Requirements on mechanistic NPP models used in CSS for diagnostics and predictions

International Nuclear Information System (INIS)

Juslin, K.

1996-01-01

Mechanistic models have for several years with good experience been used for operators' support in electric power dispatching centres. Some models of limited scope have already been in use at nuclear power plants. It is considered that also advanced mechanistic models in combination with present computer technology with preference could be used in Computerized Support Systems (CSS) for the assistance of Nuclear Power Plant (NPP) operators. Requirements with respect to accuracy, validity range, speed flexibility and level of detail on the models used for such purposes are discussed. Quality Assurance, Verification and Validation efforts are considered. A long term commitment in the field of mechanistic modelling and real time simulation is considered as the key to successful implementations. The Advanced PROcess Simulation (APROS) code system and simulation environment developed at the Technical Research Centre of Finland (VTT) is intended also for CSS applications in NPP control rooms. (author). 4 refs

Rational and Mechanistic Perspectives on Reinforcement Learning

Science.gov (United States)

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…

A Mechanistic Beta-Binomial Probability Model for mRNA Sequencing Data.

Science.gov (United States)

Smith, Gregory R; Birtwistle, Marc R

2016-01-01

A main application for mRNA sequencing (mRNAseq) is determining lists of differentially-expressed genes (DEGs) between two or more conditions. Several software packages exist to produce DEGs from mRNAseq data, but they typically yield different DEGs, sometimes markedly so. The underlying probability model used to describe mRNAseq data is central to deriving DEGs, and not surprisingly most softwares use different models and assumptions to analyze mRNAseq data. Here, we propose a mechanistic justification to model mRNAseq as a binomial process, with data from technical replicates given by a binomial distribution, and data from biological replicates well-described by a beta-binomial distribution. We demonstrate good agreement of this model with two large datasets. We show that an emergent feature of the beta-binomial distribution, given parameter regimes typical for mRNAseq experiments, is the well-known quadratic polynomial scaling of variance with the mean. The so-called dispersion parameter controls this scaling, and our analysis suggests that the dispersion parameter is a continually decreasing function of the mean, as opposed to current approaches that impose an asymptotic value to the dispersion parameter at moderate mean read counts. We show how this leads to current approaches overestimating variance for moderately to highly expressed genes, which inflates false negative rates. Describing mRNAseq data with a beta-binomial distribution thus may be preferred since its parameters are relatable to the mechanistic underpinnings of the technique and may improve the consistency of DEG analysis across softwares, particularly for moderately to highly expressed genes.

Modeling systems-level dynamics: Understanding without mechanistic explanation in integrative systems biology.

Science.gov (United States)

MacLeod, Miles; Nersessian, Nancy J

2015-02-01

In this paper we draw upon rich ethnographic data of two systems biology labs to explore the roles of explanation and understanding in large-scale systems modeling. We illustrate practices that depart from the goal of dynamic mechanistic explanation for the sake of more limited modeling goals. These processes use abstract mathematical formulations of bio-molecular interactions and data fitting techniques which we call top-down abstraction to trade away accurate mechanistic accounts of large-scale systems for specific information about aspects of those systems. We characterize these practices as pragmatic responses to the constraints many modelers of large-scale systems face, which in turn generate more limited pragmatic non-mechanistic forms of understanding of systems. These forms aim at knowledge of how to predict system responses in order to manipulate and control some aspects of them. We propose that this analysis of understanding provides a way to interpret what many systems biologists are aiming for in practice when they talk about the objective of a "systems-level understanding." Copyright © 2014 Elsevier Ltd. All rights reserved.

Mechanistic curiosity will not kill the Bayesian cat

NARCIS (Netherlands)

Borsboom, D.; Wagenmakers, E.-J.; Romeijn, J.-W.

2011-01-01

Jones & Love (J&L) suggest that Bayesian approaches to the explanation of human behavior should be constrained by mechanistic theories. We argue that their proposal misconstrues the relation between process models, such as the Bayesian model, and mechanisms. While mechanistic theories can answer

Mechanistic curiosity will not kill the Bayesian cat

NARCIS (Netherlands)

Borsboom, Denny; Wagenmakers, Eric-Jan; Romeijn, Jan-Willem

Jones & Love (J&L) suggest that Bayesian approaches to the explanation of human behavior should be constrained by mechanistic theories. We argue that their proposal misconstrues the relation between process models, such as the Bayesian model, and mechanisms. While mechanistic theories can answer

Mechanistic assessment of hillslope transpiration controls of diel subsurface flow: a steady-state irrigation approach

Science.gov (United States)

H.R. Barnard; C.B. Graham; W.J. van Verseveld; J.R. Brooks; B.J. Bond; J.J. McDonnell

2010-01-01

Mechanistic assessment of how transpiration influences subsurface flow is necessary to advance understanding of catchment hydrology. We conducted a 24-day, steady-state irrigation experiment to quantify the relationships among soil moisture, transpiration and hillslope subsurface flow. Our objectives were to: (1) examine the time lag between maximum transpiration and...

QLab 3 show control projects for live performances & installations

CERN Document Server

Hopgood, Jeromy

2013-01-01

Used from Broadway to Britain's West End, QLab software is the tool of choice for many of the world's most prominent sound, projection, and integrated media designers. QLab 3 Show Control: Projects for Live Performances & Installations is a project-based book on QLab software covering sound, video, and show control. With information on both sound and video system basics and the more advanced functions of QLab such as MIDI show control, new OSC capabilities, networking, video effects, and microphone integration, each chapter's specific projects will allow you to learn the software's capabilitie

Mechanistic effect modeling for ecological risk assessment: where to go from here?

Science.gov (United States)

Grimm, Volker; Martin, Benjamin T

2013-07-01

Mechanistic effect models (MEMs) consider the mechanisms of how chemicals affect individuals and ecological systems such as populations and communities. There is an increasing awareness that MEMs have high potential to make risk assessment of chemicals more ecologically relevant than current standard practice. Here we discuss what kinds of MEMs are needed to improve scientific and regulatory aspects of risk assessment. To make valid predictions for a wide range of environmental conditions, MEMs need to include a sufficient amount of emergence, for example, population dynamics emerging from what individual organisms do. We present 1 example where the life cycle of individuals is described using Dynamic Energy Budget theory. The resulting individual-based population model is thus parameterized at the individual level but correctly predicts multiple patterns at the population level. This is the case for both control and treated populations. We conclude that the state-of-the-art in mechanistic effect modeling has reached a level where MEMs are robust and predictive enough to be used in regulatory risk assessment. Mechanistic effect models will thus be used to advance the scientific basis of current standard practice and will, if their development follows Good Modeling Practice, be included in a standardized way in future regulatory risk assessments. Copyright © 2013 SETAC.

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

Science.gov (United States)

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

Mechanistic Indicators of Childhood Asthma (MICA): piloting ...

Science.gov (United States)

Background: Modem methods in molecular biology and advanced computational tools show promise in elucidating complex interactions that occur between genes and environmental factors in diseases such as asthma; however appropriately designed studies are critical for these methods to reach their full potential. Objective: We used a case-control study to investigate whether genomic data (blood gene expression), viewed together with a spectrum of exposure effects and susceptibility markers (blood, urine and nail), can provide a mechanistic explanation for the increased susceptibility of asthmatics to ambient air pollutants. Methods: We studied 205 non-asthmatic and asthmatic children, (9-12 years of age) who participated in a clinical study in Detroit, Michigan. The study combines a traditional epidemiological design with an integrative approach to investigate the environmental exposure of children to indoor-outdoor air. The study includes measurements of internal dose (metals, allergen specific IgE, PAH and VOC metabolites) and clinical measures of health outcome (immunological, cardiovascular and respiratory). Results: Expected immunological indications of asthma have been obtained. In addition, initial results from our analyses point to the complex nature of childhood health and risk factors linked to metabolic syndrome (obesity, blood pressure and dyslipidemia). For example, 31% and 34% of the asthmatic MICA subjects were either overweight (BMI > 25) o

Generative mechanistic explanation building in undergraduate molecular and cellular biology

Science.gov (United States)

Southard, Katelyn M.; Espindola, Melissa R.; Zaepfel, Samantha D.; Bolger, Molly S.

2017-09-01

When conducting scientific research, experts in molecular and cellular biology (MCB) use specific reasoning strategies to construct mechanistic explanations for the underlying causal features of molecular phenomena. We explored how undergraduate students applied this scientific practice in MCB. Drawing from studies of explanation building among scientists, we created and applied a theoretical framework to explore the strategies students use to construct explanations for 'novel' biological phenomena. Specifically, we explored how students navigated the multi-level nature of complex biological systems using generative mechanistic reasoning. Interviews were conducted with introductory and upper-division biology students at a large public university in the United States. Results of qualitative coding revealed key features of students' explanation building. Students used modular thinking to consider the functional subdivisions of the system, which they 'filled in' to varying degrees with mechanistic elements. They also hypothesised the involvement of mechanistic entities and instantiated abstract schema to adapt their explanations to unfamiliar biological contexts. Finally, we explored the flexible thinking that students used to hypothesise the impact of mutations on multi-leveled biological systems. Results revealed a number of ways that students drew mechanistic connections between molecules, functional modules (sets of molecules with an emergent function), cells, tissues, organisms and populations.

Mechanistic modelling of the drying behaviour of single pharmaceutical granules

DEFF Research Database (Denmark)

Thérèse F.C. Mortier, Séverine; Beer, Thomas De; Gernaey, Krist

2012-01-01

The trend to move towards continuous production processes in pharmaceutical applications enhances the necessity to develop mechanistic models to understand and control these processes. This work focuses on the drying behaviour of a single wet granule before tabletting, using a six...... phase (submodel 2), the water inside the granule evaporates. The second submodel contains an empirical power coefficient, b. A sensitivity analysis was performed to study the influence of parameters on the moisture content of single pharmaceutical granules, which clearly points towards the importance...

"Ratio via Machina": Three Standards of Mechanistic Explanation in Sociology

Science.gov (United States)

Aviles, Natalie B.; Reed, Isaac Ariail

2017-01-01

Recently, sociologists have expended much effort in attempts to define social mechanisms. We intervene in these debates by proposing that sociologists in fact have a choice to make between three standards of what constitutes a good mechanistic explanation: substantial, formal, and metaphorical mechanistic explanation. All three standards are…

Toward mechanistic classification of enzyme functions.

Science.gov (United States)

Almonacid, Daniel E; Babbitt, Patricia C

2011-06-01

Classification of enzyme function should be quantitative, computationally accessible, and informed by sequences and structures to enable use of genomic information for functional inference and other applications. Large-scale studies have established that divergently evolved enzymes share conserved elements of structure and common mechanistic steps and that convergently evolved enzymes often converge to similar mechanisms too, suggesting that reaction mechanisms could be used to develop finer-grained functional descriptions than provided by the Enzyme Commission (EC) system currently in use. Here we describe how evolution informs these structure-function mappings and review the databases that store mechanisms of enzyme reactions along with recent developments to measure ligand and mechanistic similarities. Together, these provide a foundation for new classifications of enzyme function. Copyright © 2011 Elsevier Ltd. All rights reserved.

Improving the International Agency for Research on Cancer's consideration of mechanistic evidence

International Nuclear Information System (INIS)

Goodman, Julie; Lynch, Heather

2017-01-01

Background: The International Agency for Research on Cancer (IARC) recently developed a framework for evaluating mechanistic evidence that includes a list of 10 key characteristics of carcinogens. This framework is useful for identifying and organizing large bodies of literature on carcinogenic mechanisms, but it lacks sufficient guidance for conducting evaluations that fully integrate mechanistic evidence into hazard assessments. Objectives: We summarize the framework, and suggest approaches to strengthen the evaluation of mechanistic evidence using this framework. Discussion: While the framework is useful for organizing mechanistic evidence, its lack of guidance for implementation limits its utility for understanding human carcinogenic potential. Specifically, it does not include explicit guidance for evaluating the biological significance of mechanistic endpoints, inter- and intra-individual variability, or study quality and relevance. It also does not explicitly address how mechanistic evidence should be integrated with other realms of evidence. Because mechanistic evidence is critical to understanding human cancer hazards, we recommend that IARC develop transparent and systematic guidelines for the use of this framework so that mechanistic evidence will be evaluated and integrated in a robust manner, and concurrently with other realms of evidence, to reach a final human cancer hazard conclusion. Conclusions: IARC does not currently provide a standardized approach to evaluating mechanistic evidence. Incorporating the recommendations discussed here will make IARC analyses of mechanistic evidence more transparent, and lead to assessments of cancer hazards that reflect the weight of the scientific evidence and allow for scientifically defensible decision-making. - Highlights: • IARC has a revised framework for evaluating literature on carcinogenic mechanisms. • The framework is based on 10 key characteristics of carcinogens. • IARC should develop transparent

Improving the International Agency for Research on Cancer's consideration of mechanistic evidence

Energy Technology Data Exchange (ETDEWEB)

Goodman, Julie, E-mail: jgoodman@gradientcorp.com; Lynch, Heather

2017-03-15

Background: The International Agency for Research on Cancer (IARC) recently developed a framework for evaluating mechanistic evidence that includes a list of 10 key characteristics of carcinogens. This framework is useful for identifying and organizing large bodies of literature on carcinogenic mechanisms, but it lacks sufficient guidance for conducting evaluations that fully integrate mechanistic evidence into hazard assessments. Objectives: We summarize the framework, and suggest approaches to strengthen the evaluation of mechanistic evidence using this framework. Discussion: While the framework is useful for organizing mechanistic evidence, its lack of guidance for implementation limits its utility for understanding human carcinogenic potential. Specifically, it does not include explicit guidance for evaluating the biological significance of mechanistic endpoints, inter- and intra-individual variability, or study quality and relevance. It also does not explicitly address how mechanistic evidence should be integrated with other realms of evidence. Because mechanistic evidence is critical to understanding human cancer hazards, we recommend that IARC develop transparent and systematic guidelines for the use of this framework so that mechanistic evidence will be evaluated and integrated in a robust manner, and concurrently with other realms of evidence, to reach a final human cancer hazard conclusion. Conclusions: IARC does not currently provide a standardized approach to evaluating mechanistic evidence. Incorporating the recommendations discussed here will make IARC analyses of mechanistic evidence more transparent, and lead to assessments of cancer hazards that reflect the weight of the scientific evidence and allow for scientifically defensible decision-making. - Highlights: • IARC has a revised framework for evaluating literature on carcinogenic mechanisms. • The framework is based on 10 key characteristics of carcinogens. • IARC should develop transparent

Predicting interactions from mechanistic information: Can omic data validate theories?

International Nuclear Information System (INIS)

Borgert, Christopher J.

2007-01-01

To address the most pressing and relevant issues for improving mixture risk assessment, researchers must first recognize that risk assessment is driven by both regulatory requirements and scientific research, and that regulatory concerns may expand beyond the purely scientific interests of researchers. Concepts of 'mode of action' and 'mechanism of action' are used in particular ways within the regulatory arena, depending on the specific assessment goals. The data requirements for delineating a mode of action and predicting interactive toxicity in mixtures are not well defined from a scientific standpoint due largely to inherent difficulties in testing certain underlying assumptions. Understanding the regulatory perspective on mechanistic concepts will be important for designing experiments that can be interpreted clearly and applied in risk assessments without undue reliance on extrapolation and assumption. In like fashion, regulators and risk assessors can be better equipped to apply mechanistic data if the concepts underlying mechanistic research and the limitations that must be placed on interpretation of mechanistic data are understood. This will be critically important for applying new technologies to risk assessment, such as functional genomics, proteomics, and metabolomics. It will be essential not only for risk assessors to become conversant with the language and concepts of mechanistic research, including new omic technologies, but also, for researchers to become more intimately familiar with the challenges and needs of risk assessment

Explanation and inference: Mechanistic and functional explanations guide property generalization

Directory of Open Access Journals (Sweden)

Tania eLombrozo

2014-09-01

Full Text Available 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.

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

Science.gov (United States)

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.

Controlling Kuka Industrial Robots : Flexible Communication Interface JOpenShowVar.

OpenAIRE

Sanfilippo, Filippo; Hatledal, Lars Ivar; Zhang, Houxiang; Fago, Massimiliano; Pettersen, Kristin Ytterstad

2015-01-01

JOpenShowVar is a Java open-source cross-platform communication interface to Kuka industrial robots. This novel interface allows for read-write use of the controlled manipulator variables and data structures. JOpenShowVar, which is compatible with all the Kuka industrial robots that use KUKA Robot Controller version 4 (KR C4) and KUKA Robot Controller version 2 (KR C2), runs as a client on a remote computer connected with the Kuka controller via TCP/IP. Even though only soft real-time applica...

Toward a Rational and Mechanistic Account of Mental Effort.

Science.gov (United States)

Shenhav, Amitai; Musslick, Sebastian; Lieder, Falk; Kool, Wouter; Griffiths, Thomas L; Cohen, Jonathan D; Botvinick, Matthew M

2017-07-25

In spite of its familiar phenomenology, the mechanistic basis for mental effort remains poorly understood. Although most researchers agree that mental effort is aversive and stems from limitations in our capacity to exercise cognitive control, it is unclear what gives rise to those limitations and why they result in an experience of control as costly. The presence of these control costs also raises further questions regarding how best to allocate mental effort to minimize those costs and maximize the attendant benefits. This review explores recent advances in computational modeling and empirical research aimed at addressing these questions at the level of psychological process and neural mechanism, examining both the limitations to mental effort exertion and how we manage those limited cognitive resources. We conclude by identifying remaining challenges for theoretical accounts of mental effort as well as possible applications of the available findings to understanding the causes of and potential solutions for apparent failures to exert the mental effort required of us.

The upper and lower limits of the mechanistic stoichiometry of mitochondrial oxidative phosphorylation. Stoichiometry of oxidative phosphorylation.

Science.gov (United States)

Beavis, A D; Lehninger, A L

1986-07-15

Determination of the intrinsic or mechanistic P/O ratio of oxidative phosphorylation is difficult because of the unknown magnitude of leak fluxes. Applying a new approach developed to overcome this problem (see our preceding paper in this journal), the relationships between the rate of O2 uptake [( Jo)3], the net rate of phosphorylation (Jp), the P/O ratio, and the respiratory control ratio (RCR) have been determined in rat liver mitochondria when the rate of phosphorylation was systematically varied by three specific means. (a) When phosphorylation is titrated with carboxyatractyloside, linear relationships are observed between Jp and (Jo)3. These data indicate that the upper limit of the mechanistic P/O ratio is 1.80 for succinate and 2.90 for 3-hydroxybutyrate oxidation. (b) Titration with malonate or antimycin yields linear relationships between Jp and (Jo)3. These data give the lower limit of the mechanistic P/O ratio of 1.63 for succinate and 2.66 for 3-hydroxybutyrate oxidation. (c) Titration with a protonophore yields linear relationships between Jp, (Jo)3, and (Jo)4 and between P/O and 1/RCR. Extrapolation of the P/O ratio to 1/RCR = 0 yields P/O ratios of 1.75 for succinate and 2.73 for 3-hydroxybutyrate oxidation which must be equal to or greater than the mechanistic stoichiometry. When published values for the H+/O and H+/ATP ejection ratios are taken into consideration, these measurements suggest that the mechanistic P/O ratio is 1.75 for succinate oxidation and 2.75 for NADH oxidation.

Effects of Asphalt Mix Design Properties on Pavement Performance: A Mechanistic Approach

Directory of Open Access Journals (Sweden)

Ahmad M. Abu Abdo

2016-01-01

Full Text Available The main objective of this study was to investigate the effects of hot mix asphalt material properties on the performance of flexible pavements via mechanistic approach. 3D Move Analysis software was utilized to determine rutting and cracking distresses in an asphalt concrete (AC layer. Fourteen different Superpave mixes were evaluated by utilizing results of the Dynamic Modulus (|E⁎| Test and the Dynamic Shear Modulus (|G⁎| Test. Results showed that with the increase of binder content, the tendency of rutting in AC layer increased. However, with the increase of binder content, the cracking of AC layer lessened. Furthermore, when different binder grades were evaluated, results showed that with the increase of the upper binder grade number, rutting decreased, and with the increase of the lower binder grade number, rutting increased. Furthermore, analysis showed that with the increase of the lower binder grade number, higher percent of bottom up cracks would result. As a result of the analysis, binder grade should not be solely considered for cracking in AC layer; binder content and aggregate structure play a big role. Finally, results illustrated that the mechanistic approach is a better tool to determine the performance of asphalt pavement than commonly used methods.

Managing mechanistic and organic structure in health care organizations.

Science.gov (United States)

Olden, Peter C

2012-01-01

Managers at all levels in a health care organization must organize work to achieve the organization's mission and goals. This requires managers to decide the organization structure, which involves dividing the work among jobs and departments and then coordinating them all toward the common purpose. Organization structure, which is reflected in an organization chart, may range on a continuum from very mechanistic to very organic. Managers must decide how mechanistic versus how organic to make the entire organization and each of its departments. To do this, managers should carefully consider 5 factors for the organization and for each individual department: external environment, goals, work production, size, and culture. Some factors may push toward more mechanistic structure, whereas others may push in the opposite direction toward more organic structure. Practical advice can help managers at all levels design appropriate structure for their departments and organization.

Cognitive science as an interface between rational and mechanistic explanation.

Science.gov (United States)

Chater, Nick

2014-04-01

Cognitive science views thought as computation; and computation, by its very nature, can be understood in both rational and mechanistic terms. In rational terms, a computation solves some information processing problem (e.g., mapping sensory information into a description of the external world; parsing a sentence; selecting among a set of possible actions). In mechanistic terms, a computation corresponds to causal chain of events in a physical device (in engineering context, a silicon chip; in biological context, the nervous system). The discipline is thus at the interface between two very different styles of explanation--as the papers in the current special issue well illustrate, it explores the interplay of rational and mechanistic forces. Copyright © 2014 Cognitive Science Society, Inc.

Detailed Mechanistic Studies on Palladium-Catalyzed Selective C-H Olefination with Aliphatic Alkenes: A Significant Influence of Proton Shuttling.

Science.gov (United States)

Deb, Arghya; Hazra, Avijit; Peng, Qian; Paton, Robert S; Maiti, Debabrata

2017-01-18

Directing group-assisted regioselective C-H olefination with electronically biased olefins is well studied. However, the incorporation of unactivated olefins has remained largely unsuccessful. A proper mechanistic understanding of olefination involving unactivated alkenes is therefore essential for enhancing their usage in future. In this Article, detailed experimental and computational mechanistic studies on palladium catalyzed C-H olefination with unactivated, aliphatic alkenes are described. The isolation of Pd(II) intermediates is shown to be effective for elucidating the elementary steps involved in catalytic olefination. Reaction rate and order determination, control experiments, isotopic labeling studies, and Hammett analysis have been used to understand the reaction mechanism. The results from these experimental studies implicate β-hydride elimination as the rate-determining step and that a mechanistic switch occurs between cationic and neutral pathway. Computational studies support this interpretation of the experimental evidence and are used to uncover the origins of selectivity.

Inferring the Impact of Regulatory Mechanisms that Underpin CD8+ T Cell Control of B16 Tumor Growth In vivo Using Mechanistic Models and Simulation.

Science.gov (United States)

Klinke, David J; Wang, Qing

2016-01-01

A major barrier for broadening the efficacy of immunotherapies for cancer is identifying key mechanisms that limit the efficacy of tumor infiltrating lymphocytes. Yet, identifying these mechanisms using human samples and mouse models for cancer remains a challenge. While interactions between cancer and the immune system are dynamic and non-linear, identifying the relative roles that biological components play in regulating anti-tumor immunity commonly relies on human intuition alone, which can be limited by cognitive biases. To assist natural intuition, modeling and simulation play an emerging role in identifying therapeutic mechanisms. To illustrate the approach, we developed a multi-scale mechanistic model to describe the control of tumor growth by a primary response of CD8+ T cells against defined tumor antigens using the B16 C57Bl/6 mouse model for malignant melanoma. The mechanistic model was calibrated to data obtained following adenovirus-based immunization and validated to data obtained following adoptive transfer of transgenic CD8+ T cells. More importantly, we use simulation to test whether the postulated network topology, that is the modeled biological components and their associated interactions, is sufficient to capture the observed anti-tumor immune response. Given the available data, the simulation results also provided a statistical basis for quantifying the relative importance of different mechanisms that underpin CD8+ T cell control of B16F10 growth. By identifying conditions where the postulated network topology is incomplete, we illustrate how this approach can be used as part of an iterative design-build-test cycle to expand the predictive power of the model.

A nested mechanistic sub-study into the effect of tranexamic acid versus placebo on intracranial haemorrhage and cerebral ischaemia in isolated traumatic brain injury: study protocol for a randomised controlled trial (CRASH-3 Trial Intracranial Bleeding Mechanistic Sub-Study [CRASH-3 IBMS]).

Science.gov (United States)

Mahmood, Abda; Roberts, Ian; Shakur, Haleema

2017-07-17

Tranexamic acid prevents blood clots from breaking down and reduces bleeding. However, it is uncertain whether tranexamic acid is effective in traumatic brain injury. The CRASH-3 trial is a randomised controlled trial that will examine the effect of tranexamic acid (versus placebo) on death and disability in 13,000 patients with traumatic brain injury. The CRASH-3 trial hypothesizes that tranexamic acid will reduce intracranial haemorrhage, which will reduce the risk of death. Although it is possible that tranexamic acid will reduce intracranial bleeding, there is also a potential for harm. In particular, tranexamic acid may increase the risk of cerebral thrombosis and ischaemia. The protocol detailed here is for a mechanistic sub-study nested within the CRASH-3 trial. This mechanistic sub-study aims to examine the effect of tranexamic acid (versus placebo) on intracranial bleeding and cerebral ischaemia. The CRASH-3 Intracranial Bleeding Mechanistic Sub-Study (CRASH-3 IBMS) is nested within a prospective, double-blind, multi-centre, parallel-arm randomised trial called the CRASH-3 trial. The CRASH-3 IBMS will be conducted in a cohort of approximately 1000 isolated traumatic brain injury patients enrolled in the CRASH-3 trial. In the CRASH-3 IBMS, brain scans acquired before and after randomisation are examined, using validated methods, for evidence of intracranial bleeding and cerebral ischaemia. The primary outcome is the total volume of intracranial bleeding measured on computed tomography after randomisation, adjusting for baseline bleeding volume. Secondary outcomes include progression of intracranial haemorrhage (from pre- to post-randomisation scans), new intracranial haemorrhage (seen on post- but not pre-randomisation scans), intracranial haemorrhage following neurosurgery, and new focal ischaemic lesions (seen on post-but not pre-randomisation scans). A linear regression model will examine whether receipt of the trial treatment can predict haemorrhage

Simulating the Risk of Liver Fluke Infection using a Mechanistic Hydro-epidemiological Model

Science.gov (United States)

Beltrame, Ludovica; Dunne, Toby; Rose, Hannah; Walker, Josephine; Morgan, Eric; Vickerman, Peter; Wagener, Thorsten

2016-04-01

Liver Fluke (Fasciola hepatica) is a common parasite found in livestock and responsible for considerable economic losses throughout the world. Risk of infection is strongly influenced by climatic and hydrological conditions, which characterise the host environment for parasite development and transmission. Despite on-going control efforts, increases in fluke outbreaks have been reported in recent years in the UK, and have been often attributed to climate change. Currently used fluke risk models are based on empirical relationships derived between historical climate and incidence data. However, hydro-climate conditions are becoming increasingly non-stationary due to climate change and direct anthropogenic impacts such as land use change, making empirical models unsuitable for simulating future risk. In this study we introduce a mechanistic hydro-epidemiological model for Liver Fluke, which explicitly simulates habitat suitability for disease development in space and time, representing the parasite life cycle in connection with key environmental conditions. The model is used to assess patterns of Liver Fluke risk for two catchments in the UK under current and potential future climate conditions. Comparisons are made with a widely used empirical model employing different datasets, including data from regional veterinary laboratories. Results suggest that mechanistic models can achieve adequate predictive ability and support adaptive fluke control strategies under climate change scenarios.

Mechanistic Links Between PARP, NAD, and Brain Inflammation After TBI

Science.gov (United States)

2015-10-01

1 AWARD NUMBER: W81XWH-13-2-0091 TITLE: Mechanistic Links Between PARP, NAD , and Brain Inflammation After TBI PRINCIPAL INVESTIGATOR...COVERED 25 Sep 2014 - 24 Sep 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Mechanistic Links Between PARP, NAD , and Brain Inflammation After TBI 5b. GRANT...efficacy of veliparib and NAD as agents for suppressing inflammation and improving outcomes after traumatic brain injury. The animal models include

Pathophysiology of white-nose syndrome in bats: a mechanistic model linking wing damage to mortality.

Science.gov (United States)

Warnecke, Lisa; Turner, James M; Bollinger, Trent K; Misra, Vikram; Cryan, Paul M; Blehert, David S; Wibbelt, Gudrun; Willis, Craig K R

2013-08-23

White-nose syndrome is devastating North American bat populations but we lack basic information on disease mechanisms. Altered blood physiology owing to epidermal invasion by the fungal pathogen Geomyces destructans (Gd) has been hypothesized as a cause of disrupted torpor patterns of affected hibernating bats, leading to mortality. Here, we present data on blood electrolyte concentration, haematology and acid-base balance of hibernating little brown bats, Myotis lucifugus, following experimental inoculation with Gd. Compared with controls, infected bats showed electrolyte depletion (i.e. lower plasma sodium), changes in haematology (i.e. increased haematocrit and decreased glucose) and disrupted acid-base balance (i.e. lower CO2 partial pressure and bicarbonate). These findings indicate hypotonic dehydration, hypovolaemia and metabolic acidosis. We propose a mechanistic model linking tissue damage to altered homeostasis and morbidity/mortality.

Proceedings of the international workshop on mechanistic understanding of radionuclide migration in compacted/intact systems

International Nuclear Information System (INIS)

Tachi, Yukio; Yui, Mikazu

2010-03-01

The international workshop on mechanistic understanding of radionuclide migration in compacted / intact systems was held at ENTRY, JAEA, Tokai on 21st - 23rd January, 2009. This workshop was hosted by Japan Atomic Energy Agency (JAEA) as part of the project on the mechanistic model/database development for radionuclide sorption and diffusion behavior in compacted / intact systems. The overall goal of the project is to develop the mechanistic model / database for a consistent understanding and prediction of migration parameters and its uncertainties for performance assessment of geological disposal of radioactive waste. The objective of the workshop is to integrate the state-of-the-art of mechanistic sorption and diffusion model in compacted / intact systems, especially in bentonite / clay systems, and discuss the JAEA's mechanistic approaches and future challenges, especially the following discussions points; 1) What's the status and difficulties for mechanistic model/database development? 2) What's the status and difficulties for applicability of mechanistic model to the compacted/intact system? 3) What's the status and difficulties for obtaining evidences for mechanistic model? 4) What's the status and difficulties for standardization of experimental methodology for batch sorption and diffusion? 5) What's the uncertainties of transport parameters in radionuclides migration analysis due to a lack of understanding/experimental methodologies, and how do we derive them? This report includes workshop program, overview and materials of each presentation, summary of discussions. (author)

Mechanistic evidence for a ring-opening pathway in the Pd-catalyzed direct arylation of benzoxazoles

DEFF Research Database (Denmark)

Sanchez, R.S.; Zhuravlev, Fedor

2007-01-01

The direct Pd-catalyzed arylation of 5-substituted benzoxazoles, used as a mechanistic model for 1,3-azoles, was investigated experimentally and computationally. The results of the primary deuterium kinetic isotope effect, Hammett studies, and H/D exchange were shown to be inconsistent with the r......The direct Pd-catalyzed arylation of 5-substituted benzoxazoles, used as a mechanistic model for 1,3-azoles, was investigated experimentally and computationally. The results of the primary deuterium kinetic isotope effect, Hammett studies, and H/D exchange were shown to be inconsistent...... with the rate-limiting electrophilic or concerted palladation. A mechanism, proposed on the basis of kinetic and computational studies, includes generation of isocyanophenolate as the key step. The DFT calculations suggest that the overall catalytic cycle is facile and is largely controlled by the C-H acidity...

New web-based applications for mechanistic case diagramming

Directory of Open Access Journals (Sweden)

Fred R. Dee

2014-07-01

Full Text Available The goal of mechanistic case diagraming (MCD is to provide students with more in-depth understanding of cause and effect relationships and basic mechanistic pathways in medicine. This will enable them to better explain how observed clinical findings develop from preceding pathogenic and pathophysiological events. The pedagogic function of MCD is in relating risk factors, disease entities and morphology, signs and symptoms, and test and procedure findings in a specific case scenario with etiologic pathogenic and pathophysiological sequences within a flow diagram. In this paper, we describe the addition of automation and predetermined lists to further develop the original concept of MCD as described by Engelberg in 1992 and Guerrero in 2001. We demonstrate that with these modifications, MCD is effective and efficient in small group case-based teaching for second-year medical students (ratings of ~3.4 on a 4.0 scale. There was also a significant correlation with other measures of competency, with a ‘true’ score correlation of 0.54. A traditional calculation of reliability showed promising results (α =0.47 within a low stakes, ungraded environment. Further, we have demonstrated MCD's potential for use in independent learning and TBL. Future studies are needed to evaluate MCD's potential for use in medium stakes assessment or self-paced independent learning and assessment. MCD may be especially relevant in returning students to the application of basic medical science mechanisms in the clinical years.

Conceptual models for waste tank mechanistic analysis

International Nuclear Information System (INIS)

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

LASSIM-A network inference toolbox for genome-wide mechanistic modeling.

Directory of Open Access Journals (Sweden)

Rasmus Magnusson

2017-06-01

Full Text Available Recent technological advancements have made time-resolved, quantitative, multi-omics data available for many model systems, which could be integrated for systems pharmacokinetic use. Here, we present large-scale simulation modeling (LASSIM, which is a novel mathematical tool for performing large-scale inference using mechanistically defined ordinary differential equations (ODE for gene regulatory networks (GRNs. LASSIM integrates structural knowledge about regulatory interactions and non-linear equations with multiple steady state and dynamic response expression datasets. The rationale behind LASSIM is that biological GRNs can be simplified using a limited subset of core genes that are assumed to regulate all other gene transcription events in the network. The LASSIM method is implemented as a general-purpose toolbox using the PyGMO Python package to make the most of multicore computers and high performance clusters, and is available at https://gitlab.com/Gustafsson-lab/lassim. As a method, LASSIM works in two steps, where it first infers a non-linear ODE system of the pre-specified core gene expression. Second, LASSIM in parallel optimizes the parameters that model the regulation of peripheral genes by core system genes. We showed the usefulness of this method by applying LASSIM to infer a large-scale non-linear model of naïve Th2 cell differentiation, made possible by integrating Th2 specific bindings, time-series together with six public and six novel siRNA-mediated knock-down experiments. ChIP-seq showed significant overlap for all tested transcription factors. Next, we performed novel time-series measurements of total T-cells during differentiation towards Th2 and verified that our LASSIM model could monitor those data significantly better than comparable models that used the same Th2 bindings. In summary, the LASSIM toolbox opens the door to a new type of model-based data analysis that combines the strengths of reliable mechanistic models

Mechanistic Indicators of Childhood Asthma (MICA) Study

Science.gov (United States)

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...

Mechanistic Systems Modeling to Improve Understanding and Prediction of Cardiotoxicity Caused by Targeted Cancer Therapeutics

Directory of Open Access Journals (Sweden)

Jaehee V. Shim

2017-09-01

Full Text Available Tyrosine kinase inhibitors (TKIs are highly potent cancer therapeutics that have been linked with serious cardiotoxicity, including left ventricular dysfunction, heart failure, and QT prolongation. TKI-induced cardiotoxicity is thought to result from interference with tyrosine kinase activity in cardiomyocytes, where these signaling pathways help to control critical processes such as survival signaling, energy homeostasis, and excitation–contraction coupling. However, mechanistic understanding is limited at present due to the complexities of tyrosine kinase signaling, and the wide range of targets inhibited by TKIs. Here, we review the use of TKIs in cancer and the cardiotoxicities that have been reported, discuss potential mechanisms underlying cardiotoxicity, and describe recent progress in achieving a more systematic understanding of cardiotoxicity via the use of mechanistic models. In particular, we argue that future advances are likely to be enabled by studies that combine large-scale experimental measurements with Quantitative Systems Pharmacology (QSP models describing biological mechanisms and dynamics. As such approaches have proven extremely valuable for understanding and predicting other drug toxicities, it is likely that QSP modeling can be successfully applied to cardiotoxicity induced by TKIs. We conclude by discussing a potential strategy for integrating genome-wide expression measurements with models, illustrate initial advances in applying this approach to cardiotoxicity, and describe challenges that must be overcome to truly develop a mechanistic and systematic understanding of cardiotoxicity caused by TKIs.

A preliminary study of mechanistic approach in pavement design to accommodate climate change effects

Science.gov (United States)

Harnaeni, S. R.; Pramesti, F. P.; Budiarto, A.; Setyawan, A.

2018-03-01

Road damage is caused by some factors, including climate changes, overload, and inappropriate procedure for material and development process. Meanwhile, climate change is a phenomenon which cannot be avoided. The effects observed include air temperature rise, sea level rise, rainfall changes, and the intensity of extreme weather phenomena. Previous studies had shown the impacts of climate changes on road damage. Therefore, several measures to anticipate the damage should be considered during the planning and construction in order to reduce the cost of road maintenance. There are three approaches generally applied in the design of flexible pavement thickness, namely mechanistic approach, mechanistic-empirical (ME) approach and empirical approach. The advantages of applying mechanistic approach or mechanistic-empirical (ME) approaches are its efficiency and reliability in the design of flexible pavement thickness as well as its capacity to accommodate climate changes in compared to empirical approach. However, generally, the design of flexible pavement thickness in Indonesia still applies empirical approach. This preliminary study aimed to emphasize the importance of the shifting towards a mechanistic approach in the design of flexible pavement thickness.

Mechanistic aspects of ionic reactions in flames

DEFF Research Database (Denmark)

Egsgaard, H.; Carlsen, L.

1993-01-01

Some fundamentals of the ion chemistry of flames are summarized. Mechanistic aspects of ionic reactions in flames have been studied using a VG PlasmaQuad, the ICP-system being substituted by a simple quartz burner. Simple hydrocarbon flames as well as sulfur-containing flames have been investigated...

Mechanisms of Molecular Response in the Optimal Control of Photoisomerization

International Nuclear Information System (INIS)

Dietzek, Benjamin; Brueggemann, Ben; Pascher, Torbjoern; Yartsev, Arkady

2006-01-01

We report on adaptive feedback control of photoinduced barrierless isomerization of 1,1'-diethyl-2,2'-cyanine in solution. We compare the effect of different fitness parameters and show that optimal control of the absolute yield of isomerization (photoisomer concentration versus excitation photons) can be achieved, while the relative isomerization yield (photoisomer concentration versus number of relaxed excited-state molecules) is unaffected by adaptive feedback control. The temporal structure of the optimized excitation pulses allows one to draw clear mechanistic conclusions showing the critical importance of coherent nuclear motion for the control of isomerization

Mechanistic controls on diverse fates of terrestrial organic components in the East China Sea

Science.gov (United States)

Zhu, Chun; Wagner, Thomas; Talbot, Helen M.; Weijers, Johan W. H.; Pan, Jian-Ming; Pancost, Richard D.

2013-09-01

Terrestrial carbon transferred from the land to sea is a critical component of the global carbon cycle. A range of geochemical proxies has been developed to fingerprint the fate of terrestrial organic matter (TOM) in marine sediments. However, discrepancies among different proxies limit our ability to quantify and interpret the terrestrial signals in marine sediments, with consequences for the investigation of both the modern carbon cycle and past environmental change. To mechanistically understand these discrepancies, we examined the distributions of a range of terrestrial proxies and their aquatic counterparts (i.e. marine proxies) in the Yangtze river-East China Sea (YR-ECS) shelf system, where TOM experiences extensive modification during transport and burial. TOM proxies in the YR-ECS system collectively fit a power-law model but with distinct attenuation rates (the a∗ values) for individual molecular proxy groups. Among a range of TOM proxies, the modeled a∗ values decrease in the order: soil-marker BHPs > triterpenols > lignin > HMW n-alkanols > branched GDGTs > HMW n-alkanes for biomarkers; and Rsoil > BIT > %TOMiso for proxies tracing %TOM. Rapid loss of TOM components through dissociation in the narrow estuary, followed by oxidation over the wide open shelf, are best described by power curves. Inherent chemical reactivity (i.e. the number of functional groups), responses to hydraulic sorting, and in situ production regulate the individual attenuation rates. Of them, chemical reactivity plays the most important role on proxy behavior, supported by a strong correlation between a∗ values and standard molal Gibbs energies. Both, physical protection and chemical reactivity fundamentally control the overall behavior of TOM components, with the relative importance being setting-dependant: The former is relatively important in the estuary, whereas the later is the primary control over the open shelf. Moreover, regional variation of different marine

Evaluation of mechanistic DNB models using HCLWR CHF data

International Nuclear Information System (INIS)

Iwamura, Takamichi; Watanabe, Hironori; Okubo, Tsutomu; Araya, Fumimasa; Murao, Yoshio.

1992-03-01

An onset of departure from nucleate boiling (DNB) in light water reactor (LWR) has been generally predicted with empirical correlations. Since these correlations have less physical bases and contain adjustable empirical constants determined by best fitting of test data, applicable geometries and flow conditions are limited within the original experiment ranges. In order to obtain more universal prediction method, several mechanistic DNB models based on physical approaches have been proposed in recent years. However, the predictive capabilities of mechanistic DNB models have not been verified successfully especially for advanced LWR design purposes. In this report, typical DNB mechanistic models are reviewed and compared with critical heat flux (CHF) data for high conversion light water reactor (HCLWR). The experiments were performed using triangular 7-rods array with non-uniform axial heat flux distribution. Test pressure was 16 MPa, mass velocities ranged from 800 t0 3100 kg/s·m 2 and exit qualities from -0.07 to 0.19. The evaluated models are: 1) Wisman-Pei, 2) Chang-Lee, 3) Lee-Mudawwar, 4) Lin-Lee-Pei, and 5) Katto. The first two models are based on near-wall bubble crowding model and the other three models on sublayer dryout model. The comparison with experimental data indicated that the Weisman-Pei model agreed relatively well with the CHF data. Effects of empirical constants in each model on CHF calculation were clarified by sensitivity studies. It was also found that the magnitudes of physical quantities obtained in the course of calculation were significantly different for each model. Therefore, microscopic observation of the onset of DNB on heated surface is essential to clarify the DNB mechanism and establish a general DNB mechanistic model based on physical phenomenon. (author)

Mechanistic phenotypes: an aggregative phenotyping strategy to identify disease mechanisms using GWAS data.

Directory of Open Access Journals (Sweden)

Jonathan D Mosley

Full Text Available A single mutation can alter cellular and global homeostatic mechanisms and give rise to multiple clinical diseases. We hypothesized that these disease mechanisms could be identified using low minor allele frequency (MAF<0.1 non-synonymous SNPs (nsSNPs associated with "mechanistic phenotypes", comprised of collections of related diagnoses. We studied two mechanistic phenotypes: (1 thrombosis, evaluated in a population of 1,655 African Americans; and (2 four groupings of cancer diagnoses, evaluated in 3,009 white European Americans. We tested associations between nsSNPs represented on GWAS platforms and mechanistic phenotypes ascertained from electronic medical records (EMRs, and sought enrichment in functional ontologies across the top-ranked associations. We used a two-step analytic approach whereby nsSNPs were first sorted by the strength of their association with a phenotype. We tested associations using two reverse genetic models and standard additive and recessive models. In the second step, we employed a hypothesis-free ontological enrichment analysis using the sorted nsSNPs to identify functional mechanisms underlying the diagnoses comprising the mechanistic phenotypes. The thrombosis phenotype was solely associated with ontologies related to blood coagulation (Fisher's p = 0.0001, FDR p = 0.03, driven by the F5, P2RY12 and F2RL2 genes. For the cancer phenotypes, the reverse genetics models were enriched in DNA repair functions (p = 2×10-5, FDR p = 0.03 (POLG/FANCI, SLX4/FANCP, XRCC1, BRCA1, FANCA, CHD1L while the additive model showed enrichment related to chromatid segregation (p = 4×10-6, FDR p = 0.005 (KIF25, PINX1. We were able to replicate nsSNP associations for POLG/FANCI, BRCA1, FANCA and CHD1L in independent data sets. Mechanism-oriented phenotyping using collections of EMR-derived diagnoses can elucidate fundamental disease mechanisms.

Mechanistic basis of an epistatic interaction reducing age at onset in hereditary spastic paraplegia.

Science.gov (United States)

Newton, Timothy; Allison, Rachel; Edgar, James R; Lumb, Jennifer H; Rodger, Catherine E; Manna, Paul T; Rizo, Tania; Kohl, Zacharias; Nygren, Anders O H; Arning, Larissa; Schüle, Rebecca; Depienne, Christel; Goldberg, Lisa; Frahm, Christiane; Stevanin, Giovanni; Durr, Alexandra; Schöls, Ludger; Winner, Beate; Beetz, Christian; Reid, Evan

2018-05-01

Many genetic neurological disorders exhibit variable expression within affected families, often exemplified by variations in disease age at onset. Epistatic effects (i.e. effects of modifier genes on the disease gene) may underlie this variation, but the mechanistic basis for such epistatic interactions is rarely understood. Here we report a novel epistatic interaction between SPAST and the contiguous gene DPY30, which modifies age at onset in hereditary spastic paraplegia, a genetic axonopathy. We found that patients with hereditary spastic paraplegia caused by genomic deletions of SPAST that extended into DPY30 had a significantly younger age at onset. We show that, like spastin, the protein encoded by SPAST, the DPY30 protein controls endosomal tubule fission, traffic of mannose 6-phosphate receptors from endosomes to the Golgi, and lysosomal ultrastructural morphology. We propose that additive effects on this pathway explain the reduced age at onset of hereditary spastic paraplegia in patients who are haploinsufficient for both genes.

Regulatory Technology Development Plan - Sodium Fast Reactor: Mechanistic Source Term - Trial Calculation

International Nuclear Information System (INIS)

Grabaskas, David

2016-01-01

The potential release of radioactive material during a plant incident, referred to as the source term, is a vital design metric and will be a major focus of advanced reactor licensing. The U.S. Nuclear Regulatory Commission has stated an expectation for advanced reactor vendors to present a mechanistic assessment of the potential source term in their license applications. The mechanistic source term presents an opportunity for vendors to realistically assess the radiological consequences of an incident, and may allow reduced emergency planning zones and smaller plant sites. However, the development of a mechanistic source term for advanced reactors is not without challenges, as there are often numerous phenomena impacting the transportation and retention of radionuclides. This project sought to evaluate U.S. capabilities regarding the mechanistic assessment of radionuclide release from core damage incidents at metal fueled, pool-type sodium fast reactors (SFRs). The purpose of the analysis was to identify, and prioritize, any gaps regarding computational tools or data necessary for the modeling of radionuclide transport and retention phenomena. To accomplish this task, a parallel-path analysis approach was utilized. One path, led by Argonne and Sandia National Laboratories, sought to perform a mechanistic source term assessment using available codes, data, and models, with the goal to identify gaps in the current knowledge base. The second path, performed by an independent contractor, performed sensitivity analyses to determine the importance of particular radionuclides and transport phenomena in regards to offsite consequences. The results of the two pathways were combined to prioritize gaps in current capabilities.

Descriptive and mechanistic models of crop–weed competition

NARCIS (Netherlands)

Bastiaans, L.; Storkey, J.

2017-01-01

Crop-weed competitive relations are an important element of agroecosystems. Quantifying and understanding them helps to design appropriate weed management at operational, tactical and strategic level. This chapter presents and discusses simple descriptive and more mechanistic models for crop-weed

Mechanistic Studies on the Copper-Catalyzed N-Arylation of Amides

Science.gov (United States)

Strieter, Eric R.; Bhayana, Brijesh; Buchwald, Stephen L.

2009-01-01

The copper-catalyzed N-arylation of amides, i.e., the Goldberg reaction, is an efficient method for the construction of products relevant to both industry and academic settings. Herein, we present mechanistic details concerning the catalytic and stoichiometric N-arylation of amides. In the context of the catalytic reaction, our findings reveal the importance of chelating diamine ligands in controlling the concentration of the active catalytic species. The consistency between the catalytic and stoichiometric results suggest that the activation of aryl halides occurs through a 1,2-diamine-ligated copper(I) amidate complex. Kinetic studies on the stoichiometric N-arylation of aryl iodides using 1,2-diamine ligated Cu(I) amidates also provide insights into the mechanism of aryl halide activation. PMID:19072233

Mechanistic aspects of the metal catalyzed alternating copolymerization of epoxides and carbon monoxide.

Science.gov (United States)

Allmendinger, Markus; Molnar, Ferenc; Zintl, Manuela; Luinstra, Gerrit A; Preishuber-Pflügl, Peter; Rieger, Bernhard

2005-09-05

The cobalt-catalyzed alternating copolymerization of epoxides and CO is a novel, direct approach to aliphatic polyesters, such as poly(hydroxybutyrate) (PHB). This reaction was found to be catalyzed by Ph3Si[Co(CO)4] (4) and pyridine affording in a first step the stable mono-insertion product Ph3Si-O-CH(CH3)-CH2-CO-Co(CO)4 (5). However, a profound mechanistic understanding, especially of the role of pyridine as the key component for the polymerization reaction was missing. ATR-IR online monitoring under catalytic conditions and DFT calculations were used to show that an acylpyridinium cation is formed by cleavage of the cobalt-acyl bond of 5 in the presence of pyridine. The Lewis acid thus generated activates the next incoming epoxide monomer for ring opening through [Co(CO)4]-. The catalytic cycle is completed by a subsequent CO insertion in the new cobalt-alkyl bond. The calculations are used to explore the energetic hypersurface of the polymerization reaction and are complemented by extended experimental investigations that also support the mechanistic hypotheses.

Comparison of Two-Phase Pipe Flow in OpenFOAM with a Mechanistic Model

Science.gov (United States)

Shuard, Adrian M.; Mahmud, Hisham B.; King, Andrew J.

2016-03-01

Two-phase pipe flow is a common occurrence in many industrial applications such as power generation and oil and gas transportation. Accurate prediction of liquid holdup and pressure drop is of vast importance to ensure effective design and operation of fluid transport systems. In this paper, a Computational Fluid Dynamics (CFD) study of a two-phase flow of air and water is performed using OpenFOAM. The two-phase solver, interFoam is used to identify flow patterns and generate values of liquid holdup and pressure drop, which are compared to results obtained from a two-phase mechanistic model developed by Petalas and Aziz (2002). A total of 60 simulations have been performed at three separate pipe inclinations of 0°, +10° and -10° respectively. A three dimensional, 0.052m diameter pipe of 4m length is used with the Shear Stress Transport (SST) k - ɷ turbulence model to solve the turbulent mixtures of air and water. Results show that the flow pattern behaviour and numerical values of liquid holdup and pressure drop compare reasonably well to the mechanistic model.

Evolutionary and mechanistic drivers of laterality: A review and new synthesis.

Science.gov (United States)

Wiper, Mallory L

2017-11-01

Laterality, best understood as asymmetries of bilateral structures or biases in behaviour, has been demonstrated in species from all major vertebrate classes, and in many invertebrates, showing a large degree of evolutionary conservation across vertebrate groups. Despite the establishment of this phenomenon in so many species, however, the evolutionary and mechanistic study of laterality is uneven with numerous areas in this field requiring greater attention. Here, I present a partial review of how far the study of laterality has come, outlining previous pioneering work, I discuss the hypothesized costs and benefits of a lateralized brain and the suggested path of the evolution of laterality for populations and individuals. I propose an expansion of laterality research into areas that have been touched upon in the past but require stronger evidence from which the field will greatly benefit. Namely, I suggest a continuation of the phylogenetic approach to investigating laterality to better understand its evolutionary path; and a further focus on mechanistic drivers, with special attention to genetic and environmental effects. Putting together the puzzle of laterality using as many pieces as possible will provide a stronger understanding of this field, allowing us to continue to expand the field in novel ways.

A dynamic, mechanistic model of metabolism in adipose tissue of lactating dairy cattle.

Science.gov (United States)

McNamara, J P; Huber, K; Kenéz, A

2016-07-01

Research in dairy cattle biology has resulted in a large body of knowledge on nutrition and metabolism in support of milk production and efficiency. This quantitative knowledge has been compiled in several model systems to balance and evaluate rations and predict requirements. There are also systems models for metabolism and reproduction in the cow that can be used to support research programs. Adipose tissue plays a significant role in the success and efficiency of lactation, and recent research has resulted in several data sets on genomic differences and changes in gene transcription of adipose tissue in dairy cattle. To fully use this knowledge, we need to build and expand mechanistic, dynamic models that integrate control of metabolism and production. Therefore, we constructed a second-generation dynamic, mechanistic model of adipose tissue metabolism of dairy cattle. The model describes the biochemical interconversions of glucose, acetate, β-hydroxybutyrate (BHB), glycerol, C16 fatty acids, and triacylglycerols. Data gathered from our own research and published references were used to set equation forms and parameter values. Acetate, glucose, BHB, and fatty acids are taken up from blood. The fatty acids are activated to the acyl coenzyme A moieties. Enzymatically catalyzed reactions are explicitly described with parameters including maximal velocity and substrate sensitivity. The control of enzyme activity is partially carried out by insulin and norepinephrine, portraying control in the cow. Model behavior was adequate, with sensitive responses to changing substrates and hormones. Increased nutrient uptake and increased insulin stimulate triacylglycerol synthesis, whereas a reduction in nutrient availability or increase in norepinephrine increases triacylglycerol hydrolysis and free fatty acid release to blood. This model can form a basis for more sophisticated integration of existing knowledge and future studies on metabolic efficiency of dairy cattle

Rapid Discrimination Among Putative Mechanistic Models of Biochemical Systems.

Science.gov (United States)

Lomnitz, Jason G; Savageau, Michael A

2016-08-31

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.

Mechanistic model for microbial growth on hydrocarbons

Energy Technology Data Exchange (ETDEWEB)

Mallee, F M; Blanch, H W

1977-12-01

Based on available information describing the transport and consumption of insoluble alkanes, a mechanistic model is proposed for microbial growth on hydrocarbons. The model describes the atypical growth kinetics observed, and has implications in the design of large scale equipment for single cell protein (SCP) manufacture from hydrocarbons. The model presents a framework for comparison of the previously published experimental kinetic data.

Regulatory Technology Development Plan - Sodium Fast Reactor: Mechanistic Source Term – Trial Calculation

Energy Technology Data Exchange (ETDEWEB)

Grabaskas, David [Argonne National Lab. (ANL), Argonne, IL (United States). Nuclear Engineering Division; Bucknor, Matthew [Argonne National Lab. (ANL), Argonne, IL (United States). Nuclear Engineering Division; Jerden, James [Argonne National Lab. (ANL), Argonne, IL (United States). Nuclear Engineering Division; Brunett, Acacia J. [Argonne National Lab. (ANL), Argonne, IL (United States). Nuclear Engineering Division; Denman, Matthew [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States). Nuclear Engineering Division; Clark, Andrew [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States). Nuclear Engineering Division; Denning, Richard S. [Consultant, Columbus, OH (United States)

2016-10-01

The potential release of radioactive material during a plant incident, referred to as the source term, is a vital design metric and will be a major focus of advanced reactor licensing. The U.S. Nuclear Regulatory Commission has stated an expectation for advanced reactor vendors to present a mechanistic assessment of the potential source term in their license applications. The mechanistic source term presents an opportunity for vendors to realistically assess the radiological consequences of an incident, and may allow reduced emergency planning zones and smaller plant sites. However, the development of a mechanistic source term for advanced reactors is not without challenges, as there are often numerous phenomena impacting the transportation and retention of radionuclides. This project sought to evaluate U.S. capabilities regarding the mechanistic assessment of radionuclide release from core damage incidents at metal fueled, pool-type sodium fast reactors (SFRs). The purpose of the analysis was to identify, and prioritize, any gaps regarding computational tools or data necessary for the modeling of radionuclide transport and retention phenomena. To accomplish this task, a parallel-path analysis approach was utilized. One path, led by Argonne and Sandia National Laboratories, sought to perform a mechanistic source term assessment using available codes, data, and models, with the goal to identify gaps in the current knowledge base. The second path, performed by an independent contractor, performed sensitivity analyses to determine the importance of particular radionuclides and transport phenomena in regards to offsite consequences. The results of the two pathways were combined to prioritize gaps in current capabilities.

RELATIONSHIPS BETWEEN SOIL MICROBIAL BIOMASS, AGGREGATE STABILITY AND AGGREGATE ASSOCIATED-C: A MECHANISTIC APPROACH

Directory of Open Access Journals (Sweden)

Patrizia Guidi

2014-01-01

Full Text Available For the identification of C pools involved in soil aggregation, a physically-based aggregate fractionation was proposed, and  additional pretreatments were used in the measurement of the 1-2 mm aggregate stability in order to elucidate the relevance of the role of soil microorganisms with respect to the different aggregate breakdown mechanisms. The study was carried out on three clay loam Regosols, developed on calcareous shales, known history of organic cultivation.Our results showed that the soil C pool controlling the process of stabilisation of aggregates was related to the microbial community. We identified the resistance to fast wetting as the major mechanism of aggregate stability driven by microorganims. The plausible hypothesis is that organic farming promotes fungi growth, improving water repellency of soil aggregates by fungal hydrophobic substances. By contrast, we failed in the identification of C pools controlling the formation of aggregates, probably because of the disturbance of mechanical tillage which contributes to the breakdown of soil aggregates.The physically-based aggregate fractionation proposed in this study resulted useful in the  mechanistically understanding of the role of microorganisms in soil aggregation and it might be suggested for studying the impact of management on C pools, aggregates properties and their relationships in agricultural soils.

Numerical simulation in steam injection process by a mechanistic approach

Energy Technology Data Exchange (ETDEWEB)

De Souza, J.C.Jr.; Campos, W.; Lopes, D.; Moura, L.S.S. [Petrobras, Rio de Janeiro (Brazil)

2008-10-15

Steam injection is a common thermal recovery method used in very viscous oil reservoirs. The method involves the injection of heat to reduce viscosity and mobilize oil. A steam generation and injection system consists primarily of a steam source, distribution lines, injection wells and a discarding tank. In order to optimize injection and improve the oil recovery factor, one must determine the parameters of steam flow such as pressure, temperature and steam quality. This study focused on developing a unified mathematical model by means of a mechanistic approach for two-phase steam flow in pipelines and wells. The hydrodynamic and heat transfer mechanistic model was implemented in a computer simulator to model the parameters of steam injection while trying to avoid the use of empirical correlations. A marching algorithm was used to determine the distribution of pressure and temperature along the pipelines and wellbores. The mathematical model for steam flow in injection systems, developed by a mechanistic approach (VapMec) performed well when the simulated values of pressures and temperatures were compared with the values measured during field tests. The newly developed VapMec model was incorporated in the LinVap-3 simulator that constitutes an engineering supporting tool for steam injection wells operated by Petrobras. 23 refs., 7 tabs., 6 figs.

Higher plant modelling for life support applications: first results of a simple mechanistic model

Science.gov (United States)

Hezard, Pauline; Dussap, Claude-Gilles; Sasidharan L, Swathy

2012-07-01

In the case of closed ecological life support systems, the air and water regeneration and food production are performed using microorganisms and higher plants. Wheat, rice, soybean, lettuce, tomato or other types of eatable annual plants produce fresh food while recycling CO2 into breathable oxygen. Additionally, they evaporate a large quantity of water, which can be condensed and used as potable water. This shows that recycling functions of air revitalization and food production are completely linked. Consequently, the control of a growth chamber for higher plant production has to be performed with efficient mechanistic models, in order to ensure a realistic prediction of plant behaviour, water and gas recycling whatever the environmental conditions. Purely mechanistic models of plant production in controlled environments are not available yet. This is the reason why new models must be developed and validated. This work concerns the design and test of a simplified version of a mathematical model coupling plant architecture and mass balance purposes in order to compare its results with available data of lettuce grown in closed and controlled chambers. The carbon exchange rate, water absorption and evaporation rate, biomass fresh weight as well as leaf surface are modelled and compared with available data. The model consists of four modules. The first one evaluates plant architecture, like total leaf surface, leaf area index and stem length data. The second one calculates the rate of matter and energy exchange depending on architectural and environmental data: light absorption in the canopy, CO2 uptake or release, water uptake and evapotranspiration. The third module evaluates which of the previous rates is limiting overall biomass growth; and the last one calculates biomass growth rate depending on matter exchange rates, using a global stoichiometric equation. All these rates are a set of differential equations, which are integrated with time in order to provide

SOD1 aggregation in ALS mice shows simplistic test tube behavior.

Science.gov (United States)

Lang, Lisa; Zetterström, Per; Brännström, Thomas; Marklund, Stefan L; Danielsson, Jens; Oliveberg, Mikael

2015-08-11

A longstanding challenge in studies of neurodegenerative disease has been that the pathologic protein aggregates in live tissue are not amenable to structural and kinetic analysis by conventional methods. The situation is put in focus by the current progress in demarcating protein aggregation in vitro, exposing new mechanistic details that are now calling for quantitative in vivo comparison. In this study, we bridge this gap by presenting a direct comparison of the aggregation kinetics of the ALS-associated protein superoxide dismutase 1 (SOD1) in vitro and in transgenic mice. The results based on tissue sampling by quantitative antibody assays show that the SOD1 fibrillation kinetics in vitro mirror with remarkable accuracy the spinal cord aggregate buildup and disease progression in transgenic mice. This similarity between in vitro and in vivo data suggests that, despite the complexity of live tissue, SOD1 aggregation follows robust and simplistic rules, providing new mechanistic insights into the ALS pathology and organism-level manifestation of protein aggregation phenomena in general.

Comparison of Two-Phase Pipe Flow in OpenFOAM with a Mechanistic Model

International Nuclear Information System (INIS)

Shuard, Adrian M; Mahmud, Hisham B; King, Andrew J

2016-01-01

Two-phase pipe flow is a common occurrence in many industrial applications such as power generation and oil and gas transportation. Accurate prediction of liquid holdup and pressure drop is of vast importance to ensure effective design and operation of fluid transport systems. In this paper, a Computational Fluid Dynamics (CFD) study of a two-phase flow of air and water is performed using OpenFOAM. The two-phase solver, interFoam is used to identify flow patterns and generate values of liquid holdup and pressure drop, which are compared to results obtained from a two-phase mechanistic model developed by Petalas and Aziz (2002). A total of 60 simulations have been performed at three separate pipe inclinations of 0°, +10° and -10° respectively. A three dimensional, 0.052m diameter pipe of 4m length is used with the Shear Stress Transport (SST) k - ω turbulence model to solve the turbulent mixtures of air and water. Results show that the flow pattern behaviour and numerical values of liquid holdup and pressure drop compare reasonably well to the mechanistic model. (paper)

The mechanistic bases of the power-time relationship

DEFF Research Database (Denmark)

Vanhatalo, Anni; Black, Matthew I; DiMenna, Fred J

2016-01-01

.025) and inversely correlated with muscle type IIx fibre proportion (r = -0.76, P = 0.01). There was no relationship between W' (19.4 ± 6.3 kJ) and muscle fibre type. These data indicate a mechanistic link between the bioenergetic characteristics of different muscle fibre types and the power-duration relationship...

Mechanistic studies of carbon monoxide reduction

Energy Technology Data Exchange (ETDEWEB)

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.

RNA-Seq-based toxicogenomic assessment of fresh frozen and formalin-fixed tissues yields similar mechanistic insights.

Science.gov (United States)

Auerbach, Scott S; Phadke, Dhiral P; Mav, Deepak; Holmgren, Stephanie; Gao, Yuan; Xie, Bin; Shin, Joo Heon; Shah, Ruchir R; Merrick, B Alex; Tice, Raymond R

2015-07-01

Formalin-fixed, paraffin-embedded (FFPE) pathology specimens represent a potentially vast resource for transcriptomic-based biomarker discovery. We present here a comparison of results from a whole transcriptome RNA-Seq analysis of RNA extracted from fresh frozen and FFPE livers. The samples were derived from rats exposed to aflatoxin B1 (AFB1 ) and a corresponding set of control animals. Principal components analysis indicated that samples were separated in the two groups representing presence or absence of chemical exposure, both in fresh frozen and FFPE sample types. Sixty-five percent of the differentially expressed transcripts (AFB1 vs. controls) in fresh frozen samples were also differentially expressed in FFPE samples (overlap significance: P < 0.0001). Genomic signature and gene set analysis of AFB1 differentially expressed transcript lists indicated highly similar results between fresh frozen and FFPE at the level of chemogenomic signatures (i.e., single chemical/dose/duration elicited transcriptomic signatures), mechanistic and pathology signatures, biological processes, canonical pathways and transcription factor networks. Overall, our results suggest that similar hypotheses about the biological mechanism of toxicity would be formulated from fresh frozen and FFPE samples. These results indicate that phenotypically anchored archival specimens represent a potentially informative resource for signature-based biomarker discovery and mechanistic characterization of toxicity. Copyright © 2014 John Wiley & Sons, Ltd.

Advanced reach tool (ART) : Development of the mechanistic model

NARCIS (Netherlands)

Fransman, W.; Tongeren, M. van; Cherrie, J.W.; Tischer, M.; Schneider, T.; Schinkel, J.; Kromhout, H.; Warren, N.; Goede, H.; Tielemans, E.

2011-01-01

This paper describes the development of the mechanistic model within a collaborative project, referred to as the Advanced REACH Tool (ART) project, to develop a tool to model inhalation exposure for workers sharing similar operational conditions across different industries and locations in Europe.

A 3-D CFD approach to the mechanistic prediction of forced convective critical heat flux at low quality

International Nuclear Information System (INIS)

Jean-Marie Le Corre; Cristina H Amon; Shi-Chune Yao

2005-01-01

Full text of publication follows: The prediction of the Critical Heat Flux (CHF) in a heat flux controlled boiling heat exchanger is important to assess the maximal thermal capability of the system. In the case of a nuclear reactor, CHF margin gain (using improved mixing vane grid design, for instance) can allow power up-rate and enhanced operating flexibility. In general, current nuclear core design procedures use quasi-1D approach to model the coolant thermal-hydraulic conditions within the fuel bundles coupled with fully empirical CHF prediction methods. In addition, several CHF mechanistic models have been developed in the past and coupled with 1D and quasi-1D thermal-hydraulic codes. These mechanistic models have demonstrated reasonable CHF prediction characteristics and, more remarkably, correct parametric trends over wide range of fluid conditions. However, since the phenomena leading to CHF are localized near the heater, models are needed to relate local quantities of interest to area-averaged quantities. As a consequence, large CHF prediction uncertainties may be introduced and 3D fluid characteristics (such as swirling flow) cannot be accounted properly. Therefore, a fully mechanistic approach to CHF prediction is, in general, not possible using the current approach. The development of CHF-enhanced fuel assembly designs requires the use of more advanced 3D coolant properties computations coupled with a CHF mechanistic modeling. In the present work, the commercial CFD code CFX-5 is used to compute 3D coolant conditions in a vertical heated tube with upward flow. Several CHF mechanistic models at low quality available in the literature are coupled with the CFD code by developing adequate models between local coolant properties and local parameters of interest to predict CHF. The prediction performances of these models are assessed using CHF databases available in the open literature and the 1995 CHF look-up table. Since CFD can reasonably capture 3D fluid

Development of a mechanistically based computer simulation of nitrogen oxide absorption in packed towers

International Nuclear Information System (INIS)

Counce, R.M.

