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Sample records for biologically plausible mechanistic

  1. Towards Biologically Plausible Deep Learning

    OpenAIRE

    Bengio, Yoshua; Lee, Dong-Hyun; Bornschein, Jorg; Lin, Zhouhan

    2015-01-01

    Neuroscientists have long criticised deep learning algorithms as incompatible with current knowledge of neurobiology. We explore more biologically plausible versions of deep representation learning, focusing here mostly on unsupervised learning but developing a learning mechanism that could account for supervised, unsupervised and reinforcement learning. The starting point is that the basic learning rule believed to govern synaptic weight updates (Spike-Timing-Dependent Plasticity) can be int...

  2. Associative memories: randomness, continuity and biological plausibility

    OpenAIRE

    Segura Meccia, Enrique Carlos

    2001-01-01

    A new, biologically plausible model of associative memory is presented. First, a historical perspective of the more relevant improvements to the basic Little-Hopfield model is given. Then, we introduce a stochastic system with graded response neurons and a network consisting of a non countable number of neurons organized in a continuous metric space. We do this by casting the retrieval process of an analog Hopfield model [7] into the framework of a diffusive process governed by the Fokker-Pla...

  3. Biologically plausible multi-dimensional reinforcement learning in neural networks

    NARCIS (Netherlands)

    Rombouts, J.O.; Ooyen, A. van; Roelfsema, P.R.; Bohte, S.M.

    2012-01-01

    How does the brain learn to map multi-dimensional sensory inputs to multi-dimensional motor outputs when it can only observe single rewards for the coordinated outputs of the whole network of neurons that make up the brain? We introduce Multi-AGREL, a novel, biologically plausible multi-layer neural

  4. Pulmonary phthalate exposure and asthma - is PPAR a plausible mechanistic link?

    OpenAIRE

    Bølling, Anette Kocbach; Holme, Jørn A; Bornehag, Carl Gustaf; Nygaard, Unni C.; Bertelsen, Randi J.; Nånberg, Eewa; Bodin, Johanna; Sakhi, Amrit Kaur; Thomsen, Cathrine; Becher, Rune

    2013-01-01

    Due to their extensive use as plasticisers in numerous consumer products, phthalates have become ubiquitous environmental contaminants. An increasing number of epidemiological studies suggest that exposure to phthalates may be associated with worsening or development of airway diseases. Peroxisome Proliferation Activated Receptors (PPAR)s, identified as important targets for phthalates in early studies in rodent liver, have been suggested as a possible mechanistic link. In this review we disc...

  5. Biological Sequence Mining Using Plausible Neural Network and its Application to Exon/intron Boundaries Prediction

    OpenAIRE

    Li, Kuochen; Chang, Dar-jen; Rouchka, Eric; Chen, Yuan Yan

    2007-01-01

    Biological sequence usually contains yet to find knowledge, and mining biological sequences usually involves a huge dataset and long computation time. Common tasks for biological sequence mining are pattern discovery, classification and clustering. The newly developed model, Plausible Neural Network (PNN), provides an intuitive and unified architecture for such a large dataset analysis. This paper introduces the basic concepts of the PNN, and explains how it is applied to biological sequence ...

  6. Can a biologically-plausible hierarchy effectively replace face detection, alignment, and recognition pipelines?

    OpenAIRE

    Liao, Qianli; Leibo, Joel Z.; Mroueh, Youssef; Poggio, Tomaso

    2013-01-01

    The standard approach to unconstrained face recognition in natural photographs is via a detection, alignment, recognition pipeline. While that approach has achieved impressive results, there are several reasons to be dissatisfied with it, among them is its lack of biological plausibility. A recent theory of invariant recognition by feedforward hierarchical networks, like HMAX, other convolutional networks, or possibly the ventral stream, implies an alternative approach to unconstrained face r...

  7. A swarm intelligence framework for reconstructing gene networks: searching for biologically plausible architectures.

    Science.gov (United States)

    Kentzoglanakis, Kyriakos; Poole, Matthew

    2012-01-01

    In this paper, we investigate the problem of reverse engineering the topology of gene regulatory networks from temporal gene expression data. We adopt a computational intelligence approach comprising swarm intelligence techniques, namely particle swarm optimization (PSO) and ant colony optimization (ACO). In addition, the recurrent neural network (RNN) formalism is employed for modeling the dynamical behavior of gene regulatory systems. More specifically, ACO is used for searching the discrete space of network architectures and PSO for searching the corresponding continuous space of RNN model parameters. We propose a novel solution construction process in the context of ACO for generating biologically plausible candidate architectures. The objective is to concentrate the search effort into areas of the structure space that contain architectures which are feasible in terms of their topological resemblance to real-world networks. The proposed framework is initially applied to the reconstruction of a small artificial network that has previously been studied in the context of gene network reverse engineering. Subsequently, we consider an artificial data set with added noise for reconstructing a subnetwork of the genetic interaction network of S. cerevisiae (yeast). Finally, the framework is applied to a real-world data set for reverse engineering the SOS response system of the bacterium Escherichia coli. Results demonstrate the relative advantage of utilizing problem-specific knowledge regarding biologically plausible structural properties of gene networks over conducting a problem-agnostic search in the vast space of network architectures. PMID:21576756

  8. Particulate air pollution and increased mortality: Biological plausibility for causal relationship

    International Nuclear Information System (INIS)

    Recently, a number of epidemiological studies have concluded that ambient particulate exposure is associated with increased mortality and morbidity at PM concentrations well below those previously thought to affect human health. These studies have been conducted in several different geographical locations and have involved a range of populations. While the consistency of the findings and the presence of an apparent concentration response relationship provide a strong argument for causality, epidemiological studies can only conclude this based upon inference from statistical associations. The biological plausibility of a causal relationship between low concentrations of PM and daily mortality and morbidity rates is neither intuitively obvious nor expected based on past experimental studies on the toxicity of inhaled particles. Chronic toxicity from inhaled, poorly soluble particles has been observed based on the slow accumulation of large lung burdens of particles, not on small daily fluctuations in PM levels. Acute toxicity from inhaled particles is associated mainly with acidic particles and is observed at much higher concentrations than those observed in the epidemiology studies reporting an association between PM concentrations and morbidity/mortality. To approach the difficult problem of determining if the association between PM concentrations and daily morbidity and mortality is biologically plausible and causal, one must consider (1) the chemical and physical characteristics of the particles in the inhaled atmospheres, (2) the characteristics of the morbidity/mortality observed and the people who are affected, and (3) potential mechanisms that might link the two

  9. Mechanistic Effects of Calcitriol in Cancer Biology

    Directory of Open Access Journals (Sweden)

    Lorenza Díaz

    2015-06-01

    Full Text Available Besides its classical biological effects on calcium and phosphorus homeostasis, calcitriol, the active vitamin D metabolite, has a broad variety of actions including anticancer effects that are mediated either transcriptionally and/or via non-genomic pathways. In the context of cancer, calcitriol regulates the cell cycle, induces apoptosis, promotes cell differentiation and acts as anti-inflammatory factor within the tumor microenvironment. In this review, we address the different mechanisms of action involved in the antineoplastic effects of calcitriol.

  10. Mechanistic modeling confronts the complexity of molecular cell biology

    OpenAIRE

    Phair, Robert D.

    2014-01-01

    Mechanistic modeling has the potential to transform how cell biologists contend with the inescapable complexity of modern biology. I am a physiologist–electrical engineer–systems biologist who has been working at the level of cell biology for the past 24 years. This perspective aims 1) to convey why we build models, 2) to enumerate the major approaches to modeling and their philosophical differences, 3) to address some recurrent concerns raised by experimentalists, and then 4) to imagine a fu...

  11. On the biological plausibility of grandmother cells: implications for neural network theories in psychology and neuroscience.

    Science.gov (United States)

    Bowers, Jeffrey S

    2009-01-01

    A fundamental claim associated with parallel distributed processing (PDP) theories of cognition is that knowledge is coded in a distributed manner in mind and brain. This approach rejects the claim that knowledge is coded in a localist fashion, with words, objects, and simple concepts (e.g. "dog"), that is, coded with their own dedicated representations. One of the putative advantages of this approach is that the theories are biologically plausible. Indeed, advocates of the PDP approach often highlight the close parallels between distributed representations learned in connectionist models and neural coding in brain and often dismiss localist (grandmother cell) theories as biologically implausible. The author reviews a range a data that strongly challenge this claim and shows that localist models provide a better account of single-cell recording studies. The author also contrast local and alternative distributed coding schemes (sparse and coarse coding) and argues that common rejection of grandmother cell theories in neuroscience is due to a misunderstanding about how localist models behave. The author concludes that the localist representations embedded in theories of perception and cognition are consistent with neuroscience; biology only calls into question the distributed representations often learned in PDP models. PMID:19159155

  12. Photoinduced catalytic synthesis of biologically important metabolites from formaldehyde and ammonia under plausible "prebiotic" conditions

    Science.gov (United States)

    Delidovich, I. V.; Taran, O. P.; Simonov, A. N.; Matvienko, L. G.; Parmon, V. N.

    2011-08-01

    The article analyzes new and previously reported data on several catalytic and photochemical processes yielding biologically important molecules. UV-irradiation of formaldehyde aqueous solution yields acetaldehyde, glyoxal, glycolaldehyde and glyceraldehyde, which can serve as precursors of more complex biochemically relevant compounds. Photolysis of aqueous solution of acetaldehyde and ammonium nitrate results in formation of alanine and pyruvic acid. Dehydration of glyceraldehyde catalyzed by zeolite HZSM-5-17 yields pyruvaldehyde. Monosaccharides are formed in the course of the phosphate-catalyzed aldol condensation reactions of glycolaldehyde, glyceraldehyde and formaldehyde. The possibility of the direct synthesis of tetroses, keto- and aldo-pentoses from pure formaldehyde due to the combination of the photochemical production of glycolahyde and phosphate-catalyzed carbohydrate chain growth is demonstrated. Erythrulose and 3-pentulose are the main products of such combined synthesis with selectivity up to 10%. Biologically relevant aldotetroses, aldo- and ketopentoses are more resistant to the photochemical destruction owing to the stabilization in hemiacetal cyclic forms. They are formed as products of isomerization of erythrulose and 3-pentulose. The conjugation of the concerned reactions results in a plausible route to the formation of sugars, amino and organic acids from formaldehyde and ammonia under presumed 'prebiotic' conditions.

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

    Directory of Open Access Journals (Sweden)

    Mark K Transtrum

    2016-05-01

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

  14. Bridging Mechanistic and Phenomenological Models of Complex Biological Systems

    Science.gov (United States)

    Transtrum, Mark K.; Qiu, Peng

    2016-01-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

  16. Gene-ontology enrichment analysis in two independent family-based samples highlights biologically plausible processes for autism spectrum disorders.

    LENUS (Irish Health Repository)

    Anney, Richard J L

    2012-02-01

    Recent genome-wide association studies (GWAS) have implicated a range of genes from discrete biological pathways in the aetiology of autism. However, despite the strong influence of genetic factors, association studies have yet to identify statistically robust, replicated major effect genes or SNPs. We apply the principle of the SNP ratio test methodology described by O\\'Dushlaine et al to over 2100 families from the Autism Genome Project (AGP). Using a two-stage design we examine association enrichment in 5955 unique gene-ontology classifications across four groupings based on two phenotypic and two ancestral classifications. Based on estimates from simulation we identify excess of association enrichment across all analyses. We observe enrichment in association for sets of genes involved in diverse biological processes, including pyruvate metabolism, transcription factor activation, cell-signalling and cell-cycle regulation. Both genes and processes that show enrichment have previously been examined in autistic disorders and offer biologically plausibility to these findings.

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

    International Nuclear Information System (INIS)

    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

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

    Energy Technology Data Exchange (ETDEWEB)

    Thomson, Ty M. [Selventa, One Alewife Center, Cambridge, MA 02140 (United States); Sewer, Alain, E-mail: Alain.Sewer@pmi.com [Philip Morris International R and D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel (Switzerland); Martin, Florian; Belcastro, Vincenzo [Philip Morris International R and D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel (Switzerland); Frushour, Brian P. [Selventa, One Alewife Center, Cambridge, MA 02140 (United States); Gebel, Stephan [Philip Morris International R and D, Philip Morris Research Laboratories GmbH, Edmund-Rumpler-Strasse 5, 51149 Koeln (Germany); Park, Jennifer [Selventa, One Alewife Center, Cambridge, MA 02140 (United States); Schlage, Walter K. [Philip Morris International R and D, Philip Morris Research Laboratories GmbH, Edmund-Rumpler-Strasse 5, 51149 Koeln (Germany); Talikka, Marja [Philip Morris International R and D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel (Switzerland); Vasilyev, Dmitry M.; Westra, Jurjen W. [Selventa, One Alewife Center, Cambridge, MA 02140 (United States); Hoeng, Julia; Peitsch, Manuel C. [Philip Morris International R and D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel (Switzerland)

    2013-11-01

    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

  19. Plausibility of the implausible: is it possible that ultra-high dilutions ‘without biological activity’ cause adverse effects?

    Directory of Open Access Journals (Sweden)

    Marcus Zulian Teixeira

    2013-06-01

    .7% of cases the potencies were described as below of the 12ª Centesimal, the point beyond which the likelihood of a single molecule being present in the remedy approaches zero”, the authors claim that “in the majority of cases, the possible mechanism of action involved allergic reactions or ingestion of toxic substances”. With this approach, the authors seek to dismiss the biological effects of ultra-high dilutions, because if they cause AEs would be confirming the plausibility of its possible therapeutic effects. However, toxicological tests are required to affirm that AEs are a consequence of toxic (allergic effects of the substances or of ‘imponderable’ effects of ultra-high dilutions. In view of the recent report cited in the review [12] in which a complex homeopathic medicine indicated for treating infant colic (Gali-col Baby, GCB caused apparent life-threatening events (ALTEs were described by the National Institutes of Health consensus group in 1986 as “an episode that is frightening to the observer and that is characterized by some combination of apnea (central or occasionally obstructive, color change (usually cyanotic or pallid but occasionally erythematous or plethoric, a marked change in muscle tone (usually marked limpness, choking or gagging” [13] in consequence of the ‘toxicity of active ingredients’ (Citrullus colocynthis, Matricaria chamomilla, Bryonia alba, Nux vomica, Veratrum album, Magnesia phosphorica and Cuprum metallicum at potencies between 4C and 5C, Oberbaum et al. [14] performed a toxicological study of these components showing that “doses ingested in the GCB series were 10-13 orders of magnitude smaller than those reported to cause toxic reactions in humans” and that “there was poor correlation between symptoms with GCB and toxic profiles of the components”. As alternative explanation, they suggest that “four components (Veratrum album, Cuprum metallicum, Bryonia alba and Matricaria chamomilla have an

  20. 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.

  1. Arsenic, mode of action at biologically plausible low doses: What are the implications for low dose cancer risk?

    International Nuclear Information System (INIS)

    Arsenic is an established human carcinogen. However, there has been much controversy about the shape of the arsenic response curve, particularly at low doses. This controversy has been exacerbated by the fact that the mechanism(s) of arsenic carcinogenesis are still unclear and because there are few satisfactory animal models for arsenic-induced carcinogenesis. Recent epidemiological studies have shown that the relative risk for cancer among populations exposed to ≤60 ppb As in their drinking water is often lower than the risk for the unexposed control population. We have found that treatment of human keratinocyte and fibroblast cells with 0.1 to 1 μM arsenite (AsIII) also produces a low dose protective effect against oxidative stress and DNA damage. This response includes increased transcription, protein levels and enzyme activity of several base excision repair genes, including DNA polymerase β and DNA ligase I. At higher concentrations (> 10 μM), As induces down-regulation of DNA repair, oxidative DNA damage and apoptosis. This low dose adaptive (protective) response by a toxic agent is known as hormesis and is characteristic of many agents that induce oxidative stress. A mechanistic model for arsenic carcinogenesis based on these data would predict that the low dose risk for carcinogenesis should be sub-linear. The threshold dose where toxicity outweighs protection is hard to predict based on in vitro dose response data, but might be estimated if one could determine the form (metabolite) and concentration of arsenic responsible for changes in gene regulation in the target tissues

  2. Nicotine dose-concentration relationship and pregnancy outcomes in rat: Biologic plausibility and implications for future research

    International Nuclear Information System (INIS)

    Cigarette smoke (CS) exposure during pregnancy can lead to profound adverse effects on fetal development. Although CS contains several thousand chemicals, nicotine has been widely used as its surrogate as well as in its own right as a neuroteratogen. The justification for the route and dose of nicotine administration is largely based on inferential data suggesting that nicotine 6 mg/kg/day infused continuously via osmotic mini pumps (OMP) would mimic maternal CS exposure. We provide evidence that 6 mg/kg/day nicotine dose as commonly administered to pregnant rats leads to plasma nicotine concentrations that are 3-10-fold higher than those observed in moderate to heavy smokers and pregnant mothers, respectively. Furthermore, the cumulative daily nicotine dose exceeds by several hundred fold the amount consumed by human heavy smokers. Our study does not support the widely accepted notion that regardless of the nicotine dose, a linear nicotine dose-concentration relationship exists in a steady-state OMP model. We also show that total nicotine clearance increases with advancing pregnancy but no significant change is observed between the 2nd and 3rd trimester. Furthermore, nicotine infusion even at this extremely high dose has little effect on a number of maternal and fetal biologic variables and pregnancy outcome suggesting that CS constituents other than nicotine mediate the fetal growth restriction in infants born to smoking mothers. Our current study has major implications for translational research in developmental toxicology and pharmacotherapy using nicotine replacement treatment as an aid to cessation of cigarette smoking in pregnant mothers

  3. 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

    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...... routes from primary (cell aggregates) and secondary producers (faecal pellets, carcasses, and active vertical transport). Carbon export production (PE) and ecosystems eXposure Factors (XF), which represents a nitrogen-to-oxygen 'conversion' potential, were estimated at a spatial resolution of 66 large...

  4. Chemical kinetic mechanistic models to investigate cancer biology and impact cancer medicine

    Science.gov (United States)

    Stites, Edward C.

    2013-04-01

    Traditional experimental biology has provided a mechanistic understanding of cancer in which the malignancy develops through the acquisition of mutations that disrupt cellular processes. Several drugs developed to target such mutations have now demonstrated clinical value. These advances are unequivocal testaments to the value of traditional cellular and molecular biology. However, several features of cancer may limit the pace of progress that can be made with established experimental approaches alone. The mutated genes (and resultant mutant proteins) function within large biochemical networks. Biochemical networks typically have a large number of component molecules and are characterized by a large number of quantitative properties. Responses to a stimulus or perturbation are typically nonlinear and can display qualitative changes that depend upon the specific values of variable system properties. Features such as these can complicate the interpretation of experimental data and the formulation of logical hypotheses that drive further research. Mathematical models based upon the molecular reactions that define these networks combined with computational studies have the potential to deal with these obstacles and to enable currently available information to be more completely utilized. Many of the pressing problems in cancer biology and cancer medicine may benefit from a mathematical treatment. As work in this area advances, one can envision a future where such models may meaningfully contribute to the clinical management of cancer patients.

  5. Looking for plausibility

    CERN Document Server

    Abdullah, Wan Ahmad Tajuddin Wan

    2010-01-01

    In the interpretation of experimental data, one is actually looking for plausible explanations. We look for a measure of plausibility, with which we can compare different possible explanations, and which can be combined when there are different sets of data. This is contrasted to the conventional measure for probabilities as well as to the proposed measure of possibilities. We define what characteristics this measure of plausibility should have. In getting to the conception of this measure, we explore the relation of plausibility to abductive reasoning, and to Bayesian probabilities. We also compare with the Dempster-Schaefer theory of evidence, which also has its own definition for plausibility. Abduction can be associated with biconditionality in inference rules, and this provides a platform to relate to the Collins-Michalski theory of plausibility. Finally, using a formalism for wiring logic onto Hopfield neural networks, we ask if this is relevant in obtaining this measure.

  6. NifH: Structural and Mechanistic Similarities with Proteins Involved in Diverse Biological Processes

    Directory of Open Access Journals (Sweden)

    Surobhi Lahiri

    2008-01-01

    Full Text Available The NifH protein is a subunit of the nitrogenase enzyme that catalyzes the reduction of atmospheric nitrogen to ammonia. This protein contains highly conserved regions including the nucleotide binding sites, metal center ligands and the Switch I and Switch II domains. A number of proteins have structural and mechanistic similarities as well as evolutionary relationships with the NifH protein, notable among them being: light independent protochlorophyllide (Pchlide reductase (ChlL/FrxC or bChL, arsenite pump ATPase (ArsA, 2-hydroxyglutaryl dehydratase Component A (CompA involved in glutamate degradation and MinD that functions in spatial regulation of cell division. Although involved in very diverse biological processes, these proteins share an underlying common structural framework. This review mainly focuses on the structural similarities of these proteins with the NifH protein and discusses recent reports of complementation studies involving NifH and few of the proteins mentioned.

  7. 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. PMID:26464089

  8. Mechanistically compatible mixtures of bacterial antagonists improve biological control of fire blight of pear

    Science.gov (United States)

    Mixtures of biological control agents can be superior to individual agents in suppressing plant disease, providing enhanced efficacy and reliability from field to field relative to single biocontrol strains. Nonetheless, the efficacy of combinations of Pseudomonas fluorescens A506, a commercial bio...

  9. Biological plausibility as a tool to associate analytical data for micropollutants and effect potentials in wastewater, surface water, and sediments with effects in fishes.

    Science.gov (United States)

    Maier, Diana; Blaha, Ludek; Giesy, John P; Henneberg, Anja; Köhler, Heinz-R; Kuch, Bertram; Osterauer, Raphaela; Peschke, Katharina; Richter, Doreen; Scheurer, Marco; Triebskorn, Rita

    2015-04-01

    of micronuclei in erythrocytes of chub from the river. Chemicals potentially responsible for effects on DNA were identified. Embryotoxic effects on zebrafish (Danio rerio), investigated in the laboratory, were associated with embryotoxic effects in trout exposed in streamwater bypass systems at the two rivers. In general, responses at all levels of organization were more pronounced in samples from the Schussen than in those from the Argen. These results are consistent with the magnitudes of chemical pollution in these two streams. Plausibility chains to establish causality between exposures and effects and to predict effects in biota in the river from studies in the laboratory are discussed. PMID:25260601

  10. Nonsense-mediated mRNA decay: novel mechanistic insights and biological impact.

    Science.gov (United States)

    Karousis, Evangelos D; Nasif, Sofia; Mühlemann, Oliver

    2016-09-01

    Nonsense-mediated mRNA decay (NMD) was originally coined to define a quality control mechanism that targets mRNAs with truncated open reading frames due to the presence of a premature termination codon. Meanwhile, it became clear that NMD has a much broader impact on gene expression and additional biological functions beyond quality control are continuously being discovered. We review here the current views regarding the molecular mechanisms of NMD, according to which NMD ensues on mRNAs that fail to terminate translation properly, and point out the gaps in our understanding. We further summarize the recent literature on an ever-rising spectrum of biological processes in which NMD appears to be involved, including homeostatic control of gene expression, development and differentiation, as well as viral defense. WIREs RNA 2016, 7:661-682. doi: 10.1002/wrna.1357 For further resources related to this article, please visit the WIREs website. PMID:27173476

  11. 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

  12. 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

    International Nuclear Information System (INIS)

    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

  13. Novel pyrazolopyridine derivatives as potential angiogenesis inhibitors: Synthesis, biological evaluation and transcriptome-based mechanistic analysis.

