlapping epitopes of IL-13. Separate first-in-human single ascending dose studies were conducted for each mAb. These studies had similar study designs, but mild to moderate asthmatics were recruited for the IMA-638 study and healthy subjects were recruited for the IMA-026 study. IMA-638 and IMA-026 showed similar pharmacokinetic (PK) profiles, but very different total IL-13 (free and drug bound IL-13) profiles; free IL13 was not measured. IMA-026 treatment induced a dose-dependent accumulation of total IL-13, while IMA-638 treatment led to a much smaller accumulation without any clear dose-response. To understand the differences between the two total IL-13 profiles and to predict the free IL-13 profiles for each mAb treatment, a mechanistic PK/pharmacodynamic model was developed. PK-related parameters were first fit to the mean PK profiles of each mAb separately; thereafter, the target-related parameters were fit to both total IL-13 profiles simultaneously. The IL-13 degradation rate was assumed to be the same for asthma patients and healthy subjects. The model suggests that an approximately 100× faster elimination of IL-13-IMA-638 complex than IL-13-IMA-026 complex could be responsible for the differences observed in total IL-13 profiles for the two mAbs. Furthermore, the model predicts that IMA-638 administration results in greater and more prolonged free IL-13 inhibition than equivalent dosing of IMA-026 despite similar binding KD and PK profile. In conclusion, joint modeling of two similar molecules provided mechanistic insight that the elimination rate of mAb-target complex can regulate the degree of free target inhibition. PMID:27049478

  9. Development of an in Silico Profiler for Mitochondrial Toxicity.

    PubMed

    Nelms, Mark D; Mellor, Claire L; Cronin, Mark T D; Madden, Judith C; Enoch, Steven J

    2015-10-19

    This study outlines the analysis of mitochondrial toxicity for a variety of pharmaceutical drugs extracted from Zhang et al. ((2009) Toxicol. In Vitro, 23, 134-140). These chemicals were grouped into categories based upon structural similarity. Subsequently, mechanistic analysis was undertaken for each category to identify the molecular initiating event driving mitochondrial toxicity. The mechanistic information elucidated during the analysis enabled mechanism-based structural alerts to be developed and combined together to form an in silico profiler. This profiler is envisaged to be used to develop chemical categories based upon similar mechanisms as part of the adverse outcome pathway paradigm. Additionally, the profiler could be utilized in screening large data sets in order to identify chemicals with the potential to induce mitochondrial toxicity. PMID:26375963

  10. Perspectives on the Application of Mechanistic Information in Chemical Hazard and Dose-Response Assessments

    EPA Science Inventory

    This overview summarizes several EPA Assessment publications reviewing approaches for applying mechanistic information in human health risk assessment and exploring opportunities for progress in this area.

  11. Imprecision profiling.

    PubMed

    Sadler, William A

    2008-08-01

    * Imprecision profiles express precision characteristics of an assay over a range of concentration values. They can convert large quantities of potentially complex data into an easily interpreted graphical summary. * Imprecision profile estimation does not require precisely structured data. This implies that structured method evaluation data can be easily compared with, or merged with, less structured internal quality control (QC) data (or with data from any other source). * Although originally conceived for immunoassays, imprecision profiles could, in principle, be used as a summary method with any measurement system where precision varies with level of measurand. PMID:18852854

  12. Conservative or reactive? Mechanistic chemical perspectives on organic matter stability

    NASA Astrophysics Data System (ADS)

    Koch, Boris

    2016-04-01

    Carbon fixation by terrestrial and marine primary production has a fundamental seasonal effect on the atmospheric carbon content and it profoundly contributes to long-term carbon storage in form of organic matter (OM) in soils, water, and sediments. The efficacy of this sequestration process strongly depends on the degree of OM persistence. Therefore, one of the key issues in dissolved and particulate OM research is to assess the stability of reservoirs and to quantify their contribution to global carbon fluxes. Incubation experiments are helpful to assess OM stability during the first, early diagenetic turnover induced by sunlight or microbes. However, net carbon fluxes within the global carbon cycle also act on much longer time scales, which are not amenable in experiments. It is therefore critical to improve our mechanistic understanding to be able to assess potential future changes in the organic matter cycle. This session contribution highlights some achievements and open questions in the field. An improved mechanistic understanding of OM turnover particularly depends on the molecular characterization of biogeochemical processes and their kinetics: (i) in soils and sediments, aggregation/disaggregation of OM is primarily controlled by its molecular composition. Hence, the chemical composition determines the transfer of organic carbon from the large particulate to the small dissolved organic matter reservoir - an important substrate for microbial metabolism. (ii) In estuaries, dissolved organic carbon gradients usually suggest conservative behavior, whereas molecular-level studies reveal a substantial chemical modification of terrestrial DOM along the land-ocean interface. (iii) In the ocean, previous studies have shown that the recalcitrance of OM depends on bulk concentration and energy yield. However, ultrahigh resolution mass spectrometry in combination with radiocarbon analyses also emphasized that stability is tightly connected to molecular composition

  13. A new mechanistic framework to predict OCS fluxes in soils

    NASA Astrophysics Data System (ADS)

    Sauze, Joana; Ogee, Jérôme; Launois, Thomas; Kesselmeier, Jürgen; Van Diest, Heidi; Wingate, Lisa

    2015-04-01

    A better description of the amplitude of photosynthetic and respiratory gross CO2 fluxes at large scales is needed to improve our predictions of the current and future global CO2 cycle. Carbonyl sulfide (COS) is the most abundant sulphur gas in the atmosphere and has been proposed as a new tracer of gross photosynthesis, as the uptake of COS from the atmosphere is dominated by the activity of carbonic anhydrase (CA), an enzyme abundant in leaves that also catalyses CO2 hydration during photosynthesis. However, soils also exchange COS with the atmosphere and there is growing evidence that this flux must also be accounted for in atmospheric budgets. In this context a new mechanistic description of soil-atmosphere COS exchange is clearly needed. Soils can take up COS from the atmosphere as the soil biota also contain CA, and COS emissions from soils have also been reported in agricultural fields or anoxic soils. Previous studies have also shown that soil COS fluxes present an optimum soil water content and soil temperature. Here we propose a new mechanistic framework to predict the fluxes of COS between the soils and the atmosphere. We describe the COS soil budget by a first-order reaction-diffusion-production equation, assuming that the hydrolysis of COS by CA is total and irreversible. To describe COS diffusion through the soil matrix, we use different formulations of soil air-filled pore space and temperature, depending on the turbulence level above the soil surface. Using this model we are able to explain the observed presence of an optimum temperature for soil COS uptake and show how this optimum can shift to cooler temperatures in the presence of soil COS emissions. Our model can also explain the observed optimum with soil moisture content previously described in the literature (e.g. Van Diest & Kesselmeier, 2008) as a result of diffusional constraints on COS hydrolysis. These diffusional constraints are also responsible for the response of COS uptake to soil

  14. Leadership Profiles.

    ERIC Educational Resources Information Center

    Teach, Beverly; And Others

    1994-01-01

    Presents profiles of two leaders in the field of educational media and technology: Carolyn Guss and Mendel Sherman, both retired professors from Indiana University's program in Information Systems Technology. (KRN)

  15. Pioneer Profile.

    ERIC Educational Resources Information Center

    Butcher, Channa Beth

    1987-01-01

    Profiles Herbert A. Sweet, founder and director of Acorn Farms Day Camp (Indiana) for 44 years. Includes reminiscences about the camp's program, staffing, food, World War II, affiliation with the American Camping Association, and camps/directors of today. (NEC)

  16. Mechanistic failure mode investigation and resolution of parvovirus retentive filters.

    PubMed

    LaCasse, Daniel; Lute, Scott; Fiadeiro, Marcus; Basha, Jonida; Stork, Matthew; Brorson, Kurt; Godavarti, Ranga; Gallo, Chris

    2016-07-01

    Virus retentive filters are a key product safety measure for biopharmaceuticals. A simplistic perception is that they function solely based on a size-based particle removal mechanism of mechanical sieving and retention of particles based on their hydrodynamic size. Recent observations have revealed a more nuanced picture, indicating that changes in viral particle retention can result from process pressure and/or flow interruptions. In this study, a mechanistic investigation was performed to help identify a potential mechanism leading to the reported reduced particle retention in small virus filters. Permeate flow rate or permeate driving force were varied and analyzed for their impact on particle retention in three commercially available small virus retentive filters. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:959-970, 2016. PMID:27160325

  17. Mechanistic insights into selective autophagy pathways: lessons from yeast.

    PubMed

    Farré, Jean-Claude; Subramani, Suresh

    2016-09-01

    Autophagy has burgeoned rapidly as a field of study because of its evolutionary conservation, the diversity of intracellular cargoes degraded and recycled by this machinery, the mechanisms involved, as well as its physiological relevance to human health and disease. This self-eating process was initially viewed as a non-selective mechanism used by eukaryotic cells to degrade and recycle macromolecules in response to stress; we now know that various cellular constituents, as well as pathogens, can also undergo selective autophagy. In contrast to non-selective autophagy, selective autophagy pathways rely on a plethora of selective autophagy receptors (SARs) that recognize and direct intracellular protein aggregates, organelles and pathogens for specific degradation. Although SARs themselves are not highly conserved, their modes of action and the signalling cascades that activate and regulate them are. Recent yeast studies have provided novel mechanistic insights into selective autophagy pathways, revealing principles of how various cargoes can be marked and targeted for selective degradation. PMID:27381245

  18. Mechanistic Investigations into the Application of Sulfoxides in Carbohydrate Synthesis

    PubMed Central

    Brabham, Robin

    2016-01-01

    Abstract The utility of sulfoxides in a diverse range of transformations in the field of carbohydrate chemistry has seen rapid growth since the first introduction of a sulfoxide as a glycosyl donor in 1989. Sulfoxides have since developed into more than just anomeric leaving groups, and today have multiple roles in glycosylation reactions. These include as activators for thioglycosides, hemiacetals, and glycals, and as precursors to glycosyl triflates, which are essential for stereoselective β‐mannoside synthesis, and bicyclic sulfonium ions that facilitate the stereoselective synthesis of α‐glycosides. In this review we highlight the mechanistic investigations undertaken in this area, often outlining strategies employed to differentiate between multiple proposed reaction pathways, and how the conclusions of these investigations have and continue to inform upon the development of more efficient transformations in sulfoxide‐based carbohydrate synthesis. PMID:26744250

  19. The unique enzymatic and mechanistic properties of plant myosins.

    PubMed

    Henn, Arnon; Sadot, Einat

    2014-12-01

    Myosins are molecular motors that move along actin-filament tracks. Plants express two main classes of myosins, myosin VIII and myosin XI. Along with their relatively conserved sequence and functions, plant myosins have acquired some unique features. Myosin VIII has the enzymatic characteristics of a tension sensor and/or a tension generator, similar to functions found in other eukaryotes. Interestingly, class XI plant myosins have gained a novel function that consists of propelling the exceptionally rapid cytoplasmic streaming. This specific class includes the fastest known translocating molecular motors, which can reach an extremely high velocity of about 60μms(-1). However, the enzymatic properties and mechanistic basis for these remarkable manifestations are not yet fully understood. Here we review recent progress in understanding the uniqueness of plant myosins, while emphasizing the unanswered questions. PMID:25435181

  20. Mechanistic modeling confronts the complexity of molecular cell biology.

    PubMed

    Phair, Robert D

    2014-11-01

    Mechanistic modeling has the potential to transform how cell biologists contend with the inescapable complexity of modern biology. I am a physiologist-electrical engineer-systems biologist who has been working at the level of cell biology for the past 24 years. This perspective aims 1) to convey why we build models, 2) to enumerate the major approaches to modeling and their philosophical differences, 3) to address some recurrent concerns raised by experimentalists, and then 4) to imagine a future in which teams of experimentalists and modelers build-and subject to exhaustive experimental tests-models covering the entire spectrum from molecular cell biology to human pathophysiology. There is, in my view, no technical obstacle to this future, but it will require some plasticity in the biological research mind-set. PMID:25368428

  1. A mechanistic interpretation of the resonant wave-particle interaction

    NASA Astrophysics Data System (ADS)

    Chim, Chi Yung; O'Neil, Thomas M.

    2016-05-01

    This paper provides a simple mechanistic interpretation of the resonant wave-particle interaction of Landau. For the simple case of a Langmuir wave in a Vlasov plasma, the non-resonant electrons satisfy an oscillator equation that is driven resonantly by the bare electric field from the resonant electrons, and in the case of wave damping, this complex driver field is of a phase to reduce the oscillation amplitude. The wave-particle resonant interaction also occurs in waves governed by 2D E × B drift dynamics, such as a diocotron wave. In this case, the bare electric field from the resonant electrons causes E × B drift motion back in the core plasma, reducing the amplitude of the wave.

  2. Mechanistic model for void distribution in flashing flow

    SciTech Connect

    Riznic, J.; Ishii, M.; Afgan, N.

    1987-01-01

    A problem of discharging of an initially subcooled liquid from a high pressure condition into a low pressure environment is quite important in several industrial systems such as nuclear reactors and chemical reactors. A new model for the flashing process is proposed here based on the wall nucleation theory, bubble growth model and drift-flux bubble transport model. In order to calculate the bubble number density, the bubble number transport equation with a distributed source from the wall nucleation sites is used. The model predictions in terms of the void fraction are compared to Moby Dick and BNL experimental data. It shows that satisfactory agreements could be obtained from the present model without any floating parameter to be adjusted with data. This result indicates that, at least for the experimental conditions considered here, the mechanistic prediction of the flashing phenomenon is possible based on the present wall nucleation based model. 43 refs., 4 figs.

  3. Mechanistic model for void distribution in flashing flow

    NASA Astrophysics Data System (ADS)

    Riznic, J.; Ishii, M.; Afgan, N.

    A problem of discharging of an initially subcooled liquid from a high pressure condition into a low pressure environment is quite important in several industrial systems such as nuclear reactors and chemical reactors. A new model for the flashing process is proposed here based on the wall nucleation theory, bubble growth model and drift-flux bubble transport model. In order to calculate the bubble number density, the bubble number transport equation with a distributed source from the wall nucleation sites is used. The model predictions in terms of the void fraction are compared to Moby Dick and BNL experimental data. It shows that satisfactory agreements could be obtained from the present model without any floating parameter to be adjusted with data. This result indicates that, at least for the experimental conditions considered here, the mechanistic prediction of the flashing phenomenon is possible based on the present wall nucleation based model.

  4. Atrial Fibrillation and Hypertension: Mechanistic, Epidemiologic, and Treatment Parallels

    PubMed Central

    Ogunsua, Adedotun A.; Shaikh, Amir Y.; Ahmed, Mohamed; McManus, David D.

    2015-01-01

    Atrial fibrillation (AF) is an increasingly prevalent condition and the most common sustained arrhythmia encountered in ambulatory and hospital practice. Several clinical risk factors for AF include age, sex, valvular heart disease, obesity, sleep apnea, heart failure, and hypertension (HTN). Of all the risk factors, HTN is the most commonly encountered condition in patients with incident AF. Hypertension is associated with a 1.8-fold increase in the risk of developing new-onset AF and a 1.5-fold increase in the risk of progression to permanent AF. Hypertension predisposes to cardiac structural changes that influence the development of AF such as atrial remodeling. The renin angiotensin aldosterone system has been demonstrated to be a common mechanistic link in the pathogenesis of HTN and AF. Importantly, HTN is one of the few modifiable AF risk factors, and guideline-directed management of HTN may reduce the incidence of AF. PMID:27057292

  5. Atrial Fibrillation and Hypertension: Mechanistic, Epidemiologic, and Treatment Parallels.

    PubMed

    Ogunsua, Adedotun A; Shaikh, Amir Y; Ahmed, Mohamed; McManus, David D

    2015-01-01

    Atrial fibrillation (AF) is an increasingly prevalent condition and the most common sustained arrhythmia encountered in ambulatory and hospital practice. Several clinical risk factors for AF include age, sex, valvular heart disease, obesity, sleep apnea, heart failure, and hypertension (HTN). Of all the risk factors, HTN is the most commonly encountered condition in patients with incident AF. Hypertension is associated with a 1.8-fold increase in the risk of developing new-onset AF and a 1.5-fold increase in the risk of progression to permanent AF. Hypertension predisposes to cardiac structural changes that influence the development of AF such as atrial remodeling. The renin angiotensin aldosterone system has been demonstrated to be a common mechanistic link in the pathogenesis of HTN and AF. Importantly, HTN is one of the few modifiable AF risk factors, and guideline-directed management of HTN may reduce the incidence of AF. PMID:27057292

  6. Mechanistic views on aromatic substitution reactions by gaseous cations.

    PubMed

    Fornarini, S

    1996-01-01

    Recent advances in the understanding of the gas-phase reaction of aromatics with cationic electrophiles in a thermally equilibrated domain are described. The overall substitution reaction is analyzed in terms of its elementary steps. Their contribution to the overall reactivity pattern is dissected by the use of selected systems, which allowed one to highlight the kinetic role of single elementary events. Mechanistic studies have focused on the structure and reactivity of covalent and non-covalent ionic intermediates, which display a rich chemistry and provide benchmark reactivity models. Particular interest has been devoted to proton transfer reactions, which may occur in either an intra- or intermolecular fashion in arenium intermediates. A quantitative study of their rates and associated kinetic isotope effects is reported. © 1997 John Wiley & Sons, Inc. Mass Spectrom Rev 15(6), 365-389, 1997. PMID:27082944

  7. Parameter and uncertainty estimation for mechanistic, spatially explicit epidemiological models

    NASA Astrophysics Data System (ADS)

    Finger, Flavio; Schaefli, Bettina; Bertuzzo, Enrico; Mari, Lorenzo; Rinaldo, Andrea

    2014-05-01

    Epidemiological models can be a crucially important tool for decision-making during disease outbreaks. The range of possible applications spans from real-time forecasting and allocation of health-care resources to testing alternative intervention mechanisms such as vaccines, antibiotics or the improvement of sanitary conditions. Our spatially explicit, mechanistic models for cholera epidemics have been successfully applied to several epidemics including, the one that struck Haiti in late 2010 and is still ongoing. Calibration and parameter estimation of such models represents a major challenge because of properties unusual in traditional geoscientific domains such as hydrology. Firstly, the epidemiological data available might be subject to high uncertainties due to error-prone diagnosis as well as manual (and possibly incomplete) data collection. Secondly, long-term time-series of epidemiological data are often unavailable. Finally, the spatially explicit character of the models requires the comparison of several time-series of model outputs with their real-world counterparts, which calls for an appropriate weighting scheme. It follows that the usual assumption of a homoscedastic Gaussian error distribution, used in combination with classical calibration techniques based on Markov chain Monte Carlo algorithms, is likely to be violated, whereas the construction of an appropriate formal likelihood function seems close to impossible. Alternative calibration methods, which allow for accurate estimation of total model uncertainty, particularly regarding the envisaged use of the models for decision-making, are thus needed. Here we present the most recent developments regarding methods for parameter and uncertainty estimation to be used with our mechanistic, spatially explicit models for cholera epidemics, based on informal measures of goodness of fit.

  8. Mechanistic models of biofilm growth in porous media

    NASA Astrophysics Data System (ADS)

    Jaiswal, Priyank; Al-Hadrami, Fathiya; Atekwana, Estella A.; Atekwana, Eliot A.

    2014-07-01

    Nondestructive acoustics methods can be used to monitor in situ biofilm growth in porous media. In practice, however, acoustic methods remain underutilized due to the lack of models that can translate acoustic data into rock properties in the context of biofilm. In this paper we present mechanistic models of biofilm growth in porous media. The models are used to quantitatively interpret arrival times and amplitudes recorded in the 29 day long Davis et al. (2010) physical scale biostimulation experiment in terms of biofilm morphologies and saturation. The model pivots on addressing the sediment elastic behavior using the lower Hashin-Shtrikman bounds for grain mixing and Gassmann substitution for fluid saturation. The time-lapse P wave velocity (VP; a function of arrival times) is explained by a combination of two rock models (morphologies); "load bearing" which assumes the biofilm as an additional mineral in the rock matrix and "pore filling" which assumes the biofilm as an additional fluid phase in the pores. The time-lapse attenuation (QP-1; a function of amplitudes), on the other hand, can be explained adequately in two ways; first, through squirt flow where energy is lost from relative motion between rock matrix and pore fluid, and second, through an empirical function of porosity (φ), permeability (κ), and grain size. The squirt flow model-fitting results in higher internal φ (7% versus 5%) and more oblate pores (0.33 versus 0.67 aspect ratio) for the load-bearing morphology versus the pore-filling morphology. The empirical model-fitting results in up to 10% increase in κ at the initial stages of the load-bearing morphology. The two morphologies which exhibit distinct mechanical and hydraulic behavior could be a function of pore throat size. The biofilm mechanistic models developed in this study can be used for the interpretation of seismic data critical for the evaluation of biobarriers in bioremediation, microbial enhanced oil recovery, and CO2

  9. Mechanistic information from analysis of molecular weight distributions of starch.

    PubMed

    Castro, Jeffrey V; Dumas, Céline; Chiou, Herbert; Fitzgerald, Melissa A; Gilbert, Robert G

    2005-01-01

    A methodology is developed for interpreting the molecular weight distributions of debranched amylopectin, based on techniques developed for quantitatively and qualitatively finding mechanistic information from the molecular weight distributions of synthetic polymers. If the only events occurring are random chain growth and stoppage (i.e., the rates are independent of degree of polymerization over the range in question), then the number of chains of degree of polymerization N, P(N), is linear in ln P(N) with a negative slope, where the slope gives the ratio of the stoppage and growth rates. This starting point suggests that mechanistic inferences can be made from a plot of lnP against N. Application to capillary electrophoresis data for the P(N) of debranched starch from across the major taxa, from bacteria (Escherichia coli), green algae (Chlamydomonas reinhardtii), mammals (Bos), and flowering plants (Oryza sativa, rice; Zea mays, maize; Triticum aestivum, wheat; Hordeum vulgare, barley; and Solanum tuberosum, potato), gives insights into the biosynthetic pathways, showing the differences and similarities of the alpha-1,4-glucans produced by the various species. Four characteristic regions for storage starch from the higher plants are revealed: (1) an initial increasing region corresponding to the formation of new branches, (2) a linear ln P region with negative slope, indicating random growth and stoppage, (3) a region corresponding to the formation of the crystalline lamellae and subsequent elongation of chains, and (4) a second linear ln P with negative slope region. Each region can be assigned to specific enzymatic processes in starch synthesis, including determining the ranges of degrees of polymerization which are subject to random and nonrandom processes. PMID:16004469

  10. Assembly Line Polyketide Synthases: Mechanistic Insights and Unsolved Problems

    PubMed Central

    2015-01-01

    Two hallmarks of assembly line polyketide synthases have motivated an interest in these unusual multienzyme systems, their stereospecificity and their capacity for directional biosynthesis. In this review, we summarize the state of knowledge regarding the mechanistic origins of these two remarkable features, using the 6-deoxyerythronolide B synthase as a prototype. Of the 10 stereocenters in 6-deoxyerythronolide B, the stereochemistry of nine carbon atoms is directly set by ketoreductase domains, which catalyze epimerization and/or diastereospecific reduction reactions. The 10th stereocenter is established by the sequential action of three enzymatic domains. Thus, the problem has been reduced to a challenge in mainstream enzymology, where fundamental gaps remain in our understanding of the structural basis for this exquisite stereochemical control by relatively well-defined active sites. In contrast, testable mechanistic hypotheses for the phenomenon of vectorial biosynthesis are only just beginning to emerge. Starting from an elegant theoretical framework for understanding coupled vectorial processes in biology [Jencks, W. P. (1980) Adv. Enzymol. Relat. Areas Mol. Biol. 51, 75–106], we present a simple model that can explain assembly line polyketide biosynthesis as a coupled vectorial process. Our model, which highlights the important role of domain–domain interactions, not only is consistent with recent observations but also is amenable to further experimental verification and refinement. Ultimately, a definitive view of the coordinated motions within and between polyketide synthase modules will require a combination of structural, kinetic, spectroscopic, and computational tools and could be one of the most exciting frontiers in 21st Century enzymology. PMID:24779441

  11. Unified superresolution experiments and stochastic theory provide mechanistic insight into protein ion-exchange adsorptive separations

    PubMed Central

    Kisley, Lydia; Chen, Jixin; Mansur, Andrea P.; Shuang, Bo; Kourentzi, Katerina; Poongavanam, Mohan-Vivekanandan; Chen, Wen-Hsiang; Dhamane, Sagar; Willson, Richard C.; Landes, Christy F.