1981-01-01

A computer simulation for nitrogen oxide (NO/sub x/) scrubbing in packed towers was developed for use in process design and process control. This simulation implements a mechanistically based mathematical model, which was formulated from (1) an exhaustive literature review; (2) previous NO/sub x/ scrubbing experience with sieve-plate towers; and (3) comparisons of sequential sets of experiments. Nitrogen oxide scrubbing is characterized by simultaneous absorption and desorption phenomena: the model development is based on experiments designed to feature these two phenomena. The model was then successfully tested in experiments designed to put it in jeopardy

Mechanistic modeling analysis of micro-evolutive responses from a Caenorhabditis elegans population exposed to a radioactive metallic stress

International Nuclear Information System (INIS)

Goussen, Benoit

2013-01-01

The evolution of toxic effects at a relevant scale is an important challenge for the ecosystem protection. Indeed, pollutants may impact populations over long-term and represent a new evolutionary force which can be adding itself to the natural selection forces. Thereby, it is necessary to acquire knowledge on the phenotypics and genetics changes that may appear in populations submitted to stress over several generations. Usually statistical analyses are performed to analyse such multi-generational studies. The use of a mechanistic mathematical model may provide a way to fully understand the impact of pollutants on the populations' dynamics. Such kind of model allows the integration of biological and toxic processes into the analysis of eco-toxicological data and the assessment of interactions between these processes. The aim of this Ph.D. project was to assess the contributions of the mechanistic modelling to the analysis of evolutionary experiment assessing long-term exposure. To do so, a three step strategy has been developed. Foremost, a multi-generational study was performed to assess the evolution of two populations of the ubiquitous nematode Caenorhabditis elegans in control conditions or exposed to 1.1 mM of uranium. Several generations were selected to assess growth, reproduction, and dose-responses relationships, through exposure to a range of concentrations (from 0 to 1.2 mM U) with all endpoints measured daily. A first statistical analysis was then performed. In a second step, a bio-energetic model adapted to the assessment of eco-toxicological data (DEBtox) was developed on C. elegans. Its numerical behaviour was analysed. Finally, this model was applied to all the selected generations in order to infer parameters values for the two populations and to assess their evolutions. Results highlighted an impact of the uranium starting from 0.4 mM U on both C. elegans' growth and reproduction. Results from the mechanistic analysis indicate this effect is due

Mechanistic model for void distribution in flashing flow

International Nuclear Information System (INIS)

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

Mechanistic Studies at the Interface Between Organometallic Chemistry and Homogeneous Catalysis

Energy Technology Data Exchange (ETDEWEB)

Casey, Charles P

2012-11-14

the aldehyde carbon and of a proton from the CpOH unit to the aldehyde oxygen and support reduction of the aldehyde without its prior coordination to ruthenium. Another important step in the catalysis is the regeneration of 1 from reaction of H2 with the stable diruthenium bridging hydride complex 2. Studies of the microscopic reverse of this process (hydrogen evolution from 1 which occurs at 80°C) in the presence of alcohol (the product of aldehyde hydrogenation) have shown that a dihydrogen complex is formed reversibly at a rate much faster than hydrogen evolution. Kinetic and theoretical studies in collaboration with Professor Qiang Cui of Wisconsin indicated an important role for alcohol in mediating transfer of hydrogen to ruthenium. One key to developing more active catalysts was to destabilize the bridging hydride intermediate 2 to prevent its formation or to speed its conversion to a reactive monohydride 1 by reaction with H2. We found several successful ways to destabilize the bridging hydride and to obtain more active catalysts. Most recently, we discovered related iron catalysts for hydrogenation that do not form dimers; the cost advantage of iron catalysts is spectacular. Iron Catalysts. In an exciting development, we found that a related iron complex is also a very active ketone hydrogenation catalyst. This hydrogenation catalyst shows high chemoselectivity for aldehydes, ketones, and imines and isolated C=C, CºC, C-X, -NO2, epoxides, and ester functions are unaffected by the hydrogenation conditions. Mechanistic studies have established a reversible hydrogen transfer step followed by rapid dihydrogen activation. The same iron complex also catalyzes transfer hydrogenation of ketones.

Electrochemical processes and mechanistic aspects of field-effect sensors for biomolecules

Science.gov (United States)

Huang, Weiguo; Diallo, Abdou Karim; Dailey, Jennifer L.; Besar, Kalpana

2017-01-01

Electronic biosensing is a leading technology for determining concentrations of biomolecules. In some cases, the presence of an analyte molecule induces a measured change in current flow, while in other cases, a new potential difference is established. In the particular case of a field effect biosensor, the potential difference is monitored as a change in conductance elsewhere in the device, such as across a film of an underlying semiconductor. Often, the mechanisms that lead to these responses are not specifically determined. Because improved understanding of these mechanisms will lead to improved performance, it is important to highlight those studies where various mechanistic possibilities are investigated. This review explores a range of possible mechanistic contributions to field-effect biosensor signals. First, we define the field-effect biosensor and the chemical interactions that lead to the field effect, followed by a section on theoretical and mechanistic background. We then discuss materials used in field-effect biosensors and approaches to improving signals from field-effect biosensors. We specifically cover the biomolecule interactions that produce local electric fields, structures and processes at interfaces between bioanalyte solutions and electronic materials, semiconductors used in biochemical sensors, dielectric layers used in top-gated sensors, and mechanisms for converting the surface voltage change to higher signal/noise outputs in circuits. PMID:29238595

A Physics-Inspired Mechanistic Model of Migratory Movement Patterns in Birds.

Science.gov (United States)

Revell, Christopher; Somveille, Marius

2017-08-29

In this paper, we introduce a mechanistic model of migratory movement patterns in birds, inspired by ideas and methods from physics. Previous studies have shed light on the factors influencing bird migration but have mainly relied on statistical correlative analysis of tracking data. Our novel method offers a bottom up explanation of population-level migratory movement patterns. It differs from previous mechanistic models of animal migration and enables predictions of pathways and destinations from a given starting location. We define an environmental potential landscape from environmental data and simulate bird movement within this landscape based on simple decision rules drawn from statistical mechanics. We explore the capacity of the model by qualitatively comparing simulation results to the non-breeding migration patterns of a seabird species, the Black-browed Albatross (Thalassarche melanophris). This minimal, two-parameter model was able to capture remarkably well the previously documented migration patterns of the Black-browed Albatross, with the best combination of parameter values conserved across multiple geographically separate populations. Our physics-inspired mechanistic model could be applied to other bird and highly-mobile species, improving our understanding of the relative importance of various factors driving migration and making predictions that could be useful for conservation.

Overview of the South African mechanistic pavement design analysis method

CSIR Research Space (South Africa)

Theyse, HL

1996-01-01

Full Text Available A historical overview of the South African mechanistic pavement design method, from its development in the early 1970s to the present, is presented. Material characterization, structural analysis, and pavement life prediction are discussed...

Mechanistic applicability domain classification of a local lymph node assay dataset for skin sensitization.

Science.gov (United States)

Roberts, David W; Patlewicz, Grace; Kern, Petra S; Gerberick, Frank; Kimber, Ian; Dearman, Rebecca J; Ryan, Cindy A; Basketter, David A; Aptula, Aynur O

2007-07-01

The goal of eliminating animal testing in the predictive identification of chemicals with the intrinsic ability to cause skin sensitization is an important target, the attainment of which has recently been brought into even sharper relief by the EU Cosmetics Directive and the requirements of the REACH legislation. Development of alternative methods requires that the chemicals used to evaluate and validate novel approaches comprise not only confirmed skin sensitizers and non-sensitizers but also substances that span the full chemical mechanistic spectrum associated with skin sensitization. To this end, a recently published database of more than 200 chemicals tested in the mouse local lymph node assay (LLNA) has been examined in relation to various chemical reaction mechanistic domains known to be associated with sensitization. It is demonstrated here that the dataset does cover the main reaction mechanistic domains. In addition, it is shown that assignment to a reaction mechanistic domain is a critical first step in a strategic approach to understanding, ultimately on a quantitative basis, how chemical properties influence the potency of skin sensitizing chemicals. This understanding is necessary if reliable non-animal approaches, including (quantitative) structure-activity relationships (Q)SARs, read-across, and experimental chemistry based models, are to be developed.

A tissue-engineered gastric cancer model for mechanistic study of anti-tumor drugs

International Nuclear Information System (INIS)

Gao, Ming; Cai, Yiting; Wu, Wei; Shi, Yazhou; Fei, Zhewei

2013-01-01

The use of the traditional xenograft subcutaneous tumor model has been contested because of its limitations, such as a slow tumorigenesis, inconsistent chemotherapeutic results, etc. In light of these challenges, we aim to revamp the traditional model by employing an electrospun scaffold composed of polydioxanone, gelatin and elastin to boost the tumorigenesis. The scaffold featured a highly porous microstructure and successfully supported the growth of tumor cells in vitro without provoking apoptosis. In vivo studies showed that in the scaffold model the tumor volume increased by 43.27% and the weight by 75.58%, respectively, within a 12-week period. In addition, the scaffold model saw an increase of CD24 + and CD44 + cells in the tumor mass by 42% and 313%, respectively. The scaffolding materials did not lead to phenotypic changes during the tumorigenesis. Thereafter, in the scaffold model, we found that the chemotherapeutic regimen of docetaxel, cisplatin and fluorouracil unleashed a stronger capability than the regimen comprising cisplatin and fluorouracil to deplete the CD44 + subpopulation. This discovery sheds mechanistic lights on the role of docetaxel for its future chemotherapeutic applications. This revamped model affords cancer scientists a convenient and reliable platform to mechanistically investigate the chemotherapeutic drugs on gastric cancer stem cells. (paper)

NO MECHANISTIC DEPENDENCE OF PHOTOSYNTHESIS ON CALCIFICATION IN THE COCCOLITHOPHORID EMILIANIA HUXLEYI (HAPTOPHYTA)(1).

Science.gov (United States)

Leonardos, Nikos; Read, Betsy; Thake, Brenda; Young, Jeremy R

2009-10-01

There is still considerable uncertainty about the relationship between calcification and photosynthesis. It has been suggested that since calcification in coccolithophorids is an intracellular process that releases CO2 , it enhances photosynthesis in a manner analogous to a carbon-concentrating mechanism (CCM). The ubiquitous, bloom-forming, and numerically abundant coccolithophorid Emiliania huxleyi (Lohmann) W. W. Hay et H. Mohler was studied in nutrient-replete, pH and [CO2 ] controlled, continuous cultures (turbidostats) under a range of [Ca(2+) ] from 0 to 9 mM. We examined the long-term, fully acclimated photosynthesis-light responses and analyzed the crystalline structure of the coccoliths using SEM. The E. huxleyi cells completely lost their coccosphere when grown in 0 [Ca(2+) ], while thin, undercalcified and brittle coccoliths were evident at 1 mM [Ca(2+) ]. Coccoliths showed increasing levels of calcification with increasing [Ca(2+) ]. More robust coccoliths were noted, with no discernable differences in coccolith morphology when the cells were grown in either 5 or 9 mM (ambient seawater) [Ca(2+) ]. In contrast to calcification, photosynthesis was not affected by the [Ca(2+) ] in the media. Cells showed no correlation of their light-dependent O2 evolution with [Ca(2+) ], and in all [Ca(2+) ]-containing turbidostats, there were no significant differences in growth rate. The results show unequivocally that as a process, photosynthesis in E. huxleyi is mechanistically independent from calcification. © 2009 Phycological Society of America.

Organophotocatalysis: Insights into the Mechanistic Aspects of Thiourea-Mediated Intermolecular [2+2] Photocycloadditions.

Science.gov (United States)

Vallavoju, Nandini; Selvakumar, Sermadurai; Pemberton, Barry C; Jockusch, Steffen; Sibi, Mukund P; Sivaguru, Jayaraman

2016-04-25

Mechanistic investigations of the intermolecular [2+2] photocycloaddition of coumarin with tetramethylethylene mediated by thiourea catalysts reveal that the reaction is enabled by a combination of minimized aggregation, enhanced intersystem crossing, and altered excited-state lifetime(s). These results clarify how the excited-state reactivity can be manipulated through catalyst-substrate interactions and reveal a third mechanistic pathway for thiourea-mediated organo-photocatalysis. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Identifying mechanistic similarities in drug responses

KAUST Repository

Zhao, C.

2012-05-15

Motivation: In early drug development, it would be beneficial to be able to identify those dynamic patterns of gene response that indicate that drugs targeting a particular gene will be likely or not to elicit the desired response. One approach would be to quantitate the degree of similarity between the responses that cells show when exposed to drugs, so that consistencies in the regulation of cellular response processes that produce success or failure can be more readily identified.Results: We track drug response using fluorescent proteins as transcription activity reporters. Our basic assumption is that drugs inducing very similar alteration in transcriptional regulation will produce similar temporal trajectories on many of the reporter proteins and hence be identified as having similarities in their mechanisms of action (MOA). The main body of this work is devoted to characterizing similarity in temporal trajectories/signals. To do so, we must first identify the key points that determine mechanistic similarity between two drug responses. Directly comparing points on the two signals is unrealistic, as it cannot handle delays and speed variations on the time axis. Hence, to capture the similarities between reporter responses, we develop an alignment algorithm that is robust to noise, time delays and is able to find all the contiguous parts of signals centered about a core alignment (reflecting a core mechanism in drug response). Applying the proposed algorithm to a range of real drug experiments shows that the result agrees well with the prior drug MOA knowledge. © The Author 2012. Published by Oxford University Press. All rights reserved.

Fuel swelling importance in PCI mechanistic modelling

International Nuclear Information System (INIS)

Arimescu, V.I.

2005-01-01

Under certain conditions, fuel pellet swelling is the most important factor in determining the intensity of the pellet-to-cladding mechanical interaction (PCMI). This is especially true during power ramps, which lead to a temperature increase to a higher terminal plateau that is maintained for hours. The time-dependent gaseous swelling is proportional to temperature and is also enhanced by the increased gas atom migration to the grain boundary during the power ramp. On the other hand, gaseous swelling is inhibited by a compressive hydrostatic stress in the pellet. Therefore, PCMI is the net result of combining gaseous swelling and pellet thermal expansion with the opposing feedback from the cladding mechanical reaction. The coupling of the thermal and mechanical processes, mentioned above, with various feedback loops is best simulated by a mechanistic fuel code. This paper discusses a mechanistic swelling model that is coupled with a fission gas release model as well as a mechanical model of the fuel pellet. The role of fuel swelling is demonstrated for typical power ramps at different burn-ups. Also, fuel swelling plays a significant role in avoiding the thermal instability for larger gap fuel rods, by limiting the potentially exponentially increasing gap due to the positive feedback loop effect of increasing fission gas release and the associated over-pressure inside the cladding. (author)

Multi input single output model predictive control of non-linear bio-polymerization process

Energy Technology Data Exchange (ETDEWEB)

Arumugasamy, Senthil Kumar; Ahmad, Z. [School of Chemical Engineering, Univerisiti Sains Malaysia, Engineering Campus, Seri Ampangan,14300 Nibong Tebal, Seberang Perai Selatan, Pulau Pinang (Malaysia)

2015-05-15

This paper focuses on Multi Input Single Output (MISO) Model Predictive Control of bio-polymerization process in which mechanistic model is developed and linked with the feedforward neural network model to obtain a hybrid model (Mechanistic-FANN) of lipase-catalyzed ring-opening polymerization of ε-caprolactone (ε-CL) for Poly (ε-caprolactone) production. In this research, state space model was used, in which the input to the model were the reactor temperatures and reactor impeller speeds and the output were the molecular weight of polymer (M{sub n}) and polymer polydispersity index. State space model for MISO created using System identification tool box of Matlab™. This state space model is used in MISO MPC. Model predictive control (MPC) has been applied to predict the molecular weight of the biopolymer and consequently control the molecular weight of biopolymer. The result shows that MPC is able to track reference trajectory and give optimum movement of manipulated variable.

Does Mechanistic Thinking Improve Student Success in Organic Chemistry?

Science.gov (United States)

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…

Flow-mediated dilation: can new approaches provide greater mechanistic insight into vascular dysfunction in preeclampsia and other diseases?

Science.gov (United States)

Weissgerber, Tracey L

2014-11-01

Endothelial dysfunction is a key feature of preeclampsia and may contribute to increased cardiovascular disease risk years after pregnancy. Flow-mediated dilation (FMD) is a non-invasive endothelial function test that predicts cardiovascular event risk. New protocols allow researchers to measure three components of the FMD response: FMD, low flow-mediated constriction, and shear stimulus. This review encourages researchers to think beyond "low FMD" by examining how these three components may provide additional insights into the mechanisms and location of vascular dysfunction. The review then examines what FMD studies reveal about vascular dysfunction in preeclampsia while highlighting opportunities to gain greater mechanistic insight from new protocols. Studies using traditional protocols show that FMD is low in mid-pregnancy prior to preeclampsia, at diagnosis, and for 3 years post-partum. However, FMD returns to normal by 10 years post-partum. Studies using new protocols are needed to gain more mechanistic insight.

The E. coli pET expression system revisited-mechanistic correlation between glucose and lactose uptake.

Science.gov (United States)

Wurm, David Johannes; Veiter, Lukas; Ulonska, Sophia; Eggenreich, Britta; Herwig, Christoph; Spadiut, Oliver

2016-10-01

Therapeutic monoclonal antibodies are mainly produced in mammalian cells to date. However, unglycosylated antibody fragments can also be produced in the bacterium Escherichia coli which brings several advantages, like growth on cheap media and high productivity. One of the most popular E. coli strains for recombinant protein production is E. coli BL21(DE3) which is usually used in combination with the pET expression system. However, it is well known that induction by isopropyl β-D-1-thiogalactopyranoside (IPTG) stresses the cells and can lead to the formation of insoluble inclusion bodies. In this study, we revisited the pET expression system for the production of a novel antibody single-chain variable fragment (scFv) with the goal of maximizing the amount of soluble product. Thus, we (1) investigated whether lactose favors the recombinant production of soluble scFv compared to IPTG, (2) investigated whether the formation of soluble product can be influenced by the specific glucose uptake rate (q s,glu) during lactose induction, and (3) determined the mechanistic correlation between the specific lactose uptake rate (q s,lac) and q s,glu. We found that lactose induction gave a much greater amount of soluble scFv compared to IPTG, even when the growth rate was increased. Furthermore, we showed that the production of soluble protein could be tuned by varying q s,glu during lactose induction. Finally, we established a simple model describing the mechanistic correlation between q s,lac and q s,glu allowing tailored feeding and prevention of sugar accumulation. We believe that this mechanistic model might serve as platform knowledge for E. coli.

A mechanistic nitrogen limitation model for CLM(ED)

Science.gov (United States)

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.

Existing pavement input information for the mechanistic-empirical pavement design guide.

Science.gov (United States)

2009-02-01

The objective of this study is to systematically evaluate the Iowa Department of Transportations (DOTs) existing Pavement Management Information System (PMIS) with respect to the input information required for Mechanistic-Empirical Pavement Des...

Mechanistic modeling of reactive soil nitrogen emissions across agricultural management practices

Science.gov (United States)

Rasool, Q. Z.; Miller, D. J.; Bash, J. O.; Venterea, R. T.; Cooter, E. J.; Hastings, M. G.; Cohan, D. S.

2017-12-01

The global reactive nitrogen (N) budget has increased by a factor of 2-3 from pre-industrial levels. This increase is especially pronounced in highly N fertilized agricultural regions in summer. The reactive N emissions from soil to atmosphere can be in reduced (NH3) or oxidized (NO, HONO, N2O) forms, depending on complex biogeochemical transformations of soil N reservoirs. Air quality models like CMAQ typically neglect soil emissions of HONO and N2O. Previously, soil NO emissions estimated by models like CMAQ remained parametric and inconsistent with soil NH3 emissions. Thus, there is a need to more mechanistically and consistently represent the soil N processes that lead to reactive N emissions to the atmosphere. Our updated approach estimates soil NO, HONO and N2O emissions by incorporating detailed agricultural fertilizer inputs from EPIC, and CMAQ-modeled N deposition, into the soil N pool. EPIC addresses the nitrification, denitrification and volatilization rates along with soil N pools for agricultural soils. Suitable updates to account for factors like nitrite (NO2-) accumulation not addressed in EPIC, will also be made. The NO and N2O emissions from nitrification and denitrification are computed mechanistically using the N sub-model of DAYCENT. These mechanistic definitions use soil water content, temperature, NH4+ and NO3- concentrations, gas diffusivity and labile C availability as dependent parameters at various soil layers. Soil HONO emissions found to be most probable under high NO2- availability will be based on observed ratios of HONO to NO emissions under different soil moistures, pH and soil types. The updated scheme will utilize field-specific soil properties and N inputs across differing manure management practices such as tillage. Comparison of the modeled soil NO emission rates from the new mechanistic and existing schemes against field measurements will be discussed. Our updated framework will help to predict the diurnal and daily variability

Hydrogen-bond-driven electrophilic activation for selectivity control: scope and limitations of fluorous alcohol-promoted selective formation of 1,2-disubstituted benzimidazoles and mechanistic insight for rationale of selectivity.

Science.gov (United States)

Chebolu, Rajesh; Kommi, Damodara N; Kumar, Dinesh; Bollineni, Narendra; Chakraborti, Asit K

2012-11-16

Hydrogen-bond-driven electrophilic activation for selectivity control during competitive formation of 1,2-disubstituted and 2-substituted benzimidazoles from o-phenylenediamine and aldehydes is reported. The fluorous alcohols trifluoroethanol and hexafluoro-2-propanol efficiently promote the cyclocondensation of o-phenylenediamine with aldehydes to afford selectively the 1,2-disubstituted benzimidazoles at rt in short times. A mechanistic insight is invoked by NMR, mass spectrometry, and chemical studies to rationalize the selectivity. The ability of the fluorous alcohols in promoting the reaction and controlling the selectivity can be envisaged from their better hydrogen bond donor (HBD) abilities compared to that of the other organic solvents as well as of water. Due to the better HBD values, the fluorous alcohols efficiently promote the initial bisimine formation by electrophilic activation of the aldehyde carbonyl. Subsequently the hydrogen-bond-mediated activation of the in situ-formed bisimine triggers the rearrangement via 1,3-hydride shift to form the 1,2-disubstituted benzimidazoles.

Profiling the biological activity of oxide nanomaterials with mechanistic models

NARCIS (Netherlands)

Burello, E.

2013-01-01

In this study we present three mechanistic models for profiling the potential biological and toxicological effects of oxide nanomaterials. The models attempt to describe the reactivity, protein adsorption and membrane adhesion processes of a large range of oxide materials and are based on properties

Generative Mechanistic Explanation Building in Undergraduate Molecular and Cellular Biology

Science.gov (United States)

Southard, Katelyn M.; Espindola, Melissa R.; Zaepfel, Samantha D.; Bolger, Molly S.

2017-01-01

When conducting scientific research, experts in molecular and cellular biology (MCB) use specific reasoning strategies to construct mechanistic explanations for the underlying causal features of molecular phenomena. We explored how undergraduate students applied this scientific practice in MCB. Drawing from studies of explanation building among…

Melanie Klein's metapsychology: phenomenological and mechanistic perspective.

Science.gov (United States)

Mackay, N

1981-01-01

Freud's metapsychology is the subject of an important debate. This is over whether psychoanalysis is best construed as a science of the natural science type or as a special human science. The same debate applies to Melanie Klein's work. In Klein's metapsychology are two different and incompatible models of explanation. One is taken over from Freud's structural theory and appears to be similarly mechanistic. The other is clinically based and phenomenological. These two are discussed with special reference to the concepts of "phantasy" and "internal object".

Quantitative assessment of biological impact using transcriptomic data and mechanistic network models

International Nuclear Information System (INIS)

Thomson, Ty M.; Sewer, Alain; Martin, Florian; Belcastro, Vincenzo; Frushour, Brian P.; Gebel, Stephan; Park, Jennifer; Schlage, Walter K.; Talikka, Marja; Vasilyev, Dmitry M.; Westra, Jurjen W.; Hoeng, Julia; Peitsch, Manuel C.

2013-01-01

Exposure to biologically active substances such as therapeutic drugs or environmental toxicants can impact biological systems at various levels, affecting individual molecules, signaling pathways, and overall cellular processes. The ability to derive mechanistic insights from the resulting system responses requires the integration of experimental measures with a priori knowledge about the system and the interacting molecules therein. We developed a novel systems biology-based methodology that leverages mechanistic network models and transcriptomic data to quantitatively assess the biological impact of exposures to active substances. Hierarchically organized network models were first constructed to provide a coherent framework for investigating the impact of exposures at the molecular, pathway and process levels. We then validated our methodology using novel and previously published experiments. For both in vitro systems with simple exposure and in vivo systems with complex exposures, our methodology was able to recapitulate known biological responses matching expected or measured phenotypes. In addition, the quantitative results were in agreement with experimental endpoint data for many of the mechanistic effects that were assessed, providing further objective confirmation of the approach. We conclude that our methodology evaluates the biological impact of exposures in an objective, systematic, and quantifiable manner, enabling the computation of a systems-wide and pan-mechanistic biological impact measure for a given active substance or mixture. Our results suggest that various fields of human disease research, from drug development to consumer product testing and environmental impact analysis, could benefit from using this methodology. - Highlights: • The impact of biologically active substances is quantified at multiple levels. • The systems-level impact integrates the perturbations of individual networks. • The networks capture the relationships between

Fire in the Plio-Pleistocene: the functions of hominin fire use, and the mechanistic, developmental and evolutionary consequences.

Science.gov (United States)

Attwell, Laura; Kovarovic, Kris; Kendal, Jeremy

2015-07-20

Fire is a powerful natural force that can change landscapes extremely quickly. Hominins have harnessed this resource for their own purposes, with mechanistic and developmental physiological consequences. In addition, the use of fire has niche constructive effects, altering selective environments for genetic and cultural evolution. We review the record for hominin fire use in the Plio-Pleistocene, before considering the various functions for its use, and the resultant mechanistic and developmental consequences. We also adopt the niche construction framework to consider how the use of fire can modify selective environments, and thus have evolutionary consequences at genetic and cultural levels. The light that fire produces may influence photoperiodicity and alter hormonally-controlled bodily rhythms. Fire used for cooking could have extended the range of foods hominins were able to consume, and reduced digestion costs. This may have contributed to the expansion of the hominin brain and facial anatomy, influenced by a higher quality cooked diet. Fire may also have allowed dispersal into northern areas with much cooler climates than the hominin African origin, posing novel problems that affected diet and social behaviour.

A mechanistic model on methane oxidation in the rice rhizosphere

NARCIS (Netherlands)

Bodegom, van P.M.; Leffelaar, P.A.; Goudriaan, J.

2001-01-01

A mechanistic model is presented on the processes leading to methane oxidation in rice rhizosphere. The model is driven by oxygen release from a rice root into anaerobic rice soil. Oxygen is consumed by heterotrophic and methanotrophic respiration, described by double Monod kinetics, and by iron

Mathematical Description and Mechanistic Reasoning: A Pathway toward STEM Integration

Science.gov (United States)

Weinberg, Paul J.

2017-01-01

Because reasoning about mechanism is critical to disciplined inquiry in science, technology, engineering, and mathematics (STEM) domains, this study focuses on ways to support the development of this form of reasoning. This study attends to how mechanistic reasoning is constituted through mathematical description. This study draws upon Smith's…

Mechanistic study on spraying of blended biodiesel using phase Doppler anemometry

International Nuclear Information System (INIS)

Kamrak, Juthamas; Kongsombut, Benjapol; Grehan, Gerard; Saengkaew, Sawitree; Kim, Kyo-Seon; Charinpanitkul, Tawatchai

2009-01-01

Droplet size and dynamics of blended palm oil-based fatty acid methyl ester (FAME) and diesel oil spray were mechanistically investigated using a phase Doppler anemometry. A two-fluid atomizer was applied for dispersing viscous blends of blended biodiesel oil with designated flow rates. It was experimentally found that the atomizer could generate a spray with large droplets with Sauter mean diameters of ca. 30 μm at low air injection pressure. Such large droplets traveled with a low velocity along their trajectory after emerging from the nozzle tip. The viscosity of blended biodiesel could significantly affect the atomizing process, resulting in the controlled droplet size distribution. Blended biodiesel with a certain fraction of palm oil-based FAME would be consistently atomized owing to its low viscosity. However, the viscosity could exert only a small effect on the droplet velocity profile with the air injection pressure higher than 0.2 MPa.

Empirical and mechanistic evaluation of NH4(+) release kinetic in calcareous soils.

Science.gov (United States)

Ranjbar, F; Jalali, M

2014-05-01

Release, fixation, and distribution of ammonium (NH4(+)) as a source of nitrogen can play an important role in soil fertility and plant nutrition. In this study, ten surface soils, after addition of 1,000 mg NH4(+) kg(-1,) were incubated for 1 week at the field capacity moisture and 25 ± 2 °C temperature, and then NH4(+) release kinetic was investigated by sequential extractions with 10 mM CaCl2. Furthermore, NH4(+) distribution among three fractions, including water-soluble, exchangeable, and non-exchangeable, was determined in all soil samples. NH4(+) release was initially rapid followed by a slower reaction, and this was described well with the Elovich equation as an empirical model. The cumulative NH4(+) concentration released in spiked soil samples had a positive significant correlation with sand content and negative ones with pH, exchangeable Ca(2+)m and K(+), cation exchange capacity (CEC), equivalent calcium carbonate (ECC), and clay content. The cation exchange model in the PHREEQC program was successful in mechanistic simulation of the release trend of native and added NH4(+) in all control and spiked soil samples. The results of fractionation experiments showed that the non-exchangeable fraction in control and spiked soil samples was greater than that in water-soluble and exchangeable fractions. Soil properties, such as pH, exchangeable Ca(2+) and K(+), CEC, ECC, and contents of sand and clay, had significant influences on the distribution of NH4(+) among three measured fractions. This study indicated that both native and recently fixed NH4(+), added to soil through the application of fertilizers, were readily available for plant roots during 1 week after exposure.

INCORPORATION OF MECHANISTIC INFORMATION IN THE ARSENIC PBPK MODEL DEVELOPMENT PROCESS

Science.gov (United States)

INCORPORATING MECHANISTIC INSIGHTS IN A PBPK MODEL FOR ARSENICElaina M. Kenyon, Michael F. Hughes, Marina V. Evans, David J. Thomas, U.S. EPA; Miroslav Styblo, University of North Carolina; Michael Easterling, Analytical Sciences, Inc.A physiologically based phar...

A metabonomic approach for mechanistic exploration of pre-clinical toxicology.

Science.gov (United States)

Coen, Muireann

2010-12-30

Metabonomics involves the application of advanced analytical tools to profile the diverse metabolic complement of a given biofluid or tissue. Subsequent statistical modelling of the complex multivariate spectral profiles enables discrimination between phenotypes of interest and identifies panels of discriminatory metabolites that represent candidate biomarkers. This review article presents an overview of recent developments in the field of metabonomics with a focus on application to pre-clinical toxicology studies. Recent research investigations carried out as part of the international COMET 2 consortium project on the hepatotoxic action of the aminosugar, galactosamine (galN) are presented. The application of advanced, high-field NMR spectroscopy is demonstrated, together with complementary application of a targeted mass spectrometry platform coupled with ultra-performance liquid chromatography. Much novel mechanistic information has been gleaned on both the mechanism of galN hepatotoxicity in multiple biofluids and tissues, and on the protection afforded by co-administration of glycine and uridine. The simultaneous identification of both the metabolic fate of galN and its associated endogenous consequences in spectral profiles is demonstrated. Furthermore, metabonomic assessment of inter-animal variability in response to galN presents enhanced mechanistic insight on variable response phentoypes and is relevant to understanding wider aspects of individual variability in drug response. This exemplar highlights the analytical and statistical tools commonly applied in metabonomic studies and notably, the approach is applicable to the study of any toxin/drug or intervention of interest. The metabonomic approach holds considerable promise and potential to significantly advance our understanding of the mechanistic bases for adverse drug reactions. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

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

Energy Technology Data Exchange (ETDEWEB)

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.

Ruthenium-Catalyzed Transformations of Alcohols: Mechanistic Investigations and Methodology Development

DEFF Research Database (Denmark)

Makarov, Ilya; Madsen, Robert; Fristrup, Peter

with dimethoxyisopropylidene and pyridilidene ligands could be more active than RuCl2(IiPr)(p-cymene) used in the mechanistic investigation. Two analogs of the calculated complexes were synthesized but were not isolated in a pure form. The amidation reaction catalyzed by a mixture containing the N-ethyl pyridilidene...

Mechanistic investigation on the oxidation of kinetin by Ag(III)

Indian Academy of Sciences (India)

Home; Journals; Journal of Chemical Sciences; Volume 122; Issue 6. Mechanistic investigation on the oxidation of kinetin by Ag(III) periodate complex in aqueous alkaline media: A kinetic approach. S D Lamani A M Tatagar S T Nandibewoor. Full Papers Volume 122 Issue 6 November 2010 pp 891-900 ...

An improved mechanistic critical heat flux model for subcooled flow boiling

Energy Technology Data Exchange (ETDEWEB)

Kwon, Young Min [Korea Atomic Energy Research Institute, Taejon (Korea, Republic of); Chang, Soon Heung [Korea Advanced Institute of Science and Technology, Taejon (Korea, Republic of)

1998-12-31

Based on the bubble coalescence adjacent to the heated wall as a flow structure for CHF condition, Chang and Lee developed a mechanistic critical heat flux (CHF) model for subcooled flow boiling. In this paper, improvements of Chang-Lee model are implemented with more solid theoretical bases for subcooled and low-quality flow boiling in tubes. Nedderman-Shearer`s equations for the skin friction factor and universal velocity profile models are employed. Slip effect of movable bubbly layer is implemented to improve the predictability of low mass flow. Also, mechanistic subcooled flow boiling model is used to predict the flow quality and void fraction. The performance of the present model is verified using the KAIST CHF database of water in uniformly heated tubes. It is found that the present model can give a satisfactory agreement with experimental data within less than 9% RMS error. 9 refs., 5 figs. (Author)

An improved mechanistic critical heat flux model for subcooled flow boiling

Energy Technology Data Exchange (ETDEWEB)

Kwon, Young Min [Korea Atomic Energy Research Institute, Taejon (Korea, Republic of); Chang, Soon Heung [Korea Advanced Institute of Science and Technology, Taejon (Korea, Republic of)

1997-12-31

Based on the bubble coalescence adjacent to the heated wall as a flow structure for CHF condition, Chang and Lee developed a mechanistic critical heat flux (CHF) model for subcooled flow boiling. In this paper, improvements of Chang-Lee model are implemented with more solid theoretical bases for subcooled and low-quality flow boiling in tubes. Nedderman-Shearer`s equations for the skin friction factor and universal velocity profile models are employed. Slip effect of movable bubbly layer is implemented to improve the predictability of low mass flow. Also, mechanistic subcooled flow boiling model is used to predict the flow quality and void fraction. The performance of the present model is verified using the KAIST CHF database of water in uniformly heated tubes. It is found that the present model can give a satisfactory agreement with experimental data within less than 9% RMS error. 9 refs., 5 figs. (Author)

INTEGRATION OF QSAR AND SAR METHODS FOR THE MECHANISTIC INTERPRETATION OF PREDICTIVE MODELS FOR CARCINOGENICITY

Directory of Open Access Journals (Sweden)

Natalja Fjodorova

2012-07-01

Full Text Available The knowledge-based Toxtree expert system (SAR approach was integrated with the statistically based counter propagation artificial neural network (CP ANN model (QSAR approach to contribute to a better mechanistic understanding of a carcinogenicity model for non-congeneric chemicals using Dragon descriptors and carcinogenic potency for rats as a response. The transparency of the CP ANN algorithm was demonstrated using intrinsic mapping technique specifically Kohonen maps. Chemical structures were represented by Dragon descriptors that express the structural and electronic features of molecules such as their shape and electronic surrounding related to reactivity of molecules. It was illustrated how the descriptors are correlated with particular structural alerts (SAs for carcinogenicity with recognized mechanistic link to carcinogenic activity. Moreover, the Kohonen mapping technique enables one to examine the separation of carcinogens and non-carcinogens (for rats within a family of chemicals with a particular SA for carcinogenicity. The mechanistic interpretation of models is important for the evaluation of safety of chemicals.

Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation: Report of an FDA Public Workshop.

Science.gov (United States)

Zhang, X; Duan, J; Kesisoglou, F; Novakovic, J; Amidon, G L; Jamei, M; Lukacova, V; Eissing, T; Tsakalozou, E; Zhao, L; Lionberger, R

2017-08-01

On May 19, 2016, the US Food and Drug Administration (FDA) hosted a public workshop, entitled "Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation." The topic of mechanistic oral absorption modeling, which is one of the major applications of physiologically based pharmacokinetic (PBPK) modeling and simulation, focuses on predicting oral absorption by mechanistically integrating gastrointestinal transit, dissolution, and permeation processes, incorporating systems, active pharmaceutical ingredient (API), and the drug product information, into a systemic mathematical whole-body framework. © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Fast charging technique for high power LiFePO4 batteries: A mechanistic analysis of aging

Science.gov (United States)

Anseán, D.; Dubarry, M.; Devie, A.; Liaw, B. Y.; García, V. M.; Viera, J. C.; González, M.

2016-07-01

One of the major issues hampering the acceptance of electric vehicles (EVs) is the anxiety associated with long charging time. Hence, the ability to fast charging lithium-ion battery (LIB) systems is gaining notable interest. However, fast charging is not tolerated by all LIB chemistries because it affects battery functionality and accelerates its aging processes. Here, we investigate the long-term effects of multistage fast charging on a commercial high power LiFePO4-based cell and compare it to another cell tested under standard charging. Coupling incremental capacity (IC) and IC peak area analysis together with mechanistic model simulations ('Alawa' toolbox with harvested half-cell data), we quantify the degradation modes that cause aging of the tested cells. The results show that the proposed fast charging technique caused similar aging effects as standard charging. The degradation is caused by a linear loss of lithium inventory, coupled with a less degree of linear loss of active material on the negative electrode. This study validates fast charging as a feasible mean of operation for this particular LIB chemistry and cell architecture. It also illustrates the benefits of a mechanistic approach to understand cell degradation on commercial cells.

Mechanistic facility safety and source term analysis

International Nuclear Information System (INIS)

PLYS, M.G.

1999-01-01

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

Mechanistic species distribution modeling reveals a niche shift during invasion.

Science.gov (United States)

Chapman, Daniel S; Scalone, Romain; Štefanić, Edita; Bullock, James M

2017-06-01

Niche shifts of nonnative plants can occur when they colonize novel climatic conditions. However, the mechanistic basis for niche shifts during invasion is poorly understood and has rarely been captured within species distribution models. We quantified the consequence of between-population variation in phenology for invasion of common ragweed (Ambrosia artemisiifolia L.) across Europe. Ragweed is of serious concern because of its harmful effects as a crop weed and because of its impact on public health as a major aeroallergen. We developed a forward mechanistic species distribution model based on responses of ragweed development rates to temperature and photoperiod. The model was parameterized and validated from the literature and by reanalyzing data from a reciprocal common garden experiment in which native and invasive populations were grown within and beyond the current invaded range. It could therefore accommodate between-population variation in the physiological requirements for flowering, and predict the potentially invaded ranges of individual populations. Northern-origin populations that were established outside the generally accepted climate envelope of the species had lower thermal requirements for bud development, suggesting local adaptation of phenology had occurred during the invasion. The model predicts that this will extend the potentially invaded range northward and increase the average suitability across Europe by 90% in the current climate and 20% in the future climate. Therefore, trait variation observed at the population scale can trigger a climatic niche shift at the biogeographic scale. For ragweed, earlier flowering phenology in established northern populations could allow the species to spread beyond its current invasive range, substantially increasing its risk to agriculture and public health. Mechanistic species distribution models offer the possibility to represent niche shifts by varying the traits and niche responses of individual

Mechanistic study on spraying of blended biodiesel using phase Doppler anemometry

Energy Technology Data Exchange (ETDEWEB)

Kamrak, Juthamas; Kongsombut, Benjapol; Charinpanitkul, Tawatchai [Center of Excellence in Particle Technology, Department of Chemical Engineering, Faculty of Engineering, Chulalongkorn University, Payathai Road, Patumwan, Bangkok 10330 (Thailand); Grehan, Gerard; Saengkaew, Sawitree [LESP/UMR CNRS6614/INSA et Universite de Rouen, BP 12, avenue de l' universite, 76801, Saint Etienne du Rouvray (France); Kim, Kyo-Seon [Department of Chemical Engineering, Faculty of Engineering, Kangwon National University, Chuncheon (Korea)

2009-10-15

Droplet size and dynamics of blended palm oil-based fatty acid methyl ester (FAME) and diesel oil spray were mechanistically investigated using a phase Doppler anemometry. A two-fluid atomizer was applied for dispersing viscous blends of blended biodiesel oil with designated flow rates. It was experimentally found that the atomizer could generate a spray with large droplets with Sauter mean diameters of ca. 30 {mu}m at low air injection pressure. Such large droplets traveled with a low velocity along their trajectory after emerging from the nozzle tip. The viscosity of blended biodiesel could significantly affect the atomizing process, resulting in the controlled droplet size distribution. Blended biodiesel with a certain fraction of palm oil-based FAME would be consistently atomized owing to its low viscosity. However, the viscosity could exert only a small effect on the droplet velocity profile with the air injection pressure higher than 0.2 MPa. (author)

Lipids, adiposity and tendinopathy : is there a mechanistic link? Critical review

NARCIS (Netherlands)

Scott, Alex; Zwerver, Johannes; Grewal, Navi; de Sa, Agnetha; Alktebi, Thuraya; Granville, David J.; Hart, David A.

Being overweight or obese is associated with an elevated risk of tendon pathology. However, for sportspeople the epidemiological data linking weight or adiposity on one hand, and risk of tendon pathology on the other, are less consistent. Indeed, the mechanistic links between diet, adiposity and

Mechanistic and "natural" body metaphors and their effects on attitudes to hormonal contraception.

Science.gov (United States)

Walker, Susan

2012-01-01

A small, self-selected convenience sample of male and female contraceptive users in the United Kingdom (n = 34) were interviewed between 2006 and 2008 concerning their feelings about the body and their contraceptive attitudes and experiences. The interviewees were a sub-sample of respondents (n = 188) who completed a paper-based questionnaire on similar topics, who were recruited through a poster placed in a family planning clinic, web-based advertisements on workplace and university websites, and through direct approaches to social groups. The bodily metaphors used when discussing contraception were analyzed using an interpretative phenomenological analytical approach facilitated by Atlas.ti software. The dominant bodily metaphor was mechanistic (i.e.,"body as machine"). A subordinate but influential bodily metaphor was the "natural" body, which had connotations of connection to nature and a quasi-sacred bodily order. Interviewees drew upon this "natural" metaphorical image in the context of discussing their anxieties about hormonal contraception. Drawing upon a "natural," non-mechanistic body image in the context of contraceptive decision-making contributed to reluctance to use a hormonal form of contraception. This research suggests that clinicians could improve communication and advice about contraception by recognizing that some users may draw upon non-mechanistic body imagery.

Mechanistic-empirical subgrade design model based on heavy vehicle simulator test results

CSIR Research Space (South Africa)

Theyse, HL

2006-06-01

Full Text Available Although Accelerated Pavement Testing (APT) is often done with specific objectives, valuable pavement performance data is generated over the long-term that may be used to investigate pavement behaviour in general and calibrate mechanistic...

Proposed key characteristics of male reproductive toxicants as a method for organizing and screening mechanistic evidence for non-cancer outcomes.

Science.gov (United States)

The adoption of systematic review practices for risk assessment includes integration of evidence obtained from experimental, epidemiological, and mechanistic studies. Although mechanistic evidence plays an important role in mode of action analysis, the process of sorting and anal...

Final Report for the DOE-BES Program Mechanistic Studies of Activated Hydrogen Release from Amine-Boranes

Energy Technology Data Exchange (ETDEWEB)

Larry G. Sneddon; R. Thomas Baker

2013-01-13

Effective storage of hydrogen presents one of the most significant technical gaps to successful implementation of the hydrogen economy, particularly for transportation applications. Amine boranes, such as ammonia borane H3NBH3 and ammonia triborane H3NB3H7, have been identified as promising, high-capacity chemical hydrogen storage media containing potentially readily released protic (N-H) and hydridic (B-H) hydrogens. At the outset of our studies, dehydrogenation of ammonia borane had been studied primarily in the solid state, but our DOE sponsored work clearly demonstrated that ionic liquids, base-initiators and/or metal-catalysts can each significantly increase both the rate and extent of hydrogen release from amine boranes under moderate conditions. Our studies also showed that depending upon the activation method, hydrogen release from amine boranes can occur by very different mechanistic steps and yield different types of spent-fuel materials. The fundamental understanding that was developed during this grant of the pathways and controlling factors for each of these hydrogen-release mechanisms is now enabling continuing discovery and optimization of new chemical-hydride based hydrogen storage systems.

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

Directory of Open Access Journals (Sweden)

Thibaud Rougier

Full Text Available 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

Permanent deformation testing for a new South African mechanistic pavement design method

CSIR Research Space (South Africa)

Anochie-Boateng, Joseph

2012-01-01

Full Text Available The South Africa National Road Agency Limited together with the CSIR are undertaking a research and development project to support the revision of the South African mechanistic-empirical pavement design method. An important part of this project...

Development of a mechanistic model for prediction of CO2 capture from gas mixtures by amine solutions in porous membranes.

Science.gov (United States)

Ghadiri, Mehdi; Marjani, Azam; Shirazian, Saeed

2017-06-01

A mechanistic model was developed in order to predict capture and removal of CO 2 from air using membrane technology. The considered membrane was a hollow-fiber contactor module in which gas mixture containing CO 2 was assumed as feed while 2-amino-2-metyl-1-propanol (AMP) was used as an absorbent. The mechanistic model was developed according to transport phenomena taking into account mass transfer and chemical reaction between CO 2 and amine in the contactor module. The main aim of modeling was to track the composition and flux of CO 2 and AMP in the membrane module for process optimization. For modeling of the process, the governing equations were computed using finite element approach in which the whole model domain was discretized into small cells. To confirm the simulation findings, model outcomes were compared with experimental data and good consistency was revealed. The results showed that increasing temperature of AMP solution increases CO 2 removal in the hollow-fiber membrane contactor.

The use of mechanistic descriptions of algal growth and zooplankton grazing in an estuarine eutrophication model

Science.gov (United States)

Baird, M. E.; Walker, S. J.; Wallace, B. B.; Webster, I. T.; Parslow, J. S.

2003-03-01

A simple model of estuarine eutrophication is built on biomechanical (or mechanistic) descriptions of a number of the key ecological processes in estuaries. Mechanistically described processes include the nutrient uptake and light capture of planktonic and benthic autotrophs, and the encounter rates of planktonic predators and prey. Other more complex processes, such as sediment biogeochemistry, detrital processes and phosphate dynamics, are modelled using empirical descriptions from the Port Phillip Bay Environmental Study (PPBES) ecological model. A comparison is made between the mechanistically determined rates of ecological processes and the analogous empirically determined rates in the PPBES ecological model. The rates generally agree, with a few significant exceptions. Model simulations were run at a range of estuarine depths and nutrient loads, with outputs presented as the annually averaged biomass of autotrophs. The simulations followed a simple conceptual model of eutrophication, suggesting a simple biomechanical understanding of estuarine processes can provide a predictive tool for ecological processes in a wide range of estuarine ecosystems.

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

Science.gov (United States)

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.

The attention schema theory: a mechanistic account of subjective awareness

Directory of Open Access Journals (Sweden)

Taylor W. Webb

2015-04-01

Full Text Available 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.

Mechanistic model of mass-specific basal metabolic rate: evaluation in healthy young adults.

Science.gov (United States)

Wang, Z; Bosy-Westphal, A; Schautz, B; Müller, M

2011-12-01

Mass-specific basal metabolic rate (mass-specific BMR), defined as the resting energy expenditure per unit body mass per day, is an important parameter in energy metabolism research. However, a mechanistic explanation for magnitude of mass-specific BMR remains lacking. The objective of the present study was to validate the applicability of a proposed mass-specific BMR model in healthy adults. A mechanistic model was developed at the organ-tissue level, mass-specific BMR = Σ( K i × F i ), where Fi is the fraction of body mass as individual organs and tissues, and K i is the specific resting metabolic rate of major organs and tissues. The Fi values were measured by multiple MRI scans and the K i values were suggested by Elia in 1992. A database of healthy non-elderly non-obese adults (age 20 - 49 yrs, BMI BMR of all subjects was 21.6 ± 1.9 (mean ± SD) and 21.7 ± 1.6 kcal/kg per day, respectively. The measured mass-specific BMR was correlated with the predicted mass-specific BMR (r = 0.82, P BMR, versus the average of measured and predicted mass-specific BMR. In conclusion, the proposed mechanistic model was validated in non-elderly non-obese adults and can help to understand the inherent relationship between mass-specific BMR and body composition.

The coefficient of restitution of pressurized balls: a mechanistic model

Science.gov (United States)

Georgallas, Alex; Landry, Gaëtan

2016-01-01

Pressurized, inflated balls used in professional sports are regulated so that their behaviour upon impact can be anticipated and allow the game to have its distinctive character. However, the dynamics governing the impacts of such balls, even on stationary hard surfaces, can be extremely complex. The energy transformations, which arise from the compression of the gas within the ball and from the shear forces associated with the deformation of the wall, are examined in this paper. We develop a simple mechanistic model of the dependence of the coefficient of restitution, e, upon both the gauge pressure, P_G, of the gas and the shear modulus, G, of the wall. The model is validated using the results from a simple series of experiments using three different sports balls. The fits to the data are extremely good for P_G > 25 kPa and consistent values are obtained for the value of G for the wall material. As far as the authors can tell, this simple, mechanistic model of the pressure dependence of the coefficient of restitution is the first in the literature. *%K Coefficient of Restitution, Dynamics, Inflated Balls, Pressure, Impact Model

A semi-mechanistic approach to calculate the probability of fuel defects

International Nuclear Information System (INIS)

Tayal, M.; Millen, E.; Sejnoha, R.

1992-10-01

In this paper the authors describe the status of a semi-mechanistic approach to the calculation of the probability of fuel defects. This approach expresses the defect probability in terms of fundamental parameters such as local stresses, local strains, and fission product concentration. The calculations of defect probability continue to reflect the influences of the conventional parameters like power ramp, burnup and CANLUB. In addition, the new approach provides a mechanism to account for the impacts of additional factors involving detailed fuel design and reactor operation, for example pellet density, pellet shape and size, sheath diameter and thickness, pellet/sheath clearance, and coolant temperature and pressure. The approach has been validated against a previous empirical correlation. AN illustrative example shows how the defect thresholds are influenced by changes in the internal design of the element and in the coolant pressure. (Author) (7 figs., tab., 12 refs.)

Students' Interpretations of Mechanistic Language in Organic Chemistry before Learning Reactions

Science.gov (United States)

Galloway, Kelli R.; Stoyanovich, Carlee; Flynn, Alison B.

2017-01-01

Research on mechanistic thinking in organic chemistry has shown that students attribute little meaning to the electron-pushing (i.e., curved arrow) formalism. At the University of Ottawa, a new curriculum has been developed in which students are taught the electron-pushing formalism prior to instruction on specific reactions--this formalism is…

Coupling machine learning with mechanistic models to study runoff production and river flow at the hillslope scale

Science.gov (United States)

Marçais, J.; Gupta, H. V.; De Dreuzy, J. R.; Troch, P. A. A.

2016-12-01

Geomorphological structure and geological heterogeneity of hillslopes are major controls on runoff responses. The diversity of hillslopes (morphological shapes and geological structures) on one hand, and the highly non linear runoff mechanism response on the other hand, make it difficult to transpose what has been learnt at one specific hillslope to another. Therefore, making reliable predictions on runoff appearance or river flow for a given hillslope is a challenge. Applying a classic model calibration (based on inverse problems technique) requires doing it for each specific hillslope and having some data available for calibration. When applied to thousands of cases it cannot always be promoted. Here we propose a novel modeling framework based on coupling process based models with data based approach. First we develop a mechanistic model, based on hillslope storage Boussinesq equations (Troch et al. 2003), able to model non linear runoff responses to rainfall at the hillslope scale. Second we set up a model database, representing thousands of non calibrated simulations. These simulations investigate different hillslope shapes (real ones obtained by analyzing 5m digital elevation model of Brittany and synthetic ones), different hillslope geological structures (i.e. different parametrizations) and different hydrologic forcing terms (i.e. different infiltration chronicles). Then, we use this model library to train a machine learning model on this physically based database. Machine learning model performance is then assessed by a classic validating phase (testing it on new hillslopes and comparing machine learning with mechanistic outputs). Finally we use this machine learning model to learn what are the hillslope properties controlling runoffs. This methodology will be further tested combining synthetic datasets with real ones.

Mechanistic models for the evaluation of biocatalytic reaction conditions and biosensor design optimization

DEFF Research Database (Denmark)

Semenova, Daria

. In the first case study a mechanistic model was developed to describe the enzymatic reaction of glucose oxidase and glucose in the presence of catalase inside a commercial microfluidic platform with integrated oxygen sensor spots. The simplicity of the proposed model allowed an easy calibration of the reaction...... the microfluidic device. In the second case study the flexible microfluidic platform with integrated amperometric glucose biosensors was developed for continuous monitoring of glucose consumption rates. The integration of the mixing chamber inside the platform allowed performing sample dilutions which subsequently......BRs. In the third case study the mechanistic model of the cyclic voltammetry response of the first generation glucose biosensors was developed and applied for the biosensor design optimization. Furthermore the obtained qualitative and quantitative dependencies between the model output and experimental results were...

Calibrating mechanistic-empirical pavement performance models with an expert matrix

Energy Technology Data Exchange (ETDEWEB)

Tighe, S.; AlAssar, R.; Haas, R. [Waterloo Univ., ON (Canada). Dept. of Civil Engineering; Zhiwei, H. [Stantec Consulting Ltd., Cambridge, ON (Canada)

2001-07-01

Proper management of pavement infrastructure requires pavement performance modelling. For the past 20 years, the Ontario Ministry of Transportation has used the Ontario Pavement Analysis of Costs (OPAC) system for pavement design. Pavement needs, however, have changed substantially during that time. To address this need, a new research contract is underway to enhance the model and verify the predictions, particularly at extreme points such as low and high traffic volume pavement design. This initiative included a complete evaluation of the existing OPAC pavement design method, the construction of a new set of pavement performance prediction models, and the development of the flexible pavement design procedure that incorporates reliability analysis. The design was also expanded to include rigid pavement designs and modification of the existing life cycle cost analysis procedure which includes both the agency cost and road user cost. Performance prediction and life-cycle costs were developed based on several factors, including material properties, traffic loads and climate. Construction and maintenance schedules were also considered. The methodology for the calibration and validation of a mechanistic-empirical flexible pavement performance model was described. Mechanistic-empirical design methods combine theory based design such as calculated stresses, strains or deflections with empirical methods, where a measured response is associated with thickness and pavement performance. Elastic layer analysis was used to determine pavement response to determine the most effective design using cumulative Equivalent Single Axle Loads (ESALs), below grade type and layer thickness.The new mechanistic-empirical model separates the environment and traffic effects on performance. This makes it possible to quantify regional differences between Southern and Northern Ontario. In addition, roughness can be calculated in terms of the International Roughness Index or Riding comfort Index

Task control signals in pediatric Tourette syndrome show evidence of immature and anomalous functional activity

Directory of Open Access Journals (Sweden)

Jessica A Church

2009-11-01

Full Text Available Tourette Syndrome (TS is a pediatric movement disorder that may affect control signaling in the brain. Previous work has proposed a dual-networks architecture of control processing involving a task-maintenance network and an adaptive control network (Dosenbach et al., 2008. A prior resting-state functional connectivity MRI (rs-fcMRI analysis in TS has revealed functional immaturity in both putative control networks, with “anomalous” correlations (i.e. correlations outside the typical developmental range limited to the adaptive control network (Church et al., 2009. The present study used functional MRI (fMRI to study brain activity related to adaptive control (by studying start-cues signals, and to task-maintenance (by studying signals sustained across a task set. Two hypotheses from the previous rs-fcMRI results were tested. First, adaptive control (i.e., start-cue activity will be altered in TS, including activity inconsistent with typical development (“anomalous”. Second, group differences found in task maintenance (i.e., sustained activity will be consistent with functional immaturity in TS. We examined regions found through a direct comparison of adolescents with and without TS, as well as regions derived from a previous investigation that showed differences between unaffected children and adults. The TS group showed decreased start-cue signal magnitude in regions where start-cue activity is unchanged over typical development, consistent with anomalous adaptive control. The TS group also had higher magnitude sustained signals in frontal cortex regions that overlapped with regions showing differences over typical development, consistent with immature task maintenance in TS. The results demonstrate task-related fMRI signal differences anticipated by the atypical functional connectivity found previously in adolescents with TS, strengthening the evidence for functional immaturity and anomalous signaling in control networks in adolescents

Atomization of bismuthane in a dielectric barrier discharge: A mechanistic study

Czech Academy of Sciences Publication Activity Database

Kratzer, Jan; Zelina, Ondřej; Svoboda, Milan; Sturgeon, R. E.; Mester, Z.; Dědina, Jiří

2016-01-01

Roč. 88, č. 3 (2016), s. 1804-1811 ISSN 0003-2700 R&D Projects: GA ČR GA14-23532S Grant - others:GA AV ČR(CZ) M200311202 Institutional support: RVO:68081715 Keywords : dielectric barrier discharge * hydride generation * mechanistic study Subject RIV: CB - Analytical Chemistry, Separation Impact factor: 6.320, year: 2016

Atomization of bismuthane in a dielectric barrier discharge: A mechanistic study

Czech Academy of Sciences Publication Activity Database

Kratzer, Jan; Zelina, Ondřej; Svoboda, Milan; Sturgeon, R. E.; Mester, Z.; Dědina, Jiří

2016-01-01

Roč. 88, č. 3 (2016), s. 1804-1811 ISSN 0003-2700 R&D Projects: GA ČR GA14-23532S Grant - others:GA AV ČR(CZ) M200311202 Institutional support: RVO:68081715 Keywords : dielectric barrier discharge * hydride generation * mechanistic study Subject RIV: CB - Analytical Chemistry , Separation Impact factor: 6.320, year: 2016

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

Science.gov (United States)

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…

Dynamic and accurate assessment of acetaminophen-induced hepatotoxicity by integrated photoacoustic imaging and mechanistic biomarkers in vivo.

Science.gov (United States)

Brillant, Nathalie; Elmasry, Mohamed; Burton, Neal C; Rodriguez, Josep Monne; Sharkey, Jack W; Fenwick, Stephen; Poptani, Harish; Kitteringham, Neil R; Goldring, Christopher E; Kipar, Anja; Park, B Kevin; Antoine, Daniel J

2017-10-01

The prediction and understanding of acetaminophen (APAP)-induced liver injury (APAP-ILI) and the response to therapeutic interventions is complex. This is due in part to sensitivity and specificity limitations of currently used assessment techniques. Here we sought to determine the utility of integrating translational non-invasive photoacoustic imaging of liver function with mechanistic circulating biomarkers of hepatotoxicity with histological assessment to facilitate the more accurate and precise characterization of APAP-ILI and the efficacy of therapeutic intervention. Perturbation of liver function and cellular viability was assessed in C57BL/6J male mice by Indocyanine green (ICG) clearance (Multispectral Optoacoustic Tomography (MSOT)) and by measurement of mechanistic (miR-122, HMGB1) and established (ALT, bilirubin) circulating biomarkers in response to the acetaminophen and its treatment with acetylcysteine (NAC) in vivo. We utilised a 60% partial hepatectomy model as a situation of defined hepatic functional mass loss to compared acetaminophen-induced changes to. Integration of these mechanistic markers correlated with histological features of APAP hepatotoxicity in a time-dependent manner. They accurately reflected the onset and recovery from hepatotoxicity compared to traditional biomarkers and also reported the efficacy of NAC with high sensitivity. ICG clearance kinetics correlated with histological scores for acute liver damage for APAP (i.e. 3h timepoint; r=0.90, P<0.0001) and elevations in both of the mechanistic biomarkers, miR-122 (e.g. 6h timepoint; r=0.70, P=0.005) and HMGB1 (e.g. 6h timepoint; r=0.56, P=0.04). For the first time we report the utility of this non-invasive longitudinal imaging approach to provide direct visualisation of the liver function coupled with mechanistic biomarkers, in the same animal, allowing the investigation of the toxicological and pharmacological aspects of APAP-ILI and hepatic regeneration. Copyright © 2017

Mechanistic Insight into the Dehydro-Diels-Alder Reaction of Styrene-Ynes.

Science.gov (United States)

Kocsis, Laura S; Kagalwala, Husain N; Mutto, Sharlene; Godugu, Bhaskar; Bernhard, Stefan; Tantillo, Dean J; Brummond, Kay M

2015-12-04

The Diels-Alder reaction represents one of the most thoroughly studied and well-understood synthetic transformations for the assembly of six-membered rings. Although intramolecular dehydro-Diels-Alder (IMDDA) reactions have previously been employed for the preparation of naphthalene and dihydronaphthalene substrates, low yields and product mixtures have reduced the impact and scope of this reaction. Through the mechanistic studies described within, we have confirmed that the thermal IMDDA reaction of styrene-ynes produces a naphthalene product via loss of hydrogen gas from the initially formed cycloadduct, a tetraenyl intermediate. Alternatively, the dihydronaphthalene product is afforded from the same tetraenyl intermediate via a radical isomerization process. Moreover, we have identified conditions that can be used to achieve efficient, high-yielding, and selective IMDDA reactions of styrene-ynes to form either naphthalene or dihydronaphthalene products. The operational simplicity and retrosynthetic orthogonality of this method for the preparation of naphthalenes and dihydronaphthalenes makes this transformation appealing for the synthesis of medicinal and material targets. The mechanistic studies within may impact the development of other thermal transformations.

Mechanistic Links Underlying the Impact of C-Reactive Protein on Muscle Mass in Elderly

Directory of Open Access Journals (Sweden)

Britta Wåhlin-Larsson

2017-11-01

Full Text Available Background/Aims: Mechanisms underlying the relationship between systemic inflammation and age-related decline in muscle mass are poorly defined. The purpose of this work was to investigate the relationship between the systemic inflammatory marker CRP and muscle mass in elderly and to identify mechanisms by which CRP mediates its effects on skeletal muscle, in-vitro. Methods: Muscle mass and serum CRP level were determined in a cohort of 118 older women (67±1.7 years. Human muscle cells were differentiated into myotubes and were exposed to CRP. The size of myotubes was determined after immunofluorescent staining using troponin. Muscle protein synthesis was assessed using stable isotope tracers and key signalling pathways controlling protein synthesis were determined using western-blotting. Results: We observed an inverse relationship between circulating CRP level and muscle mass (β= -0.646 (95% CI: -0.888, -0.405 p<0.05 and demonstrated a reduction (p < 0.05 in the size of human myotubes exposed to CRP for 72 h. We next showed that this morphological change was accompanied by a CRP-mediated reduction (p < 0.05 in muscle protein fractional synthetic rate of human myotubes exposed to CRP for 24 h. We also identified a CRP-mediated increased phosphorylation (p<0.05 of regulators of cellular energy stress including AMPK and downstream targets, raptor and ACC-β, together with decreased phosphorylation of Akt and rpS6, which are important factors controlling protein synthesis. Conclusion: This work established for the first time mechanistic links by which chronic elevation of CRP can contribute to age-related decline in muscle function.

Identifying a cooperative control mechanism between an applied field and the environment of open quantum systems

Science.gov (United States)

Gao, Fang; Rey-de-Castro, Roberto; Wang, Yaoxiong; Rabitz, Herschel; Shuang, Feng

2016-05-01

Many systems under control with an applied field also interact with the surrounding environment. Understanding the control mechanisms has remained a challenge, especially the role played by the interaction between the field and the environment. In order to address this need, here we expand the scope of the Hamiltonian-encoding and observable-decoding (HE-OD) technique. HE-OD was originally introduced as a theoretical and experimental tool for revealing the mechanism induced by control fields in closed quantum systems. The results of open-system HE-OD analysis presented here provide quantitative mechanistic insights into the roles played by a Markovian environment. Two model open quantum systems are considered for illustration. In these systems, transitions are induced by either an applied field linked to a dipole operator or Lindblad operators coupled to the system. For modest control yields, the HE-OD results clearly show distinct cooperation between the dynamics induced by the optimal field and the environment. Although the HE-OD methodology introduced here is considered in simulations, it has an analogous direct experimental formulation, which we suggest may be applied to open systems in the laboratory to reveal mechanistic insights.

Mechanistic-Empirical (M-E) Design Implementation & Monitoring for Flexible Pavements : 2018 PROJECT SUMMARY

Science.gov (United States)

2018-06-01

This document is a summary of the tasks performed for Project ICT-R27-149-1. Mechanistic-empirical (M-E)based flexible pavement design concepts and procedures were previously developed in Illinois Cooperative Highway Research Program projects IHR-...

A mechanistic model for electricity consumption on dairy farms: definition, validation, and demonstration.

Science.gov (United States)

Upton, J; Murphy, M; Shalloo, L; Groot Koerkamp, P W G; De Boer, I J M

2014-01-01

Our objective was to define and demonstrate a mechanistic model that enables dairy farmers to explore the impact of a technical or managerial innovation on electricity consumption, associated CO2 emissions, and electricity costs. We, therefore, (1) defined a model for electricity consumption on dairy farms (MECD) capable of simulating total electricity consumption along with related CO2 emissions and electricity costs on dairy farms on a monthly basis; (2) validated the MECD using empirical data of 1yr on commercial spring calving, grass-based dairy farms with 45, 88, and 195 milking cows; and (3) demonstrated the functionality of the model by applying 2 electricity tariffs to the electricity consumption data and examining the effect on total dairy farm electricity costs. The MECD was developed using a mechanistic modeling approach and required the key inputs of milk production, cow number, and details relating to the milk-cooling system, milking machine system, water-heating system, lighting systems, water pump systems, and the winter housing facilities as well as details relating to the management of the farm (e.g., season of calving). Model validation showed an overall relative prediction error (RPE) of less than 10% for total electricity consumption. More than 87% of the mean square prediction error of total electricity consumption was accounted for by random variation. The RPE values of the milk-cooling systems, water-heating systems, and milking machine systems were less than 20%. The RPE values for automatic scraper systems, lighting systems, and water pump systems varied from 18 to 113%, indicating a poor prediction for these metrics. However, automatic scrapers, lighting, and water pumps made up only 14% of total electricity consumption across all farms, reducing the overall impact of these poor predictions. Demonstration of the model showed that total farm electricity costs increased by between 29 and 38% by moving from a day and night tariff to a flat

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

Science.gov (United States)

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.