    Science.gov (United States)

    Michailidou, Maria; Giannouli, Vassiliki; Kotsikoris, Vasilios; Papadodima, Olga; Kontogianni, Georgia; Kostakis, Ioannis K; Lougiakis, Nikolaos; Chatziioannou, Aristotelis; Kolisis, Fragiskos N; Marakos, Panagiotis; Pouli, Nicole; Loutrari, Heleni

    2016-10-01

    Modified purine derivatives exemplified by pyrazolopyrimidines have emerged as highly selective inhibitors of several angiogenic receptor tyrosine kinases. Herein, we designed and synthesized a new series of substituted pyrazolopyridines and explored their ability to influence crucial pro-angiogenic attributes of endothelial cells. Four of the synthesized compounds, possessing analogous substitution pattern, were found able to inhibit at low micromolar concentrations endothelial cell proliferation, migration and differentiation, constitutively or in response to Vascular Endothelial Growth Factor (VEGF) and to attenuate VEGF-induced phosphorylation of VEGF receptor-2 and downstream kinases AKT and ERK1/2. Administration of effective compounds in mice delayed the growth of syngeneic Lewis lung carcinoma transplants and reduced tumor microvessel density, without causing toxicity. Genome-wide microarray and gene ontology analyses of treated endothelial cells revealed derivative 18c as the most efficient modulator of gene expression and "mitotic cell cycle/cell division" along with "cholesterol biosynthesis" as the most significantly altered biological processes. PMID:27240270

  14. Efficient, Physically Plausible Finite Elements

    OpenAIRE

    Nesme, Matthieu; Payan, Yohan; Faure, François

    2005-01-01

    This paper discusses FEM-based simulations of soft bodies in terms of speed and robustness. To be physically plausible, three fundamental laws must be respected: rotational invariance, Newton's law and Euler's law. We show that precomputed strain-displacement matrices generate nonphysical torques which can lead to visual artifacts. We then derive the fastest FEM-based method meeting our criteria of plausibility and robustness and discuss their limitations.

  15. Plausibility in DSmT

    Czech Academy of Sciences Publication Activity Database

    Daniel, Milan

    Heidelberg : Springer, 2012 - (Denoeux, T.; Masson, M.), s. 179-187 ISBN 978-3-642-29460-0. ISSN 1867-5662. - (Advances in Intelligent and Soft Computing. 164). [International Conference on Belief Functions /2./. Compiègne (FR), 09.05.2012-11.05.2012] R&D Projects: GA ČR GAP202/10/1826 Institutional research plan: CEZ:AV0Z10300504 Keywords : theory of belief functions * DSm Theory * belief function * plausibility * conflict of belief functions Subject RIV: IN - Informatics, Computer Science

  16. 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

  17. Biological and mechanistic activities of xanthorrizol and 4-(1',5'-dimethylhex-4'-enyl)-2-methylphenol isolated from Iostephane heterophylla.

    Science.gov (United States)

    Mata, R; Martínez, E; Bye, R; Morales, G; Singh, M P; Janso, J E; Maiese, W M; Timmermann, B

    2001-07-01

    Xanthorrizol (1) and 4-(1',5'-dimethylhex-4'-enyl)-2-methylphenol (2) were identified as the principal antimicrobial components of a CH(2)Cl(2)-MeOH (1:1) extract derived from Iostephane heterophylla. Compound 2 is a new natural product, but has been synthesized. Both compounds exhibited low level activity (MICs of 16-32 microg/mL) against methicillin-resistant staphylococci and vancomycin-resistant enterococci. They were either inactive or poorly active against Gram-negative bacteria and yeast. Mechanistic studies performed in Escherichia coli imp suggested nonspecific inhibition of DNA, RNA, and protein synthesis by both of these compounds. Compound 1 was tested in an in vivo model; it did not provide protection to mice infected with Staphylococcus aureus. PMID:11473422

  18. Gradient matching methods for computational inference in mechanistic models for systems biology: a review and comparative analysis

    Directory of Open Access Journals (Sweden)

    Benn eMacdonald

    2015-11-01

    Full Text Available Parameter inference in mathematical models of biological pathways, expressed as coupled ordinary differential equations (ODEs, is a challenging problem in contemporary systems biology. Conventional methods involve repeatedly solving the ODEs by numerical integration, which is computationally onerous and does not scale up to complex systems. Aimed at reducing the computational costs, new concepts based on gradient matching have recently been proposed in the computational statistics and machine learning literature. In a preliminary smoothing step, the time series data are interpolated; then, in a second step, the parameters of the ODEs are optimised so as to minimise some metric measuring the difference between the slopes of the tangents to the interpolants, and the time derivatives from the ODEs. In this way, the ODEs never have to be solved explicitly. This review provides a concise methodological overview of the current state-of-the-art methods for gradient matching in ODEs, followed by an empirical comparative evaluation based on a set of widely used and representative benchmark data.

  19. Neoproterozoic Glacial Extremes: How Plausible is the

    Science.gov (United States)

    Peltier, W. R.

    2004-05-01

    The suggestion that the glaciation events of the Neoproterozoic could have been global in extent, so-called "snowball" glaciations, during which the oceans were entirely covered by sea ice and the continents by massive continental ice sheets, is an idea tha is recurrent in the geological and climate dynamics literature. It is an idea that haa both critics and defenders but concensus concerning it's plausiblity has yet to emerge. Previous work on this problem has led to the suggestion that a more likely scenario than the "hard snowball" is one in which open water continues to persist at the equator, thus enabling biological evolution into the Cambrian to proceed, perhaps stimulated by the transition from the cold conditions of the Neoproterozoic to the warm condition of the Cambrian, thus leading to the Cambrian "explosion of life". We will discuss recent extensions of our previous efforts to model the extreme climate of the Neoproterozoic, using both the University of Toronto Glacial Systems Model and the NCAR Community Climate System Model. With an appropriate choice for the albedo of sea ice, the former model conntinues to deliver hysteresis in the surface temperature vs. CO2 concentration space when solar luminosity is reduced by 6% below modern, and thus continues to suggest the existence of the previously hypothesized "CO2 attractor". We argue here that the system could be locked onto this attractor by the strong "out of equilibrium" effects of the carbon cycle recently discussed by Rothman et al. (PNAS, 2003). The open water solution is confirmed as the preferred mode of the system by the detailed CCSM integrations that we have performed.

  20. George Pólya: el razonamiento plausible

    OpenAIRE

    Arguedas, Vernon

    2013-01-01

    Presentamos algunos aspectos de la vida del gran matemático, George Pólya así como sus ideas acerca de las técnicas para enseñar matemáticas por medio de la resolución de problemas y una aproximación a su concepto de pensamiento plausible.

  1. Anatomically Plausible Surface Alignment and Reconstruction

    DEFF Research Database (Denmark)

    Paulsen, Rasmus R.; Larsen, Rasmus

    2010-01-01

    With the increasing clinical use of 3D surface scanners, there is a need for accurate and reliable algorithms that can produce anatomically plausible surfaces. In this paper, a combined method for surface alignment and reconstruction is proposed. It is based on an implicit surface representation...... energy that has earlier proved to be particularly well suited for human surface scans. The method has been tested on full cranial scans of ten test subjects and on several scans of the outer human ear....

  2. Properties of Plausibility Conflict of Belief Functions

    Czech Academy of Sciences Publication Activity Database

    Daniel, Milan

    Berlin: Springer, 2013 - (Rutkowski, L.; Korytkowski, M.; Scherer, R.; Tadeusiewicz, R.; Zadeh, L.; Zurada, J.), s. 235-246. (Lecture Notes in Artificial Intelligence . 7894). ISBN 978-3-642-38657-2. ISSN 0302-9743. [ICAISC 2013. International Conference on Artificial Intelligence and Soft Computing /12./. Zakopane (PL), 09.06.2013-13.06.2013] R&D Projects: GA ČR GAP202/10/1826 Institutional support: RVO:67985807 Keywords : belief functions * Dempster-Shafer theory * internal conflict * conflict between belief functions * plausibility conflict * degree of conflict * uncertainty Subject RIV: BA - General Mathematics

  3. New and emerging biologic therapies for moderate-to-severe plaque psoriasis: mechanistic rationales and recent clinical data for IL-17 and IL-23 inhibitors

    OpenAIRE

    Gaspari, Anthony A.; Tyring, Stephen

    2015-01-01

    The development of effective and well-tolerated biologic therapies has advanced the management of psoriasis by enabling clinicians to treat underlying disease mechanisms. Biologics approved for the treatment of moderate-to-severe psoriasis include three tumor necrosis factor alpha inhibitors and an interleukin-12/interleukin-23 inhibitor. The establishment of the immunological basis of psoriasis has led to the development of biologic agents targeting specific downstream mediators in the psori...

  4. Transcriptomic Analysis Reveals Novel Mechanistic Insight into Murine Biological Responses to Multi-Walled Carbon Nanotubes in Lungs and Cultured Lung Epithelial Cells

    DEFF Research Database (Denmark)

    Poulsen, Sarah Søs; Jacobsen, Nicklas R.; Labib, Sarah;

    2013-01-01

    responses of multiwalled carbon nanotubes (MWCNT) to those in vitro in cultured lung epithelial cells (FE1) at the global transcriptomic level. Primary size, surface area and other properties of MWCNT-XNRI -7 (Mitsui7) were characterized using DLS, SEM and TEM. Mice were exposed via a single intratracheal...... instillation to 18, 54, or 162 mu g of Mitsui7/mouse. FE1 cells were incubated with 12.5, 25 and 100 mu g/ml of Mitsui7. Tissue and cell samples were collected at 24 hours post-exposure. DNA microarrays were employed to establish mechanistic differences and similarities between the two models. Microarray...... pathway-level, the specific genes altered under these pathways were different, suggesting that the underlying mechanisms of responses are different in cells in culture and the lung tissue. Our results suggest that careful consideration should be given in selecting relevant endpoints when substituting...

  5. Analytic Models of Plausible Gravitational Lens Potentials

    Energy Technology Data Exchange (ETDEWEB)

    Baltz, Edward A.; Marshall, Phil; Oguri, Masamune

    2007-05-04

    Gravitational lenses on galaxy scales are plausibly modeled as having ellipsoidal symmetry and a universal dark matter density profile, with a Sersic profile to describe the distribution of baryonic matter. Predicting all lensing effects requires knowledge of the total lens potential: in this work we give analytic forms for that of the above hybrid model. Emphasizing that complex lens potentials can be constructed from simpler components in linear combination, we provide a recipe for attaining elliptical symmetry in either projected mass or lens potential.We also provide analytic formulae for the lens potentials of Sersic profiles for integer and half-integer index. We then present formulae describing the gravitational lensing effects due to smoothly-truncated universal density profiles in cold dark matter model. For our isolated haloes the density profile falls off as radius to the minus fifth or seventh power beyond the tidal radius, functional forms that allow all orders of lens potential derivatives to be calculated analytically, while ensuring a non-divergent total mass. We show how the observables predicted by this profile differ from that of the original infinite-mass NFW profile. Expressions for the gravitational flexion are highlighted. We show how decreasing the tidal radius allows stripped haloes to be modeled, providing a framework for a fuller investigation of dark matter substructure in galaxies and clusters. Finally we remark on the need for finite mass halo profiles when doing cosmological ray-tracing simulations, and the need for readily-calculable higher order derivatives of the lens potential when studying catastrophes in strong lenses.

  6. Transcriptomic Analysis Reveals Novel Mechanistic Insight into Murine Biological Responses to Multi-Walled Carbon Nanotubes in Lungs and Cultured Lung Epithelial Cells

    OpenAIRE

    Sarah Søs Poulsen; Nicklas R. Jacobsen; Sarah Labib; Dongmei Wu; Mainul Husain; Andrew Williams; Bøgelund, Jesper P.; Ole Andersen; Carsten Købler; Kristian Mølhave; Kyjovska, Zdenka O.; Saber, Anne T.; Håkan Wallin; Yauk, Carole L.; Ulla Vogel

    2013-01-01

    There is great interest in substituting animal work with in vitro experimentation in human health risk assessment; however, there are only few comparisons of in vitro and in vivo biological responses to engineered nanomaterials. We used high-content genomics tools to compare in vivo pulmonary responses of multiwalled carbon nanotubes (MWCNT) to those in vitro in cultured lung epithelial cells (FE1) at the global transcriptomic level. Primary size, surface area and other properties of MWCNT- X...

  7. Transcriptomic Analysis Reveals Novel Mechanistic Insight into Murine Biological Responses to Multi-Walled Carbon Nanotubes in Lungs and Cultured Lung Epithelial Cells

    OpenAIRE

    Poulsen, Sarah Søs; Nicklas R. Jacobsen; Labib, Sarah; Wu, Dongmei; Husain, Mainul; Williams, Andrew; Bøgelund, Jesper P.; Andersen, Ole; Købler, Carsten; Mølhave, Kristian; Kyjovska, Zdenka O.; Saber, Anne T.; Wallin, Håkan; Yauk, Carole L.; Vogel, Ulla Birgitte

    2013-01-01

    There is great interest in substituting animal work with in vitro experimentation in human health risk assessment; however, there are only few comparisons of in vitro and in vivo biological responses to engineered nanomaterials. We used high-content genomics tools to compare in vivo pulmonary responses of multiwalled carbon nanotubes (MWCNT) to those in vitro in cultured lung epithelial cells (FE1) at the global transcriptomic level. Primary size, surface area and other properties of MWCNT-XN...

  8. A Three-Stage Mechanistic Model for Ammonia Borane Dehydrogenation by Shvo’s Catalyst

    OpenAIRE

    Lu, Zhiyao; Conley, Brian L.; Williams, Travis J.

    2012-01-01

    We propose a mechanistic model for three-stage dehydrogenation of ammonia borane (AB) catalyzed by Shvo’s cyclopentadienone-ligated ruthenium complex. We provide evidence for a plausible mechanism for catalyst deactivation, the transition from fast catalysis to slow catalysis, and relate those findings to the invention of a second-generation catalyst that does not suffer from the same deactivation chemistry.

  9. Is semantic preview benefit due to relatedness or plausibility?

    Science.gov (United States)

    Veldre, Aaron; Andrews, Sally

    2016-07-01

    There is increasing evidence that skilled readers of English benefit from processing a parafoveal preview of a semantically related word. However, in previous investigations of semantic preview benefit using the gaze-contingent boundary paradigm the semantic relatedness between the preview and target has been confounded with the plausibility of the preview word in the sentence. In the present study, preview relatedness and plausibility were independently manipulated in neutral sentences read by a large sample of skilled adult readers. Participants were assessed on measures of reading and spelling ability to identify possible sources of individual differences in preview effects. The results showed that readers benefited from a preview of a plausible word, regardless of the semantic relatedness of the preview and the target. However, there was limited evidence of a semantic relatedness benefit when the plausibility of the preview was controlled. The plausibility preview benefit was strongest for low proficiency readers, suggesting that poorer readers were more likely to program a forward saccade based on information extracted from the preview. High proficiency readers showed equivalent disruption from all nonidentical previews suggesting that they were more likely to suffer interference from the orthographic mismatch between preview and target. (PsycINFO Database Record PMID:26752734

  10. Negotiating plausibility: intervening in the future of nanotechnology.

    Science.gov (United States)

    Selin, Cynthia

    2011-12-01

    The national-level scenarios project NanoFutures focuses on the social, political, economic, and ethical implications of nanotechnology, and is initiated by the Center for Nanotechnology in Society at Arizona State University (CNS-ASU). The project involves novel methods for the development of plausible visions of nanotechnology-enabled futures, elucidates public preferences for various alternatives, and, using such preferences, helps refine future visions for research and outreach. In doing so, the NanoFutures project aims to address a central question: how to deliberate the social implications of an emergent technology whose outcomes are not known. The solution pursued by the NanoFutures project is twofold. First, NanoFutures limits speculation about the technology to plausible visions. This ambition introduces a host of concerns about the limits of prediction, the nature of plausibility, and how to establish plausibility. Second, it subjects these visions to democratic assessment by a range of stakeholders, thus raising methodological questions as to who are relevant stakeholders and how to activate different communities so as to engage the far future. This article makes the dilemmas posed by decisions about such methodological issues transparent and therefore articulates the role of plausibility in anticipatory governance. PMID:21984333

  11. Families of Plausible Solutions to the Puzzle of Boyajian's Star

    CERN Document Server

    Wright, Jason T

    2016-01-01

    Good explanations for the unusual light curve of Boyajian's Star have been hard to find. Recent results by Montet & Simon lend strength and plausibility to the conclusion of Schaefer that in addition to short-term dimmings, the star also experiences large, secular decreases in brightness on decadal timescales. This, combined with a lack of long-wavelength excess in the star's spectral energy distribution, strongly constrains scenarios involving circumstellar material, including hypotheses invoking a spherical cloud of artifacts. We show that the timings of the deepest dimmings appear consistent with being randomly distributed, and that the star's reddening and narrow sodium absorption is consistent with the total, long-term dimming observed. Following Montet & Simon's encouragement to generate alternative hypotheses, we attempt to circumscribe the space of possible explanations with a range of plausibilities, including: a cloud in the outer solar system, structure in the ISM, natural and artificial ma...

  12. Probabilistic reasoning in intelligent systems networks of plausible inference

    CERN Document Server

    Pearl, Judea

    1988-01-01

    Probabilistic Reasoning in Intelligent Systems is a complete and accessible account of the theoretical foundations and computational methods that underlie plausible reasoning under uncertainty. The author provides a coherent explication of probability as a language for reasoning with partial belief and offers a unifying perspective on other AI approaches to uncertainty, such as the Dempster-Shafer formalism, truth maintenance systems, and nonmonotonic logic. The author distinguishes syntactic and semantic approaches to uncertainty--and offers techniques, based on belief networks, that provid

  13. Biologic

    CERN Document Server

    Kauffman, L H

    2002-01-01

    In this paper we explore the boundary between biology and the study of formal systems (logic). In the end, we arrive at a summary formalism, a chapter in "boundary mathematics" where there are not only containers but also extainers ><, entities open to interaction and distinguishing the space that they are not. The boundary algebra of containers and extainers is to biologic what boolean algebra is to classical logic. We show how this formalism encompasses significant parts of the logic of DNA replication, the Dirac formalism for quantum mechanics, formalisms for protein folding and the basic structure of the Temperley Lieb algebra at the foundations of topological invariants of knots and links.

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

    Science.gov (United States)

    Lundengård, Karin; Cedersund, Gunnar; Sten, Sebastian; Leong, Felix; Smedberg, Alexander; Elinder, Fredrik; Engström, Maria

    2016-06-01

    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, independent validation data

  15. Belief Functions: A Revision of Plausibility Conflict and Pignistic Conflict

    Czech Academy of Sciences Publication Activity Database

    Daniel, Milan

    Berlin: Springer, 2013 - (Liu, W.; Subrahmanian, V.; Wijsen, J.), s. 190-203. (Lecture Notes in Artificial Intelligence . 8078). ISBN 978-3-642-40380-4. ISSN 0302-9743. [SUM 2013. International Conference /7./. Washington (US), 16.09.2013-18.09.2013] R&D Projects: GA ČR GAP202/10/1826 Institutional support: RVO:67985807 Keywords : belief functions * Dempster-Shafer theory * internal conflict * conflict between belief functions * plausibility conflict * pignistic conflict * degree of conflict * uncertainty Subject RIV: BA - General Mathematics

  16. A BIOMASS-BASED MODEL TO ESTIMATE THE PLAUSIBILITY OF EXOPLANET BIOSIGNATURE GASES

    International Nuclear Information System (INIS)

    Biosignature gas detection is one of the ultimate future goals for exoplanet atmosphere studies. We have created a framework for linking biosignature gas detectability to biomass estimates, including atmospheric photochemistry and biological thermodynamics. The new framework is intended to liberate predictive atmosphere models from requiring fixed, Earth-like biosignature gas source fluxes. New biosignature gases can be considered with a check that the biomass estimate is physically plausible. We have validated the models on terrestrial production of NO, H2S, CH4, CH3Cl, and DMS. We have applied the models to propose NH3 as a biosignature gas on a 'cold Haber World', a planet with a N2-H2 atmosphere, and to demonstrate why gases such as CH3Cl must have too large of a biomass to be a plausible biosignature gas on planets with Earth or early-Earth-like atmospheres orbiting a Sun-like star. To construct the biomass models, we developed a functional classification of biosignature gases, and found that gases (such as CH4, H2S, and N2O) produced from life that extracts energy from chemical potential energy gradients will always have false positives because geochemistry has the same gases to work with as life does, and gases (such as DMS and CH3Cl) produced for secondary metabolic reasons are far less likely to have false positives but because of their highly specialized origin are more likely to be produced in small quantities. The biomass model estimates are valid to one or two orders of magnitude; the goal is an independent approach to testing whether a biosignature gas is plausible rather than a precise quantification of atmospheric biosignature gases and their corresponding biomasses

  17. A BIOMASS-BASED MODEL TO ESTIMATE THE PLAUSIBILITY OF EXOPLANET BIOSIGNATURE GASES

    Energy Technology Data Exchange (ETDEWEB)

    Seager, S.; Bains, W.; Hu, R. [Department of Earth, Atmospheric, and Planetary Sciences, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139 (United States)

    2013-10-01

    Biosignature gas detection is one of the ultimate future goals for exoplanet atmosphere studies. We have created a framework for linking biosignature gas detectability to biomass estimates, including atmospheric photochemistry and biological thermodynamics. The new framework is intended to liberate predictive atmosphere models from requiring fixed, Earth-like biosignature gas source fluxes. New biosignature gases can be considered with a check that the biomass estimate is physically plausible. We have validated the models on terrestrial production of NO, H{sub 2}S, CH{sub 4}, CH{sub 3}Cl, and DMS. We have applied the models to propose NH{sub 3} as a biosignature gas on a 'cold Haber World', a planet with a N{sub 2}-H{sub 2} atmosphere, and to demonstrate why gases such as CH{sub 3}Cl must have too large of a biomass to be a plausible biosignature gas on planets with Earth or early-Earth-like atmospheres orbiting a Sun-like star. To construct the biomass models, we developed a functional classification of biosignature gases, and found that gases (such as CH{sub 4}, H{sub 2}S, and N{sub 2}O) produced from life that extracts energy from chemical potential energy gradients will always have false positives because geochemistry has the same gases to work with as life does, and gases (such as DMS and CH{sub 3}Cl) produced for secondary metabolic reasons are far less likely to have false positives but because of their highly specialized origin are more likely to be produced in small quantities. The biomass model estimates are valid to one or two orders of magnitude; the goal is an independent approach to testing whether a biosignature gas is plausible rather than a precise quantification of atmospheric biosignature gases and their corresponding biomasses.

  18. A Biomass-based Model to Estimate the Plausibility of Exoplanet Biosignature Gases

    CERN Document Server

    Seager, S; Hu, R

    2013-01-01

    Biosignature gas detection is one of the ultimate future goals for exoplanet atmosphere studies. We have created a framework for linking biosignature gas detectability to biomass estimates, including atmospheric photochemistry and biological thermodynamics. The new framework is intended to liberate predictive atmosphere models from requiring fixed, Earth-like biosignature gas source fluxes. New biosignature gases can be considered with a check that the biomass estimate is physically plausible. We have validated the models on terrestrial production of NO, H2S, CH4, CH3Cl, and DMS. We have applied the models to propose NH3 as a biosignature gas on a "cold Haber World," a planet with a N2-H2 atmosphere, and to demonstrate why gases such as CH3Cl must have too large of a biomass to be a plausible biosignature gas on planets with Earth or early-Earth-like atmospheres orbiting a Sun-like star. To construct the biomass models, we developed a functional classification of biosignature gases, and found that gases (such...

  19. Neural networks, nativism, and the plausibility of constructivism.

    Science.gov (United States)

    Quartz, S R

    1993-09-01

    Recent interest in PDP (parallel distributed processing) models is due in part to the widely held belief that they challenge many of the assumptions of classical cognitive science. In the domain of language acquisition, for example, there has been much interest in the claim that PDP models might undermine nativism. Related arguments based on PDP learning have also been given against Fodor's anti-constructivist position--a position that has contributed to the widespread dismissal of constructivism. A limitation of many of the claims regarding PDP learning, however, is that the principles underlying this learning have not been rigorously characterized. In this paper, I examine PDP models from within the framework of Valiant's PAC (probably approximately correct) model of learning, now the dominant model in machine learning, and which applies naturally to neural network learning. From this perspective, I evaluate the implications of PDP models for nativism and Fodor's influential anti-constructivist position. In particular, I demonstrate that, contrary to a number of claims, PDP models are nativist in a robust sense. I also demonstrate that PDP models actually serve as a good illustration of Fodor's anti-constructivist position. While these results may at first suggest that neural network models in general are incapable of the sort of concept acquisition that is required to refute Fodor's anti-constructivist position, I suggest that there is an alternative form of neural network learning that demonstrates the plausibility of constructivism. This alternative form of learning is a natural interpretation of the constructivist position in terms of neural network learning, as it employs learning algorithms that incorporate the addition of structure in addition to weight modification schemes. By demonstrating that there is a natural and plausible interpretation of constructivism in terms of neural network learning, the position that nativism is the only plausible model of

  20. How Physicists Made Stable Lévy Processes Physically Plausible

    Science.gov (United States)

    Schinckus, Christophe

    2013-08-01

    Stable Lévy processes have very interesting properties for describing the complex behaviour of non-equilibrium dissipative systems such as turbulence, anomalous diffusion or financial markets. However, although these processes better fit the empirical data, some of their statistical properties can raise several theoretical problems in empirical applications because they generate infinite variables. Econophysicists have developed statistical solutions to make these processes physically plausible. This paper presents a review of these analytical solutions (truncations) for stable Lévy processes and how econophysicists transformed them into data-driven processes. The evolution of these analytical solutions is presented as a progressive research programme provided by (econo)physicists for theoretical problems encountered in financial economics in the 1960s and the 1970s.