    2014-01-01

    Chromatographic protein separations, immunoassays, and biosensing all typically involve the adsorption of proteins to surfaces decorated with charged, hydrophobic, or affinity ligands. Despite increasingly widespread use throughout the pharmaceutical industry, mechanistic detail about the interactions of proteins with individual chromatographic adsorbent sites is available only via inference from ensemble measurements such as binding isotherms, calorimetry, and chromatography. In this work, we present the direct superresolution mapping and kinetic characterization of functional sites on ion-exchange ligands based on agarose, a support matrix routinely used in protein chromatography. By quantifying the interactions of single proteins with individual charged ligands, we demonstrate that clusters of charges are necessary to create detectable adsorption sites and that even chemically identical ligands create adsorption sites of varying kinetic properties that depend on steric availability at the interface. Additionally, we relate experimental results to the stochastic theory of chromatography. Simulated elution profiles calculated from the molecular-scale data suggest that, if it were possible to engineer uniform optimal interactions into ion-exchange systems, separation efficiencies could be improved by as much as a factor of five by deliberately exploiting clustered interactions that currently dominate the ion-exchange process only accidentally. PMID:24459184

  12. Angiotensin receptor neprilysin inhibition in heart failure: mechanistic action and clinical impact.

    PubMed

    Buggey, Jonathan; Mentz, Robert J; DeVore, Adam D; Velazquez, Eric J

    2015-09-01

    Heart failure (HF) is an increasingly common syndrome associated with high mortality and economic burden, and there has been a paucity over the past decade of new pharmacotherapies that improve outcomes. However, recent data from a large randomized controlled trial compared the novel agent LCZ696, a dual-acting angiotensin receptor blocker and neprilysin inhibitor (ARNi), with the well established angiotensin-converting enzyme (ACE) inhibitor enalapril and found significant reduction in mortality among the chronic reduced ejection fraction HF population. Preclinical and clinical data suggest that neprilysin inhibition provides beneficial outcomes in HF patients by preventing the degradation of natriuretic peptides and thereby promoting natriuresis and vasodilatation and counteracting the negative cardiorenal effects of the up-regulated renin-angiotensin-aldosterone system. Agents such as omapatrilat combined neprilysin and ACE inhibition but had increased rates of angioedema. Goals of an improved safety profile provided the rationale for the development of the ARNi LCZ696. Along with significant reductions in mortality and hospitalizations, clinical trials suggest that LCZ696 may improve surrogate markers of HF severity. In this paper, we review the preclinical and clinical data that led to the development of LCZ696, the understanding of the underlying mechanistic action, and the robust clinical impact that LCZ696 may have in the near future. PMID:26209000

  13. Mechanistically linked serum miRNAs distinguish between drug induced and fatty liver disease of different grades

    PubMed Central

    Liu, Zhichao; Wang, Yuping; Borlak, Jürgen; Tong, Weida

    2016-01-01

    Hepatic steatosis is characterised by excessive triglyceride accumulation in the form of lipid droplets (LD); however, mechanisms differ in drug induced (DIS) and/or non-alcoholic fatty liver disease (NAFLD). Here we hypothesized distinct molecular circuits of microRNA/LD-associated target genes and searched for mechanistically linked serum and tissue biomarkers that would distinguish between DIS and human NAFLD of different grades. We analysed >800 rat hepatic whole genome data for 17 steatotic drugs and identified 157 distinct miRNAs targeting 77 DIS regulated genes. Subsequently, genomic data of N = 105 cases of human NAFLD and N = 32 healthy controls were compared to serum miRNA profiles of N = 167 NAFLD patients. This revealed N = 195 tissue-specific miRNAs being mechanistically linked to LD-coding genes and 24 and 9 miRNAs were commonly regulated in serum and tissue of advanced and mild NAFLD, respectively. The NASH serum regulated miRNAs informed on hepatic inflammation, adipocytokine and insulin signalling, ER-and caveolae associated activities and altered glycerolipid metabolism. Conversely, serum miRNAs associated with blunt steatosis specifically highlighted activity of FOXO1&HNF4α on CPT2, the lipid droplet and ER-lipid-raft associated PLIN3 and Erlin1. Altogether, serum miRNAs informed on the molecular pathophysiology of NAFLD and permitted differentiation between DIS and NAFLD of different grades. PMID:27045805

  14. A Mechanistic Approach for the Prediction of Critical Power in BWR Fuel Bundles

    NASA Astrophysics Data System (ADS)

    Chandraker, Dinesh Kumar; Vijayan, Pallipattu Krishnan; Sinha, Ratan Kumar; Aritomi, Masanori

    The critical power corresponding to the Critical Heat Flux (CHF) or dryout condition is an important design parameter for the evaluation of safety margins in a nuclear fuel bundle. The empirical approaches for the prediction of CHF in a rod bundle are highly geometric specific and proprietary in nature. The critical power experiments are very expensive and technically challenging owing to the stringent simulation requirements for the rod bundle tests involving radial and axial power profiles. In view of this, the mechanistic approach has gained momentum in the thermal hydraulic community. The Liquid Film Dryout (LFD) in an annular flow is the mechanism of CHF under BWR conditions and the dryout modeling has been found to predict the CHF quite accurately for a tubular geometry. The successful extension of the mechanistic model of dryout to the rod bundle application is vital for the evaluation of critical power in the rod bundle. The present work proposes the uniform film flow approach around the rod by analyzing individual film of the subchannel bounded by rods with different heat fluxes resulting in different film flow rates around a rod and subsequently distributing the varying film flow rates of a rod to arrive at the uniform film flow rate as it has been found that the liquid film has a strong tendency to be uniform around the rod. The FIDOM-Rod code developed for the dryout prediction in BWR assemblies provides detailed solution of the multiple liquid films in a subchannel. The approach of uniform film flow rate around the rod simplifies the liquid film cross flow modeling and was found to provide dryout prediction with a good accuracy when compared with the experimental data of 16, 19 and 37 rod bundles under BWR conditions. The critical power has been predicted for a newly designed 54 rod bundle of the Advanced Heavy Water Reactor (AHWR). The selected constitutive models for the droplet entrainment and deposition rates validated for the dryout in tube were

  15. Profile video

    NASA Astrophysics Data System (ADS)

    Voglewede, Paul E.; Zampieron, Jeffrey

    2009-05-01

    For unattended persistent surveillance there is a need for a system which provides the following information: target classification, target quantity estimate, cargo presence and characterization, direction of travel, and action. Over highly bandwidth restricted links, such as Iridium, SATCOM or HF, the data rates of common techniques are too high, even after aggressive compression, to deliver the required intelligence in a timely, low power manner. We propose the following solution to this data rate problem: Profile Video. Profile video is a new technique which provides all of the required information in a very low data-rate package.

  16. Application of spectral deconvolution and inverse mechanistic modelling as a tool for root cause investigation in protein chromatography.

    PubMed

    Brestrich, Nina; Hahn, Tobias; Hubbuch, Jürgen

    2016-03-11

    In chromatographic protein purification, process variations, aging of columns, or processing errors can lead to deviations of the expected elution behavior of product and contaminants and can result in a decreased pool purity or yield. A different elution behavior of all or several involved species leads to a deviating chromatogram. The causes for deviations are however hard to identify by visual inspection and complicate the correction of a problem in the next cycle or batch. To overcome this issue, a tool for root cause investigation in protein chromatography was developed. The tool combines a spectral deconvolution with inverse mechanistic modelling. Mid-UV spectral data and Partial Least Squares Regression were first applied to deconvolute peaks to obtain the individual elution profiles of co-eluting proteins. The individual elution profiles were subsequently used to identify errors in process parameters by curve fitting to a mechanistic chromatography model. The functionality of the tool for root cause investigation was successfully demonstrated in a model protein study with lysozyme, cytochrome c, and ribonuclease A. Deviating chromatograms were generated by deliberately caused errors in the process parameters flow rate and sodium-ion concentration in loading and elution buffer according to a design of experiments. The actual values of the three process parameters and, thus, the causes of the deviations were estimated with errors of less than 4.4%. Consequently, the established tool for root cause investigation is a valuable approach to rapidly identify process variations, aging of columns, or processing errors. This might help to minimize batch rejections or contribute to an increased productivity. PMID:26879457

  17. A new mechanistic framework to predict OCS fluxes from soils

    NASA Astrophysics Data System (ADS)

    Ogée, J.; Sauze, J.; Kesselmeier, J.; Genty, B.; Van Diest, H.; Launois, T.; Wingate, L.

    2015-09-01

    Estimates of photosynthetic and respiratory fluxes at large scales is needed to improve our predictions of the current and future global CO2 cycle. Carbonyl sulphide (OCS) is the most abundant sulphur gas in the atmosphere and has been proposed as a new tracer of photosynthesis (GPP), as the uptake of OCS from the atmosphere is dominated by the activity of carbonic anhydrase (CA), an enzyme abundant in leaves that also catalyses CO2 hydration during photosynthesis. But soils also exchange OCS with the atmosphere which complicates the retrieval of GPP from atmospheric budgets. Indeed soils can take up large amounts of OCS from the atmosphere as soil microorganisms also contain CA, and OCS emissions from soils have been reported in agricultural fields or anoxic soils. To date no mechanistic framework exists to describe this exchange of OCS between soils and the atmosphere but empirical results, once upscaled to the global scale, indicate that OCS consumption by soils dominates over production and its contribution to the atmospheric budget is large, at about one third of the OCS uptake by vegetation, with also a large uncertainty. Here, we propose a new mechanistic model of the exchange of OCS between soils and the atmosphere that builds on our knowledge of soil CA activity from CO2 oxygen isotopes. In this model the OCS soil budget is described by a first-order reaction-diffusion-production equation, assuming that the hydrolysis of OCS by CA is total and irreversible. Using this model we are able to explain the observed presence of an optimum temperature for soil OCS uptake and show how this optimum can shift to cooler temperatures in the presence of soil OCS emissions. Our model can also explain the observed optimum with soil moisture content previously described in the literature as a result of diffusional constraints on OCS hydrolysis. These diffusional constraints are also responsible for the response of OCS uptake to soil weight and depth observed previously. In

  18. A new mechanistic framework to predict OCS fluxes from soils

    NASA Astrophysics Data System (ADS)

    Ogee, J.; Sauze, J.; Kesselmeier, J.; Genty, B.; Whelan, M.; Launois, T.; Wingate, L.

    2015-12-01

    A better description of the amplitude of photosynthetic and respiratory gross CO2 fluxes at large scales is needed to improve our predictions of the current and future global CO2 cycle. Carbonyl sulphide (OCS) has been proposed as a new tracer of gross photosynthesis (GPP), as the uptake of OCS from the atmosphere is dominated by the activity of carbonic anhydrase (CA), an enzyme abundant in leaves that also catalyses CO2 hydration during photosynthesis. But soils also exchange OCS with the atmosphere which complicates the retrieval of GPP from atmospheric budgets. Indeed soils can take up large amounts of OCS from the atmosphere as soil microorganisms also contain CA, and OCS emissions from soils have been reported in agricultural or anoxic soils. To date no mechanistic framework exists to describe this exchange of OCS between soils and the atmosphere but empirical results, once up-scaled to the global scale, indicate that OCS consumption by soils dominates over production and its contribution to the atmospheric budget is large, at about one third of the OCS uptake by vegetation, with also a large uncertainty. Here, we propose a new mechanistic model of the exchange of OCS between soils and the atmosphere that builds on our knowledge of soil CA activity from CO2 oxygen isotopes. In this model the OCS soil budget is described by a first-order reaction-diffusion-production equation, assuming that the hydrolysis of OCS by CA is total and irreversible. Using this model we are able to explain the observed presence of an optimum temperature for soil OCS uptake and show how this optimum can shift to cooler temperatures in the presence of soil OCS emissions. Our model can also explain the observed optimum with soil moisture content previously described in the literature as a result of diffusional constraints on OCS hydrolysis. In order to simulate the exact OCS uptake rates and patterns observed on several soils collected from a range of biomes, different CA activities

  19. Modeling Bird Migration under Climate Change: A Mechanistic Approach

    NASA Technical Reports Server (NTRS)

    Smith, James A.

    2009-01-01

    How will migrating birds respond to changes in the environment under climate change? What are the implications for migratory success under the various accelerated climate change scenarios as forecast by the Intergovernmental Panel on Climate Change? How will reductions or increased variability in the number or quality of wetland stop-over sites affect migratory bird species? The answers to these questions have important ramifications for conservation biology and wildlife management. Here, we describe the use of continental scale simulation modeling to explore how spatio-temporal changes along migratory flyways affect en-route migration success. We use an individually based, biophysical, mechanistic, bird migration model to simulate the movement of shorebirds in North America as a tool to study how such factors as drought and wetland loss may impact migratory success and modify migration patterns. Our model is driven by remote sensing and climate data and incorporates important landscape variables. The energy budget components of the model include resting, foraging, and flight, but presently predation is ignored. Results/Conclusions We illustrate our model by studying the spring migration of sandpipers through the Great Plains to their Arctic breeding grounds. Why many species of shorebirds have shown significant declines remains a puzzle. Shorebirds are sensitive to stop-over quality and spacing because of their need for frequent refueling stops and their opportunistic feeding patterns. We predict bird "hydrographs that is, stop-over frequency with latitude, that are in agreement with the literature. Mean stop-over durations predicted from our model for nominal cases also are consistent with the limited, but available data. For the shorebird species simulated, our model predicts that shorebirds exhibit significant plasticity and are able to shift their migration patterns in response to changing drought conditions. However, the question remains as to whether this

  20. A new mechanistic framework to predict OCS fluxes from soils

    NASA Astrophysics Data System (ADS)

    Ogée, Jérôme; Sauze, Joana; Kesselmeier, Jürgen; Genty, Bernard; Van Diest, Heidi; Launois, Thomas; Wingate, Lisa

    2016-04-01

    Estimates of photosynthetic and respiratory fluxes at large scales are needed to improve our predictions of the current and future global CO2 cycle. Carbonyl sulfide (OCS) is the most abundant sulfur gas in the atmosphere and has been proposed as a new tracer of photosynthetic gross primary productivity (GPP), as the uptake of OCS from the atmosphere is dominated by the activity of carbonic anhydrase (CA), an enzyme abundant in leaves that also catalyses CO2 hydration during photosynthesis. However soils also exchange OCS with the atmosphere, which complicates the retrieval of GPP from atmospheric budgets. Indeed soils can take up large amounts of OCS from the atmosphere as soil microorganisms also contain CA, and OCS emissions from soils have been reported in agricultural fields or anoxic soils. To date no mechanistic framework exists to describe this exchange of OCS between soils and the atmosphere, but empirical results, once upscaled to the global scale, indicate that OCS consumption by soils dominates OCS emission and its contribution to the atmospheric budget is large, at about one third of the OCS uptake by vegetation, also with a large uncertainty. Here, we propose a new mechanistic model of the exchange of OCS between soils and the atmosphere that builds on our knowledge of soil CA activity from CO2 oxygen isotopes. In this model the OCS soil budget is described by a first-order reaction-diffusion-production equation, assuming that the hydrolysis of OCS by CA is total and irreversible. Using this model we are able to explain the observed presence of an optimum temperature for soil OCS uptake and show how this optimum can shift to cooler temperatures in the presence of soil OCS emission. Our model can also explain the observed optimum with soil moisture content previously described in the literature as a result of diffusional constraints on OCS hydrolysis. These diffusional constraints are also responsible for the response of OCS uptake to soil weight and

  1. Mechanistic biomarkers for clinical decision making in rheumatic diseases

    PubMed Central

    Robinson, William H.; Lindstrom, Tamsin M.; Cheung, Regina K.; Sokolove, Jeremy

    2013-01-01

    The use of biomarkers is becoming increasingly intrinsic to the practice of medicine and holds great promise for transforming the practice of rheumatology. Biomarkers have the potential to aid clinical diagnosis when symptoms are present or to provide a means of detecting early signs of disease when they are not. Some biomarkers can serve as early surrogates of eventual clinical outcomes or guide therapeutic decision making by enabling identification of individuals likely to respond to a specific therapy. Using biomarkers might reduce the costs of drug development by enabling individuals most likely to respond to be enrolled in clinical trials, thereby minimizing the number of participants required. In this Review, we discuss the current use and the potential of biomarkers in rheumatology and in select fields at the forefront of biomarker research. We emphasize the value of different types of biomarkers, addressing the concept of ‘actionable’ biomarkers, which can be used to guide clinical decision making, and ‘mechanistic’ biomarkers, a subtype of actionable biomarker that is embedded in disease pathogenesis and, therefore, represents a superior biomarker. We provide examples of actionable and mechanistic biomarkers currently available, and discuss how development of such biomarkers could revolutionize clinical practice and drug development. PMID:23419428

  2. A mechanistic compartmental model for total antibody uptake in tumors

    PubMed Central

    Thurber, Greg M.; Dane Wittrup, K.

    2012-01-01

    Antibodies are under development to treat a variety of cancers, such as lymphomas, colon, and breast cancer. A major limitation to greater efficacy for this class of drugs is poor distribution in vivo. Localization of antibodies occurs slowly, often in insufficient therapeutic amounts, and distributes heterogeneously throughout the tumor. While the microdistribution around individual vessels is important for many therapies, the total amount of antibody localized in the tumor is paramount for many applications such as imaging, determining the therapeutic index with antibody drug conjugates, and dosing in radioimmunotherapy. With imaging and pretargeted therapeutic strategies, the time course of uptake is critical in determining when to take an image or deliver a secondary reagent. We present here a simple mechanistic model of antibody uptake and retention that captures the major rates that determine the time course of antibody concentration within a tumor including dose, affinity, plasma clearance, target expression, internalization, permeability, and vascularization. Since many of the parameters are known or can be estimated in vitro, this model can approximate the time course of antibody concentration in tumors to aid in experimental design, data interpretation, and strategies to improve localization. PMID:22974563

  3. Mechanistic Enzymology of the Radical SAM Enzyme DesII

    PubMed Central

    2016-01-01

    DesII is a member of the radical SAM family of enzymes that catalyzes radical-mediated transformations of TDP-4-amino-4,6-didexoy-D-glucose as well as other sugar nucleotide diphosphates. Like nearly all radical SAM enzymes, the reactions begin with the reductive homolysis of SAM to produce a 5′-deoxyadenosyl radical which is followed by regiospecific hydrogen atom abstraction from the substrate. What happens next, however, depends on the nature of the substrate radical so produced. In the case of the biosynthetically relevant substrate, a radical-mediated deamination ensues; however, when this amino group is replaced with a hydroxyl, one instead observes dehydrogenation. The factors that govern the fate of the initially generated substrate radical as well as the mechanistic details underlying these transformations have been a key focus of research into the chemistry of DesII. This review will discuss recent discoveries pertaining to the enzymology of DesII, how it may relate to understanding other radical-mediated lyases and dehydrogenases and the working hypotheses currently being investigated regarding the mechanism of DesII catalysis.

  4. Anti-fibro-hepatocarcinogenic Chinese herbal medicines: A mechanistic overview.

    PubMed

    Boye, Alex; Yang, Yan; Asenso, James; Wei, Wei

    2016-01-01

    Chinese herbal medicine (CHM) is an integral component of complementary/alternative medicine and it is increasingly becoming the preferred therapeutic modality for the treatment of liver fibrosis and hepatocellular carcinoma (HCC) worldwide. Accordingly, the World Health Organization (WHO) has attested to the popularity and efficacy of indigenous herbal therapies including CHM as a first line of treatment for some diseases including liver disorders. However, the WHO and drug discovery experts have always recommended that use of indigenous herbal remedies must go hand-in-hand with the requisite mechanistic elucidation so as to constitute a system of verification of efficacy within the ethnobotanical context of use. Although many CHM experts have advanced knowledge on CHM, nonetheless, more enlightenment is needed, particularly mechanisms of action of CHMs on fibro-hepato-carcinogenesis. We, herein, provide in-depth mechanisms of the action of CHMs which have demonstrated anti-fibro-hepatocarcinogenic effects, in pre-clinical and clinical studies as published in PubMed and other major scientific databases. Specifically, the review brings out the important signaling pathways, and their downstream targets which are modulated at multi-level by various anti-fibro-hepatocarcinogenic CHMs. PMID:27366355

  5. Equation-free mechanistic ecosystem forecasting using empirical dynamic modeling

    PubMed Central

    Ye, Hao; Beamish, Richard J.; Glaser, Sarah M.; Grant, Sue C. H.; Hsieh, Chih-hao; Richards, Laura J.; Schnute, Jon T.; Sugihara, George

    2015-01-01

    It is well known that current equilibrium-based models fall short as predictive descriptions of natural ecosystems, and particularly of fisheries systems that exhibit nonlinear dynamics. For example, model parameters assumed to be fixed constants may actually vary in time, models may fit well to existing data but lack out-of-sample predictive skill, and key driving variables may be misidentified due to transient (mirage) correlations that are common in nonlinear systems. With these frailties, it is somewhat surprising that static equilibrium models continue to be widely used. Here, we examine empirical dynamic modeling (EDM) as an alternative to imposed model equations and that accommodates both nonequilibrium dynamics and nonlinearity. Using time series from nine stocks of sockeye salmon (Oncorhynchus nerka) from the Fraser River system in British Columbia, Canada, we perform, for the the first time to our knowledge, real-data comparison of contemporary fisheries models with equivalent EDM formulations that explicitly use spawning stock and environmental variables to forecast recruitment. We find that EDM models produce more accurate and precise forecasts, and unlike extensions of the classic Ricker spawner–recruit equation, they show significant improvements when environmental factors are included. Our analysis demonstrates the strategic utility of EDM for incorporating environmental influences into fisheries forecasts and, more generally, for providing insight into how environmental factors can operate in forecast models, thus paving the way for equation-free mechanistic forecasting to be applied in management contexts. PMID:25733874

  6. Mechanistic modeling and correlations for pool-entrainment phenomenon

    SciTech Connect

    Kataoka, I.; Ishii, M.

    1983-04-01

    Entrainment from a liquid pool with boiling or bubbling is of considerable practical importance in safety evaluation of nuclear reactor under off-normal transients or accidents such as loss-of-coolant and loss-of-flow accidents. Droplets which are suspended from a free surface are partly carried away by streaming gas and partly returned back to free surface by the gravity. A correlation is developed for the pool entrainment amount based on simple mechanistic modeling and a number of data. This analysis reveals that there exist three regions of entrainment in the axial direction from a pool surface. In the first region (near surface region), entrainment is independent of height and gas velocity. In the second region (momentum controlled region), the amount of entrainment decreases with increasing height from the free surface and increases with increasing gas velocity. In the third region (deposition controlled region), the entrainment increases with increasing height due to deposition of droplets. The present correlation agrees well with a large number of experimental data over a wide range of pressure for air-water and steam-water systems.

  7. Bioavailability and Pharmacokinetics of Genistein: Mechanistic Studies on its ADME

    PubMed Central

    Yang, Zhen; Kulkarni, Kaustubh; Zhu, Wei; Hu, Ming

    2014-01-01

    Genistein, one of the most active natural flavonoids, exerts various biological effects including chemoprevention, antioxidation, antiproliferation and anticancer. More than 30 clinical trials of genistein with various disease indications have been conducted to evaluate its clinical efficacy. Based on many animals and human pharmacokinetic studies, it is well known that the most challenge issue for developing genistein as a chemoprevention agent is the low oral bioavailability, which may be the major reason relating to its ambiguous therapeutic effects and large interindividual variations in clinical trials. In order to better correlate pharmacokinetic to pharmacodynamics results in animals and clinical studies, an in-depth understanding of pharmacokinetic behavior of genistein and its ADME properties are needed. Numerous in vitro/in vivo ADME studies had been conducted to reveal the main factors contributing to the low oral bioavailability of genistein. Therefore, this review focuses on summarizing the most recent progress on mechanistic studies of genistein ADME and provides a systemic view of these processes to explain genistein pharmacokinetic behaviors in vivo. The better understanding of genistein ADME property may lead to development of proper strategy to improve genistein oral bioavailability via mechanism-based approaches. PMID:22583407

  8. Mechanistic insight into sonochemical biodiesel synthesis using heterogeneous base catalyst.

    PubMed

    Choudhury, Hanif A; Chakma, Sankar; Moholkar, Vijayanand S

    2014-01-01

    The beneficial effect of ultrasound on transesterification reaction is well known. Heterogeneous (or solid) catalysts for biodiesel synthesis have merit that they do not contaminate the byproduct of glycerol. In this paper, we have attempted to identify the mechanistic features of ultrasound-enhanced biodiesel synthesis with the base-catalyst of CaO. A statistical design of experiments (Box-Behnken) was used to identify the influence of temperature, alcohol to oil molar ratio and catalyst loading on transesterification yield. The optimum values of these parameters for the highest yield were identified through Response Surface Method (with a quadratic model) and ANOVA. These values are: temperature=62 °C, molar ratio=10:1 and catalyst loading=6 wt.%. The activation energy was determined as 82.3 kJ/mol, which is higher than that for homogeneous catalyzed system (for both acidic and basic catalyst). The experimental results have been analyzed vis-à-vis simulations of cavitation bubble dynamics. Due to 3-phase heterogeneity of the system, the yield was dominated by intrinsic kinetics, and the optimum temperature for the highest yield was close to boiling point of methanol. At this temperature, the influence of cavitation bubbles (in terms of both sonochemical and sonophysical effect) is negligible, and ultrasonic micro-streaming provided necessary convection in the system. The influence of all parameters on the reaction system was found to be strongly inter-dependent. PMID:23742888

  9. Environmental perception and epigenetic memory: mechanistic insight through FLC

    PubMed Central

    Berry, Scott; Dean, Caroline

    2015-01-01

    Chromatin plays a central role in orchestrating gene regulation at the transcriptional level. However, our understanding of how chromatin states are altered in response to environmental and developmental cues, and then maintained epigenetically over many cell divisions, remains poor. The floral repressor gene FLOWERING LOCUS C (FLC) in Arabidopsis thaliana is a useful system to address these questions. FLC is transcriptionally repressed during exposure to cold temperatures, allowing studies of how environmental conditions alter expression states at the chromatin level. FLC repression is also epigenetically maintained during subsequent development in warm conditions, so that exposure to cold may be remembered. This memory depends on molecular complexes that are highly conserved among eukaryotes, making FLC not only interesting as a paradigm for understanding biological decision-making in plants, but also an important system for elucidating chromatin-based gene regulation more generally. In this review, we summarize our understanding of how cold temperature induces a switch in the FLC chromatin state, and how this state is epigenetically remembered. We also discuss how the epigenetic state of FLC is reprogrammed in the seed to ensure a requirement for cold exposure in the next generation. Significance Statement FLOWERING LOCUS C (FLC) regulation provides a paradigm for understanding how chromatin can be modulated to determine gene expression in a developmental context. This review describes our current mechanistic understanding of how FLC expression is genetically specified and epigenetically regulated throughout the plant life cycle, and how this determines plant life-history strategy. PMID:25929799

  10. A global scale mechanistic model of the photosynthetic capacity

    NASA Astrophysics Data System (ADS)

    Ali, A. A.; Xu, C.; Rogers, A.; Fisher, R. A.; Wullschleger, S. D.; McDowell, N. G.; Massoud, E. C.; Vrugt, J. A.; Muss, J. D.; Fisher, J. B.; Reich, P. B.; Wilson, C. J.