Bird Migration Under Climate Change - A Mechanistic Approach Using Remote Sensing

Science.gov (United States)

Smith, James A.; Blattner, Tim; Messmer, Peter

2010-01-01

The broad-scale reductions and shifts that may be expected under climate change in the availability and quality of stopover habitat for long-distance migrants is an area of increasing concern for conservation biologists. Researchers generally have taken two broad approaches to the modeling of migration behaviour to understand the impact of these changes on migratory bird populations. These include models based on causal processes and their response to environmental stimulation, "mechanistic models", or models that primarily are based on observed animal distribution patterns and the correlation of these patterns with environmental variables, i.e. "data driven" models. Investigators have applied the latter technique to forecast changes in migration patterns with changes in the environment, for example, as might be expected under climate change, by forecasting how the underlying environmental data layers upon which the relationships are built will change over time. The learned geostatstical correlations are then applied to the modified data layers.. However, this is problematic. Even if the projections of how the underlying data layers will change are correct, it is not evident that the statistical relationships will remain the same, i.e. that the animal organism may not adapt its' behaviour to the changing conditions. Mechanistic models that explicitly take into account the physical, biological, and behaviour responses of an organism as well as the underlying changes in the landscape offer an alternative to address these shortcomings. The availability of satellite remote sensing observations at multiple spatial and temporal scales, coupled with advances in climate modeling and information technologies enable the application of the mechanistic models to predict how continental bird migration patterns may change in response to environmental change. In earlier work, we simulated the impact of effects of wetland loss and inter-annual variability on the fitness of

Mechanistic modeling of heat transfer process governing pressure tube-to-calandria tube contact and fuel channel failure

International Nuclear Information System (INIS)

Luxat, J.C.

2002-01-01

Heat transfer behaviour and phenomena associated with ballooning deformation of a pressure tube into contact with a calandria tube have been analyzed and mechanistic models have been developed to describe the heat transfer and thermal-mechanical processes. These mechanistic models are applied to analyze experiments performed in various COG funded Contact Boiling Test series. Particular attention is given in the modeling to characterization of the conditions for which fuel channel failure may occur. Mechanistic models describing the governing heat transfer and thermal-mechanical processes are presented. The technical basis for characterizing parameters of the models from the general heat transfer literature is described. The validity of the models is demonstrated by comparison with experimental data. Fuel channel integrity criteria are proposed which are based upon three necessary and sequential mechanisms: Onset of CHF and local drypatch formation at contact; sustained film boiling in the post-contact period; and creep strain to failure of the calandria tube while in sustained film boiling. (author)

Fidelity in Animal Modeling: Prerequisite for a Mechanistic Research Front Relevant to the Inflammatory Incompetence of Acute Pediatric Malnutrition

Science.gov (United States)

Woodward, Bill

2016-01-01

Inflammatory incompetence is characteristic of acute pediatric protein-energy malnutrition, but its underlying mechanisms remain obscure. Perhaps substantially because the research front lacks the driving force of a scholarly unifying hypothesis, it is adrift and research activity is declining. A body of animal-based research points to a unifying paradigm, the Tolerance Model, with some potential to offer coherence and a mechanistic impetus to the field. However, reasonable skepticism prevails regarding the relevance of animal models of acute pediatric malnutrition; consequently, the fundamental contributions of the animal-based component of this research front are largely overlooked. Design-related modifications to improve the relevance of animal modeling in this research front include, most notably, prioritizing essential features of pediatric malnutrition pathology rather than dietary minutiae specific to infants and children, selecting windows of experimental animal development that correspond to targeted stages of pediatric immunological ontogeny, and controlling for ontogeny-related confounders. In addition, important opportunities are presented by newer tools including the immunologically humanized mouse and outbred stocks exhibiting a magnitude of genetic heterogeneity comparable to that of human populations. Sound animal modeling is within our grasp to stimulate and support a mechanistic research front relevant to the immunological problems that accompany acute pediatric malnutrition. PMID:27077845

Fidelity in Animal Modeling: Prerequisite for a Mechanistic Research Front Relevant to the Inflammatory Incompetence of Acute Pediatric Malnutrition.

Science.gov (United States)

Woodward, Bill

2016-04-11

Inflammatory incompetence is characteristic of acute pediatric protein-energy malnutrition, but its underlying mechanisms remain obscure. Perhaps substantially because the research front lacks the driving force of a scholarly unifying hypothesis, it is adrift and research activity is declining. A body of animal-based research points to a unifying paradigm, the Tolerance Model, with some potential to offer coherence and a mechanistic impetus to the field. However, reasonable skepticism prevails regarding the relevance of animal models of acute pediatric malnutrition; consequently, the fundamental contributions of the animal-based component of this research front are largely overlooked. Design-related modifications to improve the relevance of animal modeling in this research front include, most notably, prioritizing essential features of pediatric malnutrition pathology rather than dietary minutiae specific to infants and children, selecting windows of experimental animal development that correspond to targeted stages of pediatric immunological ontogeny, and controlling for ontogeny-related confounders. In addition, important opportunities are presented by newer tools including the immunologically humanized mouse and outbred stocks exhibiting a magnitude of genetic heterogeneity comparable to that of human populations. Sound animal modeling is within our grasp to stimulate and support a mechanistic research front relevant to the immunological problems that accompany acute pediatric malnutrition.

Nanostructural control of methane release in kerogen and its implications to wellbore production decline

Science.gov (United States)

Ho, Tuan Anh; Criscenti, Louise J.; Wang, Yifeng

2016-06-01

Despite massive success of shale gas production in the US in the last few decades there are still major concerns with the steep decline in wellbore production and the large uncertainty in a long-term projection of decline curves. A reliable projection must rely on a mechanistic understanding of methane release in shale matrix-a limiting step in shale gas extraction. Using molecular simulations, we here show that methane release in nanoporous kerogen matrix is characterized by fast release of pressurized free gas (accounting for ~30-47% recovery) followed by slow release of adsorbed gas as the gas pressure decreases. The first stage is driven by the gas pressure gradient while the second stage is controlled by gas desorption and diffusion. We further show that diffusion of all methane in nanoporous kerogen behaves differently from the bulk phase, with much smaller diffusion coefficients. The MD simulations also indicate that a significant fraction (3-35%) of methane deposited in kerogen can potentially become trapped in isolated nanopores and thus not recoverable. Our results shed a new light on mechanistic understanding gas release and production decline in unconventional reservoirs. The long-term production decline appears controlled by the second stage of gas release.

Mechanistic modeling of CHF in forced-convection subcooled boiling

International Nuclear Information System (INIS)

Podowski, M.Z.; Alajbegovic, A.; Kurul, N.; Drew, D.A.; Lahey, R.T. Jr.

1997-05-01

Because of the complexity of phenomena governing boiling heat transfer, the approach to solve practical problems has traditionally been based on experimental correlations rather than mechanistic models. The recent progress in computational fluid dynamics (CFD), combined with improved experimental techniques in two-phase flow and heat transfer, makes the use of rigorous physically-based models a realistic alternative to the current simplistic phenomenological approach. The objective of this paper is to present a new CFD model for critical heat flux (CHF) in low quality (in particular, in subcooled boiling) forced-convection flows in heated channels

Development of Improved Mechanistic Deterioration Models for Flexible Pavements

DEFF Research Database (Denmark)

Ullidtz, Per; Ertman, Hans Larsen

1998-01-01

The paper describes a pilot study in Denmark with the main objective of developing improved mechanistic deterioration models for flexible pavements based on an accelerated full scale test on an instrumented pavement in the Danish Road Tessting Machine. The study was the first in "International...... Pavement Subgrade Performance Study" sponsored by the Federal Highway Administration (FHWA), USA. The paper describes in detail the data analysis and the resulting models for rutting, roughness, and a model for the plastic strain in the subgrade.The reader will get an understanding of the work needed...

A mechanistic model of an upper bound on oceanic carbon export as a function of mixed layer depth and temperature

Directory of Open Access Journals (Sweden)

Z. Li

2017-11-01

Full Text Available Export production reflects the amount of organic matter transferred from the ocean surface to depth through biological processes. This export is in large part controlled by nutrient and light availability, which are conditioned by mixed layer depth (MLD. In this study, building on Sverdrup's critical depth hypothesis, we derive a mechanistic model of an upper bound on carbon export based on the metabolic balance between photosynthesis and respiration as a function of MLD and temperature. We find that the upper bound is a positively skewed bell-shaped function of MLD. Specifically, the upper bound increases with deepening mixed layers down to a critical depth, beyond which a long tail of decreasing carbon export is associated with increasing heterotrophic activity and decreasing light availability. We also show that in cold regions the upper bound on carbon export decreases with increasing temperature when mixed layers are deep, but increases with temperature when mixed layers are shallow. A meta-analysis shows that our model envelopes field estimates of carbon export from the mixed layer. When compared to satellite export production estimates, our model indicates that export production in some regions of the Southern Ocean, particularly the subantarctic zone, is likely limited by light for a significant portion of the growing season.

Combating Pathogenic Microorganisms Using Plant-Derived Antimicrobials: A Minireview of the Mechanistic Basis

Directory of Open Access Journals (Sweden)

Abhinav Upadhyay

2014-01-01

Full Text Available The emergence of antibiotic resistance in pathogenic bacteria has led to renewed interest in exploring the potential of plant-derived antimicrobials (PDAs as an alternative therapeutic strategy to combat microbial infections. Historically, plant extracts have been used as a safe, effective, and natural remedy for ailments and diseases in traditional medicine. Extensive research in the last two decades has identified a plethora of PDAs with a wide spectrum of activity against a variety of fungal and bacterial pathogens causing infections in humans and animals. Active components of many plant extracts have been characterized and are commercially available; however, research delineating the mechanistic basis of their antimicrobial action is scanty. This review highlights the potential of various plant-derived compounds to control pathogenic bacteria, especially the diverse effects exerted by plant compounds on various virulence factors that are critical for pathogenicity inside the host. In addition, the potential effect of PDAs on gut microbiota is discussed.

Corrigendum: Free Will and Punishment: A Mechanistic View of Human Nature Reduces Retribution.

Science.gov (United States)

2018-02-01

Original article: Shariff, A. F., Greene, J. D., Karremans, J. C., Luguri, J. B., Clark, C. J., Schooler, J. W., . . . Vohs, K. D. (2014). Free will and punishment: A mechanistic view of human nature reduces retribution. Psychological Science, 25, 1563-1570. doi:10.1177/0956797614534693.

Corrigendum: Free will and punishment: A mechanistic view of human nature reduces retribution

NARCIS (Netherlands)

Shariff, A.F.; Greene, J.D.; Karremans, J.C.T.M.; Luguri, J.B.; Clark, C.J.; Schooler, J.W.; Baumeister, R.F.; Vohs, K.D.

2018-01-01

Original article: Shariff, A. F., Greene, J. D., Karremans, J. C., Luguri, J. B., Clark, C. J., Schooler, J. W., . . . Vohs, K. D. (2014). Free will and punishment: A mechanistic view of human nature reduces retribution. Psychological Science, 25, 1563-1570. doi:10.1177/0956797614534693

A mechanistic model for electricity consumption on dairy farms: Definition, validation, and demonstration

NARCIS (Netherlands)

Upton, J.R.; Murphy, M.; Shallo, L.; Groot Koerkamp, P.W.G.; Boer, de I.J.M.

2014-01-01

Our objective was to define and demonstrate a mechanistic model that enables dairy farmers to explore the impact of a technical or managerial innovation on electricity consumption, associated CO2 emissions, and electricity costs. We, therefore, (1) defined a model for electricity consumption on

Intake and time dependence of blueberry flavonoid-induced improvements in vascular function: a randomized, controlled, double-blind, crossover intervention study with mechanistic insights into biological activity.

Science.gov (United States)

Rodriguez-Mateos, Ana; Rendeiro, Catarina; Bergillos-Meca, Triana; Tabatabaee, Setareh; George, Trevor W; Heiss, Christian; Spencer, Jeremy Pe

2013-11-01

There are very limited data regarding the effects of blueberry flavonoid intake on vascular function in healthy humans. We investigated the impact of blueberry flavonoid intake on endothelial function in healthy men and assessed potential mechanisms of action by the assessment of circulating metabolites and neutrophil NADPH oxidase activity. Two randomized, controlled, double-blind, crossover human-intervention trials were conducted with 21 healthy men. Initially, the impact of blueberry flavonoid intake on flow-mediated dilation (FMD) and polyphenol absorption and metabolism was assessed at baseline and 1, 2, 4, and 6 h after consumption of blueberry containing 766, 1278, and 1791 mg total blueberry polyphenols or a macronutrient- and micronutrient-matched control drink (0 mg total blueberry polyphenols). Second, an intake-dependence study was conducted (from baseline to 1 h) with 319, 637, 766, 1278, and 1791 mg total blueberry polyphenols and a control. We observed a biphasic time-dependent increase in FMD, with significant increases at 1-2 and 6 h after consumption of blueberry polyphenols. No significant intake-dependence was observed between 766 and 1791 mg. However, at 1 h after consumption, FMD increased dose dependently to ≤766 mg total blueberry polyphenol intake, after which FMD plateaued. Increases in FMD were closely linked to increases in circulating metabolites and by decreases in neutrophil NADPH oxidase activity at 1-2 and 6 h. Blueberry intake acutely improves vascular function in healthy men in a time- and intake-dependent manner. These benefits may be mechanistically linked to the actions of circulating phenolic metabolites on neutrophil NADPH oxidase activity. This trial was registered at clinicaltrials.gov as NCT01292954 and NCT01829542.

Mechanistic modeling of insecticide risks to breeding birds in ...

Science.gov (United States)

Insecticide usage in the United States is ubiquitous in urban, suburban, and rural environments. In evaluating data for an insecticide registration application and for registration review, scientists at the United States Environmental Protection Agency (USEPA) assess the fate of the insecticide and the risk the insecticide poses to the environment and non-target wildlife. At the present time, current USEPA risk assessments do not include population-level endpoints. In this paper, we present a new mechanistic model, which allows risk assessors to estimate the effects of insecticide exposure on the survival and seasonal productivity of birds known to use agricultural fields during their breeding season. The new model was created from two existing USEPA avian risk assessment models, the Terrestrial Investigation Model (TIM v.3.0) and the Markov Chain Nest Productivity model (MCnest). The integrated TIM/MCnest model has been applied to assess the relative risk of 12 insecticides used to control corn pests on a suite of 31 avian species known to use cornfields in midwestern agroecosystems. The 12 insecticides that were assessed in this study are all used to treat major pests of corn (corn root worm borer, cutworm, and armyworm). After running the integrated TIM/MCnest model, we found extensive differences in risk to birds among insecticides, with chlorpyrifos and malathion (organophosphates) generally posing the greatest risk, and bifenthrin and ë-cyhalothrin (

Physiologically induced color-pattern changes in butterfly wings: mechanistic and evolutionary implications.

Science.gov (United States)

Otaki, Joji M

2008-07-01

A mechanistic understanding of the butterfly wing color-pattern determination can be facilitated by experimental pattern changes. Here I review physiologically induced color-pattern changes in nymphalid butterflies and their mechanistic and evolutionary implications. A type of color-pattern change can be elicited by elemental changes in size and position throughout the wing, as suggested by the nymphalid groundplan. These changes of pattern elements are bi-directional and bi-sided dislocation toward or away from eyespot foci and in both proximal and distal sides of the foci. The peripheral elements are dislocated even in the eyespot-less compartments. Anterior spots are more severely modified, suggesting the existence of an anterior-posterior gradient. In one species, eyespots are transformed into white spots with remnant-like orange scales, and such patterns emerge even at the eyespot-less "imaginary" foci. A series of these color-pattern modifications probably reveal "snap-shots" of a dynamic morphogenic signal due to heterochronic uncoupling between the signaling and reception steps. The conventional gradient model can be revised to account for these observed color-pattern changes.

Mechanistic modelling of a cathode-supported tubular solid oxide fuel cell

Science.gov (United States)

Suwanwarangkul, R.; Croiset, E.; Pritzker, M. D.; Fowler, M. W.; Douglas, P. L.; Entchev, E.

A two-dimensional mechanistic model of a tubular solid oxide fuel cell (SOFC) considering momentum, energy, mass and charge transport is developed. The model geometry of a single cell comprises an air-preheating tube, air channel, fuel channel, anode, cathode and electrolyte layers. The heat radiation between cell and air-preheating tube is also incorporated into the model. This allows the model to predict heat transfer between the cell and air-preheating tube accurately. The model is validated and shows good agreement with literature data. It is anticipated that this model can be used to help develop efficient fuel cell designs and set operating variables under practical conditions. The transport phenomena inside the cell, including gas flow behaviour, temperature, overpotential, current density and species concentration, are analysed and discussed in detail. Fuel and air velocities are found to vary along flow passages depending on the local temperature and species concentrations. This model demonstrates the importance of incorporating heat radiation into a tubular SOFC model. Furthermore, the model shows that the overall cell performance is limited by O 2 diffusion through the thick porous cathode and points to the development of new cathode materials and designs being important avenues to enhance cell performance.

Numerical simulation in steam injection wellbores by mechanistic approach; Simulacao numerica do escoamento de vapor em pocos por uma abordagem mecanicista

Energy Technology Data Exchange (ETDEWEB)

Souza Junior, J.C. de; Campos, W.; Lopes, D.; Moura, L.S.S. [PETROBRAS, Rio de Janeiro, RJ (Brazil); Thomas, A. Clecio F. [Universidade Estadual do Ceara (UECE), CE (Brazil)

2008-07-01

This work addresses to the development of a hydrodynamic and heat transfer mechanistic model for steam flow in injection wellbores. The problem of two-phase steam flow in wellbores has been solved recently by using available empirical correlations from petroleum industry (Lopes, 1986) and nuclear industry (Moura, 1991).The good performance achieved by mechanistic models developed by Ansari (1994), Hasan (1995), Gomez (2000) and Kaya (2001) supports the importance of the mechanistic approach for the steam flow problem in injection wellbores. In this study, the methodology to solve the problem consists in the application of a numerical method to the governing equations of steam flow and a marching algorithm to determine the distribution of the pressure and temperature along the wellbore. So, a computer code has been formulated to get numerical results, which provides a comparative study to the main models found in the literature. Finally, when compared to available field data, the mechanistic model for downward vertical steam flow in wellbores gave better results than the empirical correlations. (author)

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

Science.gov (United States)

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…

Mechanistic modeling for mammography screening risks

International Nuclear Information System (INIS)

Bijwaard, Harmen

2008-01-01

Full text: Western populations show a very high incidence of breast cancer and in many countries mammography screening programs have been set up for the early detection of these cancers. Through these programs large numbers of women (in the Netherlands, 700.000 per year) are exposed to low but not insignificant X-ray doses. ICRP based risk estimates indicate that the number of breast cancer casualties due to mammography screening can be as high as 50 in the Netherlands per year. The number of lives saved is estimated to be much higher, but for an accurate calculation of the benefits of screening a better estimate of these risks is indispensable. Here it is attempted to better quantify the radiological risks of mammography screening through the application of a biologically based model for breast tumor induction by X-rays. The model is applied to data obtained from the National Institutes of Health in the U.S. These concern epidemiological data of female TB patients who received high X-ray breast doses in the period 1930-1950 through frequent fluoroscopy of their lungs. The mechanistic model that is used to describe the increased breast cancer incidence is based on an earlier study by Moolgavkar et al. (1980), in which the natural background incidence of breast cancer was modeled. The model allows for a more sophisticated extrapolation of risks to the low dose X-ray exposures that are common in mammography screening and to the higher ages that are usually involved. Furthermore, it allows for risk transfer to other (non-western) populations. The results have implications for decisions on the frequency of screening, the number of mammograms taken at each screening, minimum and maximum ages for screening and the transfer to digital equipment. (author)

Description and evaluation of a mechanistically based conceptual model for spall

Energy Technology Data Exchange (ETDEWEB)

Hansen, F.D.; Knowles, M.K.; Thompson, T.W. [and others

1997-08-01

A mechanistically based model for a possible spall event at the WIPP site is developed and evaluated in this report. Release of waste material to the surface during an inadvertent borehole intrusion is possible if future states of the repository include high gas pressure and waste material consisting of fine particulates having low mechanical strength. The conceptual model incorporates the physics of wellbore hydraulics coupled to transient gas flow to the intrusion borehole, and mechanical response of the waste. Degraded waste properties using of the model. The evaluations include both numerical and analytical implementations of the conceptual model. A tensile failure criterion is assumed appropriate for calculation of volumes of waste experiencing fragmentation. Calculations show that for repository gas pressures less than 12 MPa, no tensile failure occurs. Minimal volumes of material experience failure below gas pressure of 14 MPa. Repository conditions dictate that the probability of gas pressures exceeding 14 MPa is approximately 1%. For these conditions, a maximum failed volume of 0.25 m{sup 3} is calculated.

Description and evaluation of a mechanistically based conceptual model for spall

International Nuclear Information System (INIS)

Hansen, F.D.; Knowles, M.K.; Thompson, T.W.

1997-08-01

A mechanistically based model for a possible spall event at the WIPP site is developed and evaluated in this report. Release of waste material to the surface during an inadvertent borehole intrusion is possible if future states of the repository include high gas pressure and waste material consisting of fine particulates having low mechanical strength. The conceptual model incorporates the physics of wellbore hydraulics coupled to transient gas flow to the intrusion borehole, and mechanical response of the waste. Degraded waste properties using of the model. The evaluations include both numerical and analytical implementations of the conceptual model. A tensile failure criterion is assumed appropriate for calculation of volumes of waste experiencing fragmentation. Calculations show that for repository gas pressures less than 12 MPa, no tensile failure occurs. Minimal volumes of material experience failure below gas pressure of 14 MPa. Repository conditions dictate that the probability of gas pressures exceeding 14 MPa is approximately 1%. For these conditions, a maximum failed volume of 0.25 m 3 is calculated

Mechanistic variables can enhance predictive models of endotherm distributions: The American pika under current, past, and future climates

Science.gov (United States)

Mathewson, Paul; Moyer-Horner, Lucas; Beever, Erik; Briscoe, Natalie; Kearney, Michael T.; Yahn, Jeremiah; Porter, Warren P.

2017-01-01

How climate constrains species’ distributions through time and space is an important question in the context of conservation planning for climate change. Despite increasing awareness of the need to incorporate mechanism into species distribution models (SDMs), mechanistic modeling of endotherm distributions remains limited in this literature. Using the American pika (Ochotona princeps) as an example, we present a framework whereby mechanism can be incorporated into endotherm SDMs. Pika distribution has repeatedly been found to be constrained by warm temperatures, so we used Niche Mapper, a mechanistic heat-balance model, to convert macroclimate data to pika-specific surface activity time in summer across the western United States. We then explored the difference between using a macroclimate predictor (summer temperature) and using a mechanistic predictor (predicted surface activity time) in SDMs. Both approaches accurately predicted pika presences in current and past climate regimes. However, the activity models predicted 8–19% less habitat loss in response to annual temperature increases of ~3–5 °C predicted in the region by 2070, suggesting that pikas may be able to buffer some climate change effects through behavioral thermoregulation that can be captured by mechanistic modeling. Incorporating mechanism added value to the modeling by providing increased confidence in areas where different modeling approaches agreed and providing a range of outcomes in areas of disagreement. It also provided a more proximate variable relating animal distribution to climate, allowing investigations into how unique habitat characteristics and intraspecific phenotypic variation may allow pikas to exist in areas outside those predicted by generic SDMs. Only a small number of easily obtainable data are required to parameterize this mechanistic model for any endotherm, and its use can improve SDM predictions by explicitly modeling a widely applicable direct physiological effect

Mechanistic variables can enhance predictive models of endotherm distributions: the American pika under current, past, and future climates.

Science.gov (United States)

Mathewson, Paul D; Moyer-Horner, Lucas; Beever, Erik A; Briscoe, Natalie J; Kearney, Michael; Yahn, Jeremiah M; Porter, Warren P

2017-03-01

How climate constrains species' distributions through time and space is an important question in the context of conservation planning for climate change. Despite increasing awareness of the need to incorporate mechanism into species distribution models (SDMs), mechanistic modeling of endotherm distributions remains limited in this literature. Using the American pika (Ochotona princeps) as an example, we present a framework whereby mechanism can be incorporated into endotherm SDMs. Pika distribution has repeatedly been found to be constrained by warm temperatures, so we used Niche Mapper, a mechanistic heat-balance model, to convert macroclimate data to pika-specific surface activity time in summer across the western United States. We then explored the difference between using a macroclimate predictor (summer temperature) and using a mechanistic predictor (predicted surface activity time) in SDMs. Both approaches accurately predicted pika presences in current and past climate regimes. However, the activity models predicted 8-19% less habitat loss in response to annual temperature increases of ~3-5 °C predicted in the region by 2070, suggesting that pikas may be able to buffer some climate change effects through behavioral thermoregulation that can be captured by mechanistic modeling. Incorporating mechanism added value to the modeling by providing increased confidence in areas where different modeling approaches agreed and providing a range of outcomes in areas of disagreement. It also provided a more proximate variable relating animal distribution to climate, allowing investigations into how unique habitat characteristics and intraspecific phenotypic variation may allow pikas to exist in areas outside those predicted by generic SDMs. Only a small number of easily obtainable data are required to parameterize this mechanistic model for any endotherm, and its use can improve SDM predictions by explicitly modeling a widely applicable direct physiological effect

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

Science.gov (United States)

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...

A MECHANISTIC STUDY OF RHODIUM TRI(ORTHO-TERT-BUTYLPHENYL)PHOSPHITE COMPLEXES AS HYDROFORMYLATION CATALYSTS

NARCIS (Netherlands)

JONGSMA, T; CHALLA, G; VANLEEUWEN, PWNM

1991-01-01

A mechanistic study of the hydroformylation cycle with a rhodium tri(o-t-butylphenyl)phosphite complex as catalyst is presented. Spectroscopic experiments prove that under hydroformylation conditions this complex is coordinated by only one phosphite. The complex has a high activity in the

Prediction of net hepatic release of glucose using a “hybrid” mechanistic model in ruminants applied to positive energy balance

OpenAIRE

Bahloul, Lahlou; Ortigues, Isabelle; Vernet, Jean; Lapierre, Helène; Noziere, Pierre; Sauvant, Daniel

2013-01-01

Ruminants depend on hepatic gluconeogenesis to meet most of their metabolic demand for glucose which relies on availability of precursors from diet supply and animal requirements (Loncke et al., 2010). Several mechanistic models of the metabolic fate of nutrients across the liver exist that have been parameterized for dairy cows. They cannot be directly used to predict hepatic gluconeogenesis in all types of ruminants in different physiological status. A hybrid mechanistic model of nutrient f...

Trichloroethylene: Mechanistic, epidemiologic and other supporting evidence of carcinogenic hazard.

Science.gov (United States)

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

2014-01-01

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 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. The 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 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. © 2013.

A Mechanistically Informed User-Friendly Model to Predict Greenhouse Gas (GHG) Fluxes and Carbon Storage from Coastal Wetlands

Science.gov (United States)

Abdul-Aziz, O. I.; Ishtiaq, K. S.

2015-12-01

We present a user-friendly modeling tool on MS Excel to predict the greenhouse gas (GHG) fluxes and estimate potential carbon sequestration from the coastal wetlands. The dominant controls of wetland GHG fluxes and their relative mechanistic linkages with various hydro-climatic, sea level, biogeochemical and ecological drivers were first determined by employing a systematic data-analytics method, including Pearson correlation matrix, principal component and factor analyses, and exploratory partial least squares regressions. The mechanistic knowledge and understanding was then utilized to develop parsimonious non-linear (power-law) models to predict wetland carbon dioxide (CO2) and methane (CH4) fluxes based on a sub-set of climatic, hydrologic and environmental drivers such as the photosynthetically active radiation, soil temperature, water depth, and soil salinity. The models were tested with field data for multiple sites and seasons (2012-13) collected from the Waquoit Bay, MA. The model estimated the annual wetland carbon storage by up-scaling the instantaneous predicted fluxes to an extended growing season (e.g., May-October) and by accounting for the net annual lateral carbon fluxes between the wetlands and estuary. The Excel Spreadsheet model is a simple ecological engineering tool for coastal carbon management and their incorporation into a potential carbon market under a changing climate, sea level and environment. Specifically, the model can help to determine appropriate GHG offset protocols and monitoring plans for projects that focus on tidal wetland restoration and maintenance.

Mechanistic studies of ethylene biosynthesis in higher plants

International Nuclear Information System (INIS)

McGeehan, G.M.

1986-01-01

Ethylene is a plant hormone that elicits a wide variety of responses in plant tissue. Among these responses are the hastening of abscission, ripening and senescence. In 1979 it was discovered that 1-amino-1-cyclopropane carboxylic acid is the immediate biosynthetic precursor to ethylene. Given the obvious economic significance of ethylene production the authors concentrated their studies on the conversion of ACC to ethylene. They delved into mechanistic aspects of ACC oxidation and they studied potential inhibitors of ethylene forming enzyme (EFE). They synthesized various analogs of ACC and found that EFE shows good stereodiscrimination among alkyl substituted ACC analogs with the 1R, 2S stereoisomer being processed nine times faster than the 1S, 2R isomer in the MeACC series. They also synthesized 2-cyclopropyl ACC which is a good competitive inhibitor of EFE. This compound also causes time dependent loss of EFE activity leading us to believe it is an irreversible inhibitor of ethylene formation. The synthesis of these analogs has also allowed them to develop a spectroscopic technique to assign the relative stereochemistry of alkyl groups. 13 C NMR allows them to assign the alkyl stereochemistry based upon gamma-shielding effects on the carbonyl resonance. Lastly, they measured kinetic isotope effects on the oxidation of ACC in vivo and in vitro and found that ACC is oxidized by a rate-determining 1-electron removal from nitrogen in close accord with mechanisms for the oxidation of other alkyl amines

Toxic neuropathies: Mechanistic insights based on a chemical perspective.

Science.gov (United States)

LoPachin, Richard M; Gavin, Terrence

2015-06-02

2,5-Hexanedione (HD) and acrylamide (ACR) are considered to be prototypical among chemical toxicants that cause central-peripheral axonopathies characterized by distal axon swelling and degeneration. Because the demise of distal regions was assumed to be causally related to the onset of neurotoxicity, substantial effort was devoted to deciphering the respective mechanisms. Continued research, however, revealed that expression of the presumed hallmark morphological features was dependent upon the daily rate of toxicant exposure. Indeed, many studies reported that the corresponding axonopathic changes were late developing effects that occurred independent of behavioral and/or functional neurotoxicity. This suggested that the toxic axonopathy classification might be based on epiphenomena related to dose-rate. Therefore, the goal of this mini-review is to discuss how quantitative morphometric analyses and the establishment of dose-dependent relationships helped distinguish primary, mechanistically relevant toxicant effects from non-specific consequences. Perhaps more importantly, we will discuss how knowledge of neurotoxicant chemical nature can guide molecular-level research toward a better, more rational understanding of mechanism. Our discussion will focus on HD, the neurotoxic γ-diketone metabolite of the industrial solvents n-hexane and methyl-n-butyl ketone. Early investigations suggested that HD caused giant neurofilamentous axonal swellings and eventual degeneration in CNS and PNS. However, as our review will point out, this interpretation underwent several iterations as the understanding of γ-diketone chemistry improved and more quantitative experimental approaches were implemented. The chemical concepts and design strategies discussed in this mini-review are broadly applicable to the mechanistic studies of other chemicals (e.g., n-propyl bromine, methyl methacrylate) that cause toxic neuropathies. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Protection by caffeine against oxic radiation damage and chemical carcinogens : mechanistic considerations

International Nuclear Information System (INIS)

Kesavan, P.C.

1992-01-01

There is little doubt that caffeine administered after exposure to UV light enhances the damage to cells and organisms by inhibiting photoreactivation, excision and/or recombinational repair. However, when already present in the system, it affords remarkable protection not only against O 2 -dependent component of radiation damage, but also against chemical carcinogens that require metabolic activation. Possible mechanistic aspects are discussed briefly. (author). 81 refs

Mechanistic study of aerosol dry deposition on vegetated canopies

International Nuclear Information System (INIS)

Petroff, A.

2005-04-01

The dry deposition of aerosols onto vegetated canopies is modelled through a mechanistic approach. The interaction between aerosols and vegetation is first formulated by using a set of parameters, which are defined at the local scale of one surface. The overall deposition is then deduced at the canopy scale through an up-scaling procedure based on the statistic distribution parameters. This model takes into account the canopy structural and morphological properties, and the main characteristics of the turbulent flow. Deposition mechanisms considered are Brownian diffusion, interception, initial and turbulent impaction, initially with coniferous branches and then with entire canopies of different roughness, such as grass, crop field and forest. (author)

Mechanistic CHF modeling for natural circulation applications in SMR

Energy Technology Data Exchange (ETDEWEB)

Luitjens, Jeffrey [Department of Nuclear Engineering and Radiation Health Physics, Oregon State University, 3451 SW Jefferson Way, Corvallis, OR 97331 (United States); Wu, Qiao, E-mail: qiao.wu@oregonstate.edu [Department of Nuclear Engineering and Radiation Health Physics, Oregon State University, 3451 SW Jefferson Way, Corvallis, OR 97331 (United States); Greenwood, Scott; Corradini, Michael [Department of Engineering Physics, University of Wisconsin, 1415 Engineering Drive, Madison, WI 53706 (United States)

2016-12-15

A mechanistic critical heat flux correlation has been developed for a wide range of operating conditions which include low mass fluxes of 540–890 kg/m{sup 2}-s, high pressures of 12–13 MPa, and critical heat fluxes of 835–1100 kW/m{sup 2}. Eleven experimental data points have been collected over these conditions to inform the development of the model using bundle geometry. Errors of within 15% have been obtained with the proposed model for predicting the critical heat flux value, location, and critical pin power for a non-uniform heat flux applied to a 2 × 2 bundle configuration.

Development of mechanistic sorption model and treatment of uncertainties for Ni sorption on montmorillonite/bentonite

International Nuclear Information System (INIS)

Ochs, Michael; Ganter, Charlotte; Tachi, Yukio; Suyama, Tadahiro; Yui, Mikazu

2011-02-01

Sorption and diffusion of radionuclides in buffer materials (bentonite) are the key processes in the safe geological disposal of radioactive waste, because migration of radionuclides in this barrier is expected to be diffusion-controlled and retarded by sorption processes. It is therefore necessary to understand the detailed/coupled processes of sorption and diffusion in compacted bentonite and develop mechanistic /predictive models, so that reliable parameters can be set under a variety of geochemical conditions relevant to performance assessment (PA). For this purpose, JAEA has developed the integrated sorption and diffusion (ISD) model/database in montmorillonite/bentonite systems. The main goal of the mechanistic model/database development is to provide a tool for a consistent explanation, prediction, and uncertainty assessment of K d as well as diffusion parameters needed for the quantification of radionuclide transport. The present report focuses on developing the thermodynamic sorption model (TSM) and on the quantification and handling of model uncertainties in applications, based on illustrating by example of Ni sorption on montmorillonite/bentonite. This includes 1) a summary of the present state of the art of thermodynamic sorption modeling, 2) a discussion of the selection of surface species and model design appropriate for the present purpose, 3) possible sources and representations of TSM uncertainties, and 4) details of modeling, testing and uncertainty evaluation for Ni sorption. Two fundamentally different approaches are presented and compared for representing TSM uncertainties: 1) TSM parameter uncertainties calculated by FITEQL optimization routines and some statistical procedure, 2) overall error estimated by direct comparison of modeled and experimental K d values. The overall error in K d is viewed as the best representation of model uncertainty in ISD model/database development. (author)

A mechanistic approach to link biological effects of radioactive substances from molecules to populations in wildlife species - A mechanistic approach to link biological effects of radionuclides from molecules to populations in wildlife species

Energy Technology Data Exchange (ETDEWEB)

Alonzo, Frederic; Parisot, Florian; Plaire, Delphine; Adam-Guillermin, Christelle; Garnier- Laplace, Jacqueline [Institut de Radioprotection et de Surete Nucleaire (IRSN), PRP-ENV, SERIS, LECO, Cadarache, Saint-Paul- Lez-Durance, 13115 (France)

2014-07-01

Understanding how toxic contaminants affect wildlife species at various levels of biological organisation (sub-cellular, histological, physiological, organism, population levels) is a major research goal in both ecotoxicology and radioecology. A mechanistic understanding of the links between the different observed perturbations is necessary to predict consequences for survival, growth and reproduction which are critical for population dynamics. However, time scales at which such links are established in the laboratory are rarely relevant for natural populations. With a small size and short life cycle, the cladoceran micro-crustacean Daphnia magna is a particularly suitable biological model for studying effects of radioactive contaminants over several generations. Multi-generational exposures are much more representative of the environmental context of field populations for which contaminations can last for durations which largely exceed individual longevity and involve exposure of many successive generations. Over the last decade, multi-generational investigations of toxic effects were conducted under controlled conditions in D. magna exposed to various radionuclides including depleted uranium, americium-241 and cesium-137, representing respectively a dominantly chemo-toxic metal, an alpha internal contamination and a gamma external radiation. Results showed in all cases that toxic effects on physiology and life history (survival, body size, fecundity) increased in severity across generations. These observations demonstrated that measured effects in one generation might not be representative of toxicity in the following offspring generations, and ultimately of the population response. Reduction in somatic growth and reproduction induced by uranium were analysed using the mechanistic modelling approach known as DEBtox (model of dynamic energy budget applied to toxicology). Modelling results suggested that uranium primarily affects assimilation. This metabolic mode

Can ligand addition to soil enhance Cd phytoextraction? A mechanistic model study.

Science.gov (United States)

Lin, Zhongbing; Schneider, André; Nguyen, Christophe; Sterckeman, Thibault

2014-11-01

Phytoextraction is a potential method for cleaning Cd-polluted soils. Ligand addition to soil is expected to enhance Cd phytoextraction. However, experimental results show that this addition has contradictory effects on plant Cd uptake. A mechanistic model simulating the reaction kinetics (adsorption on solid phase, complexation in solution), transport (convection, diffusion) and root absorption (symplastic, apoplastic) of Cd and its complexes in soil was developed. This was used to calculate plant Cd uptake with and without ligand addition in a great number of combinations of soil, ligand and plant characteristics, varying the parameters within defined domains. Ligand addition generally strongly reduced hydrated Cd (Cd(2+)) concentration in soil solution through Cd complexation. Dissociation of Cd complex ([Formula: see text]) could not compensate for this reduction, which greatly lowered Cd(2+) symplastic uptake by roots. The apoplastic uptake of [Formula: see text] was not sufficient to compensate for the decrease in symplastic uptake. This explained why in the majority of the cases, ligand addition resulted in the reduction of the simulated Cd phytoextraction. A few results showed an enhanced phytoextraction in very particular conditions (strong plant transpiration with high apoplastic Cd uptake capacity), but this enhancement was very limited, making chelant-enhanced phytoextraction poorly efficient for Cd.

Mechanistic Processes Controlling Gas Sorption in Shale Reservoirs

Science.gov (United States)

Schaef, T.; Loring, J.; Ilton, E. S.; Davidson, C. L.; Owen, T.; Hoyt, D.; Glezakou, V. A.; McGrail, B. P.; Thompson, C.

2014-12-01

Utilization of CO2 to stimulate natural gas production in previously fractured shale-dominated reservoirs where CO2 remains in place for long-term storage may be an attractive new strategy for reducing the cost of managing anthropogenic CO2. A preliminary analysis of capacities and potential revenues in US shale plays suggests nearly 390 tcf in additional gas recovery may be possible via CO2 driven enhanced gas recovery. However, reservoir transmissivity properties, optimum gas recovery rates, and ultimate fate of CO2 vary among reservoirs, potentially increasing operational costs and environmental risks. In this paper, we identify key mechanisms controlling the sorption of CH4 and CO2 onto phyllosilicates and processes occurring in mixed gas systems that have the potential of impacting fluid transfer and CO2 storage in shale dominated formations. Through a unique set of in situ experimental techniques coupled with molecular-level simulations, we identify structural transformations occurring to clay minerals, optimal CO2/CH4 gas exchange conditions, and distinguish between adsorbed and intercalated gases in a mixed gas system. For example, based on in situ measurements with magic angle spinning NMR, intercalation of CO2 within the montmorillonite structure occurs in CH4/CO2 gas mixtures containing low concentrations (hydrocarbon recovery processes.

Mechanistic analysis of cavitation assisted transesterification on biodiesel characteristics.

Science.gov (United States)

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. Copyright © 2014 Elsevier B.V. All rights reserved.

A mechanistic spatio-temporal framework for modelling individual-to-individual transmission-With an application to the 2014-2015 West Africa Ebola outbreak.

Directory of Open Access Journals (Sweden)

Max S Y Lau

2017-10-01

Full Text Available In recent years there has been growing availability of individual-level spatio-temporal disease data, particularly due to the use of modern communicating devices with GPS tracking functionality. These detailed data have been proven useful for inferring disease transmission to a more refined level than previously. However, there remains a lack of statistically sound frameworks to model the underlying transmission dynamic in a mechanistic manner. Such a development is particularly crucial for enabling a general epidemic predictive framework at the individual level. In this paper we propose a new statistical framework for mechanistically modelling individual-to-individual disease transmission in a landscape with heterogeneous population density. Our methodology is first tested using simulated datasets, validating our inferential machinery. The methodology is subsequently applied to data that describes a regional Ebola outbreak in Western Africa (2014-2015. Our results show that the methods are able to obtain estimates of key epidemiological parameters that are broadly consistent with the literature, while revealing a significantly shorter distance of transmission. More importantly, in contrast to existing approaches, we are able to perform a more general model prediction that takes into account the susceptible population. Finally, our results show that, given reasonable scenarios, the framework can be an effective surrogate for susceptible-explicit individual models which are often computationally challenging.

A mechanistic spatio-temporal framework for modelling individual-to-individual transmission—With an application to the 2014-2015 West Africa Ebola outbreak

Science.gov (United States)

McClelland, Amanda; Zelner, Jon; Streftaris, George; Funk, Sebastian; Metcalf, Jessica; Dalziel, Benjamin D.; Grenfell, Bryan T.

2017-01-01

In recent years there has been growing availability of individual-level spatio-temporal disease data, particularly due to the use of modern communicating devices with GPS tracking functionality. These detailed data have been proven useful for inferring disease transmission to a more refined level than previously. However, there remains a lack of statistically sound frameworks to model the underlying transmission dynamic in a mechanistic manner. Such a development is particularly crucial for enabling a general epidemic predictive framework at the individual level. In this paper we propose a new statistical framework for mechanistically modelling individual-to-individual disease transmission in a landscape with heterogeneous population density. Our methodology is first tested using simulated datasets, validating our inferential machinery. The methodology is subsequently applied to data that describes a regional Ebola outbreak in Western Africa (2014-2015). Our results show that the methods are able to obtain estimates of key epidemiological parameters that are broadly consistent with the literature, while revealing a significantly shorter distance of transmission. More importantly, in contrast to existing approaches, we are able to perform a more general model prediction that takes into account the susceptible population. Finally, our results show that, given reasonable scenarios, the framework can be an effective surrogate for susceptible-explicit individual models which are often computationally challenging. PMID:29084216

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

Science.gov (United States)

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...

The challenge of making ozone risk assessment for forest trees more mechanistic

International Nuclear Information System (INIS)

Matyssek, R.; Sandermann, H.; Wieser, G.; Booker, F.; Cieslik, S.; Musselman, R.; Ernst, D.

2008-01-01

Upcoming decades will experience increasing atmospheric CO 2 and likely enhanced O 3 exposure which represents a risk for the carbon sink strength of forests, so that the need for cause-effect related O 3 risk assessment increases. Although assessment will gain in reliability on an O 3 uptake basis, risk is co-determined by the effective dose, i.e. the plant's sensitivity per O 3 uptake. Recent progress in research on the molecular and metabolic control of the effective O 3 dose is reported along with advances in empirically assessing O 3 uptake at the whole-tree and stand level. Knowledge on both O 3 uptake and effective dose (measures of stress avoidance and tolerance, respectively) needs to be understood mechanistically and linked as a pre-requisite before practical use of process-based O 3 risk assessment can be implemented. To this end, perspectives are derived for validating and promoting new O 3 flux-based modelling tools. - Clarifying and linking mechanisms of O 3 uptake and effective dose are research challenges highlighted in view of recent progress and perspectives towards cause-effect based risk assessment

A dynamic and mechanistic model of PCB bioaccumulation in the European hake ( Merluccius merluccius)

Science.gov (United States)

Bodiguel, Xavier; Maury, Olivier; Mellon-Duval, Capucine; Roupsard, François; Le Guellec, Anne-Marie; Loizeau, Véronique

2009-08-01

Bioaccumulation is difficult to document because responses differ among chemical compounds, with environmental conditions, and physiological processes characteristic of each species. We use a mechanistic model, based on the Dynamic Energy Budget (DEB) theory, to take into account this complexity and study factors impacting accumulation of organic pollutants in fish through ontogeny. The bioaccumulation model proposed is a comprehensive approach that relates evolution of hake PCB contamination to physiological information about the fish, such as diet, metabolism, reserve and reproduction status. The species studied is the European hake ( Merluccius merluccius, L. 1758). The model is applied to study the total concentration and the lipid normalised concentration of 4 PCB congeners in male and female hakes from the Gulf of Lions (NW Mediterranean sea) and the Bay of Biscay (NE Atlantic ocean). Outputs of the model compare consistently to measurements over the life span of fish. Simulation results clearly demonstrate the relative effects of food contamination, growth and reproduction on the PCB bioaccumulation in hake. The same species living in different habitats and exposed to different PCB prey concentrations exhibit marked difference in the body accumulation of PCBs. At the adult stage, female hakes have a lower PCB concentration compared to males for a given length. We successfully simulated these sex-specific PCB concentrations by considering two mechanisms: a higher energy allocation to growth for females and a transfer of PCBs from the female to its eggs when allocating lipids from reserve to eggs. Finally, by its mechanistic description of physiological processes, the model is relevant for other species and sets the stage for a mechanistic understanding of toxicity and ecological effects of organic contaminants in marine organisms.

Incorporation of lysosomal sequestration in the mechanistic model for prediction of tissue distribution of basic drugs.

Science.gov (United States)

Assmus, Frauke; Houston, J Brian; Galetin, Aleksandra

2017-11-15

The prediction of tissue-to-plasma water partition coefficients (Kpu) from in vitro and in silico data using the tissue-composition based model (Rodgers & Rowland, J Pharm Sci. 2005, 94(6):1237-48.) is well established. However, distribution of basic drugs, in particular into lysosome-rich lung tissue, tends to be under-predicted by this approach. The aim of this study was to develop an extended mechanistic model for the prediction of Kpu which accounts for lysosomal sequestration and the contribution of different cell types in the tissue of interest. The extended model is based on compound-specific physicochemical properties and tissue composition data to describe drug ionization, distribution into tissue water and drug binding to neutral lipids, neutral phospholipids and acidic phospholipids in tissues, including lysosomes. Physiological data on the types of cells contributing to lung, kidney and liver, their lysosomal content and lysosomal pH were collated from the literature. The predictive power of the extended mechanistic model was evaluated using a dataset of 28 basic drugs (pK a ≥7.8, 17 β-blockers, 11 structurally diverse drugs) for which experimentally determined Kpu data in rat tissue have been reported. Accounting for the lysosomal sequestration in the extended mechanistic model improved the accuracy of Kpu predictions in lung compared to the original Rodgers model (56% drugs within 2-fold or 88% within 3-fold of observed values). Reduction in the extent of Kpu under-prediction was also evident in liver and kidney. However, consideration of lysosomal sequestration increased the occurrence of over-predictions, yielding overall comparable model performances for kidney and liver, with 68% and 54% of Kpu values within 2-fold error, respectively. High lysosomal concentration ratios relative to cytosol (>1000-fold) were predicted for the drugs investigated; the extent differed depending on the lysosomal pH and concentration of acidic phospholipids among

Combining Solvent Isotope Effects with Substrate Isotope Effects in Mechanistic Studies of Alcohol and Amine Oxidation by Enzymes*

Science.gov (United States)

Fitzpatrick, Paul F.

2014-01-01

Oxidation of alcohols and amines is catalyzed by multiple families of flavin-and pyridine nucleotide-dependent enzymes. Measurement of solvent isotope effects provides a unique mechanistic probe of the timing of the cleavage of the OH and NH bonds, necessary information for a complete description of the catalytic mechanism. The inherent ambiguities in interpretation of solvent isotope effects can be significantly decreased if isotope effects arising from isotopically labeled substrates are measured in combination with solvent isotope effects. The application of combined solvent and substrate (mainly deuterium) isotope effects to multiple enzymes is described here to illustrate the range of mechanistic insights that such an approach can provide. PMID:25448013

Toward a Mechanistic Understanding of Deuterium Excess as a Tracer for Evapotranspiration

Energy Technology Data Exchange (ETDEWEB)

Lai, Chun-Ta [Department of Biology, San Diego State University, San Diego, CA (United States)

2013-07-15

An understanding of atmospheric water vapour and its isotopic composition is useful for modelling effects of terrestrial evapotranspiration on regional hydrologic cycles. Previous studies showed diurnal and vertical patterns of water vapour isotope ratios ({delta}{sup 2}H{sub v} and {delta}{sup 18}O{sub v}) consistently observed in an old growth coniferous forest. Using a box model and a mass balance approach to simulate 'isoflux of d-excess', the effect of evapotranspiration on the d-excess in atmospheric water vapour is quantitatively demonstrated. The results suggest that d-excess can be mechanistically utilized to identify processes that contribute to the diurnal variation in atmospheric moisture. These new findings have implications for larger-scale predictions of precipitation across the terrestrial landscape. In this paper, I report the initial results of the {delta}{sup 2}H{sub v} and {delta}{sup 18}O{sub v} measurements using a cavity enhanced spectroscopy instrument. These recent data are consistent with the pattern observed by the conventional sampling method, providing new opportunities for studying d-excess as a tracer for evapotranspiration. (author)

An Emphasis on Perception: Teaching Image Formation Using a Mechanistic Model of Vision.

Science.gov (United States)

Allen, Sue; And Others

An effective way to teach the concept of image is to give students a model of human vision which incorporates a simple mechanism of depth perception. In this study two almost identical versions of a curriculum in geometrical optics were created. One used a mechanistic, interpretive eye model, and in the other the eye was modeled as a passive,…

From patterns to emerging processes in mechanistic urban ecology.

Science.gov (United States)

Shochat, Eyal; Warren, Paige S; Faeth, Stanley H; McIntyre, Nancy E; Hope, Diane

2006-04-01

Rapid urbanization has become an area of crucial concern in conservation owing to the radical changes in habitat structure and loss of species engendered by urban and suburban development. Here, we draw on recent mechanistic ecological studies to argue that, in addition to altered habitat structure, three major processes contribute to the patterns of reduced species diversity and elevated abundance of many species in urban environments. These activities, in turn, lead to changes in animal behavior, morphology and genetics, as well as in selection pressures on animals and plants. Thus, the key to understanding urban patterns is to balance studying processes at the individual level with an integrated examination of environmental forces at the ecosystem scale.

Mechanistic systems modeling to guide drug discovery and development.

Science.gov (United States)

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

2013-02-01

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. Copyright © 2012 Elsevier Ltd. All rights reserved.

A DFT study on the deprotonation antioxidant mechanistic step of ortho-substituted phenolic cation radicals

International Nuclear Information System (INIS)

Vafiadis, Anastasios P.; Bakalbassis, Evangelos G.

2005-01-01

The conformers of the 2-, 3- and 4-substituted phenolic cation radicals, 2-X-, 3-X- and 4-X-ArOH ·+ , and the respective phenoxyl radicals, ArO · , the intramolecular hydrogen bond strength (ΔH intra ) estimate along with the electronic effects of five electron withdrawing (EWG) and eight electron donating groups (EDG) on the gas-phase O-H proton dissociation enthalpies, (PDEs), of the short-lived, 2-X-ArOH ·+ , (involved in the single-electron transfer antioxidant mechanism), are studied at the DFT/B3LYP level of theory. EWG result to smaller PDEs, hence to stronger acidity; EDG to weaker acidity. The deprotonation antioxidant mechanistic step is not a rate-controlling step for 2-X-ArOH to scavenge free radicals. Approximate estimations of the ΔPDEs (hence acidities as well) can be derived from calculated structural and/or vibrational frequency values. ΔH intra s correlate reasonably with geometrical parameters for the closed-shell, neutral counterparts, in contrast with previous estimates

Mechanistic basis of infertility of mouse intersubspecific hybrids

Science.gov (United States)

Bhattacharyya, Tanmoy; Gregorova, Sona; Mihola, Ondrej; Anger, Martin; Sebestova, Jaroslava; Denny, Paul; Simecek, Petr; Forejt, Jiri

2013-01-01

According to the Dobzhansky–Muller model, hybrid sterility is a consequence of the independent evolution of related taxa resulting in incompatible genomic interactions of their hybrids. The model implies that the incompatibilities evolve randomly, unless a particular gene or nongenic sequence diverges much faster than the rest of the genome. Here we propose that asynapsis of heterospecific chromosomes in meiotic prophase provides a recurrently evolving trigger for the meiotic arrest of interspecific F1 hybrids. We observed extensive asynapsis of chromosomes and disturbance of the sex body in >95% of pachynemas of Mus m. musculus × Mus m. domesticus sterile F1 males. Asynapsis was not preceded by a failure of double-strand break induction, and the rate of meiotic crossing over was not affected in synapsed chromosomes. DNA double-strand break repair was delayed or failed in unsynapsed autosomes, and misexpression of chromosome X and chromosome Y genes was detected in single pachynemas and by genome-wide expression profiling. Oocytes of F1 hybrid females showed the same kind of synaptic problems but with the incidence reduced to half. Most of the oocytes with pachytene asynapsis were eliminated before birth. We propose the heterospecific pairing of homologous chromosomes as a preexisting condition of asynapsis in interspecific hybrids. The asynapsis may represent a universal mechanistic basis of F1 hybrid sterility manifested by pachytene arrest. It is tempting to speculate that a fast-evolving subset of the noncoding genomic sequence important for chromosome pairing and synapsis may be the culprit. PMID:23329330

Growth and lipid production of Umbelopsis isabellina on a solid substrate - Mechanistic modeling and validation

NARCIS (Netherlands)

Meeuwse, P.; Klok, A.J.; Haemers, S.; Tramper, J.; Rinzema, A.

2012-01-01

Microbial lipids are an interesting feedstock for biodiesel. Their production from agricultural waste streams by fungi cultivated in solid-state fermentation may be attractive, but the yield of this process is still quite low. In this article, a mechanistic model is presented that describes growth,

Mechanistic and kinetic aspects of pentose dehydration towards furfural in aqueous media employing homogeneous catalysis

NARCIS (Netherlands)

Danon, B.; Marcotullio, G.; De Jong, W.

2013-01-01

In this paper both the mechanistic and kinetic aspects of furfural formation from pentoses in aqueous acidic media have been reviewed. Based on the reviewed literature, a comprehensive reaction mechanism has been proposed consisting of more than one route, all starting from acyclic xylose, and

Fatigue Evaluation of Recycled Asphalt Mixture Based on Energy-Controlled Mode

Directory of Open Access Journals (Sweden)

Tao Ma

2017-01-01

Full Text Available The fatigue properties of asphalt mixtures are important inputs for mechanistic-empirical pavement design. To understand the fatigue properties of asphalt mixtures better and to predict the fatigue life of asphalt mixtures more precisely, the energy-controlled test mode was introduced. Based on the implementation theory, the laboratory practice for the energy-controlled mode was realized using a four-point-bending fatigue test with multiple-step loading. In this mode, the fatigue performance of typical AC-20 asphalt specimens with various reclaimed asphalt pavement (RAP contents was tested and evaluated. Results show that the variation regulation of the dissipated energy and accumulative energy is compatible with the loading control principle, which proves the feasibility of the method. In addition, the fatigue life of the asphalt mixture in the energy-controlled mode was between that for the stress-controlled and strain-controlled modes. The specimen with a higher RAP content has a longer fatigue life and better fatigue performance.

Arsenic Exposure and Type 2 Diabetes: MicroRNAs as Mechanistic Links?

OpenAIRE

Beck, Rowan; Styblo, Miroslav; Sethupathy, Praveen

2017-01-01

Purpose of Review The goal of this review is to delineate the following: (1) the primary means of inorganic arsenic (iAs) exposure for human populations, (2) the adverse public health outcomes associated with chronic iAs exposure, (3) the pathophysiological connection between arsenic and type 2 diabetes (T2D), and (4) the incipient evidence for microRNAs as candidate mechanistic links between iAs exposure and T2D. Recent Findings Exposure to iAs in animal models has been associated with the d...

Mechanistic insights on the cycloisomerization of polyunsaturated precursors catalyzed by platinum and gold complexes.

Science.gov (United States)

Soriano, Elena; Marco-Contelles, José

2009-08-18

Organometallic chemistry provides powerful tools for the stereocontrolled synthesis of heterocycles and carbocycles. The electrophilic transition metals Pt(II) and Au(I, III) are efficient catalysts in these transitions and promote a variety of organic transformations of unsaturated precursors. These reactions produce functionalized cyclic and acyclic scaffolds for the synthesis of natural and non-natural products efficiently, under mild conditions, and with excellent chemoselectivity. Because these transformations are strongly substrate-dependent, they are versatile and may yield diverse molecular scaffolds. Therefore, synthetic chemists need a mechanistic interpretation to optimize this reaction process and design a new generation of catalysts. However, so far, no intermediate species has been isolated or characterized, so the formulated mechanistic hypotheses have been primarily based on labeling studies or trapping reactions. Recently, theoretical DFT studies have become a useful tool in our research, giving us insights into the key intermediates and into a variety of plausible reaction pathways. In this Account, we present a comprehensive mechanistic overview of transformations promoted by Pt and Au in a non-nucleophilic medium based on quantum-mechanical studies. The calculations are consistent with the experimental observations and provide fundamental insights into the versatility of these reaction processes. The reactivity of these metals results from their peculiar Lewis acid properties: the alkynophilic character of these soft metals and the pi-acid activation of unsaturated groups promotes the intra- or intermolecular attack of a nucleophile. 1,n-Enynes (n = 3-8) are particularly important precursors, and their transformation may yield a variety of cycloadducts depending on the molecular structure. However, the calculations suggest that these different cyclizations would have closely related reaction mechanisms, and we propose a unified mechanistic

SITE-94. Adaptation of mechanistic sorption models for performance assessment calculations

International Nuclear Information System (INIS)

Arthur, R.C.

1996-10-01

Sorption is considered in most predictive models of radionuclide transport in geologic systems. Most models simulate the effects of sorption in terms of empirical parameters, which however can be criticized because the data are only strictly valid under the experimental conditions at which they were measured. An alternative is to adopt a more mechanistic modeling framework based on recent advances in understanding the electrical properties of oxide mineral-water interfaces. It has recently been proposed that these 'surface-complexation' models may be directly applicable to natural systems. A possible approach for adapting mechanistic sorption models for use in performance assessments, using this 'surface-film' concept, is described in this report. Surface-acidity parameters in the Generalized Two-Layer surface complexation model are combined with surface-complexation constants for Np(V) sorption ob hydrous ferric oxide to derive an analytical model enabling direct calculation of corresponding intrinsic distribution coefficients as a function of pH, and Ca 2+ , Cl - , and HCO 3 - concentrations. The surface film concept is then used to calculate whole-rock distribution coefficients for Np(V) sorption by altered granitic rocks coexisting with a hypothetical, oxidized Aespoe groundwater. The calculated results suggest that the distribution coefficients for Np adsorption on these rocks could range from 10 to 100 ml/g. Independent estimates of K d for Np sorption in similar systems, based on an extensive review of experimental data, are consistent, though slightly conservative, with respect to the calculated values. 31 refs

Behavioural Procedural Models – a multipurpose mechanistic account

Directory of Open Access Journals (Sweden)

Leonardo Ivarola

2012-05-01

Full Text Available In this paper we outline an epistemological defence of what wecall Behavioural Procedural Models (BPMs, which represent the processes of individual decisions that lead to relevant economic patterns as psychologically (rather than rationally driven. Their general structure, and the way in which they may be incorporated to a multipurpose view of models, where the representational and interventionist goals are combined, is shown. It is argued that BPMs may provide “mechanistic-based explanations” in the sense defended by Hedström and Ylikoski (2010, which involve invariant regularities in Woodward’s sense. Such mechanisms provide a causal sort of explanation of anomalous economic patterns, which allow for extra marketintervention and manipulability in order to correct and improve some key individual decisions. This capability sets the basis for the so called libertarian paternalism (Sunstein and Thaler 2003.

Mechanistic background and clinical applications of indocyanine green fluorescence imaging of hepatocellular carcinoma.

Science.gov (United States)

Ishizawa, Takeaki; Masuda, Koichi; Urano, Yasuteru; Kawaguchi, Yoshikuni; Satou, Shouichi; Kaneko, Junichi; Hasegawa, Kiyoshi; Shibahara, Junji; Fukayama, Masashi; Tsuji, Shingo; Midorikawa, Yutaka; Aburatani, Hiroyuki; Kokudo, Norihiro

2014-02-01

Although clinical applications of intraoperative fluorescence imaging of liver cancer using indocyanine green (ICG) have begun, the mechanistic background of ICG accumulation in the cancerous tissues remains unclear. In 170 patients with hepatocellular carcinoma cells (HCC), the liver surfaces and resected specimens were intraoperatively examined by using a near-infrared fluorescence imaging system after preoperative administration of ICG (0.5 mg/kg i.v.). Microscopic examinations, gene expression profile analysis, and immunohistochemical staining were performed for HCCs, which showed ICG fluorescence in the cancerous tissues (cancerous-type fluorescence), and HCCs showed fluorescence only in the surrounding non-cancerous liver parenchyma (rim-type fluorescence). ICG fluorescence imaging enabled identification of 273 of 276 (99%) HCCs in the resected specimens. HCCs showed that cancerous-type fluorescence was associated with higher cancer cell differentiation as compared with rim-type HCCs (P Fluorescence microscopy identified the presence of ICG in the canalicular side of the cancer cell cytoplasm, and pseudoglands of the HCCs showed a cancerous-type fluorescence pattern. The ratio of the gene and protein expression levels in the cancerous to non-cancerous tissues for Na(+)/taurocholate cotransporting polypeptide (NTCP) and organic anion-transporting polypeptide 8 (OATP8), which are associated with portal uptake of ICG by hepatocytes that tended to be higher in the HCCs that showed cancerous-type fluorescence than in those that showed rim-type fluorescence. Preserved portal uptake of ICG in differentiated HCC cells by NTCP and OATP8 with concomitant biliary excretion disorders causes accumulation of ICG in the cancerous tissues after preoperative intravenous administration. This enables highly sensitive identification of HCC by intraoperative ICG fluorescence imaging.

The Cycloaddition of the Benzimidazolium Ylides with Alkynes: New Mechanistic Insights.

Directory of Open Access Journals (Sweden)

Costel Moldoveanu

Full Text Available New insights concerning the reaction mechanism in the cycloaddition reaction of benzimidazolium ylides to activated alkynes are presented. The proposed pathway leading both to 2-(1H-pyrrol-1-ylanilines and to pyrrolo[1,2-a]quinoxalin-4(5H-ones involves an opening of the imidazole ring from the cycloaddition product, followed by a nucleophilic attack of the aminic nitrogen to a proximal carbonyl group and the elimination of a leaving group. The mechanistic considerations are fully supported by experimental data, including the XRD resolved structure of the key reaction intermediate.

The Cycloaddition of the Benzimidazolium Ylides with Alkynes: New Mechanistic Insights.

Science.gov (United States)

Moldoveanu, Costel; Zbancioc, Gheorghita; Mantu, Dorina; Maftei, Dan; Mangalagiu, Ionel

2016-01-01

New insights concerning the reaction mechanism in the cycloaddition reaction of benzimidazolium ylides to activated alkynes are presented. The proposed pathway leading both to 2-(1H-pyrrol-1-yl)anilines and to pyrrolo[1,2-a]quinoxalin-4(5H)-ones involves an opening of the imidazole ring from the cycloaddition product, followed by a nucleophilic attack of the aminic nitrogen to a proximal carbonyl group and the elimination of a leaving group. The mechanistic considerations are fully supported by experimental data, including the XRD resolved structure of the key reaction intermediate.

Diffusion theory in biology: a relic of mechanistic materialism.

Science.gov (United States)

Agutter, P S; Malone, P C; Wheatley, D N

2000-01-01

Diffusion theory explains in physical terms how materials move through a medium, e.g. water or a biological fluid. There are strong and widely acknowledged grounds for doubting the applicability of this theory in biology, although it continues to be accepted almost uncritically and taught as a basis of both biology and medicine. Our principal aim is to explore how this situation arose and has been allowed to continue seemingly unchallenged for more than 150 years. The main shortcomings of diffusion theory will be briefly reviewed to show that the entrenchment of this theory in the corpus of biological knowledge needs to be explained, especially as there are equally valid historical grounds for presuming that bulk fluid movement powered by the energy of cell metabolism plays a prominent note in the transport of molecules in the living body. First, the theory's evolution, notably from its origins in connection with the mechanistic materialist philosophy of mid nineteenth century physiology, is discussed. Following this, the entrenchment of the theory in twentieth century biology is analyzed in relation to three situations: the mechanism of oxygen transport between air and mammalian tissues; the structure and function of cell membranes; and the nature of the intermediary metalbolism, with its implicit presumptions about the intracellular organization and the movement of molecules within it. In our final section, we consider several historically based alternatives to diffusion theory, all of which have their precursors in nineteenth and twentieth century philosophy of science.

Mechanistic Prediction of the Effect of Microstructural Coarsening on Creep Response of SnAgCu Solder Joints

Science.gov (United States)

Mukherjee, S.; Chauhan, P.; Osterman, M.; Dasgupta, A.; Pecht, M.

2016-07-01

Mechanistic microstructural models have been developed to capture the effect of isothermal aging on time dependent viscoplastic response of Sn3.0Ag0.5Cu (SAC305) solders. SnAgCu (SAC) solders undergo continuous microstructural coarsening during both storage and service because of their high homologous temperature. The microstructures of these low melting point alloys continuously evolve during service. This results in evolution of creep properties of the joint over time, thereby influencing the long term reliability of microelectronic packages. It is well documented that isothermal aging degrades the creep resistance of SAC solder. SAC305 alloy is aged for (24-1000) h at (25-100)°C (~0.6-0.8 × T melt). Cross-sectioning and image processing techniques were used to periodically quantify the effect of isothermal aging on phase coarsening and evolution. The parameters monitored during isothermal aging include size, area fraction, and inter-particle spacing of nanoscale Ag3Sn intermetallic compounds (IMCs) and the volume fraction of micronscale Cu6Sn5 IMCs, as well as the area fraction of pure tin dendrites. Effects of microstructural evolution on secondary creep constitutive response of SAC305 solder joints were then modeled using a mechanistic multiscale creep model. The mechanistic phenomena modeled include: (1) dispersion strengthening by coarsened nanoscale Ag3Sn IMCs in the eutectic phase; and (2) load sharing between pro-eutectic Sn dendrites and the surrounding coarsened eutectic Sn-Ag phase and microscale Cu6Sn5 IMCs. The coarse-grained polycrystalline Sn microstructure in SAC305 solder was not captured in the above model because isothermal aging does not cause any significant change in the initial grain size and orientation of SAC305 solder joints. The above mechanistic model can successfully capture the drop in creep resistance due to the influence of isothermal aging on SAC305 single crystals. Contribution of grain boundary sliding to the creep strain of

A TAD further: exogenous control of gene activation.