  1. Spontaneous formation and base pairing of plausible prebiotic nucleotides in water.

    Science.gov (United States)

    Cafferty, Brian J; Fialho, David M; Khanam, Jaheda; Krishnamurthy, Ramanarayanan; Hud, Nicholas V

    2016-01-01

    The RNA World hypothesis presupposes that abiotic reactions originally produced nucleotides, the monomers of RNA and universal constituents of metabolism. However, compatible prebiotic reactions for the synthesis of complementary (that is, base pairing) nucleotides and mechanisms for their mutual selection within a complex chemical environment have not been reported. Here we show that two plausible prebiotic heterocycles, melamine and barbituric acid, form glycosidic linkages with ribose and ribose-5-phosphate in water to produce nucleosides and nucleotides in good yields. Even without purification, these nucleotides base pair in aqueous solution to create linear supramolecular assemblies containing thousands of ordered nucleotides. Nucleotide anomerization and supramolecular assemblies favour the biologically relevant β-anomer form of these ribonucleotides, revealing abiotic mechanisms by which nucleotide structure and configuration could have been originally favoured. These findings indicate that nucleotide formation and selection may have been robust processes on the prebiotic Earth, if other nucleobases preceded those of extant life. PMID:27108699

  2. Spontaneous formation and base pairing of plausible prebiotic nucleotides in water

    Science.gov (United States)

    Cafferty, Brian J.; Fialho, David M.; Khanam, Jaheda; Krishnamurthy, Ramanarayanan; Hud, Nicholas V.

    2016-01-01

    The RNA World hypothesis presupposes that abiotic reactions originally produced nucleotides, the monomers of RNA and universal constituents of metabolism. However, compatible prebiotic reactions for the synthesis of complementary (that is, base pairing) nucleotides and mechanisms for their mutual selection within a complex chemical environment have not been reported. Here we show that two plausible prebiotic heterocycles, melamine and barbituric acid, form glycosidic linkages with ribose and ribose-5-phosphate in water to produce nucleosides and nucleotides in good yields. Even without purification, these nucleotides base pair in aqueous solution to create linear supramolecular assemblies containing thousands of ordered nucleotides. Nucleotide anomerization and supramolecular assemblies favour the biologically relevant β-anomer form of these ribonucleotides, revealing abiotic mechanisms by which nucleotide structure and configuration could have been originally favoured. These findings indicate that nucleotide formation and selection may have been robust processes on the prebiotic Earth, if other nucleobases preceded those of extant life. PMID:27108699

  3. One-pot synthesis of tetrazole-1,2,5,6-tetrahydronicotinonitriles and cholinesterase inhibition: Probing the plausible reaction mechanism via computational studies.

    Science.gov (United States)

    Hameed, Abdul; Zehra, Syeda Tazeen; Abbas, Saba; Nisa, Riffat Un; Mahmood, Tariq; Ayub, Khurshid; Al-Rashida, Mariya; Bajorath, Jürgen; Khan, Khalid Mohammed; Iqbal, Jamshed

    2016-04-01

    In the present study, one-pot synthesis of 1H-tetrazole linked 1,2,5,6-tetrahydronicotinonitriles under solvent-free conditions have been carried out in the presence of tetra-n-butyl ammonium fluoride trihydrated (TBAF) as catalyst and solvent. Computational studies have been conducted to elaborate two plausible mechanistic pathways of this one-pot reaction. Moreover, the synthesized compounds were screened for cholinesterases (acetylcholinesterase and butyrylcholinesterase) inhibition which are consider to be major malefactors of Alzheimer's disease (AD) to find lead compounds for further research in AD therapy. PMID:26851737

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

    Science.gov (United States)

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

    2016-01-01

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

  5. Liderazgo preventivo para la universidad. Una experiencia plausible

    Directory of Open Access Journals (Sweden)

    Alejandro Rodríguez Rodríguez

    2015-06-01

    Full Text Available El desarrollo del liderazgo, en el ámbito educativo superior, busca soluciones de aplicación inmediata a contextos en que todo líder se desenvuelve, pero se diluye el sustento teórico-práctico en la formación del líder que posibilite entender los procesos intelectivos durante la toma de decisiones. El paradigma de convergencia entre el método antropológico lonerganiano, la comunidad de aprendizaje vygotskiana y una relectura del sistema preventivo salesiano se presentan como propuesta plausible de formación al liderazgo preventivo entre los diversos actores de una comunidad universitaria. Un estudio de caso de la Universidad Salesiana en México empleando un método mixto de investigación, facilita una relectura del liderazgo desde una óptica preventiva como posibilidad de convergencia en un diálogo interdisciplinar. Los resultados teórico-práctico propuestos y examinados se muestran como herramienta útil para evaluar, enriquecer y renovar la teoría sobre el líder y el desarrollo de liderazgo en las universidades frente a una sociedad globalizada.

  6. Plausible explanation for the Δ5/2+(2000) puzzle

    Science.gov (United States)

    Xie, Ju-Jun; Martínez Torres, A.; Oset, E.; González, P.

    2011-05-01

    From a Faddeev calculation for the π-(Δρ)N5/2-(1675) system we show the plausible existence of three dynamically generated I(JP)=3/2(5/2+) baryon states below 2.3 GeV, whereas only two resonances, Δ5/2+(1905)(****) and Δ5/2+(2000)(**), are cataloged in the Particle Data Book Review. Our results give theoretical support to data analyses extracting two distinctive resonances, Δ5/2+(~1740) and Δ5/2+(~2200), from which the mass of Δ5/2+(2000)(**) is estimated. We propose that these two resonances should be cataloged instead of Δ5/2+(2000). This proposal gets further support from the possible assignment of the other baryon states found in the approach in the I=1/2,3/2 with JP=1/2+,3/2+,5/2+ sectors to known baryonic resonances. In particular, Δ1/2+(1750)(*) is naturally interpreted as a πN1/2-(1650) bound state.

  7. A plausible mechanism for auxin patterning along the developing root

    Directory of Open Access Journals (Sweden)

    Kolchanov Nikolai A

    2010-07-01

    Full Text Available Abstract Background In plant roots, auxin is critical for patterning and morphogenesis. It regulates cell elongation and division, the development and maintenance of root apical meristems, and other processes. In Arabidopsis, auxin distribution along the central root axis has several maxima: in the root tip, in the basal meristem and at the shoot/root junction. The distal maximum in the root tip maintains the stem cell niche. Proximal maxima may trigger lateral or adventitious root initiation. Results We propose a reflected flow mechanism for the formation of the auxin maximum in the root apical meristem. The mechanism is based on auxin's known activation and inhibition of expressed PIN family auxin carriers at low and high auxin levels, respectively. Simulations showed that these regulatory interactions are sufficient for self-organization of the auxin distribution pattern along the central root axis under varying conditions. The mathematical model was extended with rules for discontinuous cell dynamics so that cell divisions were also governed by auxin, and by another morphogen Division Factor which combines the actions of cytokinin and ethylene on cell division in the root. The positional information specified by the gradients of these two morphogens is able to explain root patterning along the central root axis. Conclusion We present here a plausible mechanism for auxin patterning along the developing root, that may provide for self-organization of the distal auxin maximum when the reverse fountain has not yet been formed or has been disrupted. In addition, the proximal maxima are formed under the reflected flow mechanism in response to periods of increasing auxin flow from the growing shoot. These events may predetermine lateral root initiation in a rhyzotactic pattern. Another outcome of the reflected flow mechanism - the predominance of lateral or adventitious roots in different plant species - may be based on the different efficiencies

  8. A swarm intelligence framework for reconstructing gene networks: searching for biologically plausible architectures

    OpenAIRE

    Poole, Matthew; Kentzoglanakis, Kyriakos

    2011-01-01

    In this paper, we investigate the problem of reverse engineering the topology of gene regulatory networks from temporal gene expression data. We adopt a computational intelligence approach comprising swarm intelligence techniques, namely particle swarm optimization (PSO) and ant colony optimization (ACO). In addition, the recurrent neural network (RNN) formalism is employed for modelling the dynamical behaviour of gene regulatory systems. More specifically, ACO is used for searching the discre...

  9. Biologically Plausible Control of Fast Reaching Movements Using Non-Traditional Cost Functions

    OpenAIRE

    Gamble, Geoffrey

    2016-01-01

    Optimal control has been used as a technique to uncover mathematical principles which are observed regularly in the dynamics of human movement. We present two new models of human reaching movements. While both are rooted in optimal control theory, the models were conceived by questioning basic tenets and typical practices used in optimal control as applied to human movement. In the first model, we use cost functions that measure various control signals via the L_infinity norm as opposed to th...

  10. Protein Intake and Muscle Health in Old Age: From Biological Plausibility to Clinical Evidence

    Science.gov (United States)

    Landi, Francesco; Calvani, Riccardo; Tosato, Matteo; Martone, Anna Maria; Ortolani, Elena; Savera, Giulia; D’Angelo, Emanuela; Sisto, Alex; Marzetti, Emanuele

    2016-01-01

    The provision of sufficient amounts of dietary proteins is central to muscle health as it ensures the supply of essential amino acids and stimulates protein synthesis. Older persons, in particular, are at high risk of insufficient protein ingestion. Furthermore, the current recommended dietary allowance for protein (0.8 g/kg/day) might be inadequate for maintaining muscle health in older adults, probably as a consequence of “anabolic resistance” in aged muscle. Older individuals therefore need to ingest a greater quantity of protein to maintain muscle function. The quality of protein ingested is also essential to promoting muscle health. Given the role of leucine as the master dietary regulator of muscle protein turnover, the ingestion of protein sources enriched with this essential amino acid, or its metabolite β-hydroxy β-methylbutyrate, is thought to offer the greatest benefit in terms of preservation of muscle mass and function in old age. PMID:27187465

  11. Towards biological plausibility of electronic noses: A spiking neural network based approach for tea odour classification.

    Science.gov (United States)

    Sarkar, Sankho Turjo; Bhondekar, Amol P; Macaš, Martin; Kumar, Ritesh; Kaur, Rishemjit; Sharma, Anupma; Gulati, Ashu; Kumar, Amod

    2015-11-01

    The paper presents a novel encoding scheme for neuronal code generation for odour recognition using an electronic nose (EN). This scheme is based on channel encoding using multiple Gaussian receptive fields superimposed over the temporal EN responses. The encoded data is further applied to a spiking neural network (SNN) for pattern classification. Two forms of SNN, a back-propagation based SpikeProp and a dynamic evolving SNN are used to learn the encoded responses. The effects of information encoding on the performance of SNNs have been investigated. Statistical tests have been performed to determine the contribution of the SNN and the encoding scheme to overall odour discrimination. The approach has been implemented in odour classification of orthodox black tea (Kangra-Himachal Pradesh Region) thereby demonstrating a biomimetic approach for EN data analysis. PMID:26356597

  12. Warfarin and acetaminophen interaction: a summary of the evidence and biologic plausibility.

    Science.gov (United States)

    Lopes, Renato D; Horowitz, John D; Garcia, David A; Crowther, Mark A; Hylek, Elaine M

    2011-12-01

    Ms TS is a 66-year-old woman who receives warfarin for prevention of systemic embolization in the setting of hypertension, diabetes, and atrial fibrillation. She had a transient ischemic attack about 4 years ago when she was receiving aspirin. Her INR control was excellent; however, over the past few months it has become erratic, and her average dose required to maintain an INR of 2.0 to 3.0 appears to have decreased. She has had back pain over this same period and has been taking acetaminophen at doses at large as 650 mg four times daily, with her dose varying based on her symptoms. You recall a potential interaction and wonder if (1) her acetaminophen use is contributing to her loss of INR control, and (2) does this interaction place her at increased risk of warfarin-related complications? PMID:21911832

  13. A Biologically Plausible Computational Theory for Value Integration and Action Selection in Decisions with Competing Alternatives

    OpenAIRE

    Christopoulos, Vassilios; Bonaiuto, James; Andersen, Richard A.

    2015-01-01

    Decision making is a vital component of human and animal behavior that involves selecting between alternative options and generating actions to implement the choices. Although decisions can be as simple as choosing a goal and then pursuing it, humans and animals usually have to make decisions in dynamic environments where the value and the availability of an option change unpredictably with time and previous actions. A predator chasing multiple prey exemplifies how goals can dynamically chang...

  14. Protein Intake and Muscle Health in Old Age: From Biological Plausibility to Clinical Evidence

    Directory of Open Access Journals (Sweden)

    Francesco Landi

    2016-05-01

    Full Text Available The provision of sufficient amounts of dietary proteins is central to muscle health as it ensures the supply of essential amino acids and stimulates protein synthesis. Older persons, in particular, are at high risk of insufficient protein ingestion. Furthermore, the current recommended dietary allowance for protein (0.8 g/kg/day might be inadequate for maintaining muscle health in older adults, probably as a consequence of “anabolic resistance” in aged muscle. Older individuals therefore need to ingest a greater quantity of protein to maintain muscle function. The quality of protein ingested is also essential to promoting muscle health. Given the role of leucine as the master dietary regulator of muscle protein turnover, the ingestion of protein sources enriched with this essential amino acid, or its metabolite β-hydroxy β-methylbutyrate, is thought to offer the greatest benefit in terms of preservation of muscle mass and function in old age.

  15. Mechanistic investigations of shuttle glow

    Science.gov (United States)

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

    1993-01-01

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

  16. HTGR Mechanistic Source Terms White Paper

    Energy Technology Data Exchange (ETDEWEB)

    Wayne Moe

    2010-07-01

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

  17. Robustness and adaptation reveal plausible cell cycle controlling subnetwork in Saccharomyces cerevisiae.

    Science.gov (United States)

    Huang, Jiun-Yan; Huang, Chi-Wei; Kao, Kuo-Ching; Lai, Pik-Yin

    2013-04-10

    signal stimulus entries of check points into the cell cycle, which are consistent with experimental findings. This evolution strategy method can be applied adequately to extract the plausible yeast cell cycle subnetworks from the whole network. Connections between modules in the obtained cell cycle subnetworks reveal significant cell cycle control mechanisms. This method can also be useful when applied to other biological systems at various temporal and spatial scales for example, the gene transcription networks, and biological systems from mesoscopic scale, e.g cortical network in brain, to subcellular molecular networks. PMID:23274654

  18. Can readers ignore implausibility? Evidence for nonstrategic monitoring of event-based plausibility in language comprehension.

    Science.gov (United States)

    Isberner, Maj-Britt; Richter, Tobias

    2013-01-01

    We present evidence for a nonstrategic monitoring of event-based plausibility during language comprehension by showing that readers cannot ignore the implausibility of information even if it is detrimental to the task at hand. In two experiments using a Stroop-like paradigm, participants were required to provide positive and negative responses independent of plausibility in an orthographical task (Experiment 1) or a nonlinguistic color judgment task (Experiment 2) to target words that were either plausible or implausible in their context. We expected a nonstrategic assessment of plausibility to interfere with positive responses to implausible words. ANOVAs and linear mixed models analyses of the response latencies revealed a significant interaction of plausibility and required response that supported this prediction in both experiments, despite the use of two very different tasks. Moreover, it could be shown that the effect was not driven by the differential predictability of plausible and implausible words. These results suggest that plausibility monitoring is an inherent component of information processing. PMID:23165201

  19. Natural selection and mechanistic regularity.

    Science.gov (United States)

    DesAutels, Lane

    2016-06-01

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

  20. People Believe it is Plausible to have Forgotten Memories of Childhood Sexual Abuse

    OpenAIRE

    Rubin, David C.; Berntsen, Dorthe

    2007-01-01

    Pezdek, Blandon-Gitlin, and Gabbay (2006) found that perceptions of the plausibility of events increase the likelihood of imagination inducing false memories of those events. Using a survey conducted by Gallup, we asked a large sample of the general population how plausible it would be for a person with longstanding emotional problems and a need for psychotherapy to be a victim of childhood sexual abuse, even though the person could not remember the abuse. Only 18% indicated that it was impla...

  1. Plausibility and recovery from garden paths in L2 sentence processing

    OpenAIRE

    Roberts, L.; Felser, C.

    2011-01-01

    In this study, the influence of plausibility information on the real-time processing of locally ambiguous (“garden path”) sentences in a nonnative language is investigated. Using self-paced reading, we examined how advanced Greek-speaking learners of English and native speaker controls read sentences containing temporary subject–object ambiguities, with the ambiguous noun phrase being either semantically plausible or implausible as the direct object of the immediately preceding verb. Besides ...

  2. Using critical evaluation to reappraise plausibility judgments: A critical cognitive component of conceptual change

    Science.gov (United States)

    Lombardi, D.

    2011-12-01

    Plausibility judgments-although well represented in conceptual change theories (see, for example, Chi, 2005; diSessa, 1993; Dole & Sinatra, 1998; Posner et al., 1982)-have received little empirical attention until our recent work investigating teachers' and students' understanding of and perceptions about human-induced climate change (Lombardi & Sinatra, 2010, 2011). In our first study with undergraduate students, we found that greater plausibility perceptions of human-induced climate accounted for significantly greater understanding of weather and climate distinctions after instruction, even after accounting for students' prior knowledge (Lombardi & Sinatra, 2010). In a follow-up study with inservice science and preservice elementary teachers, we showed that anger about the topic of climate change and teaching about climate change was significantly related to implausible perceptions about human-induced climate change (Lombardi & Sinatra, 2011). Results from our recent studies helped to inform our development of a model of the role of plausibility judgments in conceptual change situations. The model applies to situations involving cognitive dissonance, where background knowledge conflicts with an incoming message. In such situations, we define plausibility as a judgment on the relative potential truthfulness of incoming information compared to one's existing mental representations (Rescher, 1976). Students may not consciously think when making plausibility judgments, expending only minimal mental effort in what is referred to as an automatic cognitive process (Stanovich, 2009). However, well-designed instruction could facilitate students' reappraisal of plausibility judgments in more effortful and conscious cognitive processing. Critical evaluation specifically may be one effective method to promote plausibility reappraisal in a classroom setting (Lombardi & Sinatra, in progress). In science education, critical evaluation involves the analysis of how evidentiary

  3. Opioid receptors: Structural and mechanistic insights into pharmacology and signaling.

    Science.gov (United States)

    Shang, Yi; Filizola, Marta

    2015-09-15

    Opioid receptors are important drug targets for pain management, addiction, and mood disorders. Although substantial research on these important subtypes of G protein-coupled receptors has been conducted over the past two decades to discover ligands with higher specificity and diminished side effects, currently used opioid therapeutics remain suboptimal. Luckily, recent advances in structural biology of opioid receptors provide unprecedented insights into opioid receptor pharmacology and signaling. We review here a few recent studies that have used the crystal structures of opioid receptors as a basis for revealing mechanistic details of signal transduction mediated by these receptors, and for the purpose of drug discovery. PMID:25981301

  4. Inference and Plausible Reasoning in a Natural Language Understanding System Based on Object-Oriented Semantics

    CERN Document Server

    Ostapov, Yuriy

    2012-01-01

    Algorithms of inference in a computer system oriented to input and semantic processing of text information are presented. Such inference is necessary for logical questions when the direct comparison of objects from a question and database can not give a result. The following classes of problems are considered: a check of hypotheses for persons and non-typical actions, the determination of persons and circumstances for non-typical actions, planning actions, the determination of event cause and state of persons. To form an answer both deduction and plausible reasoning are used. As a knowledge domain under consideration is social behavior of persons, plausible reasoning is based on laws of social psychology. Proposed algorithms of inference and plausible reasoning can be realized in computer systems closely connected with text processing (criminology, operation of business, medicine, document systems).

  5. Don't Plan for the Unexpected: Planning Based on Plausibility Models

    DEFF Research Database (Denmark)

    Andersen, Mikkel Birkegaard; Bolander, Thomas; Jensen, Martin Holm

    2015-01-01

    the agent achieves this goal. Conversely, a weak plan promises only the possibility of leading to the goal. In real-life planning scenarios where the planning agent is faced with a high degree of uncertainty and an almost endless number of possible exogenous events, strong epistemic planning is not......We present a framework for automated planning based on plausibility models, as well as algorithms for computing plans in this framework. Our plausibility models include postconditions, as ontic effects are essential for most planning purposes. The framework presented extends a previously developed...... framework based on dynamic epistemic logic (DEL), without plausibilities/beliefs. In the pure epistemic framework, one can distinguish between strong and weak epistemic plans for achieving some, possibly epistemic, goal. By taking all possible outcomes of actions into account, a strong plan guarantees that...

  6. “合情推理”辨析%Analysis of Plausible Reasoning

    Institute of Scientific and Technical Information of China (English)

    连四清; 方运加

    2012-01-01

    波利亚的“合情推理”模式引进我国数学课程标准后,就成了我国数学教育研究的关键词。然而,“合情推理”的科学性尚需考证:(1)它的中文意义不明确;(2)它不满足推理模式的客观性要求,存在明显的缺陷;(3)过分强调“合情推理模式”则是过分强调归纳推理和演绎推理的区别,容易割裂它们之间的关系。%After the model of "plausible inference" being introduced into the mathematics curriculum standards, it became a key word of the research on mathematics education in China. However, there are doubts on whether it is scientific. (1) Chinese meaning of plausible inference is ambiguous. (2) The plausible inference can not meet the objective requirement of the reasoning, which has obvious defects. (3) Overemphasizing the model of plausible inference would overemphasize the difference between deductive inference and inductive inference, and would dispart them.

  7. Mechanistic models in computational social science

    Science.gov (United States)

    Holme, Petter; Liljeros, Fredrik

    2015-09-01

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

  8. Molecular responses to xenoestrogens: Mechanistic insights from toxicogenomics

    International Nuclear Information System (INIS)

    The xenoestrogen group of endocrine disruptors has the potential to cause reproductive and developmental effects through stimulation or disruption of sex steroid nuclear receptor signalling pathways. A more detailed understanding of the ways in which xenoestrogens interact with biological systems at the molecular level will provide a mechanistic basis for improved safety assessment. The recent sequencing of mammalian genomes has driven the development of toxicogenomic technologies, including microarray based gene expression profiling, which allow the expression levels of thousands of genes to be measured simultaneously. Since the cellular responses to xenoestrogens are predominantly mediated by estrogen receptors, which function as ligand-activated transcription factors to regulate gene expression, the application of toxicogenomics has great potential for providing insights into the molecular mechanisms of xenoestrogen action. A major challenge in applying toxicogenomics to the field of endocrine disruption is the need to define how xenoestrogen-induced changes in gene expression relate to conventional physiological and toxicological endpoints. Gene Ontology Mapping, Pathway Mapping and Phenotypic Anchoring of xenoestrogen-induced gene expression changes to cellular pathways and processes represent key steps in defining these relationships. Mechanistic insights into how xenoestrogens target specific genes and into the functional significance of xenoestrogen-induced alterations in gene expression can be further enhanced by combining transcript profiling with transgenic animal models or cell-based systems in which the estrogen receptor signalling pathways have been modified experimentally. This review illustrates how these toxicogenomic approaches are providing an unprecedented amount of mechanistic information on the molecular responses to xenoestrogens and how they are likely to impact on hazard and risk assessment

  9. Applying mechanistic models in bioprocess development

    DEFF Research Database (Denmark)

    Lencastre Fernandes, Rita; Bodla, Vijaya Krishna; Carlquist, Magnus; Heins, Anna-Lena; Eliasson Lantz, Anna; Sin, Gürkan; Gernaey, Krist V

    2013-01-01

    incorporates process-relevant input (critical process variables)-output (product concentration and product quality attributes) relations. The model therefore has great value in planning experiments, or in determining which critical process variables need to be monitored and controlled tightly. Mechanistic...... complex case studies as well....

  10. ‘One of the Challenges that Can Plausibly Be Raised Against Them’?

    DEFF Research Database (Denmark)

    Holtermann, Jakob v. H.