    2015-08-01

    Although plant photosynthetic capacity as determined by the maximum carboxylation rate (i.e., Vc, max25) and the maximum electron transport rate (i.e., Jmax25) at a reference temperature (generally 25 °C) is known to vary substantially in space and time in response to environmental conditions, it is typically parameterized in Earth system models (ESMs) with tabulated values associated to plant functional types. In this study, we developed a mechanistic model of leaf utilization of nitrogen for assimilation (LUNA V1.0) to predict the photosynthetic capacity at the global scale under different environmental conditions, based on the optimization of nitrogen allocated among light capture, electron transport, carboxylation, and respiration. The LUNA model was able to reasonably well capture the observed patterns of photosynthetic capacity in view that it explained approximately 55 % of the variation in observed Vc, max25 and 65 % of the variation in observed Jmax25 across the globe. Our model simulations under current and future climate conditions indicated that Vc, max25 could be most affected in high-latitude regions under a warming climate and that ESMs using a fixed Vc, max25 or Jmax25 by plant functional types were likely to substantially overestimate future global photosynthesis.

  11. Neutron structure and mechanistic studies of diisopropyl fluorophosphatase (DFPase)

    SciTech Connect

    Chen, Julian C.-H.; Mustyakimov, Marat; Schoenborn, Benno P.; Langan, Paul; Blum, Marc-Michael

    2010-11-01

    The structure and mechanism of diisopropyl fluorophosphatase (DFPase) have been studied using a variety of methods, including isotopic labelling, X-ray crystallography and neutron crystallography. The neutron structure of DFPase, mechanistic studies and subsequent rational design efforts are described. Diisopropyl fluorophosphatase (DFPase) is a calcium-dependent phosphotriesterase that acts on a variety of highly toxic organophosphorus compounds that act as inhibitors of acetylcholinesterase. The mechanism of DFPase has been probed using a variety of methods, including isotopic labelling, which demonstrated the presence of a phosphoenzyme intermediate in the reaction mechanism. In order to further elucidate the mechanism of DFPase and to ascertain the protonation states of the residues and solvent molecules in the active site, the neutron structure of DFPase was solved at 2.2 Å resolution. The proposed nucleophile Asp229 is deprotonated, while the active-site solvent molecule W33 was identified as water and not hydroxide. These data support a mechanism involving direct nucleophilic attack by Asp229 on the substrate and rule out a mechanism involving metal-assisted water activation. These data also allowed for the re-engineering of DFPase through rational design to bind and productively orient the more toxic S{sub P} stereoisomers of the nerve agents sarin and cyclosarin, creating a modified enzyme with enhanced overall activity and significantly increased detoxification properties.

  12. Mechanistic modeling of aberrant energy metabolism in human disease

    PubMed Central

    Sangar, Vineet; Eddy, James A.; Simeonidis, Evangelos; Price, Nathan D.

    2012-01-01

    Dysfunction in energy metabolism—including in pathways localized to the mitochondria—has been implicated in the pathogenesis of a wide array of disorders, ranging from cancer to neurodegenerative diseases to type II diabetes. The inherent complexities of energy and mitochondrial metabolism present a significant obstacle in the effort to understand the role that these molecular processes play in the development of disease. To help unravel these complexities, systems biology methods have been applied to develop an array of computational metabolic models, ranging from mitochondria-specific processes to genome-scale cellular networks. These constraint-based (CB) models can efficiently simulate aspects of normal and aberrant metabolism in various genetic and environmental conditions. Development of these models leverages—and also provides a powerful means to integrate and interpret—information from a wide range of sources including genomics, proteomics, metabolomics, and enzyme kinetics. Here, we review a variety of mechanistic modeling studies that explore metabolic functions, deficiency disorders, and aberrant biochemical pathways in mitochondria and related regions in the cell. PMID:23112774

  13. AIR POLLUTION, INFLAMMATION AND PRETERM BIRTH: A POTENTIAL MECHANISTIC LINK

    PubMed Central

    Vadillo-Ortega, Felipe; Osornio-Vargas, Alvaro; Buxton, Miatta A.; Sánchez, Brisa N.; Rojas-Bracho, Leonora; Viveros-Alcaráz, Martin; Castillo-Castrejón, Marisol; Beltrán-Montoya, Jorge; Brown, Daniel G.; O´Neill, Marie S.

    2014-01-01

    Preterm birth is a public health issue of global significance, which may result in mortality during the perinatal period or may lead to major health and financial consequences due to lifelong impacts. Even though several risk factors for preterm birth have been identified, prevention efforts have failed to halt the increasing rates of preterm birth. Epidemiological studies have identified air pollution as an emerging potential risk factor for preterm birth. However, many studies were limited by study design and inadequate exposure assessment. Due to the ubiquitous nature of ambient air pollution and the potential public health significance of any role in causing preterm birth, a novel focus investigating possible causal mechanisms influenced by air pollution is therefore a global health priority. We hypothesize that air pollution may act together with other biological factors to induce systemic inflammation and influence the duration of pregnancy. Evaluation and testing of this hypothesis is currently being conducted in a prospective cohort study in Mexico City and will provide an understanding of the pathways that mediate the effects of air pollution on preterm birth. The important public health implication is that crucial steps in this mechanistic pathway can potentially be acted on early in pregnancy to reduce the risk of preterm birth. PMID:24382337

  14. Physical activity and its mechanistic effects on prostate cancer.

    PubMed

    Wekesa, A; Harrison, M; Watson, R W

    2015-09-01

    Beneficial effects of physical activity have been illustrated in numerous aspects of health. With the increasing incidence of prostate cancer and changes in physical activity of men, understanding the link between the two has important implications for changing this cancer burden. Both positive and negative associations between physical activity and prostate cancer have been previously demonstrated in observational epidemiological studies. Elucidating the biological mechanisms would lead to a better understanding of how physical activity influences the progression of prostate cancer. This review was undertaken to: (1) identify evidence in literature that demonstrates the effects of physical activity on skeletal muscle secretomes, (2) indicate the plausible signaling pathways these proteins might activate, and (3) identify evidence in literature that demonstrates the roles of the signaling pathways in prostate cancer progression and regression. We also discuss proposed biological mechanisms and signaling pathways by which physical activity may prevent the development and progression of prostate cancer. We discuss proteins involved in the normal and aberrant growth and development of the prostate gland that may be affected by physical activity. We further identify future directions for research, including a better understanding of the biological mechanisms, the need to standardize physical activity and identify mechanistic end points of physical activity that can then be correlated with outcomes. PMID:25800589

  15. Circadian rhythms and addiction: Mechanistic insights and future directions

    PubMed Central

    Logan, Ryan W.; Williams, Wilbur P.; McClung, Colleen A.

    2014-01-01

    Circadian rhythms are prominent in many physiological and behavioral functions. Circadian disruptions either by environmental or molecular perturbation can have profound health consequences, including the development and progression of addiction. Both animal and humans studies indicate extensive bidirectional relationships between the circadian system and drugs of abuse. Addicted individuals display disrupted rhythms, and chronic disruption or particular chronotypes, may increase the risk for substance abuse and relapse. Moreover, polymorphisms in circadian genes and an evening chronotype have been linked to mood and addiction disorders, and recent efforts suggest an association with the function of reward neurocircuitry. Animal studies are beginning to determine how altered circadian gene function results in drug induced neuroplasticity and behaviors. Many studies suggest a critical role for circadian rhythms in reward-related pathways in the brain and indicate that drugs of abuse directly affect the central circadian pacemaker. In this review, we highlight key findings demonstrating the importance of circadian rhythms in addiction, and how future studies will reveal important mechanistic insights into the involvement of circadian rhythms in drug addiction. PMID:24731209

  16. Spectroscopic and Mechanistic Investigations of Dehaloperoxidase B from Amphitrite ornata†

    PubMed Central

    D’Antonio, Jennifer; D’Antonio, Edward L.; Thompson, Matthew K.; Bowden, Edmond F.; Franzen, Stefan; Smirnova, Tatyana; Ghiladi, Reza A.

    2010-01-01

    Dehaloperoxidase (DHP) from the terebellid polychaete Amphitrite ornata is a bifunctional enzyme that possesses both hemoglobin and peroxidase activities. Of the two DHP isoenzymes identified to date, much of the recent focus has been on DHP A, whereas very little is known pertaining to the activity, substrate specificity, mechanism of function, or spectroscopic properties of DHP B. Herein, we report the recombinant expression and purification of DHP B, as well as the details of our investigations into its catalytic cycle using biochemical assays, stopped-flow UV-visible, resonance Raman and rapid-freeze-quench electron paramagnetic resonance spectroscopies, and spectroelectrochemistry. Our experimental design reveals mechanistic insights and kinetic descriptions of the dehaloperoxidase mechanism which have not been previously reported for isoenzyme A. Namely, we demonstrate a novel reaction pathway in which the products of the oxidative dehalogenation of trihalophenols (dihaloquinones) are themselves capable of inducing formation of oxyferrous DHP B, and an updated catalytic cycle for DHP is proposed. We further demonstrate that unlike the traditional monofunctional peroxidases, the oxyferrous state in DHP is a peroxidase competent starting species, which suggests that the ferric oxidation state may not be an obligatory starting point for the enzyme. The data presented herein provide a link between the peroxidase and oxygen transport activities which furthers our understanding of how this bifunctional enzyme is able to unite its two inherent functions in one system. PMID:20545299

  17. Warming will affect phytoplankton differently: evidence through a mechanistic approach

    PubMed Central

    Huertas, I. Emma; Rouco, Mónica; López-Rodas, Victoria; Costas, Eduardo

    2011-01-01

    Although the consequences of global warming in aquatic ecosystems are only beginning to be revealed, a key to forecasting the impact on aquatic communities is an understanding of individual species' vulnerability to increased temperature. Despite their microscopic size, phytoplankton support about half of the global primary production, drive essential biogeochemical cycles and represent the basis of the aquatic food web. At present, it is known that phytoplankton are important targets and, consequently, harbingers of climate change in aquatic systems. Therefore, investigating the capacity of phytoplankton to adapt to the predicted warming has become a relevant issue. However, considering the polyphyletic complexity of the phytoplankton community, different responses to increased temperature are expected. We experimentally tested the effects of warming on 12 species of phytoplankton isolated from a variety of environments by using a mechanistic approach able to assess evolutionary adaptation (the so-called ratchet technique). We found different degrees of tolerance to temperature rises and an interspecific capacity for genetic adaptation. The thermal resistance level reached by each species is discussed in relation to their respective original habitats. Our study additionally provides evidence on the most resistant phytoplankton groups in a future warming scenario. PMID:21508031

  18. A brief review of exercise, bipolar disorder, and mechanistic pathways

    PubMed Central

    Thomson, Daniel; Turner, Alyna; Lauder, Sue; Gigler, Margaret E.; Berk, Lesley; Singh, Ajeet B.; Pasco, Julie A.; Berk, Michael; Sylvia, Louisa

    2015-01-01

    Despite evidence that exercise has been found to be effective in the treatment of depression, it is unclear whether these data can be extrapolated to bipolar disorder. Available evidence for bipolar disorder is scant, with no existing randomized controlled trials having tested the impact of exercise on depressive, manic or hypomanic symptomatology. Although exercise is often recommended in bipolar disorder, this is based on extrapolation from the unipolar literature, theory and clinical expertise and not empirical evidence. In addition, there are currently no available empirical data on program variables, with practical implications on frequency, intensity and type of exercise derived from unipolar depression studies. The aim of the current paper is to explore the relationship between exercise and bipolar disorder and potential mechanistic pathways. Given the high rate of medical co-morbidities experienced by people with bipolar disorder, it is possible that exercise is a potentially useful and important intervention with regard to general health benefits; however, further research is required to elucidate the impact of exercise on mood symptomology. PMID:25788889

  19. Rapid Discrimination Among Putative Mechanistic Models of Biochemical Systems

    PubMed Central

    Lomnitz, Jason G.; Savageau, Michael A.

    2016-01-01

    An overarching goal in molecular biology is to gain an understanding of the mechanistic basis underlying biochemical systems. Success is critical if we are to predict effectively the outcome of drug treatments and the development of abnormal phenotypes. However, data from most experimental studies is typically noisy and sparse. This allows multiple potential mechanisms to account for experimental observations, and often devising experiments to test each is not feasible. Here, we introduce a novel strategy that discriminates among putative models based on their repertoire of qualitatively distinct phenotypes, without relying on knowledge of specific values for rate constants and binding constants. As an illustration, we apply this strategy to two synthetic gene circuits exhibiting anomalous behaviors. Our results show that the conventional models, based on their well-characterized components, cannot account for the experimental observations. We examine a total of 40 alternative hypotheses and show that only 5 have the potential to reproduce the experimental data, and one can do so with biologically relevant parameter values. PMID:27578053

  20. Ultrasound enhanced ethanol production from Parthenium hysterophorus: A mechanistic investigation.

    PubMed

    Singh, Shuchi; Sarma, Shyamali; Agarwal, Mayank; Goyal, Arun; Moholkar, Vijayanand S

    2015-01-01

    This study presents mechanistic investigations in ultrasound-assisted bioethanol fermentation using Parthenium hysterophorus biomass. Ultrasound (35 kHz, 10% duty cycle) has been used for sonication. Experimental results were fitted to mathematical model; the kinetic and physiological parameters in the model were obtained using Genetic Algorithm (GA) based optimization. In control experiments (mechanical shaking), maximum ethanol titer of 10.93 g/L and cell mass concentration of 5.26 g/L was obtained after 18 h. In test experiments (mechanical shaking and intermittent sonication), ethanol titer of 12.14 g/L and cell mass concentration of 5.7 g/L was obtained in 10h. This indicated ∼ 2 × enhanced productivity of ethanol and cell mass with sonication. Trends in model parameters obtained after fitting of model to experimental data essentially revealed that beneficial influence of ultrasound on fermentation is a manifestation of enhanced trans-membrane transportation and dilution of toxic substances due to strong micro-convection induced by ultrasound. PMID:25555927

  1. Mechanistic modeling of destratification in cryogenic storage tanks using ultrasonics.

    PubMed

    Jagannathan, T K; Mohanan, Srijith; Nagarajan, R

    2014-01-01

    Stratification is one of the main causes for vaporization of cryogens and increase of tank pressure during cryogenic storage. This leads subsequent problems such as cavitation in cryo-pumps, reduced length of storage time. Hence, it is vital to prevent stratification to improve the cost efficiency of storage systems. If stratified layers exist inside the tank, they have to be removed by suitable methods without venting the vapor. Sonication is one such method capable of keeping fluid layers mixed. In the present work, a mechanistic model for ultrasonic destratification is proposed and validated with destratification experiments done in water. Then, the same model is used to predict the destratification characteristics of cryogenic liquids such as liquid nitrogen (LN₂), liquid hydrogen (LH₂) and liquid ammonia (LNH₃). The destratification parameters are analysed for different frequencies of ultrasound and storage pressures by considering continuous and pulsed modes of ultrasonic operation. From the results, it is determined that use of high frequency ultrasound (low-power/continuous; high-power/pulsing) or low frequency ultrasound (continuous operation with moderate power) can both be effective in removing stratification. PMID:23810463

  2. Mechanistic studies of malonic acid-mediated in situ acylation.

    PubMed

    Chandra, Koushik; Naoum, Johnny N; Roy, Tapta Kanchan; Gilon, Chaim; Gerber, R Benny; Friedler, Assaf

    2015-09-01

    We have previously introduced an easy to perform, cost-effective and highly efficient acetylation technique for solid phase synthesis (SPPS). Malonic acid is used as a precursor and the reaction proceeds via a reactive ketene that acetylates the target amine. Here we present a detailed mechanistic study of the malonic acid-mediated acylation. The influence of reaction conditions, peptide sequence and reagents was systematically studied. Our results show that the methodology can be successfully applied to different types of peptides and nonpeptidic molecules irrespective of their structure, sequence, or conformation. Using alkyl, phenyl, and benzyl malonic acid, we synthesized various acyl peptides with almost quantitative yields. The ketenes obtained from the different malonic acid derived precursors were characterized by in situ (1) H-NMR. The reaction proceeded in short reaction times and resulted in excellent yields when using uronium-based coupling agents, DIPEA as a base, DMF/DMSO/NMP as solvents, Rink amide/Wang/Merrifield resins, temperature of 20°C, pH 8-12 and 5 min preactivation at inert atmosphere. The reaction was unaffected by Lewis acids, transition metal ions, surfactants, or salt. DFT studies support the kinetically favorable concerted mechanism for CO2 and ketene formation that leads to the thermodynamically stable acylated products. We conclude that the malonic acid-mediated acylation is a general method applicable to various target molecules. PMID:25846609

  3. A mechanistic stochastic framework for regulating bacterial cell division

    PubMed Central

    Ghusinga, Khem Raj; Vargas-Garcia, Cesar A.; Singh, Abhyudai

    2016-01-01

    How exponentially growing cells maintain size homeostasis is an important fundamental problem. Recent single-cell studies in prokaryotes have uncovered the adder principle, where cells add a fixed size (volume) from birth to division, irrespective of their size at birth. To mechanistically explain the adder principle, we consider a timekeeper protein that begins to get stochastically expressed after cell birth at a rate proportional to the volume. Cell-division time is formulated as the first-passage time for protein copy numbers to hit a fixed threshold. Consistent with data, the model predicts that the noise in division timing increases with size at birth. Intriguingly, our results show that the distribution of the volume added between successive cell-division events is independent of the newborn cell size. This was dramatically seen in experimental studies, where histograms of the added volume corresponding to different newborn sizes collapsed on top of each other. The model provides further insights consistent with experimental observations: the distribution of the added volume when scaled by its mean becomes invariant of the growth rate. In summary, our simple yet elegant model explains key experimental findings and suggests a mechanism for regulating both the mean and fluctuations in cell-division timing for controlling size. PMID:27456660

  4. Mechanistic insight into mycobacterial MmpL protein function.

    PubMed

    Székely, R; Cole, S T

    2016-03-01

    Mycobacterial cell walls are complex structures containing a broad range of unusual lipids, glycolipids and other polymers, some of which act as immunomodulators or virulence determinants. Better understanding of the enzymes involved in export processes would enlighten cell wall biogenesis. Bernut et al. () present the findings of a structural and functional investigation of one of the most important transporter families, the MmpL proteins, members of the resistance-nodulation-cell division (RND) superfamily. A Tyr842His missense mutation in the mmpL4a gene was shown to be responsible for the smooth-to-rough morphotype change of the near untreatable opportunistic pathogen Mycobacterium bolletii due to its failure to export a glycopeptidolipid (GPL). This mutation was pleiotropic and markedly increased virulence in infection models. Tyr842 is well conserved in all actinobacterial MmpL proteins suggesting that it is functionally important and this was confirmed by several approaches including replacing the corresponding residue in MmpL3 of Mycobacterium tuberculosis. Structural modelling combined with experimental results showed Tyr842 to be a critical residue for mediating the proton motive force required for GPL export. This mechanistic insight applies to all MmpL proteins and probably to all RND transporters. PMID:26710752

  5. Water in Photosystem II: structural, functional and mechanistic considerations.

    PubMed

    Linke, Katrin; Ho, Felix M

    2014-01-01

    Water is clearly important for the functioning of Photosystem II (PSII). Apart from being the very substrate that needs to be transported in this water oxidation enzyme, water is also vital for the transport of protons to and from the catalytic center as well as other important co-factors and key residues in the enzyme. The latest crystal structural data of PSII have enabled detailed analyses of the location and possible function of water molecules in the enzyme. Significant progress has also been made recently in the investigation of channels and pathways through the protein complex. Through these studies, the mechanistic significance of water for PSII is becoming increasingly clear. An overview and discussion of key aspects of the current research on water in PSII is presented here. The role of water in three other systems (aquaporin, bacteriorhodopsin and cytochrome P450) is also outlined to illustrate further points concerning the central significance that water can have, and potential applications of these ideas for continued research on PSII. It is advocated that water be seen as an integral part of the protein and far from a mere solvent. PMID:23978393

  6. Mechanistic Studies in Friction and Wear of Bulk Materials

    NASA Astrophysics Data System (ADS)

    Sawyer, W. Gregory; Argibay, Nicolas; Burris, David L.; Krick, Brandon A.

    2014-07-01

    From the context of a contemporary understanding of the phenomenological origins of friction and wear of materials, we review insightful contributions from recent experimental investigations of three classes of materials that exhibit uniquely contrasting tribological behaviors: metals, polymers, and ionic solids. We focus on the past decade of research by the community to better understand the correlations between environment parameters, materials properties, and tribological behavior in systems of increasingly greater complexity utilizing novel synthesis and in situ experimental techniques. In addition to such review, and a half-century after seminal publications on the subject, we present recently acquired evidence linking anisotropy in friction response with anisotropy in wear behavior of crystalline ionic solids as a function of crystallographic orientation. Although the tribological behaviors of metals, polymers, and ionic solids differ widely, it is increasingly more evident that the mechanistic origins (such as fatigue, corrosion, abrasion, and adhesion) are essentially the same. However, we hope to present a clear and compelling argument favoring the prominent and irreplaceable role of in situ experimental techniques as a bridge between fundamental atomistic and molecular processes and emergent behaviors governing tribological contacts.

  7. A global scale mechanistic model of the photosynthetic capacity

    NASA Astrophysics Data System (ADS)

    Xu, C.; Ali, A. A.; Fisher, R.; Wullschleger, S. D.; Rogers, A.; McDowell, N. G.; Wilson, C. J.

    2015-12-01

    Although plant photosynthetic capacity as determined by the maximum carboxylation rate (i.e., Vc,max25) and the maximum electron transport rate (i.e., Jmax25) at a reference temperature (generally 25oC) is known to vary substantially in space and time in response to environmental conditions, it is typically parameterized in Earth system models (ESMs) with tabulated values associated to plant functional types. In this study, we developed a mechanistic model of leaf utilization of nitrogen for assimilation (LUNA V1.0) to predict the photosynthetic capacity at the global scale under different environmental conditions, based on the optimization of nitrogen allocated among light capture, electron transport, carboxylation, and respiration. The LUNA model was able to reasonably well capture the observed patterns of photosynthetic capacity in view that it explained approximately 55% of the variation in observed Vc,max25 and 65% of the variation in observed Jmax25 across the globe. Our model simulations under current and future climate conditions indicated that Vc,max25 could be most affected in high-latitude regions under a warming climate and that ESMs using a fixed Vc,max25 or Jmax25 by plant functional types were likely to substantially overestimate future global photosynthesis.