Science.gov (United States)

Mapp, Anna K; Ansari, Aseem Z

2007-01-23

Designer molecules that can be used to impose exogenous control on gene transcription, artificial transcription factors (ATFs), are highly desirable as mechanistic probes of gene regulation, as potential therapeutic agents, and as components of cell-based devices. Recently, several advances have been made in the design of ATFs that activate gene transcription (activator ATFs), including reports of small-molecule-based systems and ATFs that exhibit potent activity. However, the many open mechanistic questions about transcriptional activators, in particular, the structure and function of the transcriptional activation domain (TAD), have hindered rapid development of synthetic ATFs. A compelling need thus exists for chemical tools and insights toward a more detailed portrait of the dynamic process of gene activation.

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

Science.gov (United States)

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. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

Science.gov (United States)

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

How phenyl makes a difference: mechanistic insights into the ruthenium( ii )-catalysed isomerisation of allylic alcohols

KAUST Repository

Manzini, Simone

2013-10-16

[RuCl(η5-3-phenylindenyl)(PPh3)2] (1) has been shown to be a highly active catalyst for the isomerisation of allylic alcohols to the corresponding ketones. A variety of substrates undergo the transformation, typically with 0.25-0.5 mol% of catalyst at room temperature, outperforming commonly-used complexes such as [RuCl(Cp)(PPh3) 2] and [RuCl(η5-indenyl)(PPh3) 2]. Mechanistic experiments and density functional theory have been employed to investigate the mechanism and understand the effect of catalyst structure on reactivity. These investigations suggest a oxo-π-allyl mechanism is in operation, avoiding intermediate ruthenium hydride complexes and leading to a characteristic 1,3-deuterium shift. Important mechanistic insights from DFT and experiments also allowed for the design of a protocol that expands the scope of the transformation to include primary allylic alcohols. © 2013 The Royal Society of Chemistry.

How phenyl makes a difference: mechanistic insights into the ruthenium( ii )-catalysed isomerisation of allylic alcohols

KAUST Repository

Manzini, Simone; Poater, Albert; Nelson, David J.; Cavallo, Luigi; Nolan, Steven P.

2013-01-01

[RuCl(η5-3-phenylindenyl)(PPh3)2] (1) has been shown to be a highly active catalyst for the isomerisation of allylic alcohols to the corresponding ketones. A variety of substrates undergo the transformation, typically with 0.25-0.5 mol% of catalyst at room temperature, outperforming commonly-used complexes such as [RuCl(Cp)(PPh3) 2] and [RuCl(η5-indenyl)(PPh3) 2]. Mechanistic experiments and density functional theory have been employed to investigate the mechanism and understand the effect of catalyst structure on reactivity. These investigations suggest a oxo-π-allyl mechanism is in operation, avoiding intermediate ruthenium hydride complexes and leading to a characteristic 1,3-deuterium shift. Important mechanistic insights from DFT and experiments also allowed for the design of a protocol that expands the scope of the transformation to include primary allylic alcohols. © 2013 The Royal Society of Chemistry.

Establishing appropriate inputs when using the mechanistic-empirical pavement design guide to design rigid pavements in Pennsylvania.

Science.gov (United States)

2011-03-01

Each design input in the Mechanistic-Empirical Design Guide (MEPDG) required for the design of Jointed Plain Concrete : Pavements (JPCPs) is introduced and discussed in this report. Best values for Pennsylvania conditions were established and : recom...

A mechanistic model for the evolution of multicellularity

Science.gov (United States)

Amado, André; Batista, Carlos; Campos, Paulo R. A.

2018-02-01

Through a mechanistic approach we investigate the formation of aggregates of variable sizes, accounting mechanisms of aggregation, dissociation, death and reproduction. In our model, cells can produce two metabolites, but the simultaneous production of both metabolites is costly in terms of fitness. Thus, the formation of larger groups can favor the aggregates to evolve to a configuration where division of labor arises. It is assumed that the states of the cells in a group are those that maximize organismal fitness. In the model it is considered that the groups can grow linearly, forming a chain, or compactly keeping a roughly spherical shape. Starting from a population consisting of single-celled organisms, we observe the formation of groups with variable sizes and usually much larger than two-cell aggregates. Natural selection can favor the formation of large groups, which allows the system to achieve new and larger fitness maxima.

Dual Nature of Translational Control by Regulatory BC RNAs ▿

Science.gov (United States)

Eom, Taesun; Berardi, Valerio; Zhong, Jun; Risuleo, Gianfranco; Tiedge, Henri

2011-01-01

In higher eukaryotes, increasing evidence suggests, gene expression is to a large degree controlled by RNA. Regulatory RNAs have been implicated in the management of neuronal function and plasticity in mammalian brains. However, much of the molecular-mechanistic framework that enables neuronal regulatory RNAs to control gene expression remains poorly understood. Here, we establish molecular mechanisms that underlie the regulatory capacity of neuronal BC RNAs in the translational control of gene expression. We report that regulatory BC RNAs employ a two-pronged approach in translational control. One of two distinct repression mechanisms is mediated by C-loop motifs in BC RNA 3′ stem-loop domains. These C-loops bind to eIF4B and prevent the factor's interaction with 18S rRNA of the small ribosomal subunit. In the second mechanism, the central A-rich domains of BC RNAs target eIF4A, specifically inhibiting its RNA helicase activity. Thus, BC RNAs repress translation initiation in a bimodal mechanistic approach. As BC RNA functionality has evolved independently in rodent and primate lineages, our data suggest that BC RNA translational control was necessitated and implemented during mammalian phylogenetic development of complex neural systems. PMID:21930783

Mechanistic study of manganese-substituted glycerol dehydrogenase using a kinetic and thermodynamic analysis.

Science.gov (United States)

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.

Mechanistic study of manganese-substituted glycerol dehydrogenase using a kinetic and thermodynamic analysis.

Directory of Open Access Journals (Sweden)

Baishan Fang

Full Text Available 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.

Application of mechanistic empirical approach to predict rutting of superpave mixtures in Iraq

Directory of Open Access Journals (Sweden)

Qasim Zaynab

2018-01-01

Full Text Available In Iraq rutting is considered as a real distress in flexible pavements as a result of high summer temperature, and increased axle loads. This distress majorly affects asphalt pavement performance, lessens the pavement useful service life and makes serious hazards for highway users. Performance of HMA mixtures against rutting using Mechanistic- Empirical approach is predicted by considering Wheel-Tracking test and employing the Superpave mix design requirements. Roller Wheel Compactor has been locally manufactured to prepare slab specimens. In view of study laboratory outcomes that are judged to be simulative of field loading conditions, models are developed for predicting permanent strain of compacted samples of local asphalt concrete mixtures after considering the stress level, properties of local material and environmental impacts variables. All in all, laboratory results were produced utilizing statistical analysis with the aid of SPSS software. Permanent strain models for asphalt concrete mixtures were developed as a function of: number of passes, temperature, asphalt content, viscosity, air voids and additive content. Mechanistic Empirical design approach through the MnPAVE software was applied to characterize rutting in HMA and to predict allowable number of loading repetitions of mixtures as a function of expected traffic loads, material properties, and environmental temperature.

On the antibacterial effects of manuka honey: mechanistic insights

Directory of Open Access Journals (Sweden)

Roberts AEL

2015-10-01

Full Text Available Aled Edward Lloyd Roberts,* Helen Louise Brown,* Rowena Eleri Jenkins Department of Biomedical Sciences, Cardiff Metropolitan University, Cardiff, Wales, UK *These authors contributed equally to this work Abstract: Antimicrobial resistance (AMR is an increasing clinical problem precipitated by the inappropriate use of antibiotics in the later parts of the 20th Century. This problem, coupled with the lack of novel therapeutics in the development pipeline, means AMR is reaching crisis point, with an expected annual death rate of ten million people worldwide by 2050. To reduce, and to potentially remedy this problem, many researchers are looking into natural compounds with antimicrobial and/or antivirulence activity. Manuka honey is an ancient antimicrobial remedy with a good track record against a wide range of nosocomial pathogens that have increased AMR. Its inhibitory effects are the result of its constituent components, which add varying degrees of antimicrobial efficacy to the overall activity of manuka honey. The antimicrobial efficacy of manuka honey and some of its constituent components (such as methylglyoxal and leptosperin are known to bestow some degree of antimicrobial efficacy to manuka honey. Despite growing in vitro evidence of its antimicrobial efficacy, the in vivo use of manuka honey (especially in a clinical environment has been unexpectedly slow, partly due to the lack of mechanistic data. The mechanism by which manuka honey achieves its inhibitory efficacy has recently been identified against Staphylococcus aureus and Pseudomonas aeruginosa, with both of these contrasting organisms being inhibited through different mechanisms. Manuka honey inhibits S. aureus by interfering with the cell division process, whereas P. aeruginosa cells lyse in its presence due to the reduction of a key structural protein. In addition to these inhibitory effects, manuka honey is known to reduce virulence, motility, and biofilm formation. With this

Vortexlet models of flapping flexible wings show tuning for force production and control

International Nuclear Information System (INIS)

Mountcastle, A M; Daniel, T L

2010-01-01

Insect wings are compliant structures that experience deformations during flight. Such deformations have recently been shown to substantially affect induced flows, with appreciable consequences to flight forces. However, there are open questions related to the aerodynamic mechanisms underlying the performance benefits of wing deformation, as well as the extent to which such deformations are determined by the boundary conditions governing wing actuation together with mechanical properties of the wing itself. Here we explore aerodynamic performance parameters of compliant wings under periodic oscillations, subject to changes in phase between wing elevation and pitch, and magnitude and spatial pattern of wing flexural stiffness. We use a combination of computational structural mechanics models and a 2D computational fluid dynamics approach to ask how aerodynamic force production and control potential are affected by pitch/elevation phase and variations in wing flexural stiffness. Our results show that lift and thrust forces are highly sensitive to flexural stiffness distributions, with performance optima that lie in different phase regions. These results suggest a control strategy for both flying animals and engineering applications of micro-air vehicles.

Problems in mechanistic theoretical models for cell transformation by ionizing radiation

International Nuclear Information System (INIS)

Chatterjee, Aloke; Holley, W.R.

1992-01-01

A mechanistic model based on yields of double strand breaks has been developed to determine the dose response curves for cell transformation frequencies. At its present stage the model is applicable to immortal cell lines and to various qualities (X-rays, Neon and Iron) of ionizing radiation. Presently, we have considered four types of processes which can lead to activation phenomena: (i) point mutation events on a regulatory segment of selected oncogenes, (ii) inactivation of suppressor genes, through point mutation, (iii) deletion of a suppressor gene by a single track, and (iv) deletion of a suppressor gene by two tracks. (author)

Partial oxidation of methane in a temperature-controlled dielectric barrier discharge reactor

KAUST Repository

Zhang, Xuming; Cha, Min

2015-01-01

We studied the relative importance of the reduced field intensity and the background reaction temperature in the partial oxidation of methane in a temperature-controlled dielectric barrier discharge reactor. We obtained important mechanistic insight

Prostate cancer patient subsets showing improved bNED control with adjuvant androgen deprivation

International Nuclear Information System (INIS)

Anderson, Penny R.; Hanlon, Alexandra L.; Movsas, Benjamin; Hanks, Gerald E.

1997-01-01

Purpose: Cooperative groups have investigated the outcome of androgen deprivation therapy combined with radiation therapy in prostate cancer patients with variable pretreatment prognostic indicators. This report describes an objective means of selecting patients for adjuvant hormonal therapy by a retrospective matched case/control comparison of outcome between patients with specific pretreatment characteristics who receive adjuvant hormones (RT + H) vs. patients with identical pretreatment characteristics treated with radiation therapy alone (RT). In addition, this report shows the 5-year bNED control for patients selected by this method for RT + H vs. RT alone. Methods and Materials: From (10(88)) to (12(93)), 517 T1-T3 NXM0 patients with known pretreatment PSA level were treated at Fox Chase Cancer Center. Four hundred fifty-nine of those patients were treated with RT alone while 58 were treated with RT + H. The patients were categorized according to putative prognostic factors indicative of bNED control, which include the palpation stage, Gleason score, and pretreatment PSA. We compared actuarial bNED control rates according to treatment group within each of the prognostic groups. In addition, we devised a retrospective matched case/control selection of RT patients for comparison with the RT + H group. Five-year bNED control was compared for the two treatment groups, excluding the best prognosis group, using 56 RT + H patients and 56 matched (by stage, grade, and pretreatment PSA level) controls randomly selected from the RT alone group. bNED control for the entire group of 517 patients was then analyzed multivariately using step-wise Cox regression to determine independent predictors of outcome. Covariates considered for entry into the model included stage (T1/T2AB vs. T2C/T3), grade (2-6 vs. 7-10), pretreatment PSA (0-15 vs. > 15), treatment (RT vs. RT + H), and center of prostate dose. bNED failure is defined as PSA ≥1.5 ngm/ml and rising on two consecutive

Productivity of "collisions generate heat" for reconciling an energy model with mechanistic reasoning: A case study

Science.gov (United States)

Scherr, Rachel E.; Robertson, Amy D.

2015-06-01

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 byproduct of individual particle collisions, which is represented in science education research literature as an obstacle to learning. We demonstrate that in this instructional context, the idea that individual particle collisions generate thermal energy is not an obstacle to learning, but instead is productive: it initiates intellectual progress. Specifically, this idea initiates the reconciliation of the teachers' energy model with mechanistic reasoning about adiabatic compression, and leads to a canonically correct model of the transformation of kinetic energy into thermal energy. We claim that the idea's productivity is influenced by features of our particular instructional context, including the instructional goals of the course, the culture of collaborative sense making, and the use of certain representations of energy.

Mechanistic studies of copper(I)-catalyzed 1,3-halogen migration.

Science.gov (United States)

Van Hoveln, Ryan; Hudson, Brandi M; Wedler, Henry B; Bates, Desiree M; Le Gros, Gabriel; Tantillo, Dean J; Schomaker, Jennifer M

2015-04-29

An ongoing challenge in modern catalysis is to identify and understand new modes of reactivity promoted by earth-abundant and inexpensive first-row transition metals. Herein, we report a mechanistic study of an unusual copper(I)-catalyzed 1,3-migration of 2-bromostyrenes that reincorporates the bromine activating group into the final product with concomitant borylation of the aryl halide bond. A combination of experimental and computational studies indicated this reaction does not involve any oxidation state changes at copper; rather, migration occurs through a series of formal sigmatropic shifts. Insight provided from these studies will be used to expand the utility of aryl copper species in synthesis and develop new ligands for enantioselective copper-catalyzed halogenation.

A mechanistic Eulerian-Lagrangian model for dispersed flow film boiling

International Nuclear Information System (INIS)

Andreani, M.; Yadigaroglu, G.

1991-01-01

In this paper a new mechanistic model of heat transfer in the dispersed flow regime is presented. The usual assumptions that render most of the available models unsuitable for the analysis of the reflooding phase of the LOCA are discussed, and a two-dimensional time-independent numerical model is developed. The gas temperature field is solved in a fixed-grid (Eulerian) mesh, with the droplets behaving as mass and energy sources. The histories of a large number of computational droplets are followed in a Lagrangian frame, considering evaporation, break-up and interactions with the vapor and with the wall. comparisons of calculated wall and vapor temperatures with experimental data are shown for two reflooding tests

Mechanistic rationalization of unusual sigmoidal kinetic profiles in the Machetti-De Sarlo cycloaddition reaction.

Science.gov (United States)

Mower, Matthew P; Blackmond, Donna G

2015-02-18

Unusual sigmoidal kinetic profiles in the Machetti-De Sarlo base-catalyzed 1,3-dipolar cycloaddition of acrylamide to N-methylnitroacetamide are rationalized by detailed in situ kinetic analysis. A dual role is uncovered in which a substrate acts as a precursor to catalyze its own reaction. Such kinetic studies provide a general protocol for distinguishing among different mechanistic origins of induction periods in complex organic reactions.

Linking spring phenology with mechanistic models of host movement to predict disease transmission risk

Science.gov (United States)

Merkle, Jerod A.; Cross, Paul C.; Scurlock, Brandon M.; Cole, Eric K.; Courtemanch, Alyson B.; Dewey, Sarah R.; Kauffman, Matthew J.

2018-01-01

Disease models typically focus on temporal dynamics of infection, while often neglecting environmental processes that determine host movement. In many systems, however, temporal disease dynamics may be slow compared to the scale at which environmental conditions alter host space-use and accelerate disease transmission.Using a mechanistic movement modelling approach, we made space-use predictions of a mobile host (elk [Cervus Canadensis] carrying the bacterial disease brucellosis) under environmental conditions that change daily and annually (e.g., plant phenology, snow depth), and we used these predictions to infer how spring phenology influences the risk of brucellosis transmission from elk (through aborted foetuses) to livestock in the Greater Yellowstone Ecosystem.Using data from 288 female elk monitored with GPS collars, we fit step selection functions (SSFs) during the spring abortion season and then implemented a master equation approach to translate SSFs into predictions of daily elk distribution for five plausible winter weather scenarios (from a heavy snow, to an extreme winter drought year). We predicted abortion events by combining elk distributions with empirical estimates of daily abortion rates, spatially varying elk seroprevelance and elk population counts.Our results reveal strong spatial variation in disease transmission risk at daily and annual scales that is strongly governed by variation in host movement in response to spring phenology. For example, in comparison with an average snow year, years with early snowmelt are predicted to have 64% of the abortions occurring on feedgrounds shift to occurring on mainly public lands, and to a lesser extent on private lands.Synthesis and applications. Linking mechanistic models of host movement with disease dynamics leads to a novel bridge between movement and disease ecology. Our analysis framework offers new avenues for predicting disease spread, while providing managers tools to proactively mitigate

ReactionPredictor: prediction of complex chemical reactions at the mechanistic level using machine learning.

Science.gov (United States)

Kayala, Matthew A; Baldi, Pierre

2012-10-22

Proposing reasonable mechanisms and predicting the course of chemical reactions is important to the practice of organic chemistry. Approaches to reaction prediction have historically used obfuscating representations and manually encoded patterns or rules. Here we present ReactionPredictor, a machine learning approach to reaction prediction that models elementary, mechanistic reactions as interactions between approximate molecular orbitals (MOs). A training data set of productive reactions known to occur at reasonable rates and yields and verified by inclusion in the literature or textbooks is derived from an existing rule-based system and expanded upon with manual curation from graduate level textbooks. Using this training data set of complex polar, hypervalent, radical, and pericyclic reactions, a two-stage machine learning prediction framework is trained and validated. In the first stage, filtering models trained at the level of individual MOs are used to reduce the space of possible reactions to consider. In the second stage, ranking models over the filtered space of possible reactions are used to order the reactions such that the productive reactions are the top ranked. The resulting model, ReactionPredictor, perfectly ranks polar reactions 78.1% of the time and recovers all productive reactions 95.7% of the time when allowing for small numbers of errors. Pericyclic and radical reactions are perfectly ranked 85.8% and 77.0% of the time, respectively, rising to >93% recovery for both reaction types with a small number of allowed errors. Decisions about which of the polar, pericyclic, or radical reaction type ranking models to use can be made with >99% accuracy. Finally, for multistep reaction pathways, we implement the first mechanistic pathway predictor using constrained tree-search to discover a set of reasonable mechanistic steps from given reactants to given products. Webserver implementations of both the single step and pathway versions of Reaction

A Mechanistic Reliability Assessment of RVACS and Metal Fuel Inherent Reactivity Feedbacks

Energy Technology Data Exchange (ETDEWEB)

Grabaskas, David; Brunett, Acacia J.; Passerini, Stefano; Grelle, Austin

2017-09-24

GE Hitachi Nuclear Energy (GEH) and Argonne National Laboratory (Argonne) participated in a two year collaboration to modernize and update the probabilistic risk assessment (PRA) for the PRISM sodium fast reactor. At a high level, the primary outcome of the project was the development of a next-generation PRA that is intended to enable risk-informed prioritization of safety- and reliability-focused research and development. A central Argonne task during this project was a reliability assessment of passive safety systems, which included the Reactor Vessel Auxiliary Cooling System (RVACS) and the inherent reactivity feedbacks of the metal fuel core. Both systems were examined utilizing a methodology derived from the Reliability Method for Passive Safety Functions (RMPS), with an emphasis on developing success criteria based on mechanistic system modeling while also maintaining consistency with the Fuel Damage Categories (FDCs) of the mechanistic source term assessment. This paper provides an overview of the reliability analyses of both systems, including highlights of the FMEAs, the construction of best-estimate models, uncertain parameter screening and propagation, and the quantification of system failure probability. In particular, special focus is given to the methodologies to perform the analysis of uncertainty propagation and the determination of the likelihood of violating FDC limits. Additionally, important lessons learned are also reviewed, such as optimal sampling methodologies for the discovery of low likelihood failure events and strategies for the combined treatment of aleatory and epistemic uncertainties.

A mechanistic model for electricity consumption on dairy farms: Definition, validation, and demonstration

OpenAIRE

Upton, J.R.; Murphy, M.; Shallo, L.; Groot Koerkamp, P.W.G.; Boer, de, I.J.M.

2014-01-01

Our objective was to define and demonstrate a mechanistic model that enables dairy farmers to explore the impact of a technical or managerial innovation on electricity consumption, associated CO2 emissions, and electricity costs. We, therefore, (1) defined a model for electricity consumption on dairy farms (MECD) capable of simulating total electricity consumption along with related CO2 emissions and electricity costs on dairy farms on a monthly basis; (2) validated the MECD using empirical d...

Development of a mechanistic model for release of radionuclides from spent fuel in brines: Salt Repository Project

International Nuclear Information System (INIS)

Reimus, P.W.; Windisch, C.F.

1988-03-01

At present there are no comprehensive mechanistic models describing the release of radionuclides from spent fuel in brine environments. This report provides a comprehensive review of the various factors that can affect radionuclide release from spent fuel, suggests a modeling approach, and discusses proposed experiments for obtaining a better mechanistic understanding of the radionuclide release processes. Factors affecting radionuclide release include the amount, location, and disposition of radionuclides in the fuel and environmental factors such as redox potential, pH, the presence of complexing anions, temperature, and radiolysis. It is concluded that a model describing the release of radionuclides from spent fuel should contain separate terms for release from the gap, grain boundaries, and grains of the fuel. Possible functional forms for these terms are discussed in the report. Experiments for assessing their validity and obtaining key model parameters are proposed. 71 refs., 4 figs., 6 tabs

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

Science.gov (United States)

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…

Synthetic and mechanistic aspects of titanium-mediated carbonyl olefinations

Energy Technology Data Exchange (ETDEWEB)

Petasis, N.A.; Staszewski, J.P.; Hu, Yong-Han; Lu, Shao-Po [Univ. of Southern California, Los Angeles, CA (United States)

1995-12-31

A new method for the olefination of carbonyl compounds with dimethyl titanocene, and other related bishydrocarbyl titanocene derivatives has been recently developed in the author`s laboratories. This process is experimentally convenient and works with various types of carbonyl compounds, including aldehydes, ketones, esters, lactones, carbonates, anhydrides, amides, imides, lactams, thioesters, selenoesters, and acylsilanes. More recent studies have focused on the scope and utility of this reaction, including mechanistic studies and synthetic applications. In addition to varying the reaction conditions, the authors have examined several mixed titanocene derivatives and have found ways for carrying out this type of olefination at room temperature, such as the use of tris(trimethylsilyl) titanacyclobutene. The authors have also employed this reaction in the modification of carbohydrates and cyclobutenediones. This olefination was also followed-up with subsequent transformations to produce carbocycles and heterocycles, including tetrahydrofurans and tetrahydropyrans.

A mechanistic model for long-term nuclear waste glass dissolution integrating chemical affinity and interfacial diffusion barrier

Energy Technology Data Exchange (ETDEWEB)

Ma, Teqi [Northwest Institute of Nuclear Technology, No.28 Pingyu Road, Baqiao District, Xi' an,Shaanxi, 710024 (China); Mechanics and Physics of Solids Research Group, Modelling and Simulation Centre, The University of Manchester, Oxford Road, Manchester, M13 9PL (United Kingdom); Jivkov, Andrey P., E-mail: andrey.jivkov@manchester.ac.uk [Mechanics and Physics of Solids Research Group, Modelling and Simulation Centre, The University of Manchester, Oxford Road, Manchester, M13 9PL (United Kingdom); Li, Weiping; Liang, Wei; Wang, Yu; Xu, Hui [Northwest Institute of Nuclear Technology, No.28 Pingyu Road, Baqiao District, Xi' an,Shaanxi, 710024 (China); Han, Xiaoyuan, E-mail: xyhan_nint@sina.cn [Northwest Institute of Nuclear Technology, No.28 Pingyu Road, Baqiao District, Xi' an,Shaanxi, 710024 (China)

2017-04-01

Understanding the alteration of nuclear waste glass in geological repository conditions is critical element of the analysis of repository retention function. Experimental observations of glass alterations provide a general agreement on the following regimes: inter-diffusion, hydrolysis process, rate drop, residual rate and, under very particular conditions, resumption of alteration. Of these, the mechanisms controlling the rate drop and the residual rate remain a subject of dispute. This paper offers a critical review of the two most competitive models related to these regimes: affinity–limited dissolution and diffusion barrier. The limitations of these models are highlighted by comparison of their predictions with available experimental evidence. Based on the comprehensive discussion of the existing models, a new mechanistic model is proposed as a combination of the chemical affinity and diffusion barrier concepts. It is demonstrated how the model can explain experimental phenomena and data, for which the existing models are shown to be not fully adequate.

MECHANISTIC STUDY OF COLCHICINE’s ELECTROCHEMICAL OXIDATION

International Nuclear Information System (INIS)

Bodoki, Ede; Chira, Ruxandra; Zaharia, Valentin; Săndulescu, Robert

2015-01-01

Colchicine, as one of the most ancient drugs of human kind, is still in the focal point of the current research due to its multimodal mechanism of action. The elucidation of colchicine’s still unknown redox properties may play an important role in deciphering its beneficial and harmful implications over the human body. Therefore, a systematic mechanistic study of colchicine’s oxidation has been undertaken by electrochemistry coupled to mass spectrometry using two different types of electrolytic cells, in order to clarify the existing inconsistencies with respect to this topic. At around 1 V vs. Pd/H 2 , initiated by a one-electron transfer, the oxidation of colchicine sets off leading to a cation radical, whose further oxidation may evolve on several different pathways. The main product of the anodic electrochemical reaction, regardless of the carrier solution’s pH is represented by a 7-hydroxy derivative of colchicine. At more anodic potentials (above 1.4 V vs. Pd/H 2 ) compounds arising from epoxidation and/or multiple hydroxylation occur. No di- or tridemethylated quinone structures, as previously suggested in the literature for the electrolytic oxidation of colchicine, has been detected in the mass spectra.

Mechanistic modelling of genetic and epigenetic events in radiation carcinogenesis

International Nuclear Information System (INIS)

Andreev, S. G.; Eidelman, Y. A.; Salnikov, I. V.; Khvostunov, I. K.

2006-01-01

Methodological problems arise on the way of radiation carcinogenesis modelling with the incorporation of radiobiological and cancer biology mechanistic data. The results of biophysical modelling of different endpoints [DNA DSB induction, repair, chromosome aberrations (CA) and cell proliferation] are presented and applied to the analysis of RBE-LET relationships for radiation-induced neoplastic transformation (RINT) of C3H/10T1/2 cells in culture. Predicted values for some endpoints correlate well with the data. It is concluded that slowly repaired DSB clusters, as well as some kind of CA, may be initiating events for RINT. As an alternative interpretation, it is possible that DNA damage can induce RINT indirectly via epigenetic process. A hypothetical epigenetic pathway for RINT is discussed. (authors)

Mechanistic Basis of Cocrystal Dissolution Advantage.

Science.gov (United States)

Cao, Fengjuan; Amidon, Gordon L; Rodríguez-Hornedo, Naír; Amidon, Gregory E

2018-01-01

Current interest in cocrystal development resides in the advantages that the cocrystal may have in solubility and dissolution compared with the parent drug. This work provides a mechanistic analysis and comparison of the dissolution behavior of carbamazepine (CBZ) and its 2 cocrystals, carbamazepine-saccharin (CBZ-SAC) and carbamazepine-salicylic acid (CBZ-SLC) under the influence of pH and micellar solubilization. A simple mathematical equation is derived based on the mass transport analyses to describe the dissolution advantage of cocrystals. The dissolution advantage is the ratio of the cocrystal flux to drug flux and is defined as the solubility advantage (cocrystal to drug solubility ratio) times the diffusivity advantage (cocrystal to drug diffusivity ratio). In this work, the effective diffusivity of CBZ in the presence of surfactant was determined to be different and less than those of the cocrystals. The higher effective diffusivity of drug from the dissolved cocrystals, the diffusivity advantage, can impart a dissolution advantage to cocrystals with lower solubility than the parent drug while still maintaining thermodynamic stability. Dissolution conditions where cocrystals can display both thermodynamic stability and a dissolution advantage can be obtained from the mass transport models, and this information is useful for both cocrystal selection and formulation development. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

A mechanistic model for spread of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) within a pig herd

DEFF Research Database (Denmark)

Sørensen, Anna Irene Vedel; Toft, Nils; Boklund, Anette

2017-01-01

Before an efficient control strategy for livestock-associated methicillin resistant Staphylococcus aureus (LA-MRSA) in pigs can be decided upon, it is necessary to obtain a betterunderstanding of how LA-MRSA spreads and persists within a pig herd, once it is introduced.We here present a mechanistic...... stochastic discrete-event simulation model forspread of LA-MRSA within a farrow-to-finish sow herd to aid in this. The model was individual-based and included three different disease compartments: susceptible, intermittent or persistent shedder of MRSA. The model was used for studying transmission dynamics...... and within-farm prevalence after different introductions of LA-MRSA into a farm. The spread of LA-MRSA throughout the farm mainly followed the movement of pigs. After spread of LA-MRSA had reached equilibrium, the prevalence of LA-MRSA shedders was predicted to be highest in the farrowing unit, independent...

Application of a mechanistic model as a tool for on-line monitoring of pilot scale filamentous fungal fermentation processes-The importance of evaporation effects.

Science.gov (United States)

Mears, Lisa; Stocks, Stuart M; Albaek, Mads O; Sin, Gürkan; Gernaey, Krist V

2017-03-01

A mechanistic model-based soft sensor is developed and validated for 550L filamentous fungus fermentations operated at Novozymes A/S. The soft sensor is comprised of a parameter estimation block based on a stoichiometric balance, coupled to a dynamic process model. The on-line parameter estimation block models the changing rates of formation of product, biomass, and water, and the rate of consumption of feed using standard, available on-line measurements. This parameter estimation block, is coupled to a mechanistic process model, which solves the current states of biomass, product, substrate, dissolved oxygen and mass, as well as other process parameters including k L a, viscosity and partial pressure of CO 2 . State estimation at this scale requires a robust mass model including evaporation, which is a factor not often considered at smaller scales of operation. The model is developed using a historical data set of 11 batches from the fermentation pilot plant (550L) at Novozymes A/S. The model is then implemented on-line in 550L fermentation processes operated at Novozymes A/S in order to validate the state estimator model on 14 new batches utilizing a new strain. The product concentration in the validation batches was predicted with an average root mean sum of squared error (RMSSE) of 16.6%. In addition, calculation of the Janus coefficient for the validation batches shows a suitably calibrated model. The robustness of the model prediction is assessed with respect to the accuracy of the input data. Parameter estimation uncertainty is also carried out. The application of this on-line state estimator allows for on-line monitoring of pilot scale batches, including real-time estimates of multiple parameters which are not able to be monitored on-line. With successful application of a soft sensor at this scale, this allows for improved process monitoring, as well as opening up further possibilities for on-line control algorithms, utilizing these on-line model outputs

Patients with bulimia nervosa do not show typical neurodevelopment of cognitive control under emotional influences.

Science.gov (United States)

Dreyfuss, Michael F W; Riegel, Melissa L; Pedersen, Gloria A; Cohen, Alexandra O; Silverman, Melanie R; Dyke, Jonathan P; Mayer, Laurel E S; Walsh, B Timothy; Casey, B J; Broft, Allegra I

2017-08-30

Bulimia nervosa (BN) emerges in the late teen years and is characterized by binge eating and related compensatory behaviors. These behaviors often co-occur with periods of negative affect suggesting an association between emotions and control over eating behavior. In the current study, we examined how cognitive control and neural processes change under emotional states of arousal in 46 participants with (n=19) and without (n=27) BN from the ages of 18-33 years. Participants performed a go/nogo task consisting of brief negative, positive and neutral emotional cues and sustained negative, positive and neutral emotional states of arousal during functional magnetic resonance imaging (fMRI). Overall task performance improved with age for healthy participants, but not for patients with BN. These age-dependent behavioral effects were paralleled by diminished recruitment of prefrontal control circuitry in patients with BN with age. Although patients with BN showed no difference in performance on the experimental manipulations of negative emotions, sustained positive emotions related to improved performance among patients with BN. Together the findings highlight a neurodevelopmental approach towards understanding markers of psychopathology and suggest that sustained positive affect may have potential therapeutic effects on maintaining behavioral control in BN. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Recognizing Mechanistic Reasoning in Student Scientific Inquiry: A Framework for Discourse Analysis Developed from Philosophy of Science

Science.gov (United States)

Russ, Rosemary S.; Scherr, Rachel E.; Hammer, David; Mikeska, Jamie

2008-01-01

Science education reform has long focused on assessing student inquiry, and there has been progress in developing tools specifically with respect to experimentation and argumentation. We suggest the need for attention to another aspect of inquiry, namely "mechanistic reasoning." Scientific inquiry focuses largely on understanding causal…

Children Do Show Negative Priming: Further Evidence for Early Development of an Intact Selective Control Mechanism

Science.gov (United States)

Frings, Christian; Feix, Silke; Rothig, Ulrike; Bruser, Charlotte; Junge, Miriam

2007-01-01

Reactions to stimuli that were shortly before presented as distractors are usually slowed down; this phenomenon is known as negative priming. Negative priming is an accepted index for tapping into selective control mechanisms. Although this effect is well established for adults, it has been claimed that children do not show negative priming.…

This Mechanistic Step Is ''Productive'': Organic Chemistry Students' Backward-Oriented Reasoning

Science.gov (United States)

Caspari, I.; Weinrich, M. L.; Sevian, H.; Graulich, N.

2018-01-01

If an organic chemistry student explains that she represents a mechanistic step because ''it's a productive part of the mechanism,'' what meaning could the professor teaching the class attribute to this statement, what is actually communicated, and what does it mean for the student? The professor might think that the explanation is based on…

Preparative and mechanistic studies toward the rational development of catalytic, enantioselective selenoetherification reactions.

Science.gov (United States)

Denmark, Scott E; Kalyani, Dipannita; Collins, William R

2010-11-10

A systematic investigation into the Lewis base catalyzed, asymmetric, intramolecular selenoetherification of olefins is described. A critical challenge for the development of this process was the identification and suppression of racemization pathways available to arylseleniranium ion intermediates. This report details a thorough study of the influences of the steric and electronic modulation of the arylselenenyl group on the configurational stability of enantioenriched seleniranium ions. These studies show that the 2-nitrophenyl group attached to the selenium atom significantly attenuates the racemization of seleniranium ions. A variety of achiral Lewis bases catalyze the intramolecular selenoetherification of alkenes using N-(2-nitrophenylselenenyl)succinimide as the electrophile along with a Brønsted acid. Preliminary mechanistic studies suggest the intermediacy of ionic Lewis base-selenium(II) adducts. Most importantly, a broad survey of chiral Lewis bases revealed that 1,1'-binaphthalene-2,2'-diamine (BINAM)-derived thiophosphoramides catalyze the cyclization of unsaturated alcohols in the presence of N-(2-nitrophenylselenenyl)succinimide and methanesulfonic acid. A variety of cyclic seleno ethers were produced in good chemical yields and in moderate to good enantioselectivities, which constitutes the first catalytic, enantioselective selenofunctionalization of unactivated olefins.

Mechanistic insight into oxide-promoted palladium catalysts for the electro-oxidation of ethanol.

Science.gov (United States)

Martinez, Ulises; Serov, Alexey; Padilla, Monica; Atanassov, Plamen

2014-08-01

Recent advancements in the development of alternatives to proton exchange membrane fuel cells utilizing less-expensive catalysts and renewable liquid fuels, such as alcohols, has been observed for alkaline fuel cell systems. Alcohol fuels present the advantage of not facing the challenge of storage and transportation encountered with hydrogen fuel. Oxidation of alcohols has been improved by the promotion of alloyed or secondary phases. Nevertheless, currently, there is no experimental understanding of the difference between an intrinsic and a synergistic promotion effect in high-pH environments. This report shows evidence of different types of promotion effects on palladium electrocatalysts obtained from the presence of an oxide phase for the oxidation of ethanol. The correlation of mechanistic in situ IR spectroscopic studies with electrochemical voltammetry studies on two similar electrocatalytic systems allow the role of either an alloyed or a secondary phase on the mechanism of oxidation of ethanol to be elucidated. Evidence is presented for the difference between an intrinsic effect obtained from an alloyed system and a synergistic effect produced by the presence of an oxide phase. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Fetal programming of CVD and renal disease: animal models and mechanistic considerations.

Science.gov (United States)

Langley-Evans, Simon C

2013-08-01

The developmental origins of health and disease hypothesis postulates that exposure to a less than optimal maternal environment during fetal development programmes physiological function, and determines risk of disease in adult life. Much evidence of such programming comes from retrospective epidemiological cohorts, which demonstrate associations between birth anthropometry and non-communicable diseases of adulthood. The assertion that variation in maternal nutrition drives these associations is supported by studies using animal models, which demonstrate that maternal under- or over-nutrition during pregnancy can programme offspring development. Typically, the offspring of animals that are undernourished in pregnancy exhibit a relatively narrow range of physiological phenotypes that includes higher blood pressure, glucose intolerance, renal insufficiency and increased adiposity. The observation that common phenotypes arise from very diverse maternal nutritional insults has led to the proposal that programming is driven by a small number of mechanistic processes. The remodelling of tissues during development as a consequence of maternal nutritional status being signalled by endocrine imbalance or key nutrients limiting processes in the fetus may lead to organs having irreversibly altered structures that may limit their function with ageing. It has been proposed that the maternal diet may impact upon epigenetic marks that determine gene expression in fetal tissues, and this may be an important mechanism connecting maternal nutrient intakes to long-term programming of offspring phenotype. The objective for this review is to provide an overview of the mechanistic basis of fetal programming, demonstrating the critical role of animal models as tools for the investigation of programming phenomena.

Modeling Bird Migration under Climate Change: A Mechanistic Approach

Science.gov (United States)

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

Controlling in situ crystallization of pharmaceutical particles within the spray dryer.

Science.gov (United States)

Woo, Meng Wai; Lee, May Ginn; Shakiba, Soroush; Mansouri, Shahnaz

2017-11-01

Simultaneous solidification and in situ crystallization (or partial crystallization) of droplets within the drying chamber are commonly encountered in the spray drying of pharmaceuticals. The crystallinity developed will determine the functionality of the powder and its stability during storage. This review discusses strategies that can be used to control the in situ crystallization process. Areas covered: The premise of the strategies discussed focuses on the manipulation of the droplet drying rate relative to the timescale of crystallization. This can be undertaken by the control of the spray drying operation, by the use of volatile materials and by the inclusion of additives. Several predictive approaches for in situ crystallization control and new spray dryer configuration strategies are further discussed. Expert opinion: Most reports, hitherto, have focused on the crystallinity of the spray dried material or the development of crystallinity during storage. More mechanistic understanding of the in situ crystallization process during spray drying is required to guide product formulation trials. The key challenge will be in adapting the mechanistic approach to the myriad possible formulations in the pharmaceutical industry.

Mechanistic and quantitative insight into cell surface targeted molecular imaging agent design.

Science.gov (United States)

Zhang, Liang; Bhatnagar, Sumit; Deschenes, Emily; Thurber, Greg M

2016-05-05

Molecular imaging agent design involves simultaneously optimizing multiple probe properties. While several desired characteristics are straightforward, including high affinity and low non-specific background signal, in practice there are quantitative trade-offs between these properties. These include plasma clearance, where fast clearance lowers background signal but can reduce target uptake, and binding, where high affinity compounds sometimes suffer from lower stability or increased non-specific interactions. Further complicating probe development, many of the optimal parameters vary depending on both target tissue and imaging agent properties, making empirical approaches or previous experience difficult to translate. Here, we focus on low molecular weight compounds targeting extracellular receptors, which have some of the highest contrast values for imaging agents. We use a mechanistic approach to provide a quantitative framework for weighing trade-offs between molecules. Our results show that specific target uptake is well-described by quantitative simulations for a variety of targeting agents, whereas non-specific background signal is more difficult to predict. Two in vitro experimental methods for estimating background signal in vivo are compared - non-specific cellular uptake and plasma protein binding. Together, these data provide a quantitative method to guide probe design and focus animal work for more cost-effective and time-efficient development of molecular imaging agents.

A mechanistic determination of horizontal flow regime bound using void wave celerity

Energy Technology Data Exchange (ETDEWEB)

Park, J.W. [Ajou Univ., Suwon (Korea, Republic of)

1995-09-01

The two-phase flow regime boundaries in a horizontal channel has been investigated by using the behavior of the second order void wave celerities. The average two-fluid model has been constituted with closure relations for horizontally stratified and bubbly flows. A vapor phase turbulent stress model for a smooth interface geometry has been included. It is found that the second order waves (i.e., eigenvalues) propagate in opposite direction with almost the same speed when the liquid phase is stationary. Using the well-posedness limit of the two-phase system, the dispersed-stratified flow regime boundary has been modeled. Two-phase Froude number has been theoretically found to be a convenient parameter in quantifying the flow regime boundary as a function of the void fraction. It is found that interaction between void wave celerities become stronger as the two-phase Froude number is reduced. This result should be interpreted as that gravity and the relative velocity are key parameters in determining flow regime boundaries in a horizontal flow. The influence of the vapor phase turbulent stress found to stabilize the flow stratification. This study clearly shows that the average two-fluid model is very effective for a mechanistic determination of horizontal flow regimes if appropriate closure relations are developed.

A mechanistic determination of horizontal flow regime bound using void wave celerity

International Nuclear Information System (INIS)

Park, J.W.

1995-01-01

The two-phase flow regime boundaries in a horizontal channel has been investigated by using the behavior of the second order void wave celerities. The average two-fluid model has been constituted with closure relations for horizontally stratified and bubbly flows. A vapor phase turbulent stress model for a smooth interface geometry has been included. It is found that the second order waves (i.e., eigenvalues) propagate in opposite direction with almost the same speed when the liquid phase is stationary. Using the well-posedness limit of the two-phase system, the dispersed-stratified flow regime boundary has been modeled. Two-phase Froude number has been theoretically found to be a convenient parameter in quantifying the flow regime boundary as a function of the void fraction. It is found that interaction between void wave celerities become stronger as the two-phase Froude number is reduced. This result should be interpreted as that gravity and the relative velocity are key parameters in determining flow regime boundaries in a horizontal flow. The influence of the vapor phase turbulent stress found to stabilize the flow stratification. This study clearly shows that the average two-fluid model is very effective for a mechanistic determination of horizontal flow regimes if appropriate closure relations are developed

Polyol Synthesis of Silver Nanowires by Heterogeneous Nucleation and Mechanistic Aspects Influencing its Length and Diameter

Science.gov (United States)

Schuette, Waynie Mark

Various additives are employed in the polyol synthesis of silver nanowires (Ag NWs), which are typically halide salts such as NaCl. A variety of mechanistic roles have been suggested for these additives. My research showed that the early addition of NaCl in the polyol synthesis of Ag NWs from AgNO3 in ethylene glycol results in the rapid formation of AgCl nanocubes, which induce the heterogeneous nucleation of metallic Ag upon their surfaces. Ag NWs subsequently grow from these nucleation sites. The conclusions are supported by studies using ex-situ generated AgCl nanocubes. Additionally, the final mean silver nanowire diameter is found to be independent of the size of the heterogeneous nucleant, showing that the diameter is not significantly influenced by the nucleation event. Kinetics studies determine that nanowire diameter, length, and aspect ratio grow in parallel to one another and with the extent of the Ag+ reduction reaction, demonstrating that growth is reduction-rate limited. The results are interpreted to support nanowire growth by a surface-catalyzed reduction process occurring on all nanowire surfaces, and to exclude nanoparticle aggregation or Ostwald ripening as primary components of the growth mechanism.

Mechanistic Understanding of Microbial Plugging for Improved Sweep Efficiency

Energy Technology Data Exchange (ETDEWEB)

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.

Mechanistic understanding of monosaccharide-air flow battery electrochemistry

Science.gov (United States)

Scott, Daniel M.; Tsang, Tsz Ho; Chetty, Leticia; Aloi, Sekotilani; Liaw, Bor Yann

Recently, an inexpensive monosaccharide-air flow battery configuration has been demonstrated to utilize a strong base and a mediator redox dye to harness electrical power from the partial oxidation of glucose. Here the mechanistic understanding of glucose oxidation in this unique glucose-air power source is further explored by acid-base titration experiments, 13C NMR, and comparison of results from chemically different redox mediators (indigo carmine vs. methyl viologen) and sugars (fructose vs. glucose) via studies using electrochemical techniques. Titration results indicate that gluconic acid is the main product of the cell reaction, as supported by evidence in the 13C NMR spectra. Using indigo carmine as the mediator dye and fructose as the energy source, an abiotic cell configuration generates a power density of 1.66 mW cm -2, which is greater than that produced from glucose under similar conditions (ca. 1.28 mW cm -2). A faster transition from fructose into the ene-diol intermediate than from glucose likely contributed to this difference in power density.

Predicting soil-to-plant transfer of radionuclides with a mechanistic model (BioRUR)

Energy Technology Data Exchange (ETDEWEB)

Casadesus, J. [Servei de Camps Experimentals, Universitat de Barcelona, Avda Diagonal 645, 08028 Barcelona (Spain); Sauras-Yera, T. [Departament de Biologia Vegetal, Facultat de Biologia, Universitat de Barcelona, Avda Diagonal 645, 08028 Barcelona (Spain)], E-mail: msauras@ub.edu; Vallejo, V.R. [Departament de Biologia Vegetal, Facultat de Biologia, Universitat de Barcelona, Avda Diagonal 645, 08028 Barcelona (Spain); Centro de Estudios Ambientales del Mediterraneo, Charles Darwin 14, Parc Tecnologic, 46980 Paterna, Valencia (Spain)

2008-05-15

BioRUR model has been developed for the simulation of radionuclide (RN) transfer through physical and biological compartments, based on the available information on the transfer of their nutrient analogues. The model assumes that radionuclides are transferred from soil to plant through the same pathways as their nutrient analogues, where K and Ca are the analogues of Cs and Sr, respectively. Basically, the transfer of radionuclide between two compartments is calculated as the transfer of nutrient multiplied by the ratio of concentrations of RN to nutrient, corrected by a selectivity coefficient. Hydroponic experiments showed the validity of this assumption for root uptake of Cs and Sr and reported a selectivity coefficient around 1.0 for both. However, the application of this approach to soil-to-plant transfer raises some questions on which are the effective concentrations of RN and nutrient detected by the plant uptake mechanism. This paper describes the evaluation of two configurations of BioRUR, one which simplifies the soil as an homogeneous pool, and the other which considers that some concentration gradients develop around roots and therefore ion concentrations at the root surface are different from those of the bulk soil. The results show a good fit between the observed Sr transfer and the mechanistic simulations, even when a homogeneous soil is considered. On the other hand, Cs transfer is overestimated by two orders of magnitude if the development of a decreasing K profile around roots is not taken into account.

Predicting soil-to-plant transfer of radionuclides with a mechanistic model (BioRUR)

International Nuclear Information System (INIS)

Casadesus, J.; Sauras-Yera, T.; Vallejo, V.R.

2008-01-01

BioRUR model has been developed for the simulation of radionuclide (RN) transfer through physical and biological compartments, based on the available information on the transfer of their nutrient analogues. The model assumes that radionuclides are transferred from soil to plant through the same pathways as their nutrient analogues, where K and Ca are the analogues of Cs and Sr, respectively. Basically, the transfer of radionuclide between two compartments is calculated as the transfer of nutrient multiplied by the ratio of concentrations of RN to nutrient, corrected by a selectivity coefficient. Hydroponic experiments showed the validity of this assumption for root uptake of Cs and Sr and reported a selectivity coefficient around 1.0 for both. However, the application of this approach to soil-to-plant transfer raises some questions on which are the effective concentrations of RN and nutrient detected by the plant uptake mechanism. This paper describes the evaluation of two configurations of BioRUR, one which simplifies the soil as an homogeneous pool, and the other which considers that some concentration gradients develop around roots and therefore ion concentrations at the root surface are different from those of the bulk soil. The results show a good fit between the observed Sr transfer and the mechanistic simulations, even when a homogeneous soil is considered. On the other hand, Cs transfer is overestimated by two orders of magnitude if the development of a decreasing K profile around roots is not taken into account

Mechanistic failure mode investigation and resolution of parvovirus retentive filters.

Science.gov (United States)

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

2016-07-08

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. © 2016 American Institute of Chemical Engineers.

On board catalytic NOx control: mechanistic aspects of the regeneration of Lean NOx Traps with H2

International Nuclear Information System (INIS)

Forzatti, Pio; Lietti, Luca; Nova, Isabella

2008-01-01

Mechanistic aspects of the reduction with H 2 of NO x stored on Lean NO x Trap catalysts are critically reviewed. It was shown that, under nearly isothermal conditions nitrogen formation occurs via an in series two-step process involving the participation of ammonia as an intermediate. The first step of this process is ammonia formation through the reaction of H 2 with stored nitrates; ammonia then reacts with the nitrates left on the catalysts surface leading to the formation of nitrogen. Over the investigated Ba-containing catalysts, the first step (i.e. NH 3 formation) is much faster than the second one which, therefore, is rate determining in the formation of nitrogen. Both steps are catalyzed by Pt and, under nearly isothermal conditions, do not involve the occurrence of a thermal decomposition step of the stored nitrates. Due to the fast reaction of the adsorbed nitrates with H 2 to give ammonia and to the integral behaviour of the trap, an H 2 front develops in the trap which travels along the reactor axis. Ammonia formed upon reaction of nitrates with H 2 reacts downstream of the H 2 front with nitrates leading to N 2 formation, if the temperature is high enough. This explains both the observed change in the selectivity of the process with time upon regeneration of the trap (with selectivity changing from N 2 to NH 3 ), and the increase in the N 2 selectivity with temperature as well. The identification of the pathway for the reduction of stored NO x , where ammonia is suggested as the intermediate product in the formation of nitrogen, may favour the improvement of the combined NSR + SCR technology that has been proposed by several car manufacturers to make NO x removal by NSR more effective and to simultaneously limit the ammonia slip (GB)

Quantum control of the photoinduced Wolff rearrangement of diazonaphthoquinone in the condensed phase

Energy Technology Data Exchange (ETDEWEB)

Wolpert, Daniel; Gerber, Gustav; Brixner, Tobias [Physikalisches Institut, Universitaet Wuerzburg, Am Hubland, 97074 Wuerzburg (Germany); Schade, Marco; Langhojer, Florian [Institut fuer Physikalische Chemie, Universitaet Wuerzburg, Am Hubland, 97074 Wuerzburg (Germany)], E-mail: brixner@phys-chemie.uni-wuerzburg.de

2008-04-14

A shaped UV pump-MIR probe setup is employed for quantum control of the photoinduced Wolff rearrangement reaction of diazonaphthoquinone (DNQ) dissolved in methanol, yielding a ketene photoproduct. Time-resolved vibrational spectroscopy is a well-suited tool to monitor a photoreaction in the liquid phase as the narrow vibrational lines allow the observation of structural changes. Especially in the mid-infrared region, marker modes originating from different photoproducts can be identified unambiguously providing suitable feedback signals for open-loop or closed-loop control schemes. We report an experiment where the initiation of a complicated structural change of a molecule, involving bond cleavage and rearrangement, in the liquid phase can be controlled and mechanistic insight is obtained. Single-parameter scans show that the molecule is sensitive to intrapulse dumping during the excitation. Adaptive optimizations lead to pulse structures which can be understood consistently with this dumping mechanism.

Comparative ecophysiology of two sympatric lizards. Laying the groundwork for mechanistic distribution models

Directory of Open Access Journals (Sweden)

Enrique García-Muñoz

2013-12-01

Full Text Available Distribution modelling usually makes inferences correlating species presence and environmental variables but does not take biotic relations into account. Alternative approaches based on a mechanistic understanding of biological processes are now being applied. Regarding lacertid lizards, physiological traits such as preferred body temperature (Tp are well known to correlate with several physiological optima. Much less is known about their water ecology although body temperature and evaporative water loss (Wl may trade-off. Two saxicolous lacertids, Algyroides marchi and Podarcis hispanica ss are sympatric in the Subbetic Mountains (SE Spain were they can be found in syntopy. Previous distribution modelling indicates the first species is associated with mountains, low temperatures; high precipitation and forest cover whereas the second one is more generalistic. Here, we perform two ecophysiological tests with both species: a Tp experiment in thermal gradient and a Wl experiment in sealed chambers. Although both species attained similar body temperatures, A. marchi lost more water and more uniformly in time than P. hispanica ss that displayed an apparent response to dehydration. These results suggest that water loss rather temperature is crucial to explain the distribution patterns of A. marchi in relation to P. hispanica ss, the former risking dehydration in dry areas no matter what temperature is. Ecophysiological traits represent a promising tool to build future mechanistic models for (lacertid lizards. Additionally, the implications for their biogeography and conservation are discussed.

Time Course of Brain Network Reconfiguration Supporting Inhibitory Control.

Science.gov (United States)

Popov, Tzvetan; Westner, Britta U; Silton, Rebecca L; Sass, Sarah M; Spielberg, Jeffrey M; Rockstroh, Brigitte; Heller, Wendy; Miller, Gregory A

2018-05-02

Hemodynamic research has recently clarified key nodes and links in brain networks implementing inhibitory control. Although fMRI methods are optimized for identifying the structure of brain networks, the relatively slow temporal course of fMRI limits the ability to characterize network operation. The latter is crucial for developing a mechanistic understanding of how brain networks shift dynamically to support inhibitory control. To address this critical gap, we applied spectrally resolved Granger causality (GC) and random forest machine learning tools to human EEG data in two large samples of adults (test sample n = 96, replication sample n = 237, total N = 333, both sexes) who performed a color-word Stroop task. Time-frequency analysis confirmed that recruitment of inhibitory control accompanied by slower behavioral responses was related to changes in theta and alpha/beta power. GC analyses revealed directionally asymmetric exchanges within frontal and between frontal and parietal brain areas: top-down influence of superior frontal gyrus (SFG) over both dorsal ACC (dACC) and inferior frontal gyrus (IFG), dACC control over middle frontal gyrus (MFG), and frontal-parietal exchanges (IFG, precuneus, MFG). Predictive analytics confirmed a combination of behavioral and brain-derived variables as the best set of predictors of inhibitory control demands, with SFG theta bearing higher classification importance than dACC theta and posterior beta tracking the onset of behavioral response. The present results provide mechanistic insight into the biological implementation of a psychological phenomenon: inhibitory control is implemented by dynamic routing processes during which the target response is upregulated via theta-mediated effective connectivity within key PFC nodes and via beta-mediated motor preparation. SIGNIFICANCE STATEMENT Hemodynamic neuroimaging research has recently clarified regional structures in brain networks supporting inhibitory control. However, due to

Iterative Systems Biology for Medicine – time for advancing from network signature to mechanistic equations

KAUST Repository

Gomez-Cabrero, David

2017-05-09

The rise and growth of Systems Biology following the sequencing of the human genome has been astounding. Early on, an iterative wet-dry methodology was formulated which turned out as a successful approach in deciphering biological complexity. Such type of analysis effectively identified and associated molecular network signatures operative in biological processes across different systems. Yet, it has proven difficult to distinguish between causes and consequences, thus making it challenging to attack medical questions where we require precise causative drug targets and disease mechanisms beyond a web of associated markers. Here we review principal advances with regard to identification of structure, dynamics, control, and design of biological systems, following the structure in the visionary review from 2002 by Dr. Kitano. Yet, here we find that the underlying challenge of finding the governing mechanistic system equations enabling precision medicine remains open thus rendering clinical translation of systems biology arduous. However, stunning advances in raw computational power, generation of high-precision multi-faceted biological data, combined with powerful algorithms hold promise to set the stage for data-driven identification of equations implicating a fundamental understanding of living systems during health and disease.

Phenomenological and mechanistic modeling of melt-structure-water interactions in a light water reactor severe accident

International Nuclear Information System (INIS)

Bui, V.A.

1998-01-01

The objective of this work is to address the modeling of the thermal hydrodynamic phenomena and interactions occurring during the progression of reactor severe accidents. Integrated phenomenological models are developed to describe the accident scenarios, which consist of many processes, while mechanistic modeling, including direct numerical simulation, is carried out to describe separate effects and selected physical phenomena of particular importance

Applicability of one-dimensional mechanistic post-dryout prediction model

International Nuclear Information System (INIS)

Jeong, Hae Yong; No Hee Cheon

1996-01-01

Through the analysis of many experimental post-dryout data, it is shown that the most probable flow regime near dryout or quench front is not annular flow but churn-turbulent flow when the mass flux is low. A correlation describing the initial droplet size just after the CHF position at low mass flux is low. A correlation describing the initial droplet size just after the CHF position at low mass flux is suggested through regression analysis. In the post-dryout region at low pressure and low flow, it is found that the suggested one-dimensional mechanistic model is not applicable when the vapor superficial velocity is very low, i. e., when the flow is bubbly or slug flow regime. This is explained by the change of main entrainment mechanism with the change of flow regime. Therefore, the suggested correlation is valid only in the churn-turbulent flow regime (j * g = 0.5 ∼ 4.5)

Utilizing Mechanistic Cross-Linking Technology to Study Protein-Protein Interactions: An Experiment Designed for an Undergraduate Biochemistry Lab

Science.gov (United States)

Finzel, Kara; Beld, Joris; Burkart, Michael D.; Charkoudian, Louise K.

2017-01-01

Over the past decade, mechanistic cross-linking probes have been used to study protein-protein interactions in natural product biosynthetic pathways. This approach is highly interdisciplinary, combining elements of protein biochemistry, organic chemistry, and computational docking. Herein, we described the development of an experiment to engage…

Kinetics and Mechanistic Chemistry of Oxidation of Butacaine Sulfate by Chloramine-B in Acid Medium

International Nuclear Information System (INIS)

Shubha, Jayachamarajapura Pranesh; Kotabagi, Vinutha; Puttaswamy

2012-01-01

Butacaine sulfate is an ester of p-aminobenzoic acid which has been widely used as a local anaesthetic and it is a long standing agent particularly for spinal anaesthesia. For this reason, a kinetic study of oxidation of butacaine sulfate by sodium N-chlorobenzenesulfonamide (chloramine-B or CAB) has been carried out in HClO 4 medium at 303 K in order to explore this redox system mechanistic chemistry. The rate shows a first-order dependence on both [CAB] o , and [substrate] o , and a fractional-order dependence on acid concentration. Decrease of dielectric constant of the medium, by adding methanol, increases the rate of the reaction. Variation of ionic strength and addition of benzenesulfonamide or NaCl have no significant effect on the rate. The reaction was studied at different temperatures and the activation parameters have been evaluated. The stoichiometry of the reaction has been found to be 1:2 and the oxidation products have been identified by spectral analysis. The observed results have been explained by plausible mechanism and the related rate law has been deduced

SENSITIVITY ANALYSIS IN FLEXIBLE PAVEMENT PERFORMANCE USING MECHANISTIC EMPIRICAL METHOD (CASE STUDY: CIREBON–LOSARI ROAD SEGMENT, WEST JAVA

Directory of Open Access Journals (Sweden)

E. Samad

2012-02-01

Full Text Available Cirebon – Losari flexible pavement which is located on the North Coast of Java, Indonesia, is in the severe damage condition caused by overloading vehicles passing the road. The need for developing improved pavement design and analysis methods is very necessary. The increment of loads and quality of material properties can be evaluated through Mechanistic-Empirical (M-E method. M-E software like KENLAYER has been developed to facilitate the transition from empirical to mechanistic design methods. From the KENLAYER analysis, it can be concluded that the effect of overloading to the pavement structure performance is difficult to minimize even though the first two layers have relatively high modulus of elasticity. The occurrence of 150%, 200%, and 250% overloading have a very significant effect in reducing 84%, 95%, and 98% of the pavement design life, respectively. For the purpose of increasing the pavement service life, it is more effective to manage the allowable load.

Mechanistic approach for the kinetics of the decomposition of nitrous oxide over calcined hydrotalcites

Energy Technology Data Exchange (ETDEWEB)

Dandl, H.; Emig, G. [Lehrstuhl fuer Technische Chemie I, Erlangen (Germany)

1998-03-27

A highly active catalyst for the decomposition of N{sub 2}O was prepared by the thermal treatment of CoLaAl-hydrotalcite. For this catalyst the reaction rate was determined at various partial pressures of N{sub 2}O, O{sub 2} and H{sub 2}O in a temperature range from 573K to 823K. The kinetic simulation resulted in a mechanistic model. The energies of activation and rate coefficients are estimated for the main steps of the reaction

Mechanistic and kinetic insights into the thermally induced rearrangement of alpha-pinene.

Science.gov (United States)

Stolle, Achim; Ondruschka, Bernd; Findeisen, Matthias

2008-11-07

The thermal rearrangement of alpha-pinene (1) is interesting from mechanistic as well as kinetic point of view. Carrier gas pyrolyses with 1 and its acyclic isomers ocimene (2) and alloocimene (3) were performed to investigate the thermal network of these hydrocarbons. Kinetic analysis of the major reaction steps allows for a deeper insight in the reaction mechanism. Thus it was possible to explain the racemization of 1, the formation of racemic limonene (4), and the absence of the primary pyrolysis product 2 in the reaction mixture resulting from thermal rearrangement of 1. Results supported the conclusion that the reactions starting with 1 involve biradical transition states.

Use of mechanistic simulations as a quantitative risk-ranking tool within the quality by design framework.

Science.gov (United States)

Stocker, Elena; Toschkoff, Gregor; Sacher, Stephan; Khinast, Johannes G

2014-11-20

The purpose of this study is to evaluate the use of computer simulations for generating quantitative knowledge as a basis for risk ranking and mechanistic process understanding, as required by ICH Q9 on quality risk management systems. In this specific publication, the main focus is the demonstration of a risk assessment workflow, including a computer simulation for the generation of mechanistic understanding of active tablet coating in a pan coater. Process parameter screening studies are statistically planned under consideration of impacts on a potentially critical quality attribute, i.e., coating mass uniformity. Based on computer simulation data the process failure mode and effects analysis of the risk factors is performed. This results in a quantitative criticality assessment of process parameters and the risk priority evaluation of failure modes. The factor for a quantitative reassessment of the criticality and risk priority is the coefficient of variation, which represents the coating mass uniformity. The major conclusion drawn from this work is a successful demonstration of the integration of computer simulation in the risk management workflow leading to an objective and quantitative risk assessment. Copyright © 2014. Published by Elsevier B.V.

A mechanistic ecohydrological model to investigate complex interactions in cold and warm water-controlled environments. 2. Spatiotemporal analyses

Directory of Open Access Journals (Sweden)

Simone Fatichi

2012-05-01

Full Text Available An ecohydrological model Tethys-Chloris (T&C described in the companion paper is applied to two semiarid systems characterized by different climate and vegetation cover conditions. The Lucky Hills watershed in Arizona represents a typical small, ``unit-source'' catchment of a desert shrub system of the U.S. southwest. Two nested basins of the Reynolds Creek Experimental watershed (Idaho, U.S.A., the Reynolds Creek Mountain East and Tollgate catchments, are representative of a semiarid cold climate with seasonal snow cover. Both exhibit a highly non-uniform vegetation cover. A range of ecohydrological metrics of the long-term model performance is presented to highlight the model capabilities in reproducing hydrological and vegetation dynamics both at the plot and the watershed scales. A diverse set of observations is used to confirm the simulated dynamics. Highly satisfactory results are obtained without significant (or any calibration efforts despite the large phase-space dimensionality of the model, the uncertainty of imposed boundary conditions, and limited data availability. It is argued that a significant investment into the model design based on the description of physical, biophysical, and ecological processes leads to such a consistent simulation skill. The simulated patterns mimic the outcome of hydrological and vegetation dynamics with high realism, as confirmed from spatially distributed remote sensing data. Further community efforts are warranted to address the issue of thorough quantitative assessment. The current lack of appropriate data hampers the development and testing of process-based ecohydrological models. It is further argued that the mechanistic nature of the T&C model can be valuable for designing virtual experiments and developing questions of scientific inquiry at a range of spatiotemporal scales.

Flow regimes and mechanistic modeling of critical heat flux under subcooled flow boiling conditions

Science.gov (United States)

Le Corre, Jean-Marie

Thermal performance of heat flux controlled boiling heat exchangers are usually limited by the Critical Heat Flux (CHF) above which the heat transfer degrades quickly, possibly leading to heater overheating and destruction. In an effort to better understand the phenomena, a literature review of CHF experimental visualizations under subcooled flow boiling conditions was performed and systematically analyzed. Three major types of CHF flow regimes were identified (bubbly, vapor clot and slug flow regime) and a CHF flow regime map was developed, based on a dimensional analysis of the phenomena and available data. It was found that for similar geometric characteristics and pressure, a Weber number (We)/thermodynamic quality (x) map can be used to predict the CHF flow regime. Based on the experimental observations and the review of the available CHF mechanistic models under subcooled flow boiling conditions, hypothetical CHF mechanisms were selected for each CHF flow regime, all based on a concept of wall dry spot overheating, rewetting prevention and subsequent dry spot spreading. It is postulated that a high local wall superheat occurs locally in a dry area of the heated wall, due to a cyclical event inherent to the considered CHF two-phase flow regime, preventing rewetting (Leidenfrost effect). The selected modeling concept has the potential to span the CHF conditions from highly subcooled bubbly flow to early stage of annular flow. A numerical model using a two-dimensional transient thermal analysis of the heater undergoing nucleation was developed to mechanistically predict CHF in the case of a bubbly flow regime. In this type of CHF two-phase flow regime, the high local wall superheat occurs underneath a nucleating bubble at the time of bubble departure. The model simulates the spatial and temporal heater temperature variations during nucleation at the wall, accounting for the stochastic nature of the boiling phenomena. The model has also the potential to evaluate

In Vitro–In Vivo Correlation for Gliclazide Immediate-Release Tablets Based on Mechanistic Absorption Simulation

OpenAIRE

Grbic, Sandra; Parojcic, Jelena; Ibric, Svetlana; Djuric, Zorica

2010-01-01

The aim of this study was to develop a drug-specific absorption model for gliclazide (GLK) using mechanistic gastrointestinal simulation technology (GIST) implemented in GastroPlusTM software package. A range of experimentally determined, in silico predicted or literature data were used as input parameters. Experimentally determined pH-solubility profile was used for all simulations. The human jejunum effective permeability (Peff) value was estimated on the basis of in vitro measured Caco-2 p...