    2016-01-01

    the truth-finding aspect of ICTs plays only a very limited role in the often heated debates about their legitimacy. Furthermore, those who actually do address the issue seem widely divided as to whether critiques of the epistemic function of ICTs in fact constitute, in Andreas Føllesdal’s words, one...... of ‘the challenges that can plausibly be raised against them’ – and if so, in what ways. In this paper, I address the first of these questions asking whether truth-finding should at all be considered a desideratum for ICTs. To this end, I discuss the widespread claim that it should not because the...... under-stood, truth in law is intimately connected to ordinary truth. Truth-finding capacity therefore does belong in legitimacy debates as a challenge that can plausibly be raised against them. This, in turn makes it relevant, in future research, to map, analyse and interrelate the various critiques...

  11. Spelling in oral deaf and hearing dyslexic children: A comparison of phonologically plausible errors.

    Science.gov (United States)

    Roy, P; Shergold, Z; Kyle, F E; Herman, R

    2014-11-01

    A written single word spelling to dictation test and a single word reading test were given to 68 severe-profoundly oral deaf 10-11-year-old children and 20 hearing children with a diagnosis of dyslexia. The literacy scores of the deaf children and the hearing children with dyslexia were lower than expected for children of their age and did not differ from each other. Three quarters of the spelling errors of hearing children with dyslexia compared with just over half the errors of the oral deaf group were phonologically plausible. Expressive vocabulary and speech intelligibility predicted the percentage of phonologically plausible errors in the deaf group only. Implications of findings for the phonological decoding self-teaching model and for supporting literacy development are discussed. PMID:25462488

  12. Resolution of cosmological singularity and a plausible mechanism of the big bang

    International Nuclear Information System (INIS)

    The initial cosmological singularity in the framework of the general theory of relativity is resolved by introducing the effect of the uncertainty principle of quantum theory without violating conventional laws of physics. A plausible account of the mechanism of the big bang, analogous to that of a nuclear explosion, is given and the currently accepted Planck temperature of ≅1032 K at the beginning of the big bang is predicted

  13. Unified Description of Plausible Cause and Effect of the Big Bang

    OpenAIRE

    Choudhury, D. C.

    2001-01-01

    Plausible cause and effect of the big bang model are presented without violating conventional laws of physics. The initial cosmological singularity is resolved by introducing the uncertainty principle of quantum theory. We postulate that, preceding the big bang at the end of the gravitational collapse, the total observed mass including all forms of energy of the universe condensed into the primordial black hole (PBH) in a state of isotropic and minimal chaos (i.e., nearest to the absolute zer...

  14. Motion in Augmented Reality Games: An Engine for Creating Plausible Physical Interactions in Augmented Reality Games

    OpenAIRE

    Brian Mac Namee; David Beaney; Qingqing Dong

    2010-01-01

    The next generation of Augmented Reality (AR) games will require real and virtual objects to coexist in motion in immersive game environments. This will require the illusion that real and virtual objects interact physically together in a plausible way. The Motion in Augmented Reality Games (MARG) engine described in this paper has been developed to allow these kinds of game environments. The paper describes the design and implementation of the MARG engine and presents two pr...

  15. Spontaneous formation and base pairing of plausible prebiotic nucleotides in water

    OpenAIRE

    Cafferty, Brian J.; Fialho, David M.; Khanam, Jaheda; Krishnamurthy, Ramanarayanan; Hud, Nicholas V.

    2016-01-01

    The RNA World hypothesis presupposes that abiotic reactions originally produced nucleotides, the monomers of RNA and universal constituents of metabolism. However, compatible prebiotic reactions for the synthesis of complementary (that is, base pairing) nucleotides and mechanisms for their mutual selection within a complex chemical environment have not been reported. Here we show that two plausible prebiotic heterocycles, melamine and barbituric acid, form glycosidic linkages with ribose and ...

  16. Mechanistic modelling of genetic and epigenetic events in radiation carcinogenesis

    International Nuclear Information System (INIS)

    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)

  17. Plausibility of stromal initiation of epithelial cancers without a mutation in the epithelium: a computer simulation of morphostats

    Directory of Open Access Journals (Sweden)

    Cappuccio Antonio

    2009-03-01

    Full Text Available Abstract Background There is experimental evidence from animal models favoring the notion that the disruption of interactions between stroma and epithelium plays an important role in the initiation of carcinogenesis. These disrupted interactions are hypothesized to be mediated by molecules, termed morphostats, which diffuse through the tissue to determine cell phenotype and maintain tissue architecture. Methods We developed a computer simulation based on simple properties of cell renewal and morphostats. Results Under the computer simulation, the disruption of the morphostat gradient in the stroma generated epithelial precursors of cancer without any mutation in the epithelium. Conclusion The model is consistent with the possibility that the accumulation of genetic and epigenetic changes found in tumors could arise after the formation of a founder population of aberrant cells, defined as cells that are created by low or insufficient morphostat levels and that no longer respond to morphostat concentrations. Because the model is biologically plausible, we hope that these results will stimulate further experiments.

  18. Mechanistic Studies of Vertebrate Hedgehog Signaling

    OpenAIRE

    Tukachinsky, Hanna

    2012-01-01

    Metazoans use Hedgehog signaling to direct many stages of embryonic development, and deregulation of this pathway is implicated in many types of cancer. I investigated several steps of Hedgehog pathway transduction that were poorly understood in mechanistic terms. The mature Hedgehog ligand is produced by a self-proteolysis reaction that covalently attaches a cholesterol molecule to the signaling half of the protein. I showed that the catalytic cysteine forms a disulfide bridge that is essent...

  19. New mechanistic model to simulate microalgae growth

    OpenAIRE

    Solimeno, Alessandro; Samsó Campà, Roger; Uggetti, Enrica; Sialve, Bruno; Steyer, J. P.; Gabarró, Adrián; García Serrano, Joan

    2015-01-01

    The prospect of treating wastewater and at the same time producing microalgae biomass is receiving increasing attention. Mechanistic models for microalgae growth in wastewater are currently being developed for new systems design as well as to improve the understanding of the involved biokinetic processes. However, mathematical models able to describe the complexity of microalgal cultures are still not a common practice. The aim of the present study is to present and calibrate a new mechanisti...

  20. A mechanistic analysis of the Birch Reduction.

    Science.gov (United States)

    Zimmerman, Howard E

    2012-02-21

    The Birch Reduction is one of the main reactions of organic chemistry. The reaction involves the reaction of dissolving metals in ammonia with aromatic compounds to produce 1,4-cyclohexadienes. Discovered by Arthur Birch in 1944, the reaction occupies 300 pages in Organic Reactions to describe its synthetic versatility. Thus, it is remarkable that the reaction mechanism has been so very controversial and only relatively recently has been firmly established. Perhaps this is not that surprising, since the reaction also has many unusual and esoteric mechanistic facets. Here, I provide a description of how I have applied ever-evolving levels of quantum mechanics and a novel experimental test to understand details of the mechanism and the origins of the selectivities observed in the Birch reduction. The reaction involves an initial radical anion resulting from introduction of an electron from the blue liquid ammonia solution of free electrons formed by the dissolution of Li or related metals. This radical anion is protonated by an alcohol and then further reduced to a carbanion. Finally, the carbanion is protonated using a second proton to afford a nonconjugated cyclohexadiene. The regiochemistry depends on substituents present. With 18 resonance structures in the case of anisole radical anion, prediction of the initial protonation site would seem difficult. Nevertheless, computational methods from Hückel theory through modern density functional calculations do correctly predict the site of protonation. An esoteric test established this mechanism experimentally. The nature of the carbanion also is of mechanistic interest, and the preponderance of the resonance structure shown was revealed from Hückel calculations involving variable bond orders. For the trianion from benzoic acid, parallel questions about structure are apparent, and have been answered. Some mechanistic questions are answered experimentally and some by modern computations. Recently, our mechanistic

  1. Plausibility and the Theoreticians' Regress: Constructing the evolutionary fate of stars

    Science.gov (United States)

    Ipe, Alex Ike

    2002-10-01

    This project presents a case-study of a scientific controversy that occurred in theoretical astrophysics nearly seventy years ago following the conceptual discovery of a novel phenomenon relating to the evolution and structure of stellar matter, known as the limiting mass. The ensuing debate between the author of the finding, Subrahmanyan Chandrasekhar and his primary critic, Arthur Stanley Eddington, witnessed both scientists trying to convince one another, as well as the astrophysical community, that their respective positions on the issue was the correct one. Since there was no independent criterion—that is, no observational evidence—at the time of the dispute that could have been drawn upon to test the validity of the limiting mass concept, a logical, objective resolution to the controversy was not possible. In this respect, I argue that the dynamics of the Chandrasekhar-Eddington debate succinctly resonates with Kennefick's notion of the Theoreticians' Regress. However, whereas this model predicts that such a regress can be broken if both parties in a dispute come to agree on who was in error and collaborate on a calculation whose technical foundation can be agreed to, I argue that a more pragmatic path by which the Theoreticians' Regress is broken is when one side in a dispute is able to construct its argument as being more plausible than that of its opponent, and is so successful in doing so, that its opposition is subsequently forced to withdraw from the debate. In order to adequately deal with the construction of plausibility in the context of scientific controversies, I draw upon Harvey's Plausibility Model as well as Pickering's work on the role socio-cultural factors play in the resolution of intellectual disputes. It is believed that the ideas embedded in these social- relativist-constructivist perspectives provide the most parsimonious explanation as to the reasons for the genesis and ultimate closure of this particular scientific controversy.

  2. Resolution of Cosmological Singularity and a Plausible Mechanism of the Big Bang

    OpenAIRE

    Choudhury, D. C.

    2001-01-01

    The initial cosmological singularity in the framework of the general theory of relativity is resolved by introducing the effect of the uncertainty principle of quantum theory without violating conventional laws of physics. A plausible account of the mechanism of the big bang, analogous to that of a nuclear explosion, is given and the currently accepted Planck temperature of about 10^(32)K at the beginning of the big bang is predicted. Subj-class: cosmology: theory-pre-big bang; mechanism of t...

  3. Exploring discrepancies between quantitative validation results and the geomorphic plausibility of statistical landslide susceptibility maps

    Science.gov (United States)

    Steger, Stefan; Brenning, Alexander; Bell, Rainer; Petschko, Helene; Glade, Thomas

    2016-06-01

    Empirical models are frequently applied to produce landslide susceptibility maps for large areas. Subsequent quantitative validation results are routinely used as the primary criteria to infer the validity and applicability of the final maps or to select one of several models. This study hypothesizes that such direct deductions can be misleading. The main objective was to explore discrepancies between the predictive performance of a landslide susceptibility model and the geomorphic plausibility of subsequent landslide susceptibility maps while a particular emphasis was placed on the influence of incomplete landslide inventories on modelling and validation results. The study was conducted within the Flysch Zone of Lower Austria (1,354 km2) which is known to be highly susceptible to landslides of the slide-type movement. Sixteen susceptibility models were generated by applying two statistical classifiers (logistic regression and generalized additive model) and two machine learning techniques (random forest and support vector machine) separately for two landslide inventories of differing completeness and two predictor sets. The results were validated quantitatively by estimating the area under the receiver operating characteristic curve (AUROC) with single holdout and spatial cross-validation technique. The heuristic evaluation of the geomorphic plausibility of the final results was supported by findings of an exploratory data analysis, an estimation of odds ratios and an evaluation of the spatial structure of the final maps. The results showed that maps generated by different inventories, classifiers and predictors appeared differently while holdout validation revealed similar high predictive performances. Spatial cross-validation proved useful to expose spatially varying inconsistencies of the modelling results while additionally providing evidence for slightly overfitted machine learning-based models. However, the highest predictive performances were obtained for

  4. Higher Data Quality by Online Data-Entry and Automated Plausibility Checks

    Science.gov (United States)

    Pietragalla, Barbara; Sigg, Christian; Güsewell, Sabine; Clot, Bernard

    2014-05-01

    Long-term phenological observations are now recognized as important indicators for climate change impact studies. With the increased need for phenological data, there is also an increased need for higher data quality. Since 1951 MeteoSwiss has been operating a national phenological observation network. Currently the network consists of about 150 active stations observing up to 69 different phenophases. An important aim of a running three years project at MeteoSwiss is a further increase of the quality of the collected data. The higher data quality will be achieved by an automated procedure performing plausibility checks on the data and by online data-entry. Further measures such as intensified observer instructions and collection of more detailed metadata also contribute to a high data quality standard. The plausibility checks include the natural order of the phenophases within a species and also between different species (with regard to possible natural deviation). Additionally it will be checked if the observed date differs by less than two standard deviations from the average for this phenophase at the altitude of the station. A value outside of these limits is not necessarily a false value, since occurrences of extreme values will be beyond these limits. Therefore, within this check of the limits, the timing of the season of the respective year will also be taken into account. In case of an implausible value a comparison with other stations of the same region and sea level is proposed. A further possibility of data quality control could be to model the different phenophases statistically and to use this model for estimating the likelihood of observed values. An overall exploratory data analysis is currently performed providing a solid basis to implement the best possible methods for the plausibility checks. Important advantages of online data-entry are the near real-time availability of the data as well as the avoidance of various kinds of typical mistakes

  5. Emergent structured transition from variation to repetition in a biologically-plausible model of learning in basal ganglia.

    Directory of Open Access Journals (Sweden)

    AshvinShah

    2014-02-01

    Full Text Available Often, when animals encounter an unexpected sensory event, they transition from executing a variety of movements to repeating the movement(s that may have caused the event. According to a recent theory of action discovery (Redgrave and Gurney 2006, repetition allows the animal to represent those movements, and the outcome, as an action for later recruitment. The transition from variation to repetition often follows a non-random, structured, pattern. While the structure of the pattern can be explained by sophisticated cognitive mechanisms, simpler mechanisms based on dopaminergic modulation of basal ganglia (BG activity are thought to underlie action discovery (Redgrave and Gurney 2006. In this paper we ask the question: can simple BG-mediated mechanisms account for a structured transition from variation to repetition, or are more sophisticated cognitive mechanisms always necessary?To address this question, we present a computational model of BG-mediated biasing of behavior. In our model, unlike most other models of BG function, the BG biases behaviour through modulation of cortical response to excitation; many possible movements are represented by the cortical area; and excitation to the cortical area is topographically-organized. We subject the model to simple reaching tasks, inspired by behavioral studies, in which a location to which to reach must be selected. Locations within a target area elicit a reinforcement signal. A structured transition from variation to repetition emerges from simple BG-mediated biasing of cortical response to excitation. We show how the structured pattern influences behavior in simple and complicated tasks. We also present analyses that describe the structured transition from variation to repetition due to BG-mediated biasing and from biasing that would be expected from a type of cognitive biasing, allowing us to compare behaviour resulting from these types of biasing and make connections with future behavioural experiments.

  6. Gene ontology enrichment analysis in two independent family-based samples highlights biologically plausible processes for autism spectrum disorders

    OpenAIRE

    Anney, Richard JL; Heron, Elizabeth A; Segurado, Ricardo; Kenny, Elaine M.; O'Dushlaine, Colm; Yaspan, Brian L.; Parkhomenko, Elena; Autism Genome Project, The; Buxbaum, Joseph,; Sutcliffe, James S; Gill, Micheal; Gallagher, Louise

    2011-01-01

    We gratefully acknowledge the families participating in the study and the main funders of the AGP: Autism Speaks (USA), the Health Research Board (HRB, Ireland; AUT/2006/1, AUT/2006/2, PD/2006/48), The Medical Research Council (MRC, UK), Genome Canada/Ontario Genomics Institute and the Hilibrand Foundation (USA). Additional support for individual groups was provided by the US National Institutes of Health (NIH Grants: HD055751, HD055782, HD055784, MH52708, MH55284, MH061009,...

  7. Morality Principles for Risk Modelling: Needs and Links with the Origins of Plausible Inference

    Science.gov (United States)

    Solana-Ortega, Alberto; Solana, Vicente

    2009-12-01

    In comparison with the foundations of probability calculus, the inescapable and controversial issue of how to assign probabilities has only recently become a matter of formal study. The introduction of information as a technical concept was a milestone, but the most promising entropic assignment methods still face unsolved difficulties, manifesting the incompleteness of plausible inference theory. In this paper we examine the situation faced by risk analysts in the critical field of extreme events modelling, where the former difficulties are especially visible, due to scarcity of observational data, the large impact of these phenomena and the obligation to assume professional responsibilities. To respond to the claim for a sound framework to deal with extremes, we propose a metafoundational approach to inference, based on a canon of extramathematical requirements. We highlight their strong moral content, and show how this emphasis in morality, far from being new, is connected with the historic origins of plausible inference. Special attention is paid to the contributions of Caramuel, a contemporary of Pascal, unfortunately ignored in the usual mathematical accounts of probability.

  8. Neural correlates of early-closure garden-path processing: Effects of prosody and plausibility.

    Science.gov (United States)

    den Ouden, Dirk-Bart; Dickey, Michael Walsh; Anderson, Catherine; Christianson, Kiel

    2016-01-01

    Functional magnetic resonance imaging (fMRI) was used to investigate neural correlates of early-closure garden-path sentence processing and use of extrasyntactic information to resolve temporary syntactic ambiguities. Sixteen participants performed an auditory picture verification task on sentences presented with natural versus flat intonation. Stimuli included sentences in which the garden-path interpretation was plausible, implausible because of a late pragmatic cue, or implausible because of a semantic mismatch between an optionally transitive verb and the following noun. Natural sentence intonation was correlated with left-hemisphere temporal activation, but also with activation that suggests the allocation of more resources to interpretation when natural prosody is provided. Garden-path processing was associated with upregulation in bilateral inferior parietal and right-hemisphere dorsolateral prefrontal and inferior frontal cortex, while differences between the strength and type of plausibility cues were also reflected in activation patterns. Region of interest (ROI) analyses in regions associated with complex syntactic processing are consistent with a role for posterior temporal cortex supporting access to verb argument structure. Furthermore, ROI analyses within left-hemisphere inferior frontal gyrus suggest a division of labour, with the anterior-ventral part primarily involved in syntactic-semantic mismatch detection, the central part supporting structural reanalysis, and the posterior-dorsal part showing a general structural complexity effect. PMID:25801097

  9. Climate dynamics in deep time: Modeling the [snowball bifurcation] and assessing the plausibility of its occurrence

    Science.gov (United States)

    Peltier, W. R.; Tarasov, L.; Vettoretti, G.; Solheim, L. P.

    The apparently global scale glaciation events that occurred during the Neoproterozoic era, in the interval from 750 Ma to 550 Ma, represent a significant challenge to our understanding of climate system behavior. If these episodes of glaciation were truly of "snowball" type, with the continents covered by thick ice-sheets and the oceans entirely capped by sea ice, then special pleading is required to understand the Cambrian explosion of life that occurred subsequently. Detailed models of Neoproterozoic climate, however, suggest the plausibility of preference for "equatorial refugium" or "oasis" solutions in which significant regions of open water are able to persist at the equator. We describe further analyses of such solutions in this paper, using both simple EBM coupled ice sheet models and fully articulated atmosphere-ocean-sea ice coupled models of climate evolution. Recently published analyses of the dynamics of the Neoproterozoic carbon cycle, taken together with the predictions of the models discussed herein, are strongly supportive of the equatorial refugium solutions as the most plausible form of the Neoproterozoic cooling events.

  10. Assembly line polyketide synthases: mechanistic insights and unsolved problems.

    Science.gov (United States)

    Khosla, Chaitan; Herschlag, Daniel; Cane, David E; Walsh, Christopher T

    2014-05-13

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

  11. Causation at Different Levels: Tracking the Commitments of Mechanistic Explanations

    DEFF Research Database (Denmark)

    Fazekas, Peter; Kertész, Gergely

    2011-01-01

    This paper tracks the commitments of mechanistic explanations focusing on the relation between activities at different levels. It is pointed out that the mechanistic approach is inherently committed to identifying causal connections at higher levels with causal connections at lower levels. For the...... connections transparent. These general commitments get confronted with two claims made by certain proponents of the mechanistic approach: William Bechtel often argues that within the mechanistic framework it is possible to balance between reducing higher levels and maintaining their autonomy at the same time......, whereas, in a recent paper, Craver and Bechtel argue that the mechanistic approach is able to make downward causation intelligible. The paper concludes that the mechanistic approach imbued with identity statements is no better candidate for anchoring higher levels to lower ones while maintaining their...

  12. The supernova remnant W51C: a plausible source of galactic cosmic rays?

    Science.gov (United States)

    Gozzini, S. R.; Carmona, E.; Jankowski, F.; Krause, J.; Reichardt, I.; MAGIC Collaboration

    2013-02-01

    Supernova remnants are a probable site of acceleration of particles via diffusive shock processes. High energies carried by electrons or protons are radiated into photons detectable from radio to γ rays. MAGIC has recently observed W51C, one of the most luminous galactic supernova remnants, and completed its spectrum between 50 GeV and 5 TeV. We modelled different processes for high energy photon emission of this source, and compared the predictions with the measured spectral energy distribution. It is plausible that hadrons are accelerated in the expansion front of this source, in interaction with the surrounding molecular cloud, and photons are produced in the decay of neutral mesons created in hadronic collisions.

  13. Signature of Plausible Accreting Supermassive Black Holes in Mrk 261/262 and Mrk 266

    Directory of Open Access Journals (Sweden)

    Gagik Ter-Kazarian

    2013-01-01

    Full Text Available We address the neutrino radiation of plausible accreting supermassive black holes closely linking to the 5 nuclear components of galaxy samples of Mrk 261/262 and Mrk 266. We predict a time delay before neutrino emission of the same scale as the age of the Universe. The ultrahigh energy neutrinos are produced in superdense protomatter medium via simple (quark or pionic reactions or modified URCA processes (G. Gamow was inspired to name the process URCA after the name of a casino in Rio de Janeiro. The resulting neutrino fluxes for quark reactions are ranging from to , where is the opening parameter. For pionic and modified URCA reactions, the fluxes are and , respectively. These fluxes are highly beamed along the plane of accretion disk, peaked at ultrahigh energies, and collimated in smaller opening angle .

  14. Quantum theory as plausible reasoning applied to data obtained by robust experiments.

    Science.gov (United States)

    De Raedt, H; Katsnelson, M I; Michielsen, K

    2016-05-28

    We review recent work that employs the framework of logical inference to establish a bridge between data gathered through experiments and their objective description in terms of human-made concepts. It is shown that logical inference applied to experiments for which the observed events are independent and for which the frequency distribution of these events is robust with respect to small changes of the conditions under which the experiments are carried out yields, without introducing any concept of quantum theory, the quantum theoretical description in terms of the Schrödinger or the Pauli equation, the Stern-Gerlach or Einstein-Podolsky-Rosen-Bohm experiments. The extraordinary descriptive power of quantum theory then follows from the fact that it is plausible reasoning, that is common sense, applied to reproducible and robust experimental data. PMID:27091169

  15. Oxidation of cefazolin by potassium permanganate: Transformation products and plausible pathways.

    Science.gov (United States)

    Li, Liping; Wei, Dongbin; Wei, Guohua; Du, Yuguo

    2016-04-01

    Cefazolin was demonstrated to exert high reactivity toward permanganate (Mn(VII)), a common oxidant in water pre-oxidation treatment. In this study, five transformation products were found to be classified into three categories according to the contained characteristic functional groups: three (di-)sulfoxide products, one sulfone product and one di-ketone product. Products analyses showed that two kinds of reactions including oxidation of thioether and the cleavage of unsaturated CC double bond occurred during transformation of cefazolin by Mn(VII). Subsequently, the plausible transformation pathways under different pH conditions were proposed based on the identified products and chemical reaction principles. More importantly, the simulation with real surface water matrix indicated that the proposed transformation pathways of cefazolin could be replayed in real water treatment practices. PMID:26872071

  16. A simple plausible path from QCD to successful prediction of e+e-→hadronization data

    International Nuclear Information System (INIS)

    We find a remarkably simple path emerging which begins with QCD and endswith rather accurate predictions of detailed hadronic production data (flavors, distributions, correlations) in electron-positron interactions, the cleanest situation in which to study such hadronization phenomena. This path involves relatively few significant parameters and many plausible physical ideas. The predictions are especially clean (only two 'natural' parameters and no 'ad hoc' ones) and accurate for the production of various flavored light-quark mesons, the most fundamental and elementary tests of color-field behavior. This appears to improve our understanding of the physics of the meson formation process and forms a foundation for further development of other more complex areas (e.g., baryon production, PT effects) which we currently predict adequately, but where we must employ a small number of 'ad hoc' parameters. The physics of our approach resembles that of a relativistic string and, in fact, historically is a spin-off from the very successful Lund modeling. However, our model's conceptual basis represents a paradigm shift away from emphasizing intermediate stages in an event and toward an emphasis on the total transition from the e+e- initial state to the entire set of final state hadrons. The model's central feature is a simple event weight function incorporating a QCD-motivated space-time area law which, on the one hand, leads with very few assumptions to predictions agreeing remarkably well with e+e-→hadronization data, and, on the other hand, can also be plausibly related to strong-coupling soft QCD and can form a 'target' for non-perturbative calculational approaches. Our approach avoids most of the parameters employed by traditional relativistic string models. (orig.)