  8. Mechanistic evaluation of virus clearance by depth filtration.

    PubMed

    Venkiteshwaran, Adith; Fogle, Jace; Patnaik, Purbasa; Kowle, Ron; Chen, Dayue

    2015-01-01

    Virus clearance by depth filtration has not been well-understood mechanistically due to lack of quantitative data on filter charge characteristics and absence of systematic studies. It is generally believed that both electrostatic interactions and sized based mechanical entrapment contribute to virus clearance by depth filtration. In order to establish whether the effectiveness of virus clearance correlates with the charge characteristics of a given depth filter, a counter-ion displacement technique was employed to determine the ionic capacity for several depth filters. Two depth filters (Millipore B1HC and X0HC) with significant differences in ionic capacities were selected and evaluated for their ability to eliminate viruses. The high ionic capacity X0HC filter showed complete porcine parvovirus (PPV) clearance (eliminating the spiked viruses to below the limit of detection) under low conductivity conditions (≤2.5 mS/cm), achieving a log10 reduction factor (LRF) of > 4.8. On the other hand, the low ionic capacity B1HC filter achieved only ∼2.1-3.0 LRF of PPV clearance under the same conditions. These results indicate that parvovirus clearance by these two depth filters are mainly achieved via electrostatic interactions between the filters and PPV. When much larger xenotropic murine leukemia virus (XMuLV) was used as the model virus, complete retrovirus clearance was obtained under all conditions evaluated for both depth filters, suggesting the involvement of mechanisms other than just electrostatic interactions in XMuLV clearance. PMID:25683459

  9. Stem cell guidance through the mechanistic target of rapamycin

    PubMed Central

    Maiese, Kenneth

    2015-01-01

    Stem cells offer great promise for the treatment of multiple disorders throughout the body. Critical to this premise is the ability to govern stem cell pluripotency, proliferation, and differentiation. The mechanistic target of rapamycin (mTOR), 289-kDa serine/threonine protein kinase, that is a vital component of mTOR Complex 1 and mTOR Complex 2 represents a critical pathway for the oversight of stem cell maintenance. mTOR can control the programmed cell death pathways of autophagy and apoptosis that can yield variable outcomes in stem cell survival and be reliant upon proliferative pathways that include Wnt signaling, Wnt1 inducible signaling pathway protein 1 (WISP1), silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), and trophic factors. mTOR also is a necessary component for the early development and establishment of stem cells as well as having a significant impact in the regulation of the maturation of specific cell phenotypes. Yet, as a proliferative agent, mTOR can not only foster cancer stem cell development and tumorigenesis, but also mediate cell senescence under certain conditions to limit invasive cancer growth. mTOR offers an exciting target for the oversight of stem cell therapies but requires careful consideration of the diverse clinical outcomes that can be fueled by mTOR signaling pathways. PMID:26328016

  10. A Mechanistic Stochastic Ricker Model: Analytical and Numerical Investigations

    NASA Astrophysics Data System (ADS)

    Gadrich, Tamar; Katriel, Guy

    The Ricker model is one of the simplest and most widely-used ecological models displaying complex nonlinear dynamics. We study a discrete-time population model, which is derived from simple assumptions concerning individual organisms’ behavior, using the “site-based” approach, developed by Brännström, Broomhead, Johansson and Sumpter. In the large-population limit the model converges to the Ricker model, and can thus be considered a mechanistic version of the Ricker model, derived from basic ecological principles, and taking into account the demographic stochasticity inherent to finite populations. We employ several analytical and precise numerical methods to study the model, showing how each approach contributes to understanding the model’s dynamics. Expressing the model as a Markov chain, we employ the concept of quasi-stationary distributions, which are computed numerically, and used to examine the interaction between complex deterministic dynamics and demographic stochasticity, as well as to calculate mean times to extinction. A Gaussian Markov chain approximation is used to obtain quantitative asymptotic approximations for the size of fluctuations of the stochastic model’s time series around the deterministic trajectory, and for the correlations between successive fluctuations. Results of these approximations are compared to results obtained from quasi-stationary distributions and from direct simulations, and are shown to be in good agreement.

  11. Mechanistic Perspectives of Maslinic Acid in Targeting Inflammation

    PubMed Central

    Yap, Wei Hsum; Lim, Yang Mooi

    2015-01-01

    Chronic inflammation drives the development of various pathological diseases such as rheumatoid arthritis, atherosclerosis, multiple sclerosis, and cancer. The arachidonic acid pathway represents one of the major mechanisms for inflammation. Prostaglandins (PGs) are lipid products generated from arachidonic acid by the action of cyclooxygenase (COX) enzymes and their activity is blocked by nonsteroidal anti-inflammatory drugs (NSAIDS). The use of natural compounds in regulation of COX activity/prostaglandins production is receiving increasing attention. In Mediterranean diet, olive oil and table olives contain significant dietary sources of maslinic acid. Maslinic acid is arising as a safe and novel natural pentacyclic triterpene which has protective effects against chronic inflammatory diseases in various in vivo and in vitro experimental models. Understanding the anti-inflammatory mechanism of maslinic acid is crucial for its development as a potential dietary nutraceutical. This review focuses on the mechanistic action of maslinic acid in regulating the inflammation pathways through modulation of the arachidonic acid metabolism including the nuclear factor-kappa B (NF-κB)/COX-2 expression, upstream protein kinase signaling, and phospholipase A2 enzyme activity. Further investigations may provide insight into the mechanism of maslinic acid in regulating the molecular targets and their associated pathways in response to specific inflammatory stimuli. PMID:26491566

  12. A mechanistic stochastic framework for regulating bacterial cell division.

    PubMed

    Ghusinga, Khem Raj; Vargas-Garcia, Cesar A; Singh, Abhyudai

    2016-01-01

    How exponentially growing cells maintain size homeostasis is an important fundamental problem. Recent single-cell studies in prokaryotes have uncovered the adder principle, where cells add a fixed size (volume) from birth to division, irrespective of their size at birth. To mechanistically explain the adder principle, we consider a timekeeper protein that begins to get stochastically expressed after cell birth at a rate proportional to the volume. Cell-division time is formulated as the first-passage time for protein copy numbers to hit a fixed threshold. Consistent with data, the model predicts that the noise in division timing increases with size at birth. Intriguingly, our results show that the distribution of the volume added between successive cell-division events is independent of the newborn cell size. This was dramatically seen in experimental studies, where histograms of the added volume corresponding to different newborn sizes collapsed on top of each other. The model provides further insights consistent with experimental observations: the distribution of the added volume when scaled by its mean becomes invariant of the growth rate. In summary, our simple yet elegant model explains key experimental findings and suggests a mechanism for regulating both the mean and fluctuations in cell-division timing for controlling size. PMID:27456660

  13. Multiscale mechanistic modeling in pharmaceutical research and development.

    PubMed

    Kuepfer, Lars; Lippert, Jörg; Eissing, Thomas

    2012-01-01

    Discontinuation of drug development projects due to lack of efficacy or adverse events is one of the main cost drivers in pharmaceutical research and development (R&D). Investments have to be written-off and contribute to the total costs of a successful drug candidate receiving marketing authorization and allowing return on invest. A vital risk for pharmaceutical innovator companies is late stage clinical failure since costs for individual clinical trials may exceed the one billion Euro threshold. To guide investment decisions and to safeguard maximum medical benefit and safety for patients recruited in clinical trials, it is therefore essential to understand the clinical consequences of all information and data generated. The complexity of the physiological and pathophysiological processes and the sheer amount of information available overcharge the mental capacity of any human being and prevent a prediction of the success in clinical development. A rigorous integration of knowledge, assumption, and experimental data into computational models promises a significant improvement of the rationalization of decision making in pharmaceutical industry. We here give an overview of the current status of modeling and simulation in pharmaceutical R&D and outline the perspectives of more recent developments in mechanistic modeling. Specific modeling approaches for different biological scales ranging from intracellular processes to whole organism physiology are introduced and an example for integrative multiscale modeling of therapeutic efficiency in clinical oncology trials is showcased. PMID:22161351

  14. Microneedle/nanoencapsulation-mediated transdermal delivery: Mechanistic insights

    PubMed Central

    Gomaa, Yasmine A.; Garland, Martin J.; McInnes, Fiona J.; Donnelly, Ryan F.; El-Khordagui, Labiba K.; Wilson, Clive G.

    2014-01-01

    A systematic study was undertaken to gain more insight into the mechanism of transdermal delivery of nanoencapsulated model dyes across microneedle (MN)-treated skin, a complex process not yet explored. Rhodamine B (Rh B) and fluorescein isothiocyanate (FITC) as model hydrophilic and hydrophobic small/medium-size molecules, respectively, were encapsulated in poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) and delivered through full thickness porcine skin pretreated with MN array. Permeation through MN-treated skin was affected by physicochemical characteristics of NPs and the encapsulated dyes. Dye flux was enhanced by smaller particle size, hydrophilicity, and negative zeta potential of NPs. Regarding encapsulated dyes, solubility at physiological pH and potential interaction with skin proteins proved to outweigh molecular weight as determinants of skin permeation. Data were verified using confocal laser scanning microscopy imaging. Findings coupled with the literature data are supportive of a mechanism involving influx of NPs, particularly of smaller size, deep into MN-created channels, generating depot dye-rich reservoirs. Molecular diffusion of the released dye across viable skin layers proceeds at a rate determined by its molecular characteristics. Data obtained provide mechanistic information of importance to the development of formulation strategies for more effective intradermal and transdermal MN-mediated delivery of nanoencapsulated therapeutic agents. PMID:23461860

  15. Equation-free mechanistic ecosystem forecasting using empirical dynamic modeling.

    PubMed

    Ye, Hao; Beamish, Richard J; Glaser, Sarah M; Grant, Sue C H; Hsieh, Chih-Hao; Richards, Laura J; Schnute, Jon T; Sugihara, George

    2015-03-31

    It is well known that current equilibrium-based models fall short as predictive descriptions of natural ecosystems, and particularly of fisheries systems that exhibit nonlinear dynamics. For example, model parameters assumed to be fixed constants may actually vary in time, models may fit well to existing data but lack out-of-sample predictive skill, and key driving variables may be misidentified due to transient (mirage) correlations that are common in nonlinear systems. With these frailties, it is somewhat surprising that static equilibrium models continue to be widely used. Here, we examine empirical dynamic modeling (EDM) as an alternative to imposed model equations and that accommodates both nonequilibrium dynamics and nonlinearity. Using time series from nine stocks of sockeye salmon (Oncorhynchus nerka) from the Fraser River system in British Columbia, Canada, we perform, for the the first time to our knowledge, real-data comparison of contemporary fisheries models with equivalent EDM formulations that explicitly use spawning stock and environmental variables to forecast recruitment. We find that EDM models produce more accurate and precise forecasts, and unlike extensions of the classic Ricker spawner-recruit equation, they show significant improvements when environmental factors are included. Our analysis demonstrates the strategic utility of EDM for incorporating environmental influences into fisheries forecasts and, more generally, for providing insight into how environmental factors can operate in forecast models, thus paving the way for equation-free mechanistic forecasting to be applied in management contexts. PMID:25733874

  16. Anti-fibro-hepatocarcinogenic Chinese herbal medicines: A mechanistic overview

    PubMed Central

    Boye, Alex; Yang, Yan; Asenso, James; Wei, Wei

    2016-01-01

    Chinese herbal medicine (CHM) is an integral component of complementary/alternative medicine and it is increasingly becoming the preferred therapeutic modality for the treatment of liver fibrosis and hepatocellular carcinoma (HCC) worldwide. Accordingly, the World Health Organization (WHO) has attested to the popularity and efficacy of indigenous herbal therapies including CHM as a first line of treatment for some diseases including liver disorders. However, the WHO and drug discovery experts have always recommended that use of indigenous herbal remedies must go hand-in-hand with the requisite mechanistic elucidation so as to constitute a system of verification of efficacy within the ethnobotanical context of use. Although many CHM experts have advanced knowledge on CHM, nonetheless, more enlightenment is needed, particularly mechanisms of action of CHMs on fibro-hepato-carcinogenesis. We, herein, provide in-depth mechanisms of the action of CHMs which have demonstrated anti-fibro-hepatocarcinogenic effects, in pre-clinical and clinical studies as published in PubMed and other major scientific databases. Specifically, the review brings out the important signaling pathways, and their downstream targets which are modulated at multi-level by various anti-fibro-hepatocarcinogenic CHMs. PMID:27366355

  17. Mechanistic Differences Leading to Infectious and Sterile Inflammation.

    PubMed

    Behnia, Faranak; Sheller, Samantha; Menon, Ramkumar

    2016-05-01

    Inflammation is a physiologic component of pregnancy and parturition. Overwhelming intrauterine inflammatory load promotes quiescent feto-maternal tissues into a contractile phenotype. Like inflammation, oxidative stress is an inevitable component of both pregnancy and parturition. Pathologic activation of host innate immune response to adverse pregnancy conditions can lead to premature activation of inflammatory and oxidative stress. Inflammation and oxidative stress markers seen with both sterile and infectious inflammation are often similar; therefore, it is difficult to understand causality of conditions like spontaneous preterm birth. This review demonstrates potential mechanistic pathways of activation of sterile and infectious inflammation. We demonstrate the activation of two unique pathways of inflammation by factors that are well-documented proxies for oxidative stress (cigarette smoke extract) and infection (lipopolysaccharide). Sterile inflammation seen after exposure to an oxidative stress inducer is due to cellular elemental damage resulting in p38 mitogen-activated protein kinase (MAPK) induced cellular senescence. Infectious inflammation is through activation of transcription factor NF-κB and independent of oxidative stress-associated damages and p38 MAPK-induced senescence. Understanding the differences in the inflammatory pathway activation by various risk factors is important to design better screening, diagnostic and intervention strategies to reduce the risks of adverse pregnancy outcomes. PMID:26840942

  18. Mechanistic aspects of photooxidation of polyhydroxylated molecules on metal oxides.

    SciTech Connect

    Shkrob, I. A.; Marin, T. M.; Sevilla, M. D.; Chemerisov, S.

    2011-03-24

    Polyhydroxylated molecules, including natural carbohydrates, are known to undergo photooxidation on wide-gap transition-metal oxides irradiated by ultraviolet light. In this study, we examine mechanistic aspects of this photoreaction on aqueous TiO{sub 2}, {alpha}-FeOOH, and {alpha}-Fe{sub 2}O{sub 3} particles using electron paramagnetic resonance (EPR) spectroscopy and site-selective deuteration. We demonstrate that the carbohydrates are oxidized at sites involved in the formation of oxo bridges between the chemisorbed carbohydrate molecule and metal ions at the oxide surface. This bridging inhibits the loss of water (which is the typical reaction of the analogous free radicals in bulk solvent) promoting instead a rearrangement that leads to elimination of the formyl radical. For natural carbohydrates, the latter reaction mainly involves carbon-1, whereas the main radical products of the oxidation are radical arising from H atom loss centered on carbon-1, -2, and -3 sites. Photoexcited TiO{sub 2} oxidizes all of the carbohydrates and polyols, whereas {alpha}-FeOOH oxidizes some of the carbohydrates, and {alpha}-Fe{sub 2}O{sub 3} is unreactive. These results serve as a stepping stone for understanding the photochemistry on mineral surfaces of more complex biomolecules such as nucleic acids.

  19. Thermal hydrogen-atom transfer from methane: A mechanistic exercise

    NASA Astrophysics Data System (ADS)

    Schwarz, Helmut

    2015-06-01

    Hydrogen-atom transfer (HAT) constitutes a key process in a broad range of chemical transformations as it covers heterogeneous, homogeneous, and enzymatic reactions. While open-shell metal oxo species [MO]rad are no longer regarded as being involved in the heterogeneously catalyzed oxidative coupling of methane (2CH4 + → C2H6 + H2O), these reagents are rather versatile in bringing about (gas-phase) hydrogen-atom transfer, even from methane at ambient conditions. In this mini-review, various mechanistic scenarios will be presented, and it will be demonstrated how these are affected by the composition of the metal-oxide cluster ions. Examples will be discussed, how 'doping' the clusters permits the control of the charge and spin situation at the active site and, thus, the course of the reaction. Also, the interplay between supposedly inert support material and the active site - the so-called 'aristocratic atoms' - of the gas-phase catalyst will be addressed. Finally, gas-phase HAT from methane will be analyzed in the broader context of thermal activation of inert Csbnd H bonds by metal-oxo species.

  20. A mechanistic model for permeability evolution in fractured sorbing media

    NASA Astrophysics Data System (ADS)

    Wang, Shugang; Elsworth, Derek; Liu, Jishan

    2012-06-01

    A mechanistic model is presented to represent the evolution of permeability in fractured sorbing media such as coal beds and organic-rich shales. This model accommodates key competing processes of poromechanical dilation and sorption-induced swelling. We show that the significant difference in stiffness between fracture and matrix transforms the composite system from globally unconstrained to locally constrained by the development of a virtual "stiff shell" that envelops the perimeter of a representative elementary volume containing a fracture. It is this transformation that results in swelling-induced permeability reduction at low (sorbing) gas pressures and self consistently allows competitive dilation of the fracture as gas pressures are increased. Importantly, net dilation is shown to require a mismatch in the Biot coefficients of fracture and matrix with the coefficient for the fracture exceeding that for the matrix—a condition that is logically met. Permeability evolution is cast in terms of series and parallel models with the series model better replicating observational data. The model may be cast in terms of nondimensional parameters representing sorptive and poromechanical effects and modulated by the sensitivity of the fracture network to dilation or compaction of the individual fractures. This latter parameter encapsulates the effects of fracture spacing and initial permeability and scale changes in permeability driven by either sorption or poromechanical effects. This model is applied to well-controlled observational data for different ranks of coals and different gases (He, CO2) and satisfactory agreement is obtained.

  1. The road to advanced glycation end products: a mechanistic perspective.

    PubMed

    Cho, S-J; Roman, G; Yeboah, F; Konishi, Y

    2007-01-01

    Protein glycation is a slow natural process involving the chemical modification of the reactive amino and guanidine functions in amino acids by sugars and carbohydrates-derived reactive carbonyls. Its deleterious consequences are obvious in the case of long-lived proteins in aged people and are exacerbated by the high blood concentration of sugars in diabetic patients. The non-enzymatic glycation of proteins occurs through a wide range of concurrent processes comprising condensation, rearrangement, fragmentation, and oxidation reactions. Using a few well established intermediates such as Schiff base, Amadori product and reactive a-dicarbonyls as milestones and the results of in vitro glycation investigations, an overall detailed mechanistic analysis of protein glycation is presented for the first time. The pathways leading to several advanced glycation end products (AGEs) such as (carboxymethyl)lysine, pentosidine, and glucosepane are outlined, whereas other AGEs useful as potential biomarkers of glycation are only briefly mentioned. The current stage of the development of glycation inhibitors has been reviewed with an emphasis on their mechanism of action. PMID:17584071

  2. Patent profiles

    SciTech Connect

    Not Available

    1980-01-01

    This report presents profiles of US patents in the area of solar energy technology, and in the related areas of wind, geothermal and tide and wave energy. Each profile is divided into three parts. The first part identifies the area which is examined, lists the pertinent US Patent Classification(s), and graphically illustrates patent activity across a designated 10-year span. The second part tabulates the data upon which the graphs of the first part were based, provides a list of assignees for the period 1969 to 1978 both by the number of patents and alphabetically, and presents on alphabetical listing of inventors of unassigned patents. The third part updates the preceding material for the period January-October 1979. (SPH)

  3. A mechanistic accounting of SOM speciation and kinetics in soils

    NASA Astrophysics Data System (ADS)

    Maggi, F.; Riley, W. J.; Guerry, N.; Torn, M. S.; Kleber, M.

    2012-12-01

    The nature and dynamics of soil organic matter (SOM) are arguably far from being understood and accurately represented in current site, regional, and global land use and climate models. Whereas consolidated models make use of aggregated pools describing SOM with characteristic turnover times such as inert, passive, slow cycling, and fast cycling, or linking the turnover time to the molecular weight of the compound, recent analyses of SOM below the top soil suggest that those approaches only partially capture SOM dynamics, and that SOM stability may largely be determined by biological and chemical protection as well as other environmental factors rather than the molecular structure of the compound and its molecular weight. We introduce here a new paradigm of SOM speciation and kinetics that explicitly decouples the assumed recalcitrance and turnover time from the SOM molecular density and structure in favour of a mechanistic accounting of microbially mediated processes and chemo-physical interactions among the various SOM species and soil environment. These processes include microbial assimilation, respiration and C recycling; depolymerization of solid litter, root exudates, and dead cells into various decomposed SOM groups; and incorporation of soluble SOM species into a protected phase not available to chemical and biological agents. SOM was described by means of functional compounds including mono- and polysaccharides, lignin, amino compounds, organic acids, nucleic acids, lipids, and phenols, each being accounted for by one or more representative species in the model. Fungal and bacterial microbial functional groups were used to characterize depolymerization and respiration rates. The SOM reaction network and characteristics, its mathematical inclusion within the TOUGHREACT framework, and some preliminary results of modeling grasslands and forested ecosystems are presented here. Biogeochemical reaction network of SOC pathways. Steady state vertical contentration

  4. Conceptualising population health: from mechanistic thinking to complexity science

    PubMed Central

    2011-01-01

    The mechanistic interpretation of reality can be traced to the influential work by René Descartes and Sir Isaac Newton. Their theories were able to accurately predict most physical phenomena relating to motion, optics and gravity. This paradigm had at least three principles and approaches: reductionism, linearity and hierarchy. These ideas appear to have influenced social scientists and the discourse on population health. In contrast, Complexity Science takes a more holistic view of systems. It views natural systems as being 'open', with fuzzy borders, constantly adapting to cope with pressures from the environment. These are called Complex Adaptive Systems (CAS). The sub-systems within it lack stable hierarchies, and the roles of agency keep changing. The interactions with the environment and among sub-systems are non-linear interactions and lead to self-organisation and emergent properties. Theoretical frameworks such as epi+demos+cracy and the ecosocial approach to health have implicitly used some of these concepts of interacting dynamic sub-systems. Using Complexity Science we can view population health outcomes as an emergent property of CAS, which has numerous dynamic non-linear interactions among its interconnected sub-systems or agents. In order to appreciate these sub-systems and determinants, one should acquire a basic knowledge of diverse disciplines and interact with experts from different disciplines. Strategies to improve health should be multi-pronged, and take into account the diversity of actors, determinants and contexts. The dynamic nature of the system requires that the interventions are constantly monitored to provide early feedback to a flexible system that takes quick corrections. PMID:21247500

  5. Toward a mechanistic understanding and prediction of biotic homogenization.

    PubMed

    Olden, Julian D; Poff, N LeRoy

    2003-10-01

    The widespread replacement of native species with cosmopolitan, nonnative species is homogenizing the global fauna and flora. While the empirical study of biotic homogenization is substantial and growing, theoretical aspects have yet to be explored. Consequently, the breadth of possible ecological mechanisms that can shape current and future patterns and rates of homogenization remain largely unknown. Here, we develop a conceptual model that describes 14 potential scenarios by which species invasions and/or extinctions can lead to various trajectories of biotic homogenization (increased community similarity) or differentiation (decreased community similarity); we then use a simulation approach to explore the model's predictions. We found changes in community similarity to vary with the type and number of nonnative and native species, the historical degree of similarity among the communities, and, to a lesser degree, the richness of the recipient communities. Homogenization is greatest when similar species invade communities, causing either no extinction or differential extinction of native species. The model predictions are consistent with current empirical data for fish, bird, and plant communities and therefore may represent the dominant mechanisms of contemporary homogenization. We present a unifying model illustrating how the balance between invading and extinct species dictates the outcome of biotic homogenization. We conclude by discussing a number of critical but largely unrecognized issues that bear on the empirical study of biotic homogenization, including the importance of spatial scale, temporal scale, and data resolution. We argue that the study of biotic homogenization needs to be placed in a more mechanistic and predictive framework in order for studies to provide adequate guidance in conservation efforts to maintain regional distinctness of the global biota. PMID:14582007

  6. Toward a mechanistic modeling of nitrogen limitation on vegetation dynamics

    SciTech Connect

    Xu, Chonggang; Fisher, Rosie; Wullschleger, Stan D; Wilson, Cathy; Cai, Michael; McDowell, Nathan

    2012-01-01

    Nitrogen is a dominant regulator of vegetation dynamics, net primary production, and terrestrial carbon cycles; however, most ecosystem models use a rather simplistic relationship between leaf nitrogen content and photosynthetic capacity. Such an approach does not consider how patterns of nitrogen allocation may change with differences in light intensity, growing-season temperature and CO{sub 2} concentration. To account for this known variability in nitrogen-photosynthesis relationships, we develop a mechanistic nitrogen allocation model based on a trade-off of nitrogen allocated between growth and storage, and an optimization of nitrogen allocated among light capture, electron transport, carboxylation, and respiration. The developed model is able to predict the acclimation of photosynthetic capacity to changes in CO{sub 2} concentration, temperature, and radiation when evaluated against published data of V{sub c,max} (maximum carboxylation rate) and J{sub max} (maximum electron transport rate). A sensitivity analysis of the model for herbaceous plants, deciduous and evergreen trees implies that elevated CO{sub 2} concentrations lead to lower allocation of nitrogen to carboxylation but higher allocation to storage. Higher growing-season temperatures cause lower allocation of nitrogen to carboxylation, due to higher nitrogen requirements for light capture pigments and for storage. Lower levels of radiation have a much stronger effect on allocation of nitrogen to carboxylation for herbaceous plants than for trees, resulting from higher nitrogen requirements for light capture for herbaceous plants. As far as we know, this is the first model of complete nitrogen allocation that simultaneously considers nitrogen allocation to light capture, electron transport, carboxylation, respiration and storage, and the responses of each to altered environmental conditions. We expect this model could potentially improve our confidence in simulations of carbon-nitrogen interactions