Mechanistic Basis for Regioselection and Regiodivergence in Nickel-Catalyzed Reductive Couplings

Science.gov (United States)

Jackson, Evan P.; Malik, Hasnain A.; Sormunen, Grant J.; Baxter, Ryan D.; Liu, Peng; Wang, Hengbin; Shareef, Abdur-Rafay; Montgomery, John

2015-01-01

CONSPECTUS The control of regiochemistry is a considerable challenge in the development of a wide array of catalytic processes. Simple π-components such as alkenes, alkynes, 1,3-dienes, and allenes are among the many classes of substrates that present complexities in regioselective catalysis. Considering an internal alkyne as a representative example, when steric and electronic differences between the two substituents are minimal, differentiating among the two termini of the alkyne presents a great challenge. In cases where the differences between the alkyne substituents are substantial, overcoming those biases to access the regioisomer opposite that favored by substrate biases often presents an even greater challenge. Nickel-catalyzed reductive couplings of unsymmetrical π-components make up a group of reactions where control of regiochemistry presents a challenging but important objective. In the course of our studies of aldehyde-alkyne reductive couplings, complementary solutions to challenges in regiocontrol have been developed. Through careful selection of the ligand and reductant, as well as the more subtle reaction variables such as temperature and concentration, effective protocols have been established that allow highly selective access to either regiosiomer of the the allylic alcohol products using a wide range of unsymmetrical alkynes. Computational studies and an evaluation of reaction kinetics have provided an understanding of the origin of the regioselectivity control. Throughout the various procedures described, the development of ligand-substrate interactions play a key role, and the overall kinetic descriptions were found to differ between protocols. Rational alteration of the rate-determining step plays a key role in the regiochemistry reversal strategy, and in one instance, the two possible regioisomeric outcomes in a single reaction were found to operate by different kinetic descriptions. With this mechanistic information in hand, the

Mechanistic investigation on microbial toxicity of nano hydroxyapatite on implant associated pathogens

Energy Technology Data Exchange (ETDEWEB)

Baskar, K. [Department of Biotechnology, University of Madras, Guindy Campus, Chennai, Tamil Nadu (India); Anusuya, T. [Department of Nanotechnology, SRM University, Kattankulathur, Tamil Nadu (India); Devanand Venkatasubbu, G., E-mail: gdevanandvenkatasubbu@gmail.com [Department of Nanotechnology, SRM University, Kattankulathur, Tamil Nadu (India)

2017-04-01

The use of atomic scale inorganic nanoparticles (NPs) to fight against pathogenic microorganisms is a recent trend in biomedical area which overcomes the limitations of organic compounds in terms of stability, shelf life and bioactivity. One such Calcium phosphate based biomaterial is hydroxyapatite (HA), considered as potential bioactive compound with excellent biocompatibility, osteointegrity and biodegradability. Osteomyelitis, the implant associated infection, is the major problem worldwide responsible for the majority of implant failure cases. Since HA is used as a coating material of implants, only few reports were available on its antimicrobial activity and cytotoxicity whereas no reports on its possible antimicrobial mechanism. In this present study, the HA-NPs were synthesized by wet chemical precipitation and were characterized using X-ray diffraction (XRD), Transmission Electron Microscopy (TEM) and Fourier transform infrared spectroscopy (FTIR). The synthesized HA-NPs were evaluated for antimicrobial activity against implant associated bacterial pathogens. The study also explores the mechanistic action of HA-NPs in killing of bacteria by determining the reactive oxygen species (ROS) generation, DNA fragmentation, Lactate dehydrogenase (LDH) leakage and cellular interaction. In addition the cytotoxicity of HA-NPs was determined by MTT assay and Fluorescence Microscopic analysis. The results revealed that, the synthesized HA-NPs showed good antibacterial activity for tested bacterial species and the possible antibacterial mechanism were due to the lack of membrane integrity and cytotoxic studies shows the concentration dependent changes in cell viability. - Highlights: • Antibacterial activity against Gram − ve bacterium • Mechanism of antibacterial activity is analyzed. • DNA fragmentation, growth curve, LDH, ROS are analyzed. • The mechanism is by damaging cell membrane. • Hydroxyapatite is biocompatible.

The kinetic and mechanistic aspects of the oxidative dehydrogenation of ethane over Li/Na/MgO catalysts

NARCIS (Netherlands)

Swaan, H.M.; Swaan, H.M.; Toebes, A.; Toebes, A.; van Ommen, J.G.; Seshan, Kulathuiyer; Ross, J.R.H.; Ross, J.R.H.

1992-01-01

Kinetic and mechanistic aspects of the oxidative dehydrogenation of ethane catalysed by Li/MgO and Li/Na/MgO have been investigated. Initial rate measurements at 600°C; revealed that the Li/MgO catalyst produced C2H4, CO2, CO and H2 by parallel reactions whereas the sodium-promoted catalyst produced

Phenomenological and mechanistic modeling of melt-structure-water interactions in a light water reactor severe accident

Energy Technology Data Exchange (ETDEWEB)

Bui, V.A

1998-10-01

The objective of this work is to address the modeling of the thermal hydrodynamic phenomena and interactions occurring during the progression of reactor severe accidents. Integrated phenomenological models are developed to describe the accident scenarios, which consist of many processes, while mechanistic modeling, including direct numerical simulation, is carried out to describe separate effects and selected physical phenomena of particular importance 88 refs, 54 figs, 7 tabs

A simple coculture system shows mutualism between anaerobic faecalibacteria and epithelial Caco-2 cells

NARCIS (Netherlands)

Sadaghian, Mehdi; von Martels, Julius Z. H.; Khan, Muhammad; Blokzijl, Tjasso; Paglia, Giuseppe; Dijkstra, Gerard; Harmsen, Hermie J. M.; Faber, Klaas Nico

2015-01-01

Most gut bacteria are obligate anaerobes and are important for human health. However, little mechanistic insight is available on the health benefits of specific anaerobic gut bacteria. A main obstacle in generating such knowledge is the lack of simple and robust coculturing methods for anaerobic

Mechanistic studies of thioxanthone–carbazole as a one-component type II photoinitiator

Energy Technology Data Exchange (ETDEWEB)

Karaca, Nurcan; Karaca Balta, Demet; Ocal, Nuket; Arsu, Nergis, E-mail: nergisarsu@gmail.com

2014-02-15

A mechanistic study concerning photoinitiated free radical polymerization using Thioxanthone–Carbazole (TX–Cz) as a one-component Type II photoinitiator was performed. TX–Cz presented visible initiator characteristics with absorptions at 434 and 414 nm where the molar absorption coefficients were 2014 and 1754 L mol{sup −1} cm{sup −1}, respectively. Fluorescence and phosphorescence spectroscopy, as well as laser flash photolysis was employed to study the photophysical properties of TX–Cz. In addition, photopolymerization of methyl methacrylate (MMA) showed that TX–Cz is efficient photoinitiator. To explain the initiation mechanism of TX–Cz, fluorescence and phosphorescence emission spectra of poly (methyl methacrylate) (PMMA) were also taken to see whether the initiator covalently bonded to the polymer. The postulated mechanism is based on inter- molecular reaction of the triplet, {sup 3}(TX–Cz){sup ⁎} with the carbazole moiety at ground state, TX–Cz. The photoinitiation efficiency of TX–Cz during gelation of multifunctional acrylates was also investigated by Photo-Differential Scanning Calorimetry (Photo-DSC) technique and high polymerization rates were obtained. -- Highlights: • Thioxanthone–Carbazole was used as visible light photoinitiator for radical polymerization of meth(acrylates). • The detailed photophysical properties of TX–Cz was reported. • Fluorescence quantum yield, phosphorescence lifetime , triplet energy and triplet lifetime were determined. • Photo-DSC was used to follow photopolymerizatin kinetics of acrylates.

Mutual Dependence Between Sedimentary Organic Carbon and Infaunal Macrobenthos Resolved by Mechanistic Modeling

Science.gov (United States)

Zhang, Wenyan; Wirtz, Kai

2017-10-01

The mutual dependence between sedimentary total organic carbon (TOC) and infaunal macrobenthos is here quantified by a mechanistic model. The model describes (i) the vertical distribution of infaunal macrobenthic biomass resulting from a trade-off between nutritional benefit (quantity and quality of TOC) and the costs of burial (respiration) and mortality, and (ii) the variable vertical distribution of TOC being in turn shaped by bioturbation of local macrobenthos. In contrast to conventional approaches, our model emphasizes variations of bioturbation both spatially and temporally depending on local food resources and macrobenthic biomass. Our implementation of the dynamic interaction between TOC and infaunal macrobenthos is able to capture a temporal benthic response to both depositional and erosional environments and provides improved estimates of the material exchange flux at the sediment-water interface. Applications to literature data for the North Sea demonstrate the robustness and accuracy of the model and its potential as an analysis tool for the status of TOC and macrobenthos in marine sediments. Results indicate that the vertical distribution of infaunal biomass is shaped by both the quantity and the quality of OC, while the community structure is determined only by the quality of OC. Bioturbation intensity may differ by 1 order of magnitude over different seasons owing to variations in the OC input, resulting in a significant modulation on the distribution of OC. Our relatively simple implementation may further improve models of early diagenesis and marine food web dynamics by mechanistically connecting the vertical distribution of both TOC and macrobenthic biomass.

Exploring the pros and cons of mechanistic case diagrams for problem-based learning

Directory of Open Access Journals (Sweden)

Minjeong Kim

2017-09-01

Full Text Available Purpose Mechanistic case diagram (MCD was recommended for increasing the depth of understanding of disease, but with few articles on its specific methods. We address the experience of making MCD in the fullest depth to identify the pros and cons of using MCDs in such ways. Methods During problem-based learning, we gave guidelines of MCD for its mechanistic exploration from subcellular processes to clinical features, being laid out in as much detail as possible. To understand the students’ attitudes and depth of study using MCDs, we analyzed the results of a questionnaire in an open format about experiencing MCDs and examined the resulting products. Results Through the responses to questionnaire, we found several favorable outcomes, major of which was deeper insight and comprehensive understanding of disease facilitated by the process of making well-organized diagram. The main disadvantages of these guidelines were the feeling of too much workload and difficulty of finding mechanisms. Students gave suggestions to overcome these problems: cautious reading of comprehensive texts, additional guidance from staff about depth and focus of mechanisms, and cooperative group work. From the analysis of maps, we recognized there should be allowance of diversities in the appearance of maps and many hypothetical connections, which could be related to an insufficient understanding of mechanisms in nature. Conclusion The more detailed an MCD task is, the better students can become acquainted with deep knowledges. However, this advantage should be balanced by the results that there are many ensuing difficulties for the work and deliberate help plans should be prepared.

Validation of mechanistic models for gas precipitation in solids during postirradiation annealing experiments

Science.gov (United States)

Rest, J.

1989-12-01

A number of different phenomenological models for gas precipitation in solids during postirradiation annealing experiments have been proposed. Validation of such mechanistic models for gas release and swelling is complicated by the use of data containing large systematic errors, and phenomena characterized by synergistic effects as well as uncertainties in materials properties. Statistical regression analysis is recommended for the selection of a reasonably well characterized data base for gas release from irradiated fuel under transient heating conditions. It is demonstrated that an appropriate data selection method is required in order to realistically examine the impact of differing descriptions of the phenomena, and uncertainties in selected materials properties, on the validation results. The results of the analysis show that the kinetics of gas precipitation in solids depend on bubble overpressurization effects and need to be accounted for during the heatup phase of isothermal heating experiments. It is shown that if only the total gas release values (as opposed to time-dependent data) were available, differentiation between different gas precipitation models would be ambiguous. The observed sustained increase in the fractional release curve at relatively high temperatures after the total precipitation of intragranular gas in fission gas bubbles is ascribed to the effects of a grain-growth/grain-boundary sweeping mechanism.

Validation of mechanistic models for gas precipitation in solids during postirradiation annealing experiments

International Nuclear Information System (INIS)

Rest, J.

1989-01-01

A number of different phenomenological models for gas precipitation in solids during postirradiation annealing experiments have been proposed. Validation of such mechanistic models for gas release and swelling is complicated by the use of data containing large systematic errors, and phenomena characterized by synergistic effects as well as uncertainties in materials properties. Statistical regression analysis is recommended for the selection of a reasonably well characterized data base for gas release from irradiated fuel under transient heating conditions. It is demonstrated that an appropriate data selection method is required in order to realistically examine the impact of differing descriptions of the phenomena, and uncertainties in selected materials properties, on the validation results. The results of the analysis show that the kinetics of gas precipitation in solid depend on bubble overpressurization effects and need to be accounted for during the heatup phase of isothermal heating experiments. It is shown that if only the total gas release values (as opposed to time-dependent data) were available, differentiation between different gas precipitation models would be ambiguous. The observed sustained increase in the fractional release curve at relatively high temperatures after the total precipitation of intragranular gas in fission gas bubbles is ascribed to the effects of a grain-growth/grain-boundary sweeping mechanism. (orig.)

Testing the molecular clock using mechanistic models of fossil preservation and molecular evolution.

Science.gov (United States)

Warnock, Rachel C M; Yang, Ziheng; Donoghue, Philip C J

2017-06-28

Molecular sequence data provide information about relative times only, and fossil-based age constraints are the ultimate source of information about absolute times in molecular clock dating analyses. Thus, fossil calibrations are critical to molecular clock dating, but competing methods are difficult to evaluate empirically because the true evolutionary time scale is never known. Here, we combine mechanistic models of fossil preservation and sequence evolution in simulations to evaluate different approaches to constructing fossil calibrations and their impact on Bayesian molecular clock dating, and the relative impact of fossil versus molecular sampling. We show that divergence time estimation is impacted by the model of fossil preservation, sampling intensity and tree shape. The addition of sequence data may improve molecular clock estimates, but accuracy and precision is dominated by the quality of the fossil calibrations. Posterior means and medians are poor representatives of true divergence times; posterior intervals provide a much more accurate estimate of divergence times, though they may be wide and often do not have high coverage probability. Our results highlight the importance of increased fossil sampling and improved statistical approaches to generating calibrations, which should incorporate the non-uniform nature of ecological and temporal fossil species distributions. © 2017 The Authors.

Mechanistic insights of intestinal absorption and renal conservation of folate in chronic alcoholism.

Science.gov (United States)

Wani, Nissar Ahmad; Thakur, Shilpa; Najar, Rauf Ahmad; Nada, Ritambhara; Khanduja, Krishan Lal; Kaur, Jyotdeep

2013-03-01

Folate mediated one-carbon metabolism is of fundamental importance for various cellular processes, including DNA synthesis and methylation of biological molecules. Due to the exogenous requirement of folate in mammals, there exists a well developed epithelial folate transport system for regulation of normal folate homeostasis. The intestinal and renal folate uptake is tightly and diversely regulated and disturbances in folate homeostasis like in alcoholism have pathological consequences. The study was sought to delineate the regulatory mechanism of folate uptake in intestine and reabsorption in renal tubular cells that could evaluate insights of malabsorption during alcoholism. The folate transporters PCFT and RFC were found to be associated with lipid rafts of membrane surfaces in intestine and kidney. Importantly, the observed lower intestinal and renal folate uptake was associated with decreased levels of folate transporter viz. PCFT and RFC in lipid rafts of intestinal and renal membrane surfaces. The decreased association of folate transporters in lipid rafts was associated with decreased protein and mRNA levels. In addition, immunohistochemical studies showed that alcoholic conditions deranged that localization of PCFT and RFC. These findings could explain the possible mechanistic insights that may result in folate malabsorption during alcoholism. Copyright © 2013 Elsevier Inc. All rights reserved.

APPswe/PS1dE9 mice with cortical amyloid pathology show a reduced NAA/Cr ratio without apparent brain atrophy: A MRS and MRI study.

Science.gov (United States)

Kuhla, Angela; Rühlmann, Claire; Lindner, Tobias; Polei, Stefan; Hadlich, Stefan; Krause, Bernd J; Vollmar, Brigitte; Teipel, Stefan J

2017-01-01

Transgenic animal models of Aβ pathology provide mechanistic insight into some aspects of Alzheimer disease (AD) pathology related to Aβ accumulation. Quantitative neuroimaging is a possible aid to improve translation of mechanistic findings in transgenic models to human end phenotypes of brain morphology or function. Therefore, we combined MRI-based morphometry, MRS-based NAA-assessment and quantitative histology of neurons and amyloid plaque load in the APPswe/PS1dE9 mouse model to determine the interrelationship between morphological changes, changes in neuron numbers and amyloid plaque load with reductions of NAA levels as marker of neuronal functional viability. The APPswe/PS1dE9 mouse showed an increase of Aβ plaques, loss of neurons and an impairment of NAA/Cr ratio, which however was not accompanied with brain atrophy. As brain atrophy is one main characteristic in human AD, conclusions from murine to human AD pathology should be drawn with caution.

Confinement effects and mechanistic aspects for montmorillonite nanopores.

Science.gov (United States)

Li, Xiong; Zhu, Chang; Jia, Zengqiang; Yang, Gang

2018-08-01

Owing to the ubiquity, critical importance and special properties, confined microenvironments have recently triggered overwhelming interest. In this work, all-atom molecular dynamics simulations have been conducted to address the confinement effects and ion-specific effects for electrolyte solutions within montmorillonite nanopores, where the pore widths vary with a wide range. The adsorption number, structure, dynamics and stability of inner- and outer-sphere metal ions are affected by the change of pore widths (confinement effects), while the extents are significantly dependent on the type of adsorbed species. The type of adsorbed species is, however, not altered by the magnitude of confinement effects, and confinement effects are similar for different electrolyte concentrations. Ion-specific effects are pronounced for all magnitudes of confinement effects (from non- to strong confined conditions), and Hofmeister sequences of outer-sphere species are closely associated with the magnitude of confinement effects while those of inner-sphere species remain consistent. In addition, mechanistic aspects of confinement have been posed using the electrical double layer theories, and the results can be generalized to other confined systems that are ubiquitous in biology, chemistry, geology and nanotechnology. Copyright © 2018 Elsevier Inc. All rights reserved.

Reward value-based gain control: divisive normalization in parietal cortex.

Science.gov (United States)

Louie, Kenway; Grattan, Lauren E; Glimcher, Paul W

2011-07-20

The representation of value is a critical component of decision making. Rational choice theory assumes that options are assigned absolute values, independent of the value or existence of other alternatives. However, context-dependent choice behavior in both animals and humans violates this assumption, suggesting that biological decision processes rely on comparative evaluation. Here we show that neurons in the monkey lateral intraparietal cortex encode a relative form of saccadic value, explicitly dependent on the values of the other available alternatives. Analogous to extra-classical receptive field effects in visual cortex, this relative representation incorporates target values outside the response field and is observed in both stimulus-driven activity and baseline firing rates. This context-dependent modulation is precisely described by divisive normalization, indicating that this standard form of sensory gain control may be a general mechanism of cortical computation. Such normalization in decision circuits effectively implements an adaptive gain control for value coding and provides a possible mechanistic basis for behavioral context-dependent violations of rationality.

Cognitive control, cognitive reserve, and memory in the aging bilingual brain

OpenAIRE

Grant, Angela; Dennis, Nancy A.; Li, Ping

2014-01-01

In recent years bilingualism has been linked to both advantages in executive control and positive impacts on aging. Such positive cognitive effects of bilingualism have been attributed to the increased need for language control during bilingual processing and increased cognitive reserve, respectively. However, a mechanistic explanation of how bilingual experience contributes to cognitive reserve is still lacking. The current paper proposes a new focus on bilingual memory as an avenue to explo...

A novel model-based control strategy for aerobic filamentous fungal fed-batch fermentation processes.

Science.gov (United States)

Mears, Lisa; Stocks, Stuart M; Albaek, Mads O; Cassells, Benny; Sin, Gürkan; Gernaey, Krist V

2017-07-01

A novel model-based control strategy has been developed for filamentous fungal fed-batch fermentation processes. The system of interest is a pilot scale (550 L) filamentous fungus process operating at Novozymes A/S. In such processes, it is desirable to maximize the total product achieved in a batch in a defined process time. In order to achieve this goal, it is important to maximize both the product concentration, and also the total final mass in the fed-batch system. To this end, we describe the development of a control strategy which aims to achieve maximum tank fill, while avoiding oxygen limited conditions. This requires a two stage approach: (i) calculation of the tank start fill; and (ii) on-line control in order to maximize fill subject to oxygen transfer limitations. First, a mechanistic model was applied off-line in order to determine the appropriate start fill for processes with four different sets of process operating conditions for the stirrer speed, headspace pressure, and aeration rate. The start fills were tested with eight pilot scale experiments using a reference process operation. An on-line control strategy was then developed, utilizing the mechanistic model which is recursively updated using on-line measurements. The model was applied in order to predict the current system states, including the biomass concentration, and to simulate the expected future trajectory of the system until a specified end time. In this way, the desired feed rate is updated along the progress of the batch taking into account the oxygen mass transfer conditions and the expected future trajectory of the mass. The final results show that the target fill was achieved to within 5% under the maximum fill when tested using eight pilot scale batches, and over filling was avoided. The results were reproducible, unlike the reference experiments which show over 10% variation in the final tank fill, and this also includes over filling. The variance of the final tank fill is

A Mechanistic Link from GABA to Cortical Architecture and Perception.

Science.gov (United States)

Kolasinski, James; Logan, John P; Hinson, Emily L; Manners, Daniel; Divanbeighi Zand, Amir P; Makin, Tamar R; Emir, Uzay E; Stagg, Charlotte J

2017-06-05

Understanding both the organization of the human cortex and its relation to the performance of distinct functions is fundamental in neuroscience. The primary sensory cortices display topographic organization, whereby receptive fields follow a characteristic pattern, from tonotopy to retinotopy to somatotopy [1]. GABAergic signaling is vital to the maintenance of cortical receptive fields [2]; however, it is unclear how this fine-grain inhibition relates to measurable patterns of perception [3, 4]. Based on perceptual changes following perturbation of the GABAergic system, it is conceivable that the resting level of cortical GABAergic tone directly relates to the spatial specificity of activation in response to a given input [5-7]. The specificity of cortical activation can be considered in terms of cortical tuning: greater cortical tuning yields more localized recruitment of cortical territory in response to a given input. We applied a combination of fMRI, MR spectroscopy, and psychophysics to substantiate the link between the cortical neurochemical milieu, the tuning of cortical activity, and variability in perceptual acuity, using human somatosensory cortex as a model. We provide data that explain human perceptual acuity in terms of both the underlying cellular and metabolic processes. Specifically, higher concentrations of sensorimotor GABA are associated with more selective cortical tuning, which in turn is associated with enhanced perception. These results show anatomical and neurochemical specificity and are replicated in an independent cohort. The mechanistic link from neurochemistry to perception provides a vital step in understanding population variability in sensory behavior, informing metabolic therapeutic interventions to restore perceptual abilities clinically. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Assessing first-order emulator inference for physical parameters in nonlinear mechanistic models

Science.gov (United States)

Hooten, Mevin B.; Leeds, William B.; Fiechter, Jerome; Wikle, Christopher K.

2011-01-01

We present an approach for estimating physical parameters in nonlinear models that relies on an approximation to the mechanistic model itself for computational efficiency. The proposed methodology is validated and applied in two different modeling scenarios: (a) Simulation and (b) lower trophic level ocean ecosystem model. The approach we develop relies on the ability to predict right singular vectors (resulting from a decomposition of computer model experimental output) based on the computer model input and an experimental set of parameters. Critically, we model the right singular vectors in terms of the model parameters via a nonlinear statistical model. Specifically, we focus our attention on first-order models of these right singular vectors rather than the second-order (covariance) structure.

Improving the prediction of methane production and representation of rumen fermentation for finishing beef cattle within a mechanistic model

NARCIS (Netherlands)

Ellis, J.L.; Dijkstra, J.; Bannink, A.; Kebreab, E.; Archibeque, S.; Benchaar, C.; Beauchemin, K.; Nkrumah, D.J.; France, J.

2014-01-01

The purpose of this study was to evaluate prediction of methane emissions from finishing beef cattle using an extant mechanistic model with pH-independent or pH-dependent VFA stoichiometries, a recent stoichiometry adjustment for the use of monensin, and adaptation of the underlying model structure,

Oxidation of alginate and pectate biopolymers by cerium(IV) in perchloric and sulfuric acid solutions: A comparative kinetic and mechanistic study.

Science.gov (United States)

Fawzy, Ahmed

2016-03-15

The kinetics of oxidation of alginate (Alg) and pectate (Pec) carbohydrate biopolymers was studied by spectrophotometry in aqueous perchloric and sulfuric acid solutions at fixed ionic strengths and temperature. In both acids, the reactions showed a first order dependence on [Ce(IV)], whereas the orders with respect to biopolymer concentrations are less than unity. In perchloric acid, the reactions exhibited less than unit orders with respect to [H(+)] whereas those proceeded in sulfuric acid showed negative fractional-first order dependences on [H(+)]. The effect of ionic strength and dielectric constant was studied. Probable mechanistic schemes for oxidation reactions were proposed. In both acids, the final oxidation products were characterized as mono-keto derivatives of both biopolymers. The activation parameters with respect to the slow step of the mechanisms were computed and discussed. The rate laws were derived and the reaction constants involved in the different steps of the mechanisms were calculated. Copyright © 2015 Elsevier Ltd. All rights reserved.

Life at the Common Denominator: Mechanistic and Quantitative Biology for the Earth and Space Sciences

Science.gov (United States)

Hoehler, Tori M.

2010-01-01

The remarkable challenges and possibilities of the coming few decades will compel the biogeochemical and astrobiological sciences to characterize the interactions between biology and its environment in a fundamental, mechanistic, and quantitative fashion. The clear need for integrative and scalable biology-environment models is exemplified in the Earth sciences by the challenge of effectively addressing anthropogenic global change, and in the space sciences by the challenge of mounting a well-constrained yet sufficiently adaptive and inclusive search for life beyond Earth. Our understanding of the life-planet interaction is still, however, largely empirical. A variety of approaches seek to move from empirical to mechanistic descriptions. One approach focuses on the relationship between biology and energy, which is at once universal (all life requires energy), unique (life manages energy flow in a fashion not seen in abiotic systems), and amenable to characterization and quantification in thermodynamic terms. Simultaneously, a focus on energy flow addresses a critical point of interface between life and its geological, chemical, and physical environment. Characterizing and quantifying this relationship for life on Earth will support the development of integrative and predictive models for biology-environment dynamics. Understanding this relationship at its most fundamental level holds potential for developing concepts of habitability and biosignatures that can optimize astrobiological exploration strategies and are extensible to all life.

Ob/ob mouse livers show decreased oxidative phosphorylation efficiencies and anaerobic capacities after cold ischemia.

Directory of Open Access Journals (Sweden)

Michael J J Chu

Full Text Available BACKGROUND: Hepatic steatosis is a major risk factor for graft failure in liver transplantation. Hepatic steatosis shows a greater negative influence on graft function following prolonged cold ischaemia. As the impact of steatosis on hepatocyte metabolism during extended cold ischaemia is not well-described, we compared markers of metabolic capacity and mitochondrial function in steatotic and lean livers following clinically relevant durations of cold preservation. METHODS: Livers from 10-week old leptin-deficient obese (ob/ob, n = 9 and lean C57 mice (n = 9 were preserved in ice-cold University of Wisconsin solution. Liver mitochondrial function was then assessed using high resolution respirometry after 1.5, 3, 5, 8, 12, 16 and 24 hours of storage. Metabolic marker enzymes for anaerobiosis and mitochondrial mass were also measured in conjunction with non-bicarbonate tissue pH buffering capacity. RESULTS: Ob/ob and lean mice livers showed severe (>60% macrovesicular and mild (<30% microvesicular steatosis on Oil Red O staining, respectively. Ob/ob livers had lower baseline enzymatic complex I activity but similar adenosine triphosphate (ATP levels compared to lean livers. During cold storage, the respiratory control ratio and complex I-fueled phosphorylation deteriorated approximately twice as fast in ob/ob livers compared to lean livers. Ob/ob livers also demonstrated decreased ATP production capacities at all time-points analyzed compared to lean livers. Ob/ob liver baseline lactate dehydrogenase activities and intrinsic non-bicarbonate buffering capacities were depressed by 60% and 40%, respectively compared to lean livers. CONCLUSIONS: Steatotic livers have impaired baseline aerobic and anaerobic capacities compared to lean livers, and mitochondrial function indices decrease particularly from after 5 hours of cold preservation. These data provide a mechanistic basis for the clinical recommendation of shorter cold storage durations in

Mechanistic modeling of aberrant energy metabolism in human disease

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Vineet eSangar

2012-10-01

Full Text Available 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 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.

A mechanistic approach to postirradiation spoilage kinetics of fish

International Nuclear Information System (INIS)

Tukenmez, I.

2004-01-01

Full text: In order to simulate postirradiation spoilage of fish, the mechanistic aspects of the growth of surviving microorganisms during chill storage and their product formation in irradiated fish were analyzed. Anchovy (Engraulis encrasicholus) samples those unirradiated and irradiated at 1, 2 and 3 kGy doses of gamma radiation were stored at +2 o C for 21 days. Total bacterial counts (TBC) and trimethylamine (TMA) analysis of the samples were done periodically during storage. Depending on the proposed spoilage mechanism, kinetic model equations were derived. By using experimental data of TBC and TMA in the developed model, the postirradiation spoilage parameters including growth rate constant, inital and maximum attainable TBC, lag time and TMA yield were evaluated and microbial spoilage of fish was simulated for postirradiation storage. Shelf life of irradiated fish was estimated depending on the spoilage kinetics. Dose effects on the kinetic parameters were analyzed. It is suggested that the kinetic evaluation method developed in this study may be used for quality assessment, shelf life determination and dose optimization for radiation preservation of fish

Enzymatic Halogenation and Dehalogenation Reactions: Pervasive and Mechanistically Diverse.

Science.gov (United States)

Agarwal, Vinayak; Miles, Zachary D; Winter, Jaclyn M; Eustáquio, Alessandra S; El Gamal, Abrahim A; Moore, Bradley S

2017-04-26

Naturally produced halogenated compounds are ubiquitous across all domains of life where they perform a multitude of biological functions and adopt a diversity of chemical structures. Accordingly, a diverse collection of enzyme catalysts to install and remove halogens from organic scaffolds has evolved in nature. Accounting for the different chemical properties of the four halogen atoms (fluorine, chlorine, bromine, and iodine) and the diversity and chemical reactivity of their organic substrates, enzymes performing biosynthetic and degradative halogenation chemistry utilize numerous mechanistic strategies involving oxidation, reduction, and substitution. Biosynthetic halogenation reactions range from simple aromatic substitutions to stereoselective C-H functionalizations on remote carbon centers and can initiate the formation of simple to complex ring structures. Dehalogenating enzymes, on the other hand, are best known for removing halogen atoms from man-made organohalogens, yet also function naturally, albeit rarely, in metabolic pathways. This review details the scope and mechanism of nature's halogenation and dehalogenation enzymatic strategies, highlights gaps in our understanding, and posits where new advances in the field might arise in the near future.

Measuring performance at trade shows

DEFF Research Database (Denmark)

Hansen, Kåre

2004-01-01

Trade shows is an increasingly important marketing activity to many companies, but current measures of trade show performance do not adequately capture dimensions important to exhibitors. Based on the marketing literature's outcome and behavior-based control system taxonomy, a model is built...... that captures a outcome-based sales dimension and four behavior-based dimensions (i.e. information-gathering, relationship building, image building, and motivation activities). A 16-item instrument is developed for assessing exhibitors perceptions of their trade show performance. The paper presents evidence...

Mechanistic target of rapamycin (MTOR) protein expression in the tumor and its microenvironment correlates with more aggressive pathology at cystectomy

NARCIS (Netherlands)

Winters, B.R. (Brian R.); Vakar-Lopez, F. (Funda); Brown, L. (Lisha); Montgomery, B. (Bruce); Seiler, R. (Roland); P.C. Black (Peter C.); J.L. Boormans (Joost); Dall′Era, M. (Marc); Davincioni, E. (Elai); Douglas, J. (James); Gibb, E.A. (Ewan A.); B.W. van Rhijn (Bas); M.S. van der Heijden (Michiel); Hsieh, A.C. (Andrew C.); Wright, J.L. (Jonathan L.); Lam, H.-M. (Hung-Ming)

2018-01-01

textabstractBackground: The mechanistic target of rapamycin (mTOR) has been implicated in driving tumor biology in multiple malignancies, including urothelial carcinoma (UC). We investigate how mTOR and phosphorylated mTOR (pmTOR) protein expression correlate with chemoresponsiveness in the tumor

Imbalanced functional link between executive control network and reward network explain the online-game seeking behaviors in Internet gaming disorder.

Science.gov (United States)

Dong, Guangheng; Lin, Xiao; Hu, Yanbo; Xie, Chunming; Du, Xiaoxia

2015-03-17

Literatures have shown that Internet gaming disorder (IGD) subjects show impaired executive control and enhanced reward sensitivities than healthy controls. However, how these two networks jointly affect the valuation process and drive IGD subjects' online-game-seeking behaviors remains unknown. Thirty-five IGD and 36 healthy controls underwent a resting-states scan in the MRI scanner. Functional connectivity (FC) was examined within control and reward network seeds regions, respectively. Nucleus accumbens (NAcc) was selected as the node to find the interactions between these two networks. IGD subjects show decreased FC in the executive control network and increased FC in the reward network when comparing with the healthy controls. When examining the correlations between the NAcc and the executive control/reward networks, the link between the NAcc - executive control network is negatively related with the link between NAcc - reward network. The changes (decrease/increase) in IGD subjects' brain synchrony in control/reward networks suggest the inefficient/overly processing within neural circuitry underlying these processes. The inverse proportion between control network and reward network in IGD suggest that impairments in executive control lead to inefficient inhibition of enhanced cravings to excessive online game playing. This might shed light on the mechanistic understanding of IGD.

In Vitro Efficacy and Mechanistic Role of Indocyanine Green as a Photodynamic Therapy Agent for Human Melanoma

Energy Technology Data Exchange (ETDEWEB)

Mamoon, A.; Gamal-Eldeen, A; Ruppel, M; Smith, R; Tsang, T; Miller, L

2009-01-01

Photodynamic therapy (PDT) is a promising treatment for superficial cancer. However, poor therapeutic results have been reported for melanoma, due to the high melanin content. Indocyanine green (ICG) has near infrared absorption (700-800nm) and melanins do not absorb strongly in this area. This study explores the efficiency of ICG as a PDT agent for human melanoma, and its mechanistic role in the cell death pathway.

Imaging pain relief in osteoarthritis (IPRO): protocol of a double-blind randomised controlled mechanistic study assessing pain relief and prediction of duloxetine treatment outcome.

Science.gov (United States)

Reckziegel, Diane; Bailey, Helen; Cottam, William J; Tench, Christopher R; Mahajan, Ravi P; Walsh, David A; Knaggs, Roger D; Auer, Dorothee P

2017-06-26

Osteoarthritis (OA) pain is a major cause of long-term disability and chronic pain in the adult population. One in five patients does not receive satisfactory pain relief, which reflects the complexity of chronic pain and the current lack of understanding of mechanisms of chronic pain. Recently, duloxetine has demonstrated clinically relevant pain relief, but only in half of treated patients with OA. Here, the aim is to investigate the neural mechanisms of pain relief and neural signatures that may predict treatment response to duloxetine in chronic knee OA pain. This is an ongoing single-centre randomised placebo-controlled mechanistic study (2:1 (placebo) allocation), using a multimodal neuroimaging approach, together with psychophysiological (quantitative sensory testing), genetics and questionnaire assessments. Eighty-one subjects with chronic knee OA pain are planned to power for between-group comparisons (placebo, duloxetine responder and duloxetine non-responder). Participants have a baseline assessment and, following 6 weeks of duloxetine (30 mg for 2 weeks, then 60 mg for 4 weeks), a follow-up evaluation. Brain imaging is performed at 3T with blood-oxygen-level dependent functional MRI at rest and during pin-prick nociceptive stimulation for main outcome assessment; arterial spin labelling and structural imaging (T1-weighted) for secondary outcome assessment. Questionnaires evaluate pain, negative affect, quality of sleep and cognition. The study has been approved by the East Midlands, Nottingham and is being carried out under the principles of the Declaration of Helsinki (64th, 2013) and Good Clinical Practice standards. Results will be disseminated in peer-reviewed journals and at scientific conferences. This trial is registered at ClinicalTrials.gov (NCT02208778).This work was supported by Arthritis Research UK (Grant 18769). © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights

Four Mechanistic Models of Peer Influence on Adolescent Cannabis Use.

Science.gov (United States)

Caouette, Justin D; Feldstein Ewing, Sarah W

2017-06-01

Most adolescents begin exploring cannabis in peer contexts, but the neural mechanisms that underlie peer influence on adolescent cannabis use are still unknown. This theoretical overview elucidates the intersecting roles of neural function and peer factors in cannabis use in adolescents. Novel paradigms using functional magnetic resonance imaging (fMRI) in adolescents have identified distinct neural mechanisms of risk decision-making and incentive processing in peer contexts, centered on reward-motivation and affect regulatory neural networks; these findings inform a theoretical model of peer-driven cannabis use decisions in adolescents. We propose four "mechanistic profiles" of social facilitation of cannabis use in adolescents: (1) peer influence as the primary driver of use; (2) cannabis exploration as the primary driver, which may be enhanced in peer contexts; (3) social anxiety; and (4) negative peer experiences. Identification of "neural targets" involved in motivating cannabis use may inform clinicians about which treatment strategies work best in adolescents with cannabis use problems, and via which social and neurocognitive processes.

Mechanistic Approach to Understanding the Toxicity of the Azole Fungicide Triadimefon to a Nontarget Aquatic Insect and Implications for Exposure Assessment

Science.gov (United States)

We utilized mechanistic and stereoselective based in vitro metabolism assays and sublethal exposures of triadimefon to gain insight into the extent of carbonyl reduction and the toxic mode of action of triadimefon with black fly (Diptera: Simuliidae) larvae.

Mechanistic Drifting Forecast Model for A Small Semi-Submersible Drifter Under Tide-Wind-Wave Conditions

Science.gov (United States)

Zhang, Wei-Na; Huang, Hui-ming; Wang, Yi-gang; Chen, Da-ke; Zhang, lin

2018-03-01

Understanding the drifting motion of a small semi-submersible drifter is of vital importance regarding monitoring surface currents and the floating pollutants in coastal regions. This work addresses this issue by establishing a mechanistic drifting forecast model based on kinetic analysis. Taking tide-wind-wave into consideration, the forecast model is validated against in situ drifting experiment in the Radial Sand Ridges. Model results show good performance with respect to the measured drifting features, characterized by migrating back and forth twice a day with daily downwind displacements. Trajectory models are used to evaluate the influence of the individual hydrodynamic forcing. The tidal current is the fundamental dynamic condition in the Radial Sand Ridges and has the greatest impact on the drifting distance. However, it loses its leading position in the field of the daily displacement of the used drifter. The simulations reveal that different hydrodynamic forces dominate the daily displacement of the used drifter at different wind scales. The wave-induced mass transport has the greatest influence on the daily displacement at Beaufort wind scale 5-6; while wind drag contributes mostly at wind scale 2-4.

Mechanistic insights into the role of river sediment in the attenuation of the herbicide isoproturon.

Science.gov (United States)

Trinh, Son B; Hiscock, Kevin M; Reid, Brian J

2012-11-01

Mechanistic insights into the relative contribution of sorption and biodegradation on the removal of the herbicide isoproturon (IPU) are reported. (14)C-radiorespirometry indicated very low levels of catabolic activity in IPU-undosed and IPU-dosed (0.1, 1, 100 μg L(-1)) river water (RW) and groundwater (GW) (mineralisation: <2%). In contrast, levels of catabolic activity in IPU-undosed and IPU-dosed river sediment (RS) were significantly higher (mineralisation: 14.5-36.9%). Levels of IPU catabolic competence showed a positive log-linear relationship (r(2) = 0.768) with IPU concentration present. A threshold IPU concentration of between 0.1 μg L(-1) and 1 μg L(-1) was required to significantly (p < 0.05) increase levels of catabolic activity. Given the EU Drinking Water Directive limit for a single pesticide in drinking water of <0.1 μg L(-1) this result suggests that riverbed sediment infiltration is potentially an appropriate 'natural' means of improving water quality in terms of pesticide levels at concentrations that are in keeping with regulatory limits. Copyright © 2012 Elsevier Ltd. All rights reserved.

Mechanistic Perspectives of Maslinic Acid in Targeting Inflammation

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Wei Hsum Yap

2015-01-01

Full Text Available 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.

Isolation, characterization, and mechanistic studies of (-)-alpha-gurjunene synthase from Solidago canadensis.

Science.gov (United States)

Schmidt, C O; Bouwmeester, H J; Bülow, N; König, W A

1999-04-15

The leaves of the composite Solidago canadensis (goldenrod) were shown to contain (-)-alpha-gurjunene synthase activity. This sesquiterpene is likely to be the precursor for cyclocolorenone, a sesquiterpene ketone present in high amounts in S. canadensis leaves. (-)-alpha-Gurjunene synthase was purified to apparent homogeneity (741-fold) by anion-exchange chromatography (on several matrices), dye ligand chromatography, hydroxylapatite chromatography, and gel filtration. Chromatography on a gel filtration matrix indicated a native molecular mass of 48 kDa, and SDS-PAGE showed the enzyme to be composed of one subunit with a denatured mass of 60 kDa. Its maximum activity was observed at pH 7.8 in the presence of 10 mM Mg2+ and the KM value for the substrate farnesyl diphosphate was 5.5 microM. Over a range of purification steps (-)-alpha-gurjunene and (+)-gamma-gurjunene synthase activities copurified. In addition, the product ratio of the enzyme activity under several different assay conditions was always 91% (-)-alpha-gurjunene and 9% (+)-gamma-gurjunene. This suggests that the formation of these two structurally related products is catalyzed by one enzyme. For further confirmation, we carried out a number of mechanistic studies with (-)-alpha-gurjunene synthase, in which an enzyme preparation was incubated with deuterated substrate analogues. Based on mass spectrometry analysis of the products formed, a cyclization mechanism was postulated which makes it plausible that the synthase catalyzes the formation of both sesquiterpenes. Copyright 1999 Academic Press.

Fractal growth of tumors and other cellular populations: Linking the mechanistic to the phenomenological modeling and vice versa

International Nuclear Information System (INIS)

D'Onofrio, Alberto

2009-01-01

In this paper we study and extend the mechanistic mean field theory of growth of cellular populations proposed by Mombach et al. [Mombach JCM, Lemke N, Bodmann BEJ, Idiart MAP. A mean-field theory of cellular growth. Europhys Lett 2002;59:923-928] (MLBI model), and we demonstrate that the original model and our generalizations lead to inferences of biological interest. In the first part of this paper, we show that the model in study is widely general since it admits, as particular cases, the main phenomenological models of cellular growth. In the second part of this work, we generalize the MLBI model to a wider family of models by allowing the cells to have a generic unspecified biologically plausible interaction. Then, we derive a relationship between this generic microscopic interaction function and the growth rate of the corresponding macroscopic model. Finally, we propose to use this relationship in order to help the investigation of the biological plausibility of phenomenological models of cancer growth.

Hierarchical modeling of activation mechanisms in the ABL and EGFR kinase domains: thermodynamic and mechanistic catalysts of kinase activation by cancer mutations.

Directory of Open Access Journals (Sweden)

Anshuman Dixit

2009-08-01

Full Text Available Structural and functional studies of the ABL and EGFR kinase domains have recently suggested a common mechanism of activation by cancer-causing mutations. However, dynamics and mechanistic aspects of kinase activation by cancer mutations that stimulate conformational transitions and thermodynamic stabilization of the constitutively active kinase form remain elusive. We present a large-scale computational investigation of activation mechanisms in the ABL and EGFR kinase domains by a panel of clinically important cancer mutants ABL-T315I, ABL-L387M, EGFR-T790M, and EGFR-L858R. We have also simulated the activating effect of the gatekeeper mutation on conformational dynamics and allosteric interactions in functional states of the ABL-SH2-SH3 regulatory complexes. A comprehensive analysis was conducted using a hierarchy of computational approaches that included homology modeling, molecular dynamics simulations, protein stability analysis, targeted molecular dynamics, and molecular docking. Collectively, the results of this study have revealed thermodynamic and mechanistic catalysts of kinase activation by major cancer-causing mutations in the ABL and EGFR kinase domains. By using multiple crystallographic states of ABL and EGFR, computer simulations have allowed one to map dynamics of conformational fluctuations and transitions in the normal (wild-type and oncogenic kinase forms. A proposed multi-stage mechanistic model of activation involves a series of cooperative transitions between different conformational states, including assembly of the hydrophobic spine, the formation of the Src-like intermediate structure, and a cooperative breakage and formation of characteristic salt bridges, which signify transition to the active kinase form. We suggest that molecular mechanisms of activation by cancer mutations could mimic the activation process of the normal kinase, yet exploiting conserved structural catalysts to accelerate a conformational transition

A mechanistic modelling and data assimilation approach to estimate the carbon/chlorophyll and carbon/nitrogen ratios in a coupled hydrodynamical-biological model

Directory of Open Access Journals (Sweden)

B. Faugeras

2004-01-01

Full Text Available The principal objective of hydrodynamical-biological models is to provide estimates of the main carbon fluxes such as total and export oceanic production. These models are nitrogen based, that is to say that the variables are expressed in terms of their nitrogen content. Moreover models are calibrated using chlorophyll data sets. Therefore carbon to chlorophyll (C:Chl and carbon to nitrogen (C:N ratios have to be assumed. This paper addresses the problem of the representation of these ratios. In a 1D framework at the DYFAMED station (NW Mediterranean Sea we propose a model which enables the estimation of the basic biogeochemical fluxes and in which the spatio-temporal variability of the C:Chl and C:N ratios is fully represented in a mechanical way. This is achieved through the introduction of new state variables coming from the embedding of a phytoplankton growth model in a more classical Redfieldian NNPZD-DOM model (in which the C:N ratio is assumed to be a constant. Following this modelling step, the parameters of the model are estimated using the adjoint data assimilation method which enables the assimilation of chlorophyll and nitrate data sets collected at DYFAMED in 1997.Comparing the predictions of the new Mechanistic model with those of the classical Redfieldian NNPZD-DOM model which was calibrated with the same data sets, we find that both models reproduce the reference data in a comparable manner. Both fluxes and stocks can be equally well predicted by either model. However if the models are coinciding on an average basis, they are diverging from a variability prediction point of view. In the Mechanistic model biology adapts much faster to its environment giving rise to higher short term variations. Moreover the seasonal variability in total production differs from the Redfieldian NNPZD-DOM model to the Mechanistic model. In summer the Mechanistic model predicts higher production values in carbon unit than the Redfieldian NNPZD

Mechanistic modelling of the corrosion behaviour of copper nuclear fuel waste containers

Energy Technology Data Exchange (ETDEWEB)

King, F; Kolar, M

1996-10-01

A mechanistic model has been developed to predict the long-term corrosion behaviour of copper nuclear fuel waste containers in a Canadian disposal vault. The model is based on a detailed description of the electrochemical, chemical, adsorption and mass-transport processes involved in the uniform corrosion of copper, developed from the results of an extensive experimental program. Predictions from the model are compared with the results of some of these experiments and with observations from a bronze cannon submerged in seawater saturated clay sediments. Quantitative comparisons are made between the observed and predicted corrosion potential, corrosion rate and copper concentration profiles adjacent to the corroding surface, as a way of validating the long-term model predictions. (author). 12 refs., 5 figs.

Blood-brain barrier disruption: mechanistic links between Western diet consumption and dementia

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Ted Menghsiung Hsu

2014-05-01

Full Text Available Both obesity and Alzheimer’s disease are major health burdens in Western societies. While commonly viewed as having separate etiologies, this review highlights data suggesting that intake of Western diets, diets high in saturated fatty acids and simple carbohydrates, may pose a common environmental risk factor contributing to the development of both of these adverse pathologies. We discuss the effects of Western Diet intake on learning and memory processes that are dependent on the hippocampus, as well as the importance of this brain region in both obesity development and the onset of Alzheimer’s and other dementias. A putative mechanism is discussed that mechanistically links Western diet consumption, blood brain barrier degradation, and subsequent hippocampal damage and dementia pathology.

Regulatory Technology Development Plan - Sodium Fast Reactor. Mechanistic Source Term - Metal Fuel Radionuclide Release

International Nuclear Information System (INIS)

Grabaskas, David; Bucknor, Matthew; Jerden, James

2016-01-01

The development of an accurate and defensible mechanistic source term will be vital for the future licensing efforts of metal fuel, pool-type sodium fast reactors. To assist in the creation of a comprehensive mechanistic source term, the current effort sought to estimate the release fraction of radionuclides from metal fuel pins to the primary sodium coolant during fuel pin failures at a variety of temperature conditions. These release estimates were based on the findings of an extensive literature search, which reviewed past experimentation and reactor fuel damage accidents. Data sources for each radionuclide of interest were reviewed to establish release fractions, along with possible release dependencies, and the corresponding uncertainty levels. Although the current knowledge base is substantial, and radionuclide release fractions were established for the elements deemed important for the determination of offsite consequences following a reactor accident, gaps were found pertaining to several radionuclides. First, there is uncertainty regarding the transport behavior of several radionuclides (iodine, barium, strontium, tellurium, and europium) during metal fuel irradiation to high burnup levels. The migration of these radionuclides within the fuel matrix and bond sodium region can greatly affect their release during pin failure incidents. Post-irradiation examination of existing high burnup metal fuel can likely resolve this knowledge gap. Second, data regarding the radionuclide release from molten high burnup metal fuel in sodium is sparse, which makes the assessment of radionuclide release from fuel melting accidents at high fuel burnup levels difficult. This gap could be addressed through fuel melting experimentation with samples from the existing high burnup metal fuel inventory.

Regulatory Technology Development Plan - Sodium Fast Reactor. Mechanistic Source Term - Metal Fuel Radionuclide Release

Energy Technology Data Exchange (ETDEWEB)

Grabaskas, David [Argonne National Lab. (ANL), Argonne, IL (United States); Bucknor, Matthew [Argonne National Lab. (ANL), Argonne, IL (United States); Jerden, James [Argonne National Lab. (ANL), Argonne, IL (United States)

2016-02-01

The development of an accurate and defensible mechanistic source term will be vital for the future licensing efforts of metal fuel, pool-type sodium fast reactors. To assist in the creation of a comprehensive mechanistic source term, the current effort sought to estimate the release fraction of radionuclides from metal fuel pins to the primary sodium coolant during fuel pin failures at a variety of temperature conditions. These release estimates were based on the findings of an extensive literature search, which reviewed past experimentation and reactor fuel damage accidents. Data sources for each radionuclide of interest were reviewed to establish release fractions, along with possible release dependencies, and the corresponding uncertainty levels. Although the current knowledge base is substantial, and radionuclide release fractions were established for the elements deemed important for the determination of offsite consequences following a reactor accident, gaps were found pertaining to several radionuclides. First, there is uncertainty regarding the transport behavior of several radionuclides (iodine, barium, strontium, tellurium, and europium) during metal fuel irradiation to high burnup levels. The migration of these radionuclides within the fuel matrix and bond sodium region can greatly affect their release during pin failure incidents. Post-irradiation examination of existing high burnup metal fuel can likely resolve this knowledge gap. Second, data regarding the radionuclide release from molten high burnup metal fuel in sodium is sparse, which makes the assessment of radionuclide release from fuel melting accidents at high fuel burnup levels difficult. This gap could be addressed through fuel melting experimentation with samples from the existing high burnup metal fuel inventory.

Simulating the Epidemiological and Economic Impact of Paratuberculosis Control Actions in Dairy Cattle

DEFF Research Database (Denmark)

Kirkeby, Carsten Thure; Græsbøll, Kaare; Nielsen, Søren Saxmose

2016-01-01

We describe a new mechanistic bioeconomic model for simulating the spread of Mycobacterium avium subsp. paratuberculosis (MAP) within a dairy cattle herd. The model includes age-dependent susceptibility for infection; age-dependent sensitivity for detection; environmental MAP build up in five...... control actions from the Danish MAP control program, it was not economically attractive since the expenses for the control actions outweigh the benefits. Furthermore, the three most popular control actions against the spread of MAP on the farm were found to be costly and inefficient in lowering...

REM sleep behaviour disorder: prodromal and mechanistic insights for Parkinson's disease.

Science.gov (United States)

Tekriwal, Anand; Kern, Drew S; Tsai, Jean; Ince, Nuri F; Wu, Jianping; Thompson, John A; Abosch, Aviva

2017-05-01

Rapid eye movement (REM) sleep behaviour disorder (RBD) is characterised by complex motor enactment of dreams and is a potential prodromal marker of Parkinson's disease (PD). Of note, patients with PD observed during RBD episodes exhibit improved motor function, relative to baseline states during wake periods. Here, we review recent epidemiological and mechanistic findings supporting the prodromal value of RBD for PD, incorporating clinical and electrophysiological studies. Explanations for the improved motor function during RBD episodes are evaluated in light of recent publications. In addition, we present preliminary findings describing changes in the activity of the basal ganglia across the sleep-wake cycle that contribute to our understanding of RBD. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Mechanistic Insights into Dye-Decolorizing Peroxidase Revealed by Solvent Isotope and Viscosity Effects

Energy Technology Data Exchange (ETDEWEB)

Shrestha, Ruben [Department; Huang, Gaochao [Department; Meekins, David A. [Department; Geisbrecht, Brian V. [Department; Li, Ping [Department

2017-08-18

Dye-decolorizing peroxidases (DyPs) are a family of H2O2-dependent heme peroxidases that have shown potential applications in lignin degradation and valorization. However, the DyP kinetic mechanism remains underexplored. Using structural biology and solvent isotope (sKIE) and viscosity effects, many mechanistic characteristics have been determined for the B-class ElDyP from Enterobacter lignolyticus. Its structure revealed that a water molecule acts as the sixth axial ligand and two channels at diameters of ~3.0 and 8.0 Å lead to the heme center. A conformational change of ERS* to ERS, which have identical spectral characteristics, was proposed as the final step in DyPs’ bisubstrate Ping-Pong mechanism. This step is also the rate-determining step in ABTS oxidation. The normal KIE of wild-type ElDyP with D2O2 at pD 3.5 suggested that compound 0 deprotonation by the distal aspartate is rate-limiting in the formation of compound I, which is more reactive under acidic pH than under neutral or alkaline pH. The viscosity effects and other biochemical methods implied that the reducing substrate binds with compound I instead of the free enzyme. The significant inverse sKIEs of kcat/KM and kERS* suggested that the aquo release in ElDyP is mechanistically important and may explain the enzyme’s adoption of two-electron reduction for compound I. The distal aspartate is catalytically more important than the distal arginine and plays key roles in determining ElDyP’s optimum acidic pH. The kinetic mechanism of D143H-ElDyP was also briefly studied. The results obtained will pave the way for future protein engineering to improve DyPs’ lignolytic activity.

Evaluating the mechanistic evidence and key data gaps in assessing the potential carcinogenicity of carbon nanotubes and nanofibers in humans

NARCIS (Netherlands)

Kuempel, Eileen D; Jaurand, Marie-Claude; Møller, Peter; Morimoto, Yasuo; Kobayashi, Norihiro; Pinkerton, Kent E; Sargent, Linda M; Vermeulen, Roel C H; Fubini, Bice; Kane, Agnes B

2017-01-01

In an evaluation of carbon nanotubes (CNTs) for the IARC Monograph 111, the Mechanisms Subgroup was tasked with assessing the strength of evidence on the potential carcinogenicity of CNTs in humans. The mechanistic evidence was considered to be not strong enough to alter the evaluations based on the

Modeling of the pyruvate production with Escherichia coli: comparison of mechanistic and neural networks-based models.

Science.gov (United States)

Zelić, B; Bolf, N; Vasić-Racki, D

2006-06-01

Three different models: the unstructured mechanistic black-box model, the input-output neural network-based model and the externally recurrent neural network model were used to describe the pyruvate production process from glucose and acetate using the genetically modified Escherichia coli YYC202 ldhA::Kan strain. The experimental data were used from the recently described batch and fed-batch experiments [ Zelić B, Study of the process development for Escherichia coli-based pyruvate production. PhD Thesis, University of Zagreb, Faculty of Chemical Engineering and Technology, Zagreb, Croatia, July 2003. (In English); Zelić et al. Bioproc Biosyst Eng 26:249-258 (2004); Zelić et al. Eng Life Sci 3:299-305 (2003); Zelić et al Biotechnol Bioeng 85:638-646 (2004)]. The neural networks were built out of the experimental data obtained in the fed-batch pyruvate production experiments with the constant glucose feed rate. The model validation was performed using the experimental results obtained from the batch and fed-batch pyruvate production experiments with the constant acetate feed rate. Dynamics of the substrate and product concentration changes was estimated using two neural network-based models for biomass and pyruvate. It was shown that neural networks could be used for the modeling of complex microbial fermentation processes, even in conditions in which mechanistic unstructured models cannot be applied.

Mechanistic Modeling of Water Replenishment Rate of Zeer Refrigerator

Directory of Open Access Journals (Sweden)

B. N. Nwankwojike

2017-06-01

Full Text Available A model for predicting the water replenishment rate of zeer pot refrigerator was developed in this study using mechanistic modeling approach and evaluated at Obowo, Imo State, Nigeria using six fruits, tomatoes, guava, okra, banana, orange and avocado pear. The developed model confirmed zeer pot water replenishment rate as a function of ambient temperature, relative humidity, wind speed, thermal conductivity of the pot materials and sand, density of air and water vapor, permeability coefficient of clay and heat transfer coefficient of water into air, circumferential length, height of pot, geometrical profile of the pot, heat load of the food preserved, heat flow into the device and gradient at which the pot is placed above ground level. Compared to the conventional approach of water replenishment, performance analysis results revealed 44% to 58% water economy when the zeer pot’s water was replenished based on the model’s prediction; while there was no significant difference in the shelf-life of the fruits preserved with both replenishment methods. Application of the developed water replenishment model facilitates optimal water usage in this system, thereby reducing operational cost of zeer pot refrigerator.

Refined pipe theory for mechanistic modeling of wood development.

Science.gov (United States)

Deckmyn, Gaby; Evans, Sam P; Randle, Tim J

2006-06-01

We present a mechanistic model of wood tissue development in response to changes in competition, management and climate. The model is based on a refinement of the pipe theory, where the constant ratio between sapwood and leaf area (pipe theory) is replaced by a ratio between pipe conductivity and leaf area. Simulated pipe conductivity changes with age, stand density and climate in response to changes in allocation or pipe radius, or both. The central equation of the model, which calculates the ratio of carbon (C) allocated to leaves and pipes, can be parameterized to describe the contrasting stem conductivity behavior of different tree species: from constant stem conductivity (functional homeostasis hypothesis) to height-related reduction in stem conductivity with age (hydraulic limitation hypothesis). The model simulates the daily growth of pipes (vessels or tracheids), fibers and parenchyma as well as vessel size and simulates the wood density profile and the earlywood to latewood ratio from these data. Initial runs indicate the model yields realistic seasonal changes in pipe radius (decreasing pipe radius from spring to autumn) and wood density, as well as realistic differences associated with the competitive status of trees (denser wood in suppressed trees).

Malaria's missing number: calculating the human component of R0 by a within-host mechanistic model of Plasmodium falciparum infection and transmission.

Directory of Open Access Journals (Sweden)

Geoffrey L Johnston

2013-04-01

Full Text Available Human infection by malarial parasites of the genus Plasmodium begins with the bite of an infected Anopheles mosquito. Current estimates place malaria mortality at over 650,000 individuals each year, mostly in African children. Efforts to reduce disease burden can benefit from the development of mathematical models of disease transmission. To date, however, comprehensive modeling of the parameters defining human infectivity to mosquitoes has remained elusive. Here, we describe a mechanistic within-host model of Plasmodium falciparum infection in humans and pathogen transmission to the mosquito vector. Our model incorporates the entire parasite lifecycle, including the intra-erythrocytic asexual forms responsible for disease, the onset of symptoms, the development and maturation of intra-erythrocytic gametocytes that are transmissible to Anopheles mosquitoes, and human-to-mosquito infectivity. These model components were parameterized from malaria therapy data and other studies to simulate individual infections, and the ensemble of outputs was found to reproduce the full range of patient responses to infection. Using this model, we assessed human infectivity over the course of untreated infections and examined the effects in relation to transmission intensity, expressed by the basic reproduction number R0 (defined as the number of secondary cases produced by a single typical infection in a completely susceptible population. Our studies predict that net human-to-mosquito infectivity from a single non-immune individual is on average equal to 32 fully infectious days. This estimate of mean infectivity is equivalent to calculating the human component of malarial R0 . We also predict that mean daily infectivity exceeds five percent for approximately 138 days. The mechanistic framework described herein, made available as stand-alone software, will enable investigators to conduct detailed studies into theories of malaria control, including the effects of

The effect of targeted treatment on people with patellofemoral pain: a pragmatic, randomised controlled feasibility study.

Science.gov (United States)

Drew, Benjamin T; Conaghan, Philip G; Smith, Toby O; Selfe, James; Redmond, Anthony C

2017-08-04

Targeted treatment, matched according to specific clinical criteria e.g. hip muscle weakness, may result in better outcomes for people with patellofemoral pain (PFP). However, to ensure the success of future trials, a number of questions on the feasibility of a targeted treatment need clarification. The aim of the study was to explore the feasibility of matched treatment (MT) compared to usual care (UC) management for a subgroup of people with PFP determined to have hip weakness and to explore the mechanism of effect for hip strengthening. In a pragmatic, randomised controlled feasibility study, 24 participants with PFP (58% female; mean age 29 years) were randomly allocated to receive either MT aimed specifically at hip strengthening, or UC over an eight-week period. The primary outcomes were feasibility outcomes, which included rates of adherence, attrition, eligibility, missing data and treatment efficacy. Secondary outcomes focused on the mechanistic outcomes of the intervention, which included hip kinematics. Conversion to consent (100%), missing data (0%), attrition rate (8%) and adherence to both treatment and appointments (>90%) were deemed successful endpoints. The analysis of treatment efficacy showed that the MT group reported a greater improvement for the Global Rating of Change Scale (62% vs. 9%) and the Anterior Knee Pain Scale (-5.23 vs. 1.18) but no between-group differences for either average or worst pain. Mechanistic outcomes showed a greatest reduction in peak hip internal rotation angle for the MT group (13.1% vs. -2.7%). This feasibility study indicates that a definitive randomised controlled trial investigating a targeted treatment approach is achievable. Findings suggest the mechanism of effect of hip strengthening may be to influence kinematic changes in hip function in the transverse plane. This study was registered retrospectively. ISRCTN74560952 . Registration date: 2017-02-06.

Qigong and Fibromyalgia: Randomized Controlled Trials and Beyond

Directory of Open Access Journals (Sweden)

Jana Sawynok

2014-01-01

Full Text Available Introduction. Qigong is currently considered as meditative movement, mindful exercise, or complementary exercise and is being explored for relief of symptoms in fibromyalgia. Aim. This narrative review summarizes randomized controlled trials, as well as additional studies, of qigong published to the end of 2013 and discusses relevant methodological issues. Results. Controlled trials indicate regular qigong practice (daily, 6–8 weeks produces improvements in core domains for fibromyalgia (pain, sleep, impact, and physical and mental function that are maintained at 4–6 months compared to wait-list subjects or baselines. Comparisons with active controls show little difference, but compared to baseline there are significant and comparable effects in both groups. Open-label studies provide information that supports benefit but remain exploratory. An extension trial and case studies involving extended practice (daily, 6–12 months indicate marked benefits but are limited by the number of participants. Benefit appears to be related to amount of practice. Conclusions. There is considerable potential for qigong to be a useful complementary practice for the management of fibromyalgia. However, there are unique methodological challenges, and exploration of its clinical potential will need to focus on pragmatic issues and consider a spectrum of trial designs. Mechanistic considerations need to consider both system-wide and more specific effects.

Mechanistic studies related to the safety of Li/SOCl2 cells

Science.gov (United States)

Carter, B. J.; Williams, R. M.; Tsay, F. D.; Rodriguez, A.; Kim, S.; Evans, M. M.; Frank, H.

1985-01-01

Mechanistic studies of the reactions in Li-SOCl2 cells have been undertaken to improve understanding of the safety problems of these cells. The electrochemical reduction of 1.5M LiAlCl4/SOCl2 has been investigated using gas chromatography, electron spin resonance spectroscopy, and infrared spectroscopy. Cl2 and S2Cl2 have been identified as intermediates in the reduction of SOCl2, along with a radical species (g/xx/ = 2.004, g/yy/ = 2.016, g/zz/ = 2.008) and the proposed triplet ground-state dimer of this radical. SO2 and sulfur have been identified as products. Based upon these findings, a mechanism for the electrochemical reduction of 1.5M LiAlCl4/SOCl2 has been proposed, and its implications for safety of Li-SOCl2 cells during discharge to +0.5V at 25-30 C are discussed.

Mechanistic origin of dragon-kings in a population of competing agents

Science.gov (United States)

Johnson, N.; Tivnan, B.

2012-05-01

We analyze the mechanistic origins of the extreme behaviors that arise in an idealized model of a population of competing agents, such as traders in a market. These extreme behaviors exhibit the defining characteristics of `dragon-kings'. Our model comprises heterogeneous agents who repeatedly compete for some limited resource, making binary choices based on the strategies that they have in their possession. It generalizes the well-known Minority Game by allowing agents whose strategies have not made accurate recent predictions, to step out of the competition until their strategies improve. This generates a complex dynamical interplay between the number V of active agents (mimicking market volume) and the imbalance D between the decisions made (mimicking excess demand). The wide spectrum of extreme behaviors which emerge, helps to explain why no unique relationship has been identified between the price and volume during real market crashes and rallies.

Mechanistic movement models to understand epidemic spread.