  17. 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

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

    Science.gov (United States)

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

    2015-01-01

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

  19. Mechanistic and Correlative Models of Ecological Niches

    Directory of Open Access Journals (Sweden)

    Peterson A. Townsend

    2015-12-01

    Full Text Available The suite of factors that drives where and under what conditions a species occurs has become the focus of intense research interest. Three general categories of methods have emerged by which researchers address questions in this area: mechanistic models of species’ requirements in terms of environmental conditions that are based on first principles of biophysics and physiology, correlational models based on environmental associations derived from analyses of geographic occurrences of species, and process-based simulations that estimate occupied distributional areas and associated environments from assumptions about niche dimensions and dispersal abilities. We review strengths and weaknesses of these sets of approaches, and identify significant advantages and disadvantages of each. Rather than identifying one or the other as ‘better,’ we suggest that researchers take great care to use the method best-suited to each specific research question, and be conscious of the weaknesses of any method, such that inappropriate interpretations are avoided.

  20. Reaction Coordinates and Mechanistic Hypothesis Tests.

    Science.gov (United States)

    Peters, Baron

    2016-05-27

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

  1. 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.

  2. Mechanistic modeling of aberrant energy metabolism in human disease

    Directory of Open Access Journals (Sweden)

    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.

  3. 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. PMID:22161351

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

    Science.gov (United States)

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

    2013-11-01

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

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

    Science.gov (United States)

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

    2012-12-01

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

  6. 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

  7. Plausible ergogenic effects of vitamin D on athletic performance and recovery.

    Science.gov (United States)

    Dahlquist, Dylan T; Dieter, Brad P; Koehle, Michael S

    2015-01-01

    The purpose of this review is to examine vitamin D in the context of sport nutrition and its potential role in optimizing athletic performance. Vitamin D receptors (VDR) and vitamin D response elements (VDREs) are located in almost every tissue within the human body including skeletal muscle. The hormonally-active form of vitamin D, 1,25-dihydroxyvitamin D, has been shown to play critical roles in the human body and regulates over 900 gene variants. Based on the literature presented, it is plausible that vitamin D levels above the normal reference range (up to 100 nmol/L) might increase skeletal muscle function, decrease recovery time from training, increase both force and power production, and increase testosterone production, each of which could potentiate athletic performance. Therefore, maintaining higher levels of vitamin D could prove beneficial for athletic performance. Despite this situation, large portions of athletic populations are vitamin D deficient. Currently, the research is inconclusive with regards to the optimal intake of vitamin D, the specific forms of vitamin D one should ingest, and the distinct nutrient-nutrient interactions of vitamin D with vitamin K that affect arterial calcification and hypervitaminosis. Furthermore, it is possible that dosages exceeding the recommendations for vitamin D (i.e. dosages up to 4000-5000 IU/day), in combination with 50 to 1000 mcg/day of vitamin K1 and K2 could aid athletic performance. This review will investigate these topics, and specifically their relevance to athletic performance. PMID:26288575

  8. From ether to acid: A plausible degradation pathway of glycerol dialkyl glycerol tetraethers

    Science.gov (United States)

    Liu, Xiao-Lei; Birgel, Daniel; Elling, Felix J.; Sutton, Paul A.; Lipp, Julius S.; Zhu, Rong; Zhang, Chuanlun; Könneke, Martin; Peckmann, Jörn; Rowland, Steven J.; Summons, Roger E.; Hinrichs, Kai-Uwe

    2016-06-01

    Glycerol dialkyl glycerol tetraethers (GDGTs) are ubiquitous microbial lipids with extensive demonstrated and potential roles as paleoenvironmental proxies. Despite the great attention they receive, comparatively little is known regarding their diagenetic fate. Putative degradation products of GDGTs, identified as hydroxyl and carboxyl derivatives, were detected in lipid extracts of marine sediment, seep carbonate, hot spring sediment and cells of the marine thaumarchaeon Nitrosopumilus maritimus. The distribution of GDGT degradation products in environmental samples suggests that both biotic and abiotic processes act as sinks for GDGTs. More than a hundred newly recognized degradation products afford a view of the stepwise degradation of GDGT via (1) ether bond hydrolysis yielding hydroxyl isoprenoids, namely, GDGTol (glycerol dialkyl glycerol triether alcohol), GMGD (glycerol monobiphytanyl glycerol diether), GDD (glycerol dibiphytanol diether), GMM (glycerol monobiphytanol monoether) and bpdiol (biphytanic diol); (2) oxidation of isoprenoidal alcohols into corresponding carboxyl derivatives and (3) chain shortening to yield C39 and smaller isoprenoids. This plausible GDGT degradation pathway from glycerol ethers to isoprenoidal fatty acids provides the link to commonly detected head-to-head linked long chain isoprenoidal hydrocarbons in petroleum and sediment samples. The problematic C80 to C82 tetraacids that cause naphthenate deposits in some oil production facilities can be generated from H-shaped glycerol monoalkyl glycerol tetraethers (GMGTs) following the same process, as indicated by the distribution of related derivatives in hydrothermally influenced sediments.

  9. Plausible impact of global climate change on water resources in the Tarim River Basin

    Institute of Scientific and Technical Information of China (English)

    CHEN Yaning; XU Zongxue

    2005-01-01

    Combining the temperature and precipitation data from 77 climatological stations and the climatic and hydrological change data from three headstreams of the Tarim River: Hotan, Yarkant, and Aksu in the study area, the plausible association between climate change and the variability of water resources in the Tarim River Basin in recent years was investigated, the long-term trend of the hydrological time series including temperature, precipitation, and streamflow was detected, and the possible association between the El Ni(n)o/Southern Oscillation (ENSO) and these three kinds of time series was tested. The results obtained in this study show that during the past years, the temperature experienced a significant monotonic increase at the speed of 5%, nearly 1℃ rise; the precipitation showed a significant decrease in the 1970s, and a significant increase in the1980s and 1990s, the average annual precipitation was increased with the magnitude of 6.8 mm per decade. A step change occurred in both temperature and precipitation time series around 1986, which may be influenced by the global climate change. Climate change resulted in the increase of the streamflow at the headwater of the Tarim River, but the anthropogenic activities such as over-depletion of the surface water resulted in the decrease of the streamflow at the lower reaches of the Tarim River. The study result also showed that there is no significant association between the ENSO and the temperature, precipitation and streamflow.

  10. A plausible mechanism of biosorption in dual symbioses by vesicular-arbuscular mycorrhizal in plants.

    Science.gov (United States)

    Azmat, Rafia; Hamid, Neelofer

    2015-03-01

    Dual symbioses of vesicular-arbuscular mycorrhizal (VAM) fungi with growth of Momordica charantia were elucidated in terms of plausible mechanism of biosorption in this article. The experiment was conducted in green house and mixed inoculum of the VAM fungi was used in the three replicates. Results demonstrated that the starch contents were the main source of C for the VAM to builds their hyphae. The increased plant height and leaves surface area were explained in relation with an increase in the photosynthetic rates to produce rapid sugar contents for the survival of plants. A decreased in protein, and amino acid contents and increased proline and protease activity in VAM plants suggested that these contents were the main bio-indicators of the plants under biotic stress. The decline in protein may be due to the degradation of these contents, which later on converted into dextrose where it can easily be absorbed by for the period of symbioses. A mechanism of C chemisorption in relation with physiology and morphology of plant was discussed. PMID:25730809

  11. Somatodendritic dopamine release: recent mechanistic insights.

    Science.gov (United States)

    Rice, Margaret E; Patel, Jyoti C

    2015-07-01

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

  12. Structural and mechanistic insights on nitrate reductases.

    Science.gov (United States)

    Coelho, Catarina; Romão, Maria João

    2015-12-01

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

  13. The chemical biology of sirtuins.

    Science.gov (United States)

    Chen, Bing; Zang, Wenwen; Wang, Juan; Huang, Yajun; He, Yanhua; Yan, Lingling; Liu, Jiajia; Zheng, Weiping

    2015-08-01

    The sirtuin family of enzymes are able to catalyze the N(ε)-acyl-lysine deacylation reaction on histone and non-histone protein substrates. Over the past years since the discovery of its founding member (i.e. the yeast silent information regulator 2 (sir2) protein) in 2000, the sirtuin-catalyzed deacylation reaction has been demonstrated to play an important regulatory role in multiple crucial cellular processes such as transcription, DNA damage repair, and metabolism. This reaction has also been regarded as a current therapeutic target for human diseases such as cancer, and metabolic and neurodegenerative diseases. The unique β-nicotinamide adenine dinucleotide (β-NAD(+) or NAD(+))-dependent nature of the sirtuin-catalyzed deacylation reaction has also engendered extensive mechanistic studies, resulting in a mechanistic view of the enzyme chemistry supported by several lines of experimental evidence. On the journey toward these knowledge advances, chemical biological means have constituted an important functional arsenal; technically, a variety of chemical probes and modulators (inhibitors and activators) have been developed and some of them have been employed toward an enhanced mechanistic and functional (pharmacological) understanding of the sirtuin-catalyzed deacylation reaction. On the other hand, an enhanced mechanistic understanding has also facilitated the development of a variety of chemical probes and modulators. This article will review the tremendous accomplishments achieved during the past few years in the field of sirtuin chemical biology. It is hoped that this would also help to set a stage for how outstanding mechanistic and functional questions for the sirtuin-catalyzed deacylation reaction could be addressed in the future from the chemical biology perspective. PMID:25955411

  14. Identifying plausible adverse drug reactions using knowledge extracted from the literature.

    Science.gov (United States)

    Shang, Ning; Xu, Hua; Rindflesch, Thomas C; Cohen, Trevor

    2014-12-01

    Pharmacovigilance involves continually monitoring drug safety after drugs are put to market. To aid this process; algorithms for the identification of strongly correlated drug/adverse drug reaction (ADR) pairs from data sources such as adverse event reporting systems or Electronic Health Records have been developed. These methods are generally statistical in nature, and do not draw upon the large volumes of knowledge embedded in the biomedical literature. In this paper, we investigate the ability of scalable Literature Based Discovery (LBD) methods to identify side effects of pharmaceutical agents. The advantage of LBD methods is that they can provide evidence from the literature to support the plausibility of a drug/ADR association, thereby assisting human review to validate the signal, which is an essential component of pharmacovigilance. To do so, we draw upon vast repositories of knowledge that has been extracted from the biomedical literature by two Natural Language Processing tools, MetaMap and SemRep. We evaluate two LBD methods that scale comfortably to the volume of knowledge available in these repositories. Specifically, we evaluate Reflective Random Indexing (RRI), a model based on concept-level co-occurrence, and Predication-based Semantic Indexing (PSI), a model that encodes the nature of the relationship between concepts to support reasoning analogically about drug-effect relationships. An evaluation set was constructed from the Side Effect Resource 2 (SIDER2), which contains known drug/ADR relations, and models were evaluated for their ability to "rediscover" these relations. In this paper, we demonstrate that both RRI and PSI can recover known drug-adverse event associations. However, PSI performed better overall, and has the additional advantage of being able to recover the literature underlying the reasoning pathways it used to make its predictions. PMID:25046831

  15. Climate change impacts on agriculture in 2050 under a range of plausible socioeconomic and emissions scenarios

    International Nuclear Information System (INIS)

    Previous studies have combined climate, crop and economic models to examine the impact of climate change on agricultural production and food security, but results have varied widely due to differences in models, scenarios and input data. Recent work has examined (and narrowed) these differences through systematic model intercomparison using a high-emissions pathway to highlight the differences. This paper extends that analysis to explore a range of plausible socioeconomic scenarios and emission pathways. Results from multiple climate and economic models are combined to examine the global and regional impacts of climate change on agricultural yields, area, production, consumption, prices and trade for coarse grains, rice, wheat, oilseeds and sugar crops to 2050. We find that climate impacts on global average yields, area, production and consumption are similar across shared socioeconomic pathways (SSP 1, 2 and 3, as we implement them based on population, income and productivity drivers), except when changes in trade policies are included. Impacts on trade and prices are higher for SSP 3 than SSP 2, and higher for SSP 2 than for SSP 1. Climate impacts for all variables are similar across low to moderate emissions pathways (RCP 4.5 and RCP 6.0), but increase for a higher emissions pathway (RCP 8.5). It is important to note that these global averages may hide regional variations. Projected reductions in agricultural yields due to climate change by 2050 are larger for some crops than those estimated for the past half century, but smaller than projected increases to 2050 due to rising demand and intrinsic productivity growth. Results illustrate the sensitivity of climate change impacts to differences in socioeconomic and emissions pathways. Yield impacts increase at high emissions levels and vary with changes in population, income and technology, but are reduced in all cases by endogenous changes in prices and other variables. (paper)

  16. Multiple Solutions to the Same Problem: Utilization of Plausibility and Syntax in Sentence Comprehension by Older Adults with Impaired Hearing

    Science.gov (United States)

    Amichetti, Nicole M.; White, Alison G.; Wingfield, Arthur

    2016-01-01

    A fundamental question in psycholinguistic theory is whether equivalent success in sentence comprehension may come about by different underlying operations. Of special interest is whether adult aging, especially when accompanied by reduced hearing acuity, may shift the balance of reliance on formal syntax vs. plausibility in determining sentence meaning. In two experiments participants were asked to identify the thematic roles in grammatical sentences that contained either plausible or implausible semantic relations. Comprehension of sentence meanings was indexed by the ability to correctly name the agent or the recipient of an action represented in the sentence. In Experiment 1 young and older adults’ comprehension was tested for plausible and implausible sentences with the meaning expressed with either an active-declarative or a passive syntactic form. In Experiment 2 comprehension performance was examined for young adults with age-normal hearing, older adults with good hearing acuity, and age-matched older adults with mild-to-moderate hearing loss for plausible or implausible sentences with meaning expressed with either a subject-relative (SR) or an object-relative (OR) syntactic structure. Experiment 1 showed that the likelihood of interpreting a sentence according to its literal meaning was reduced when that meaning expressed an implausible relationship. Experiment 2 showed that this likelihood was further decreased for OR as compared to SR sentences, and especially so for older adults whose hearing impairment added to the perceptual challenge. Experiment 2 also showed that working memory capacity as measured with a letter-number sequencing task contributed to the likelihood that listeners would base their comprehension responses on the literal syntax even when this processing scheme yielded an implausible meaning. Taken together, the results of both experiments support the postulate that listeners may use more than a single uniform processing strategy for

  17. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Shubha, Jayachamarajapura Pranesh; Kotabagi, Vinutha [Bosco Institute of Technology, Bangalore (India); Puttaswamy [Bangalore Univ., Bangalore (India)

    2012-11-15

    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{sub 4} medium at 303 K in order to explore this redox system mechanistic chemistry. The rate shows a first-order dependence on both [CAB]{sub o}, and [substrate]{sub 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.

  19. 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.

  20. CuH-Catalysed Hydroamination of Styrene with Hydroxylamine Esters: A Coupled Cluster Scrutiny of Mechanistic Pathways.

    Science.gov (United States)

    Tobisch, Sven

    2016-06-01

    A detailed computational exploration of mechanistic intricacies of the copper(I) hydride (CuH)-catalysed hydroamination of styrene with a prototype hydroxylamine ester by a recently reported [(dppbz)CuH] catalyst (dppbz≡{P^P}≡1,2-bis(diphenylphosphino)-benzene) is presented. A variety of plausible mechanistic avenues have been pursued by means of a sophisticated computational methodology, from which a general understanding of the factors controlling hydroamination catalysis emerged. The catalytically competent {P^P}Cu(I) hydride, which is predominantly present as its dimer, involves in irreversible hydrocupration proceeding with complete 2,1 regioselectivity to form a secondary {P^P}Cu(I) benzyl intermediate. Its interception with benzylamine ester produces the branched tertiary amine product and {P^P}Cu(I) benzoate upon intramolecular SN 2 disruption of the amine electrophile's N-O linkage, to precede a highly rapid, strongly exergonic C-N bond-forming reductive elimination. The {P^P}Cu(I) benzoate corresponds to the catalyst resting state and its conversion back into the {P^P}Cu(I) hydride upon transmetalation with a hydrosilane is turnover limiting. The effect of electronic perturbations at the amine electrophile upon the reaction rate for productive hydroamination catalysis and also non-productive reduction of the hydroxylamine ester has been gauged, which unveiled a more fundamental insight into catalytic structure-performance relationships. PMID:27138470

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

    OpenAIRE

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

    2010-01-01

    The structure and mechanism of diisopropyl fluorophosphatase (DFPase) have been studied using a variety of methods, including isotopic labelling, X-ray crystallography and neutron crystallography. The neutron structure of DFPase, mechanistic studies and subsequent rational design efforts are described.

  2. Lead-induced SCC of alloy 600 in plausible steam generator crevice environments

    International Nuclear Information System (INIS)

    Laboratory stress corrosion cracking (SCC) test environments developed to simulate representative BNGS-A steam generator (SG) crevice chemistries have been used to determine the susceptibility of Alloy 600 to lead-induced SCC under plausible SG conditions. Test environments were based on plant SG hideout return data and analysis of removed tubes and deposits. Deviations from the normal near neutral crevice pH environment were considered to simulate possible faulted excursion crevice chemistry and to bound the postulated crevice pH range of 3-9 (at temperature). The effect of lead contamination up to 1000 ppm, but with an emphasis on the 100 to 500 ppm range, was determined. SCC susceptibility was investigated using constant extension rate tensile (CERT) tests and encapsulated C-ring tests. CERT tests were performed at 305 degrees C on tubing representative of BNGS-A SG U-bends. The C-ring test method allowed a wider test matrix covering three temperatures (280, 304 and 315 degrees C), three strain levels (0.2%, 2% and 4%) and tubing representative of U-bends plus tubing given a simulated stress relief to represent material at the tubesheet. The results of this test program confirmed that in the absence of lead contamination, cracking does not occur in these concentrated, 3.3 to 8.9 pH range, crevice environments. Also, it appears that the concentrated crevice environments suppress lead-induced cracking relative to that seen in all-volatile-treatment (AVT) water. For the (static) C-ring tests, lead-induced SCC was only produced in the near-neutral crevice environment and was more severe at 500 ppm than 100 ppm PbO. This trend was also observed in CERT tests but some cracking/grain boundary attack occurred in acidic (pH 3.3) and alkaline (pH 8.9) environments. The C-ring tests indicated that a certain amount of resistance to cracking was imparted by simulated stress relief of the tubing. This heat treatment, confirmed to have resulted in sensitization, promoted

  3. Plausibility check of a redesigned rain-on-snow simulator (RASA)

    Science.gov (United States)

    Rössler, Ole; Probst, Sabine; Weingartner, Rolf

    2016-04-01

    Rain-on-snow events are fascinating but still not completely understood processes. Although, several studies and equations have been published since decades that describe past events and theoretical descriptions, empirical data of what is happening in the snow cover is far less available. A way to fill this gap of empirical data, rain-on-snow-simulators might be of help. In 2013, Juras et al. published their inspiring idea of a portable rain-on-snow simulator. The huge advantage of this devise - in contrast to other purely field-based experiments - are their fixed, and mostly standardized conditions and the possibility to measure all required data to monitor the water fluxes and melting processes at a time. Mounted in a convenient location, a large number of experiments are relatively easy conductible. We applied and further developed the original device and plausified the results of this redesigned version, called RASA. The principal design was borrowed from the original version being a frame with a sprinkler on top and a snow sample in a box at the bottom, from which the outflow is measured with a tipping gauge. We added a moving sprinkling plate to ensure a uniform distribution of raindrops on the snow, and - most importantly - we suspended the watered snow sampled on weighting cells. The latter enables to continuous measurement of the snow sample throughout the experiment and thus the indirect quantification of liquid water saturation, water holding capacity, and snowmelt amount via balance equations. As it is remains unclear if this device is capable to reproduce known processes, a hypothesis based plausibility check was accomplished. Thus, eight hypothesizes were derived from literature and tested in 28 experiments with the RASA mounted at 2000 m elevation. In general, we were able to reproduce most of the hypotheses. The RASA proved to be a very valuable device that can generate suitable results and has the potential to extend the empirical-experimental data

  4. Lead-induced stress-corrosion cracking of alloy 600 in plausible steam generator crevice environments

    International Nuclear Information System (INIS)

    Laboratory stress-corrosion cracking (SCC) test environments were developed to simulate crevice chemistries representative of Bruce Nuclear Generating Station A (BNPD A) steam generators (SGs); these test environments were used to determine the susceptibility of Alloy 600 to lead-induced SCC under plausible SG conditions. Test environments were based on plant SG hideout return data and analysis of removed tubes and deposits. Deviations from the normal near-neutral crevice pH environment were considered to simulate possible faulted excursion crevice chemistry and to bound the postulated crevice pH range of 3 to 9 (at temperature). The effect of lead contamination up to 1000 ppm, but with an emphasis on the 100- to 500-ppm range, was determined. SCC susceptibility was investigated using constant extension rate tensile (CERT) tests and encapsulated C-ring tests. CERT tests were performed at 305 degrees C on tubing representative of BNPD A SG U-bends. The C-ring test method allowed a wider test matrix, covering 3 temperatures (280 degrees C, 304 degrees C and 315 degrees C), 3 strain levels (0.2%, 2% and 4%), and tubing representative of U-bends plus tubing given a simulated stress relief to represent material at the tube sheet. The results of this test program confirmed that in the absence of lead contamination, cracking does not occur in these concentrated, 3.3 to 8.9 pH range, crevice environments. Also, it appears that the concentrated crevice environments suppress lead-induced cracking relative to that seen in all-volatile-treatment (AVT) water. For the (static) C-ring tests, lead-induced SCC was only produced in the near-neutral crevice environment and was more severe at 500 ppm than at 100 ppm PbO. This trend was also observed in CERT tests, but some cracking-grain boundary attack occurred in acidic (pH 3.3) and alkaline (pH 8.9) environments. The C-ring tests indicated that a certain amount of resistance to cracking was imparted by simulated stress relief of

  5. New web-based applications for mechanistic case diagramming

    OpenAIRE

    Fred R. Dee; Haugen, Thomas H.; Clarence D. Kreiter

    2014-01-01

    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 etio...

  6. A Comparison of Plausibility Conflict and of Degree of Conflict Based on Amount of Uncertainty of Belief Functions

    Czech Academy of Sciences Publication Activity Database

    Daniel, Milan

    Cham: Springer, 2015 - (Destercke, S.; Denoeux, T.), s. 440-450. (Lecture Notes in Artificial Intelligence. 9161,). ISBN 978-3-319-20806-0. ISSN 0302-9743. [ECSQARU 2015. European Conference /13./. Compiegne (FR), 15.07.2015-17.07.2015] Institutional support: RVO:67985807 Keywords : belief function * Dempster-Shafer theory * internal conflict * conflict between belief functions * plausibility conflict * amount uncertainty * conflict based on amount of uncertainty Subject RIV: BA - General Mathematics

  7. Effective Teacher Practice on the Plausibility of Human-Induced Climate Change

    Science.gov (United States)

    Niepold, F.; Sinatra, G. M.; Lombardi, D.