  7. Mechanistic analysis of cavitation assisted transesterification on biodiesel characteristics.

    PubMed

    Sajjadi, Baharak; Abdul Aziz, A R; Ibrahim, Shaliza

    2015-01-01

    The influence of sonoluminescence transesterification on biodiesel physicochemical properties was investigated and the results were compared to those of traditional mechanical stirring. This study was conducted to identify the mechanistic features of ultrasonication by coupling statistical analysis of the experiments into the simulation of cavitation bubble. Different combinations of operational variables were employed for alkali-catalysis transesterification of palm oil. The experimental results showed that transesterification with ultrasound irradiation could change the biodiesel density by about 0.3kg/m(3); the viscosity by 0.12mm(2)/s; the pour point by about 1-2°C and the flash point by 5°C compared to the traditional method. Furthermore, 93.84% of yield with alcohol to oil molar ratio of 6:1 could be achieved through ultrasound assisted transesterification within only 20min. However, only 89.09% of reaction yield was obtained by traditional macro mixing/heating under the same condition. Based on the simulated oscillation velocity value, the cavitation phenomenon significantly contributed to generation of fine micro emulsion and was able to overcome mass transfer restriction. It was found that the sonoluminescence bubbles reached the temperature of 758-713K, pressure of 235.5-159.55bar, oscillation velocity of 3.5-6.5cm/s, and equilibrium radius of 17.9-13.7 times greater than its initial size under the ambient temperature of 50-64°C at the moment of collapse. This showed that the sonoluminescence bubbles were in the condition in which the decomposition phenomena were activated and the reaction rate was accelerated together with a change in the biodiesel properties. PMID:24981808

  8. Two Mechanistic Pathways for Thienopyridine-Associated Thrombotic Thrombocytopenic Purpura

    PubMed Central

    Bennett, Charles L.; Kim, Benjamin; Zakarija, Anaadriana; Bandarenko, Nicholas; Pandey, Dilip K.; Buffie, Charlie G.; McKoy, June M.; Tevar, Amul D.; Cursio, John F.; Yarnold, Paul R.; Kwaan, Hau C.; De Masi, Davide; Sarode, Ravindra; Raife, Thomas J.; Kiss, Joseph E.; Raisch, Dennis W.; Davidson, Charles; Sadler, J. Evan; Ortel, Thomas L.; Zheng, X. Long; Kato, Seiji; Matsumoto, Masanori; Uemura, Masahito; Fujimura, Yoshihiro

    2011-01-01

    Objectives We sought to describe clinical and laboratory findings for a large cohort of patients with thienopyridine-associated thrombotic thrombocytopenic purpura (TTP). Background The thienopyridine derivatives, ticlopidine and clopidogrel, are the 2 most common drugs associated with TTP in databases maintained by the U.S. Food and Drug Administration (FDA). Methods Clinical reports of TTP associated with clopidogrel and ticlopidine were identified from medical records, published case reports, and FDA case reports (n = 128). Duration of thienopyridine exposure, clinical and laboratory findings, and survival were recorded. ADAMTS13 activity (n = 39) and inhibitor (n = 30) were measured for a subset of individuals. Results Compared with clopidogrel-associated TTP cases (n = 35), ticlopidine-associated TTP cases (n = 93) were more likely to have received more than 2 weeks of drug (90% vs. 26%), to be severely thrombocytopenic (84% vs. 60%), and to have normal renal function (72% vs. 45%) (p < 0.01 for each). Compared with TTP patients with ADAMTS13 activity >15% (n = 13), TTP patients with severely deficient ADAMTS13 activity (n = 26) were more likely to have received ticlopidine (92.3% vs. 46.2%, p < 0.003). Among patients who developed TTP >2 weeks after thienopyridine, therapeutic plasma exchange (TPE) increased likelihood of survival (84% vs. 38%, p < 0.05). Among patients who developed TTP within 2 weeks of starting thienopyridines, survival was 77% with TPE and 78% without. Conclusions Thrombotic thrombocytopenic purpura is a rare complication of thienopyridine treatment. This drug toxicity appears to occur by 2 different mechanistic pathways, characterized primarily by time of onset before versus after 2 weeks of thienopyridine administration. If TTP occurs after 2 weeks of ticlopidine or clopidogrel therapy, therapeutic plasma exchange must be promptly instituted to enhance likelihood of survival. PMID:17868804

  9. The attention schema theory: a mechanistic account of subjective awareness

    PubMed Central

    Graziano, Michael S. A.; Webb, Taylor W.

    2015-01-01

    We recently proposed the attention schema theory, a novel way to explain the brain basis of subjective awareness in a mechanistic and scientifically testable manner. The theory begins with attention, the process by which signals compete for the brain’s limited computing resources. This internal signal competition is partly under a bottom–up influence and partly under top–down control. We propose that the top–down control of attention is improved when the brain has access to a simplified model of attention itself. The brain therefore constructs a schematic model of the process of attention, the ‘attention schema,’ in much the same way that it constructs a schematic model of the body, the ‘body schema.’ The content of this internal model leads a brain to conclude that it has a subjective experience. One advantage of this theory is that it explains how awareness and attention can sometimes become dissociated; the brain’s internal models are never perfect, and sometimes a model becomes dissociated from the object being modeled. A second advantage of this theory is that it explains how we can be aware of both internal and external events. The brain can apply attention to many types of information including external sensory information and internal information about emotions and cognitive states. If awareness is a model of attention, then this model should pertain to the same domains of information to which attention pertains. A third advantage of this theory is that it provides testable predictions. If awareness is the internal model of attention, used to help control attention, then without awareness, attention should still be possible but should suffer deficits in control. In this article, we review the existing literature on the relationship between attention and awareness, and suggest that at least some of the predictions of the theory are borne out by the evidence. PMID:25954242

  10. The ecological impacts of nighttime light pollution: a mechanistic appraisal.

    PubMed

    Gaston, Kevin J; Bennie, Jonathan; Davies, Thomas W; Hopkins, John

    2013-11-01

    The ecological impacts of nighttime light pollution have been a longstanding source of concern, accentuated by realized and projected growth in electrical lighting. As human communities and lighting technologies develop, artificial light increasingly modifies natural light regimes by encroaching on dark refuges in space, in time, and across wavelengths. A wide variety of ecological implications of artificial light have been identified. However, the primary research to date is largely focused on the disruptive influence of nighttime light on higher vertebrates, and while comprehensive reviews have been compiled along taxonomic lines and within specific research domains, the subject is in need of synthesis within a common mechanistic framework. Here we propose such a framework that focuses on the cross-factoring of the ways in which artificial lighting alters natural light regimes (spatially, temporally, and spectrally), and the ways in which light influences biological systems, particularly the distinction between light as a resource and light as an information source. We review the evidence for each of the combinations of this cross-factoring. As artificial lighting alters natural patterns of light in space, time and across wavelengths, natural patterns of resource use and information flows may be disrupted, with downstream effects to the structure and function of ecosystems. This review highlights: (i) the potential influence of nighttime lighting at all levels of biological organisation (from cell to ecosystem); (ii) the significant impact that even low levels of nighttime light pollution can have; and (iii) the existence of major research gaps, particularly in terms of the impacts of light at population and ecosystem levels, identification of intensity thresholds, and the spatial extent of impacts in the vicinity of artificial lights. PMID:23565807

  11. Mechanistic Study of Plasma Damage of Low k Dielectric Surfaces

    SciTech Connect

    Bao Junjing; Shi Hualiang; Huang Huai; Ho, P. S.; Liu Junjun; Goodner, M. D.; Moinpour, M.; Kloster, G. M.

    2007-10-31

    Plasma damage to low k dielectric materials was investigated from a mechanistic point of view. Low k dielectric films were treated by plasma Ar, O{sub 2}, N{sub 2}/H{sub 2}, N{sub 2} and H{sub 2} in a standard RIE chamber and the damage was characterized by Angle Resolved X-ray Photoelectron Spectroscopy (ARXPS), X-Ray Reflectivity (XRR), Fourier Transform Infrared Spectroscopy (FTIR) and Contact Angle measurements. Both carbon depletion and surface densification were observed on the top surface of damaged low k materials while the bulk remained largely unaffected. Plasma damage was found to be a complicated phenomenon involving both chemical and physical effects, depending on chemical reactivity and the energy and mass of the plasma species. A downstream hybrid plasma source with separate ions and atomic radicals was employed to study their respective roles in the plasma damage process. Ions were found to play a more important role in the plasma damage process. The dielectric constant of low k materials can increase up to 20% due to plasma damage and we attributed this to the removal of the methyl group making the low k surface hydrophilic. Annealing was generally effective in mitigating moisture uptake to restore the k value but the recovery was less complete for higher energy plasmas. Quantum chemistry calculation confirmed that physisorbed water in low k materials induces the largest increase of dipole moments in comparison with changes of surface bonding configurations, and is primarily responsible for the dielectric constant increase.

  12. A Mechanistic Link between Olfaction and Autism Spectrum Disorder

    PubMed Central

    Rozenkrantz, Liron; Zachor, Ditza; Heller, Iris; Plotkin, Anton; Weissbrod, Aharon; Snitz, Kobi; Secundo, Lavi; Sobel, Noam

    2015-01-01

    Summary Internal action models (IAMs) are brain templates for sensory-motor coordination underlying diverse behaviors [1]. An emerging theory suggests that impaired IAMs are a common theme in autism spectrum disorder (ASD) [2–4]. However, whether impaired IAMs occur across sensory systems and how they relate to the major phenotype of ASD, namely impaired social communication [5], remains unclear. Olfaction relies on an IAM known as the sniff response, where sniff magnitude is automatically modulated to account for odor valence [6–12]. To test the failed IAM theory in olfaction, we precisely measured the non-verbal non-task-dependent sniff response concurrent with pleasant and unpleasant odors in 36 children—18 with ASD and 18 matched typically developing (TD) controls. We found that whereas TD children generated a typical adult-like sniff response within 305 ms of odor onset, ASD children had a profoundly altered sniff response, sniffing equally regardless of odor valance. This difference persisted despite equal reported odor perception and allowed for 81% correct ASD classification based on the sniff response alone (binomial, p < 0.001). Moreover, increasingly aberrant sniffing was associated with increasingly severe ASD (r = −0.75, p < 0.001), specifically with social (r = −0.72, p < 0.001), but not motor (r < −0.38, p > 0.18), impairment. These results uncover a novel ASD marker implying a mechanistic link between the underpinnings of olfaction and ASD and directly linking an impaired IAM with impaired social abilities. PMID:26144969

  13. Radiation induced base excision repair (BER): a mechanistic mathematical approach.

    PubMed

    Rahmanian, Shirin; Taleei, Reza; Nikjoo, Hooshang

    2014-10-01

    This paper presents a mechanistic model of base excision repair (BER) pathway for the repair of single-stand breaks (SSBs) and oxidized base lesions produced by ionizing radiation (IR). The model is based on law of mass action kinetics to translate the biochemical processes involved, step-by-step, in the BER pathway to translate into mathematical equations. The BER is divided into two subpathways, short-patch repair (SPR) and long-patch repair (LPR). SPR involves in replacement of single nucleotide via Pol β and ligation of the ends via XRCC1 and Ligase III, while LPR involves in replacement of multiple nucleotides via PCNA, Pol δ/ɛ and FEN 1, and ligation via Ligase I. A hallmark of IR is the production of closely spaced lesions within a turn of DNA helix (named complex lesions), which have been attributed to a slower repair process. The model presented considers fast and slow component of BER kinetics by assigning SPR for simple lesions and LPR for complex lesions. In the absence of in vivo reaction rate constants for the BER proteins, we have deduced a set of rate constants based on different published experimental measurements including accumulation kinetics obtained from UVA irradiation, overall SSB repair kinetic experiments, and overall BER kinetics from live-cell imaging experiments. The model was further used to calculate the repair kinetics of complex base lesions via the LPR subpathway and compared to foci kinetic experiments for cells irradiated with γ rays, Si, and Fe ions. The model calculation show good agreement with experimental measurements for both overall repair and repair of complex lesions. Furthermore, using the model we explored different mechanisms responsible for inhibition of repair when higher LET and HZE particles are used and concluded that increasing the damage complexity can inhibit initiation of LPR after the AP site removal step in BER. PMID:25117268

  14. A partial mechanistic understanding of the North American monsoon

    NASA Astrophysics Data System (ADS)

    Erfani, Ehsan; Mitchell, David

    2014-12-01

    An understanding of the major governing processes of North American monsoon (NAM) is necessary to guide improvement in global and regional climate modeling of the NAM, as well as NAM's impacts on the summer circulation, precipitation, and drought over North America. A mechanistic understanding of the NAM is suggested by incorporating local- and synoptic-scale processes. The local-scale mechanism describes the effect of the temperature inversion over the Gulf of California (GC) on controlling low-level moisture during the 2004 NAM. The strong low-level inversion inhibits the exchange between the moist air in the marine boundary layer (MBL) and the overlying dry air. This inversion weakens with increasing sea surface temperatures (SSTs) in GC and generally disappears once SSTs exceed 29.5°C, allowing the moist air, trapped in the MBL, to mix with free tropospheric air. This leads to a deep, moist layer that can be transported by across-gulf (along-gulf) flow toward the NAM core region (southwestern U.S.) to form thunderstorms. On the synoptic scale, climatologies from 1983 to 2010 exhibit a temporal correspondence between coastal warm tropical surface water, NAM deep convection, NAM anticyclone center, and NAM-induced strong descent. A hypothesis is proposed to explain this correspondence, based on limited soundings at the GC entrance (suggesting this local mechanism may also be active in that region), the climatologies, and the relevant literature. The warmest SSTs moving up the coast may initiate NAM convection and atmospheric heating, advancing the position of the anticyclone and the region of descent northward.

  15. A mechanistic nitrogen limitation model for CLM(ED)

    NASA Astrophysics Data System (ADS)

    Ali, A. A.; Xu, C.; McDowell, N. G.; Rogers, A.; Wullschleger, S. D.; Fisher, R.; Vrugt, J. A.

    2014-12-01

    Photosynthetic capacity is a key plant trait that determines the rate of photosynthesis; however, in Earth System Models it is either a fixed value or derived from a linear function of leaf nitrogen content. A mechanistic leaf nitrogen allocation model have been developed for a DOE-sponsored Community Land Model coupled to the Ecosystem Demography model (CLM-ED) to predict the photosynthetic capacity [Vc,max25 (μmol CO2 m-2 s-1)] under different environmental conditions at the global scale. We collected more than 800 data points of photosynthetic capacity (Vc,max25) for 124 species from 57 studies with the corresponding leaf nitrogen content and environmental conditions (temperature, radiation, humidity and day length) from literature and the NGEE arctic site (Barrow). Based on the data, we found that environmental control of Vc,max25 is about 4 times stronger than the leaf nitrogen content. Using the Markov-Chain Monte Carlo simulation approach, we fitted the collected data to our newly developed nitrogen allocation model, which predict the leaf nitrogen investment in different components including structure, storage, respiration, light capture, carboxylation and electron transport at different environmental conditions. Our results showed that our nitrogen allocation model explained 52% of variance in observed Vc,max25 and 65% variance in observed Jmax25 using a single set of fitted model parameters for all species. Across the growing season, we found that the modeled Vc,max25 explained 49% of the variability in measured Vc,max25. In the context of future global warming, our model predicts that a temperature increase by 5oC and the doubling of atmospheric carbon dioxide reduced the Vc,max25 by 5%, 11%, respectively.

  16. Mechanistic Understanding of Microbial Plugging for Improved Sweep Efficiency

    SciTech Connect

    Steven Bryant; Larry Britton

    2008-09-30

    Microbial plugging has been proposed as an effective low cost method of permeability reduction. Yet there is a dearth of information on the fundamental processes of microbial growth in porous media, and there are no suitable data to model the process of microbial plugging as it relates to sweep efficiency. To optimize the field implementation, better mechanistic and volumetric understanding of biofilm growth within a porous medium is needed. In particular, the engineering design hinges upon a quantitative relationship between amount of nutrient consumption, amount of growth, and degree of permeability reduction. In this project experiments were conducted to obtain new data to elucidate this relationship. Experiments in heterogeneous (layered) beadpacks showed that microbes could grow preferentially in the high permeability layer. Ultimately this caused flow to be equally divided between high and low permeability layers, precisely the behavior needed for MEOR. Remarkably, classical models of microbial nutrient uptake in batch experiments do not explain the nutrient consumption by the same microbes in flow experiments. We propose a simple extension of classical kinetics to account for the self-limiting consumption of nutrient observed in our experiments, and we outline a modeling approach based on architecture and behavior of biofilms. Such a model would account for the changing trend of nutrient consumption by bacteria with the increasing biomass and the onset of biofilm formation. However no existing model can explain the microbial preference for growth in high permeability regions, nor is there any obvious extension of the model for this observation. An attractive conjecture is that quorum sensing is involved in the heterogeneous bead packs.

  17. Vitamins C and E: Beneficial effects from a mechanistic perspective

    PubMed Central

    Traber, Maret G.; Stevens, Jan F.

    2011-01-01

    The mechanistic properties of two dietary antioxidants that are required by humans, vitamins C and E, are discussed relative to their biological effects. Vitamin C (ascorbic acid) is an essential cofactor for α-ketoglutarate-dependent dioxygenases. Examples are prolyl hydroxylases, which play a role in the biosynthesis of collagen and in down-regulation of hypoxia-inducible factor (HIF)-1, a transcription factor that regulates many genes responsible for tumor growth, energy metabolism, and neutrophil function and apoptosis. Vitamin C-dependent inhibition of the HIF pathway may provide alternative or additional approaches for controlling tumor progression, infections and inflammation. Vitamin E (α-tocopherol) functions as an essential lipid soluble antioxidant, scavenging hydroperoxyl radicals in lipid milieu. Human symptoms of vitamin E deficiency suggest that its antioxidant properties play a major role in protecting erythrocyte membranes and nervous tissues. As an antioxidant, vitamin C provides protection against oxidative stress-induced cellular damage by scavenging of reactive oxygen species, vitamin E-dependent neutralization of lipid hydroperoxyl radicals, and by protecting proteins from alkylation by electrophilic lipid peroxidation products. These bioactivities bear relevance to inflammatory disorders. Vitamin C plays also a role in the function of endothelial nitric oxide synthase (eNOS) by recycling the eNOS cofactor, tetrahydrobiopterin, which is relevant to arterial elasticity and blood pressure regulation. Evidence from plants supports a role for vitamin C in the formation of covalent adducts with electrophilic secondary metabolites. Mechanism-based effects of vitamin C and E supplementation on biomarkers and on clinical outcomes from randomized, placebo-controlled trials are emphasized in this review. PMID:21664268

  18. Mechanistic evaluation of alginate-HEC gelisphere compacts for controlled intrastriatal nicotine release in Parkinson's disease.

    PubMed

    Choonara, Yahya E; Pillay, Viness; Khan, Riaz A; Singh, Neha; du Toit, Lisa C

    2009-06-01

    This study focused on elucidating a mechanistic understanding in support of the multiple mechanisms which govern the formation of crosslinked alginate-hydroxyethylcellulose (Alg-HEC) gelispheres intended for the controlled intrastriatal release of nicotine as a neuroprotectant in Parkinson's Disease. HEC was incorporated as a reinforcing "protective" colloidal polymer to induce interactions between the free carboxyl groups of alginate with hydroxylated HEC monomers. Gelispheres were compressed within an external poly(lactic-co-glycolic acid) (PLGA) matrix to further prolong the release of nicotine. Sol-gel interconversion mechanisms, matrix deformability moduli, matrix fracture energies and chemometric models of the associated energy paradigms were analyzed for their influence on the mechanism and extent of nicotine release. Textural profiling demonstrated higher fracture energies (7.94-26.69 x 10(-4) J) and lower deformability moduli (12.24-58.36 N/mm) when gelispheres were cured in 2 M HCl as a postcuring step. Ba(2+) crosslinked gelispheres resulted in superiorly compact matrices with an increase in volume of 201-329% as compared to the Ca(2+) and Zn(2+) crosslinked matrices. The order of matrix compactness was as follows: Zn(2+) < Ca(2+) < Ba(2+). Molecular mechanisms of formation, interaction, conversion, and stability of sol-gel transitions depended on the type of crosslinker, crosslinking time, energy transactions, and interactions with molecules of the hydration medium. Ba(2+) crosslinked gelispheres released nicotine slower than Ca(2+) and Zn(2+) crosslinked gelispheres due to the higher energy requirement for interconversion to sol while the energy requirements for Ca(2+) and Zn(2+) was at a lower demand. Ba(2+) crosslinked gelispheres within PLGA matrices therefore retarded nicotine release in a pseudo-zero-order manner over 21 days. PMID:18823012

  19. UTILITY OF MECHANISTIC MODELS FOR DIRECTING ADVANCED SEPARATIONS RESEARCH & DEVELOPMENT ACTIVITIES: Electrochemically Modulated Separation Example

    SciTech Connect

    Schwantes, Jon M.

    2009-06-01

    The objective for this work was to demonstrate the utility of mechanistic computer models designed to simulate actinide behavior for use in efficiently and effectively directing advanced laboratory R&D activities associated with developing advanced separations methods.

  20. ASSESSING POPULATION EXPOSURES TO MULTIPLE AIR POLLUTANTS USING A MECHANISTIC SOURCE-TO-DOSE MODELING FRAMEWORK

    EPA Science Inventory

    The Modeling Environment for Total Risks studies (MENTOR) system, combined with an extension of the SHEDS (Stochastic Human Exposure and Dose Simulation) methodology, provide a mechanistically consistent framework for conducting source-to-dose exposure assessments of multiple pol...

  1. Use of Gene Expression Changes in Blood to Elucidate Mechanistic Indicators of Childhood Asthma (MICA)

    EPA Science Inventory

    Risk assessment increasingly relies more heavily on mode of action, thus the identification of human bioindicators of disease becomes all the more important. Genomic methods represent a tool for both mode of action determination and bioindicator identification. The Mechanistic In...

  2. Dose-response relationships and extrapolation in toxicology - Mechanistic and statistical considerations

    EPA Science Inventory

    Controversy on toxicological dose-response relationships and low-dose extrapolation of respective risks is often the consequence of misleading data presentation, lack of differentiation between types of response variables, and diverging mechanistic interpretation. In this chapter...

  3. MPI Profiling

    SciTech Connect

    Han, D K; Jones, T R

    2005-02-11

    The Message Passing Interface (MPI) is the de facto message-passing standard for massively parallel programs. It is often the case that application performance is a crucial factor, especially for solving grand challenge problems. While there have been many studies on the scalability of applications, there have not been many focusing on the specific types of MPI calls being made and their impact on application performance. Using a profiling tool called mpiP, a large spectrum of parallel scientific applications were surveyed and their performance results analyzed.

  4. Daphnia magna ecotoxicogenomics provides mechanistic insights into metal toxicity.

    PubMed

    Poynton, Helen C; Varshavsky, Julia R; Chang, Bonnie; Cavigiolio, Giorgio; Chan, Sarah; Holman, Patricia S; Loguinov, Alexandre V; Bauer, Darren J; Komachi, Kelly; Theil, Elizabeth C; Perkins, Edward J; Hughes, Owen; Vulpe, Chris D

    2007-02-01

    Toxicogenomics has provided innovative approaches to chemical screening, risk assessment, and predictive toxicology. If applied to ecotoxicology, genomics tools could greatly enhance the ability to understand the modes of toxicity in environmentally relevant organisms. Daphnia magna, a small aquatic crustacean, is considered a "keystone" species in ecological food webs and is an indicator species for toxicant exposure. Our objective was to demonstrate the potential utility of gene expression profiling in ecotoxicology by identifying novel biomarkers and uncovering potential modes of action in D. magna. Using a custom D. magna cDNA microarray, we identified distinct expression profiles in response to sublethal copper, cadmium, and zinc exposures and discovered specific biomarkers of exposure including two probable metallothioneins, and a ferritin mRNA with a functional IRE. The gene expression patterns support known mechanisms of metal toxicity and reveal novel modes of action including zinc inhibition of chitinase activity. By integrating gene expression profiling into an environmentally important organism, this study provides experimental support for the utility of ecotoxicogenomics. PMID:17328222

  5. Mechanistic species distribution modelling as a link between physiology and conservation

    PubMed Central

    Evans, Tyler G.; Diamond, Sarah E.; Kelly, Morgan W.