Science.gov (United States)

Fofana, Abdou Moutalab; Hurford, Amy

2017-05-05

An overlooked aspect of disease ecology is considering how and why animals come into contact with one and other resulting in disease transmission. Mathematical models of disease spread frequently assume mass-action transmission, justified by stating that susceptible and infectious hosts mix readily, and foregoing any detailed description of host movement. Numerous recent studies have recorded, analysed and modelled animal movement. These movement models describe how animals move with respect to resources, conspecifics and previous movement directions and have been used to understand the conditions for the occurrence and the spread of infectious diseases when hosts perform a type of movement. Here, we summarize the effect of the different types of movement on the threshold conditions for disease spread. We identify gaps in the literature and suggest several promising directions for future research. The mechanistic inclusion of movement in epidemic models may be beneficial for the following two reasons. Firstly, the estimation of the transmission coefficient in an epidemic model is possible because animal movement data can be used to estimate the rate of contacts between conspecifics. Secondly, unsuccessful transmission events, where a susceptible host contacts an infectious host but does not become infected can be quantified. Following an outbreak, this enables disease ecologists to identify 'near misses' and to explore possible alternative epidemic outcomes given shifts in ecological or immunological parameters.This article is part of the themed issue 'Opening the black box: re-examining the ecology and evolution of parasite transmission'. © 2017 The Author(s).

Mechanistic insight into neurotoxicity induced by developmental insults

International Nuclear Information System (INIS)

Tamm, Christoffer; Ceccatelli, Sandra

2017-01-01

Epidemiological and/or experimental studies have shown that unfavorable prenatal environmental factors, such as stress or exposure to certain neurotoxic environmental contaminants, may have adverse consequences for neurodevelopment. Alterations in neurogenesis can have harmful effects not only for the developing nervous system, but also for the adult brain where neurogenesis is believed to play a role in learning, memory, and even in depression. Many recent advances in the understanding of the complex process of nervous system development can be integrated into the field of neurotoxicology. In the past 15 years we have been using cultured neural stem or progenitor cells to investigate the effects of neurotoxic stimuli on cell survival, proliferation and differentiation, with special focus on heritable effects. This is an overview of the work performed by our group in the attempt to elucidate the mechanisms of developmental neurotoxicity and possibly provide relevant information for the understanding of the etiopathogenesis of complex brain disorders. - Highlights: • The developing nervous system is highly sensitive to toxic insults. • Neural stem cells are relevant models for mechanistic studies as well as for identifying heritable effects due to epigenetic changes. • Depending on the dose, the outcome of exposure to neurotoxicants ranges from altered proliferation and differentiation to cell death. • The elucidation of neurotoxicity mechanisms is relevant for understanding the etiopathogenesis of developmental and adult nervous system disorders.

Multiscale mechanistic modeling in pharmaceutical research and development.

Science.gov (United States)

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.

Analytical techniques for mechanistic characterization of EUV photoresists

Science.gov (United States)

Grzeskowiak, Steven; Narasimhan, Amrit; Murphy, Michael; Ackerman, Christian; Kaminsky, Jake; Brainard, Robert L.; Denbeaux, Greg

2017-03-01

Extreme ultraviolet (EUV, 13.5 nm) lithography is the prospective technology for high volume manufacturing by the microelectronics industry. Significant strides towards achieving adequate EUV source power and availability have been made recently, but a limited rate of improvement in photoresist performance still delays the implementation of EUV. Many fundamental questions remain to be answered about the exposure mechanisms of even the relatively well understood chemically amplified EUV photoresists. Moreover, several groups around the world are developing revolutionary metal-based resists whose EUV exposure mechanisms are even less understood. Here, we describe several evaluation techniques to help elucidate mechanistic details of EUV exposure mechanisms of chemically amplified and metal-based resists. EUV absorption coefficients are determined experimentally by measuring the transmission through a resist coated on a silicon nitride membrane. Photochemistry can be evaluated by monitoring small outgassing reaction products to provide insight into photoacid generator or metal-based resist reactivity. Spectroscopic techniques such as thin-film Fourier transform infrared (FTIR) spectroscopy can measure the chemical state of a photoresist system pre- and post-EUV exposure. Additionally, electrolysis can be used to study the interaction between photoresist components and low energy electrons. Collectively, these techniques improve our current understanding of photomechanisms for several EUV photoresist systems, which is needed to develop new, better performing materials needed for high volume manufacturing.

A recovery principle provides insight into auxin pattern control in the Arabidopsis root

Science.gov (United States)

Moore, Simon; Liu, Junli; Zhang, Xiaoxian; Lindsey, Keith

2017-01-01

Regulated auxin patterning provides a key mechanism for controlling root growth and development. We have developed a data-driven mechanistic model using realistic root geometry and formulated a principle to theoretically investigate quantitative auxin pattern recovery following auxin transport perturbation. This principle reveals that auxin patterning is potentially controlled by multiple combinations of interlinked levels and localisation of influx and efflux carriers. We demonstrate that (1) when efflux carriers maintain polarity but change levels, maintaining the same auxin pattern requires non-uniform and polar distribution of influx carriers; (2) the emergence of the same auxin pattern, from different levels of influx carriers with the same nonpolar localisation, requires simultaneous modulation of efflux carrier level and polarity; and (3) multiple patterns of influx and efflux carriers for maintaining an auxin pattern do not have spatially proportional correlation. This reveals that auxin pattern formation requires coordination between influx and efflux carriers. We further show that the model makes various predictions that can be experimentally validated. PMID:28220889

Mechanistic Basis for Plant Responses to Drought Stress : Regulatory Mechanism of Abscisic Acid Signaling

Science.gov (United States)

Miyakawa, Takuya; Tanokura, Masaru

The phytohormone abscisic acid (ABA) plays a key role in the rapid adaptation of plants to environmental stresses such as drought and high salinity. Accumulated ABA in plant cells promotes stomatal closure in guard cells and transcription of stress-tolerant genes. Our understanding of ABA responses dramatically improved by the discovery of both PYR/PYL/RCAR as a soluble ABA receptor and inhibitory complex of a protein phospatase PP2C and a protein kinase SnRK2. Moreover, several structural analyses of PYR/PYL/RCAR revealed the mechanistic basis for the regulatory mechanism of ABA signaling, which provides a rational framework for the design of alternative agonists in future.

Uncertainty, sensitivity analysis and the role of data based mechanistic modeling in hydrology

Science.gov (United States)

Ratto, M.; Young, P. C.; Romanowicz, R.; Pappenberger, F.; Saltelli, A.; Pagano, A.

2007-05-01

calibration of mechanistic hydrological models, making their properties more transparent. It also helps to highlight possible mis-specification problems, if these are identified. The results of the exercise show that the two modelling methodologies have good synergy; combining well to produce a complete joint modelling approach that has the kinds of checks-and-balances required in practical data-based modelling of rainfall-flow systems. Such a combined approach also produces models that are suitable for different kinds of application. As such, the DBM model considered in the paper is developed specifically as a vehicle for flow and flood forecasting (although the generality of DBM modelling means that a simulation version of the model could be developed if required); while TOPMODEL, suitably calibrated (and perhaps modified) in the light of the DBM and GSA results, immediately provides a simulation model with a variety of potential applications, in areas such as catchment management and planning.

Impulse control disorders in Parkinson's disease: recent advances.

Science.gov (United States)

Voon, Valerie; Mehta, Arpan R; Hallett, Mark

2011-08-01

The aim is to review the recent advances in the epidemiology and pathophysiology of impulse control disorders (ICDs) in Parkinson's disease. Large cross-sectional and case-control multicentre studies show that ICDs in Parkinson's disease are common, with a frequency of 13.6%. These behaviours are associated with impaired functioning and with depressive, anxiety and obsessive symptoms, novelty seeking and impulsivity. Behavioural subtypes demonstrate differences in novelty seeking and impulsivity, suggesting pathophysiological differences. Observational and neurophysiological studies point towards a potential mechanistic overlap between behavioural (ICDs) and motor (dyskinesias) dopaminergic sequelae. Converging data suggest dopamine agonists in ICDs appear to enhance learning from rewarding outcomes and impulsive choice. ICD patients also have enhanced risk preference and impaired working memory. Neuroimaging data point towards enhanced bottom-up ventral striatal dopamine release to incentive cues, gambling tasks and reward prediction, and possible inhibition of top-down orbitofrontal influences. Dopamine agonist-related ventral striatal hypoactivity to risk is consistent with impaired risk evaluation. Recent large-scale studies and converging findings are beginning to provide an understanding of mechanisms underlying ICDs in Parkinson's disease, which can guide prevention of these behaviours and optimize therapeutic approaches.

Viruses' life history: towards a mechanistic basis of a trade-off between survival and reproduction among phages.

Directory of Open Access Journals (Sweden)

Marianne De Paepe

2006-07-01

Full Text Available Life history theory accounts for variations in many traits involved in the reproduction and survival of living organisms, by determining the constraints leading to trade-offs among these different traits. The main life history traits of phages-viruses that infect bacteria-are the multiplication rate in the host, the survivorship of virions in the external environment, and their mode of transmission. By comparing life history traits of 16 phages infecting the bacteria Escherichia coli, we show that their mortality rate is constant with time and positively [corrected] correlated to their multiplication rate in the bacterial host. Even though these viruses do not age, this result is in line with the trade-off between survival and reproduction previously observed in numerous aging organisms. Furthermore, a multiple regression shows that the combined effects of two physical parameters, namely, the capsid thickness and the density of the packaged genome, account for 82% of the variation in the mortality rate. The correlations between life history traits and physical characteristics of virions may provide a mechanistic explanation of this trade-off. The fact that this trade-off is present in this very simple biological situation suggests that it might be a fundamental property of evolving entities produced under constraints. Moreover, such a positive correlation between mortality and multiplication reveals an underexplored trade-off in host-parasite interactions.

Mechanistic features of isomerizing alkoxycarbonylation of methyl oleate

KAUST Repository

Roesle, Philipp

2012-10-24

The weakly coordinated triflate complex [(P̂P)Pd(OTf)] +(OTf)- (1) (P̂P = 1,3-bis(di-tert- butylphosphino)propane) is a suitable reactive precursor for mechanistic studies of the isomerizing alkoxcarbonylation of methyl oleate. Addition of CH 3OH or CD3OD to 1 forms the hydride species [(P ̂P)PdH(CH3OH)]+(OTf)- (2-CH3OH) or the deuteride [(P̂P)PdD(CD 3OD)]+(OTf)- (2D-CD3OD), respectively. Further reaction with pyridine cleanly affords the stable and isolable hydride [(P̂P)PdH(pyridine)]+(OTf) - (2-pyr). This complex yields the hydride fragment free of methanol by abstraction of pyridine with BF3OEt2, and thus provides an entry to mechanistic observations including intermediates reactive toward methanol. Exposure of methyl oleate (100 equiv) to 2D-CD 3OD resulted in rapid isomerization to the thermodynamic isomer distribution, 94.3% of internal olefins, 5.5% of α,β-unsaturated ester and <0.2% of terminal olefin. Reaction of 2-pyr/BF3OEt 2 with a stoichiometric amount of 1-13C-labeled 1-octene at -80 °C yields a 50:50 mixture of the linear alkyls [(P ̂P)Pd13CH2(CH2) 6CH3]+ and [(P̂P)PdCH 2(CH2)6 13CH3] + (4a and 4b). Further reaction with 13CO yields the linear acyls [(P̂P)Pd13C(=O)12/13CH 2(CH2)6 12/13CH3(L)] + (5-L; L = solvent or 13CO). Reaction of 2-pyr/BF 3·OEt2 with a stoichiometric amount of methyl oleate at -80 °C also resulted in fast isomerization to form a linear alkyl species [(P̂P)PdCH2(CH2) 16C(=O)OCH3]+ (6) and a branched alkyl stabilized by coordination of the ester carbonyl group as a four membered chelate [(P̂P)PdCH{(CH2)15CH 3}C(=O)OCH3]+ (7). Addition of carbon monoxide (2.5 equiv) at -80 °C resulted in insertion to form the linear acyl carbonyl [(P̂P)PdC(=O)(CH2)17C(=O)OCH 3(CO)]+ (8-CO) and the five-membered chelate [(P ̂P)PdC(=O)CH{(CH2)15CH3}C(=O) OCH3]+ (9). Exposure of 8-CO and 9 to 13CO at -50 °C results in gradual incorporation of the 13C label. Reversibility of 7 + CO ⇄ 9 is also evidenced by ΔG = -2.9 kcal mol-1 and

Mechanistic model for Sr and Ba release from severely damaged fuel

International Nuclear Information System (INIS)

Rest, J.; Cronenberg, A.W.

1985-11-01

Among radionuclides associated with fission product release during severe accidents, the primary ones with health consequences are the volatile species of I, Te, and Cs, and the next most important are Sr, Ba, and Ru. Considerable progress has been made in the mechanistic understanding of I, Cs, Te, and noble gas release; however, no capability presently exists for estimating the release of Sr, Ba, and Ru. This paper presents a description of the primary physical/chemical models recently incorporated into the FASTGRASS-VFP (volatile fission product) code for the estimation of Sr and Ba release. FASTGRASS-VFP release predictions are compared with two data sets: (1) data from out-of-reactor induction-heating experiments on declad low-burnup (1000 and 4000 MWd/t) pellets, and (2) data from the more recent in-reactor PBF Severe Fuel Damage Tests, in which one-meter-long, trace-irradiated (89 MWd/t) and normally irradiated (approx.35,000 MWd/t) fuel rods were tested under accident conditions. 10 refs

Tomato (Lycopersicon esculentum) or lycopene supplementation attenuates ventricular remodeling after myocardial infarction through different mechanistic pathways.

Science.gov (United States)

Pereira, Bruna L B; Reis, Patrícia P; Severino, Fábio E; Felix, Tainara F; Braz, Mariana G; Nogueira, Flávia R; Silva, Renata A C; Cardoso, Ana C; Lourenço, Maria A M; Figueiredo, Amanda M; Chiuso-Minicucci, Fernanda; Azevedo, Paula S; Polegato, Bertha F; Okoshi, Katashi; Fernandes, Ana A H; Paiva, Sergio A R; Zornoff, Leonardo A M; Minicucci, Marcos F

2017-08-01

The objective of this study was to evaluate the influence of tomato or lycopene supplementation on cardiac remodeling after myocardial infarction (MI). Male Wistar rats were assigned to four groups: the sham group (animals that underwent simulated surgery) that received a standard chow (S; n=18), the infarcted group that received a standard chow (MI; n=13), the infarcted group supplemented with lycopene (1 mg of lycopene/kg body weight/day) (MIL; n=16) and the infarcted group supplemented with tomato (MIT; n=16). After 3 months, morphological, functional and biochemical analyses were performed. The groups MIL and MIT showed decreased interstitial fibrosis induced by infarction. Tomato supplementation attenuated the hypertrophy induced by MI. In addition, tomato and lycopene improved diastolic dysfunction evaluated by echocardiographic and isolated heart studies, respectively. The MI group showed higher levels of cardiac TNF-α compared to the MIL and MIT groups. Decreased nuclear factor E2-related factor 2 was measured in the MIL group. Lipid hydroperoxide levels were higher in the infarcted groups; however, the MIT group had a lower concentration than did the MI group [S=223±20.8, MI=298±19.5, MIL=277±26.6, MIT=261±28.8 (nmol/g); n=8; Ptomato or lycopene supplementation attenuated the cardiac remodeling process and improved diastolic function after MI. However, the effect of lycopene and tomato supplementation occurred through different mechanistic pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

Improving Predictive Modeling in Pediatric Drug Development: Pharmacokinetics, Pharmacodynamics, and Mechanistic Modeling

Energy Technology Data Exchange (ETDEWEB)

Slikker, William; Young, John F.; Corley, Rick A.; Dorman, David C.; Conolly, Rory B.; Knudsen, Thomas; Erstad, Brian L.; Luecke, Richard H.; Faustman, Elaine M.; Timchalk, Chuck; Mattison, Donald R.

2005-07-26

A workshop was conducted on November 18?19, 2004, to address the issue of improving predictive models for drug delivery to developing humans. Although considerable progress has been made for adult humans, large gaps remain for predicting pharmacokinetic/pharmacodynamic (PK/PD) outcome in children because most adult models have not been tested during development. The goals of the meeting included a description of when, during development, infants/children become adultlike in handling drugs. The issue of incorporating the most recent advances into the predictive models was also addressed: both the use of imaging approaches and genomic information were considered. Disease state, as exemplified by obesity, was addressed as a modifier of drug pharmacokinetics and pharmacodynamics during development. Issues addressed in this workshop should be considered in the development of new predictive and mechanistic models of drug kinetics and dynamics in the developing human.

Characterization of cementitiously stabilized subgrades for mechanistic-empirical pavement design

Science.gov (United States)

Solanki, Pranshoo

Pavements are vulnerable to subgrade layer performance because it acts as a foundation. Due to increase in the truck traffic, pavement engineers are challenged to build more strong and long-lasting pavements. To increase the load-bearing capacity of pavements, subgrade layer is often stabilized with cementitious additives. Thus, an overall characterization of stabilized subgrade layer is important for enhanced short- and long-term pavement performance. In this study, the effect of type and amount of additive on the short-term performance in terms of material properties recommended by the new Mechanistic-Empirical Pavement Design Guide (MEPDG) is examined. A total of four soils commonly encountered as subgrades in Oklahoma are utilized. Results show that the changes in the Mr, ME and UCS values stabilized specimens depend on the soil type and properties of additives. The long-term performance (or durability) of stabilized soil specimens is investigated by conducting freeze-thaw (F-T) cycling, vacuum saturation and tube suction tests on 7-day cured P-, K- and C-soil specimens stabilized with 6% lime, 10% CFA and 10% CKD. This study is motivated by the fact that during the service life of pavement stabilized layers are subjected to F-T cycles and moisture variations. It is found that that UCS value of all the stabilized specimens decreased with increase in the number of F-T cycles. A strong correlation was observed between UCS values retained after vacuum saturation and F-T cycles indicating that vacuum saturation could be used as a time-efficient and inexpensive method for evaluating durability of stabilized soils. In this study, short- and long-term observations from stabilization of sulfate bearing soil with locally available low (CFA), moderate (CKD) and high (lime) calcium-based stabilizers are determined to evaluate and compare the effect of additive type on the phenomenon of sulfate-induced heave. The impact of different factors on the development of the

Respiratory cancer risks associated with low-level nickel exposure: an integrated assessment based on animal, epidemiological, and mechanistic data.

Science.gov (United States)

Seilkop, Steven K; Oller, Adriana R

2003-04-01

Increased lung and nasal cancer risks have been reported in several cohorts of nickel refinery workers, but in more than 90% of the nickel-exposed workers that have been studied there is little, if any evidence of excess risk. This investigation utilizes human exposure measurements, animal data from cancer bioassays of three nickel compounds, and a mechanistic theory of nickel carcinogenesis to reconcile the disparities in lung cancer risk among nickel-exposed workers. Animal data and mechanistic theory suggest that the apparent absence of risk in workers with low nickel exposures is due to threshold-like responses in lung tumor incidence (oxidic nickel), tumor promotion (soluble nickel), and genetic damage (sulfidic nickel). When animal-based lung cancer dose-response functions for these compounds are extrapolated to humans, taking into account interspecies differences in deposition and clearance, differences in particle size distributions, and human work activity patterns, the predicted risks at occupational exposures are remarkably similar to those observed in nickel-exposed workers. This provides support for using the animal-based dose-response functions to estimate occupational exposure limits, which are found to be comparable to those in current use.

Cross-study and cross-omics comparisons of three nephrotoxic compounds reveal mechanistic insights and new candidate biomarkers

International Nuclear Information System (INIS)

Matheis, Katja A.; Com, Emmanuelle; Gautier, Jean-Charles; Guerreiro, Nelson; Brandenburg, Arnd; Gmuender, Hans; Sposny, Alexandra; Hewitt, Philip; Amberg, Alexander; Boernsen, Olaf; Riefke, Bjoern; Hoffmann, Dana; Mally, Angela; Kalkuhl, Arno; Suter, Laura; Dieterle, Frank; Staedtler, Frank

2011-01-01

The European InnoMed-PredTox project was a collaborative effort between 15 pharmaceutical companies, 2 small and mid-sized enterprises, and 3 universities with the goal of delivering deeper insights into the molecular mechanisms of kidney and liver toxicity and to identify mechanism-linked diagnostic or prognostic safety biomarker candidates by combining conventional toxicological parameters with 'omics' data. Mechanistic toxicity studies with 16 different compounds, 2 dose levels, and 3 time points were performed in male Crl: WI(Han) rats. Three of the 16 investigated compounds, BI-3 (FP007SE), Gentamicin (FP009SF), and IMM125 (FP013NO), induced kidney proximal tubule damage (PTD). In addition to histopathology and clinical chemistry, transcriptomics microarray and proteomics 2D-DIGE analysis were performed. Data from the three PTD studies were combined for a cross-study and cross-omics meta-analysis of the target organ. The mechanistic interpretation of kidney PTD-associated deregulated transcripts revealed, in addition to previously described kidney damage transcript biomarkers such as KIM-1, CLU and TIMP-1, a number of additional deregulated pathways congruent with histopathology observations on a single animal basis, including a specific effect on the complement system. The identification of new, more specific biomarker candidates for PTD was most successful when transcriptomics data were used. Combining transcriptomics data with proteomics data added extra value.

Indian Hedgehog Controls Proliferation and Differentiation in Skin Tumorigenesis and Protects against Malignant Progression

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Parisa Kakanj

2013-07-01

Full Text Available Mutations in the hedgehog pathway drive the formation of tumors in many different organs, including the development of basal cell carcinoma in the skin. However, little is known about the role of epidermal Indian hedgehog (Ihh in skin physiology. Using mouse genetics, we identified overlapping and distinct functions of Ihh in different models of epidermal tumorigenesis. Epidermal deletion of Ihh resulted in increased formation of benign squamous papilloma. Strikingly, Ihh-deficient mice showed an increase in malignant squamous cell carcinoma and developed lung and lymph node metastases. In a sebaceous gland tumor model, Ihh deficiency inhibited tumor cell differentiation. More mechanistically, IHH stimulated cell proliferation by activating the transcription factor GLI2 in human keratinocytes and human tumors. Thus, our results uncover important functions for Ihh signaling in controlling proliferation, differentiation, malignant progression, and metastasis of epithelial cancer, establishing Ihh as a gatekeeper for controlling the grade of tumor malignancy.

A rigorous mechanistic model for predicting gas hydrate formation kinetics: The case of CO2 recovery and sequestration

International Nuclear Information System (INIS)

ZareNezhad, Bahman; Mottahedin, Mona

2012-01-01

Highlights: ► A mechanistic model for predicting gas hydrate formation kinetics is presented. ► A secondary nucleation rate model is proposed for the first time. ► Crystal–crystal collisions and crystal–impeller collisions are distinguished. ► Simultaneous determination of nucleation and growth kinetics are established. ► Important for design of gas hydrate based energy storage and CO 2 recovery systems. - Abstract: A rigorous mechanistic model for predicting gas hydrate formation crystallization kinetics is presented and the special case of CO 2 gas hydrate formation regarding CO 2 recovery and sequestration processes has been investigated by using the proposed model. A physical model for prediction of secondary nucleation rate is proposed for the first time and the formation rates of secondary nuclei by crystal–crystal collisions and crystal–impeller collisions are formulated. The objective functions for simultaneous determination of nucleation and growth kinetics are presented and a theoretical framework for predicting the dynamic behavior of gas hydrate formation is presented. Predicted time variations of CO 2 content, total number and surface area of produced hydrate crystals are in good agreement with the available experimental data. The proposed approach can have considerable application for design of gas hydrate converters regarding energy storage and CO 2 recovery processes.

Reducing Uncertainty in the Daycent Model of Heterotrophic Respiration with a More Mechanistic Representation of Microbial Processes.

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Berardi, D.; Gomez-Casanovas, N.; Hudiburg, T. W.

2017-12-01

Improving the certainty of ecosystem models is essential to ensuring their legitimacy, value, and ability to inform management and policy decisions. With more than a century of research exploring the variables controlling soil respiration, a high level of uncertainty remains in the ability of ecosystem models to accurately estimate respiration with changing climatic conditions. Refining model estimates of soil carbon fluxes is a high priority for climate change scientists to determine whether soils will be carbon sources or sinks in the future. We found that DayCent underestimates heterotrophic respiration by several magnitudes for our temperate mixed conifer forest site. While traditional ecosystem models simulate decomposition through first order kinetics, recent research has found that including microbial mechanisms explains 20 percent more spatial heterogeneity. We manipulated the DayCent heterotrophic respiration model to include a more mechanistic representation of microbial dynamic and compared the new model with continuous and survey observations from our experimental forest site in the Northern Rockies ecoregion. We also calibrated the model's sensitivity to soil moisture and temperature to our experimental data. We expect to improve the accuracy of the model by 20-30 percent. By using a more representative and calibrated model of soil carbon dynamics, we can better predict feedbacks between climate and soil carbon pools.

Ionizing radiation induced cataracts: Recent biological and mechanistic developments and perspectives for future research.

Science.gov (United States)

Ainsbury, Elizabeth A; Barnard, Stephen; Bright, Scott; Dalke, Claudia; Jarrin, Miguel; Kunze, Sarah; Tanner, Rick; Dynlacht, Joseph R; Quinlan, Roy A; Graw, Jochen; Kadhim, Munira; Hamada, Nobuyuki

The lens of the eye has long been considered as a radiosensitive tissue, but recent research has suggested that the radiosensitivity is even greater than previously thought. The 2012 recommendation of the International Commission on Radiological Protection (ICRP) to substantially reduce the annual occupational equivalent dose limit for the ocular lens has now been adopted in the European Union and is under consideration around the rest of the world. However, ICRP clearly states that the recommendations are chiefly based on epidemiological evidence because there are a very small number of studies that provide explicit biological, mechanistic evidence at doses <2Gy. This paper aims to present a review of recently published information on the biological and mechanistic aspects of cataracts induced by exposure to ionizing radiation (IR). The data were compiled by assessing the pertinent literature in several distinct areas which contribute to the understanding of IR induced cataracts, information regarding lens biology and general processes of cataractogenesis. Results from cellular and tissue level studies and animal models, and relevant human studies, were examined. The main focus was the biological effects of low linear energy transfer IR, but dosimetry issues and a number of other confounding factors were also considered. The results of this review clearly highlight a number of gaps in current knowledge. Overall, while there have been a number of recent advances in understanding, it remains unknown exactly how IR exposure contributes to opacification. A fuller understanding of how exposure to relatively low doses of IR promotes induction and/or progression of IR-induced cataracts will have important implications for prevention and treatment of this disease, as well as for the field of radiation protection. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

Coupling Temperature Control with Electrochemically Modulated Liquid Chromatography: Fundamental Aspects and Applications

Energy Technology Data Exchange (ETDEWEB)

Ponton, Lisa M. [Iowa State Univ., Ames, IA (United States)

2004-12-19

The primary focus of the doctoral research presented herein has been the integration of temperature control into electrochemically modulated liquid chromatography (EMLC). The combination of temperature control and the tunable characteristics of carbonaceous EMLC stationary phases have been invaluable in deciphering the subtleties of the retention mechanism. The effects of temperature and E_app on the retention of several naphthalene disulfonates were therefore examined by the van' Hoff relationship. The results indicate that while the retention of both compounds is exothermic at levels comparable to that in many reversed-phase separations, the potential dependence of the separation is actually entropically affected in a manner paralleling that of several classical ion exchange systems. Furthermore, the retention of small inorganic anions at constant temperature also showed evidence of an ion exchange type of mechanism. While a more complete mechanistic description will come from examining the thermodynamics of retention for a wider variety of analytes, this research has laid the groundwork for full exploitation of temperature as a tool to develop retention rules for EMLC. Operating EMLC at elevated temperature and flow conditions has decreased analysis time and has enabled the separation of analytes not normally achievable on a carbon stationary phase. The separation of several aromatic sulfonates was achieved in less than 1 min, a reduction of analysis time by more than a factor of 20 as compared to room temperature separations. The use of higher operating temperatures also facilitated the separation of this mixture with an entirely aqueous mobile phase in less than 2 min. This methodology was extended to the difficult separation of polycyclic aromatic hydrocarbons on PGC. This study also brought to light the mechanistic implications of the unique retention behavior of these analytes through variations of the mobile phase composition.

Abscisic Acid: A Novel Nutraceutical for Glycemic Control

Science.gov (United States)

Zocchi, Elena; Hontecillas, Raquel; Leber, Andrew; Einerhand, Alexandra; Carbo, Adria; Bruzzone, Santina; Tubau-Juni, Nuria; Philipson, Noah; Zoccoli-Rodriguez, Victoria; Sturla, Laura; Bassaganya-Riera, Josep

2017-01-01

Abscisic acid is naturally present in fruits and vegetables, and it plays an important role in managing glucose homeostasis in humans. According to the latest U.S. dietary survey, about 92% of the population might have a deficient intake of ABA due to their deficient intake of fruits and vegetables. This review summarizes the in vitro, preclinical, mechanistic, and human translational findings obtained over the past 15 years in the study of the role of ABA in glycemic control. In 2007, dietary ABA was first reported to ameliorate glucose tolerance and obesity-related inflammation in mice. The most recent findings regarding the topic of ABA and its proposed receptor lanthionine synthetase C-like 2 in glycemic control and their interplay with insulin and glucagon-like peptide-1 suggest a major role for ABA in the physiological response to a glucose load in humans. Moreover, emerging evidence suggests that the ABA response might be dysfunctional in diabetic subjects. Follow on intervention studies in healthy individuals show that low-dose dietary ABA administration exerts a beneficial effect on the glycemia and insulinemia profiles after oral glucose load. These recent findings showing benefits in humans, together with extensive efficacy data in mouse models of diabetes and inflammatory disease, suggest the need for reference ABA values and its possible exploitation of the glycemia-lowering effects of ABA for preventative purposes. Larger clinical studies on healthy, prediabetic, and diabetic subjects are needed to determine whether addressing the widespread dietary ABA deficiency improves glucose control in humans. PMID:28660193

Clinical evidence and mechanistic basis for vildagliptin’s effect in combination with insulin

Science.gov (United States)

Schweizer, Anja; Foley, James E; Kothny, Wolfgang; Ahrén, Bo

2013-01-01

Due to the progressive nature of type 2 diabetes, many patients need insulin as add-on to oral antidiabetic drugs (OADs) in order to maintain adequate glycemic control. Insulin therapy primarily targets elevated fasting glycemia but is less effective to reduce postprandial hyperglycemia. In addition, the risk of hypoglycemia limits its effectiveness and there is a concern of weight gain. These drawbacks may be overcome by combining insulin with incretin-based therapies as these increase glucose sensitivity of both the α- and β-cells, resulting in improved postprandial glycemia without the hypoglycemia and weight gain associated with increasing the dose of insulin. The dipeptidyl peptidase-IV (DPP-4) inhibitor vildagliptin has also been shown to protect from hypoglycemia by enhancing glucagon counterregulation. The effectiveness of combining vildagliptin with insulin was demonstrated in three different studies in which vildagliptin decreased A1C levels when added to insulin therapy without increasing hypoglycemia. This was established with and without concomitant metformin therapy. Furthermore, the effectiveness of vildagliptin appears to be greater when insulin is used as a basal regimen as opposed to being used to reduce postprandial hyperglycemia, since improvement in insulin secretion likely plays a minor role when relatively high doses of insulin are administered before meals. This article reviews the clinical experience with the combination of vildagliptin and insulin and discusses the mechanistic basis for the beneficial effects of the combination. The data support the use of vildagliptin in combination with insulin in general and, in line with emerging clinical practice, suggest that treating patients with vildagliptin, metformin, and basal insulin could be an attractive therapeutic option. PMID:23431062

Toward a mechanistic modeling of nitrogen limitation for photosynthesis

Science.gov (United States)

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

Acridone derivative 8a induces oxidative stress-mediated apoptosis in CCRF-CEM leukemia cells: application of metabolomics in mechanistic studies of antitumor agents.

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Yini Wang

Full Text Available A new acridone derivative, 2-aminoacetamido-10-(3, 5-dimethoxy-benzyl-9(10H-acridone hydrochloride (named 8a synthesized in our lab shows potent antitumor activity, but the mechanism of action remains unclear. Herein, we report the use of an UPLC/Q-TOF MS metabolomic approach to study the effects of three compounds with structures optimized step-by-step, 9(10H-acridone (A, 10-(3,5-dimethoxybenzyl-9(10H-acridone (I, and 8a, on CCRF-CEM leukemia cells and to shed new light on the probable antitumor mechanism of 8a. Acquired data were processed by principal component analysis (PCA and orthogonal partial least squares discriminant analysis (OPLS-DA to identify potential biomarkers. Comparing 8a-treated CCRF-CEM leukemia cells with vehicle control (DMSO, 23 distinct metabolites involved in five metabolic pathways were identified. Metabolites from glutathione (GSH and glycerophospholipid metabolism were investigated in detail, and results showed that GSH level and the reduced/oxidized glutathione (GSH/GSSG ratio were significantly decreased in 8a-treated cells, while L-cysteinyl-glycine (L-Cys-Gly and glutamate were greatly increased. In glycerophospholipid metabolism, cell membrane components phosphatidylcholines (PCs were decreased in 8a-treated cells, while the oxidative products lysophosphatidylcholines (LPCs were significantly increased. We further found that in 8a-treated cells, the reactive oxygen species (ROS and lipid peroxidation product malondialdehyde (MDA were notably increased, accompanied with decrease of mitochondrial transmembrane potential, release of cytochrome C and activation of caspase-3. Taken together our results suggest that the acridone derivative 8a induces oxidative stress-mediated apoptosis in CCRF-CEM leukemia cells. The UPLC/Q-TOF MS based metabolomic approach provides novel insights into the mechanistic studies of antitumor drugs from a point distinct from traditional biological investigations.

Anodic Cyclization Reactions and the Mechanistic Strategies That Enable Optimization.

Science.gov (United States)

Feng, Ruozhu; Smith, Jake A; Moeller, Kevin D

2017-09-19

Oxidation reactions are powerful tools for synthesis because they allow us to reverse the polarity of electron-rich functional groups, generate highly reactive intermediates, and increase the functionality of molecules. For this reason, oxidation reactions have been and continue to be the subject of intense study. Central to these efforts is the development of mechanism-based strategies that allow us to think about the reactive intermediates that are frequently central to the success of the reactions and the mechanistic pathways that those intermediates trigger. For example, consider oxidative cyclization reactions that are triggered by the removal of an electron from an electron-rich olefin and lead to cyclic products that are functionalized for further elaboration. For these reactions to be successful, the radical cation intermediate must first be generated using conditions that limit its polymerization and then channeled down a productive desired pathway. Following the cyclization, a second oxidation step is necessary for product formation, after which the resulting cation must be quenched in a controlled fashion to avoid undesired elimination reactions. Problems can arise at any one or all of these steps, a fact that frequently complicates reaction optimization and can discourage the development of new transformations. Fortunately, anodic electrochemistry offers an outstanding opportunity to systematically probe the mechanism of oxidative cyclization reactions. The use of electrochemical methods allows for the generation of radical cations under neutral conditions in an environment that helps prevent polymerization of the intermediate. Once the intermediates have been generated, a series of "telltale indicators" can be used to diagnose which step in an oxidative cyclization is problematic for less successful transformation. A set of potential solutions to address each type of problem encountered has been developed. For example, problems with the initial

Linking metabolic QTLs with network and cis-eQTLs controlling biosynthetic pathways.

Directory of Open Access Journals (Sweden)

Adam M Wentzell

2007-09-01

Full Text Available Phenotypic variation between individuals of a species is often under quantitative genetic control. Genomic analysis of gene expression polymorphisms between individuals is rapidly gaining popularity as a way to query the underlying mechanistic causes of variation between individuals. However, there is little direct evidence of a linkage between global gene expression polymorphisms and phenotypic consequences. In this report, we have mapped quantitative trait loci (QTLs-controlling glucosinolate content in a population of 403 Arabidopsis Bay x Sha recombinant inbred lines, 211 of which were previously used to identify expression QTLs controlling the transcript levels of biosynthetic genes. In a comparative study, we have directly tested two plant biosynthetic pathways for association between polymorphisms controlling biosynthetic gene transcripts and the resulting metabolites within the Arabidopsis Bay x Sha recombinant inbred line population. In this analysis, all loci controlling expression variation also affected the accumulation of the resulting metabolites. In addition, epistasis was detected more frequently for metabolic traits compared to transcript traits, even when both traits showed similar distributions. An analysis of candidate genes for QTL-controlling networks of transcripts and metabolites suggested that the controlling factors are a mix of enzymes and regulatory factors. This analysis showed that regulatory connections can feedback from metabolism to transcripts. Surprisingly, the most likely major regulator of both transcript level for nearly the entire pathway and aliphatic glucosinolate accumulation is variation in the last enzyme in the biosynthetic pathway, AOP2. This suggests that natural variation in transcripts may significantly impact phenotypic variation, but that natural variation in metabolites or their enzymatic loci can feed back to affect the transcripts.

A Divergent Mechanistic Course of Pd(0)-Catalyzed Aza-Claisen Rearrangement and Aza-Rautenstrauch-Type Cyclization of N-Allyl-Ynamides

Science.gov (United States)

DeKorver, Kyle A.; Hsung, Richard P.; Lohse, Andrew G.; Zhang, Yu

2010-01-01

A fascinating mechanistic study of ynamido-palladium-π-allyl complexes is described that features isolation of a unique silyl-ketenimine via aza-Claisen rearrangement, which can be accompanied by an unusual thermal N-to-C 1,3-Ts shift in the formation of tertiary nitriles, and a novel cyclopentenimine formation via a palladium catalyzed aza-Rautenstrauch-type cyclization pathway. PMID:20337418

Modeling and validation of a mechanistic tool (MEFISTO) for the prediction of critical power in BWR fuel assemblies

International Nuclear Information System (INIS)

Adamsson, Carl; Le Corre, Jean-Marie

2011-01-01

Highlights: → The MEFISTO code efficiently and accurately predicts the dryout event in a BWR fuel bundle, using a mechanistic model. → A hybrid approach between a fast and robust sub-channel analysis and a three-field two-phase analysis is adopted. → MEFISTO modeling approach, calibration, CPU usage, sensitivity, trend analysis and performance evaluation are presented. → The calibration parameters and process were carefully selected to preserve the mechanistic nature of the code. → The code dryout prediction performance is near the level of fuel-specific empirical dryout correlations. - Abstract: Westinghouse is currently developing the MEFISTO code with the main goal to achieve fast, robust, practical and reliable prediction of steady-state dryout Critical Power in Boiling Water Reactor (BWR) fuel bundle based on a mechanistic approach. A computationally efficient simulation scheme was used to achieve this goal, where the code resolves all relevant field (drop, steam and multi-film) mass balance equations, within the annular flow region, at the sub-channel level while relying on a fast and robust two-phase (liquid/steam) sub-channel solution to provide the cross-flow information. The MEFISTO code can hence provide highly detailed solution of the multi-film flow in BWR fuel bundle while enhancing flexibility and reducing the computer time by an order of magnitude as compared to a standard three-field sub-channel analysis approach. Models for the numerical computation of the one-dimensional field flowrate distributions in an open channel (e.g. a sub-channel), including the numerical treatment of field cross-flows, part-length rods, spacers grids and post-dryout conditions are presented in this paper. The MEFISTO code is then applied to dryout prediction in BWR fuel bundle using VIPRE-W as a fast and robust two-phase sub-channel driver code. The dryout power is numerically predicted by iterating on the bundle power so that the minimum film flowrate in the

Migraine patients consistently show abnormal vestibular bedside tests.

Science.gov (United States)

Maranhão, Eliana Teixeira; Maranhão-Filho, Péricles; Luiz, Ronir Raggio; Vincent, Maurice Borges

2016-01-01

Migraine and vertigo are common disorders, with lifetime prevalences of 16% and 7% respectively, and co-morbidity around 3.2%. Vestibular syndromes and dizziness occur more frequently in migraine patients. We investigated bedside clinical signs indicative of vestibular dysfunction in migraineurs. To test the hypothesis that vestibulo-ocular reflex, vestibulo-spinal reflex and fall risk (FR) responses as measured by 14 bedside tests are abnormal in migraineurs without vertigo, as compared with controls. Cross-sectional study including sixty individuals - thirty migraineurs, 25 women, 19-60 y-o; and 30 gender/age healthy paired controls. Migraineurs showed a tendency to perform worse in almost all tests, albeit only the Romberg tandem test was statistically different from controls. A combination of four abnormal tests better discriminated the two groups (93.3% specificity). Migraine patients consistently showed abnormal vestibular bedside tests when compared with controls.

A mechanistic compartmental model for total antibody uptake in tumors.

Science.gov (United States)

Thurber, Greg M; Dane Wittrup, K

2012-12-07

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. Copyright © 2012 Elsevier Ltd. All rights reserved.

Mechanistic Features of Nanodiamonds in the Lapping of Magnetic Heads

Directory of Open Access Journals (Sweden)

Xionghua Jiang

2014-01-01

Full Text Available Nanodiamonds, which are the main components of slurry in the precision lapping process of magnetic heads, play an important role in surface quality. This paper studies the mechanistic features of nanodiamond embedment into a Sn plate in the lapping process. This is the first study to develop mathematical models for nanodiamond embedment. Such models can predict the optimum parameters for particle embedment. From the modeling calculations, the embedded pressure satisfies p0=3/2·W/πa2 and the indentation depth satisfies δ=k1P/HV. Calculation results reveal that the largest embedded pressure is 731.48 GPa and the critical indentation depth δ is 7 nm. Atomic force microscopy (AFM, scanning electron microscopy (SEM, and Auger electron spectroscopy (AES were used to carry out surface quality detection and analysis of the disk head. Both the formation of black spots on the surface and the removal rate have an important correlation with the size of nanodiamonds. The results demonstrate that an improved removal rate (21 nm·min−1 can be obtained with 100 nm diamonds embedded in the plate.

Mechanistic features of nanodiamonds in the lapping of magnetic heads.

Science.gov (United States)

Jiang, Xionghua; Chen, Zhenxing; Wolfram, Joy; Yang, Zhizhou

2014-01-01

Nanodiamonds, which are the main components of slurry in the precision lapping process of magnetic heads, play an important role in surface quality. This paper studies the mechanistic features of nanodiamond embedment into a Sn plate in the lapping process. This is the first study to develop mathematical models for nanodiamond embedment. Such models can predict the optimum parameters for particle embedment. From the modeling calculations, the embedded pressure satisfies p 0 = (3/2) · (W/πa (2)) and the indentation depth satisfies δ = k1√P/HV. Calculation results reveal that the largest embedded pressure is 731.48 GPa and the critical indentation depth δ is 7 nm. Atomic force microscopy (AFM), scanning electron microscopy (SEM), and Auger electron spectroscopy (AES) were used to carry out surface quality detection and analysis of the disk head. Both the formation of black spots on the surface and the removal rate have an important correlation with the size of nanodiamonds. The results demonstrate that an improved removal rate (21 nm · min(-1)) can be obtained with 100 nm diamonds embedded in the plate.

Identification of a set of genes showing regionally enriched expression in the mouse brain

Directory of Open Access Journals (Sweden)

Marra Marco A

2008-07-01

Full Text Available Abstract Background The Pleiades Promoter Project aims to improve gene therapy by designing human mini-promoters ( Results We have utilized LongSAGE to identify regionally enriched transcripts in the adult mouse brain. As supplemental strategies, we also performed a meta-analysis of published literature and inspected the Allen Brain Atlas in situ hybridization data. From a set of approximately 30,000 mouse genes, 237 were identified as showing specific or enriched expression in 30 target regions of the mouse brain. GO term over-representation among these genes revealed co-involvement in various aspects of central nervous system development and physiology. Conclusion Using a multi-faceted expression validation approach, we have identified mouse genes whose human orthologs are good candidates for design of mini-promoters. These mouse genes represent molecular markers in several discrete brain regions/cell-types, which could potentially provide a mechanistic explanation of unique functions performed by each region. This set of markers may also serve as a resource for further studies of gene regulatory elements influencing brain expression.

Mechanistic Target of Rapamycin Is a Novel Molecular Mechanism Linking Folate Availability and Cell Function.

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Silva, Elena; Rosario, Fredrick J; Powell, Theresa L; Jansson, Thomas

2017-07-01

Folate deficiency has been linked to a wide range of disorders, including cancer, neural tube defects, and fetal growth restriction. Folate regulates cellular function mediated by its involvement in the synthesis of nucleotides, which are needed for DNA synthesis, and its function as a methyl donor, which is critical for DNA methylation. Here we review current data showing that folate sensing by mechanistic target of rapamycin (mTOR) constitutes a novel and distinct pathway by which folate modulates cell functions such as nutrient transport, protein synthesis, and mitochondrial respiration. The mTOR signaling pathway responds to growth factors and changes in nutrient availability to control cell growth, proliferation, and metabolism. mTOR exists in 2 complexes, mTOR complex (mTORC) 1 and mTORC2, which have distinct upstream regulators and downstream targets. Folate deficiency in pregnant mice caused a marked inhibition of mTORC1 and mTORC2 signaling in multiple maternal and fetal tissues, downregulation of placental amino acid transporters, and fetal growth restriction. In addition, folate deficiency in primary human trophoblast (PHT) cells resulted in inhibition of mTORC1 and mTORC2 signaling and decreased the activity of key amino acid transporters. Folate sensing by mTOR in PHT cells is independent of the accumulation of homocysteine and requires the proton-coupled folate transporter (PCFT; solute carrier 46A1). Furthermore, mTORC1 and mTORC2 regulate trophoblast folate uptake by modulating the cell surface expression of folate receptor α and the reduced folate carrier. These findings, which provide a novel link between folate availability and cell function, growth, and proliferation, may have broad biological significance given the critical role of folate in normal cell function and the multiple diseases that have been associated with decreased or excessive folate availability. Low maternal folate concentrations are linked to restricted fetal growth, and we

Anodal Transcranial Direct Current Stimulation Shows Minimal, Measure-Specific Effects on Dynamic Postural Control in Young and Older Adults: A Double Blind, Sham-Controlled Study.

Science.gov (United States)

Craig, Chesney E; Doumas, Michail

2017-01-01

We investigated whether stimulating the cerebellum and primary motor cortex (M1) using transcranial direct current stimulation (tDCS) could affect postural control in young and older adults. tDCS was employed using a double-blind, sham-controlled design, in which young (aged 18-35) and older adults (aged 65+) were assessed over three sessions, one for each stimulatory condition-M1, cerebellar and sham. The effect of tDCS on postural control was assessed using a sway-referencing paradigm, which induced platform rotations in proportion to the participant's body sway, thus assessing sensory reweighting processes. Task difficulty was manipulated so that young adults experienced a support surface that was twice as compliant as that of older adults, in order to minimise baseline age differences in postural sway. Effects of tDCS on postural control were assessed during, immediately after and 30 minutes after tDCS. Additionally, the effect of tDCS on corticospinal excitability was measured by evaluating motor evoked potentials using transcranial magnetic stimulation immediately after and 30 minutes after tDCS. Minimal effects of tDCS on postural control were found in the eyes open condition only, and this was dependent on the measure assessed and age group. For young adults, stimulation had only offline effects, as cerebellar stimulation showed higher mean power frequency (MPF) of sway 30 minutes after stimulation. For older adults, both stimulation conditions delayed the increase in sway amplitude witnessed between blocks one and two until stimulation was no longer active. In conclusion, despite tDCS' growing popularity, we would caution researchers to consider carefully the type of measures assessed and the groups targeted in tDCS studies of postural control.

Semi-mechanistic partial buffer approach to modeling pH, the buffer properties, and the distribution of ionic species in complex solutions.

Science.gov (United States)

Dougherty, Daniel P; Da Conceicao Neta, Edith Ramos; McFeeters, Roger F; Lubkin, Sharon R; Breidt, Frederick

2006-08-09

In many biological science and food processing applications, it is very important to control or modify pH. However, the complex, unknown composition of biological media and foods often limits the utility of purely theoretical approaches to modeling pH and calculating the distributions of ionizable species. This paper provides general formulas and efficient algorithms for predicting the pH, titration, ionic species concentrations, buffer capacity, and ionic strength of buffer solutions containing both defined and undefined components. A flexible, semi-mechanistic, partial buffering (SMPB) approach is presented that uses local polynomial regression to model the buffering influence of complex or undefined components in a solution, while identified components of known concentration are modeled using expressions based on extensions of the standard acid-base theory. The SMPB method is implemented in a freeware package, (pH)Tools, for use with Matlab. We validated the predictive accuracy of these methods by using strong acid titrations of cucumber slurries to predict the amount of a weak acid required to adjust pH to selected target values.

Diethylene glycol-induced toxicities show marked threshold dose response in rats

Energy Technology Data Exchange (ETDEWEB)

Landry, Greg M., E-mail: Landry.Greg@mayo.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Dunning, Cody L., E-mail: cdunni@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Abreo, Fleurette, E-mail: fabreo@lsuhsc.edu [Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Latimer, Brian, E-mail: blatim@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Orchard, Elysse, E-mail: eorcha@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Division of Animal Resources, Louisiana State University Health Sciences Center, Shreveport, LA (United States); McMartin, Kenneth E., E-mail: kmcmar@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States)

2015-02-01

Diethylene glycol (DEG) exposure poses risks to human health because of widespread industrial use and accidental exposures from contaminated products. To enhance the understanding of the mechanistic role of metabolites in DEG toxicity, this study used a dose response paradigm to determine a rat model that would best mimic DEG exposure in humans. Wistar and Fischer-344 (F-344) rats were treated by oral gavage with 0, 2, 5, or 10 g/kg DEG and blood, kidney and liver tissues were collected at 48 h. Both rat strains treated with 10 g/kg DEG had equivalent degrees of metabolic acidosis, renal toxicity (increased BUN and creatinine and cortical necrosis) and liver toxicity (increased serum enzyme levels, centrilobular necrosis and severe glycogen depletion). There was no liver or kidney toxicity at the lower DEG doses (2 and 5 g/kg) regardless of strain, demonstrating a steep threshold dose response. Kidney diglycolic acid (DGA), the presumed nephrotoxic metabolite of DEG, was markedly elevated in both rat strains administered 10 g/kg DEG, but no DGA was present at 2 or 5 g/kg, asserting its necessary role in DEG-induced toxicity. These results indicate that mechanistically in order to produce toxicity, metabolism to and significant target organ accumulation of DGA are required and that both strains would be useful for DEG risk assessments. - Highlights: • DEG produces a steep threshold dose response for kidney injury in rats. • Wistar and F-344 rats do not differ in response to DEG-induced renal injury. • The dose response for renal injury closely mirrors that for renal DGA accumulation. • Results demonstrate the importance of DGA accumulation in producing kidney injury.

Migraine patients consistently show abnormal vestibular bedside tests

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Eliana Teixeira Maranhão

2015-01-01

Full Text Available Migraine and vertigo are common disorders, with lifetime prevalences of 16% and 7% respectively, and co-morbidity around 3.2%. Vestibular syndromes and dizziness occur more frequently in migraine patients. We investigated bedside clinical signs indicative of vestibular dysfunction in migraineurs.Objective To test the hypothesis that vestibulo-ocular reflex, vestibulo-spinal reflex and fall risk (FR responses as measured by 14 bedside tests are abnormal in migraineurs without vertigo, as compared with controls.Method Cross-sectional study including sixty individuals – thirty migraineurs, 25 women, 19-60 y-o; and 30 gender/age healthy paired controls.Results Migraineurs showed a tendency to perform worse in almost all tests, albeit only the Romberg tandem test was statistically different from controls. A combination of four abnormal tests better discriminated the two groups (93.3% specificity.Conclusion Migraine patients consistently showed abnormal vestibular bedside tests when compared with controls.

In silico, experimental, mechanistic model for extended-release felodipine disposition exhibiting complex absorption and a highly variable food interaction.

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Sean H J Kim

Full Text Available 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.

ALIX and ESCRT-III coordinately control cytokinetic abscission during germline stem cell division in vivo.

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Åsmund H Eikenes

2015-01-01

Full Text Available Abscission is the final step of cytokinesis that involves the cleavage of the intercellular bridge connecting the two daughter cells. Recent studies have given novel insight into the spatiotemporal regulation and molecular mechanisms controlling abscission in cultured yeast and human cells. The mechanisms of abscission in living metazoan tissues are however not well understood. Here we show that ALIX and the ESCRT-III component Shrub are required for completion of abscission during Drosophila female germline stem cell (fGSC division. Loss of ALIX or Shrub function in fGSCs leads to delayed abscission and the consequent formation of stem cysts in which chains of daughter cells remain interconnected to the fGSC via midbody rings and fusome. We demonstrate that ALIX and Shrub interact and that they co-localize at midbody rings and midbodies during cytokinetic abscission in fGSCs. Mechanistically, we show that the direct interaction between ALIX and Shrub is required to ensure cytokinesis completion with normal kinetics in fGSCs. We conclude that ALIX and ESCRT-III coordinately control abscission in Drosophila fGSCs and that their complex formation is required for accurate abscission timing in GSCs in vivo.

Mechanistic Implications for the Ni(I-Catalyzed Kumada Cross-Coupling Reaction

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Linda Iffland

2017-11-01

Full Text Available Herein we report on the cross-coupling reaction of phenylmagnesium bromide with aryl halides using the well-defined tetrahedral Ni(I complex, [(TriphosNiICl] (Triphos = 1,1,1-tris(diphenylphosphinomethylethane. In the presence of 0.5 mol % [(TriphosNiICl], good to excellent yields (75–97% of the respective coupling products within a reaction time of only 2.5 h at room temperature were achieved. Likewise, the tripodal Ni(IIcomplexes [(κ2-TriphosNiIICl2] and [(κ3-TriphosNiIICl](X (X = ClO4, BF4 were tested as potential pre-catalysts for the Kumada cross-coupling reaction. While the Ni(II complexes also afford the coupling products in comparable yields, mechanistic investigations by UV/Vis and electron paramagnetic resonance (EPR spectroscopy indicate a Ni(I intermediate as the catalytically active species in the Kumada cross-coupling reaction. Based on experimental findings and density functional theory (DFT calculations, a plausible Ni(I-catalyzed reaction mechanism for the Kumada cross-coupling reaction is presented.

Galvanic Replacement Coupled to Seeded Growth as a Route for Shape-Controlled Synthesis of Plasmonic Nanorattles.

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Polavarapu, Lakshminarayana; Zanaga, Daniele; Altantzis, Thomas; Rodal-Cedeira, Sergio; Pastoriza-Santos, Isabel; Pérez-Juste, Jorge; Bals, Sara; Liz-Marzán, Luis M

2016-09-14

Shape-controlled synthesis of metal nanoparticles (NPs) requires mechanistic understanding toward the development of modern nanoscience and nanotechnology. We demonstrate here an unconventional shape transformation of Au@Ag core-shell NPs (nanorods and nanocubes) into octahedral nanorattles via room-temperature galvanic replacement coupled with seeded growth. The corresponding morphological and chemical transformations were investigated in three dimensions, using state-of-the-art X-ray energy-dispersive spectroscopy (XEDS) tomography. The addition of a reducing agent (ascorbic acid) plays a key role in this unconventional mechanistic path, in which galvanic replacement is found to dominate initially when the shell is made of Ag, while seeded growth suppresses transmetalation when a composition of Au:Ag (∼60:40) is reached in the shell, as revealed by quantitative XEDS tomography. This work not only opens new avenues toward the shape control of hollow NPs beyond the morphology of sacrificial templates, but also expands our understanding of chemical transformations in nanoscale galvanic replacement reactions. The XEDS electron tomography study presented here can be generally applied to investigate a wide range of nanoscale morphological and chemical transformations.

Mechanistic approach to the sodium leakage and fire analysis

International Nuclear Information System (INIS)

Yamaguchi, Akira; Muramatsu, Toshiharu; Ohira, Hiroaki; Ida, Masao

1997-04-01

In December 1995, a thermocouple well was broken and liquid sodium leaked out of the intermediate heat transport system of the prototype fast breeder reactor Monju. In the initiating process of the incident, liquid sodium flowed out through the hollow thermocouple well, nipple and connector. As a result, liquid sodium, following ignition and combustion, was dropping from the connector to colide with the duct and grating placed below. The collision may cause fragmentation and scattering of the sodium droplet that finally was piled up on the floor. This report deals with the development of computer programs for the phenomena based on mechanistics approach. Numerical analyses are also made for fundamental sodium leakage and combustion phenomenon, sodium combustion experiment, and Monju incident condition. The contents of this report is listed below: (1) Analysis of chemical reaction process based on molecular orbital method, (2) Thermalhy draulic analysis of the sodium combustion experiment II performed in 1996 at O-arai Engineering Center, PNC, (3) Thermalhy draulic analysis of room A-446 of Monju reactor when the sodium leakage took place, (4) Direct numerical simulation of sodium droplet, (5) Sodium leakage and scattering analysis using three dimensional particle method, (6) Multi-dimensional combustion analysis and multi-point approximation combustion analysis code. Subsequent to the development work of the programs, they are to be applied to the safety analysis of the Fast Breeder Reactor. (author)

Hidden Hydride Transfer as a Decisive Mechanistic Step in the Reactions of the Unligated Gold Carbide [AuC]+ with Methane under Ambient Conditions.

Science.gov (United States)

Li, Jilai; Zhou, Shaodong; Schlangen, Maria; Weiske, Thomas; Schwarz, Helmut

2016-10-10

The reactivity of the cationic gold carbide [AuC] + (bearing an electrophilic carbon atom) towards methane has been studied using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS). The product pairs generated, that is, Au + /C 2 H 4 , [Au(C 2 H 2 )] + /H 2 , and [C 2 H 3 ] + /AuH, point to the breaking and making of C-H, C-C, and H-H bonds under single-collision conditions. The mechanisms of these rather efficient reactions have been elucidated by high-level quantum-chemical calculations. As a major result, based on molecular orbital and NBO-based charge analysis, an unprecedented hydride transfer from methane to the carbon atom of [AuC] + has been identified as a key step. Also, the origin of this novel mechanistic scenario has been addressed. The mechanistic insights derived from this study may provide guidance for the rational design of carbon-based catalysts. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Quality control in aminoacyl-tRNA synthesis its role in translational fidelity

DEFF Research Database (Denmark)

Yadavalli, Srujana S; Ibba, Michael

2012-01-01

mechanisms to achieve high levels of accuracy in aminoacylation. Editing functions in aaRSs contribute to the overall low error rate in protein synthesis. Over 40 years of research on aaRSs using structural, biochemical, and kinetic approaches has expanded our knowledge of their cellular roles and quality...... control mechanisms. Here, we review aaRS editing with an emphasis on the mechanistic and kinetic details of the process....

A Mechanistic Source Term Calculation for a Metal Fuel Sodium Fast Reactor

Energy Technology Data Exchange (ETDEWEB)

Grabaskas, David; Bucknor, Matthew; Jerden, James

2017-06-26

A mechanistic source term (MST) calculation attempts to realistically assess the transport and release of radionuclides from a reactor system to the environment during a specific accident sequence. The U.S. Nuclear Regulatory Commission (NRC) has repeatedly stated its expectation that advanced reactor vendors will utilize an MST during the U.S. reactor licensing process. As part of a project to examine possible impediments to sodium fast reactor (SFR) licensing in the U.S., an analysis was conducted regarding the current capabilities to perform an MST for a metal fuel SFR. The purpose of the project was to identify and prioritize any gaps in current computational tools, and the associated database, for the accurate assessment of an MST. The results of the study demonstrate that an SFR MST is possible with current tools and data, but several gaps exist that may lead to possibly unacceptable levels of uncertainty, depending on the goals of the MST analysis.

Exposure factors for marine eutrophication impacts assessment based on a mechanistic biological model

DEFF Research Database (Denmark)

Cosme, Nuno Miguel Dias; Koski, Marja; Hauschild, Michael Zwicky

2015-01-01

marine ecosystem (LME), five climate zones, and site-generic. The XFs obtained range from 0.45 (Central Arctic Ocean) to 15.9kgO2kgN-1 (Baltic Sea). While LME resolution is recommended, aggregated PE or XF per climate zone can be adopted, but not global aggregation due to high variability. The XF......Emissions of nitrogen (N) from anthropogenic sources enrich marine waters and promote planktonic growth. This newly synthesised organic carbon is eventually exported to benthic waters where aerobic respiration by heterotrophic bacteria results in the consumption of dissolved oxygen (DO......). This pathway is typical of marine eutrophication. A model is proposed to mechanistically estimate the response of coastal marine ecosystems to N inputs. It addresses the biological processes of nutrient-limited primary production (PP), metazoan consumption, and bacterial degradation, in four distinct sinking...

Pre-schoolers suffering from psychiatric disorders show increased cortisol secretion and poor sleep compared to healthy controls.

Science.gov (United States)

Hatzinger, Martin; Brand, Serge; Perren, Sonja; von Wyl, Anges; Stadelmann, Stephanie; von Klitzing, Kai; Holsboer-Trachsler, Edith

2012-05-01

Various studies of child cortisol secretion and sleep show a close association between poor sleep, deterioration of the HPA axis and unfavorable psychological functioning. However, there is little evidence as to whether these associations are clearly present in pre-school children suffering from psychiatric disorders. A total of 30 pre-schoolers suffering from psychiatric disorders (anxiety, adjustment disorders, emotional and attachment disorder; hyperactivity or oppositional disorder) and 35 healthy controls took part in the study. Saliva cortisol secretion was assessed both at baseline and under challenge conditions. Sleep was assessed via activity monitoring for seven consecutive days and nights, using a digital movement-measuring instrument. Parents and teachers completed questionnaires assessing children's cognitive, emotional and social functioning. The Berkeley Puppet Interview provided child-based reports of cognitive-emotional processes. Compared to healthy controls, children suffering from psychiatric disorders had much higher cortisol secretion both at baseline and under challenge conditions. Sleep was also more disturbed, and parents and teachers rated children suffering from psychiatric disorders as cognitively, emotionally and behaviorally more impaired, relative to healthy controls. Children with psychiatric disorders reported being more bullied and victimized. In five-year old children the presence of psychiatric disorders is reflected not only at psychological, social and behavioral, but also at neuroendocrine and sleep-related levels. It is likely that these children remain at increased risk for suffering from psychiatric difficulties later in life. Copyright © 2012 Elsevier Ltd. All rights reserved.

Dopamine Gene Profiling to Predict Impulse Control and Effects of Dopamine Agonist Ropinirole.

Science.gov (United States)

MacDonald, Hayley J; Stinear, Cathy M; Ren, April; Coxon, James P; Kao, Justin; Macdonald, Lorraine; Snow, Barry; Cramer, Steven C; Byblow, Winston D

2016-07-01

Dopamine agonists can impair inhibitory control and cause impulse control disorders for those with Parkinson disease (PD), although mechanistically this is not well understood. In this study, we hypothesized that the extent of such drug effects on impulse control is related to specific dopamine gene polymorphisms. This double-blind, placebo-controlled study aimed to examine the effect of single doses of 0.5 and 1.0 mg of the dopamine agonist ropinirole on impulse control in healthy adults of typical age for PD onset. Impulse control was measured by stop signal RT on a response inhibition task and by an index of impulsive decision-making on the Balloon Analogue Risk Task. A dopamine genetic risk score quantified basal dopamine neurotransmission from the influence of five genes: catechol-O-methyltransferase, dopamine transporter, and those encoding receptors D1, D2, and D3. With placebo, impulse control was better for the high versus low genetic risk score groups. Ropinirole modulated impulse control in a manner dependent on genetic risk score. For the lower score group, both doses improved response inhibition (decreased stop signal RT) whereas the lower dose reduced impulsiveness in decision-making. Conversely, the higher score group showed a trend for worsened response inhibition on the lower dose whereas both doses increased impulsiveness in decision-making. The implications of the present findings are that genotyping can be used to predict impulse control and whether it will improve or worsen with the administration of dopamine agonists.

Application of a Mechanistic Model as a Tool for On-line Monitoring of Pilot Scale Filamentous Fungal Fermentation Processes - The Importance of Evaporation Effects

DEFF Research Database (Denmark)

Mears, Lisa; Stocks, Stuart M.; Albæk, Mads Orla

2017-01-01

A mechanistic model-based soft sensor is developed and validated for 550L filamentous fungus fermentations operated at Novozymes A/S. The soft sensor is comprised of a parameter estimation block based on a stoichiometric balance, coupled to a dynamic process model. The on-line parameter estimation...... a historical dataset of eleven batches from the fermentation pilot plant (550L) at Novozymes A/S. The model is then implemented on-line in 550L fermentation processes operated at Novozymes A/S in order to validate the state estimator model on fourteen new batches utilizing a new strain. The product...... block models the changing rates of formation of product, biomass, and water, and the rate of consumption of feed using standard, available on-line measurements. This parameter estimation block, is coupled to a mechanistic process model, which solves the current states of biomass, product, substrate...

Cationic Pd(II-catalyzed C–H activation/cross-coupling reactions at room temperature: synthetic and mechanistic studies

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Takashi Nishikata

2016-05-01

Full Text Available Cationic palladium(II complexes have been found to be highly reactive towards aromatic C–H activation of arylureas at room temperature. A commercially available catalyst [Pd(MeCN4](BF42 or a nitrile-free cationic palladium(II complex generated in situ from the reaction of Pd(OAc2 and HBF4, effectively catalyzes C–H activation/cross-coupling reactions between aryl iodides, arylboronic acids and acrylates under milder conditions than those previously reported. The nature of the directing group was found to be critical for achieving room temperature conditions, with the urea moiety the most effective in promoting facile coupling reactions at an ortho C–H position. This methodology has been utilized in a streamlined and efficient synthesis of boscalid, an agent produced on the kiloton scale annually and used to control a range of plant pathogens in broadacre and horticultural crops. Mechanistic investigations led to a proposed catalytic cycle involving three steps: (1 C–H activation to generate a cationic palladacycle; (2 reaction of the cationic palladacycle with an aryl iodide, arylboronic acid or acrylate, and (3 regeneration of the active cationic palladium catalyst. The reaction between a cationic palladium(II complex and arylurea allowed the formation and isolation of the corresponding palladacycle intermediate, characterized by X-ray analysis. Roles of various additives in the stepwise process have also been studied.

Global scale analysis and evaluation of an improved mechanistic representation of plant nitrogen and carbon dynamics in the Community Land Model (CLM)

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Ghimire, B.; Riley, W. J.; Koven, C. D.; Randerson, J. T.; Mu, M.; Kattge, J.; Rogers, A.; Reich, P. B.