    2013-12-01

    Climate change education programs in the United States seek to promote a deeper understanding of the science of climate change, behavior change and stewardship, and support informed decision making by individuals, organizations, and institutions--all of which are summarized under the term 'climate literacy.' The ultimate goal of climate literacy is to enable actors to address climate change, both in terms of stabilizing and reducing emissions of greenhouse gases, but also an increased capacity to prepare for the consequences and opportunities of climate change. However, the long-term nature of climate change and the required societal response involve the changing students' ideas about controversial scientific issues which presents unique challenges for educators (Lombardi & Sinatra, 2010; Sinatra & Mason, 2008). This session will explore how the United States educational efforts focus on three distinct, but related, areas: the science of climate change, the human-climate interaction, and using climate education to promote informed decision making. Each of these approaches are represented in the Atlas of Science Literacy (American Association for the Advancement of Science, 2007) and in the conceptual framework for science education developed at the National Research Council (NRC) in 2012. Instruction to develop these fundamental thinking skills (e.g., critical evaluation and plausibility reappraisal) has been called for by the Next Generation Science Standards (NGSS) (Achieve, 2013), an innovative and research based way to address climate change education within the decentralized U.S. education system. However, the promise of the NGSS is that students will have more time to build mastery on the subjects, but the form of that instructional practice has been show to be critical. Research has show that effective instructional activities that promote evaluation of evidence improve students' understanding and acceptance toward the scientifically accepted model of human

  8. Uncertain socioeconomic projections used in travel demand and emissions models: could plausible errors result in air quality nonconformity?

    International Nuclear Information System (INIS)

    A sensitivity analysis of plausible errors in population, employment, fuel price, and income projections is conducted using the travel demand and emissions models of the Sacramento, CA, USA, region for their transportation plan. The results of the analyses indicate that plausible error ranges for household income and fuel prices are not a significant source of uncertainty with respect to the region's travel demand and emissions projections. However, plausible errors in population and employment projections (within approximately one standard deviation) may result in the region's transportation plan not meeting the conformity test for nitrogens of oxides (NOx) in the year 2005 (i.e., an approximately 16% probability). This outcome is also possible in the year 2015 but less likely (within approximately two standard deviations or a 2.5% probability). Errors in socioeconomic projections are only one of many sources of error in travel demand and emissions models. These results have several policy implications. First, regions like Sacramento that meet their conformity tests by a very small margin should rethink new highway investment and consider contingency transportation plans that incorporate more aggressive emissions reduction policies. Second, regional transportation planning agencies should conduct sensitivity analyses as part of their conformity analysis to make explicit significant uncertainties in the methods and to identify the probability of their transportation plan not conforming. Third, the US Environmental Protection Agency (EPA) should clarify the interpretation of ''demonstrate'' conformity of transportation plans; that is, specify the level of certainty that it considers a sufficient demonstration of conformity. (author)

  9. Upgrading protein synthesis for synthetic biology

    OpenAIRE

    O’Donoghue, Patrick; Ling, Jiqiang; Wang, Yane-Shih; Söll, Dieter

    2013-01-01

    Genetic code expansion for synthesis of proteins containing noncanonical amino acids is a rapidly growing field in synthetic biology. Creating optimal orthogonal translation systems will require re-engineering central components of the protein synthesis machinery on the basis of a solid mechanistic biochemical understanding of the synthetic process.

  10. Molecular biology of the honey bee

    DEFF Research Database (Denmark)

    Munk, Kathe

    While hoeneybees represent model organisms with complex social structures within populations, a comprehensive understanding of developmental regulation in relation to sexual development as well as cast determination still remains. Despite decades of research explanations on mechanistics underlyin...... functional molecular biological techniques to advance current interpretations of heneybee development...

  11. Biological mechanisms, one molecule at a time

    OpenAIRE

    Tinoco, Ignacio; Gonzalez, Ruben L.

    2011-01-01

    The last 15 years have witnessed the development of tools that allow the observation and manipulation of single molecules. The rapidly expanding application of these technologies for investigating biological systems of ever-increasing complexity is revolutionizing our ability to probe the mechanisms of biological reactions. Here, we compare the mechanistic information available from single-molecule experiments with the information typically obtained from ensemble studies and show how these tw...

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

    International Nuclear Information System (INIS)

    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

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

    Science.gov (United States)

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

    2013-02-28

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

  14. 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

  15. Modelling soil-plant-atmosphere interactions by coupling the regional weather model WRF to mechanistic plant models

    Science.gov (United States)

    Klein, C.; Hoffmann, P.; Priesack, E.

    2012-04-01

    Climate change causes altering distributions of meteorological factors influencing plant growth and its interactions between the land surface and the atmosphere. Recent studies show, that uncertainties in regional and global climate simulations are also caused by lacking descriptions of the soil-plant-atmosphere system. Therefore, we couple a mechanistic soil-plant model to a regional climate and forecast model. The detailed simulation of the water and energy exchanges, especially the transpiration of grassland and forests stands, are the key features of the modelling framework. The Weather Research and Forecasting model (WRF) (Skamarock 2008) is an open source mesoscale numerical weather prediction model. The WRF model was modified in a way, to either choose its native, static land surface model NOAH or the mechanistic eco-system model Expert-N 5.0 individually for every single grid point within the simulation domain. The Expert-N 5.0 modelling framework provides a highly modular structure, enabling the development and use of a large variety of different plant and soil models, including heat transfer, nitrogen uptake/turnover/transport as well as water uptake/transport and crop management. To represent the key landuse types grassland and forest, we selected two mechanistic plant models: The Hurley Pasture model (Thornley 1998) and a modified TREEDYN3 forest simulation model (Bossel 1996). The models simulate plant growth, water, nitrogen and carbon flows for grassland and forest stands. A mosaic approach enables Expert-N to use high resolution land use data e.g. CORINE Land Cover data (CLC, 2006) for the simulation, making it possible to simulate different land use distributions within a single grid cell. The coupling results are analyzed for plausibility and compared with the results of the default land surface model NOAH (Fei Chen and Jimy Dudhia 2010). We show differences between the mechanistic and the static model coupling, with focus on the feedback effects

  16. Computational Biology: A Programming Perspective

    DEFF Research Database (Denmark)

    Hartmann, Lars; Jones, Neil; Simonsen, Jakob Grue;

    2011-01-01

    Computation via biological devices has been the subject of close scrutiny since von Neumann’s early work some 60 years ago. In spite of the many relevant works in this field, the notion of programming biological devices seems to be, at best, ill-defined. While many devices are claimed or proved...... identify some strengths and shortcomings from a programming perspective. To show concretely what one could see as programming in biocomputing, we outline (from recent work) a computation model and a small programming language that are biologically more plausible than existing silicon-inspired models...... to be computationally universal in some sense, the full step to a bona fide programming language is rarely taken, and one question is noticeable by its absence: If the device is universal, where are the programs? We begin with an extensive review of the literature on programming-related biocomputing; and briefly...

  17. Biological Threats

    Science.gov (United States)

    ... Workplace Plans School Emergency Plans Main Content Biological Threats Biological agents are organisms or toxins that can ... for Disease Control and Prevention . Before a Biological Threat Unlike an explosion, a biological attack may or ...

  18. Mechanistic Insights of Vitamin D Anticancer Effects.

    Science.gov (United States)

    Ma, Yingyu; Johnson, Candace S; Trump, Donald L

    2016-01-01

    Vitamin D is a secosteroid hormone that regulates many biological functions in addition to its classical role in maintaining calcium homeostasis and bone metabolism. Vitamin D deficiency appears to predispose individuals to increased risk of developing a number of cancers. Compelling epidemiological and experimental evidence supports a role for vitamin D in cancer prevention and treatment in many types of cancers. Preclinical studies show that 1,25D3, the active metabolite of vitamin D, and its analogs have antitumor effects in vitro and in vivo through multiple mechanisms including the induction of cell cycle arrest, apoptosis, differentiation and the suppression of inflammation, angiogenesis, invasion, and metastasis. 1,25D3 also potentiates the effect of chemotherapeutic agents and other agents in the combination treatment. In this review, the antitumor effects of 1,25D3 and the potential underlying mechanisms will be discussed. The current findings support the application of 1,25D3 in cancer prevention and treatment. PMID:26827961

  19. Molecular mechanistic associations of human diseases

    Directory of Open Access Journals (Sweden)

    Stegmaier Philip

    2010-09-01

    Full Text Available Abstract Background The study of relationships between human diseases provides new possibilities for biomedical research. Recent achievements on human genetic diseases have stimulated interest to derive methods to identify disease associations in order to gain further insight into the network of human diseases and to predict disease genes. Results Using about 10000 manually collected causal disease/gene associations, we developed a statistical approach to infer meaningful associations between human morbidities. The derived method clustered cardiometabolic and endocrine disorders, immune system-related diseases, solid tissue neoplasms and neurodegenerative pathologies into prominent disease groups. Analysis of biological functions confirmed characteristic features of corresponding disease clusters. Inference of disease associations was further employed as a starting point for prediction of disease genes. Efforts were made to underpin the validity of results by relevant literature evidence. Interestingly, many inferred disease relationships correspond to known clinical associations and comorbidities, and several predicted disease genes were subjects of therapeutic target research. Conclusions Causal molecular mechanisms present a unifying principle to derive methods for disease classification, analysis of clinical disorder associations, and prediction of disease genes. According to the definition of causal disease genes applied in this study, these results are not restricted to genetic disease/gene relationships. This may be particularly useful for the study of long-term or chronic illnesses, where pathological derangement due to environmental or as part of sequel conditions is of importance and may not be fully explained by genetic background.

  20. Sex ratio meiotic drive as a plausible evolutionary mechanism for hybrid male sterility.

    Directory of Open Access Journals (Sweden)

    Linbin Zhang

    2015-03-01

    Full Text Available Biological diversity on Earth depends on the multiplication of species or speciation, which is the evolution of reproductive isolation such as hybrid sterility between two new species. An unsolved puzzle is the exact mechanism(s that causes two genomes to diverge from their common ancestor so that some divergent genes no longer function properly in the hybrids. Here we report genetic analyses of divergent genes controlling male fertility and sex ratio in two very young fruitfly species, Drosophila albomicans and D. nasuta. A majority of the genetic divergence for both traits is mapped to the same regions by quantitative trait loci mappings. With introgressions, six major loci are found to contribute to both traits. This genetic colocalization implicates that genes for hybrid male sterility have evolved primarily for controlling sex ratio. We propose that genetic conflicts over sex ratio may operate as a perpetual dynamo for genome divergence. This particular evolutionary mechanism may largely contribute to the rapid evolution of hybrid male sterility and the disproportionate enrichment of its underlying genes on the X chromosome--two patterns widely observed across animals.

  1. Mechanistic considerations in benzene physiological model development

    Energy Technology Data Exchange (ETDEWEB)

    Medinsky, M.A.; Kenyon, E.M.; Seaton, M.J.; Schlosser, P.M. [Chemical Industry Institute of Toxicology, Research Triangle Park, NC (United States)

    1996-12-01

    Benzene, an important industrial solvent, is also present in unleaded gasoline and cigarette smoke. The hematotoxic effects of benzene in humans are well documented and include aplastic anemia, pancytopenia, and acute myelogenous leukemia. However, the risks of leukemia at low exposure concentrations have not been established. A combination of metabolites (hydroquinone and phenol, for example) may be necessary to duplicate the hematotoxic effect of benzene, perhaps due in part to the synergistic effect of phenol on myeloperoxidase-mediated oxidation of hydroquinone to the reactive metabolite benzoquinone. Because benzene and its hydroxylated metabolites (phenol, hydroquinone, and catechol) are substrates for the same cytochrome P450 enzymes, competitive interactions among the metabolites are possible. In vivo data on metabolite formation by mice exposed to various benzene concentrations are consistent with competitive inhibition of phenol oxidation by benzene. In vitro studies of the metabolic oxidation of benzene, phenol, and hydroquinone are consistent with the mechanism of competitive interaction among the metabolites. The dosimetry of benzene and its metabolites in the target tissue, bone marrow, depends on the balance of activation processes such as enzymatic oxidation and deactivation processes such as conjugation and excretion. Phenol, the primary benzene metabolite, can undergo both oxidation and conjugation. Thus the potential exists for competition among various enzymes for phenol. Zonal localization of phase I and phase 11 enzymes in various regions of the liver acinus also impacts this competition. Biologically based dosimetry models that incorporate the important determinants of benzene flux, including interactions with other chemicals, will enable prediction of target tissue doses of benzene and metabolites at low exposure concentrations relevant for humans. 39 refs., 4 figs., 2 tabs.

  2. A Note on Unified Statistics Including Fermi-Dirac, Bose-Einstein, and Tsallis Statistics, and Plausible Extension to Anisotropic Effect

    Directory of Open Access Journals (Sweden)

    Christianto V.

    2007-04-01

    Full Text Available In the light of some recent hypotheses suggesting plausible unification of thermostatistics where Fermi-Dirac, Bose-Einstein and Tsallis statistics become its special subsets, we consider further plausible extension to include non-integer Hausdorff dimension, which becomes realization of fractal entropy concept. In the subsequent section, we also discuss plausible extension of this unified statistics to include anisotropic effect by using quaternion oscillator, which may be observed in the context of Cosmic Microwave Background Radiation. Further observation is of course recommended in order to refute or verify this proposition.

  3. Virtual neurorobotics (VNR to accelerate development of plausible neuromorphic brain architectures

    Directory of Open Access Journals (Sweden)

    Philip H Goodman

    2007-11-01

    Full Text Available Traditional research in artificial intelligence and machine learning has viewed the brain as a specially adapted information-processing system. More recently the field of social robotics has been advanced to capture the important dynamics of human cognition and interaction. An overarching societal goal of this research is to incorporate the resultant knowledge about intelligence into technology for prosthetic, assistive, security, and decision support applications. However, despite many decades of investment in learning and classification systems, this paradigm has yet to yield truly “intelligent” systems. For this reason, many investigators are now attempting to incorporate more realistic neuromorphic properties into machine learning systems, encouraged by over two decades of neuroscience research that has provided parameters that characterize the brain’s interdependent genomic, proteomic, metabolomic, anatomic, and electrophysiological networks. Given the complexity of neural systems, developing tenable models to capture the essence of natural intelligence for real-time application requires that we discriminate features underlying information processing and intrinsic motivation from those reflecting biological constraints (such as maintaining structural integrity and transporting metabolic products. We propose herein a conceptual framework and an iterative method of virtual neurorobotics (VNR intended to rapidly forward-engineer and test progressively more complex putative neuromorphic brain prototypes for their ability to support intrinsically intelligent, intentional interaction with humans. The VNR system is based on the viewpoint that a truly intelligent system must be driven by emotion rather than programmed tasking, incorporating intrinsic motivation and intentionality. We report pilot results of a closed-loop, real-time interactive VNR system with a spiking neural brain, and provide a video demonstration as online supplemental

  4. A mechanistic niche model for measuring species' distributional responses to seasonal temperature gradients.

    Directory of Open Access Journals (Sweden)

    William B Monahan

    Full Text Available Niche theory is central to understanding how species respond geographically to climate change. It defines a species' realized niche in a biological community, its fundamental niche as determined by physiology, and its potential niche--the fundamental niche in a given environment or geographic space. However, most predictions of the effects of climate change on species' distributions are limited to correlative models of the realized niche, which assume that species are in distributional equilibrium with respect to the variables or gradients included in the model. Here, I present a mechanistic niche model that measures species' responses to major seasonal temperature gradients that interact with the physiology of the organism. I then use lethal physiological temperatures to parameterize the model for bird species in North and South America and show that most focal bird species are not in direct physiological equilibrium with the gradients. Results also show that most focal bird species possess broad thermal tolerances encompassing novel climates that could become available with climate change. I conclude with discussion of how mechanistic niche models may be used to (i gain insights into the processes that cause species to respond to climate change and (ii build more accurate correlative distribution models in birds and other species.

  5. 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.

  6. A Mechanistic Explanation Linking Adaptive Mutation, Niche Change, and Fitness Advantage for the Wrinkly Spreader

    Directory of Open Access Journals (Sweden)

    Andrew J. Spiers

    2014-01-01

    Full Text Available Experimental evolution studies have investigated adaptive radiation in static liquid microcosms using the environmental bacterium Pseudomonas fluorescens SBW25. In evolving populations a novel adaptive mutant known as the Wrinkly Spreader arises within days having significant fitness advantage over the ancestral strain. A molecular investigation of the Wrinkly Spreader has provided a mechanistic explanation linking mutation with fitness improvement through the production of a cellulose-based biofilm at the air-liquid interface. Colonisation of this niche provides greater access to oxygen, allowing faster growth than that possible for non-biofilm—forming competitors located in the lower anoxic region of the microcosm. Cellulose is probably normally used for attachment to plant and soil aggregate surfaces and to provide protection in dehydrating conditions. However, the evolutionary innovation of the Wrinkly Spreader in static microcosms is the use of cellulose as the matrix of a robust biofilm, and is achieved through mutations that deregulate multiple diguanylate cyclases leading to the over-production of cyclic-di-GMP and the stimulation of cellulose expression. The mechanistic explanation of the Wrinkly Spreader success is an exemplar of the modern evolutionary synthesis, linking molecular biology with evolutionary ecology, and provides an insight into the phenomenal ability of bacteria to adapt to novel environments.

  7. Using mechanistic Bayesian networks to identify downstream targets of the Sonic Hedgehog pathway

    Directory of Open Access Journals (Sweden)

    McMahon Andrew P

    2009-12-01

    Full Text Available Abstract Background The topology of a biological pathway provides clues as to how a pathway operates, but rationally using this topology information with observed gene expression data remains a challenge. Results We introduce a new general-purpose analytic method called Mechanistic Bayesian Networks (MBNs that allows for the integration of gene expression data and known constraints within a signal or regulatory pathway to predict new downstream pathway targets. The MBN framework is implemented in an open-source Bayesian network learning package, the Python Environment for Bayesian Learning (PEBL. We demonstrate how MBNs can be used by modeling the early steps of the sonic hedgehog pathway using gene expression data from different developmental stages and genetic backgrounds in mouse. Using the MBN approach we are able to automatically identify many of the known downstream targets of the hedgehog pathway such as Gas1 and Gli1, along with a short list of likely targets such as Mig12. Conclusions The MBN approach shown here can easily be extended to other pathways and data types to yield a more mechanistic framework for learning genetic regulatory models.

  8. Mechanistic simulation of the vertical structure of mixed swards

    NARCIS (Netherlands)

    Schulte, R.P.O.; Lantinga, E.A.

    2002-01-01

    The vertical structure is an important feature of mixed swards, as it influences the inter-species competition for light, as well as the patterns of grazing. Although the experimental measurement of the vertical sward structure is relatively straightforward, the mechanistic and dynamic modelling of

  9. 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…

  10. 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...

  11. Comparison and analysis of DNB mechanistic models in round tube

    International Nuclear Information System (INIS)

    The five kinds of mechanistic models for departure from nucleate boiling (DNB) are investigated particularly based on bubble crowding model and liquid sublayer dryout model. These models are compared with DNB experimental data, respectively. Advantage and shortage of these models are discussed at last

  12. Mechanistic approaches to palladium-catalyzed alkene difunctionalization reactions

    OpenAIRE

    Jensen, Katrina H.; Sigman, Matthew S.

    2008-01-01

    Alkene difunctionalization, the addition of two functional groups across a double bond, exemplifies a class of reactions with significant synthetic potential. This emerging area examines recent developments of palladium-catalyzed difunctionalization reactions, with a focus on mechanistic strategies that allow for functionalization of a common palladium alkyl intermediate.

  13. A modified echocardiographic protocol with intrinsic plausibility control to determine intraventricular asynchrony based on TDI and TSI

    Directory of Open Access Journals (Sweden)

    Baumann Gert

    2009-09-01

    Full Text Available Abstract Background Established methods to determine asynchrony suffer from high intra- and interobserver variability and failed to improve patient selection for cardiac resynchronization therapy (CRT. Thus, there is a need for easy and robust approaches to reliably assess cardiac asynchrony. Methods and Results We performed echocardiography in 100 healthy subjects and 33 patients with left bundle branch block (LBBB. To detect intraventricular asynchrony, we combined two established methods, i.e., tissue synchronization imaging (TSI and tissue Doppler imaging (TDI. The time intervals from the onset of aortic valve opening (AVO to the peak systolic velocity (S' were measured separately in six basal segments in the apical four-, two-, and three-chamber view. Color-coded TSI served as an intrinsic plausibility control and helped to identify the correct S' measuring point in the TDI curves. Next, we identified the segment with the shortest AVO-S' interval. Since this segment most likely represents vital and intact myocardium it served as a reference for other segments. Segments were considered asynchronous when the delay between the segment in question and the reference segment was above the upper limit of normal delays derived from the control population. Intra- and interobserver variability were 7.0% and 7.7%, respectively. Conclusion Our results suggest that combination of TDI and TSI with intrinsic plausibility control improves intra- and interobserver variability and allows easy and reliable assessment of cardiac asynchrony.

  14. Ionic liquid pretreatment of biomass for sugars production: Driving factors with a plausible mechanism for higher enzymatic digestibility.

    Science.gov (United States)

    Raj, Tirath; Gaur, Ruchi; Dixit, Pooja; Gupta, Ravi P; Kagdiyal, V; Kumar, Ravindra; Tuli, Deepak K

    2016-09-20

    In this study, five ionic liquids (ILs) have been explored for biomass pretreatment for the production of fermentable sugar. We also investigated the driving factors responsible for improved enzymatic digestibility of various ILs treated biomass along with postulating the plausible mechanism thereof. Post pretreatment, mainly two factors impacted the enzymatic digestibility (i) structural deformation (cellulose I to II) along with xylan/lignin removal and (ii) properties of ILs; wherein, K-T parameters, viscosity and surface tension had a direct influence on pretreatment. A systematic investigation of these parameters and their impact on enzymatic digestibility is drawn. [C2mim][OAc] with β-value 1.32 resulted 97.7% of glucose yield using 10 FPU/g of biomass. A closer insight into the cellulose structural transformation has prompted a plausible mechanism explaining the better digestibility. The impact of these parameters on the digestibility can pave the way to customize the process to make biomass vulnerable to enzymatic attack. PMID:27261761

  15. Mechanistic investigation of a hemostatic keratin biomaterial

    Science.gov (United States)

    Rahmany, Maria Bahawdory

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

  16. Palladium(II)-catalyzed oxidation of L-tryptophan by hexacyanoferrate(III) in perchloric acid medium: a kinetic and mechanistic approach

    Indian Academy of Sciences (India)

    Ahmed Fawzy

    2016-02-01

    The catalytic effect of palladium(II) on the oxidation of L-tryptophan by potassium hexacyanoferrate( III) has been investigated spectrophotometrically in aqueous perchloric acid medium. A first order dependence in [hexacyanoferrate(III)] and fractional-first order dependences in both [L-tryptophan] and [palladium(II)] were obtained. The reaction exhibits fractional-second order kinetics with respect to [H+]. Reaction rate increased with increase in ionic strength and dielectric constant of the medium. The effect of temperature on the reaction rate has also been studied and activation parameters have been evaluated and discussed. Initial addition of the reaction product, hexacyanoferrate(II), does not affect the rate significantly. A plausible mechanistic scheme explaining all the observed kinetic results has been proposed. The final oxidation products are identified as indole-3-acetaldehyde, ammonium ion and carbon dioxide. The rate law associated with the reaction mechanism is derived.