    2015-01-01

    Climate change conservation planning relies heavily on correlative species distribution models that estimate future areas of occupancy based on environmental conditions encountered in present-day ranges. The approach benefits from rapid assessment of vulnerability over a large number of organisms, but can have poor predictive power when transposed to novel environments and reveals little in the way of causal mechanisms that define changes in species distribution or abundance. Having conservation planning rely largely on this single approach also increases the risk of policy failure. Mechanistic models that are parameterized with physiological information are expected to be more robust when extrapolating distributions to future environmental conditions and can identify physiological processes that set range boundaries. Implementation of mechanistic species distribution models requires knowledge of how environmental change influences physiological performance, and because this information is currently restricted to a comparatively small number of well-studied organisms, use of mechanistic modelling in the context of climate change conservation is limited. In this review, we propose that the need to develop mechanistic models that incorporate physiological data presents an opportunity for physiologists to contribute more directly to climate change conservation and advance the field of conservation physiology. We begin by describing the prevalence of species distribution modelling in climate change conservation, highlighting the benefits and drawbacks of both mechanistic and correlative approaches. Next, we emphasize the need to expand mechanistic models and discuss potential metrics of physiological performance suitable for integration into mechanistic models. We conclude by summarizing other factors, such as the need to consider demography, limiting broader application of mechanistic models in climate change conservation. Ideally, modellers, physiologists and

  6. Mechanistic species distribution modelling as a link between physiology and conservation.

    PubMed

    Evans, Tyler G; Diamond, Sarah E; Kelly, Morgan W

    2015-01-01

    Climate change conservation planning relies heavily on correlative species distribution models that estimate future areas of occupancy based on environmental conditions encountered in present-day ranges. The approach benefits from rapid assessment of vulnerability over a large number of organisms, but can have poor predictive power when transposed to novel environments and reveals little in the way of causal mechanisms that define changes in species distribution or abundance. Having conservation planning rely largely on this single approach also increases the risk of policy failure. Mechanistic models that are parameterized with physiological information are expected to be more robust when extrapolating distributions to future environmental conditions and can identify physiological processes that set range boundaries. Implementation of mechanistic species distribution models requires knowledge of how environmental change influences physiological performance, and because this information is currently restricted to a comparatively small number of well-studied organisms, use of mechanistic modelling in the context of climate change conservation is limited. In this review, we propose that the need to develop mechanistic models that incorporate physiological data presents an opportunity for physiologists to contribute more directly to climate change conservation and advance the field of conservation physiology. We begin by describing the prevalence of species distribution modelling in climate change conservation, highlighting the benefits and drawbacks of both mechanistic and correlative approaches. Next, we emphasize the need to expand mechanistic models and discuss potential metrics of physiological performance suitable for integration into mechanistic models. We conclude by summarizing other factors, such as the need to consider demography, limiting broader application of mechanistic models in climate change conservation. Ideally, modellers, physiologists and

  7. Adsorption kinetic and mechanistic studies for pharmaceutical spherical carbon adsorbents: comparison of a brand product and two generics.

    PubMed

    Abe, Hiroyuki; Morikawa, Risa; Otsuka, Makoto

    2013-03-01

    The kinetic and mechanistic profiles of three pharmaceutical spherical carbon adsorbents, Kremezin as the brand product and two generics (Merckmezin and spherical carbon adsorbent "Mylan"), were compared. Five non-ionic active pharmaceutical ingredients with molecular weights of 136.1-424.1 Da were used as adsorbates. The results of Boehm titration, the standard method to qualify acidic or basic functional groups on a carbon surface, suggested distinctly different quantitative characteristics of each functional group among the three adsorbents. But those differences do not affect the adsorption to non-ionic adsorbates. The amount of theophylline adsorbed at equilibrium and surface area well correlated, suggesting that adsorptive ability was defined by surface area. In the tested molecular weight range, the order in terms of adsorption kinetics was spherical carbon adsorbent "Mylan">Kremezin>Merkmezin. The adsorption profile in the equilibrium and kinetic experiments, and the lack of an effect of pH on adsorption quantity suggested that the mechanism of adsorption for non-ionic substances to be Langmuir type monolayer adsorption. Kremezin and spherical carbon adsorbent "Mylan" are more likely to adsorb co-administered drugs than Merckmezin. PMID:23261577

  8. Mechanistic, Mutational, and Structural Evaluation of a Taxus Phenylalanine Aminomutase

    SciTech Connect

    Feng, Lei; Wanninayake, Udayanga; Strom, Susan; Geiger, James; Walker, Kevin D.

    2014-10-02

    The structure of a phenylalanine aminomutase (TcPAM) from Taxus canadensis has been determined at 2.4 {angstrom} resolution. The active site of the TcPAM contains the signature 4-methylidene-1H-imidazol-5(4H)-one prosthesis, observed in all catalysts of the class I lyase-like family. This catalyst isomerizes (S)-{alpha}-phenylalanine to the (R)-{beta}-isomer by exchange of the NH{sub 2}/H pair. The stereochemistry of the TcPAM reaction product is opposite of the (S)-{beta}-tyrosine made by the mechanistically related tyrosine aminomutase (SgTAM) from Streptomyces globisporus. Since TcPAM and SgTAM share similar tertiary- and quaternary-structures and have several highly conserved aliphatic residues positioned analogously in their active sites for substrate recognition, the divergent product stereochemistries of these catalysts likely cannot be explained by differences in active site architecture. The active site of the TcPAM structure also is in complex with (E)-cinnamate; the latter functions as both a substrate and an intermediate. To account for the distinct (3R)-{beta}-amino acid stereochemistry catalyzed by TcPAM, the cinnamate skeleton must rotate the C{sub 1}-C{sub {alpha}} and C{sub ipso}-C{sub {beta}} bonds 180{sup o} in the active site prior to exchange and rebinding of the NH{sub 2}/H pair to the cinnamate, an event that is not required for the corresponding acrylate intermediate in the SgTAM reaction. Moreover, the aromatic ring of the intermediate makes only one direct hydrophobic interaction with Leu-104. A L104A mutant of TcPAM demonstrated an 1.5-fold increase in k{sub cat} and a decrease in K{sub M} values for sterically demanding 3'-methyl-{alpha}-phenylalanine and styryl-{alpha}-alanine substrates, compared to the kinetic parameters for TcPAM. These parameters did not change significantly for the mutant with 4'-methyl-{alpha}-phenylalanine compared to those for TcPAM.

  9. A mechanistic model of the cysteine synthase complex.

    PubMed

    Feldman-Salit, Anna; Wirtz, Markus; Hell, Ruediger; Wade, Rebecca C

    2009-02-13

    OAS-TL with E. coli SAT. The proposed models of the enzymes and their complexes provide mechanistic insights into CS complexation. PMID:18801369

  10. Mechanistic, kinetic, and processing aspects of tungsten chemical mechanical polishing

    NASA Astrophysics Data System (ADS)

    Stein, David

    This dissertation presents an investigation into tungsten chemical mechanical polishing (CMP). CMP is the industrially predominant unit operation that removes excess tungsten after non-selective chemical vapor deposition (CVD) during sub-micron integrated circuit (IC) manufacture. This work explores the CMP process from process engineering and fundamental mechanistic perspectives. The process engineering study optimized an existing CMP process to address issues of polish pad and wafer carrier life. Polish rates, post-CMP metrology of patterned wafers, electrical test data, and synergy with a thermal endpoint technique were used to determine the optimal process. The oxidation rate of tungsten during CMP is significantly lower than the removal rate under identical conditions. Tungsten polished without inhibition during cathodic potentiostatic control. Hertzian indenter model calculations preclude colloids of the size used in tungsten CMP slurries from indenting the tungsten surface. AFM surface topography maps and TEM images of post-CMP tungsten do not show evidence of plow marks or intergranular fracture. Polish rate is dependent on potassium iodate concentration; process temperature is not. The colloid species significantly affects the polish rate and process temperature. Process temperature is not a predictor of polish rate. A process energy balance indicates that the process temperature is predominantly due to shaft work, and that any heat of reaction evolved during the CMP process is negligible. Friction and adhesion between alumina and tungsten were studied using modified AFM techniques. Friction was constant with potassium iodate concentration, but varied with applied pressure. This corroborates the results from the energy balance. Adhesion between the alumina and the tungsten was proportional to the potassium iodate concentration. A heuristic mechanism, which captures the relationship between polish rate, pressure, velocity, and slurry chemistry, is presented

  11. Toward a mechanistic modeling of nitrogen limitation for photosynthesis

    NASA Astrophysics Data System (ADS)

    Xu, C.; Fisher, R. A.; Travis, B. J.; Wilson, C. J.; McDowell, N. G.

    2011-12-01

    The nitrogen limitation is an important regulator for vegetation growth and global carbon cycle. Most current ecosystem process models simulate nitrogen effects on photosynthesis based on a prescribed relationship between leaf nitrogen and photosynthesis; however, there is a large amount of variability in this relationship with different light, temperature, nitrogen availability and CO2 conditions, which can affect the reliability of photosynthesis prediction under future climate conditions. To account for the variability in nitrogen-photosynthesis relationship under different environmental conditions, in this study, we developed a mechanistic model of nitrogen limitation for photosynthesis based on nitrogen trade-offs among light absorption, electron transport, carboxylization and carbon sink. Our model shows that strategies of nitrogen storage allocation as determined by tradeoff among growth and persistence is a key factor contributing to the variability in relationship between leaf nitrogen and photosynthesis. Nitrogen fertilization substantially increases the proportion of nitrogen in storage for coniferous trees but much less for deciduous trees, suggesting that coniferous trees allocate more nitrogen toward persistence compared to deciduous trees. The CO2 fertilization will cause lower nitrogen allocation for carboxylization but higher nitrogen allocation for storage, which leads to a weaker relationship between leaf nitrogen and maximum photosynthesis rate. Lower radiation will cause higher nitrogen allocation for light absorption and electron transport but less nitrogen allocation for carboxylyzation and storage, which also leads to weaker relationship between leaf nitrogen and maximum photosynthesis rate. At the same time, lower growing temperature will cause higher nitrogen allocation for carboxylyzation but lower allocation for light absorption, electron transport and storage, which leads to a stronger relationship between leaf nitrogen and maximum

  12. Mechanistically Driven Development of Iridium Catalysts for Asymmetric Allylic Substitution

    PubMed Central

    Hartwig, John F.; Stanley, Levi M.

    2010-01-01

    , with high branched-to-linear ratios and high enantioselectivities. Parallel mechanistic studies had revealed the metallacyclic structure of the active catalyst, and subsequent experiments with the purposefully formed metallacycle increased the reaction scope dramatically. Aromatic amines, azoles, ammonia, and amides and carbamates as ammonia equivalents all reacted with high selectivities and yields. Moreover, weakly basic enolates (such as silyl enol ethers) and enolate equivalents (such as enamines) also reacted, and other research groups have used this catalyst to conduct reactions of stabilized carbon nucleophiles in the absence of additional base. One hallmark of the reactions catalyzed by this iridium system is the invariably high enantioselectivity, which reflects a high stereoselectivity for formation of the allyl intermediate. Enantioselectivity typically exceeds 95%, regioselectivity for formation of branched over linear products is usually near 20:1, and yields generally exceed 75% and are often greater than 90%. Thus, the development of iridium catalysts for enantioselective allylic substitution shows how studies of reaction mechanism can lead to a particularly active and a remarkably general system for an enantioselective process. In this case, a readily accessible catalyst effects allylic substitution, with high enantioselectivity and regioselectivity complementary to that of the venerable palladium systems. PMID:20873839

  13. Ferritin Diversity: Mechanistic Studies, Disease Implications, and Materials Chemistry

    NASA Astrophysics Data System (ADS)

    Hilton, Robert J.

    2011-07-01

    The study of ferritin includes a rich history of discoveries and scientific progress. Initially, the composition of ferritin was determined. Soon, it was shown that ferritin is a spherical, hollow protein. Eventually, over several decades of research, the structure and some function of this interesting protein was elucidated. However, the ferritin field was not completely satisfied. Today, for example, researchers are interested in refining the details of ferritin function, in discovering the role of ferritin in a variety of diseases, and in using ferritin for materials chemistry applications. The work presented in this dissertation highlights the progress that we have made in each of these three areas: (1) Mechanistic studies: The buffer used during horse spleen ferritin iron loading significantly influences the mineralization process and the quantity of iron deposited in ferritin. The ferrihydrite core of ferritin is crystalline and ordered when iron is loaded into ferritin in the presence of imidazole buffer. On the other hand, when iron is loaded into ferritin in the presence of MOPS buffer, the ferrihydrite core is less crystalline and less ordered, and a smaller amount of total iron is loaded in ferritin. We also show that iron can be released from the ferritin core in a non-reductive manner. The rate of Fe3+ release from horse spleen ferritin was measured using the Fe3+-specific chelator desferoxamine. We show that iron release occurs by three kinetic events. (2) Disease studies: In order to better understand iron disruption during disease states, we performed in vitro assays that mimicked chronic kidney disease. We tested the hypothesis that elevated levels of serum phosphate interrupted normal iron binding by transferrin and ferritin. Results show that phosphate competes for iron, forming an iron(III)-phosphate complex that is inaccessible to either transferrin or ferritin. Ferritin samples separated from the iron(III)-phosphate complex shows that as the

  14. Mechanistic pharmacokinetic modeling for the prediction of transporter-mediated disposition in humans from sandwich culture human hepatocyte data.

    PubMed

    Jones, Hannah M; Barton, Hugh A; Lai, Yurong; Bi, Yi-An; Kimoto, Emi; Kempshall, Sarah; Tate, Sonya C; El-Kattan, Ayman; Houston, J Brian; Galetin, Aleksandra; Fenner, Katherine S

    2012-05-01

    With efforts to reduce cytochrome P450-mediated clearance (CL) during the early stages of drug discovery, transporter-mediated CL mechanisms are becoming more prevalent. However, the prediction of plasma concentration-time profiles for such compounds using physiologically based pharmacokinetic (PBPK) modeling is far less established in comparison with that for compounds with passively mediated pharmacokinetics (PK). In this study, we have assessed the predictability of human PK for seven organic anion-transporting polypeptide (OATP) substrates (pravastatin, cerivastatin, bosentan, fluvastatin, rosuvastatin, valsartan, and repaglinide) for which clinical intravenous data were available. In vitro data generated from the sandwich culture human hepatocyte system were simultaneously fit to estimate parameters describing both uptake and biliary efflux. Use of scaled active uptake, passive distribution, and biliary efflux parameters as inputs into a PBPK model resulted in the overprediction of exposure for all seven drugs investigated, with the exception of pravastatin. Therefore, fitting of in vivo data for each individual drug in the dataset was performed to establish empirical scaling factors to accurately capture their plasma concentration-time profiles. Overall, active uptake and biliary efflux were under- and overpredicted, leading to average empirical scaling factors of 58 and 0.061, respectively; passive diffusion required no scaling factor. This study illustrates the mechanistic and model-driven application of in vitro uptake and efflux data for human PK prediction for OATP substrates. A particular advantage is the ability to capture the multiphasic plasma concentration-time profiles for such compounds using only preclinical data. A prediction strategy for novel OATP substrates is discussed. PMID:22344703

  15. Enhanced Identification of Transcriptional Enhancers Provides Mechanistic Insights into Diseases.

    PubMed

    Murakawa, Yasuhiro; Yoshihara, Masahito; Kawaji, Hideya; Nishikawa, Miki; Zayed, Hatem; Suzuki, Harukazu; Fantom Consortium; Hayashizaki, Yoshihide

    2016-02-01

    Enhancers are distal cis-regulatory DNA elements that increase the expression of target genes. Various experimental and computational approaches including chromatin signature profiling have been developed to predict enhancers on a genome-wide scale, although each method has its advantages and disadvantages. Here we overview an emerging method to identify transcribed enhancers at exceedingly high nucleotide resolution based on enhancer RNA transcripts captured by Cap Analysis of Gene Expression (CAGE) technology. We further argue that disease-causative regulatory mutations at enhancers are increasingly recognized, emphasizing the importance of enhancer identification in functional and clinical genomics including, but not limited to, genome-wide association studies (GWASs) and cancer genomics studies. PMID:26780995

  16. Mechanistic study of the rubber-brass adhesion interphase

    NASA Astrophysics Data System (ADS)

    Ashirgade, Akshay

    Brass-plated steel tire cords form an essential strengthening component of a radial automobile tire. Adhesion between rubber compound and brass-plated steel tire cord is crucial in governing the overall performance of tires. The rubber-brass interfacial adhesion is influenced by the chemical composition and thickness of the interfacial layer. It has been shown that the interfacial layer consists mainly of sulfides and oxides of copper and zinc. This thesis discusses the effect of changes in the chemical composition and the structure of the interfacial layers due to addition of adhesion promoter resins. Grazing incidence X-Ray Diffraction (GIXRD) experiments were run on sulfidized polished brass coupons previously bonded to six experimental rubber compounds. It was confirmed that heat and humidity conditions lead to physical and chemical changes of the rubber-steel tire cord interfacial layer, closely related to the degree of rubber-brass adhesion. Morphological transformation of the interfacial layer led to loss of adhesion after aging. The adhesion promoter resins inhibit unfavorable morphological changes in the interfacial layer thus stabilizing it during aging and prolonging failure. Tire cord adhesion tests illustrated that the one-component resins improved adhesion after aging using a rubber compound with lower cobalt loading. Based on the acquired diffraction profiles, these resins were also found to impede crystallization of the sulfide layer after aging leading to improved adhesion. Secondary Ion Mass Spectrometry (SIMS) depth profiles, SEM micrographs and AFM images strongly corroborated the findings from GIXRD. FTIR was utilized in a novel way to understand the degradation mechanism due to aging. A model for rubber and interfacial layer degradation is proposed to illustrate the effect of aging and the one-component resins. This interfacial analysis adds valuable new information to our understanding of the complex nature of the rubber-brass bonding

  17. Performance modeling of the Ballard Mark IV solid polymer electrolyte fuel cell. 1: Mechanistic model development

    SciTech Connect

    Amphlett, J.C.; Baumert, R.M.; Mann, R.F.; Peppley, B.A.; Roberge, P.R. ); Harris, T.J. )

    1995-01-01

    A parametric model predicting the performance of a solid polymer electrolyte, proton exchange membrane (PEM) fuel cell has been developed using a combination of mechanistic and empirical modeling techniques. This paper details the mechanistic model development. Mass transport properties are considered in the mechanistic development via Stefan-Maxwell equations. Thermodynamic equilibrium potentials are defined using the Nernst equation. Activation overvoltages are defined via a Tafel equation, and internal resistance are defined via the Nernst-Planck equation, leading to a definition of ohmic overvoltage via an Ohm's law equation. The mechanistic model cannot adequately model fuel cell performance, since several simplifying approximations have been used in order to facilitate model development. Additionally, certain properties likely to be observed in operational fuel cells, such as thermal gradients, have not been considered. Nonetheless, the insights gained from the mechanistic assessment of fuel cell processes were found to give the resulting empirical model a firmer theoretical basis than many of the models presently available in the literature. Correlation of the empirical model to actual experimental data was very good.

  18. Using a Mechanistic Reactive Transport Model to Represent Soil Organic Matter Dynamics and Climate Sensitivity

    NASA Astrophysics Data System (ADS)

    Guerry, N.; Riley, W. J.; Maggi, F.; Torn, M. S.; Kleber, M.

    2011-12-01

    The nature of long term Soil Organic Matter (SOM) dynamics is uncertain and the mechanisms involved are crudely represented in site, regional, and global models. Recent work challenging the paradigm that SOM is stabilized because of its sequential transformations to more intrinsically recalcitrant compounds motivated us to develop a mechanistic modeling framework that can be used to test hypotheses of SOM dynamics. We developed our C cycling model in TOUGHREACT, an established 3-dimensional reactive transport solver that accounts for multiple phases (aqueous, gaseous, sorbed), multiple species, advection and diffusion, and multiple microbial populations. Energy and mass exchange through the soil boundaries are accounted for via ground heat flux, rainfall, C sources (e.g., exudation, woody, leaf, root litter) and C losses (e.g., CO2 emissions and DOC deep percolation). SOM is categorized according to the various types of compounds commonly found in the above mentioned C sources and microbial byproducts, including poly- and monosaccharides, lignin, amino compounds, organic acids, nucleic acids, lipids, and phenols. Each of these compounds is accounted for by one or more representative species in the model. A reaction network was developed to describe the microbially-mediated processes and chemical interactions of these species, including depolymerization, microbial assimilation, respiration and deposition of byproducts, and incorporation of dead biomass into SOM stocks. Enzymatic reactions are characterized by Michaelis-Menten kinetics, with maximum reaction rates determined by the species' O/C ratio. Microbial activity is further regulated by soil moisture content, O2 availability, pH, and temperature. For the initial set of simulations, literature values were used to constrain microbial Monod parameters, Michaelis-Menten parameters, sorption parameters, physical protection, partitioning of microbial byproducts, and partitioning of litter inputs, although there is

  19. Mechanistic modeling of vacuum UV advanced oxidation process in an annular photoreactor.

    PubMed

    Crapulli, F; Santoro, D; Sasges, M R; Ray, A K

    2014-11-01

    A novel mechanistic model that describes the vacuum UV advanced oxidation process in an annular photoreactor initiated by 172 nm and 185 nm (in combination with 253.7 nm, with and without exogenous H2O2) is presented in this paper. The model was developed from first principles by incorporating the vacuum UV-AOP kinetics into the theoretical framework of in-series continuous flow stirred tank reactors. After conducting a sensitivity analysis, model predictions were compared against experiments conducted under a variety of conditions: (a) photo-induced formation of hydrogen peroxide by water photolysis at 172 nm (for both air- and oxygen-saturated conditions); (b) photo-induced formation of hydrogen peroxide by water photolysis at 185 + 253.7 nm (in the presence of formic acid, with and without the initial addition of hydrogen peroxide); (c) direct photolysis of hydrogen peroxide by 253.7 nm; (d) degradation of formic acid by 185 + 253.7 nm (with and without initial addition of hydrogen peroxide); and (e) degradation of formic acid by 253.7 nm (with the addition of exogenous hydrogen peroxide). In all cases, the model was able to accurately predict the time-dependent profiles of hydrogen peroxide and formic acid concentrations. Two newly recognized aspects associated with water photolysis were identified through the use of the validated model. Firstly, unlike the 185 nm and 253.7 nm cases, water photolysis by the 172 nm wavelength revealed a depth of photoactive water layer an order of magnitude greater (∼230-390 μm, depending on the specific operating conditions) than the 1-log photon penetration layer (∼18 μm). To further investigate this potentially very important finding, a computational fluid dynamics model was set up to assess the role of transport mechanisms and species distributions within the photoreactor annulus. The model confirmed that short-lived hydroxyl radicals were present at a radial distance far beyond the ∼18 μm photon

  20. Chemoselective Transformation of Diarylethanones to Arylmethanoic Acids and Diarylmethanones and Mechanistic Insights.