2014-12-01

In many ecosystems, nitrogen is the most limiting nutrient for plant growth and productivity. However mechanistic representation of nitrogen uptake linked to root traits, and functional nitrogen allocation among different leaf enzymes involved in respiration and photosynthesis is currently lacking in Earth System models. The linkage between nitrogen availability and plant productivity is simplistically represented by potential photosynthesis rates, and is subsequently downregulated depending on nitrogen supply and other nitrogen consumers in the model (e.g., nitrification). This type of potential photosynthesis rate calculation is problematic for several reasons. Firstly, plants do not photosynthesize at potential rates and then downregulate. Secondly, there is considerable subjectivity on the meaning of potential photosynthesis rates. Thirdly, there exists lack of understanding on modeling these potential photosynthesis rates in a changing climate. In addition to model structural issues in representing photosynthesis rates, the role of plant roots in nutrient acquisition have been largely ignored in Earth System models. For example, in CLM4.5, nitrogen uptake is linked to leaf level processes (e.g., primarily productivity) rather than root scale process involved in nitrogen uptake. We present a new plant model for CLM with an improved mechanistic presentation of plant nitrogen uptake based on root scale Michaelis Menten kinetics, and stronger linkages between leaf nitrogen and plant productivity by inferring relationships observed in global databases of plant traits (including the TRY database and several individual studies). We also incorporate improved representation of plant nitrogen leaf allocation, especially in tropical regions where significant over-prediction of plant growth and productivity in CLM4.5 simulations exist. We evaluate our improved global model simulations using the International Land Model Benchmarking (ILAMB) framework. We conclude that

Mechanistic Mathematical Modeling Tests Hypotheses of the Neurovascular Coupling in fMRI.

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Karin Lundengård

2016-06-01

Full Text Available Functional magnetic resonance imaging (fMRI measures brain activity by detecting the blood-oxygen-level dependent (BOLD response to neural activity. The BOLD response depends on the neurovascular coupling, which connects cerebral blood flow, cerebral blood volume, and deoxyhemoglobin level to neuronal activity. The exact mechanisms behind this neurovascular coupling are not yet fully investigated. There are at least three different ways in which these mechanisms are being discussed. Firstly, mathematical models involving the so-called Balloon model describes the relation between oxygen metabolism, cerebral blood volume, and cerebral blood flow. However, the Balloon model does not describe cellular and biochemical mechanisms. Secondly, the metabolic feedback hypothesis, which is based on experimental findings on metabolism associated with brain activation, and thirdly, the neurotransmitter feed-forward hypothesis which describes intracellular pathways leading to vasoactive substance release. Both the metabolic feedback and the neurotransmitter feed-forward hypotheses have been extensively studied, but only experimentally. These two hypotheses have never been implemented as mathematical models. Here we investigate these two hypotheses by mechanistic mathematical modeling using a systems biology approach; these methods have been used in biological research for many years but never been applied to the BOLD response in fMRI. In the current work, model structures describing the metabolic feedback and the neurotransmitter feed-forward hypotheses were applied to measured BOLD responses in the visual cortex of 12 healthy volunteers. Evaluating each hypothesis separately shows that neither hypothesis alone can describe the data in a biologically plausible way. However, by adding metabolism to the neurotransmitter feed-forward model structure, we obtained a new model structure which is able to fit the estimation data and successfully predict new

Exploring BSEP Inhibition-Mediated Toxicity with a Mechanistic Model of Drug-Induced Liver Injury

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Jeffrey L Woodhead

2014-11-01

Full Text Available Inhibition of the bile salt export pump (BSEP has been linked to incidence of drug-induced liver injury (DILI, presumably by the accumulation of toxic bile acids in the liver. We have previously constructed and validated a model of bile acid disposition within DILIsym®, a mechanistic model of DILI. In this paper, we use DILIsym® to simulate the DILI response of the hepatotoxic BSEP inhibitors bosentan and CP-724,714 and the non-hepatotoxic BSEP inhibitor telmisartan in humans in order to explore whether we can predict that hepatotoxic BSEP inhibitors can cause bile acid accumulation to reach toxic levels. We also simulate bosentan in rats in order to illuminate potential reasons behind the lack of toxicity in rats compared to the toxicity observed in humans. DILIsym® predicts that bosentan, but not telmisartan, will cause mild hepatocellular ATP decline and serum ALT elevation in a simulated population of humans. The difference in hepatotoxic potential between bosentan and telmisartan is consistent with clinical observations. However, DILIsym® underpredicts the incidence of bosentan toxicity. DILIsym® also predicts that bosentan will not cause toxicity in a simulated population of rats, and that the difference between the response to bosentan in rats and in humans is primarily due to the less toxic bile acid pool in rats. Our simulations also suggest a potential synergistic role for bile acid accumulation and mitochondrial electron transport chain inhibition in producing the observed toxicity in CP-724,714, and suggest that CP-724,714 metabolites may also play a role in the observed toxicity. Our work also compares the impact of competitive and noncompetitive BSEP inhibition for CP-724,714 and demonstrates that noncompetitive inhibition leads to much greater bile acid accumulation and potential toxicity. Our research demonstrates the potential for mechanistic modeling to contribute to the understanding of how bile acid transport inhibitors

Modified Smith-predictor multirate control utilizing secondary process measurements

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Rolf Ergon

2007-01-01

Full Text Available The Smith-predictor is a well-known control structure for industrial time delay systems, where the basic idea is to estimate the non-delayed process output by use of a process model, and to use this estimate in an inner feedback control loop combined with an outer feedback loop based on the delayed estimation error. The model used may be either mechanistic or identified from input-output data. The paper discusses improvements of the Smith-predictor for systems where also secondary process measurements without time delay are available as a basis for the primary output estimation. The estimator may then be identified also in the common case with primary outputs sampled at a lower rate than the secondary outputs. A simulation example demonstrates the feasibility and advantages of the suggested control structure.

Neo-Geometric Copper Nanocrystals by Competitive, Dual Surfactant-Mediated Facet Adsorption Controlling Skin Permeation

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Karmani Murugan

2016-11-01

Full Text Available Neogeometric copper nanoparticles (CuNPs have various applications yet its synthesis still proves to be challenging with regards to self-assembly and uniformity control. This study aimed to synthesize shape-specific CuNPs in the biomedical application of ascertaining skin permeation and retention of the CuNPs as a drug delivery system. The approach to the shape design involved the dual control of two surfactants to direct the shape organisation of the nanoparticles (NPs while an interesting aspect of the study showed the competitive adsorption of the surfactants onto the nanocrystal facets to direct facet growth. The resulting copper nanoparticles were characterised using X-ray diffraction (XRD and electron diffraction spectra analysis (EDS for elemental and crystalline analysis. Thermogravimetric Analysis (TGA identified the degradation of the surfactant coat and the synthesis of a novel copper-polymer complex and extensive transmission electron microscopy (TEM was conducted to determine the nanoparticle morphology. Epidermal skin tissue served as the model for permeation studies of five idealistic nano-geometries and investigated its application in drug delivery with regards to cellular internalisation and transbarrier transport of the geometric CuNPs. A mechanistic consideration for shape control is discussed.

Polymerization kinetics of wheat gluten upon thermosetting. A mechanistic model.

Science.gov (United States)

Domenek, Sandra; Morel, Marie-Hélène; Bonicel, Joëlle; Guilbert, Stéphane

2002-10-09

Size exclusion high-performance liquid chromatography analysis was carried out on wheat gluten-glycerol blends subjected to different heat treatments. The elution profiles were analyzed in order to follow the solubility loss of protein fractions with specific molecular size. Owing to the known biochemical changes involved during the heat denaturation of gluten, a mechanistic mathematical model was developed, which divided the protein denaturation into two distinct reaction steps: (i) reversible change in protein conformation and (ii) protein precipitation through disulfide bonding between initially SDS-soluble and SDS-insoluble reaction partners. Activation energies of gluten unfolding, refolding, and precipitation were calculated with the Arrhenius law to 53.9 kJ x mol(-1), 29.5 kJ x mol(-1), and 172 kJ x mol(-1), respectively. The rate of protein solubility loss decreased as the cross-linking reaction proceeded, which may be attributed to the formation of a three-dimensional network progressively hindering the reaction. The enhanced susceptibility to aggregation of large molecules was assigned to a risen reaction probability due to their higher number of cysteine residues and to the increased percentage of unfolded and thereby activated proteins as complete protein refolding seemed to be an anticooperative process.

Serial assessment of cardiovascular control shows early signs of developing pre-eclampsia

NARCIS (Netherlands)

Rang, Sasika; Wolf, H.; van Montfrans, G. A.; Karemaker, J. M.

2004-01-01

Purpose To evaluate whether differences in autonomic cardiovascular control between normal pregnant women and women who develop pre-eclampsia later in pregnancy can be detected even before or early in pregnancy. Design We studied 42 women, 21 multigravid with a history of pre-eclampsia and 21

Mechanistic differences between methanol and dimethyl ether carbonylation in side pockets and large channels of mordenite.

Science.gov (United States)

Boronat, Mercedes; Martínez, Cristina; Corma, Avelino

2011-02-21

The activity and selectivity towards carbonylation presented by Brønsted acid sites located inside the 8MR pockets or in the main 12MR channels of mordenite is studied by means of quantum-chemical calculations, and the mechanistic differences between methanol and DME carbonylation are investigated. The selectivity towards carbonylation is higher inside the 8MR pockets, where the competitive formation of DME and hydrocarbons that finally leads to catalyst deactivation is sterically impeded. Moreover, inclusion of dispersion interactions in the calculations leads to agreement between the calculated activation barriers for the rate determining step and the experimentally observed higher reactivity of methoxy groups located inside the 8MR channels.

Projected Climate Impacts to South African Maize and Wheat Production in 2055: A Comparison of Empirical and Mechanistic Modeling Approaches

Science.gov (United States)

Estes, Lyndon D.; Beukes, Hein; Bradley, Bethany A.; Debats, Stephanie R.; Oppenheimer, Michael; Ruane, Alex C.; Schulze, Roland; Tadross, Mark

2013-01-01

Crop model-specific biases are a key uncertainty affecting our understanding of climate change impacts to agriculture. There is increasing research focus on intermodel variation, but comparisons between mechanistic (MMs) and empirical models (EMs) are rare despite both being used widely in this field. We combined MMs and EMs to project future (2055) changes in the potential distribution (suitability) and productivity of maize and spring wheat in South Africa under 18 downscaled climate scenarios (9 models run under 2 emissions scenarios). EMs projected larger yield losses or smaller gains than MMs. The EMs' median-projected maize and wheat yield changes were 3.6% and 6.2%, respectively, compared to 6.5% and 15.2% for the MM. The EM projected a 10% reduction in the potential maize growing area, where the MM projected a 9% gain. Both models showed increases in the potential spring wheat production region (EM = 48%, MM = 20%), but these results were more equivocal because both models (particularly the EM) substantially overestimated the extent of current suitability. The substantial water-use efficiency gains simulated by the MMs under elevated CO2 accounted for much of the EMMM difference, but EMs may have more accurately represented crop temperature sensitivities. Our results align with earlier studies showing that EMs may show larger climate change losses than MMs. Crop forecasting efforts should expand to include EMMM comparisons to provide a fuller picture of crop-climate response uncertainties.

Dynamin-dependent amino acid endocytosis activates mechanistic target of rapamycin complex 1 (mTORC1).

Science.gov (United States)

Shibutani, Shusaku; Okazaki, Hana; Iwata, Hiroyuki

2017-11-03

The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of protein synthesis and potential target for modifying cellular metabolism in various conditions, including cancer and aging. mTORC1 activity is tightly regulated by the availability of extracellular amino acids, and previous studies have revealed that amino acids in the extracellular fluid are transported to the lysosomal lumen. There, amino acids induce recruitment of cytoplasmic mTORC1 to the lysosome by the Rag GTPases, followed by mTORC1 activation by the small GTPase Ras homolog enriched in brain (Rheb). However, how the extracellular amino acids reach the lysosomal lumen and activate mTORC1 remains unclear. Here, we show that amino acid uptake by dynamin-dependent endocytosis plays a critical role in mTORC1 activation. We found that mTORC1 is inactivated when endocytosis is inhibited by overexpression of a dominant-negative form of dynamin 2 or by pharmacological inhibition of dynamin or clathrin. Consistently, the recruitment of mTORC1 to the lysosome was suppressed by the dynamin inhibition. The activity and lysosomal recruitment of mTORC1 were rescued by increasing intracellular amino acids via cycloheximide exposure or by Rag overexpression, indicating that amino acid deprivation is the main cause of mTORC1 inactivation via the dynamin inhibition. We further show that endocytosis inhibition does not induce autophagy even though mTORC1 inactivation is known to strongly induce autophagy. These findings open new perspectives for the use of endocytosis inhibitors as potential agents that can effectively inhibit nutrient utilization and shut down the upstream signals that activate mTORC1. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Mechanistic reappraisal of early stage photochemistry in the light-driven enzyme protochlorophyllide oxidoreductase.

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Derren J Heyes

Full Text Available The light-driven enzyme protochlorophyllide oxidoreductase (POR catalyzes the reduction of protochlorophyllide (Pchlide to chlorophyllide (Chlide. This reaction is a key step in the biosynthesis of chlorophyll. Ultrafast photochemical processes within the Pchlide molecule are required for catalysis and previous studies have suggested that a short-lived excited-state species, known as I675*, is the first catalytic intermediate in the reaction and is essential for capturing excitation energy to drive subsequent hydride and proton transfers. The chemical nature of the I675* excited state species and its role in catalysis are not known. Here, we report time-resolved pump-probe spectroscopy measurements to study the involvement of the I675* intermediate in POR photochemistry. We show that I675* is not unique to the POR-catalyzed photoreduction of Pchlide as it is also formed in the absence of the POR enzyme. The I675* species is only produced in samples that contain both Pchlide substrate and Chlide product and its formation is dependent on the pump excitation wavelength. The rate of formation and the quantum yield is maximized in 50∶50 mixtures of the two pigments (Pchlide and Chlide and is caused by direct energy transfer between Pchlide and neighboring Chlide molecules, which is inhibited in the polar solvent methanol. Consequently, we have re-evaluated the mechanism for early stage photochemistry in the light-driven reduction of Pchlide and propose that I675* represents an excited state species formed in Pchlide-Chlide dimers, possibly an excimer. Contrary to previous reports, we conclude that this excited state species has no direct mechanistic relevance to the POR-catalyzed reduction of Pchlide.

Daughter-specific transcription factors regulate cell size control in budding yeast.

Science.gov (United States)

Di Talia, Stefano; Wang, Hongyin; Skotheim, Jan M; Rosebrock, Adam P; Futcher, Bruce; Cross, Frederick R

2009-10-01

In budding yeast, asymmetric cell division yields a larger mother and a smaller daughter cell, which transcribe different genes due to the daughter-specific transcription factors Ace2 and Ash1. Cell size control at the Start checkpoint has long been considered to be a main regulator of the length of the G1 phase of the cell cycle, resulting in longer G1 in the smaller daughter cells. Our recent data confirmed this concept using quantitative time-lapse microscopy. However, it has been proposed that daughter-specific, Ace2-dependent repression of expression of the G1 cyclin CLN3 had a dominant role in delaying daughters in G1. We wanted to reconcile these two divergent perspectives on the origin of long daughter G1 times. We quantified size control using single-cell time-lapse imaging of fluorescently labeled budding yeast, in the presence or absence of the daughter-specific transcriptional regulators Ace2 and Ash1. Ace2 and Ash1 are not required for efficient size control, but they shift the domain of efficient size control to larger cell size, thus increasing cell size requirement for Start in daughters. Microarray and chromatin immunoprecipitation experiments show that Ace2 and Ash1 are direct transcriptional regulators of the G1 cyclin gene CLN3. Quantification of cell size control in cells expressing titrated levels of Cln3 from ectopic promoters, and from cells with mutated Ace2 and Ash1 sites in the CLN3 promoter, showed that regulation of CLN3 expression by Ace2 and Ash1 can account for the differential regulation of Start in response to cell size in mothers and daughters. We show how daughter-specific transcriptional programs can interact with intrinsic cell size control to differentially regulate Start in mother and daughter cells. This work demonstrates mechanistically how asymmetric localization of cell fate determinants results in cell-type-specific regulation of the cell cycle.

Daughter-Specific Transcription Factors Regulate Cell Size Control in Budding Yeast

Science.gov (United States)

Di Talia, Stefano; Wang, Hongyin; Skotheim, Jan M.; Rosebrock, Adam P.; Futcher, Bruce; Cross, Frederick R.

2009-01-01

In budding yeast, asymmetric cell division yields a larger mother and a smaller daughter cell, which transcribe different genes due to the daughter-specific transcription factors Ace2 and Ash1. Cell size control at the Start checkpoint has long been considered to be a main regulator of the length of the G1 phase of the cell cycle, resulting in longer G1 in the smaller daughter cells. Our recent data confirmed this concept using quantitative time-lapse microscopy. However, it has been proposed that daughter-specific, Ace2-dependent repression of expression of the G1 cyclin CLN3 had a dominant role in delaying daughters in G1. We wanted to reconcile these two divergent perspectives on the origin of long daughter G1 times. We quantified size control using single-cell time-lapse imaging of fluorescently labeled budding yeast, in the presence or absence of the daughter-specific transcriptional regulators Ace2 and Ash1. Ace2 and Ash1 are not required for efficient size control, but they shift the domain of efficient size control to larger cell size, thus increasing cell size requirement for Start in daughters. Microarray and chromatin immunoprecipitation experiments show that Ace2 and Ash1 are direct transcriptional regulators of the G1 cyclin gene CLN3. Quantification of cell size control in cells expressing titrated levels of Cln3 from ectopic promoters, and from cells with mutated Ace2 and Ash1 sites in the CLN3 promoter, showed that regulation of CLN3 expression by Ace2 and Ash1 can account for the differential regulation of Start in response to cell size in mothers and daughters. We show how daughter-specific transcriptional programs can interact with intrinsic cell size control to differentially regulate Start in mother and daughter cells. This work demonstrates mechanistically how asymmetric localization of cell fate determinants results in cell-type-specific regulation of the cell cycle. PMID:19841732

Daughter-specific transcription factors regulate cell size control in budding yeast.

Directory of Open Access Journals (Sweden)

Stefano Di Talia

2009-10-01

Full Text Available In budding yeast, asymmetric cell division yields a larger mother and a smaller daughter cell, which transcribe different genes due to the daughter-specific transcription factors Ace2 and Ash1. Cell size control at the Start checkpoint has long been considered to be a main regulator of the length of the G1 phase of the cell cycle, resulting in longer G1 in the smaller daughter cells. Our recent data confirmed this concept using quantitative time-lapse microscopy. However, it has been proposed that daughter-specific, Ace2-dependent repression of expression of the G1 cyclin CLN3 had a dominant role in delaying daughters in G1. We wanted to reconcile these two divergent perspectives on the origin of long daughter G1 times. We quantified size control using single-cell time-lapse imaging of fluorescently labeled budding yeast, in the presence or absence of the daughter-specific transcriptional regulators Ace2 and Ash1. Ace2 and Ash1 are not required for efficient size control, but they shift the domain of efficient size control to larger cell size, thus increasing cell size requirement for Start in daughters. Microarray and chromatin immunoprecipitation experiments show that Ace2 and Ash1 are direct transcriptional regulators of the G1 cyclin gene CLN3. Quantification of cell size control in cells expressing titrated levels of Cln3 from ectopic promoters, and from cells with mutated Ace2 and Ash1 sites in the CLN3 promoter, showed that regulation of CLN3 expression by Ace2 and Ash1 can account for the differential regulation of Start in response to cell size in mothers and daughters. We show how daughter-specific transcriptional programs can interact with intrinsic cell size control to differentially regulate Start in mother and daughter cells. This work demonstrates mechanistically how asymmetric localization of cell fate determinants results in cell-type-specific regulation of the cell cycle.

Clinical evidence and mechanistic basis for vildagliptin's effect in combination with insulin

Directory of Open Access Journals (Sweden)

Schweizer A

2013-02-01

Full Text Available Anja Schweizer,1 James E Foley,2 Wolfgang Kothny,2 Bo Ahrén31Novartis Pharma AG, Basel, Switzerland; 2Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 3Department of Clinical Sciences, Lund University, Lund, SwedenAbstract: Due to the progressive nature of type 2 diabetes, many patients need insulin as add-on to oral antidiabetic drugs (OADs in order to maintain adequate glycemic control. Insulin therapy primarily targets elevated fasting glycemia but is less effective to reduce postprandial hyperglycemia. In addition, the risk of hypoglycemia limits its effectiveness and there is a concern of weight gain. These drawbacks may be overcome by combining insulin with incretin-based therapies as these increase glucose sensitivity of both the α- and β-cells, resulting in improved postprandial glycemia without the hypoglycemia and weight gain associated with increasing the dose of insulin. The dipeptidyl peptidase-IV (DPP-4 inhibitor vildagliptin has also been shown to protect from hypoglycemia by enhancing glucagon counterregulation. The effectiveness of combining vildagliptin with insulin was demonstrated in three different studies in which vildagliptin decreased A1C levels when added to insulin therapy without increasing hypoglycemia. This was established with and without concomitant metformin therapy. Furthermore, the effectiveness of vildagliptin appears to be greater when insulin is used as a basal regimen as opposed to being used to reduce postprandial hyperglycemia, since improvement in insulin secretion likely plays a minor role when relatively high doses of insulin are administered before meals. This article reviews the clinical experience with the combination of vildagliptin and insulin and discusses the mechanistic basis for the beneficial effects of the combination. The data support the use of vildagliptin in combination with insulin in general and, in line with emerging clinical practice, suggest that treating patients with

Semi-Mechanistic Population Pharmacokinetic Modeling of L-Histidine Disposition and Brain Uptake in Wildtype and Pht1 Null Mice.

Science.gov (United States)

Wang, Xiao-Xing; Li, Yang-Bing; Feng, Meihua R; Smith, David E

2018-01-05

To develop a semi-mechanistic population pharmacokinetic (PK) model to quantitate the disposition kinetics of L-histidine, a peptide-histidine transporter 1 (PHT1) substrate, in the plasma, cerebrospinal fluid and brain parenchyma of wildtype (WT) and Pht1 knockout (KO) mice. L-[ 14 C]Hisidine (L-His) was administrated to WT and KO mice via tail vein injection, after which plasma, cerebrospinal fluid (CSF) and brain parenchyma samples were collected. A PK model was developed using non-linear mixed effects modeling (NONMEM). The disposition of L-His between the plasma, brain, and CSF was described by a combination of PHT1-mediated uptake, CSF bulk flow and first-order micro-rate constants. The PK profile of L-His was best described by a four-compartment model. A more rapid uptake of L-His in brain parenchyma was observed in WT mice due to PHT1-mediated uptake, a process characterized by a Michaelis-Menten component (V max  = 0.051 nmoL/min and K m  = 34.94 μM). A semi-mechanistic population PK model was successfully developed, for the first time, to quantitatively characterize the disposition kinetics of L-His in brain under in vivo conditions. This model may prove a useful tool in predicting the uptake of L-His, and possibly other PHT1 peptide/mimetic substrates, for drug delivery to the brain.

Verification of a mechanistic model for the strain rate of zircaloy-4 fuel sheaths during transient heating

International Nuclear Information System (INIS)

Hunt, C.E.L.

1980-10-01

A mechanistic strain rate model for Zircaloy-4, named NIRVANA, was tested against experiments where pressurized fuel sheaths were strained during complex temperature-stress-time histories. The same histories were then examined to determine the spread in calculated strain which may be expected because of variations in dimensions, chemical content and mechanical properties which are allowed in the fuel sheath specifications. It was found that the variations allowed by the specifications could result in a probable spread in the predicted strain of plus or minus a factor of two from the mean value. The experimental results were well within this range. (auth)

Ancient Chinese medicine and mechanistic evidence of acupuncture physiology.

Science.gov (United States)

Yang, Edward S; Li, Pei-Wen; Nilius, Bernd; Li, Geng

2011-11-01

Acupuncture has been widely used in China for three millennia as an art of healing. Yet, its physiology is not yet understood. The current interest in acupuncture started in 1971. Soon afterward, extensive research led to the concept of neural signaling with possible involvement of opioid peptides, glutamate, adenosine and identifying responsive parts in the central nervous system. In the last decade scientists began investigating the subject with anatomical and molecular imaging. It was found that mechanical movements of the needle, ignored in the past, appear to be central to the method and intracellular calcium ions may play a pivotal role. In this review, we trace the technique of clinical treatment from the first written record about 2,200 years ago to the modern time. The ancient texts have been used to introduce the concepts of yin, yang, qi, de qi, and meridians, the traditional foundation of acupuncture. We explore the sequence of the physiological process, from the turning of the needle, the mechanical wave activation of calcium ion channel to beta-endorphin secretion. By using modern terminology to re-interpret the ancient texts, we have found that the 2nd century B.C.: physiologists were meticulous investigators and their explanation fits well with the mechanistic model derived from magnetic resonance imaging (MRI) and confocal microscopy. In conclusion, the ancient model appears to have withstood the test of time surprisingly well confirming the popular axiom that the old wine is better than the new.

A mechanistic approach to the generation of sorption databases

International Nuclear Information System (INIS)

Bradbury, M.H.; Baeyens, B.

1992-01-01

Sorption of radionuclides in the near and far fields of an underground nuclear waste repository is one of the most important processes retarding their release to the environment. In the vast majority of cases sorption data have been presented in terms of empirical parameters such as distribution coefficients and isotherm equations. A consequence of this empirical methodology is that the sorption data are only strictly valid under the experimental conditions at which they were measured. Implicit in this approach is the need to generate large amounts of data and fitting parameters necessary for an empirical description of sorption under all realistically conceivable conditions which may arise in space and time along the migration pathway to Man. An alternative approach to the problem is to try to understand, and develop model descriptions of, underlying retention mechanisms and to identify those systems parameters which essentially determine the extent of sorption. The aim of this work is to see to what extent currently existing mechanistic models, together with their associated data, can be applied to predict sorption data from laboratory experiments on natural systems. This paper describes the current status of this work which is very much in an early stage of development. An example is given whereby model predictions are compared with laboratory results for the sorption of Np at trace concentrations under oxidizing conditions on a series of minerals relevant to granite formations. 31 refs., 11 figs., 5 tabs

Heterogeneity of pulmonary perfusion as a mechanistic image-based phenotype in emphysema susceptible smokers.

Science.gov (United States)

Alford, Sara K; van Beek, Edwin J R; McLennan, Geoffrey; Hoffman, Eric A

2010-04-20

Recent evidence suggests that endothelial dysfunction and pathology of pulmonary vascular responses may serve as a precursor to smoking-associated emphysema. Although it is known that emphysematous destruction leads to vasculature changes, less is known about early regional vascular dysfunction which may contribute to and precede emphysematous changes. We sought to test the hypothesis, via multidetector row CT (MDCT) perfusion imaging, that smokers showing early signs of emphysema susceptibility have a greater heterogeneity in regional perfusion parameters than emphysema-free smokers and persons who had never smoked (NS). Assuming that all smokers have a consistent inflammatory response, increased perfusion heterogeneity in emphysema-susceptible smokers would be consistent with the notion that these subjects may have the inability to block hypoxic vasoconstriction in patchy, small regions of inflammation. Dynamic ECG-gated MDCT perfusion scans with a central bolus injection of contrast were acquired in 17 NS, 12 smokers with normal CT imaging studies (SNI), and 12 smokers with subtle CT findings of centrilobular emphysema (SCE). All subjects had normal spirometry. Quantitative image analysis determined regional perfusion parameters, pulmonary blood flow (PBF), and mean transit time (MTT). Mean and coefficient of variation were calculated, and statistical differences were assessed with one-way ANOVA. MDCT-based MTT and PBF measurements demonstrate globally increased heterogeneity in SCE subjects compared with NS and SNI subjects but demonstrate similarity between NS and SNI subjects. These findings demonstrate a functional lung-imaging measure that provides a more mechanistically oriented phenotype that differentiates smokers with and without evidence of emphysema susceptibility.

Prediction of warfarin maintenance dose in Han Chinese patients using a mechanistic model based on genetic and non-genetic factors.

Science.gov (United States)

Lu, Yuan; Yang, Jinbo; Zhang, Haiyan; Yang, Jin

2013-07-01

Many attempts have been made to predict the warfarin maintenance dose in patients beginning warfarin therapy using a descriptive model based on multiple linear regression. Here we report the first attempt to develop a comprehensive mechanistic model integrating in vitro-in vivo extrapolation (IVIVE) with a pharmacokinetic-pharmacodynamic model to predict the warfarin maintenance dose in Han Chinese patients. The model incorporates demographic factors [sex, age, body weight (BW)] and the genetic polymorphisms of cytochrome P450 (CYP) 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1). Information on the various factors, mean warfarin daily dose and International Normalized Ratio (INR) was available for a cohort of 197 Han Chinese patients. Based on in vitro enzyme kinetic parameters for S-warfarin metabolism, demographic data for Han Chinese and some scaling factors, the S-warfarin clearance (CL) was predicted for patients in the cohort with different CYP2C9 genotypes using IVIVE. The plasma concentration of S-warfarin after a single oral dose was simulated using a one-compartment pharmacokinetic model with first-order absorption and a lag time and was combined with a mechanistic coagulation model to simulate the INR response. The warfarin maintenance dose was then predicted based on the demographic data and genotypes of CYP2C9 and VKORC1 for each patient and using the observed steady-state INR (INRss) as a target value. Finally, sensitivity analysis was carried out to determine which factor(s) affect the warfarin maintenance dose most strongly. The predictive performance of this mechanistic model is not inferior to that of our previous descriptive model. There were significant differences in the mean warfarin daily dose in patients with different CYP2C9 and VKORC1 genotypes. Using IVIVE, the predicted mean CL of S-warfarin for patients with CYP2C9*1/*3 (0.092 l/h, n = 11) was 57 % less than for those with wild-type *1/*1 (0.215 l/h, n

Integration of genome-scale metabolic networks into whole-body PBPK models shows phenotype-specific cases of drug-induced metabolic perturbation.

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Cordes, Henrik; Thiel, Christoph; Baier, Vanessa; Blank, Lars M; Kuepfer, Lars

2018-01-01

Drug-induced perturbations of the endogenous metabolic network are a potential root cause of cellular toxicity. A mechanistic understanding of such unwanted side effects during drug therapy is therefore vital for patient safety. The comprehensive assessment of such drug-induced injuries requires the simultaneous consideration of both drug exposure at the whole-body and resulting biochemical responses at the cellular level. We here present a computational multi-scale workflow that combines whole-body physiologically based pharmacokinetic (PBPK) models and organ-specific genome-scale metabolic network (GSMN) models through shared reactions of the xenobiotic metabolism. The applicability of the proposed workflow is illustrated for isoniazid, a first-line antibacterial agent against Mycobacterium tuberculosis , which is known to cause idiosyncratic drug-induced liver injuries (DILI). We combined GSMN models of a human liver with N-acetyl transferase 2 (NAT2)-phenotype-specific PBPK models of isoniazid. The combined PBPK-GSMN models quantitatively describe isoniazid pharmacokinetics, as well as intracellular responses, and changes in the exometabolome in a human liver following isoniazid administration. Notably, intracellular and extracellular responses identified with the PBPK-GSMN models are in line with experimental and clinical findings. Moreover, the drug-induced metabolic perturbations are distributed and attenuated in the metabolic network in a phenotype-dependent manner. Our simulation results show that a simultaneous consideration of both drug pharmacokinetics at the whole-body and metabolism at the cellular level is mandatory to explain drug-induced injuries at the patient level. The proposed workflow extends our mechanistic understanding of the biochemistry underlying adverse events and may be used to prevent drug-induced injuries in the future.

A Three-Stage Mechanistic Model for Solidification Cracking During Welding of Steel

Science.gov (United States)

Aucott, L.; Huang, D.; Dong, H. B.; Wen, S. W.; Marsden, J.; Rack, A.; Cocks, A. C. F.

2018-03-01

A three-stage mechanistic model for solidification cracking during TIG welding of steel is proposed from in situ synchrotron X-ray imaging of solidification cracking and subsequent analysis of fracture surfaces. Stage 1—Nucleation of inter-granular hot cracks: cracks nucleate inter-granularly in sub-surface where maximum volumetric strain is localized and volume fraction of liquid is less than 0.1; the crack nuclei occur at solute-enriched liquid pockets which remain trapped in increasingly impermeable semi-solid skeleton. Stage 2—Coalescence of cracks via inter-granular fracture: as the applied strain increases, cracks coalesce through inter-granular fracture; the coalescence path is preferential to the direction of the heat source and propagates through the grain boundaries to solidifying dendrites. Stage 3—Propagation through inter-dendritic hot tearing: inter-dendritic hot tearing occurs along the boundaries between solidifying columnar dendrites with higher liquid fraction. It is recommended that future solidification cracking criterion shall be based on the application of multiphase mechanics and fracture mechanics to the failure of semi-solid materials.

['Anatomia actuosa et apta'. The mechanist 'proto'-physiology of B.S. Albinus].

Science.gov (United States)

van der Korst, J K

1993-01-01

Already during his tenure as professor of anatomy and surgery (1721-1746) and before he became a professor of physiology and medicine at the University of Leiden, Bernard Siegfried Albinus held private lecture courses on physiology. In these lectures he pleaded for a separation of physiology from theoretical medicine, which was still its customary place in the medical curriculum of the first half of the eighteenth century. According to Albinus, physiology was a science in its own right and should be solely based on the careful observation of forms and structures of the human body. From the 'fabrica', the function ('aptitudo') could be derived by careful reasoning. As shown by a set of lecture notes, which recently came to light, Albinus adhered, initially, to a strictly mechanistic explanatory model, which was almost completely based on the physiological concepts of Herman Boerhaave. However, in contrast to the latter, he even rejected the involvement of chemical processes in digestion. Although his lectures were highly acclaimed as demonstrations of minute anatomy, Albinus met with little or no direct response in regard to his concept of physiology.

Study of n-Butyl Acrylate Self-Initiation Reaction Experimentally and via Macroscopic Mechanistic Modeling

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Ahmad Arabi Shamsabadi

2016-04-01

Full Text Available This paper presents an experimental study of the self-initiation reaction of n-butyl acrylate (n-BA in free-radical polymerization. For the first time, the frequency factor and activation energy of the monomer self-initiation reaction are estimated from measurements of n-BA conversion in free-radical homo-polymerization initiated only by the monomer. The estimation was carried out using a macroscopic mechanistic mathematical model of the reactor. In addition to already-known reactions that contribute to the polymerization, the model considers a n-BA self-initiation reaction mechanism that is based on our previous electronic-level first-principles theoretical study of the self-initiation reaction. Reaction rate equations are derived using the method of moments. The reaction-rate parameter estimates obtained from conversion measurements agree well with estimates obtained via our purely-theoretical quantum chemical calculations.

Mechanistic modelling of gaseous fission product behaviour in UO2 fuel by Rtop code

International Nuclear Information System (INIS)

Kanukova, V.D.; Khoruzhii, O.V.; Kourtchatov, S.Y.; Likhanskii, V.V.; Matveew, L.V.

2002-01-01

The current status of a mechanistic modelling by the RTOP code of the fission product behaviour in polycrystalline UO 2 fuel is described. An outline of the code and implemented physical models is presented. The general approach to code validation is discussed. It is exemplified by the results of validation of the models of fuel oxidation and grain growth. The different models of intragranular and intergranular gas bubble behaviour have been tested and the sensitivity of the code in the framework of these models has been analysed. An analysis of available models of the resolution of grain face bubbles is also presented. The possibilities of the RTOP code are presented through the example of modelling behaviour of WWER fuel over the course of a comparative WWER-PWR experiment performed at Halden and by comparison with Yanagisawa experiments. (author)

Control of Growth Within Drosophila Peripheral Nerves by Ras and Protein Kinase A

Science.gov (United States)

2009-02-01

Genes Dev 17:2006 –2020. Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry MJ, Waterfield MD, Downward J (1994...we hope that these methodologies will enable us ultimately to identify all of the relevant genes that interact with NF1 to control growth, and place...NF1 and these partner genes in as complete a mechanistic context as possible. Then this mechanism could be tested and refined in systems more

The Mediator subunit MED23 couples H2B mono-ubiquitination to transcriptional control and cell fate determination.

Science.gov (United States)

Yao, Xiao; Tang, Zhanyun; Fu, Xing; Yin, Jingwen; Liang, Yan; Li, Chonghui; Li, Huayun; Tian, Qing; Roeder, Robert G; Wang, Gang

2015-12-02

The Mediator complex orchestrates multiple transcription factors with the Pol II apparatus for precise transcriptional control. However, its interplay with the surrounding chromatin remains poorly understood. Here, we analyze differential histone modifications between WT and MED23(-/-) (KO) cells and identify H2B mono-ubiquitination at lysine 120 (H2Bub) as a MED23-dependent histone modification. Using tandem affinity purification and mass spectrometry, we find that MED23 associates with the RNF20/40 complex, the enzyme for H2Bub, and show that this association is critical for the recruitment of RNF20/40 to chromatin. In a cell-free system, Mediator directly and substantially increases H2Bub on recombinant chromatin through its cooperation with RNF20/40 and the PAF complex. Integrative genome-wide analyses show that MED23 depletion specifically reduces H2Bub on a subset of MED23-controlled genes. Importantly, MED23-coupled H2Bub levels are oppositely regulated during myogenesis and lung carcinogenesis. In sum, these results establish a mechanistic link between the Mediator complex and a critical chromatin modification in coordinating transcription with cell growth and differentiation. © 2015 The Authors.

Mechanistic Insights into the Unique Role of Copper in CO2 Electroreduction Reactions.

Science.gov (United States)

Liu, Shan Ping; Zhao, Ming; Gao, Wang; Jiang, Qing

2017-01-20

Cu demonstrates a unique capability towards CO 2 electroreduction that can close the anthropogenic carbon cycle; however, its reaction mechanism remains elusive, owing to the obscurity of the solid-liquid interface on Cu surfaces where electrochemical reactions occur. Using a genetic algorithm method in addition to density functional theory, we explicitly identify the configuration of a water bilayer on Cu(2 1 1) and build electrochemical models. These enable us to reveal a mechanistic picture for CO 2 electroreduction, finding the key intermediates CCO* for the C 2 H 4 pathway and CH* for the CH 4 pathway, which rationalize a series of experimental observations. Furthermore, we find that the interplay between the Cu surfaces, carbon monomers, and water network (but not the binding of CO*) essentially determine the unique capability of Cu towards CO 2 electroreduction, proposing a new and effective descriptor for exploiting optimal catalysts. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Determining environmental causes of biological effects: the need for a mechanistic physiological dimension in conservation biology.

Science.gov (United States)

Seebacher, Frank; Franklin, Craig E

2012-06-19

The emerging field of Conservation Physiology links environmental change and ecological success by the application of physiological theory, approaches and tools to elucidate and address conservation problems. Human activity has changed the natural environment to a point where the viability of many ecosystems is now under threat. There are already many descriptions of how changes in biological patterns are correlated with environmental changes. The next important step is to determine the causative relationship between environmental variability and biological systems. Physiology provides the mechanistic link between environmental change and ecological patterns. Physiological research, therefore, should be integrated into conservation to predict the biological consequences of human activity, and to identify those species or populations that are most vulnerable.

Simulating the Epidemiological and Economic Impact of Paratuberculosis Control Actions in Dairy Cattle

Directory of Open Access Journals (Sweden)

Carsten Kirkeby

2016-10-01

Full Text Available We describe a new mechanistic bio-economic model for simulating the spread of Mycobacterium avium ssp. paratuberculosis (MAP within a dairy cattle herd. The model includes age-dependent susceptibility for infection; age-dependent sensitivity for detection; environmental MAP build-up in five separate areas of the farm; in utero infection; infection via colostrum and waste milk, and it allows for realistic culling (i.e. due to other diseases by including a ranking system. We calibrated the model using a unique dataset from Denmark, including 102 random farms with no control actions against spread of MAP. Likewise, four control actions recommended in the Danish MAP control program were implemented in the model based on reported management strategies in Danish dairy herds in a MAP control scheme. We tested the model parameterization in a sensitivity analysis. We show that a test-and-cull strategy is on average the most cost-effective solution to decrease the prevalence and increase the total net revenue on a farm with low hygiene, but not more profitable than no control strategy on a farm with average hygiene. Although it is possible to eradicate MAP from the farm by implementing all four control actions from the Danish MAP control program, it was not economically attractive since the expenses for the control actions outweigh the benefits. Furthermore, the three most popular control actions against the spread of MAP on the farm were found to be costly and inefficient in lowering the prevalence when used independently.

Epithelial-mesenchymal transition transcription factors control pluripotent adult stem cell migration in vivo in planarians

Science.gov (United States)

Abnave, Prasad; Aboukhatwa, Ellen; Kosaka, Nobuyoshi; Thompson, James; Hill, Mark A.

2017-01-01

Migration of stem cells underpins the physiology of metazoan animals. For tissues to be maintained, stem cells and their progeny must migrate and differentiate in the correct positions. This need is even more acute after tissue damage by wounding or pathogenic infection. Inappropriate migration also underpins metastasis. Despite this, few mechanistic studies address stem cell migration during repair or homeostasis in adult tissues. Here, we present a shielded X-ray irradiation assay that allows us to follow stem cell migration in planarians. We demonstrate the use of this system to study the molecular control of stem cell migration and show that snail-1, snail-2 and zeb-1 EMT transcription factor homologs are necessary for cell migration to wound sites and for the establishment of migratory cell morphology. We also observed that stem cells undergo homeostatic migration to anterior regions that lack local stem cells, in the absence of injury, maintaining tissue homeostasis. This requires the polarity determinant notum. Our work establishes planarians as a suitable model for further in-depth study of the processes controlling stem cell migration in vivo. PMID:28893948

Kinetic and mechanistic studies of reactive intermediates in photochemical and transition metal-assisted oxidation, decarboxylation and alkyl transfer reactions

Energy Technology Data Exchange (ETDEWEB)

Carraher, Jack McCaslin [Iowa State Univ., Ames, IA (United States)

2014-01-01

Reactive species like high-valent metal-oxo complexes and carbon and oxygen centered radicals are important intermediates in enzymatic systems, atmospheric chemistry, and industrial processes. Understanding the pathways by which these intermediates form, their relative reactivity, and their fate after reactions is of the utmost importance. Herein are described the mechanistic detail for the generation of several reactive intermediates, synthesis of precursors, characterization of precursors, and methods to direct the chemistry to more desirable outcomes yielding ‘greener’ sources of commodity chemicals and fuels.

TGF-β-induced IκB-ζ controls Foxp3 gene expression

Energy Technology Data Exchange (ETDEWEB)

MaruYama, Takashi, E-mail: ta-maru@umin.ac.jp [Laboratory of Cell Recognition and Response, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8578 (Japan); School of Medicine, Gifu University, Gifu 501-1194 (Japan)

2015-08-21

Inhibitor of kappa B (IκB)-ζ, a member of the nuclear IκB family of proteins, is induced by the transforming growth factor (TGF)-β signaling pathway and plays a pivotal role in maintaining the balance of T helper (Th) cell subsets. IκB-ζ deficiency results in reduced percentages of Th17 cells and increased percentages of Th1 cells. In this study, the effects of IκB-ζ deficiency on T-cell subsets were examined further. The data showed that IκB-ζ-deficient T cells had a high capacity for generation of regulatory T cells (Tregs) when T cells were cultured under TGF-β stimulation in the presence of cytokine-neutralizing antibodies. Mechanistically, IκB-ζ itself negatively regulated activation of the Foxp3 promoter in a nuclear factor of kappaB-dependent manner. Thus, this study showed that IκB-ζ controlled Treg differentiation. - Highlights: • IκB-ζ-deficient T cells exhibited increased generation of Foxp3{sup +} Tregs. • IκB-ζ played a key role in Foxp3 gene expression. • Retroviral overexpression of IκB-ζ was achieved in T cells.

TGF-β-induced IκB-ζ controls Foxp3 gene expression

International Nuclear Information System (INIS)

MaruYama, Takashi

2015-01-01

Inhibitor of kappa B (IκB)-ζ, a member of the nuclear IκB family of proteins, is induced by the transforming growth factor (TGF)-β signaling pathway and plays a pivotal role in maintaining the balance of T helper (Th) cell subsets. IκB-ζ deficiency results in reduced percentages of Th17 cells and increased percentages of Th1 cells. In this study, the effects of IκB-ζ deficiency on T-cell subsets were examined further. The data showed that IκB-ζ-deficient T cells had a high capacity for generation of regulatory T cells (Tregs) when T cells were cultured under TGF-β stimulation in the presence of cytokine-neutralizing antibodies. Mechanistically, IκB-ζ itself negatively regulated activation of the Foxp3 promoter in a nuclear factor of kappaB-dependent manner. Thus, this study showed that IκB-ζ controlled Treg differentiation. - Highlights: • IκB-ζ-deficient T cells exhibited increased generation of Foxp3 + Tregs. • IκB-ζ played a key role in Foxp3 gene expression. • Retroviral overexpression of IκB-ζ was achieved in T cells

Mechanistic Distinctions between CHK1 and WEE1 Inhibition Guide the Scheduling of Triple Therapy with Gemcitabine.

Science.gov (United States)

Koh, Siang-Boon; Wallez, Yann; Dunlop, Charles R; Bernaldo de Quirós Fernández, Sandra; Bapiro, Tashinga E; Richards, Frances M; Jodrell, Duncan I

2018-06-01

Combination of cytotoxic therapy with emerging DNA damage response inhibitors (DDRi) has been limited by tolerability issues. However, the goal of most combination trials has been to administer DDRi with standard-of-care doses of chemotherapy. We hypothesized that mechanism-guided treatment scheduling could reduce the incidence of dose-limiting toxicities and enable tolerable multitherapeutic regimens. Integrative analyses of mathematical modeling and single-cell assays distinguished the synergy kinetics of WEE1 inhibitor (WEE1i) from CHEK1 inhibitor (CHK1i) by potency, spatiotemporal perturbation, and mitotic effects when combined with gemcitabine. These divergent properties collectively supported a triple-agent strategy, whereby a pulse of gemcitabine and CHK1i followed by WEE1i durably suppressed tumor cell growth. In xenografts, CHK1i exaggerated replication stress without mitotic CDK hyperactivation, enriching a geminin-positive subpopulation and intratumoral gemcitabine metabolite. Without overt toxicity, addition of WEE1i to low-dose gemcitabine and CHK1i was most effective in tumor control compared with single and double agents. Overall, our work provides quantitative insights into the mechanisms of DDRi chemosensitization, leading to the rational development of a tolerable multitherapeutic regimen. Significance: Multiple lines of mechanistic insight regarding DNA damage response inhibitors rationally guide the preclinical development of a tolerable multitherapeutic regimen. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/11/3054/F1.large.jpg Cancer Res; 78(11); 3054-66. ©2018 AACR . ©2018 American Association for Cancer Research.

Polymer Film Dewetting by Water/Surfactant/Good-Solvent Mixtures: A Mechanistic Insight and Its Implications for the Conservation of Cultural Heritage.

Science.gov (United States)

Baglioni, Michele; Montis, Costanza; Chelazzi, David; Giorgi, Rodorico; Berti, Debora; Baglioni, Piero

2018-06-18

Aqueous nanostructured fluids (NSFs) have been proposed to remove polymer coatings from the surface of works of art; this process usually involves film dewetting. The NSF cleaning mechanism was studied using several techniques that were employed to obtain mechanistic insight on the interaction of a methacrylic/acrylic copolymer (Paraloid B72) film laid on glass surfaces and several NSFs, based on two solvents and two surfactants. The experimental results provide a detailed picture of the dewetting process. The gyration radius and the reduction of the T g of Paraloid B72 fully swollen in the two solvents is larger for propylene carbonate than for methyl ethyl ketone, suggesting higher mobility of polymer chains for the former, while a nonionic alcohol ethoxylate surfactant was more effective than sodium dodecylsulfate in favoring the dewetting process. FTIR 2D imaging showed that the dewetting patterns observed on model samples are also present on polymer-coated mortar tiles when exposed to NSFs. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Feedforward and feedback motor control abnormalities implicate cerebellar dysfunctions in autism spectrum disorder.

Science.gov (United States)

Mosconi, Matthew W; Mohanty, Suman; Greene, Rachel K; Cook, Edwin H; Vaillancourt, David E; Sweeney, John A

2015-02-04

Sensorimotor abnormalities are common in autism spectrum disorder (ASD) and among the earliest manifestations of the disorder. They have been studied far less than the social-communication and cognitive deficits that define ASD, but a mechanistic understanding of sensorimotor abnormalities in ASD may provide key insights into the neural underpinnings of the disorder. In this human study, we examined rapid, precision grip force contractions to determine whether feedforward mechanisms supporting initial motor output before sensory feedback can be processed are disrupted in ASD. Sustained force contractions also were examined to determine whether reactive adjustments to ongoing motor behavior based on visual feedback are altered. Sustained force was studied across multiple force levels and visual gains to assess motor and visuomotor mechanisms, respectively. Primary force contractions of individuals with ASD showed greater peak rate of force increases and large transient overshoots. Individuals with ASD also showed increased sustained force variability that scaled with force level and was more severe when visual gain was highly amplified or highly degraded. When sustaining a constant force level, their reactive adjustments were more periodic than controls, and they showed increased reliance on slower feedback mechanisms. Feedforward and feedback mechanism alterations each were associated with more severe social-communication impairments in ASD. These findings implicate anterior cerebellar circuits involved in feedforward motor control and posterior cerebellar circuits involved in transforming visual feedback into precise motor adjustments in ASD. Copyright © 2015 the authors 0270-6474/15/352015-11$15.00/0.

Optical coherence tomography assessment of the mechanistic effects of rotational and orbital atherectomy in severely calcified coronary lesions.

Science.gov (United States)

Kini, Annapoorna S; Vengrenyuk, Yuliya; Pena, Jacobo; Motoyama, Sadako; Feig, Jonathan E; Meelu, Omar A; Rajamanickam, Anitha; Bhat, Arjun M; Panwar, Sadik; Baber, Usman; Sharma, Samin K

2015-11-15

This study sought to assess the mechanistic effect of rotational atherectomy (RA) and orbital atherectomy (OA) on heavily calcified coronary lesions and subsequent stent placement using optical coherence tomography (OCT). RA and OA are two main approaches to ablate coronary calcium. While small case reports have described the mechanistic effect of RA in calcified coronary lesions, there has been no imaging study to assess the effect of OA on coronary artery architecture and/or compare the effects of two atherectomy devices. This study analyzed 20 consecutive patients with OCT imaging performed after atherectomy and after stent implantation, RA (n = 10) and OA (n = 10). Postatherectomy OCT analysis identified tissue modification with deep dissections in around a third of lesions after RA and OA; however, post OA dissections ("lacunae") were significantly deeper (1.14 vs. 0.82 mm, P = 0.048). Post OA/RA lesions with dissections had significantly higher percentage of lipid rich plaques and smaller calcification arcs as compared to plaques without dissections. Stents after OA were associated with a significantly lower percent of stent strut malapposition than post RA stents (4.36 vs. 8.02%, P = 0.038). Although the incidence of dissections was comparable between RA and OA cases, OA resulted in deeper tissue modifications (lacunae) as shown by OCT imaging. The finding might provide an explanation for a better stent apposition after OA as compared to RA. Their impact on long-term outcome needs to be determined. © 2015 Wiley Periodicals, Inc.

At the intersection of attention and memory: the mechanistic role of the posterior parietal lobe in working memory

Science.gov (United States)

Berryhill, Marian E.; Chein, Jason; Olson, Ingrid R.

2011-01-01

Portions of the posterior parietal cortex (PPC) play a role in working memory (WM) yet the precise mechanistic function of this region remains poorly understood. The pure storage hypothesis proposes that this region functions as a short-lived modality-specific memory store. Alternatively, the internal attention hypothesis proposes that the PPC functions as an attention-based storage and refreshing mechanism deployable as an alternative to material-specific rehearsal. These models were tested in patients with bilateral PPC lesions. Our findings discount the pure storage hypothesis because variables indexing storage capacity and longevity were not disproportionately affected by PPC damage. Instead, our data support the internal attention account by showing that (a) normal participants tend to use a rehearsal-based WM maintenance strategy for recall tasks but not for recognition tasks; (b) patients with PPC lesions performed normally on WM tasks that relied on material-specific rehearsal strategies but poorly on WM tasks that relied on attention-based maintenance strategies and patient strategy usage could be shifted by task or instructions; (c) patients’ memory deficits extended into the long-term domain. These findings suggest that the PPC maintains or shifts internal attention among the representations of items in WM. PMID:21345344

At the intersection of attention and memory: the mechanistic role of the posterior parietal lobe in working memory.

Science.gov (United States)

Berryhill, Marian E; Chein, Jason; Olson, Ingrid R

2011-04-01

Portions of the posterior parietal cortex (PPC) play a role in working memory (WM) yet the precise mechanistic function of this region remains poorly understood. The pure storage hypothesis proposes that this region functions as a short-lived modality-specific memory store. Alternatively, the internal attention hypothesis proposes that the PPC functions as an attention-based storage and refreshing mechanism deployable as an alternative to material-specific rehearsal. These models were tested in patients with bilateral PPC lesions. Our findings discount the pure storage hypothesis because variables indexing storage capacity and longevity were not disproportionately affected by PPC damage. Instead, our data support the internal attention account by showing that (a) normal participants tend to use a rehearsal-based WM maintenance strategy for recall tasks but not for recognition tasks; (b) patients with PPC lesions performed normally on WM tasks that relied on material-specific rehearsal strategies but poorly on WM tasks that relied on attention-based maintenance strategies and patient strategy usage could be shifted by task or instructions; (c) patients' memory deficits extended into the long-term domain. These findings suggest that the PPC maintains or shifts internal attention among the representations of items in WM. Copyright © 2011 Elsevier Ltd. All rights reserved.

Control room habitability during severe accidents

International Nuclear Information System (INIS)

Siu, R.P.

1989-01-01

The requirements for protection of control room personnel against radiation hazards are specified in 10CFR50, Appendix A, GDC 19. The conventional approach involves a mechanistic evaluation of the radiation doses to control room personnel during design-basis accidents. In this study, an assessment of control room habitability during severe accidents is conducted. The potential levels of radiation hazards to control room personnel are evaluated in terms of both magnitude and probability of occurrence. The expected values for the probabilities of exceeding GDC-19 limits and the cumulative probability distributions of control room doses are determined. In this study, a pressurized water reactor with a large dry containment has been selected for analysis. The types of control rooms evaluated in this study include designs with: (a) filtered local intakes only, (b) filtered recirculation only, (c) filtered local intakes and recirculation, and (d) filtered dual remote intakes and recirculation. From the observations, it is concluded that, except for control room D, all other control room designs may require improvements in order to provide adequate radiation protection during severe accidents, particularly in terms of reducing whole-body gamma doses and skin doses. Potential design improvements include reduction of intake flows for concepts relying on pressurization, reduction in overall leakages, and control room pressurization through the use of bottled air supply

Conceptualising population health: from mechanistic thinking to complexity science

Directory of Open Access Journals (Sweden)

Jayasinghe Saroj

2011-01-01

Full Text Available Abstract 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.

Mechanistic kinetic models of enzymatic cellulose hydrolysis-A review.

Science.gov (United States)

Jeoh, Tina; Cardona, Maria J; Karuna, Nardrapee; Mudinoor, Akshata R; Nill, Jennifer

2017-07-01

Bioconversion of lignocellulose forms the basis for renewable, advanced biofuels, and bioproducts. Mechanisms of hydrolysis of cellulose by cellulases have been actively studied for nearly 70 years with significant gains in understanding of the cellulolytic enzymes. Yet, a full mechanistic understanding of the hydrolysis reaction has been elusive. We present a review to highlight new insights gained since the most recent comprehensive review of cellulose hydrolysis kinetic models by Bansal et al. (2009) Biotechnol Adv 27:833-848. Recent models have taken a two-pronged approach to tackle the challenge of modeling the complex heterogeneous reaction-an enzyme-centric modeling approach centered on the molecularity of the cellulase-cellulose interactions to examine rate limiting elementary steps and a substrate-centric modeling approach aimed at capturing the limiting property of the insoluble cellulose substrate. Collectively, modeling results suggest that at the molecular-scale, how rapidly cellulases can bind productively (complexation) and release from cellulose (decomplexation) is limiting, while the overall hydrolysis rate is largely insensitive to the catalytic rate constant. The surface area of the insoluble substrate and the degrees of polymerization of the cellulose molecules in the reaction both limit initial hydrolysis rates only. Neither enzyme-centric models nor substrate-centric models can consistently capture hydrolysis time course at extended reaction times. Thus, questions of the true reaction limiting factors at extended reaction times and the role of complexation and decomplexation in rate limitation remain unresolved. Biotechnol. Bioeng. 2017;114: 1369-1385. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Conceptualising population health: from mechanistic thinking to complexity science.

Science.gov (United States)

Jayasinghe, Saroj

2011-01-20

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.

O-O Radical Coupling: From Detailed Mechanistic Understanding to Enhanced Water Oxidation Catalysis.

Science.gov (United States)

Xie, Yan; Shaffer, David W; Concepcion, Javier J

2018-04-30

A deeper mechanistic understanding of the key O-O bond formation step of water oxidation by the [Ru(bda)(L) 2 ] (bdaH 2 = 2,2'-bipyridine-6,6'-dicarboxylic acid; L is a pyridine or isoquinoline derivative) family of catalysts is reached through harmonious experimental and computational studies of two series of modified catalysts with systematic variations in the axial ligands. The introduction of halogen and electron-donating substituents in [Ru(bda)(4-X-py) 2 ] and [Ru(bda)(6-X-isq) 2 ] (X is H, Cl, Br, and I for the pyridine series and H, F, Cl, Br, and OMe for the isoquinoline series) enhances the noncovalent interactions between the axial ligands in the transition state for the bimolecular O-O coupling, resulting in a lower activation barrier and faster catalysis. From detailed transition state calculations in combination with experimental kinetic studies, we find that the main contributor to the free energy of activation is entropy due to the highly organized transition states, which is contrary to other reports. Previous work has considered only the electronic influence of the substituents, suggesting electron-withdrawing groups accelerate catalysis, but we show that a balance between polarizability and favorable π-π interactions is the key, leading to rationally devised improvements. Our calculations predict the catalysts with the lowest Δ G ⧧ for the O-O coupling step to be [Ru(bda)(4-I-py) 2 ] and [Ru(bda)(6,7-(OMe) 2 -isq) 2 ] for the pyridine and isoquinoline families, respectively. Our experimental results corroborate these predictions: the turnover frequency for [Ru(bda)(4-I-py) 2 ] (330 s -1 ) is a 10-fold enhancement with respect to that of [Ru(bda)(py) 2 ], and the turnover frequency for [Ru(bda)(6-OMe-isq) 2 ] reaches 1270 s -1 , two times faster than [Ru(bda)(isq) 2 ].

Advantageous use of HepaRG cells for the screening and mechanistic study of drug-induced steatosis

Energy Technology Data Exchange (ETDEWEB)

Tolosa, Laia [Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia 46026 (Spain); Gómez-Lechón, M. José [Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia 46026 (Spain); CIBERehd, FIS, Barcelona 08036 (Spain); Jiménez, Nuria [Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia 46026 (Spain); Hervás, David [Biostatistics Unit, Instituto de Investigación Sanitaria La Fe, Valencia 46026 (Spain); Jover, Ramiro [Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia 46026 (Spain); CIBERehd, FIS, Barcelona 08036 (Spain); Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Valencia 46010 (Spain); Donato, M. Teresa, E-mail: donato_mte@gva.es [Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia 46026 (Spain); CIBERehd, FIS, Barcelona 08036 (Spain); Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Valencia 46010 (Spain)

2016-07-01

Only a few in vitro assays have been proposed to evaluate the steatotic potential of new drugs. The present study examines the utility of HepaRG cells as a cell-based assay system for screening drug-induced liver steatosis. A high-content screening assay was run to evaluate multiple toxicity-related cell parameters in HepaRG cells exposed to 28 compounds, including drugs reported to cause steatosis through different mechanisms and non-steatotic compounds. Lipid content was the most sensitive parameter for all the steatotic drugs, whereas no effects on lipid levels were produced by non-steatotic compounds. Apart from fat accumulation, increased ROS production and altered mitochondrial membrane potential were also found in the cells exposed to steatotic drugs, which indicates that all these cellular events contributed to drug-induced hepatotoxicity. These findings are of clinical relevance as most effects were observed at drug concentrations under 100-fold of the therapeutic peak plasmatic concentration. HepaRG cells showed increased lipid overaccumulation vs. HepG2 cells, which suggests greater sensitivity to drug-induced steatosis. An altered expression profile of transcription factors and the genes that code key proteins in lipid metabolism was also found in the cells exposed to drugs capable of inducing liver steatosis. Our results generally indicate the value of HepaRG cells for assessing the risk of liver damage associated with steatogenic compounds and for investigating the molecular mechanisms involved in drug-induced steatosis. - Highlights: • HepaRG cells were explored as an in vitro model to detect steatogenic potential. • Multiple toxicity-related endpoints were analysed by HCS. • HepaRG showed a greater sensitivity to drug-induced steatosis than HepG2 cells. • Changes in the expression of genes related to lipid metabolism were revealed. • HepaRG allow mechanistic understanding of liver damage induced by steatogenic drugs.

Advantageous use of HepaRG cells for the screening and mechanistic study of drug-induced steatosis

International Nuclear Information System (INIS)

Tolosa, Laia; Gómez-Lechón, M. José; Jiménez, Nuria; Hervás, David; Jover, Ramiro; Donato, M. Teresa

2016-01-01

Only a few in vitro assays have been proposed to evaluate the steatotic potential of new drugs. The present study examines the utility of HepaRG cells as a cell-based assay system for screening drug-induced liver steatosis. A high-content screening assay was run to evaluate multiple toxicity-related cell parameters in HepaRG cells exposed to 28 compounds, including drugs reported to cause steatosis through different mechanisms and non-steatotic compounds. Lipid content was the most sensitive parameter for all the steatotic drugs, whereas no effects on lipid levels were produced by non-steatotic compounds. Apart from fat accumulation, increased ROS production and altered mitochondrial membrane potential were also found in the cells exposed to steatotic drugs, which indicates that all these cellular events contributed to drug-induced hepatotoxicity. These findings are of clinical relevance as most effects were observed at drug concentrations under 100-fold of the therapeutic peak plasmatic concentration. HepaRG cells showed increased lipid overaccumulation vs. HepG2 cells, which suggests greater sensitivity to drug-induced steatosis. An altered expression profile of transcription factors and the genes that code key proteins in lipid metabolism was also found in the cells exposed to drugs capable of inducing liver steatosis. Our results generally indicate the value of HepaRG cells for assessing the risk of liver damage associated with steatogenic compounds and for investigating the molecular mechanisms involved in drug-induced steatosis. - Highlights: • HepaRG cells were explored as an in vitro model to detect steatogenic potential. • Multiple toxicity-related endpoints were analysed by HCS. • HepaRG showed a greater sensitivity to drug-induced steatosis than HepG2 cells. • Changes in the expression of genes related to lipid metabolism were revealed. • HepaRG allow mechanistic understanding of liver damage induced by steatogenic drugs.

Combined In Situ Illumination-NMR-UV/Vis Spectroscopy: A New Mechanistic Tool in Photochemistry.

Science.gov (United States)

Seegerer, Andreas; Nitschke, Philipp; Gschwind, Ruth M

2018-06-18

Synthetic applications in photochemistry are booming. Despite great progress in the development of new reactions, mechanistic investigations are still challenging. Therefore, we present a fully automated in situ combination of NMR spectroscopy, UV/Vis spectroscopy, and illumination to allow simultaneous and time-resolved detection of paramagnetic and diamagnetic species. This optical fiber-based setup enables the first acquisition of combined UV/Vis and NMR spectra in photocatalysis, as demonstrated on a conPET process. Furthermore, the broad applicability of combined UVNMR spectroscopy for light-induced processes is demonstrated on a structural and quantitative analysis of a photoswitch, including rate modulation and stabilization of transient species by temperature variation. Owing to the flexibility regarding the NMR hardware, temperature, and light sources, we expect wide-ranging applications of this setup in various research fields. © 2018 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Mechanistic basis of otolith formation during teleost inner ear development.

Science.gov (United States)

Wu, David; Freund, Jonathan B; Fraser, Scott E; Vermot, Julien

2011-02-15

Otoliths, which are connected to stereociliary bundles in the inner ear, serve as inertial sensors for balance. In teleostei, otolith development is critically dependent on flow forces generated by beating cilia; however, the mechanism by which flow controls otolith formation remains unclear. Here, we have developed a noninvasive flow probe using optical tweezers and a viscous flow model in order to demonstrate how the observed hydrodynamics influence otolith assembly. We show that rotational flow stirs and suppresses precursor agglomeration in the core of the cilia-driven vortex. The velocity field correlates with the shape of the otolith and we provide evidence that hydrodynamics is actively involved in controlling otolith morphogenesis. An implication of this hydrodynamic effect is that otolith self-assembly is mediated by the balance between Brownian motion and cilia-driven flow. More generally, this flow feature highlights an alternative biological strategy for controlling particle localization in solution. Copyright © 2011 Elsevier Inc. All rights reserved.

The quest for a mechanistic understanding of biodiversity-ecosystem services relationships.

Science.gov (United States)

Duncan, Clare; Thompson, Julian R; Pettorelli, Nathalie

2015-10-22

Ecosystem services (ES) approaches to biodiversity conservation are currently high on the ecological research and policy agendas. However, despite a wealth of studies into biodiversity's role in maintaining ES (B-ES relationships) across landscapes, we still lack generalities in the nature and strengths of these linkages. Reasons for this are manifold, but can largely be attributed to (i) a lack of adherence to definitions and thus a confusion between final ES and the ecosystem functions (EFs) underpinning them, (ii) a focus on uninformative biodiversity indices and singular hypotheses and (iii) top-down analyses across large spatial scales and overlooking of context-dependency. The biodiversity-ecosystem functioning (B-EF) field provides an alternate context for examining biodiversity's mechanistic role in shaping ES, focusing on species' characteristics that may drive EFs via multiple mechanisms across contexts. Despite acknowledgements of a need for B-ES research to look towards underlying B-EF linkages, the connections between these areas of research remains weak. With this review, we pull together recent B-EF findings to identify key areas for future developments in B-ES research. We highlight a means by which B-ES research may begin to identify how and when multiple underlying B-EF relationships may scale to final ES delivery and trade-offs. © 2015 The Author(s).

Mechanistic aspects of radioprotection by todralazine hydrochloride, a hematopoietic stem cell expanding agent

International Nuclear Information System (INIS)

Dimri, Manali; Joshi, Jaidev; Jain, Sanjoli; Ghosh, Subhajit; Srivastva, Nitisha; Prem Kumar, Indracanti; Chakrabarti, Rina

2014-01-01

Previously, we have reported todralazine hydrochloride, an antihypertensive drug, as a radioprotector and hematopoietic stem cell (HSC) expanding agent. The present study aims at unraveling mechanistic aspects of its radioprotective and HSC expanding potential. Zebrafish Tg (cmyb:GFP) embryos treated with 5 μM todralazine from 24-36 hours post fertilization (hpf), increased the number of HSCs (∼ 2 folds) at aorta gonad mesonephros (AGM) region. Similarly, the expression of HSC marker genes, runx1 (3.3 folds) and cMyb (1.4 folds) were also found to be increased. Further, todralazine also accelerated hematopoietic lineage production, erythropoiesis, as evaluated in chemical induced anemic model in zebrafish. Genome wide expression changes in todralazine treated embryos (from 24-36 hpf) using microarray, revealed up and down regulation of 645 and 429 genes respectively. Pathway analysis using DAVID database strongly suggested up regulation of wnt pathway (p<0.019253), which is known to involve in HSC expansion, in todralazine pre-treated embryos. NOS1, known to have its role in HSC expansion through wnt pathway, has been significantly upregulated (1.54 folds; q PCR) by todralazine treatment (from 24-36 hpf). Todralazine treatment (∼30 minutes; 20 Gy) led to a significant upregulation of antioxidant genes (SOD, catalase), DNA damage response genes (p53, p21, GADD45) and nucleotide excision repair genes (XPC, XPA, XPF, XPD) when compared to irradiated control. Immunohistochemical analysis of DNA damage marker (γH2AX) (30 minutes post irradiation), further supported radiation induced DNA damage and protection by todralazine pre-treatment. Corroborating these results, pre-irradiation treatment of todralazine reduced radiation induced apoptosis (caspase 3 assay). Overall, the results suggest that, todralazine protects zebrafish from radiation induced damages by upregulating antioxidant defense system, DNA damage recognition, DNA repair machinery and by reducing cell

The central extended amygdala in fear and anxiety: Closing the gap between mechanistic and neuroimaging research.