  17. Mechanistic Studies of Planetary Haze Formation

    Science.gov (United States)

    Hicks, Raea Kay

    2015-10-01

    Planetary atmospheres can be thought of as global-scale reactors capable of synthesizing large, complex molecules from small gases such as methane (CH4), carbon dioxide (CO2), and nitrogen (N2). The atmosphere of Titan, the largest moon of Saturn covered by a thick organic haze, contains trace amounts (2%) of CH4 in an atmosphere of N2 at a surface pressure of 1.5 bar. This is similar to the Earth's Archaean atmosphere, which possibly contained trace amounts of CH4 and CO2 (˜1,000 ppmv each) in an N2 -dominant atmosphere before the rise of biogenic oxygen. Laboratory simulations of the atmospheric chemistry on Titan and the early Earth have shown that these atmospheres are capable of generating biologically-relevant molecules that condense to form particles which can then settle to the surface of the planetary body, possibly providing the molecules required for the emergence of life. The work presented here examines the mechanisms by which FUV photochemistry initiates incorporation of N atoms into Titan aerosol analogs, and C atoms into early Earth aerosol analogs. Results from the Aerosol Collector and Pyrolyser onboard the Huygens lander reveal the presence of nitrogen in Titan's aerosols. This nitrogen incorporation is thought to occur primarily by extreme-UV photons or energetic electrons. However, recent results from our laboratory indicate a surprising amount of nitrogen incorporation- up to 16% by mass- in Titan aerosol analogs produced by photochemistry initiated by FUV irradiation of CH4/N 2 mixtures. The termolecular reaction CH+N2 +M → HCN2 has been proposed to account for this observation. Here, we test this hypothesis by using a high- resolution time-of-flight aerosol mass spectrometer (HR-ToF-AMS) to measure the mass loading and chemical composition of aerosol produced at a range of pressures from roughly 0.1 to 1 atm. We report a 10-fold increase in aerosol mass loading across the range of pressures studied, indicating that the mechanism

  18. Drug targeting strategies for the treatment of inflammatory bowel disease: a mechanistic update.

    Science.gov (United States)

    Dahan, Arik; Amidon, Gordon L; Zimmermann, Ellen M

    2010-07-01

    The therapeutic management of inflammatory bowel disease (IBD) represents the perfect scenario for drug targeting to the site(s) of action. While existing formulation-based targeting strategies include rectal dosage forms and oral systems that target the colon by pH-, time-, microflora- and pressure-triggered drug release, novel approaches for site-specific delivery in IBD therapy will target the inflamed intestine per se rather than intestinal region. The purpose of this article is to present a mechanistic update on the strategies employed to achieve minimal systemic exposure accompanied by maximal drug levels in the inflamed intestinal tissue. The introduction of biological agents, micro/nanoparticulate carriers including liposomes, transgenic bacteria, and gene therapy opportunities are discussed, as well as the challenges remaining to be achieved in the targeted treatment of IBD. PMID:20594127

  19. Inhibition of the Mechanistic Target of Rapamycin (mTOR)-Rapamycin and Beyond.

    Science.gov (United States)

    Lamming, Dudley W

    2016-01-01

    Rapamycin is a Food and Drug Administration (FDA)-approved immunosuppressant and anticancer agent discovered in the soil of Easter Island in the early 1970s. Rapamycin is a potent and selective inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase, which acts as a central integrator of nutrient signaling pathways. During the last decade, genetic and pharmaceutical inhibition of mTOR pathway signaling has been found to promote longevity in yeast, worms, flies, and mice. In this article, we will discuss the molecular biology underlying the effects of rapamycin and its physiological effects, evidence for rapamycin as an antiaging compound, mechanisms by which rapamycin may extend life span, and the potential limitations of rapamycin as an antiaging molecule. Finally, we will discuss possible strategies that may allow us to inhibit mTOR signaling safely while minimizing side effects, and reap the health, social, and economic benefits from slowing the aging process. PMID:27048303

  20. Biological models for active vision: Towards a unified architecture

    OpenAIRE

    Terzic K.; Lobato D.; Saleiro M.; Martins J; Farrajota M.; Rodrigues J.M.F.; Du Buf J.M.H.

    2013-01-01

    Building a general-purpose, real-time active vision system completely based on biological models is a great challenge. We apply a number of biologically plausible algorithms which address different aspects of vision, such as edge and keypoint detection, feature extraction,optical flow and disparity, shape detection, object recognition and scene modelling into a complete system. We present some of the experiments from our ongoing work, where our system leverages a combination of algorithms to ...

  1. Beyond Correlation in the Detection of Climate Change Impacts: Testing a Mechanistic Hypothesis for Climatic Influence on Sockeye Salmon (Oncorhynchus nerka) Productivity

    Science.gov (United States)

    Tillotson, Michael D.; Quinn, Thomas P.

    2016-01-01

    Detecting the biological impacts of climate change is a current focus of ecological research and has important applications in conservation and resource management. Owing to a lack of suitable control systems, measuring correlations between time series of biological attributes and hypothesized environmental covariates is a common method for detecting such impacts. These correlative approaches are particularly common in studies of exploited fish species because rich biological time-series data are often available. However, the utility of species-environment relationships for identifying or predicting biological responses to climate change has been questioned because strong correlations often deteriorate as new data are collected. Specifically stating and critically evaluating the mechanistic relationship(s) linking an environmental driver to a biological response may help to address this problem. Using nearly 60 years of data on sockeye salmon from the Kvichak River, Alaska we tested a mechanistic hypothesis linking water temperatures experienced during freshwater rearing to population productivity by modeling a series of intermediate, deterministic relationships and evaluating temporal trends in biological and environmental time-series. We found that warming waters during freshwater rearing have profoundly altered patterns of growth and life history in this population complex yet there has been no significant correlation between water temperature and metrics of productivity commonly used in fisheries management. These findings demonstrate that pairing correlative approaches with careful consideration of the mechanistic links between populations and their environments can help to both avoid spurious correlations and identify biologically important, but not statistically significant relationships, and ultimately producing more robust conclusions about the biological impacts of climate change. PMID:27123845

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

    International Nuclear Information System (INIS)

    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

  3. A hitherto undescribed case of cerebellar ataxia as the sole presentation of thyrotoxicosis in a young man: a plausible association.

    Science.gov (United States)

    Elhadd, Tarik Abdelkareim; Linton, Kathryn; McCoy, Caoihme; Saha, Subrata; Holden, Roger

    2014-01-01

    A 16-year-old male presented to hospital following an episode of unusual behavior on the football pitch, where he was witnessed as grossly ataxic by his teammates. The assessment demonstrated marked cerebellar signs on examination but no other neurological deficit. The investigation showed the evidence of biochemical thyrotoxicosis with free T4 at 37 pmol/L (normal reference range: 11-27) and thyrotropin (TSH) relationship is plausible because alternative etiologies were excluded, and the normalization of thyroid function with treatment was coupled with complete resolution of the neurological syndrome. Cerebellar syndromes may well be one of the presenting features of thyrotoxicosis, and this should be in the list of its differential diagnosis. PMID:25827703

  4. Bethe-Heitler cascades as a plausible origin of hard spectra in distant TeV blazars

    Science.gov (United States)

    Zheng, Y. G.; Yang, C. Y.; Kang, S. J.

    2016-01-01

    Context. Very high-energy (VHE) γ-ray measurements of distant TeV blazars can be nicely explained by TeV spectra induced by ultra high-energy cosmic rays. Aims: We develop a model for a plausible origin of hard spectra in distant TeV blazars. Methods: In the model, the TeV emission in distant TeV blazars is dominated by two mixed components. The first is the internal component with the photon energy around 1 TeV produced by inverse Compton scattering of the relativistic electrons on the synchrotron photons (SSC) with a correction for extragalactic background light absorbtion and the other is the external component with the photon energy more than 1 TeV produced by the cascade emission from high-energy protons propagating through intergalactic space. Results: Assuming suitable model parameters, we apply the model to observed spectra of distant TeV blazars of 1ES 0229+200. Our results show that 1) the observed spectrum properties of 1ES 0229+200, especially the TeV γ-ray tail of the observed spectra, could be reproduced in our model and 2) an expected TeV γ-ray spectrum with photon energy >1 TeV of 1ES 0229+200 should be comparable with the 50-h sensitivity goal of the Cherenkov Telescope Array (CTA) and the differential sensitivity curve for the one-year observation with the Large High Altitude Air Shower Observatory (LHAASO). Conclusions: We argue that strong evidence for the Bethe-Heitler cascades along the line of sight as a plausible origin of hard spectra in distant TeV blazars could be obtained from VHE observations with CTA, LHAASO, HAWC, and HiSCORE.

  5. Biology of infantile hemangioma.

    Science.gov (United States)

    Itinteang, Tinte; Withers, Aaron H J; Davis, Paul F; Tan, Swee T

    2014-01-01

    Infantile hemangioma (IH), the most common tumor of infancy, is characterized by an initial proliferation during infancy followed by spontaneous involution over the next 5-10 years, often leaving a fibro-fatty residuum. IH is traditionally considered a tumor of the microvasculature. However, recent data show the critical role of stem cells in the biology of IH with emerging evidence suggesting an embryonic developmental anomaly due to aberrant proliferation and differentiation of a hemogenic endothelium with a neural crest phenotype that possesses the capacity for endothelial, hematopoietic, mesenchymal, and neuronal differentiation. Current evidence suggests a putative placental chorionic mesenchymal core cell embolic origin of IH during the first trimester. This review outlines the emerging role of stem cells and their interplay with the cytokine niche that promotes a post-natal environment conducive for vasculogenesis involving VEGFR-2 and its ligand VEGF-A and the IGF-2 ligand in promoting cellular proliferation, and the TRAIL-OPG anti-apoptotic pathway in preventing cellular apoptosis in IH. The discovery of the role of the renin-angiotensin system in the biology of IH provides a plausible explanation for the programed biologic behavior and the β-blocker-induced accelerated involution of this enigmatic condition. This crucially involves the vasoactive peptide, angiotensin II, that promotes cellular proliferation in IH predominantly via its action on the ATIIR2 isoform. The role of the RAS in the biology of IH is further supported by the effect of captopril, an ACE inhibitor, in inducing accelerated involution of IH. The discovery of the critical role of RAS in IH represents a novel and fascinating paradigm shift in the understanding of human development, IH, and other tumors in general. PMID:25593962

  6. Sensitivity analysis in severe accidents semi-mechanistic modeling

    International Nuclear Information System (INIS)

    A sensitivity analysis to determine the most influent phenomena in the core melt progression to be considered in a semi-mechanistic modeling have been performed in the present work. The semi-mechanistic program MARCH3 and the TMI-2 plant parameters were used in the TMI-2 severe accident. The sensitivity analysis was performed with the comparison of the results obtained by the program with the plant data recorded during the accident. The results enabled us to verify that although many phenomena are present in the accident, the modelling of the most important ones was enough to reproduce, at least in a qualitative way, the accident progression. This fact reflects the importance of the sensitivity analysis to select the most influent phenomena in a core melting process. (author). 48 refs., 28 figs., 6 tabs

  7. Mechanistic approaches and the development of alternative toxicity test methods.

    OpenAIRE

    Balls, M

    1998-01-01

    A mechanism can be defined as an explanation of an observed phenomenon that explains the processes underlying the phenomenon in terms of events at lower levels of organization. A prerequisite for new, more mechanistic, approaches, which would use in vitro systems rather than conventional animal analogy models, is a strengthening of the underlying scientific basis of toxicity testing. This will require greater recognition of the differences between fidelity and discrimination models and betwee...

  8. Evaluation of mechanistic DNB models using HCLWR CHF data

    International Nuclear Information System (INIS)

    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·m2 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)

  9. Approximate Bayesian inference in semi-mechanistic models

    OpenAIRE

    Aderhold, Andrej; Husmeier, Dirk; Grzegorczyk, Marco

    2016-01-01

    Inference of interaction networks represented by systems of differential equations is a challenging problem in many scientific disciplines. In the present article, we follow a semi-mechanistic modelling approach based on gradient matching. We investigate the extent to which key factors, including the kinetic model, statistical formulation and numerical methods, impact upon performance at network reconstruction. We emphasize general lessons for computational statisticians when faced with the c...

  10. Novel approaches for mechanistic understanding and predicting preeclampsia

    OpenAIRE

    Kalkunte, Satyan; Lai, Zhongbin; Norris, Wendy E.; Pietras, Linda A; Tewari, Neetu; Boij, Roland; Neubeck, Stefan; Markert, Udo R.; Sharma, Surendra

    2009-01-01

    Despite intense investigation, preeclampsia (PE) remains largely enigmatic. Relatively late onset of diagnostic signs and heterogeneous nature of the disease further contribute to poor understanding of its etiology and clinical management. There exist no concrete animal models that can provide mechanistic underpinnings for evaluating targeted therapeutic intervention. Poor cross-sectional findings with potential biochemical markers reported so far have proved counterintuitive and suggest a ne...

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

    Science.gov (United States)

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

    2015-11-10

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

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

    OpenAIRE

    Khosla, Chaitan; Herschlag, Daniel; Cane, David E.; Walsh, Christopher T.

    2014-01-01

    Two hallmarks of assembly line polyketide synthases have motivated an interest in these unusual multienzyme systems, their stereospecificity and their capacity for directional biosynthesis. In this review, we summarize the state of knowledge regarding the mechanistic origins of these two remarkable features, using the 6-deoxyerythronolide B synthase as a prototype. Of the 10 stereocenters in 6-deoxyerythronolide B, the stereochemistry of nine carbon atoms is directly set by ketoreductase doma...

  13. ELECTROCHEMICAL REDUCTION OF DODECYLPYRIDINIUM BROMIDE IN APROTIC SOLVENTS: MECHANISTIC STUDIES

    Czech Academy of Sciences Publication Activity Database

    Hromadová, Magdaléna; Pospíšil, Lubomír; Sokolová, Romana; Kolivoška, Viliam

    2011-01-01

    Roč. 76, č. 12 (2011), s. 1895-1908. ISSN 0010-0765 R&D Projects: GA AV ČR IAA400400802; GA ČR GA203/08/1157; GA ČR GA203/09/0705; GA MŠk(CZ) MEB041006 Institutional research plan: CEZ:AV0Z40400503 Keywords : spectroelectrochemistry * dodecylpyridinium bromide * mechanistic studies Subject RIV: CG - Electrochemistry Impact factor: 1.283, year: 2011

  14. Development and Mechanistic Investigations of Gold-Catalyzed Reactions

    OpenAIRE

    Shapiro, Nathan David

    2010-01-01

    Historically, chemists have been motivated by problems in total synthesis or by a desire to develop reactions of broad utility. In answer to these challenges, several approaches to fundamental research have been developed. In chapter 1, we describe how our reactivity-driven approach has led to the discovery of numerous synthetic tools. The development of new synthetically useful methodology often rests on an understanding of the mechanistic underpinnings of the desired transformation. This is...

  15. Oleanolic acid (OA) as an antileishmanial agent: Biological evaluation and in silico mechanistic insights.

    Science.gov (United States)

    Melo, Tahira Souza; Gattass, Cerli Rocha; Soares, Deivid Costa; Cunha, Micael Rodrigues; Ferreira, Christian; Tavares, Maurício Temotheo; Saraiva, Elvira; Parise-Filho, Roberto; Braden, Hannah; Delorenzi, Jan Carlo

    2016-06-01

    Although a worldwide health problem, leishmaniasis is considered a highly neglected disease, lacking efficient and low toxic treatment. The efforts for new drug development are based on alternatives such as new uses for well-known drugs, in silico and synthetic studies and naturally derived compounds. Oleanolic acid (OA) is a pentacyclic triterpenoid widely distributed throughout the Plantae kingdom that displays several pharmacological activities. OA showed potent leishmancidal effects in different Leishmania species, both against promastigotes (IC(50 L. braziliensis) 30.47 ± 6.35 μM; IC(50 L. amazonensis) 40.46 ± 14.21 μM; IC(50 L. infantum) 65.93 ± 15.12 μM) and amastigotes (IC(50 L. braziliensis) 68.75 ± 16.55 μM; IC(50 L. amazonensis) 38.45 ± 12.05 μM; IC(50 L. infantum) 64.08 ± 23.52 μM), with low cytotoxicity against mouse peritoneal macrophages (CC(50) 235.80 ± 36.95 μM). Moreover, in silico studies performed to evaluate OA molecular properties and to elucidate the possible mechanism of action over the Leishmania enzyme sterol 14α-demethylase (CYP51) suggested that OA interacts efficiently with CYP51 and could inhibit the ergosterol synthesis pathway. Collectively, these data indicate that OA is a good candidate as leading compound for the development of a new leishmaniasis treatment. PMID:26772973

  16. Mechanistic aspects of biologically synthesized silver nanoparticles against food- and water-borne microbes.

    Science.gov (United States)

    Krishnaraj, Chandran; Harper, Stacey L; Choe, Ho Sung; Kim, Kwang-Pyo; Yun, Soon-Il

    2015-10-01

    In the present study, silver nanoparticles (AgNPs) synthesized from aqueous leaves extract of Malva crispa and their mode of interaction with food- and water-borne microbes were investigated. Formation of AgNPs was conformed through UV-Vis, FE-SEM, EDS, AFM, and HR-TEM analyses. Further the concentration of silver (Ag) in the reaction mixture was conformed through ICP-MS analysis. Different concentration of nanoparticles (1-3 mM) tested to know the inhibitory effect of bacterial pathogens such as Bacillus cereus, Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, Salmonella typhi, Salmonella enterica and the fungal pathogens of Penicillium expansum, Penicillium citrinum, Aspergillus oryzae, Aspergillus sojae and Aspergillus niger. Interestingly, nanoparticles synthesized from 2 to 3 mM concentration of AgNO3 showed excellent inhibitory activities against both bacterial and fungal pathogens which are well demonstrated through well diffusion, poison food technique, minimum inhibitory concentration (MIC), and minimum fungicidal concentration (MFC). In addition, mode of interaction of nanoparticles into both bacterial and fungal pathogens was documented through Bio-TEM analysis. Further the genomic DNA isolated from test bacterial strains and their interaction with nanoparticles was carried out to elucidate the possible mode of action of nanoparticles against bacteria. Interestingly, AgNPs did not show any genotoxic effect against all the tested bacterial strains which are pronounced well in agarose gel electrophoresis and for supporting this study, UV-Vis and Bio-TEM analyses were carried out in which no significant changes observed compared with control. Hence, the overall results concluded that the antimicrobial activity of biogenic AgNPs occurred without any DNA damage. PMID:26178241

  17. Pathways to plausibility

    DEFF Research Database (Denmark)

    Wahlberg, Ayo

    2008-01-01

    Herbal medicine has long been contrasted to modern medicine in terms of a holistic approach to healing, vitalistic theories of health and illness and an emphasis on the body’s innate self-healing capacities. At the same time, since the early 20th century, the cultivation, preparation and mass...

  18. Biological atomism and cell theory.

    Science.gov (United States)

    Nicholson, Daniel J

    2010-09-01

    Biological atomism postulates that all life is composed of elementary and indivisible vital units. The activity of a living organism is thus conceived as the result of the activities and interactions of its elementary constituents, each of which individually already exhibits all the attributes proper to life. This paper surveys some of the key episodes in the history of biological atomism, and situates cell theory within this tradition. The atomistic foundations of cell theory are subsequently dissected and discussed, together with the theory's conceptual development and eventual consolidation. This paper then examines the major criticisms that have been waged against cell theory, and argues that these too can be interpreted through the prism of biological atomism as attempts to relocate the true biological atom away from the cell to a level of organization above or below it. Overall, biological atomism provides a useful perspective through which to examine the history and philosophy of cell theory, and it also opens up a new way of thinking about the epistemic decomposition of living organisms that significantly departs from the physicochemical reductionism of mechanistic biology. PMID:20934641

  19. 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. PMID

  20. 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. PMID:27326762

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

    Directory of Open Access Journals (Sweden)

    Gregory R Smith

    Full Text Available 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.

  2. Mechanistic model for interpreting the toxic effects of sulfonamides on nitrification.

    Science.gov (United States)

    Huang, Xiangfeng; Feng, Yi; Hu, Cui; Xiao, Xiaoyu; Yu, Daliang; Zou, Xiaoming

    2016-03-15

    Antibiotics are categorized as pseudopersistent compounds because of their widespread use and continuous emission into the environment. Biological systems such as active sludge and biofilms are still the principal tools used to remove antibiotics in wastewater treatment plants (WWTPs). Consequently, it is important to determine the relationship between toxic effects in biological WWTPs and the structural characteristics of antibiotics. In the present study, toxic effects of 10 sulfonamides (SAs) on nitrification in an active sludge system were studied. The toxicity results (half-effective concentrations, EC50) indicated that the toxicity of sulfadimethoxine (SDM) is approximately 4 times as large as that of sulfadiazine (SD). Based on the toxicity mechanism and the partial least squares regression (PLS) method, an optimum quantitative structure-activity relationship (QSAR) model was developed for the test system. The mechanistic model showed that the pKa, the binding energies between SAs with dihydropteroate synthetase ( [Formula: see text] ) and the binding energies between SAs with ammonia monooxygenase ( [Formula: see text] ) are the key factors affecting the toxic effects of SAs on nitration process in active sludge system, following an order of importance of [Formula: see text] > [Formula: see text] >pKa. PMID:26651069

  3. X-ray investigation of the diffuse emission around plausible gamma-ray emitting pulsar wind nebulae in Kookaburra region

    CERN Document Server

    Kishishita, Tetsuichi; Uchiyama, Yasunobu; Tanaka, Yasuyuki; Takahashi, Tadayuki

    2012-01-01

    We report on the results from {\\it Suzaku} X-ray observations of the radio complex region called Kookaburra, which includes two adjacent TeV $\\gamma$-ray sources HESS J1418-609 and HESS J1420-607. The {\\it Suzaku} observation revealed X-ray diffuse emission around a middle-aged pulsar PSR J1420-6048 and a plausible PWN Rabbit with elongated sizes of $\\sigma_{\\rm X}=1^{\\prime}.66$ and $\\sigma_{\\rm X}=1^{\\prime}.49$, respectively. The peaks of the diffuse X-ray emission are located within the $\\gamma$-ray excess maps obtained by H.E.S.S. and the offsets from the $\\gamma$-ray peaks are $2^{\\prime}.8$ for PSR J1420-6048 and $4^{\\prime}.5$ for Rabbit. The X-ray spectra of the two sources were well reproduced by absorbed power-law models with $\\Gamma=1.7-2.3$. The spectral shapes tend to become softer according to the distance from the X-ray peaks. Assuming the one zone electron emission model as the first order approximation, the ambient magnetic field strengths of HESS J1420-607 and HESS J1418-609 can be estimate...

  4. Bethe-Heitler cascades as a plausible origin of hard spectra in distant TeV blazars

    CERN Document Server

    Zheng, Y G; Kang, S J

    2016-01-01

    Context. Very high-energy (VHE) $\\gamma$-ray measurements of distant TeV blazars can be nicely explained by TeV spectra induced by ultra high-energy cosmic rays. Aims. We develop a model for a plausible origin of hard spectra in distant TeV blazars. Methods. In the model, the TeV emission in distant TeV blazars is dominated by two mixed components. The first is the internal component with the photon energy around 1 TeV produced by inverse Compton scattering of the relativistic electrons on the synchrotron photons (SSC) with a correction for extragalactic background light absorbtion and the other is the external component with the photon energy more than 1 TeV produced by the cascade emission from high-energy protons propagating through intergalactic space. Results. Assuming suitable model parameters, we apply the model to observed spectra of distant TeV blazars of 1ES 0229+200. Our results show that 1) the observed spectrum properties of 1ES 0229+200, especially the TeV $\\gamma$-ray tail of the observed spect...

  5. Factors Influencing the Decisions and Actions of Pilots and Air Traffic Controllers in Three Plausible NextGen Environments

    Science.gov (United States)

    Vu, Kim-Phuong L.; Strybel, Thomas Z.; Battiste, Vernol; Johnson, Walter

    2011-01-01

    In the current air traffic management (ATM) system, pilots and air traffic controllers have well-established roles and responsibilities: pilots fly aircraft and are concerned with energy management, fuel efficiency, and passenger comfort; controllers separate aircraft and are concerned with safety and management of traffic flows. Despite having different goals and obligations, both groups must be able to effectively communicate and interact with each other for the ATM system to work. This interaction will become even more challenging as traffic volume increases dramatically in the near future. To accommodate this increase, by 2025 the national air transportation system in the U.S. will go through a transformation that will modernize the ATM system and make it safer, more effective, and more efficient. This new system, NextGen, will change how pilots and controllers perform their tasks by incorporating advanced technologies and employing new procedures. It will also distribute responsibility between pilots, controllers and automation over such tasks as maintaining aircraft separation. The present chapter describes three plausible concepts of operations that allocate different ATM responsibilities to these groups. We describe how each concept changes the role of each operator and the types of decisions and actions performed by them.

  6. A mechanistic soil biogeochemistry model with explicit representation of microbial and macrofaunal activities and nutrient cycles

    Science.gov (United States)

    Fatichi, Simone; Manzoni, Stefano; Or, Dani; Paschalis, Athanasios

    2016-04-01

    The potential of a given ecosystem to store and release carbon is inherently linked to soil biogeochemical processes. These processes are deeply connected to the water, energy, and vegetation dynamics above and belowground. Recently, it has been advocated that a mechanistic representation of soil biogeochemistry require: (i) partitioning of soil organic carbon (SOC) pools according to their functional role; (ii) an explicit representation of microbial dynamics; (iii) coupling of carbon and nutrient cycles. While some of these components have been introduced in specialized models, they have been rarely implemented in terrestrial biosphere models and tested in real cases. In this study, we combine a new soil biogeochemistry model with an existing model of land-surface hydrology and vegetation dynamics (T&C). Specifically the soil biogeochemistry component explicitly separates different litter pools and distinguishes SOC in particulate, dissolved and mineral associated fractions. Extracellular enzymes and microbial pools are explicitly represented differentiating the functional roles of bacteria, saprotrophic and mycorrhizal fungi. Microbial activity depends on temperature, soil moisture and litter or SOC stoichiometry. The activity of macrofauna is also modeled. Nutrient dynamics include the cycles of nitrogen, phosphorous and potassium. The model accounts for feedbacks between nutrient limitations and plant growth as well as for plant stoichiometric flexibility. In turn, litter input is a function of the simulated vegetation dynamics. Root exudation and export to mycorrhiza are computed based on a nutrient uptake cost function. The combined model is tested to reproduce respiration dynamics and nitrogen cycle in few sites where data were available to test plausibility of results across a range of different metrics. For instance in a Swiss grassland ecosystem, fine root, bacteria, fungal and macrofaunal respiration account for 40%, 23%, 33% and 4% of total belowground

  7. 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...