    PubMed

    Wang, Xing; Chen, Rui-Xi; Wei, Zeng-Feng; Zhang, Chen-Yang; Tu, Hai-Yang; Zhang, Ai-Dong

    2016-01-01

    The chemoselective transformation of diarylethanones via either aerobic oxidative cleavage to give arylmethanoic acids or tandem aerobic oxidation/benzilic acid rearrangement/decarboxylation to give diarylmethanones has been developed. The transformation is controllable and applicable to a broad spectrum of substrates and affords the desired products in good to excellent yields. Mechanistic insights with control reactions, (1)H NMR tracking, and single-crystal X-ray diffraction reveal a complex mechanistic network in which two common intermediates, α-ketohydroperoxide and diarylethanedione, and three plausible pathways are proposed and verified. These pathways are interlinked and can be switched reasonably by changing the reaction conditions. This method enables scalable synthesis and access to a number of valuable compounds, including vitamin B3, diphenic acid, and the nonsteroidal anti-inflammatory drug ketoprofen. The present protocol represents a step forward in exploiting complex mechanistic networks to control reaction pathways, achieving divergent syntheses from the same class of starting materials. PMID:26618373

  1. Mechanistic similarity and diversity among the guanidine-modifying members of the pentein superfamily

    PubMed Central

    Linsky, Thomas; Fast, Walter

    2014-01-01

    The pentein superfamily is a mechanistically diverse superfamily encompassing both noncatalytic proteins and enzymes that catalyze hydrolase, dihydrolase and amidinotransfer reactions on guanidine substrates. Despite generally low sequence identity, they possess a conserved structural fold and display common mechanistic themes in catalysis. The structurally characterized catalytic penteins possess a conserved core of residues that include a Cys, His and two polar, guanidine-binding residues. All known catalytic penteins use the core Cys to attack the substrate’s guanidine moiety to form a covalent thiouronium adduct and all cleave one or more of the guanidine C–N bonds. The mechanistic information compiled to date supports the hypothesis that this superfamily may have evolved divergently from a catalytically promiscuous ancestor. PMID:20654741

  2. Mechanistic bases for modelling space radiation risk and planning radiation protection of astronauts.

    PubMed

    Ottolenghi, A; Ballarini, F; Biaggi, M

    2001-01-01

    The approaches generally adopted for planning radiation protection in ground-based facilities cannot be applied straightforward for astronaut protection in space. Indeed in such extreme conditions, modelling methods and shielding design must be based on a detailed mechanistic knowledge of the peculiar astronauts irradiation conditions. Great help can derive from mechanistic modelling, generally aimed to better understand the intermediate steps leading from the initial energy depositions to different biological endpoints, up to organ and organism level. In the present work, criteria will be illustrated for using mechanistic approaches in developing practical tools for astronauts radioprotection, once the external field and the interaction cross sections with the spacecraft walls are known; particular attention will be given to the treatment of mixed fields. Techniques for integrating into condensed-history codes stochastic information provided by event-by-event simulations will be presented. PMID:11780618

  3. Mechanistic investigation on pressure dependency of Heckel parameter.

    PubMed

    Patel, Sarsvatkumar; Kaushal, Aditya Mohan; Bansal, Arvind Kumar

    2010-04-15

    This work proposed to study the influence of varying compaction pressure on the plastic energy, elasticity (Young's modulus), particle yield strength, strain hardening, and applied pressures on derived Heckel parameter using material with different densification and deformation mechanisms: ibuprofen (IBN), paracetamol (PCM) (elastic behavior), methyl cellulose (Me-Cel), microcrystalline cellulose (MCC), sodium chloride (NaCl) (plastic behavior), and dicalcium phosphate (DCP) (brittle fracture). Force-displacement data were captured during in-die compaction for all materials having different deformation behavior. The apparent mean yield pressure (Py), plastic energy, Young's moduli, strain hardening parameter and rate of increase in Py were calculated from force-displacement compaction profiles obtained across a pressure range of 65-260 MPa. Materials under confined compression loading showed pressure dependent biphasic behavior in Py upon increasing pressure from 65 MPa to 260 MPa. IBN and PCM showed pressure dependency due to simultaneous elasticity and strain hardening upon increasing applied pressure. Me-Cel, MCC, and NaCl showed lower pressure dependency while DCP showed higher change in Py upon increasing pressure as a result of higher yield strength of DCP particles. Apparent mean yield pressure from Heckel analysis was significantly affected by the applied pressure, viscoelastic behavior, particle yield strength, and strain hardening. The simultaneously occurring events of elastic deformation and strain hardening give a false increase in Py at higher applied pressures. PMID:20083173

  4. Mechanistic insights into the mode of action of anticandidal sesamol.

    PubMed

    Ansari, Moiz A; Fatima, Zeeshan; Hameed, Saif

    2016-09-01

    Previously we have deciphered the antifungal effect of sesamol (Ses), a phenolic compound obtained from sesame oil, against human fungal pathogen Candida albicans. To gain deeper insights into the possible mechanisms involved, transcription profiling was done in presence of Ses which revealed various targets through which Ses was barricading the growth of C. albicans. We observed that Ses perturbs membrane integrity confirming our previous observations and displayed disrupted plasma membrane ATPase activity. We further investigated that Ses leads to inhibited morphological transition, biofilm formation and epithelial cell adhesion which are significant virulence attributes required for pathogenesis. Interestingly, Ses also causes amendment in iron homeostasis as revealed by hypersensitivity under iron deprivation, ferroxidase assay to estimate iron levels and concomitant upregulation of FTR2, a high affinity iron transporter. Finally we assessed that Ses causes defect in mitochondrial functioning and DNA repair mechanism. Together, being source of consumable natural product, further studies on Ses are warranted so that it can be exploited as effective antifungal agent. PMID:27392701

  5. Serum Metabolomic Profiling and Liver Transcriptomic Analysis Provide Mechanistic Evidence of Ozone (O3)- Induced Systemic Metabolic Impairment

    EPA Science Inventory

    Recently, air pollution has been linked to insulin resistance and obesity but the mechanisms remain to be elucidated. We have recently shown that acute O3 exposure induces glucose intolerance, hyperglycemia and increases in leptin and epinephrine in rats. Here, we hypothesized th...

  6. Periodic table-based descriptors to encode cytotoxicity profile of metal oxide nanoparticles: a mechanistic QSTR approach.

    PubMed

    Kar, Supratik; Gajewicz, Agnieszka; Puzyn, Tomasz; Roy, Kunal; Leszczynski, Jerzy

    2014-09-01

    Nanotechnology has evolved as a frontrunner in the development of modern science. Current studies have established toxicity of some nanoparticles to human and environment. Lack of sufficient data and low adequacy of experimental protocols hinder comprehensive risk assessment of nanoparticles (NPs). In the present work, metal electronegativity (χ), the charge of the metal cation corresponding to a given oxide (χox), atomic number and valence electron number of the metal have been used as simple molecular descriptors to build up quantitative structure-toxicity relationship (QSTR) models for prediction of cytotoxicity of metal oxide NPs to bacteria Escherichia coli. These descriptors can be easily obtained from molecular formula and information acquired from periodic table in no time. It has been shown that a simple molecular descriptor χox can efficiently encode cytotoxicity of metal oxides leading to models with high statistical quality as well as interpretability. Based on this model and previously published experimental results, we have hypothesized the most probable mechanism of the cytotoxicity of metal oxide nanoparticles to E. coli. Moreover, the required information for descriptor calculation is independent of size range of NPs, nullifying a significant problem that various physical properties of NPs change for different size ranges. PMID:24949897

  7. Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal-antiplasmodial activity.

    PubMed

    Sola, Irene; Castellà, Sílvia; Viayna, Elisabet; Galdeano, Carles; Taylor, Martin C; Gbedema, Stephen Y; Pérez, Belén; Clos, M Victòria; Jones, Deuan C; Fairlamb, Alan H; Wright, Colin W; Kelly, John M; Muñoz-Torrero, Diego

    2015-08-15

    Dual submicromolar trypanocidal-antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different structural classes. In Trypanosoma brucei, inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers, although it is probably not the main biological target. Regarding antiplasmodial activity, the heterodimers seem to share the mode of action of the antimalarial drug chloroquine, which involves inhibition of the haem detoxification process. Interestingly, all of these heterodimers display good brain permeabilities, thereby being potentially useful for late stage human African trypanosomiasis. Future optimization of these compounds should focus mainly on decreasing cytotoxicity and acetylcholinesterase inhibitory activity. PMID:25678015

  8. Metabolomic profiling in Selaginella lepidophylla at various hydration states provides new insights into the mechanistic basis of desiccation tolerance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Selaginella lepidophylla is one of only a few species of spike mosses (Selaginellaceae) that have evolved desiccation tolerance (DT) or the ability to ‘resurrect’ from an air-dried state. In order to understand the metabolic basis of DT, S. lepidophylla was subjected to a five-stage, rehydration/de...

  9. Integrating mechanistic organism--environment interactions into the basic theory of community and evolutionary ecology.

    PubMed

    Baskett, Marissa L

    2012-03-15

    This paper presents an overview of how mechanistic knowledge of organism-environment interactions, including biomechanical interactions of heat, mass and momentum transfer, can be integrated into basic theoretical population biology through mechanistic functional responses that quantitatively describe how organisms respond to their physical environment. Integrating such functional responses into simple community and microevolutionary models allows scaling up of the organism-level understanding from biomechanics both ecologically and temporally. For community models, Holling-type functional responses for predator-prey interactions provide a classic example of the functional response affecting qualitative model dynamics, and recent efforts are expanding analogous models to incorporate environmental influences such as temperature. For evolutionary models, mechanistic functional responses dependent on the environment can serve as fitness functions in both quantitative genetic and game theoretic frameworks, especially those concerning function-valued traits. I present a novel comparison of a mechanistic fitness function based on thermal performance curves to a commonly used generic fitness function, which quantitatively differ in their predictions for response to environmental change. A variety of examples illustrate how mechanistic functional responses enhance model connections to biologically relevant traits and processes as well as environmental conditions and therefore have the potential to link theoretical and empirical studies. Sensitivity analysis of such models can provide biologically relevant insight into which parameters and processes are important to community and evolutionary responses to environmental change such as climate change, which can inform conservation management aimed at protecting response capacity. Overall, the distillation of detailed knowledge or organism-environment interactions into mechanistic functional responses in simple population

  10. Enantioselective and Regiodivergent Functionalization of N-Allylcarbamates by Mechanistically Divergent Multicatalysis.

    PubMed

    Richmond, Edward; Khan, Ismat Ullah; Moran, Joseph

    2016-08-22

    A pair of mechanistically divergent multicatalytic reaction sequences has been developed consisting of nickel-catalyzed isomerization of N-allylcarbamates and subsequent phosphoric-acid-catalyzed enantioselective functionalization of the resulting intermediates. By appropriate selection of reaction partners, in situ generated imines and ene-carbamates are mechanistically partitioned to yield opposing functionalized products. Formal α-functionalization to give protected α-arylamines is achieved upon enantioselective Friedel-Crafts reaction with arene nucleophiles, whereas formal β-functionalization is achieved upon reaction with diarylimine electrophiles in an enantioselective Povarov-[4+2] cycloaddition. PMID:27461524

  11. Mechanistic Considerations in the Synthesis of 2-Aryl-Indole Analogues under Bischler-Mohlau Conditions

    PubMed Central

    MacDonough, Matthew T.; Shi, Zhe; Pinney, Kevin G.

    2015-01-01

    Mechanistic insight into the pathway of the Bischler-Mohlau indole formation reaction is provided by isotopic labeling utilizing judicious incorporation of a 13C atom within the α-bromoacetophenone analogue reactant. The resulting rearranged 2-aryl indole, isolated as the major product, located the 13C isotope label at the methine carbon of the fused five-membered heterocyclic ring, which suggested that the mechanistic pathway of cyclization, in this specific example, required two equivalents of the aniline analogue reactant partner and proceeded through an imine intermediate rather than by direct formation of the corresponding 3-aryl indole accompanied by a concomitant 1,2-aryl shift rearrangement. PMID:26973358

  12. Profiling and Racial Profiling: An Interactive Exercise

    ERIC Educational Resources Information Center

    Semple, Philip

    2013-01-01

    Racial Profiling has been recognized as a serious problem that affects many segments of our society and is especially notable in law enforcement. Governments and police services have pronounced that racial profiling is not acceptable and will not be tolerated. They have gone to great lengths in trying to eradicate racial profiling through…

  13. Mechanistic studies of the agmatine deiminase from Listeria monocytogenes

    PubMed Central

    Soares, Charles A.; Knuckley, Bryan

    2016-01-01

    Listeria monocytogenes is a Gram-positive food-borne pathogen that is capable of living within extreme environments (i.e. low temperatures and pH). This ability to survive in such conditions may arise, at least in part, from agmatine catabolism via the agmatine deiminase system (AgDS). This catabolic pathway utilizes an agmatine deiminase (AgD) to hydrolyse agmatine into N-carbamoylputrescine (NCP), with concomitant release of ammonia, which increases the pH, thus mitigating the ill effects of the acidic environment. Given the potential significance of this pathway for cell survival, we set out to study the catalytic mechanism of the AgD encoded by L. monocytogenes. In the present paper, we describe the catalytic mechanism employed by this enzyme based on pH profiles, pKa measurements of the active site cysteine and solvent isotope effects (SIE). In addition, we report inhibition of this enzyme by two novel AgD inhibitors, i.e. N-(4-aminobutyl)-2-fluoro-ethanimidamide (ABFA) and N-(4-aminobutyl)-2-chloro-ethanimidamide (ABCA). In contrast with other orthologues, L. monocytogenes AgD does not use the reverse protonation or substrate-assisted mechanism, which requires an active site cysteine with a high pKa and has been commonly seen in other members of the guanidinium-modifying enzyme (GME) superfamily. Instead, the L. monocytogenes AgD has a low pKa cysteine in the active site leading to an alternative mechanism of catalysis. This is the first time that this mechanism has been observed in the GME superfamily and is significant because it explains why previously developed mechanism-based inactivators of AgDs are ineffective against this orthologue. PMID:27034081

  14. PTN signaling: Components and mechanistic insights in human ovarian cancer.

    PubMed

    Sethi, Geetika; Kwon, Youngjoo; Burkhalter, Rebecca J; Pathak, Harsh B; Madan, Rashna; McHugh, Sarah; Atay, Safinur; Murthy, Smruthi; Tawfik, Ossama W; Godwin, Andrew K

    2015-12-01

    Molecular vulnerabilities represent promising candidates for the development of targeted therapies that hold the promise to overcome the challenges encountered with non-targeted chemotherapy for the treatment of ovarian cancer. Through a synthetic lethality screen, we previously identified pleiotrophin (PTN) as a molecular vulnerability in ovarian cancer and showed that siRNA-mediated PTN knockdown induced apoptotic cell death in epithelial ovarian cancer (EOC) cells. Although, it is well known that PTN elicits its pro-tumorigenic effects through its receptor, protein tyrosine phosphatase receptor Z1 (PTPRZ1), little is known about the potential importance of this pathway in the pathogenesis of ovarian cancer. In this study, we show that PTN is expressed, produced, and secreted in a panel of EOC cell lines. PTN levels in serous ovarian tumor tissues are on average 3.5-fold higher relative to normal tissue and PTN is detectable in serum samples of patients with EOC. PTPRZ1 is also expressed and produced by EOC cells and is found to be up-regulated in serous ovarian tumor tissue relative to normal ovarian surface epithelial tissue (P < 0.05). Gene silencing of PTPRZ1 in EOC cell lines using siRNA-mediated knockdown shows that PTPRZ1 is essential for viability and results in significant apoptosis with no effect on the cell cycle phase distribution. In order to determine how PTN mediates survival, we silenced the gene using siRNA mediated knockdown and performed expression profiling of 36 survival-related genes. Through computational mapping of the differentially expressed genes, members of the MAPK (mitogen-activated protein kinase) family were found to be likely effectors of PTN signaling in EOC cells. Our results provide the first experimental evidence that PTN and its signaling components may be of significance in the pathogenesis of epithelial ovarian cancer and provide a rationale for clinical evaluation of MAPK inhibitors in PTN and/or PTPRZ1 expressing ovarian

  15. Mechanistic studies of the agmatine deiminase from Listeria monocytogenes.

    PubMed

    Soares, Charles A; Knuckley, Bryan

    2016-06-01

    Listeria monocytogenes is a Gram-positive food-borne pathogen that is capable of living within extreme environments (i.e. low temperatures and pH). This ability to survive in such conditions may arise, at least in part, from agmatine catabolism via the agmatine deiminase system (AgDS). This catabolic pathway utilizes an agmatine deiminase (AgD) to hydrolyse agmatine into N-carbamoylputrescine (NCP), with concomitant release of ammonia, which increases the pH, thus mitigating the ill effects of the acidic environment. Given the potential significance of this pathway for cell survival, we set out to study the catalytic mechanism of the AgD encoded by L. monocytogenes In the present paper, we describe the catalytic mechanism employed by this enzyme based on pH profiles, pKa measurements of the active site cysteine and solvent isotope effects (SIE). In addition, we report inhibition of this enzyme by two novel AgD inhibitors, i.e. N-(4-aminobutyl)-2-fluoro-ethanimidamide (ABFA) and N-(4-aminobutyl)-2-chloro-ethanimidamide (ABCA). In contrast with other orthologues, L. monocytogenes AgD does not use the reverse protonation or substrate-assisted mechanism, which requires an active site cysteine with a high pKa and has been commonly seen in other members of the guanidinium-modifying enzyme (GME) superfamily. Instead, the L. monocytogenes AgD has a low pKa cysteine in the active site leading to an alternative mechanism of catalysis. This is the first time that this mechanism has been observed in the GME superfamily and is significant because it explains why previously developed mechanism-based inactivators of AgDs are ineffective against this orthologue. PMID:27034081

  16. Syphilis Profiles, 2012

    MedlinePlus

    ... STD on Facebook Data & Statistics Sexually Transmitted Diseases Syphilis Profiles, 2012 Recommend on Facebook Tweet Share Compartir ... Profiles The following profiles provide an overview of syphilis morbidity in each of the 50 states, the ...

  17. COMPENDEX Profiling Guide.

    ERIC Educational Resources Information Center

    Standera, Oldrich

    This manual provides instructions for completing the COMPENDEX (Computerized Engineering Index) Profile Submission Form used to prepare Current Information Selection (CIS) profiles. An annotated bibliography lists nine items useful in searching for proper profile words. (AB)

  18. Functional and mechanistic studies of XPC DNA-repair complex as transcriptional coactivator in embryonic stem cells

    PubMed Central

    Cattoglio, Claudia; Zhang, Elisa T.; Grubisic, Ivan; Chiba, Kunitoshi; Fong, Yick W.; Tjian, Robert

    2015-01-01

    The embryonic stem cell (ESC) state is transcriptionally controlled by OCT4, SOX2, and NANOG with cofactors, chromatin regulators, noncoding RNAs, and other effectors of signaling pathways. Uncovering components of these regulatory circuits and their interplay provides the knowledge base to deploy ESCs and induced pluripotent stem cells. We recently identified the DNA-repair complex xeroderma pigmentosum C (XPC)-RAD23B-CETN2 as a stem cell coactivator (SCC) required for OCT4/SOX2 transcriptional activation. Here we investigate the role of SCC genome-wide in murine ESCs by mapping regions bound by RAD23B and analyzing transcriptional profiles of SCC-depleted ESCs. We establish OCT4 and SOX2 as the primary transcription factors recruiting SCC to regulatory regions of pluripotency genes and identify the XPC subunit as essential for interaction with the two proteins. The present study reveals new mechanistic and functional aspects of SCC transcriptional activity, and thus underscores the diversified functions of this regulatory complex. PMID:25901318

  19. A Quantitative Toxicogenomics Assay for High-throughput and Mechanistic Genotoxicity Assessment and Screening of Environmental Pollutants.

    PubMed

    Lan, Jiaqi; Gou, Na; Rahman, Sheikh Mokhles; Gao, Ce; He, Miao; Gu, April Z

    2016-03-15

    The ecological and health concern of mutagenicity and carcinogenicity potentially associated with an overwhelmingly large and ever-increasing number of chemicals demands for cost-effective and feasible method for genotoxicity screening and risk assessment. This study proposed a genotoxicity assay using GFP-tagged yeast reporter strains, covering 38 selected protein biomarkers indicative of all the seven known DNA damage repair pathways. The assay was applied to assess four model genotoxic chemicals, eight environmental pollutants and four negative controls across six concentrations. Quantitative molecular genotoxicity end points were derived based on dose response modeling of a newly developed integrated molecular effect quantifier, Protein Effect Level Index (PELI). The molecular genotoxicity end points were consistent with multiple conventional in vitro genotoxicity assays, as well as with in vivo carcinogenicity assay results. Further more, the proposed genotoxicity end point PELI values quantitatively correlated with both comet assay in human cell and carcinogenicity potency assay in mice, providing promising evidence for linking the molecular disturbance measurements to adverse outcomes at a biological relevant level. In addition, the high-resolution DNA damaging repair pathway alternated protein expression profiles allowed for chemical clustering and classification. This toxicogenomics-based assay presents a promising alternative for fast, efficient and mechanistic genotoxicity screening and assessment of drugs, foods, and environmental contaminants. PMID:26855253

  20. Mechanistic Modeling of Pitavastatin Disposition in Sandwich-Cultured Human Hepatocytes: A Proteomics-Informed Bottom-Up Approach.

    PubMed

    Vildhede, Anna; Mateus, André; Khan, Elin K; Lai, Yurong; Karlgren, Maria; Artursson, Per; Kjellsson, Maria C

    2016-04-01

    Isolated human hepatocytes are commonly used to predict transporter-mediated clearance in vivo. Such predictions, however, do not provide estimations of transporter contributions and consequently do not allow predictions of the outcome resulting from a change in the activity of a certain transporter, for example, by inhibition or a genetic variant with reduced function. Pitavastatin is a drug that is heavily dependent on hepatic transporters for its elimination, and it is excreted mainly as unchanged drug in the bile. For this reason, pitavastatin was used as a model drug to demonstrate the applicability of a bottom-up approach to predict transporter-mediated disposition in sandwich-cultured human hepatocytes (SCHHs), allowing for the estimation of transporter contributions. Transport experiments in transfected human embryonic kidney cells (HEK293 cell lines) and inverted membrane vesicles overexpressing each of the relevant transport proteins were used to generate parameter estimates for the mechanistic model. By adjusting for differences in transporter abundance between the in vitro systems and individual SCHH batches, the model successfully predicted time profiles of medium and intracellular accumulation. Our predictions of pitavastatin bile accumulation could not be confirmed, however, because of a very low biliary excretion of pitavastatin in relation to the hepatic uptake in our SCHHs. This study is, to our knowledge, the first to successfully simulate transporter-mediated processes in a complex system such as SCHHs at the level of individual transport proteins using a bottom-up approach. PMID:26842596

  1. Target biomarker profile for the clinical management of paracetamol overdose.

    PubMed

    Vliegenthart, A D Bastiaan; Antoine, Daniel J; Dear, James W

    2015-09-01

    Paracetamol (acetaminophen) overdose is one of the most common causes of acute liver injury in the Western world. To improve patient care and reduce pressure on already stretched health care providers new biomarkers are needed that identify or exclude liver injury soon after an overdose of paracetamol is ingested. This review highlights the current state of paracetamol poisoning management and how novel biomarkers could improve patient care and save healthcare providers money. Based on the widely used concept of defining a target product profile, a target biomarker profile is proposed that identifies desirable and acceptable key properties for a biomarker in development to enable the improved treatment of this patient population. The current biomarker candidates, with improved hepatic specificity and based on the fundamental mechanistic basis of paracetamol-induced liver injury, are reviewed and their performance compared with our target profile. PMID:26076366

  2. New Simulation Methods to Facilitate Achieving a Mechanistic Understanding of Basic Pharmacology Principles in the Classroom

    ERIC Educational Resources Information Center

    Grover, Anita; Lam, Tai Ning; Hunt, C. Anthony

    2008-01-01

    We present a simulation tool to aid the study of basic pharmacology principles. By taking advantage of the properties of agent-based modeling, the tool facilitates taking a mechanistic approach to learning basic concepts, in contrast to the traditional empirical methods. Pharmacodynamics is a particular aspect of pharmacology that can benefit from…

  3. Territoriality and home-range dynamics in meerkats, Suricata suricatta: a mechanistic modelling approach.

    PubMed

    Bateman, Andrew W; Lewis, Mark A; Gall, Gabriella; Manser, Marta B; Clutton-Brock, Tim H

    2015-01-01

    Multiple approaches exist to model patterns of space use across species, among them resource selection analysis, statistical home-range modelling and mechanistic movement modelling. Mechanistic home-range models combine the benefits of these approaches, describing emergent territorial patterns based on fine-scale individual- or group-movement rules and incorporating interactions with neighbours and the environment. These models have not, to date, been extended to dynamic contexts. Using mechanistic home-range models, we explore meerkat (Suricata suricatta) territorial patterns, considering scent marking, direct group interactions and habitat selection. We also extend the models to accommodate dynamic aspects of meerkat territoriality (territory development and territory shift). We fit models, representing multiple working hypotheses, to data from a long-term meerkat study in South Africa, and we compare models using Akaike's and Bayesian Information Criteria. Our results identify important features of meerkat territorial patterns. Notably, larger groups do not seem to control larger territories, and groups apparently prefer dune edges along a dry river bed. Our model extensions capture instances in which 1) a newly formed group interacts more strongly with its parent groups over time and 2) a group moves its territory core out of aversive habitat. This extends our mechanistic modelling framework in previously unexplored directions. PMID:24995457

  4. DEVELOPING MECHANISTIC DATA FOR INCORPORATION INTO CANCER AND GENETIC RISK ASSESSMENTS: OLD PROBLEMS AND NEW APPROACHES

    EPA Science Inventory

    26th Lauriston S. Taylor Lecture
    DEVELOPING MECHANISTIC DATA FOR INCORPORATION INTO CANCER AND
    GENETIC RISK ASSESSMENTS: OLD PROBLEMS AND NEW APPROACHES
    R. Julian Preston, Environmental Carcinogenesis Division, U.S. Environmental Protection
    Agency, NHEERL, Research Tr...

  5. Legitimising data-driven models: exemplification of a new data-driven mechanistic modelling framework

    NASA Astrophysics Data System (ADS)

    Mount, N. J.; Dawson, C. W.; Abrahart, R. J.