Science.gov (United States)

Fox, Andrew S; Shackman, Alexander J

2017-11-30

Anxiety disorders impose a staggering burden on public health, underscoring the need to develop a deeper understanding of the distributed neural circuits underlying extreme fear and anxiety. Recent work highlights the importance of the central extended amygdala, including the central nucleus of the amygdala (Ce) and neighboring bed nucleus of the stria terminalis (BST). Anatomical data indicate that the Ce and BST form a tightly interconnected unit, where different kinds of threat-relevant information can be integrated to assemble states of fear and anxiety. Neuroimaging studies show that the Ce and BST are engaged by a broad spectrum of potentially threat-relevant cues. Mechanistic work demonstrates that the Ce and BST are critically involved in organizing defensive responses to a wide range of threats. Studies in rodents have begun to reveal the specific molecules, cells, and microcircuits within the central extended amygdala that underlie signs of fear and anxiety, but the relevance of these tantalizing discoveries to human experience and disease remains unclear. Using a combination of focal perturbations and whole-brain imaging, a new generation of nonhuman primate studies is beginning to close this gap. This work opens the door to discovering the mechanisms underlying neuroimaging measures linked to pathological fear and anxiety, to understanding how the Ce and BST interact with one another and with distal brain regions to govern defensive responses to threat, and to developing improved intervention strategies. Copyright © 2017. Published by Elsevier B.V.

Mechanistic studies aimed at the development of single site metal alkoxide catalysts for the production of polyoxygenates from renewable resources.

Energy Technology Data Exchange (ETDEWEB)

Chisholm, Malcolm H. [The Ohio State Univ., Columbus, OH (United States)

2015-12-15

The work proposed herein follows on directly from the existing 3 year grant and the request for funding is for 12 months to allow completion of this work and graduation of current students supported by DOE. The three primary projects are as follows. 1.) A comparative study of the reactivity of LMg(OR) (solvent), where L= a β-diiminate or pyrromethene ligand, in the ring-opening of cyclic esters. 2.) The homopolymerization of expoxides, particularly propylene oxide and styrene oxide, and their copolymerizations with carbon dioxide or organic anhydrides to yield polycarbonates or polyesters, respectively. 3.) The development of well-defined bismuth (III) complexes for ring-opening polymerizations that are tolerant of both air and water. In each of these topics special emphasis is placed on developing a detailed mechanistic understanding of the ring-opening event and how this is modified by the employment of specific metal and ligand combinations. This document also provides a report on findings of the past grant period that are not yet in the public domain/published and shows how the proposed work will bring the original project to conclusion.

Active Inference, homeostatic regulation and adaptive behavioural control.

Science.gov (United States)

Pezzulo, Giovanni; Rigoli, Francesco; Friston, Karl

2015-11-01

We review a theory of homeostatic regulation and adaptive behavioural control within the Active Inference framework. Our aim is to connect two research streams that are usually considered independently; namely, Active Inference and associative learning theories of animal behaviour. The former uses a probabilistic (Bayesian) formulation of perception and action, while the latter calls on multiple (Pavlovian, habitual, goal-directed) processes for homeostatic and behavioural control. We offer a synthesis these classical processes and cast them as successive hierarchical contextualisations of sensorimotor constructs, using the generative models that underpin Active Inference. This dissolves any apparent mechanistic distinction between the optimization processes that mediate classical control or learning. Furthermore, we generalize the scope of Active Inference by emphasizing interoceptive inference and homeostatic regulation. The ensuing homeostatic (or allostatic) perspective provides an intuitive explanation for how priors act as drives or goals to enslave action, and emphasises the embodied nature of inference. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling.

Science.gov (United States)

He, Xi C; Zhang, Jiwang; Tong, Wei-Gang; Tawfik, Ossama; Ross, Jason; Scoville, David H; Tian, Qiang; Zeng, Xin; He, Xi; Wiedemann, Leanne M; Mishina, Yuji; Li, Linheng

2004-10-01

In humans, mutations in BMPR1A, SMAD4 and PTEN are responsible for juvenile polyposis syndrome, juvenile intestinal polyposis and Cowden disease, respectively. The development of polyposis is a common feature of these diseases, suggesting that there is an association between BMP and PTEN pathways. The mechanistic link between BMP and PTEN pathways and the related etiology of juvenile polyposis is unresolved. Here we show that conditional inactivation of Bmpr1a in mice disturbs homeostasis of intestinal epithelial regeneration with an expansion of the stem and progenitor cell populations, eventually leading to intestinal polyposis resembling human juvenile polyposis syndrome. We show that BMP signaling suppresses Wnt signaling to ensure a balanced control of stem cell self-renewal. Mechanistically, PTEN, through phosphatidylinosital-3 kinase-Akt, mediates the convergence of the BMP and Wnt pathways on control of beta-catenin. Thus, BMP signaling may control the duplication of intestinal stem cells, thereby preventing crypt fission and the subsequent increase in crypt number.

Identification of Orch3, a locus controlling dominant resistance to autoimmune orchitis, as kinesin family member 1C.

Directory of Open Access Journals (Sweden)

Roxana del Rio

Full Text Available Experimental autoimmune orchitis (EAO, the principal model of non-infectious testicular inflammatory disease, can be induced in susceptible mouse strains by immunization with autologous testicular homogenate and appropriate adjuvants. As previously established, the genome of DBA/2J mice encodes genes that are capable of conferring dominant resistance to EAO, while the genome of BALB/cByJ mice does not and they are therefore susceptible to EAO. In a genome scan, we previously identified Orch3 as the major quantitative trait locus controlling dominant resistance to EAO and mapped it to chromosome 11. Here, by utilizing a forward genetic approach, we identified kinesin family member 1C (Kif1c as a positional candidate for Orch3 and, using a transgenic approach, demonstrated that Kif1c is Orch3. Mechanistically, we showed that the resistant Kif1c(D2 allele leads to a reduced antigen-specific T cell proliferative response as a consequence of decreased MHC class II expression by antigen presenting cells, and that the L(578 → P(578 and S(1027 → P(1027 polymorphisms distinguishing the BALB/cByJ and DBA/2J alleles, respectively, can play a role in transcriptional regulation. These findings may provide mechanistic insight into how polymorphism in other kinesins such as KIF21B and KIF5A influence susceptibility and resistance to human autoimmune diseases.

Spatially confined photoinactivation of bacteria: towards novel tools for detailed mechanistic studies

Science.gov (United States)

Thomsen, Hanna; James, Jeemol; Farewell, Anne; Ericson, Marica B.

2018-02-01

Antimicrobial resistance is a serious global threat fueling an accelerated field of research aimed at developing novel antimicrobial therapies. A particular challenge is the treatment of microbial biofilms formed upon bacterial growth and often associated with chronic infections. Biofilms comprise bacteria that have adhered to a surface and formed 3D microcolonies, and demonstrate significantly increased antimicrobial resistance compared to the planktonic counterpart. A challenge in developing novel strategies for fighting these chronic infections is a lack of mechanistic understanding of what primarily contributes to enhanced drug resistance. Tools for noninvasive study of live biofilms are necessary to begin to understand these mechanisms on both a single cell and 3D level. Herein, a method by which multiphoton microscopy is implemented to study a biofilm model of Staphylococcus epidermidis to noninvasively visualize and measure penetration of compounds in 3D biofilm structure and two photon excitation was exploited for spatially confined photoinactivation and microscopy optimized for evaluation of microbiological viability at a microscopic level. Future studies are aimed at future development of the proposed techniques for detailed studies of, e.g., quorum sensing and mechanisms contributing to antimicrobial resistance.

Controls on Filling and Evacuation of Sediment in Waterfall Plunge Pools

Science.gov (United States)

Scheingross, J. S.; Lamb, M. P.

2014-12-01

Many waterfalls are characterized by the presence of deep plunge pools that experience periods of sediment fill and evacuation. These cycles of sediment fill are a first order control on the relative magnitude of lateral versus vertical erosion at the base of waterfalls, as vertical incision requires cover-free plunge pools to expose the bedrock floor, while lateral erosion can occur when pools are partially filled and plunge-pool walls are exposed. Currently, there exists no mechanistic model describing sediment transport through waterfall plunge pools, limiting our ability to predict waterfall retreat. To address this knowledge gap, we performed detailed laboratory experiments measuring plunge-pool sediment transport capacity (Qsc_pool) under varying waterfall and plunge-pool geometries, flow hydraulics, and sediment size. Our experimental plunge-pool sediment transport capacity measurements match well with a mechanistic model we developed which combines existing waterfall jet theory with a modified Rouse profile to predict sediment transport capacity as a function of water discharge and suspended sediment concentration at the plunge-pool lip. Comparing the transport capacity of plunge pools to lower gradient portions of rivers (Qsc_river) shows that, for transport limited conditions, plunge pools fill with sediment under modest water discharges when Qsc_river > Qsc_pool, and empty to bedrock under high discharges when Qsc_pool > Qsc_river. These results are consistent with field observations of sand-filled plunge pools with downstream boulder rims, implying filling and excavation of plunge pools over single-storm timescales. Thus, partial filling of waterfall plunge pools may provide a mechanism to promote lateral undercutting and retreat of waterfalls in homogeneous rock in which plunge-pool vertical incision occurs during brief large floods that expose bedrock, whereas lateral erosion may prevail during smaller events.

Comparative investigation on cation-cation (Al-Sn) and cation-anion (Al-F) co-doping in RF sputtered ZnO thin films: Mechanistic insight

Energy Technology Data Exchange (ETDEWEB)

Mallick, Arindam; Basak, Durga, E-mail: sspdb@iacs.res.in

2017-07-15

Highlights: • Comparative study on Al, Al-Sn and Al-F doped ZnO films has been carried out. • High transparent Al-F co-doped film shows three times enhanced carrier density. • Al-F co-doped film shows larger carrier relaxation time. • Al-Sn co-doped films shows carrier transport dominated by impurity scattering. • Al-F co-doped ZnO film can be applied as transparent electrode. - Abstract: Herein, we report a comparative mechanistic study on cation-cation (Al-Sn) and cation-anion (Al-F) co-doped nanocrystalline ZnO thin films grown on glass substrate by RF sputtering technique. Through detailed analyses of crystal structure, surface morphology, microstructure, UV-VIS-NIR transmission-reflection and electrical transport property, the inherent characteristics of the co-doped films were revealed and compared. All the nanocrystalline films retain the hexagonal wurtzite structure of ZnO and show transparency above 90% in the visible and NIR region. As opposed to expectation, Al-Sn (ATZO) co-doped film show no enhanced carrier concentration consistent with the probable formation of SnO{sub 2} clusters supported by the X-ray photoelectron spectroscopy study. Most interestingly, it has been found that Al-F (AFZO) co-doped film shows three times enhanced carrier concentration as compared to Al doped and Al-Sn co-doped films attaining a value of ∼9 × 10{sup 20} cm{sup −3} due to the respective cation and anion substitution. The carrier relaxation time increases in AFZO while it decreases significantly for ATZO film consistent with the concurrence of the impurity scattering in the latter.

Mechanistic study of fuel freezing, channel plugging, and continued coolability during fast reactor overpower excursions

International Nuclear Information System (INIS)

Wong, K.W.; Catton, I.; Kastenberg, W.E.

1977-07-01

A mechanistic model is presented which describes events following fuel pin failure which may lead to in-channel fuel plate-out. The thermal and hydraulic effects of the plate-out fuel are also evaluated. Given the amount and particle size of the fuel injected into the coolant channel during fuel pin failure, and the initial conditions of the interaction zone, the physical states of the fuel particles and the coolant in the interaction zone can be determined. The trajectories of the fuel particles in the coolant channel are determined by assuming a slip factor between the local tangential velocities of the coolant and the fuel particles. The time and distance after which a fuel particle hits a wire wrap are then determined and the impact stresses induced in the thin solid fuel crust can be evaluated

Biomeasures and mechanistic modeling highlight PK/PD risks for a monoclonal antibody targeting Fn14 in kidney disease.

Science.gov (United States)

Chen, Xiaoying; Farrokhi, Vahid; Singh, Pratap; Ocana, Mireia Fernandez; Patel, Jenil; Lin, Lih-Ling; Neubert, Hendrik; Brodfuehrer, Joanne

2018-01-01

Discovery of the upregulation of fibroblast growth factor-inducible-14 (Fn14) receptor following tissue injury has prompted investigation into biotherapeutic targeting of the Fn14 receptor for the treatment of conditions such as chronic kidney diseases. In the development of monoclonal antibody (mAb) therapeutics, there is an increasing trend to use biomeasures combined with mechanistic pharmacokinetic/pharmacodynamic (PK/PD) modeling to enable decision making in early discovery. With the aim of guiding preclinical efforts on designing an antibody with optimized properties, we developed a mechanistic site-of-action (SoA) PK/PD model for human application. This model incorporates experimental biomeasures, including concentration of soluble Fn14 (sFn14) in human plasma and membrane Fn14 (mFn14) in human kidney tissue, and turnover rate of human sFn14. Pulse-chase studies using stable isotope-labeled amino acids and mass spectrometry indicated the sFn14 half-life to be approximately 5 hours in healthy volunteers. The biomeasures (concentration, turnover) of sFn14 in plasma reveals a significant hurdle in designing an antibody against Fn14 with desired characteristics. The projected dose (>1 mg/kg/wk for 90% target coverage) derived from the human PK/PD model revealed potential high and frequent dosing requirements under certain conditions. The PK/PD model suggested a unique bell-shaped relationship between target coverage and antibody affinity for anti-Fn14 mAb, which could be applied to direct the antibody engineering towards an optimized affinity. This investigation highlighted potential applications, including assessment of PK/PD risks during early target validation, human dose prediction and drug candidate optimization.

Application of response surface methodology and semi-mechanistic model to optimize fluoride removal using crushed concrete in a fixed-bed column.

Science.gov (United States)

Gu, Bon-Wun; Lee, Chang-Gu; Park, Seong-Jik

2018-03-01

The aim of this study was to investigate the removal of fluoride from aqueous solutions by using crushed concrete fines as a filter medium under varying conditions of pH 3-7, flow rate of 0.3-0.7 mL/min, and filter depth of 10-20 cm. The performance of fixed-bed columns was evaluated on the basis of the removal ratio (Re), uptake capacity (qe), degree of sorbent used (DoSU), and sorbent usage rate (SUR) obtained from breakthrough curves (BTCs). Three widely used semi-mechanistic models, that is, Bohart-Adams, Thomas, and Yoon-Nelson models, were applied to simulate the BTCs and to derive the design parameters. The Box-Behnken design of response surface methodology (RSM) was used to elucidate the individual and interactive effects of the three operational parameters on the column performance and to optimize these parameters. The results demonstrated that pH is the most important factor in the performance of fluoride removal by a fixed-bed column. The flow rate had a significant negative influence on Re and DoSU, and the effect of filter depth was observed only in the regression model for DoSU. Statistical analysis indicated that the model attained from the RSM study is suitable for describing the semi-mechanistic model parameters.

A Mechanistic Model of Human Recall of Social Network Structure and Relationship Affect.

Science.gov (United States)

Omodei, Elisa; Brashears, Matthew E; Arenas, Alex

2017-12-07

The social brain hypothesis argues that the need to deal with social challenges was key to our evolution of high intelligence. Research with non-human primates as well as experimental and fMRI studies in humans produce results consistent with this claim, leading to an estimate that human primary groups should consist of roughly 150 individuals. Gaps between this prediction and empirical observations can be partially accounted for using "compression heuristics", or schemata that simplify the encoding and recall of social information. However, little is known about the specific algorithmic processes used by humans to store and recall social information. We describe a mechanistic model of human network recall and demonstrate its sufficiency for capturing human recall behavior observed in experimental contexts. We find that human recall is predicated on accurate recall of a small number of high degree network nodes and the application of heuristics for both structural and affective information. This provides new insight into human memory, social network evolution, and demonstrates a novel approach to uncovering human cognitive operations.

Malaria's Missing Number: Calculating the Human Component of R0 by a Within-Host Mechanistic Model of Plasmodium falciparum Infection and Transmission

OpenAIRE

Johnston, Geoffrey L.; Smith, David L.; Fidock, David A.

2013-01-01

Human infection by malarial parasites of the genus Plasmodium begins with the bite of an infected Anopheles mosquito. Current estimates place malaria mortality at over 650,000 individuals each year, mostly in African children. Efforts to reduce disease burden can benefit from the development of mathematical models of disease transmission. To date, however, comprehensive modeling of the parameters defining human infectivity to mosquitoes has remained elusive. Here, we describe a mechanistic wi...

On the closed form mechanistic modeling of milling: Specific cutting energy, torque, and power

Science.gov (United States)

Bayoumi, A. E.; Yücesan, G.; Hutton, D. V.

1994-02-01

Specific energy in metal cutting, defined as the energy expended in removing a unit volume of workpiece material, is formulated and determined using a previously developed closed form mechanistic force model for milling operations. Cutting power is computed from the cutting torque, cutting force, kinematics of the cutter, and the volumetric material removal rate. Closed form expressions for specific cutting energy were formulated and found to be functions of the process parameters: pressure and friction for both rake and flank surfaces and chip flow angle at the rake face of the tool. Friction is found to play a very important role in cutting torque and power. Experiments were carried out to determine the effects of feedrate, cutting speed, workpiece material, and flank wear land width on specific cutting energy. It was found that the specific cutting energy increases with a decrease in the chip thickness and with an increase in flank wear land.

A holistic approach to anesthesia-induced neurotoxicity and its implications for future mechanistic studies.

Science.gov (United States)

Zanghi, Christine N; Jevtovic-Todorovic, Vesna

The year 2016 marked the 15th anniversary since anesthesia-induced developmental neurotoxicity and its resulting cognitive dysfunction were first described. Since that time, multiple scientific studies have supported these original findings and investigated possible mechanisms behind anesthesia-induced neurotoxicity. This paper reviews the existing mechanistic literature on anesthesia-induced neurotoxicity in the context of a holistic approach that emphasizes the importance of both neuronal and non-neuronal cells during early postnatal development. Sections are divided into key stages in early neural development; apoptosis, neurogenesis, migration, differentiation, synaptogenesis, gliogenesis, myelination and blood brain barrier/cerebrovasculature. In addition, the authors combine the established literature in the field of anesthesia-induced neurotoxicity with literature from other related scientific fields to speculate on the potential role of non-neuronal cells and to generate new future hypotheses for understanding anesthetic toxicity and its application to the practice of pediatric anesthesia. Copyright © 2017 Elsevier Inc. All rights reserved.

A new mechanistic and engineering fission gas release model for a uranium dioxide fuel

International Nuclear Information System (INIS)

Lee, Chan Bock; Yang, Yong Sik; Kim, Dae Ho; Kim, Sun Ki; Bang, Je Geun

2008-01-01

A mechanistic and engineering fission gas release model (MEGA) for uranium dioxide (UO 2 ) fuel was developed. It was based upon the diffusional release of fission gases from inside the grain to the grain boundary and the release of fission gases from the grain boundary to the external surface by the interconnection of the fission gas bubbles in the grain boundary. The capability of the MEGA model was validated by a comparison with the fission gas release data base and the sensitivity analyses of the parameters. It was found that the MEGA model correctly predicts the fission gas release in the broad range of fuel burnups up to 98 MWd/kgU. Especially, the enhancement of fission gas release in a high-burnup fuel, and the reduction of fission gas release at a high burnup by increasing the UO 2 grain size were found to be correctly predicted by the MEGA model without using any artificial factor. (author)

Mechanistic Analysis of Cocrystal Dissolution as a Function of pH and Micellar Solubilization.

Science.gov (United States)

Cao, Fengjuan; Amidon, Gordon L; Rodriguez-Hornedo, Nair; Amidon, Gregory E

2016-03-07

The purpose of this work is to provide a mechanistic understanding of the dissolution behavior of cocrystals under the influence of ionization and micellar solubilization. Mass transport models were developed by applying Fick's law of diffusion to dissolution with simultaneous chemical reactions in the hydrodynamic boundary layer adjacent to the dissolving cocrystal surface to predict the pH at the dissolving solid-liquid interface (i.e., interfacial pH) and the flux of cocrystals. To evaluate the predictive power of these models, dissolution studies of carbamazepine-saccharin (CBZ-SAC) and carbamazepine-salicylic acid (CBZ-SLC) cocrystals were performed at varied pH and surfactant concentrations above the critical stabilization concentration (CSC), where the cocrystals were thermodynamically stable. The findings in this work demonstrate that the pH dependent dissolution behavior of cocrystals with ionizable components is dependent on interfacial pH. This mass transport analysis demonstrates the importance of pH, cocrystal solubility, diffusivity, and micellar solubilization on the dissolution rates of cocrystals.

Bistable switches control memory and plasticity in cellular differentiation

Science.gov (United States)

Wang, Lei; Walker, Brandon L.; Iannaccone, Stephen; Bhatt, Devang; Kennedy, Patrick J.; Tse, William T.

2009-01-01

Development of stem and progenitor cells into specialized tissues in multicellular organisms involves a series of cell fate decisions. Cellular differentiation in higher organisms is generally considered irreversible, and the idea of developmental plasticity in postnatal tissues is controversial. Here, we show that inhibition of mitogen-activated protein kinase (MAPK) in a human bone marrow stromal cell-derived myogenic subclone suppresses their myogenic ability and converts them into satellite cell-like precursors that respond to osteogenic stimulation. Clonal analysis of the induced osteogenic response reveals ultrasensitivity and an “all-or-none” behavior, hallmarks of a bistable switch mechanism with stochastic noise. The response demonstrates cellular memory, which is contingent on the accumulation of an intracellular factor and can be erased by factor dilution through cell divisions or inhibition of protein synthesis. The effect of MAPK inhibition also exhibits memory and appears to be controlled by another bistable switch further upstream that determines cell fate. Once the memory associated with osteogenic differentiation is erased, the cells regain their myogenic ability. These results support a model of cell fate decision in which a network of bistable switches controls inducible production of lineage-specific differentiation factors. A competitive balance between these factors determines cell fate. Our work underscores the dynamic nature of cellular differentiation and explains mechanistically the dual properties of stability and plasticity associated with the process. PMID:19366677

Network-based discovery through mechanistic systems biology. Implications for applications--SMEs and drug discovery: where the action is.

Science.gov (United States)

Benson, Neil

2015-08-01

Phase II attrition remains the most important challenge for drug discovery. Tackling the problem requires improved understanding of the complexity of disease biology. Systems biology approaches to this problem can, in principle, deliver this. This article reviews the reports of the application of mechanistic systems models to drug discovery questions and discusses the added value. Although we are on the journey to the virtual human, the length, path and rate of learning from this remain an open question. Success will be dependent on the will to invest and make the most of the insight generated along the way. Copyright © 2015 Elsevier Ltd. All rights reserved.

Mechanistic Insight into Bunyavirus-Induced Membrane Fusion from Structure-Function Analyses of the Hantavirus Envelope Glycoprotein Gc.

Directory of Open Access Journals (Sweden)

Pablo Guardado-Calvo

2016-10-01

Full Text Available Hantaviruses are zoonotic viruses transmitted to humans by persistently infected rodents, giving rise to serious outbreaks of hemorrhagic fever with renal syndrome (HFRS or of hantavirus pulmonary syndrome (HPS, depending on the virus, which are associated with high case fatality rates. There is only limited knowledge about the organization of the viral particles and in particular, about the hantavirus membrane fusion glycoprotein Gc, the function of which is essential for virus entry. We describe here the X-ray structures of Gc from Hantaan virus, the type species hantavirus and responsible for HFRS, both in its neutral pH, monomeric pre-fusion conformation, and in its acidic pH, trimeric post-fusion form. The structures confirm the prediction that Gc is a class II fusion protein, containing the characteristic β-sheet rich domains termed I, II and III as initially identified in the fusion proteins of arboviruses such as alpha- and flaviviruses. The structures also show a number of features of Gc that are distinct from arbovirus class II proteins. In particular, hantavirus Gc inserts residues from three different loops into the target membrane to drive fusion, as confirmed functionally by structure-guided mutagenesis on the HPS-inducing Andes virus, instead of having a single "fusion loop". We further show that the membrane interacting region of Gc becomes structured only at acidic pH via a set of polar and electrostatic interactions. Furthermore, the structure reveals that hantavirus Gc has an additional N-terminal "tail" that is crucial in stabilizing the post-fusion trimer, accompanying the swapping of domain III in the quaternary arrangement of the trimer as compared to the standard class II fusion proteins. The mechanistic understandings derived from these data are likely to provide a unique handle for devising treatments against these human pathogens.

Mechanistic insights into nanotoxicity determined by synchrotron radiation-based Fourier-transform infrared imaging and multivariate analysis.

Science.gov (United States)

Riding, Matthew J; Trevisan, Júlio; Hirschmugl, Carol J; Jones, Kevin C; Semple, Kirk T; Martin, Francis L

2012-12-01

Our ability to identify the mechanisms by which carbon-based nanomaterials (CBNs) exert toxicity in cells is constrained by the lack of standardized methodologies to assay endpoint effects. Herein we describe a method of mechanistically identifying the effects of various CBN types in both prokaryotic and eukaryotic cells using multi-beam synchrotron radiation-based Fourier-transform infrared imaging (SR-FTIRI) at diffraction-limited resolution. This technique overcomes many of the inherent difficulties of assaying nanotoxicity and demonstrates exceptional sensitivity in identifying the effects of CBNs in cells at environmentally-relevant concentrations. We identify key mechanisms of nanotoxicity as the alteration of Amide and lipid biomolecules, but propose more specific bioactivity of CBNs occurs as a result of specific interactions between CBN structural conformation and cellular characteristics. Copyright © 2012 Elsevier Ltd. All rights reserved.

A mechanistic understanding of allosteric immune escape pathways in the HIV-1 envelope glycoprotein.

Directory of Open Access Journals (Sweden)

Anurag Sethi

Full Text Available The HIV-1 envelope (Env spike, which consists of a compact, heterodimeric trimer of the glycoproteins gp120 and gp41, is the target of neutralizing antibodies. However, the high mutation rate of HIV-1 and plasticity of Env facilitates viral evasion from neutralizing antibodies through various mechanisms. Mutations that are distant from the antibody binding site can lead to escape, probably by changing the conformation or dynamics of Env; however, these changes are difficult to identify and define mechanistically. Here we describe a network analysis-based approach to identify potential allosteric immune evasion mechanisms using three known HIV-1 Env gp120 protein structures from two different clades, B and C. First, correlation and principal component analyses of molecular dynamics (MD simulations identified a high degree of long-distance coupled motions that exist between functionally distant regions within the intrinsic dynamics of the gp120 core, supporting the presence of long-distance communication in the protein. Then, by integrating MD simulations with network theory, we identified the optimal and suboptimal communication pathways and modules within the gp120 core. The results unveil both strain-dependent and -independent characteristics of the communication pathways in gp120. We show that within the context of three structurally homologous gp120 cores, the optimal pathway for communication is sequence sensitive, i.e. a suboptimal pathway in one strain becomes the optimal pathway in another strain. Yet the identification of conserved elements within these communication pathways, termed inter-modular hotspots, could present a new opportunity for immunogen design, as this could be an additional mechanism that HIV-1 uses to shield vulnerable antibody targets in Env that induce neutralizing antibody breadth.

A mechanistic modeling and data assimilation framework for Mojave Desert ecohydrology

Science.gov (United States)

Ng, Gene-Hua Crystal; Bedford, David R.; Miller, David M.

2014-06-01

This study demonstrates and addresses challenges in coupled ecohydrological modeling in deserts, which arise due to unique plant adaptations, marginal growing conditions, slow net primary production rates, and highly variable rainfall. We consider model uncertainty from both structural and parameter errors and present a mechanistic model for the shrub Larrea tridentata (creosote bush) under conditions found in the Mojave National Preserve in southeastern California (USA). Desert-specific plant and soil features are incorporated into the CLM-CN model by Oleson et al. (2010). We then develop a data assimilation framework using the ensemble Kalman filter (EnKF) to estimate model parameters based on soil moisture and leaf-area index observations. A new implementation procedure, the "multisite loop EnKF," tackles parameter estimation difficulties found to affect desert ecohydrological applications. Specifically, the procedure iterates through data from various observation sites to alleviate adverse filter impacts from non-Gaussianity in small desert vegetation state values. It also readjusts inconsistent parameters and states through a model spin-up step that accounts for longer dynamical time scales due to infrequent rainfall in deserts. Observation error variance inflation may also be needed to help prevent divergence of estimates from true values. Synthetic test results highlight the importance of adequate observations for reducing model uncertainty, which can be achieved through data quality or quantity.

A mechanistic modeling and data assimilation framework for Mojave Desert ecohydrology

Science.gov (United States)

Ng, Gene-Hua Crystal.; Bedford, David; Miller, David

2014-01-01

This study demonstrates and addresses challenges in coupled ecohydrological modeling in deserts, which arise due to unique plant adaptations, marginal growing conditions, slow net primary production rates, and highly variable rainfall. We consider model uncertainty from both structural and parameter errors and present a mechanistic model for the shrub Larrea tridentata (creosote bush) under conditions found in the Mojave National Preserve in southeastern California (USA). Desert-specific plant and soil features are incorporated into the CLM-CN model by Oleson et al. (2010). We then develop a data assimilation framework using the ensemble Kalman filter (EnKF) to estimate model parameters based on soil moisture and leaf-area index observations. A new implementation procedure, the “multisite loop EnKF,” tackles parameter estimation difficulties found to affect desert ecohydrological applications. Specifically, the procedure iterates through data from various observation sites to alleviate adverse filter impacts from non-Gaussianity in small desert vegetation state values. It also readjusts inconsistent parameters and states through a model spin-up step that accounts for longer dynamical time scales due to infrequent rainfall in deserts. Observation error variance inflation may also be needed to help prevent divergence of estimates from true values. Synthetic test results highlight the importance of adequate observations for reducing model uncertainty, which can be achieved through data quality or quantity.

Mitochondrial structure, function and dynamics are temporally controlled by c-Myc.

Directory of Open Access Journals (Sweden)

J Anthony Graves

Full Text Available Although the c-Myc (Myc oncoprotein controls mitochondrial biogenesis and multiple enzymes involved in oxidative phosphorylation (OXPHOS, the coordination of these events and the mechanistic underpinnings of their regulation remain largely unexplored. We show here that re-expression of Myc in myc-/- fibroblasts is accompanied by a gradual accumulation of mitochondrial biomass and by increases in membrane polarization and mitochondrial fusion. A correction of OXPHOS deficiency is also seen, although structural abnormalities in electron transport chain complexes (ETC are not entirely normalized. Conversely, the down-regulation of Myc leads to a gradual decrease in mitochondrial mass and a more rapid loss of fusion and membrane potential. Increases in the levels of proteins specifically involved in mitochondrial fission and fusion support the idea that Myc affects mitochondrial mass by influencing both of these processes, albeit favoring the latter. The ETC defects that persist following Myc restoration may represent metabolic adaptations, as mitochondrial function is re-directed away from producing ATP to providing a source of metabolic precursors demanded by the transformed cell.

Simulating soil C stability with mechanistic systems models: a multisite comparison of measured fractions and modelled pools

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Robertson, Andy; Schipanski, Meagan; Sherrod, Lucretia; Ma, Liwang; Ahuja, Lajpat; McNamara, Niall; Smith, Pete; Davies, Christian

2016-04-01

.0 tC ha-1 yr-1. At the US site, however, topsoil C sequestration was less consistent noting considerable variation over the 12 years of measured data. Both sites showed noteworthy discrepancies when model-simulated C was compared with measured C. While all three models were able to simulate the bulk C stocks within reasonable degrees of uncertainty, the accuracy broke down considerably when this bulk soil was split into fractions/pools. Using the data collected and accounting for the differences in model structure, we present potential next steps in model development as well as the variables that should be measured when aiming to reduce the uncertainties inherent in mechanistic systems models. References 1 - Zimmermann et al., 2007. Measured soil organic matter fractions can be related to pools in the RothC model. European Journal of Soil Science, 58:658-667.

Mechanistic insights into the use of oxide nanoparticles coated asymmetric electrodes for capacitive deionization

International Nuclear Information System (INIS)

Han, Linchen; Karthikeyan, K.G.; Anderson, M.A.; Wouters, J.J.; Gregory, Kelvin B.

2013-01-01

Highlights: ► Capacitive deionization is an emerging, low-pressure desalination method that can compete with the current mainstream technologies. ► Novel electrode materials (i.e., porous conducting carbon modified with non-conducting oxides applied as nanoporous (NP) films) were tested. ► The NP-oxide coatings increased the sorption capacity and process efficiency by shifting the working potential to a higher efficiency range. ► Experimental data were described using both mechanistic and empirical models to elucidate underlying process mechanisms. ► Our results are expected to facilitate future CDI system design and development of appropriate electrode materials. -- Abstract: Capacitive deionization (CDI) is an emerging water desalination method, which employs high surface area porous electrode materials for electro-sorption of ions. We used an asymmetric CDI cell constructed with alumina and silica nanoparticle (NP) coated electrodes and KCl as a probe electrolyte to gain insights into electro-sorption behavior and elucidate underlying process mechanisms. This CDI system is efficient for use in desalination and up to 15 to 60 μmol/g (total electrode) sorption capacity was achieved. Higher removal of K + compared to Cl − was obtained attributable to competition between OH − and Cl − . The presence of NPs not only creates highly accessible surface area but also increases the charge efficiency by shifting the applied potential to a high efficiency range due to protonation/deprotonation occurring on metal oxide surfaces. Data were described using both mechanistic electrical double layer (EDL) based Gouy–Chapman–Stern (GCS) formulation and empirical Freundlich equations. Our results suggest that the presence of metal oxide NPs can effectively modify the isoelectric points and an increase in planar charge efficiency of up to 20% could be achieved. However, global charge efficiency was still severely constrained by backward thermal diffusion and

Human-itarian aid? Two forms of dehumanization and willingness to help after natural disasters.

Science.gov (United States)

Andrighetto, Luca; Baldissarri, Cristina; Lattanzio, Sara; Loughnan, Steve; Volpato, Chiara

2014-09-01

The present research explores the distinct effects of animalistic and mechanistic dehumanization on willingness to help natural disaster victims. We examined Japanese and Haitians, two national groups recently struck by earthquakes. We showed that Italian participants differently dehumanized the two outgroups: Japanese were attributed low human nature (dehumanized as automata), whereas Haitians were attributed low human uniqueness (dehumanized as animal-like). Ninety participants were then randomly assigned to the Japanese or Haitian target group condition. Mediation analyses showed that animalistic dehumanization decreased willingness to help Haitians, whereas mechanistic dehumanization decreased willingness to help Japanese, even when controlling for attitudes. Importantly, reduced empathy explained the effects of both forms of dehumanization on intergroup helping. © 2014 The British Psychological Society.

Regulation of antiapoptotic MCL-1 function by gossypol: mechanistic insights from in vitro reconstituted systems.

Science.gov (United States)

Etxebarria, Aitor; Landeta, Olatz; Antonsson, Bruno; Basañez, Gorka

2008-12-01

Small-molecule drugs that induce apoptosis in tumor cells by activation of the BCL-2-regulated mitochondrial outer membrane permeabilization (MOMP) pathway hold promise for rational anticancer therapies. Accumulating evidence indicates that the natural product gossypol and its derivatives can kill tumor cells by targeting antiapoptotic BCL-2 family members in such a manner as to trigger MOMP. However, due to the inherent complexity of the cellular apoptotic network, the precise mechanisms by which interactions between gossypol and individual BCL-2 family members lead to MOMP remain poorly understood. Here, we used simplified systems bearing physiological relevance to examine the impact of gossypol on the function of MCL-1, a key determinant for survival of various human malignancies that has become a highly attractive target for anticancer drug design. First, using a reconstituted liposomal system that recapitulates basic aspects of the BCL-2-regulated MOMP pathway, we demonstrate that MCL-1 inhibits BAX permeabilizing function via a "dual-interaction" mechanism, while submicromolar concentrations of gossypol reverse MCL-1-mediated inhibition of functional BAX activation. Solution-based studies showed that gossypol competes with BAX/BID BH3 ligands for binding to MCL-1 hydrophobic groove, thereby providing with a mechanistic explanation for how gossypol restores BAX permeabilizing function in the presence of MCL-1. By contrast, no evidence was found indicating that gossypol transforms MCL-1 into a BAX-like pore-forming molecule. Altogether, our findings validate MCL-1 as a direct target of gossypol, and highlight that making this antiapoptotic protein unable to inhibit BAX-driven MOMP may represent one important mechanism by which gossypol exerts its cytotoxic effect in selected cancer cells.

Polysomnographic characteristics in nonmalignant chronic pain populations: A review of controlled studies.

Science.gov (United States)

Bjurstrom, Martin F; Irwin, Michael R

2016-04-01

Sleep and pain are critical homeostatic systems that interact in a bidirectional manner. Complaints of sleep disturbance are ubiquitous among patients with chronic pain disorders, and conversely, patients with persistent insomnia symptoms commonly report suffering from chronic pain. Sleep deprivation paradigms demonstrate that partial or complete sleep loss induce hyperalgesia, possibly due to shared mechanistic pathways including neuroanatomic and molecular substrates. Further, chronic pain conditions and sleep disturbances are intertwined through comorbidities, which together cause detrimental psychological and physical consequences. This critical review examines 29 polysomnography studies to evaluate whether nonmalignant chronic pain patients, as compared to controls, show differences in objective measures of sleep continuity and sleep architecture. Whereas these controlled studies did not reveal a consistent pattern of objective sleep disturbances, alterations of sleep continuity were commonly reported. Alterations of sleep architecture such as increases in light sleep or decreases in slow-wave sleep were less commonly reported and findings were mixed and also inconsistent. Methodological flaws were identified, which complicated interpretation and limited conclusions; hence, recommendations for future research are suggested. Knowledge of abnormalities in the sleep process has implications for understanding the pathophysiology of chronic pain conditions, which might also direct the development of novel intervention strategies. Copyright © 2015 Elsevier Ltd. All rights reserved.

Mechanistic Study of the Oxidative Coupling of Styrene with 2-Phenylpyridine Derivatives Catalyzed by Cationic Rhodium( III) via C–H Activation

Science.gov (United States)

Brasse, Mikaël; Cámpora, Juan; Ellman, Jonathan A.; Bergman, Robert G.

2013-01-01

The Rh(III) catalyzed oxidative coupling of alkenes with arenes provides a greener alternative to the classical Heck reaction for the synthesis of arene-functionalized alkenes. The present mechanistic study gives insights for the rational development of this key transformation. The catalyst resting states and the rate law of the reaction have been identified. The reaction rate is solely dependent on catalyst and alkene concentrations and the rate determining step is the migratory insertion of alkene into a Rh–C(aryl) bond. PMID:23590843

The value of mechanistic biophysical information for systems-level understanding of complex biological processes such as cytokinesis.

Science.gov (United States)

Pollard, Thomas D

2014-12-02

This review illustrates the value of quantitative information including concentrations, kinetic constants and equilibrium constants in modeling and simulating complex biological processes. Although much has been learned about some biological systems without these parameter values, they greatly strengthen mechanistic accounts of dynamical systems. The analysis of muscle contraction is a classic example of the value of combining an inventory of the molecules, atomic structures of the molecules, kinetic constants for the reactions, reconstitutions with purified proteins and theoretical modeling to account for the contraction of whole muscles. A similar strategy is now being used to understand the mechanism of cytokinesis using fission yeast as a favorable model system. Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Epithelial-mesenchymal transition transcription factors control pluripotent adult stem cell migration in vivo in planarians.

Science.gov (United States)

Abnave, Prasad; Aboukhatwa, Ellen; Kosaka, Nobuyoshi; Thompson, James; Hill, Mark A; Aboobaker, A Aziz

2017-10-01

Migration of stem cells underpins the physiology of metazoan animals. For tissues to be maintained, stem cells and their progeny must migrate and differentiate in the correct positions. This need is even more acute after tissue damage by wounding or pathogenic infection. Inappropriate migration also underpins metastasis. Despite this, few mechanistic studies address stem cell migration during repair or homeostasis in adult tissues. Here, we present a shielded X-ray irradiation assay that allows us to follow stem cell migration in planarians. We demonstrate the use of this system to study the molecular control of stem cell migration and show that snail-1 , snail-2 and zeb-1 EMT transcription factor homologs are necessary for cell migration to wound sites and for the establishment of migratory cell morphology. We also observed that stem cells undergo homeostatic migration to anterior regions that lack local stem cells, in the absence of injury, maintaining tissue homeostasis. This requires the polarity determinant notum Our work establishes planarians as a suitable model for further in-depth study of the processes controlling stem cell migration in vivo . © 2017. Published by The Company of Biologists Ltd.

Therapeutic Targeting of the IL-6 Trans-Signaling/Mechanistic Target of Rapamycin Complex 1 Axis in Pulmonary Emphysema.

Science.gov (United States)

Ruwanpura, Saleela M; McLeod, Louise; Dousha, Lovisa F; Seow, Huei J; Alhayyani, Sultan; Tate, Michelle D; Deswaerte, Virginie; Brooks, Gavin D; Bozinovski, Steven; MacDonald, Martin; Garbers, Christoph; King, Paul T; Bardin, Philip G; Vlahos, Ross; Rose-John, Stefan; Anderson, Gary P; Jenkins, Brendan J

2016-12-15

The potent immunomodulatory cytokine IL-6 is consistently up-regulated in human lungs with emphysema and in mouse emphysema models; however, the mechanisms by which IL-6 promotes emphysema remain obscure. IL-6 signals using two distinct modes: classical signaling via its membrane-bound IL-6 receptor (IL-6R), and trans-signaling via a naturally occurring soluble IL-6R. To identify whether IL-6 trans-signaling and/or classical signaling contribute to the pathogenesis of emphysema. We used the gp130 F/F genetic mouse model for spontaneous emphysema and cigarette smoke-induced emphysema models. Emphysema in mice was quantified by various methods including in vivo lung function and stereology, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to assess alveolar cell apoptosis. In mouse and human lung tissues, the expression level and location of IL-6 signaling-related genes and proteins were measured, and the levels of IL-6 and related proteins in sera from emphysematous mice and patients were also assessed. Lung tissues from patients with emphysema, and from spontaneous and cigarette smoke-induced emphysema mouse models, were characterized by excessive production of soluble IL-6R. Genetic blockade of IL-6 trans-signaling in emphysema mouse models and therapy with the IL-6 trans-signaling antagonist sgp130Fc ameliorated emphysema by suppressing augmented alveolar type II cell apoptosis. Furthermore, IL-6 trans-signaling-driven emphysematous changes in the lung correlated with mechanistic target of rapamycin complex 1 hyperactivation, and treatment of emphysema mouse models with the mechanistic target of rapamycin complex 1 inhibitor rapamycin attenuated emphysematous changes. Collectively, our data reveal that specific targeting of IL-6 trans-signaling may represent a novel treatment strategy for emphysema.

IFNγ signaling endows DCs with the capacity to control type I inflammation during parasitic infection through promoting T-bet+ regulatory T cells.

Directory of Open Access Journals (Sweden)

Hyang-Mi Lee

2015-02-01

Full Text Available IFNγ signaling drives dendritic cells (DCs to promote type I T cell (Th1 immunity. Here, we show that activation of DCs by IFNγ is equally crucial for the differentiation of a population of T-bet+ regulatory T (Treg cells specialized to inhibit Th1 immune responses. Conditional deletion of IFNγ receptor in DCs but not in Treg cells resulted in a severe defect in this specific Treg cell subset, leading to exacerbated immune pathology during parasitic infections. Mechanistically, IFNγ-unresponsive DCs failed to produce sufficient amount of IL-27, a cytokine required for optimal T-bet induction in Treg cells. Thus, IFNγ signalling endows DCs with the ability to efficiently control a specific type of T cell immunity through promoting a corresponding Treg cell population.

Recent Developments in Shape-Controlled Synthesis of Silver Nanocrystals.

Science.gov (United States)

Xia, Xiaohu; Zeng, Jie; Zhang, Qiang; Moran, Christine H; Xia, Younan

2012-01-01

This feature article introduces our recent work on understanding the roles played by citrate and poly(vinyl pyrrolidone) (PVP) as capping agents in seed-mediated syntheses of Ag nanocrystals with controlled shapes. We have demonstrated that citrate and PVP selectively bind to Ag(111) and Ag(100) surfaces, respectively, and thus favor the formation of Ag nanocrystals enclosed preferentially by {111} or {100} facets. In addition, we have quantified the coverage density of PVP adsorbed on the surface of Ag nanocubes. Based on the mechanistic understanding, a series of Ag nanocrystals with controlled shapes and sizes have been successfully synthesized by using different combinations of seeds and capping agents: single-crystal spherical/cubic seeds with citrate for cuboctahedrons and octahedrons or with PVP for cubes and bars; and plate-like seeds with citrate for enlarged thin plates or with PVP for thickened plates.

Novel strategies for control of fermentation processes

DEFF Research Database (Denmark)

Mears, Lisa

to highly optimised industrial host strains. The focus of this project is instead on en-gineering of the process. The question to be answered in this thesis is, given a highly optimised industrial host strain, how can we operate the fermentation process in order to maximise the productivity of the system...... (2012). This model describes the fungal processes operated in the fermentation pilot plant at Novozymes A/S. This model is investigated using uncertainty analysis methods in order to as-sess the applicability to control applications. A mechanistic model approach is desirable, as it is a predictive....... This provides a prediction of the future trajectory of the process, so that it is possible to guide the system to the desired target mass. The control strategy is applied on-line at 550L scale in the Novozymes A/S fermentation pilot plant, and the method is challenged with four different sets of process...

Elements in nucleotide sensing and hydrolysis of the AAA+ disaggregation machine ClpB: a structure-based mechanistic dissection of a molecular motor

Energy Technology Data Exchange (ETDEWEB)

Zeymer, Cathleen, E-mail: cathleen.zeymer@mpimf-heidelberg.mpg.de; Barends, Thomas R. M.; Werbeck, Nicolas D.; Schlichting, Ilme; Reinstein, Jochen, E-mail: cathleen.zeymer@mpimf-heidelberg.mpg.de [Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg (Germany)

2014-02-01

High-resolution crystal structures together with mutational analysis and transient kinetics experiments were utilized to understand nucleotide sensing and the regulation of the ATPase cycle in an AAA+ molecular motor. ATPases of the AAA+ superfamily are large oligomeric molecular machines that remodel their substrates by converting the energy from ATP hydrolysis into mechanical force. This study focuses on the molecular chaperone ClpB, the bacterial homologue of Hsp104, which reactivates aggregated proteins under cellular stress conditions. Based on high-resolution crystal structures in different nucleotide states, mutational analysis and nucleotide-binding kinetics experiments, the ATPase cycle of the C-terminal nucleotide-binding domain (NBD2), one of the motor subunits of this AAA+ disaggregation machine, is dissected mechanistically. The results provide insights into nucleotide sensing, explaining how the conserved sensor 2 motif contributes to the discrimination between ADP and ATP binding. Furthermore, the role of a conserved active-site arginine (Arg621), which controls binding of the essential Mg{sup 2+} ion, is described. Finally, a hypothesis is presented as to how the ATPase activity is regulated by a conformational switch that involves the essential Walker A lysine. In the proposed model, an unusual side-chain conformation of this highly conserved residue stabilizes a catalytically inactive state, thereby avoiding unnecessary ATP hydrolysis.

Elements in nucleotide sensing and hydrolysis of the AAA+ disaggregation machine ClpB: a structure-based mechanistic dissection of a molecular motor

International Nuclear Information System (INIS)

Zeymer, Cathleen; Barends, Thomas R. M.; Werbeck, Nicolas D.; Schlichting, Ilme; Reinstein, Jochen

2014-01-01

High-resolution crystal structures together with mutational analysis and transient kinetics experiments were utilized to understand nucleotide sensing and the regulation of the ATPase cycle in an AAA+ molecular motor. ATPases of the AAA+ superfamily are large oligomeric molecular machines that remodel their substrates by converting the energy from ATP hydrolysis into mechanical force. This study focuses on the molecular chaperone ClpB, the bacterial homologue of Hsp104, which reactivates aggregated proteins under cellular stress conditions. Based on high-resolution crystal structures in different nucleotide states, mutational analysis and nucleotide-binding kinetics experiments, the ATPase cycle of the C-terminal nucleotide-binding domain (NBD2), one of the motor subunits of this AAA+ disaggregation machine, is dissected mechanistically. The results provide insights into nucleotide sensing, explaining how the conserved sensor 2 motif contributes to the discrimination between ADP and ATP binding. Furthermore, the role of a conserved active-site arginine (Arg621), which controls binding of the essential Mg 2+ ion, is described. Finally, a hypothesis is presented as to how the ATPase activity is regulated by a conformational switch that involves the essential Walker A lysine. In the proposed model, an unusual side-chain conformation of this highly conserved residue stabilizes a catalytically inactive state, thereby avoiding unnecessary ATP hydrolysis

Structural, mechanistic and functional insight into gliotoxin bis-thiomethylation in Aspergillus fumigatus.

Science.gov (United States)

Dolan, Stephen K; Bock, Tobias; Hering, Vanessa; Owens, Rebecca A; Jones, Gary W; Blankenfeldt, Wulf; Doyle, Sean

2017-02-01

Gliotoxin is an epipolythiodioxopiperazine (ETP) class toxin, contains a disulfide bridge that mediates its toxic effects via redox cycling and is produced by the opportunistic fungal pathogen Aspergillus fumigatus Self-resistance against gliotoxin is effected by the gliotoxin oxidase GliT, and attenuation of gliotoxin biosynthesis is catalysed by gliotoxin S -methyltransferase GtmA. Here we describe the X-ray crystal structures of GtmA-apo (1.66 Å), GtmA complexed to S -adenosylhomocysteine (1.33 Å) and GtmA complexed to S -adenosylmethionine (2.28 Å), providing mechanistic insights into this important biotransformation. We further reveal that simultaneous elimination of the ability of A. fumigatus to dissipate highly reactive dithiol gliotoxin, via deletion of GliT and GtmA, results in the most significant hypersensitivity to exogenous gliotoxin observed to date. Indeed, quantitative proteomic analysis of Δ gliT ::Δ gtmA reveals an uncontrolled over-activation of the gli -cluster upon gliotoxin exposure. The data presented herein reveal, for the first time, the extreme risk associated with intracellular dithiol gliotoxin biosynthesis-in the absence of an efficient dismutation capacity. Significantly, a previously concealed protective role for GtmA and functionality of ETP bis -thiomethylation as an ancestral protection strategy against dithiol compounds is now evident. © 2017 The Authors.

Disruption of steroidogenesis: Cell models for mechanistic investigations and as screening tools.

Science.gov (United States)

Odermatt, Alex; Strajhar, Petra; Engeli, Roger T

2016-04-01

In the modern world, humans are exposed during their whole life to a large number of synthetic chemicals. Some of these chemicals have the potential to disrupt endocrine functions and contribute to the development and/or progression of major diseases. Every year approximately 1000 novel chemicals, used in industrial production, agriculture, consumer products or as pharmaceuticals, are reaching the market, often with limited safety assessment regarding potential endocrine activities. Steroids are essential endocrine hormones, and the importance of the steroidogenesis pathway as a target for endocrine disrupting chemicals (EDCs) has been recognized by leading scientists and authorities. Cell lines have a prominent role in the initial stages of toxicity assessment, i.e. for mechanistic investigations and for the medium to high throughput analysis of chemicals for potential steroidogenesis disrupting activities. Nevertheless, the users have to be aware of the limitations of the existing cell models in order to apply them properly, and there is a great demand for improved cell-based testing systems and protocols. This review intends to provide an overview of the available cell lines for studying effects of chemicals on gonadal and adrenal steroidogenesis, their use and limitations, as well as the need for future improvements of cell-based testing systems and protocols. Copyright © 2016 Elsevier Ltd. All rights reserved.

Rotary ultrasonic machining of CFRP: a mechanistic predictive model for cutting force.

Science.gov (United States)

Cong, W L; Pei, Z J; Sun, X; Zhang, C L

2014-02-01

Cutting force is one of the most important output variables in rotary ultrasonic machining (RUM) of carbon fiber reinforced plastic (CFRP) composites. Many experimental investigations on cutting force in RUM of CFRP have been reported. However, in the literature, there are no cutting force models for RUM of CFRP. This paper develops a mechanistic predictive model for cutting force in RUM of CFRP. The material removal mechanism of CFRP in RUM has been analyzed first. The model is based on the assumption that brittle fracture is the dominant mode of material removal. CFRP micromechanical analysis has been conducted to represent CFRP as an equivalent homogeneous material to obtain the mechanical properties of CFRP from its components. Based on this model, relationships between input variables (including ultrasonic vibration amplitude, tool rotation speed, feedrate, abrasive size, and abrasive concentration) and cutting force can be predicted. The relationships between input variables and important intermediate variables (indentation depth, effective contact time, and maximum impact force of single abrasive grain) have been investigated to explain predicted trends of cutting force. Experiments are conducted to verify the model, and experimental results agree well with predicted trends from this model. Copyright © 2013 Elsevier B.V. All rights reserved.

The gustin (CA6) gene polymorphism, rs2274333 (A/G), as a mechanistic link between PROP tasting and fungiform taste papilla density and maintenance.

Science.gov (United States)

Melis, Melania; Atzori, Elena; Cabras, Stefano; Zonza, Andrea; Calò, Carla; Muroni, Patrizia; Nieddu, Mariella; Padiglia, Alessandra; Sogos, Valeria; Tepper, Beverly J; Tomassini Barbarossa, Iole

2013-01-01

Taste sensitivity to PROP varies greatly among individuals and is associated with polymorphisms in the bitter receptor gene TAS2R38, and with differences in fungiform papilla density on the anterior tongue surface. Recently we showed that the PROP non-taster phenotype is strongly associated with the G variant of polymorphism rs2274333 (A/G) of the gene that controls the salivary trophic factor, gustin. The aims of this study were 1) to investigate the role of gustin gene polymorphism rs2274333 (A/G), in PROP sensitivity and fungiform papilla density and morphology, and 2) to investigate the effect of this gustin gene polymorphism on cell proliferation and metabolic activity. Sixty-four subjects were genotyped for both genes by PCR techniques, their PROP sensitivity was assessed by scaling and threshold methods, and their fungiform papilla density, diameter and morphology were determined. In vitro experiments examined cell proliferation and metabolic activity, following treatment with saliva of individuals with and without the gustin gene mutation, and with isolated protein, in the two iso-forms. Gustin and TAS2R38 genotypes were associated with PROP threshold (p=0.0001 and p=0.0042), but bitterness intensity was mostly determined by TAS2R38 genotypes (pTreatment of isolated cells with saliva from individuals with the AA form of gustin or direct application of the active iso-form of gustin protein increased cell proliferation and metabolic activity (p<0.0135). These novel findings suggest that the rs2274333 polymorphism of the gustin gene affects PROP sensitivity by acting on fungiform papilla development and maintenance, and could provide the first mechanistic explanation for why PROP super-tasters are more responsive to a broad range of oral stimuli.

Show-Bix &

DEFF Research Database (Denmark)

2014-01-01

The anti-reenactment 'Show-Bix &' consists of 5 dias projectors, a dial phone, quintophonic sound, and interactive elements. A responsive interface will enable the Dias projectors to show copies of original dias slides from the Show-Bix piece ”March på Stedet”, 265 images in total. The copies are...

'You don't show everyone your weakness': Older adults' views on using Family Group Conferencing to regain control and autonomy.

Science.gov (United States)

Metze, Rosalie N; Kwekkeboom, Rick H; Abma, Tineke A

2015-08-01

Family Group Conferencing (FGC), a model in which a person and his or her social network make their own 'care' plan, is used in youth care and might also be useful in elderly care to support older persons living at home. In Amsterdam, the Netherlands, FGC was implemented for older adults but they showed resistance. Reasons for this resistance have been researched and are described in this article. We examine existing views and attitudes of older adults concerning the use of FGC, and report on how older adults see the possibility to regain control over their lives using FGC. To do this, focus group sessions, duo interviews and individual interviews were held with older adults with varying characteristics: living at home, in sheltered housing, or in a home for the elderly; and living in urban, suburban or rural areas. Themes were: views on and contentment with the control and autonomy that they experience in their lives, and the willingness to use FGC to improve this. The main reasons for our respondents to resist FGC were: expecting people to be there for them without a FGC, not feeling ready yet for a FGC, feeling embarrassed when asking for help, being reluctant to open up about their problems, and having the fear of losing control when organizing a FGC. We conclude that, for this generation of older adults, FGC means losing control and autonomy rather than gaining it. To be appealing to older adults, a relational empowerment strengthening model should most likely be focused on reciprocity, peer-to-peer support, and solutions instead of problems. Copyright © 2015 Elsevier Inc. All rights reserved.

Understanding the influence of biofilm accumulation on the hydraulic properties of soils: a mechanistic approach based on experimental data

Science.gov (United States)

Carles Brangarí, Albert; Sanchez-Vila, Xavier; Freixa, Anna; Romaní, Anna M.; Fernàndez-Garcia, Daniel

2017-04-01

The distribution, amount, and characteristics of biofilms and its components govern the capacity of soils to let water through, to transport solutes, and the reactions occurring. Therefore, unraveling the relationship between microbial dynamics and the hydraulic properties of soils is of concern for the management of natural systems and many technological applications. However, the increased complexity of both the microbial communities and the geochemical processes entailed by them causes that the phenomenon of bioclogging remains poorly understood. This highlights the need for a better understanding of the microbial components such as live and dead bacteria and extracellular polymeric substances (EPS), as well as of their spatial distribution. This work tries to shed some light on these issues, providing experimental data and a new mechanistic model that predicts the variably saturated hydraulic properties of bio-amended soils based on these data. We first present a long-term laboratory infiltration experiment that aims at studying the temporal variation of selected biogeochemical parameters along the infiltration path. The setup consists of a 120-cm-high soil tank instrumented with an array of sensors plus soil and liquid samplers. Sensors measured a wide range of parameters in continuous, such as volumetric water content, electrical conductivity, temperature, water pressure, soil suction, dissolved oxygen, and pH. Samples were kept for chemical and biological analyses. Results indicate that: i) biofilm is present at all depths, denoting the potential for deep bioclogging, ii) the redox conditions profile shows different stages, indicating that the community was adapted to changing redox conditions, iii) bacterial activity, richness and diversity also exhibit zonation with depth, and iv) the hydraulic properties of the soil experienced significant changes as biofilm proliferated. Based on experimental evidences, we propose a tool to predict changes in the

Messenger RNA Interferase RelE Controls relBE Transcription by Conditional Cooperativity

DEFF Research Database (Denmark)

Overgaard, Martin; Borch, Jonas; Jørgensen, Mikkel G

2008-01-01

Prokaryotic toxin-antitoxin (TA) loci consist of two genes in an operon that encodes a metabolically stable toxin and an unstable antitoxin. The antitoxin neutralises its cognate toxin by forming a tight complex with it. In all cases known, the antitoxin autoregulates TA operon transcription by b...... operator DNA. A mutational analysis of the operator-sites showed that RelE in excess counteracted cooperative binding of the RelB(2)*RelE complexes to the operator-sites. Thus, RelE controls relBE transcription by conditional cooperativity.......Prokaryotic toxin-antitoxin (TA) loci consist of two genes in an operon that encodes a metabolically stable toxin and an unstable antitoxin. The antitoxin neutralises its cognate toxin by forming a tight complex with it. In all cases known, the antitoxin autoregulates TA operon transcription...... by binding to one or more operators in the promoter region while the toxin functions as a co-repressor of transcription. Interestingly, the toxin can also stimulate TA operon transcription. Here we analyse mechanistic aspects of how RelE of Escherichia coli can function both as a co-repressor and derepressor...

Mechanisms Controlling Species Responses to Climate Change: Thermal Tolerances and Shifting Range Limits. (Invited)

Science.gov (United States)

Sage, R. F.; Bykova, O.; Coiner, H.

2010-12-01

One of the main effects of anthropogenic climate change will be widespread shifts in species distribution, with the common assumption that they will migrate to higher elevation and latitude. While this assumption is supported by migration patterns following climate warming in the past 20,000 years, it has not been rigorously evaluated in terms of physiological mechanism, despite the implication that migration in response to climate warming is controlled by some form of thermal adaptation. We have been evaluating the degree to which species range limits are controlled by physiological patterns of thermal tolerance in bioinvaders of North America. Bioinvaders presumably have few biotic controls over their distribution and thus are more likely to fully exploit their thermal niche. In cheatgrass (Bromus tectorum), the minimum lethal temperature in winter is -32C, which corresponds to the mean winter minimum temperature at its northern range limit. In red brome (Bromus rubens), the minimum lethal temperature is also near -32C, which is well below the minimum winter temperature near -20C that corresponds to its northern distribution limit. In kudzu (Pueraria lobata), the minimum lethal temperature is near -20C, which corresponds to the midwinter minimum at its northern distribution limit; however, overwintering kudzu tissues are insulated by soil and snow cover, and thus do not experience lethal temperatures at kudzu's northern range limit. These results demonstrate that some invasive species can exploit the potential range defined by their low temperature tolerance and thus can be predicted by mechanistic models to migrate to higher latitudes with moderation of winter cold. The distribution of other invaders such as kudzu and red brome are not controlled by tolerance of midwinter cold. Developing mechanistic models of their distributions, and how these might change with climate warming, will require extensive physiological study.

Liquid State Thermochemical Decomposition of Neat 1,3,5,5-Tetranitrohexahydropyrimidine (DNNC) and its DNNC-d2, DNNC-d4, DNNC-d6 Structural Isotopomers: Mechanistic Entrance into the DNNC Molecule

National Research Council Canada - National Science Library

Shackelford, S. A; Menapace, J. A; Goldman, J. F

2007-01-01

... thermochemical decomposition process. Using IDSC-based KDIE comparisons with the DNNC-d2, DNNC-d4, and DNNC-d6 isotopomers, a more detailed chemical structure/mechanistic relationship emerged by entering the interior of the DNNC molecule...

Design control for clinical translation of 3D printed modular scaffolds.

Science.gov (United States)

Hollister, Scott J; Flanagan, Colleen L; Zopf, David A; Morrison, Robert J; Nasser, Hassan; Patel, Janki J; Ebramzadeh, Edward; Sangiorgio, Sophia N; Wheeler, Matthew B; Green, Glenn E

2015-03-01

The primary thrust of tissue engineering is the clinical translation of scaffolds and/or biologics to reconstruct tissue defects. Despite this thrust, clinical translation of tissue engineering therapies from academic research has been minimal in the 27 year history of tissue engineering. Academic research by its nature focuses on, and rewards, initial discovery of new phenomena and technologies in the basic research model, with a view towards generality. Translation, however, by its nature must be directed at specific clinical targets, also denoted as indications, with associated regulatory requirements. These regulatory requirements, especially design control, require that the clinical indication be precisely defined a priori, unlike most academic basic tissue engineering research where the research target is typically open-ended, and furthermore requires that the tissue engineering therapy be constructed according to design inputs that ensure it treats or mitigates the clinical indication. Finally, regulatory approval dictates that the constructed system be verified, i.e., proven that it meets the design inputs, and validated, i.e., that by meeting the design inputs the therapy will address the clinical indication. Satisfying design control requires (1) a system of integrated technologies (scaffolds, materials, biologics), ideally based on a fundamental platform, as compared to focus on a single technology, (2) testing of design hypotheses to validate system performance as opposed to mechanistic hypotheses of natural phenomena, and (3) sequential testing using in vitro, in vivo, large preclinical and eventually clinical tests against competing therapies, as compared to single experiments to test new technologies or test mechanistic hypotheses. Our goal in this paper is to illustrate how design control may be implemented in academic translation of scaffold based tissue engineering therapies. Specifically, we propose to (1) demonstrate a modular platform approach

Oxide-ion and proton conducting electrolyte materials for clean energy applications: structural and mechanistic features.

Science.gov (United States)

Malavasi, Lorenzo; Fisher, Craig A J; Islam, M Saiful

2010-11-01

This critical review presents an overview of the various classes of oxide materials exhibiting fast oxide-ion or proton conductivity for use as solid electrolytes in clean energy applications such as solid oxide fuel cells. Emphasis is placed on the relationship between structural and mechanistic features of the crystalline materials and their ion conduction properties. After describing well-established classes such as fluorite- and perovskite-based oxides, new materials and structure-types are presented. These include a variety of molybdate, gallate, apatite silicate/germanate and niobate systems, many of which contain flexible structural networks, and exhibit different defect properties and transport mechanisms to the conventional materials. It is concluded that the rich chemistry of these important systems provides diverse possibilities for developing superior ionic conductors for use as solid electrolytes in fuel cells and related applications. In most cases, a greater atomic-level understanding of the structures, defects and conduction mechanisms is achieved through a combination of experimental and computational techniques (217 references).

Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase

Science.gov (United States)

Hutchinson, Jonathan P.; Rowland, Paul; Taylor, Mark R. D.; Christodoulou, Erica M.; Haslam, Carl; Hobbs, Clare I.; Holmes, Duncan S.; Homes, Paul; Liddle, John; Mole, Damian J.; Uings, Iain; Walker, Ann L.; Webster, Scott P.; Mowat, Christopher G.; Chung, Chun-Wa

2017-06-01

Kynurenine-3-monooxygenase (KMO) is a key FAD-dependent enzyme of tryptophan metabolism. In animal models, KMO inhibition has shown benefit in neurodegenerative diseases such as Huntington's and Alzheimer's. Most recently it has been identified as a target for acute pancreatitis multiple organ dysfunction syndrome (AP-MODS); a devastating inflammatory condition with a mortality rate in excess of 20%. Here we report and dissect the molecular mechanism of action of three classes of KMO inhibitors with differentiated binding modes and kinetics. Two novel inhibitor classes trap the catalytic flavin in a previously unobserved tilting conformation. This correlates with picomolar affinities, increased residence times and an absence of the peroxide production seen with previous substrate site inhibitors. These structural and mechanistic insights culminated in GSK065(C1) and GSK366(C2), molecules suitable for preclinical evaluation. Moreover, revising the repertoire of flavin dynamics in this enzyme class offers exciting new opportunities for inhibitor design.