    2013-07-01

    In this paper the difficult problem of how to legitimise data-driven hydrological models is addressed using an example of a simple artificial neural network modelling problem. Many data-driven models in hydrology have been criticised for their black-box characteristics, which prohibit adequate understanding of their mechanistic behaviour and restrict their wider heuristic value. In response, presented here is a new generic data-driven mechanistic modelling framework. The framework is significant because it incorporates an evaluation of the legitimacy of a data-driven model's internal modelling mechanism as a core element in the modelling process. The framework's value is demonstrated by two simple artificial neural network river forecasting scenarios. We develop a novel adaptation of first-order partial derivative, relative sensitivity analysis to enable each model's mechanistic legitimacy to be evaluated within the framework. The results demonstrate the limitations of standard, goodness-of-fit validation procedures by highlighting how the internal mechanisms of complex models that produce the best fit scores can have lower mechanistic legitimacy than simpler counterparts whose scores are only slightly inferior. Thus, our study directly tackles one of the key debates in data-driven, hydrological modelling: is it acceptable for our ends (i.e. model fit) to justify our means (i.e. the numerical basis by which that fit is achieved)?

  6. Legitimising neural network river forecasting models: a new data-driven mechanistic modelling framework

    NASA Astrophysics Data System (ADS)

    Mount, N. J.; Dawson, C. W.; Abrahart, R. J.

    2013-01-01

    In this paper we address the difficult problem of gaining an internal, mechanistic understanding of a neural network river forecasting (NNRF) model. Neural network models in hydrology have long been criticised for their black-box character, which prohibits adequate understanding of their modelling mechanisms and has limited their broad acceptance by hydrologists. In response, we here present a new, data-driven mechanistic modelling (DDMM) framework that incorporates an evaluation of the legitimacy of a neural network's internal modelling mechanism as a core element in the model development process. The framework is exemplified for two NNRF modelling scenarios, and uses a novel adaptation of first order, partial derivate, relative sensitivity analysis methods as the means by which each model's mechanistic legitimacy is explored. The results demonstrate the limitations of standard, goodness-of-fit validation procedures applied by NNRF modellers, by highlighting how the internal mechanisms of complex models that produce the best fit scores can have much lower legitimacy than simpler counterparts whose scores are only slightly inferior. The study emphasises the urgent need for better mechanistic understanding of neural network-based hydrological models and the further development of methods for elucidating their mechanisms.

  7. A Mechanistic Study of Arsenic (III) Rejection by Reverse Osmosis and Nanofiltration Membranes

    ERIC Educational Resources Information Center

    Suzuki, Tasuma

    2009-01-01

    Reverse osmosis/nanofiltration (RO/NF) membranes are capable to provide an effective barrier for a wide range of contaminants (including disinfection by-products precursors) in a single treatment step. However, solute rejection mechanisms by RO/NF membranes are not well understood. The lack of mechanistic information arises from experimental…

  8. A mechanistic detachment rate model to predict soil erodibility due to fluvial and seepage forces

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The erosion rate of cohesive soils is typically computed using an excess shear stress model based on the applied fluvial shear stress. However, no mechanistic approaches are available for incorporating additional forces such as localized groundwater seepage forces into the excess shear stress model...

  9. Predictive mechanistic bioenergetics to model habitat suitability of shellfish culture in coastal lakes

    NASA Astrophysics Data System (ADS)

    Rinaldi, A.; Montalto, V.; Manganaro, A.; Mazzola, A.; Mirto, S.; Sanfilippo, M.; Sarà, G.

    2014-05-01

    Quantitative tools based on mechanistic modelling of functional traits able to enhance the sustainability of aquaculture and most other human activities (i.e. reducing the likelihood of detrimental impacts optimising productions), are especially important factors in the decision to site aquaculture facilities in coastal lakes, ponds and lagoons and, in the case of detrimental impact, to adopt mitigation measures. We tested the ability of mechanistic functional trait based models to predict life history traits of cultivable shellfish in shallow coastal lakes. Dynamic Energy Budget (DEB) models were run to generate spatially explicit predictions of Mytilus galloprovincialis life history (LH) traits (e.g. body size and fecundity). Using fortnightly data of food supply and hourly data of body temperatures, and exploiting the power of mechanistic rules, we estimated the amount of faeces ejected by a fixed quantity of organisms cultivated in two shallow Southern Mediterranean (Sicily) lakes. These differed in terms of temperature and food density, implying large differences in life history traits of mussels in the two study areas. This information could help facilitate the selection of sites where environmental conditions are more suitable for aquaculture and contextually compatible with sustainability. The validation exercise obtained by comparing the predicted and observed data was nearly consistent. Therefore, a mechanistic functional traits-based model seems able to capture the link between habitat characteristics and functional traits of organisms, delineating the fundamental portion of an ecological niche, the possibility of predicting LH traits and potential ecological applications in the management of natural coastal resources.

  10. A mechanistic treatment of the dominant soil nitrogen cycling processes: Model development, testing, and application

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The development and initial application of a mechanistic model (TOUGHREACT-N) designed to characterize soil nitrogen (N) cycling and losses are described. The model couples advective and diffusive nutrient transport, multiple microbial biomass dynamics, and equilibrium and kinetic chemical reactions...

  11. From Source to Sink: Mechanistic Reasoning Using the Electron-Pushing Formalism

    ERIC Educational Resources Information Center

    Bhattacharyya, Gautam

    2013-01-01

    Since the introduction of Morrison and Boyd's textbook in organic chemistry over 50 years ago, reaction mechanisms and mechanistic reasoning using the electron-pushing formalism (EPF) have become a mainstay of organic chemistry courses. In recent years there have even been several papers in this Journal and others detailing research on how…

  12. Assessing Metal Levels in Children from the Mechanistic Indicators of Childhood Asthma(MICA) study

    EPA Science Inventory

    Toxic and essential metals levels can be used as health indicators. Here, we quantitatively compare and contrast toxic and essential metals levels in vacuum dust, urine, and fingernail samples of 109 children in Detroit, Michigan as part of The Mechanistic Indicators of Childhood...

  13. CHEMICAL MUTAGENESIS AND CARCINOGENESIS: INCORPORATION OF MECHANISTIC DATA INTO RISK ASSESSMENT

    EPA Science Inventory

    CHEMICAL MUTAGENESIS AND CARCINOGENESIS: INCORPORATION OF MECHANISTIC DATA INTO RISK ASSESSMENT

    The current understanding of cancer as a genetic disease, requiring a specific set of genomic alterations for a normal cell to form a metastatic tumor, has provided the oppor...

  14. Productivity of "Collisions Generate Heat" for Reconciling an Energy Model with Mechanistic Reasoning: A Case Study

    ERIC Educational Resources Information Center

    Scherr, Rachel E.; Robertson, Amy D.

    2015-01-01

    We observe teachers in professional development courses about energy constructing mechanistic accounts of energy transformations. We analyze a case in which teachers investigating adiabatic compression develop a model of the transformation of kinetic energy to thermal energy. Among their ideas is the idea that thermal energy is generated as a…

  15. REDUCING UNCERTAINTY IN RISK ASSESSMENT USING MECHANISTIC DATA: ENHANCING THE U.S. EPA DEVELOPMENTAL NEUROTOXICITY TESTING GUIDELINES

    EPA Science Inventory

    SUMMARY: Mechanistic data should provide the Agency with a more accurate basis to estimate risk than do the Agency’s default assumptions (10x uncertainty factors, etc.), thereby improving risk assessment decisions. NTD is providing mechanistic data for toxicant effects on two maj...

  16. Main individual and product characteristics influencing in-mouth flavour release during eating masticated food products with different textures: mechanistic modelling and experimental validation.

    PubMed

    Doyennette, M; Déléris, I; Féron, G; Guichard, E; Souchon, I; Trelea, I C

    2014-01-01

    A mechanistic model predicting flavour release during oral processing of masticated foods was developed. The description of main physiological steps (product mastication and swallowing) and physical mechanisms (mass transfer, product breakdown and dissolution) occurring while eating allowed satisfactory simulation of in vivo release profiles of ethyl propanoate and 2-nonanone, measured by Atmospheric Pressure Chemical Ionization Mass Spectrometry on ten representative subjects during the consumption of four cheeses with different textures. Model sensitivity analysis showed that the main parameters affecting release intensity were the product dissolution rate in the mouth, the mass transfer coefficient in the bolus, the air-bolus contact area in the mouth and the respiratory frequency. Parameters furthermore affecting release dynamics were the mastication phase duration, the velopharynx opening and the rate of saliva incorporation into the bolus. Specific retention of 2-nonanone on mucosa was assumed to explain aroma release kinetics and confirmed when gaseous samples were consumed. PMID:24045155

  17. The Combined Use of Correlative and Mechanistic Species Distribution Models Benefits Low Conservation Status Species.

    PubMed

    Rougier, Thibaud; Lassalle, Géraldine; Drouineau, Hilaire; Dumoulin, Nicolas; Faure, Thierry; Deffuant, Guillaume; Rochard, Eric; Lambert, Patrick

    2015-01-01

    Species can respond to climate change by tracking appropriate environmental conditions in space, resulting in a range shift. Species Distribution Models (SDMs) can help forecast such range shift responses. For few species, both correlative and mechanistic SDMs were built, but allis shad (Alosa alosa), an endangered anadromous fish species, is one of them. The main purpose of this study was to provide a framework for joint analyses of correlative and mechanistic SDMs projections in order to strengthen conservation measures for species of conservation concern. Guidelines for joint representation and subsequent interpretation of models outputs were defined and applied. The present joint analysis was based on the novel mechanistic model GR3D (Global Repositioning Dynamics of Diadromous fish Distribution) which was parameterized on allis shad and then used to predict its future distribution along the European Atlantic coast under different climate change scenarios (RCP 4.5 and RCP 8.5). We then used a correlative SDM for this species to forecast its distribution across the same geographic area and under the same climate change scenarios. First, projections from correlative and mechanistic models provided congruent trends in probability of habitat suitability and population dynamics. This agreement was preferentially interpreted as referring to the species vulnerability to climate change. Climate change could not be accordingly listed as a major threat for allis shad. The congruence in predicted range limits between SDMs projections was the next point of interest. The difference, when noticed, required to deepen our understanding of the niche modelled by each approach. In this respect, the relative position of the northern range limit between the two methods strongly suggested here that a key biological process related to intraspecific variability was potentially lacking in the mechanistic SDM. Based on our knowledge, we hypothesized that local adaptations to cold

  18. The Combined Use of Correlative and Mechanistic Species Distribution Models Benefits Low Conservation Status Species

    PubMed Central

    Rougier, Thibaud; Lassalle, Géraldine; Drouineau, Hilaire; Dumoulin, Nicolas; Faure, Thierry; Deffuant, Guillaume; Rochard, Eric; Lambert, Patrick

    2015-01-01

    Species can respond to climate change by tracking appropriate environmental conditions in space, resulting in a range shift. Species Distribution Models (SDMs) can help forecast such range shift responses. For few species, both correlative and mechanistic SDMs were built, but allis shad (Alosa alosa), an endangered anadromous fish species, is one of them. The main purpose of this study was to provide a framework for joint analyses of correlative and mechanistic SDMs projections in order to strengthen conservation measures for species of conservation concern. Guidelines for joint representation and subsequent interpretation of models outputs were defined and applied. The present joint analysis was based on the novel mechanistic model GR3D (Global Repositioning Dynamics of Diadromous fish Distribution) which was parameterized on allis shad and then used to predict its future distribution along the European Atlantic coast under different climate change scenarios (RCP 4.5 and RCP 8.5). We then used a correlative SDM for this species to forecast its distribution across the same geographic area and under the same climate change scenarios. First, projections from correlative and mechanistic models provided congruent trends in probability of habitat suitability and population dynamics. This agreement was preferentially interpreted as referring to the species vulnerability to climate change. Climate change could not be accordingly listed as a major threat for allis shad. The congruence in predicted range limits between SDMs projections was the next point of interest. The difference, when noticed, required to deepen our understanding of the niche modelled by each approach. In this respect, the relative position of the northern range limit between the two methods strongly suggested here that a key biological process related to intraspecific variability was potentially lacking in the mechanistic SDM. Based on our knowledge, we hypothesized that local adaptations to cold

  19. Proposal of an in silico profiler for categorisation of repeat dose toxicity data of hair dyes.

    PubMed

    Nelms, M D; Ates, G; Madden, J C; Vinken, M; Cronin, M T D; Rogiers, V; Enoch, S J

    2015-05-01

    This study outlines the analysis of 94 chemicals with repeat dose toxicity data taken from Scientific Committee on Consumer Safety opinions for commonly used hair dyes in the European Union. Structural similarity was applied to group these chemicals into categories. Subsequent mechanistic analysis suggested that toxicity to mitochondria is potentially a key driver of repeat dose toxicity for chemicals within each of the categories. The mechanistic hypothesis allowed for an in silico profiler consisting of four mechanism-based structural alerts to be proposed. These structural alerts related to a number of important chemical classes such as quinones, anthraquinones, substituted nitrobenzenes and aromatic azos. This in silico profiler is intended for grouping chemicals into mechanism-based categories within the adverse outcome pathway paradigm. PMID:24888375

  20. Mechanistic modelling of cancer: some reflections from software engineering and philosophy of science.

    PubMed

    Cañete-Valdeón, José M; Wieringa, Roel; Smallbone, Kieran

    2012-12-01

    There is a growing interest in mathematical mechanistic modelling as a promising strategy for understanding tumour progression. This approach is accompanied by a methodological change of making research, in which models help to actively generate hypotheses instead of waiting for general principles to become apparent once sufficient data are accumulated. This paper applies recent research from philosophy of science to uncover three important problems of mechanistic modelling which may compromise its mainstream application, namely: the dilemma of formal and informal descriptions, the need to express degrees of confidence and the need of an argumentation framework. We report experience and research on similar problems from software engineering and provide evidence that the solutions adopted there can be transferred to the biological domain. We hope this paper can provoke new opportunities for further and profitable interdisciplinary research in the field. PMID:23149931

  1. Mechanistic modelling of cancer: some reflections from software engineering and philosophy of science

    NASA Astrophysics Data System (ADS)

    Cañete-Valdeón, José M.; Wieringa, Roel; Smallbone, Kieran

    2012-12-01

    There is a growing interest in mathematical mechanistic modelling as a promising strategy for understanding tumour progression. This approach is accompanied by a methodological change of making research, in which models help to actively generate hypotheses instead of waiting for general principles to become apparent once sufficient data are accumulated. This paper applies recent research from philosophy of science to uncover three important problems of mechanistic modelling which may compromise its mainstream application, namely: the dilemma of formal and informal descriptions, the need to express degrees of confidence and the need of an argumentation framework. We report experience and research on similar problems from software engineering and provide evidence that the solutions adopted there can be transferred to the biological domain. We hope this paper can provoke new opportunities for further and profitable interdisciplinary research in the field.

  2. Aortic Binding of AZD5248: Mechanistic Insight and Reactivity Assays To Support Lead Optimzation.

    PubMed

    Bragg, Ryan A; Brocklehurst, Simon; Gustafsson, Frida; Goodman, James; Hickling, Kevin; MacFaul, Philip A; Swallow, Steve; Tugwood, Jonathan

    2015-10-19

    The oral dipeptidyl peptidase 1 (DPP1) inhibitor AZD5248 showed aortic binding in a rat quantitative whole-body autoradiography (QWBA) study, and its development was terminated prior to human dosing. A mechanistic hypothesis for this finding was established invoking reactivity with aldehydes involved in the cross-linking of elastin, a major component of aortic tissue. This was tested by developing a simple aldehyde chemical reactivity assay and a novel in vitro competitive covalent binding assay. Results obtained with AZD5248, literature compounds, and close analogues of AZD5248 support the mechanistic hypothesis and provide validation for the use of these assays in a two tier screening approach to support lead optimization. The strengths and limitations of these assays are discussed. PMID:26351880

  3. Synthesis, cytotoxicity and mechanistic evaluation of 4-oxoquinoline-3-carboxamide derivatives: finding new potential anticancer drugs.

    PubMed

    Forezi, Luana da S M; Tolentino, Nathalia M C; de Souza, Alessandra M T; Castro, Helena C; Montenegro, Raquel C; Dantas, Rafael F; Oliveira, Maria E I M; Silva, Floriano P; Barreto, Leilane H; Burbano, Rommel M R; Abrahim-Vieira, Bárbara; de Oliveira, Riethe; Ferreira, Vitor F; Cunha, Anna C; Boechat, Fernanda da C S; de Souza, Maria Cecília B V

    2014-01-01

    As part of a continuing search for new potential anticancer candidates, we describe the synthesis, cytotoxicity and mechanistic evaluation of a series of 4-oxoquinoline-3-carboxamide derivatives as novel anticancer agents. The inhibitory activity of compounds 10-18 was determined against three cancer cell lines using the MTT colorimetric assay. The screening revealed that derivatives 16b and 17b exhibited significant cytotoxic activity against the gastric cancer cell line but was not active against a normal cell line, in contrast to doxorubicin, a standard chemotherapeutic drug in clinical use. Interestingly, no hemolytical activity was observed when the toxicity of 16b and 17b was tested against blood cells. The in silico and in vitro mechanistic evaluation indicated the potential of 16b as a lead for the development of novel anticancer agents against gastric cancer cells. PMID:24858098

  4. Mechanistic basis of resistance to PCBs in Atlantic tomcod from the Hudson River.

    PubMed

    Wirgin, Isaac; Roy, Nirmal K; Loftus, Matthew; Chambers, R Christopher; Franks, Diana G; Hahn, Mark E

    2011-03-11

    The mechanistic basis of resistance of vertebrate populations to contaminants, including Atlantic tomcod from the Hudson River (HR) to polychlorinated biphenyls (PCBs), is unknown. HR tomcod exhibited variants in the aryl hydrocarbon receptor 2 (AHR2) that were nearly absent elsewhere. In ligand-binding assays, AHR2-1 protein (common in the HR) was impaired as compared to widespread AHR2-2 in binding TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) and in driving expression in reporter gene assays in AHR-deficient cells treated with TCDD or PCB126. We identified a six-base deletion in AHR2 as the basis of resistance and suggest that the HR population has undergone rapid evolution, probably due to contaminant exposure. This mechanistic basis of resistance in a vertebrate population provides evidence of evolutionary change due to selective pressure at a single locus. PMID:21330491

  5. Mechanistic exploration of a bi-directional PDT-based combination in pancreatic cancer (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Huang, Huang-Chiao; Mallidi, Srivalleesha; Liu, Joyce; Chiang, Chun-Te; Mai, Zhiming; Goldschmidt, Ruth; Rizvi, Imran; Ebrahim-Zadeh, Neema; Hasan, Tayyaba

    2016-03-01

    It is increasingly evident that the most effective cancer treatments will involve interactive regimens that target multiple non-overlapping pathways, preferably such that each component enhances the others to improve outcomes while minimizing systemic toxicities. Toward this goal, we developed a combination of photodynamic therapy and irinotecan, which mechanistically cooperate with each other, beyond their individual tumor destruction pathways, to cause synergistic reduction in orthotopic pancreatic tumor burden. A three-way mechanistic basis of the observed the synergism will be discussed: (i) PDT downregulates drug efflux transporters to increase intracellular irinotecan levels. (ii) Irinotecan reduces the expression of hypoxia-induced marker, which is upregulated by PDT. (iii) PDT downregulates irinotecan-induced survivin expression to amplify the apoptotic and anti-proliferative effects. The clinical translation potential of the combination will also be highlighted.

  6. Mechanistic determinants of the directionality and energetics of active export by a heterodimeric ABC transporter

    NASA Astrophysics Data System (ADS)

    Grossmann, Nina; Vakkasoglu, Ahmet S.; Hulpke, Sabine; Abele, Rupert; Gaudet, Rachelle; Tampé, Robert

    2014-11-01

    The ATP-binding cassette (ABC) transporter associated with antigen processing (TAP) participates in immune surveillance by moving proteasomal products into the endoplasmic reticulum (ER) lumen for major histocompatibility complex class I loading and cell surface presentation to cytotoxic T cells. Here we delineate the mechanistic basis for antigen translocation. Notably, TAP works as a molecular diode, translocating peptide substrates against the gradient in a strict unidirectional way. We reveal the importance of the D-loop at the dimer interface of the two nucleotide-binding domains (NBDs) in coupling substrate translocation with ATP hydrolysis and defining transport vectoriality. Substitution of the conserved aspartate, which coordinates the ATP-binding site, decreases NBD dimerization affinity and turns the unidirectional primary active pump into a passive bidirectional nucleotide-gated facilitator. Thus, ATP hydrolysis is not required for translocation per se, but is essential for both active and unidirectional transport. Our data provide detailed mechanistic insight into how heterodimeric ABC exporters operate.

  7. A data-intensive approach to mechanistic elucidation applied to chiral anion catalysis

    PubMed Central

    Milo, Anat; Neel, Andrew J.; Toste, F. Dean; Sigman, Matthew S.

    2015-01-01

    Knowledge of chemical reaction mechanisms can facilitate catalyst optimization, but extracting that knowledge from a complex system is often challenging. Here we present a data-intensive method for deriving and then predictively applying a mechanistic model of an enantioselective organic reaction. As a validating case study, we selected an intramolecular dehydrogenative C-N coupling reaction, catalyzed by chiral phosphoric acid derivatives, in which catalyst-substrate association involves weak, non-covalent interactions. Little was previously understood regarding the structural origin of enantioselectivity in this system. Catalyst and substrate substituent effects were probed by systematic physical organic trend analysis. Plausible interactions between the substrate and catalyst that govern enantioselectivity were identified and supported experimentally, indicating that such an approach can afford an efficient means of leveraging mechanistic insight to optimize catalyst design. PMID:25678656

  8. Conceptual models for waste tank mechanistic analysis. Status report, January 1991

    SciTech Connect

    Allemann, R. T.; Antoniak, Z. I.; Eyler, L. L.; Liljegren, L. M.; Roberts, J. S.

    1992-02-01

    Pacific Northwest Laboratory (PNL) is conducting a study for Westinghouse Hanford Company (Westinghouse Hanford), a contractor for the US Department of Energy (DOE). The purpose of the work is to study possible mechanisms and fluid dynamics contributing to the periodic release of gases from double-shell waste storage tanks at the Hanford Site in Richland, Washington. This interim report emphasizing the modeling work follows two other interim reports, Mechanistic Analysis of Double-Shell Tank Gas Release Progress Report -- November 1990 and Collection and Analysis of Existing Data for Waste Tank Mechanistic Analysis Progress Report -- December 1990, that emphasized data correlation and mechanisms. The approach in this study has been to assemble and compile data that are pertinent to the mechanisms, analyze the data, evaluate physical properties and parameters, evaluate hypothetical mechanisms, and develop mathematical models of mechanisms.

  9. Formalising a mechanistic linkage between heterotrophic feeding and thermal bleaching resistance

    NASA Astrophysics Data System (ADS)

    Wooldridge, Scott A.

    2014-12-01

    In this paper, I utilise the CO2 (sink) limitation model of coral bleaching to propose a new biochemical framework that explains how certain (well-adapted) coral species can utilise heterotrophic carbon acquisition to combat the damaging algal photoinhibition response sequence that underpins thermal bleaching, thereby increasing thermal bleaching resistance. This mechanistic linkage helps to clarify a number of previously challenging experimental responses arising from feeding (versus starved) temperature stress experiments, and isotope labelling (tracer) experiments with heterotrophic carbon sources (e.g., zooplankton). In an era of rapidly warming surface ocean temperatures, the conferred fitness benefits arising from such a mechanistic linkage are considerable. Yet, various ecological constraints are outlined which caution against the ultimate benefit of the mechanism for raising bleaching thresholds at the coral community (reef) scale. Future experiments are suggested that can strengthen these proposed arguments.

  10. Substrate inhibition in the heterogeneous catalyzed aldol condensation: A mechanistic study of supported organocatalysts

    SciTech Connect

    Kandel, Kapil; Althaus, Stacey M.; Peeraphatdit, Chorthip; Kobayashi, Takeshi; Trewyn, Brian G.; Pruski, Marek; Slowing, Igor I.

    2012-05-23

    In this study, we demonstrate how materials science can be combined with the established methods of organic chemistry to find mechanistic bottlenecks and redesign heterogeneous catalysts for improved performance. By using solid-state NMR, infrared spectroscopy, surface and kinetic analysis, we prove the existence of a substrate inhibition in the aldol condensation catalyzed by heterogeneous amines. We show that modifying the structure of the supported amines according to the proposed mechanism dramatically enhances the activity of the heterogeneous catalyst. We also provide evidence that the reaction benefits significantly from the surface chemistry of the silica support, which plays the role of a co-catalyst, giving activities up to two orders of magnitude larger than those of homogeneous amines. This study confirms that the optimization of a heterogeneous catalyst depends as much on obtaining organic mechanistic information as it does on controlling the structure of the support.