  8. Mechanistic study of aerosol dry deposition on vegetated canopies

    International Nuclear Information System (INIS)

    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)

  9. Organic Matter in SNC Meteorites: Is It Time to Re-Evaluate the Viking Biology Experimental Data?

    Science.gov (United States)

    Warmflash, D.; Clemett, S. J.; McKay, D. S.

    2001-01-01

    New data from SNC meteorites suggests that organic material may be present in the martian upper crust. This adds to possibility that the Viking biology experiments may have plausible biological interpretations as well as inorganic chemical interpretations Additional information is contained in the original extended abstract..

  10. Determination of nitric oxide metabolites, nitrate and nitrite, in Anopheles culicifacies mosquito midgut and haemolymph by anion exchange high-performance liquid chromatography: plausible mechanism of refractoriness

    Directory of Open Access Journals (Sweden)

    Adak Tridibesh

    2008-04-01

    Full Text Available Abstract Background The diverse physiological and pathological role of nitric oxide in innate immune defenses against many intra and extracellular pathogens, have led to the development of various methods for determining nitric oxide (NO synthesis. NO metabolites, nitrite (NO2- and nitrate (NO3- are produced by the action of an inducible Anopheles culicifacies NO synthase (AcNOS in mosquito mid-guts and may be central to anti-parasitic arsenal of these mosquitoes. Method While exploring a plausible mechanism of refractoriness based on nitric oxide synthase physiology among the sibling species of An. culicifacies, a sensitive, specific and cost effective high performance liquid chromatography (HPLC method was developed, which is not influenced by the presence of biogenic amines, for the determination of NO2- and NO3- from mosquito mid-guts and haemolymph. Results This method is based on extraction, efficiency, assay reproducibility and contaminant minimization. It entails de-proteinization by centrifugal ultra filtration through ultracel 3 K filter and analysis by high performance anion exchange liquid chromatography (Sphereclone, 5 μ SAX column with UV detection at 214 nm. The lower detection limit of the assay procedure is 50 pmoles in all midgut and haemolymph samples. Retention times for NO2- and NO3- in standards and in mid-gut samples were 3.42 and 4.53 min. respectively. Assay linearity for standards ranged between 50 nM and 1 mM. Recoveries of NO2- and NO3- from spiked samples (1–100 μM and from the extracted standards (1–100 μM were calculated to be 100%. Intra-assay and inter assay variations and relative standard deviations (RSDs for NO2- and NO3- in spiked and un-spiked midgut samples were 5.7% or less. Increased levels NO2- and NO3- in midguts and haemolymph of An. culicifacies sibling species B in comparison to species A reflect towards a mechanism of refractoriness based on AcNOS physiology. Conclusion HPLC is a sensitive

  11. 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. PMID:23973663

  12. Centrifugal pumping of gas-liquid mixtures: a mechanistic approach

    Energy Technology Data Exchange (ETDEWEB)

    Estevam, Valdir [PETROBRAS, Rio de Janeiro, RJ (Brazil); Franca, Fernando A. [Universidade Estadual de Campinas, SP (Brazil); Alhanati, Francisco J.S. [C-Fer Technologies, Edmonton, Alberta (Canada)

    2004-07-01

    Centrifugal pumps are known to show a 'surging' behavior at certain conditions of free gas and liquid flow rate at the intake. In the 'surging region' on a pump characteristic curve, the head generated is significantly lower than if the pump were handling a gas-liquid homogeneous mixture. The surging happens, as one shows in this paper, due to the existence of a gas pocket, referred as 'elongated bubble', at the pump impeller inlet region. Therefore, to be able to predict the performance of centrifugal pumps under two-phase conditions, one has to disclose and model the mechanisms that set existence of the elongated bubble at the impeller inlet, besides calculating its length inside the impeller. This paper reports on the results of experimental and mechanistic modelling work conducted with the objective of better predicting the gas-liquid performance of centrifugal pumps under all range of conditions, including those characterized by 'surging'. The focus was on small diameter centrifugal pumps used to produce oil wells. A mechanistic two-fluid model devised to calculate the head generated by the pump was developed. The predictions of the model show good agreement with data collected for this study, and with data recently collected by other research organizations. (author)

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

    Science.gov (United States)

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

    2005-07-01

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

  14. 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.

  15. Mechanistic and Economical Characteristics of Asphalt Rubber Mixtures

    Directory of Open Access Journals (Sweden)

    Mena I. Souliman

    2016-01-01

    Full Text Available Load associated fatigue cracking is one of the major distress types occurring in flexible pavement systems. Flexural bending beam fatigue laboratory test has been used for several decades and is considered to be an integral part of the new superpave advanced characterization procedure. One of the most significant solutions to prolong the fatigue life for an asphaltic mixture is to utilize flexible materials as rubber. A laboratory testing program was performed on a conventional and Asphalt Rubber- (AR- gap-graded mixtures to investigate the impact of added rubber on the mechanical, mechanistic, and economical attributes of asphaltic mixtures. Strain controlled fatigue tests were conducted according to American Association of State Highway and Transportation Officials (AASHTO procedures. The results from the beam fatigue tests indicated that the AR-gap-graded mixtures would have much longer fatigue life compared with the reference (conventional mixtures. In addition, a mechanistic analysis using 3D-Move software coupled with a cost analysis study based on the fatigue performance on the two mixtures was performed. Overall, analysis showed that AR modified asphalt mixtures exhibited significantly lower cost of pavement per 1000 cycles of fatigue life per mile compared to conventional HMA mixture.

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

    Science.gov (United States)

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

    2014-08-01

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

  17. On Matrix Sampling and Imputation of Context Questionnaires with Implications for the Generation of Plausible Values in Large-Scale Assessments

    Science.gov (United States)

    Kaplan, David; Su, Dan

    2016-01-01

    This article presents findings on the consequences of matrix sampling of context questionnaires for the generation of plausible values in large-scale assessments. Three studies are conducted. Study 1 uses data from PISA 2012 to examine several different forms of missing data imputation within the chained equations framework: predictive mean…

  18. In Silico Structure Prediction of Human Fatty Acid Synthase-Dehydratase: A Plausible Model for Understanding Active Site Interactions.

    Science.gov (United States)

    John, Arun; Umashankar, Vetrivel; Samdani, A; Sangeetha, Manoharan; Krishnakumar, Subramanian; Deepa, Perinkulam Ravi

    2016-01-01

    Fatty acid synthase (FASN, UniProt ID: P49327) is a multienzyme dimer complex that plays a critical role in lipogenesis. Consequently, this lipogenic enzyme has gained tremendous biomedical importance. The role of FASN and its inhibition is being extensively researched in several clinical conditions, such as cancers, obesity, and diabetes. X-ray crystallographic structures of some of its domains, such as β-ketoacyl synthase, acetyl transacylase, malonyl transacylase, enoyl reductase, β-ketoacyl reductase, and thioesterase, (TE) are already reported. Here, we have attempted an in silico elucidation of the uncrystallized dehydratase (DH) catalytic domain of human FASN. This theoretical model for DH domain was predicted using comparative modeling methods. Different stand-alone tools and servers were used to validate and check the reliability of the predicted models, which suggested it to be a highly plausible model. The stereochemical analysis showed 92.0% residues in favorable region of Ramachandran plot. The initial physiological substrate β-hydroxybutyryl group was docked into active site of DH domain using Glide. The molecular dynamics simulations carried out for 20 ns in apo and holo states indicated the stability and accuracy of the predicted structure in solvated condition. The predicted model provided useful biochemical insights into the substrate-active site binding mechanisms. This model was then used for identifying potential FASN inhibitors using high-throughput virtual screening of the National Cancer Institute database of chemical ligands. The inhibitory efficacy of the top hit ligands was validated by performing molecular dynamics simulation for 20 ns, where in the ligand NSC71039 exhibited good enzyme inhibition characteristics and exhibited dose-dependent anticancer cytotoxicity in retinoblastoma cancer cells in vitro. PMID:27559295

  19. Effects of high-dilutions in behavioural models: a commentary on critical issues, from reproducibility to plausibility

    Directory of Open Access Journals (Sweden)

    Elisabetta Zanolin

    2011-12-01

    Full Text Available As part of a rigorous investigation into the effects of Gelsemium sempervirens on laboratory mice, we performed two complete series of experiments and published three scientific papers. A recent commentary has, however, called into question the reproducibility and validity of these findings. In this article we discuss the major issues raised by this critique within the framework of methodological aspects and the interpretation of results of high-dilution and homeopathic research. The charge of non-reproducibility is shown to be unfounded, because a same homeopathic medicine displayed the same direction of effects in two well-validated models (light-dark and open-field, albeit with nonlinear patterns. The double-blind protocols and statistics by means of ANOVA were performed appropriately and the difference between dilutions of Gelsemium (5cH, 7cH, 9cH and 30cH with variations according to model and placebo was statistically highly significant. Our investigations brought to light some problems related with the lack of activity of buspirone and diazepam (conventional anxiolytic drugs used as control on some behavioural parameters, suggesting that Gelsemium may have broader action, and raising doubts as to the reliability of benzodiazepines as positive controls for homeopathic treatments. Concerning the plausibility of experiments in this field, disputed on the grounds of alleged lack of dose-response effect, we note that the latter is not at all uncommon, and can be accounted for by a host of possible reasons. In conclusion, our research line showed reproducible and consistent effects of Gelsemium in laboratory mice.

  20. Deep determinism and the assessment of mechanistic interaction between categorical and continuous variables

    OpenAIRE

    Berzuini, Carlo; Dawid, A. Philip

    2010-01-01

    Our aim is to detect mechanistic interaction between the effects of two causal factors on a binary response, as an aid to identifying situations where the effects are mediated by a common mechanism. We propose a formalization of mechanistic interaction which acknowledges asymmetries of the kind "factor A interferes with factor B, but not viceversa". A class of tests for mechanistic interaction is proposed, which works on discrete or continuous causal variables, in any combination. Conditions ...

  1. Application of mechanistic models to fermentation and biocatalysis for next-generation processes

    DEFF Research Database (Denmark)

    Gernaey, Krist; Eliasson Lantz, Anna; Tufvesson, Pär;

    2010-01-01

    Mechanistic models are based on deterministic principles, and recently, interest in them has grown substantially. Herein we present an overview of mechanistic models and their applications in biotechnology, including future perspectives. Model utility is highlighted with respect to selection of...... variables required for measurement, control and process design. In the near future, mechanistic models with a higher degree of detail will play key roles in the development of efficient next-generation fermentation and biocatalytic processes. Moreover, mechanistic models will be used increasingly in the...

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

    Science.gov (United States)

    Koch, Boris

    2016-04-01

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

  3. Chemical foundations of hydrogen sulfide biology.

    Science.gov (United States)

    Li, Qian; Lancaster, Jack R

    2013-11-30

    Following nitric oxide (nitrogen monoxide) and carbon monoxide, hydrogen sulfide (or its newer systematic name sulfane, H2S) became the third small molecule that can be both toxic and beneficial depending on the concentration. In spite of its impressive therapeutic potential, the underlying mechanisms for its beneficial effects remain unclear. Any novel mechanism has to obey fundamental chemical principles. H2S chemistry was studied long before its biological relevance was discovered, however, with a few exceptions, these past works have received relatively little attention in the path of exploring the mechanistic conundrum of H2S biological functions. This review calls attention to the basic physical and chemical properties of H2S, focuses on the chemistry between H2S and its three potential biological targets: oxidants, metals and thiol derivatives, discusses the applications of these basics into H2S biology and methodology, and introduces the standard terminology to this youthful field. PMID:23850631

  4. Clinical pharmacology considerations in biologics development

    Institute of Scientific and Technical Information of China (English)

    Liang ZHAO; Tian-hua REN; Diane D WANG

    2012-01-01

    Biologics,including monoclonal antibodies (mAbs) and other therapeutic proteins such as cytokines and growth hormones,have unique characteristics compared to small molecules.This paper starts from an overview of the pharmacokinetics (PK) of biologics from a mechanistic perspective,the determination of a starting dose for first-in-human(FIH) studies,and dosing regimen optimisation for phase Ⅱ/Ⅲ clinical trials.Subsequently,typical clinical pharmacology issues along the corresponding pathways for biologics development are summarised,including drug-drug interactions,QTc prolongation,immunogenicity,and studies in specific populations.The relationships between the molecular structure of biologics,their pharmacokinetic and pharmacodynamic characteristics,and the corresponding clinical pharmacology strategies are summarised and depicted in a schematic diagram.

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

    Science.gov (United States)

    Fornarini, S

    1996-01-01

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

  6. Towards a mechanistic understanding of actinide retention by cementitious materials

    International Nuclear Information System (INIS)

    Full text of publication follows. Calcium silicate hydrate (C-S-H) are considered to be the most important constituent of hardened cement paste (HCP) with respect to their abundance and the diversity of structural sites exposed for cation and anion binding. Furthermore, C-S-H phases may control the long term release of radionuclides due to their stability during the evolution of the cementitious near field. The retention of Nd (III) by crystalline C-S-H phases has been studied by combined use of wet chemical methods, synchrotron based spectroscopic, laboratory-based X-ray diffraction techniques and an appropriate theoretical approach. The investigations enable us to propose a mechanistic model for the immobilisation of trivalent lanthanides and actinides in crystalline C-S-H phases. (authors)

  7. A General Mechanistic Model of Solid Oxide Fuel Cells

    Institute of Scientific and Technical Information of China (English)

    SHI Yixiang; CAI Ningsheng

    2006-01-01

    A comprehensive model considering all forms of polarization was developed. The model considers the intricate interdependency among the electrode microstructure, the transport phenomena, and the electrochemical processes. The active three-phase boundary surface was expressed as a function of electrode microstructure parameters (porosity, coordination number, contact angle, etc.). The exchange current densities used in the simulation were obtained by fitting a general formulation to the polarization curves proposed as a function of cell temperature and oxygen partial pressure. A validation study shows good agreement with published experimental data. Distributions of overpotentials, gas component partial pressures, and electronic/ionic current densities have been calculated. The effects of a porous electrode structure and of various operation conditions on cell performance were also predicted. The mechanistic model proposed can be used to interpret experimental observations and optimize cell performance by incorporating reliable experimental data.

  8. Mechanistic Multidimensional Modeling of Forced Convection Boiling Heat Transfer

    Directory of Open Access Journals (Sweden)

    Michael Z. Podowski

    2009-01-01

    Full Text Available Due to the importance of boiling heat transfer in general, and boiling crisis in particular, for the analysis of operation and safety of both nuclear reactors and conventional thermal power systems, extensive efforts have been made in the past to develop a variety of methods and tools to evaluate the boiling heat transfer coefficient and to assess the onset of temperature excursion and critical heat flux (CHF at various operating conditions of boiling channels. The objective of this paper is to present mathematical modeling concepts behind the development of mechanistic multidimensional models of low-quality forced convection boiling, including the mechanisms leading to temperature excursion and the onset of CHF.

  9. Beyond Hebb: exclusive-OR and biological learning.

    Science.gov (United States)

    Klemm, K; Bornholdt, S; Schuster, H G

    2000-03-27

    A learning algorithm for multilayer neural networks based on biologically plausible mechanisms is studied. Motivated by findings in experimental neurobiology, we consider synaptic averaging in the induction of plasticity changes, which happen on a slower time scale than firing dynamics. This mechanism is shown to enable learning of the exclusive-OR (XOR) problem without the aid of error backpropagation, as well as to increase robustness of learning in the presence of noise. PMID:11018999

  10. Beyond Hebb: Exclusive-OR and Biological Learning

    OpenAIRE

    Klemm, Konstantin; Bornholdt, Stefan; Schuster, Heinz Georg

    1999-01-01

    A learning algorithm for multilayer neural networks based on biologically plausible mechanisms is studied. Motivated by findings in experimental neurobiology, we consider synaptic averaging in the induction of plasticity changes, which happen on a slower time scale than firing dynamics. This mechanism is shown to enable learning of the exclusive-OR (XOR) problem without the aid of error back-propagation, as well as to increase robustness of learning in the presence of noise.

  11. Evolutionary cell biology: two origins, one objective.

    Science.gov (United States)

    Lynch, Michael; Field, Mark C; Goodson, Holly V; Malik, Harmit S; Pereira-Leal, José B; Roos, David S; Turkewitz, Aaron P; Sazer, Shelley

    2014-12-01

    All aspects of biological diversification ultimately trace to evolutionary modifications at the cellular level. This central role of cells frames the basic questions as to how cells work and how cells come to be the way they are. Although these two lines of inquiry lie respectively within the traditional provenance of cell biology and evolutionary biology, a comprehensive synthesis of evolutionary and cell-biological thinking is lacking. We define evolutionary cell biology as the fusion of these two eponymous fields with the theoretical and quantitative branches of biochemistry, biophysics, and population genetics. The key goals are to develop a mechanistic understanding of general evolutionary processes, while specifically infusing cell biology with an evolutionary perspective. The full development of this interdisciplinary field has the potential to solve numerous problems in diverse areas of biology, including the degree to which selection, effectively neutral processes, historical contingencies, and/or constraints at the chemical and biophysical levels dictate patterns of variation for intracellular features. These problems can now be examined at both the within- and among-species levels, with single-cell methodologies even allowing quantification of variation within genotypes. Some results from this emerging field have already had a substantial impact on cell biology, and future findings will significantly influence applications in agriculture, medicine, environmental science, and synthetic biology. PMID:25404324

  12. Biology Notes.

    Science.gov (United States)

    School Science Review, 1982

    1982-01-01

    Presents procedures, exercises, demonstrations, and information on a variety of biology topics including labeling systems, biological indicators of stream pollution, growth of lichens, reproductive capacity of bulbous buttercups, a straw balance to measure transpiration, interaction of fungi, osmosis, and nitrogen fixation and crop production. (DC)

  13. Mechanistic aspects of ingested chlorine dioxide on thyroid function: impact of oxidants on iodide metabolism

    International Nuclear Information System (INIS)

    Toxicological studies dealing with recent findings of health effects of drinking water disinfectants are reviewed. Experiments with monkeys and rodents indicate that the biological activity of ingested disinfectants is expressed via their chemical interaction with the mucosal epithelia, secretory products, and nutritional contents of the alimentary tract. Evidence exists that a principal partner of this redox interaction is the iodide of nutritional origin that is ubiquitous in the gastrointestinal tract. Thus the observation that subchronic exposure to chlorine dioxide (ClO2) in drinking water decreases serum thyroxine levels in mammalian species can be best explained with changes produced in the chemical form of the bioavailable iodide. Ongoing and previously reported mechanistic studies indicate that oxidizing agents such as chlorine-based disinfectants oxidize the basal iodide content of the gastrointestinal tract. The resulting reactive iodine species readily attaches to organic matter by covalent bonding. Evidence suggests that the extent to which such iodinated organics are formed is proportional to the magnitude of the electromotive force and stoichiometry of the redox couple between iodide and the disinfectant. Because the extent of thyroid uptake of the bioavailable iodide does not decrease during ClO2 ingestion, it seems that ClO2 does not cause iodide deficiency of sufficient magnitude to account for the decease in hormonogenesis. Absorption of one or more of iodinated molecules, e.g., nutrient, hormones, or cellular constituents of the alimentary tract having thyromimetic or thyroid inhibitory properties, is a better hypothesis for the effects seen

  14. Reactivities of d~0 transition metal complexes toward oxygen:Synthetic and mechanistic studies

    Institute of Scientific and Technical Information of China (English)

    CHEN ShuJian; ZHANG XinHao; LIN ZhenYang; WU YunDong; XUE ZiLing

    2009-01-01

    Transition metals such as Fe in porphyrin complexes are known to bind or react with O_2,and such reactions are critical to many biological functions and catalytic oxidation using O_2.The transition metals in these reactions often contain valence d electrons,and oxidation of metals is an important step.In recent years,reactions of O_2 with d~0 transition metal complexes such as Hf(NR_2)_4 (R=alkyl) have been used to make metal oxide thin films as insulating gate materials in new microelectronic devices.This feature article discusses our recent studies of such reactions and the formation of TiO_2 thin films.In contrast to the reactions of many d~n complexes where metals are often oxidized,reactions of d~0 complexes such as Hf(Nme_2)_4 and Ta(Nme_2)_4(SiR_3) with O_2 usually lead to the oxidation of ligands,forming,e.g.,-ONMe_2 and-OSiR_3 from-Nme_2 and-SiR_3 ligands,respectively.Mechanistic and theoretical studies of these reactions have revealed pathways in the formation of the metal oxide thin films as microelectronic materials.

  15. Exploring novel mechanistic insights in Alzheimer's disease by assessing reliability of protein interactions.

    Science.gov (United States)

    Malhotra, Ashutosh; Younesi, Erfan; Sahadevan, Sudeep; Zimmermann, Joerg; Hofmann-Apitius, Martin

    2015-01-01

    Protein interaction networks are widely used in computational biology as a graphical means of representing higher-level systemic functions in a computable form. Although, many algorithms exist that seamlessly collect and measure protein interaction information in network models, they often do not provide novel mechanistic insights using quantitative criteria. Measuring information content and knowledge representation in network models about disease mechanisms becomes crucial particularly when exploring new target candidates in a well-defined functional context of a potential disease mechanism. To this end, we have developed a knowledge-based scoring approach that uses literature-derived protein interaction features to quantify protein interaction confidence. Thereby, we introduce the novel concept of knowledge cliffs, regions of the interaction network where a significant gap between high scoring and low scoring interactions is observed, representing a divide between established and emerging knowledge on disease mechanism. To show the application of this approach, we constructed and assessed reliability of a protein-protein interaction model specific to Alzheimer's disease, which led to screening, and prioritization of four novel protein candidates. Evaluation of the identified candidates showed that two of them are already followed in clinical trials for testing potential AD drugs. PMID:26346705

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

    Science.gov (United States)

    Maggi, F.; Gu, C.; Riley, W. J.; Hornberger, G. M.; Venterea, R. T.; Xu, T.; Spycher, N.; Steefel, C.; Miller, N. L.; Oldenburg, C. M.

    2008-06-01

    The development and initial application of a mechanistic model (TOUGHREACT-N) designed to characterize soil nitrogen (N) cycling and losses are described. The model couples advective and diffusive nutrient transport, multiple microbial biomass dynamics, and equilibrium and kinetic chemical reactions. TOUGHREACT-N was calibrated and tested against field measurements to assess pathways of N loss as either gas emission or solute leachate following fertilization and irrigation in a Central Valley, California, agricultural field as functions of fertilizer application rate and depth, and irrigation water volume. Our results, relative to the period before plants emerge, show that an increase in fertilizer rate produced a nonlinear response in terms of N losses. An increase of irrigation volume produced NO2- and NO3- leaching, whereas an increase in fertilization depth mainly increased leaching of all N solutes. In addition, nitrifying bacteria largely increased in mass with increasing fertilizer rate. Increases in water application caused nitrifiers and denitrifiers to decrease and increase their mass, respectively, while nitrifiers and denitrifiers reversed their spatial stratification when fertilizer was applied below 15 cm depth. Coupling aqueous advection and diffusion, and gaseous diffusion with biological processes, closely captured actual conditions and, in the system explored here, significantly clarified interpretation of field measurements.

  17. A Mechanistic Treatment of the Dominant Soil Nitrogen Cycling Processes: Model Development, Testing, and Application

    Energy Technology Data Exchange (ETDEWEB)

    Riley, William; Maggi, F.; Gu, C.; Riley, W.J.; Hornberger, G.M.; Venterea, R.T.; Xu, T.; Spycher, N.; Steefel, C.; Miller, N.L.; Oldenburg, C.M.

    2008-05-01

    The development and initial application of a mechanistic model (TOUGHREACT-N) designed to characterize soil nitrogen (N) cycling and losses are described. The model couples advective and diffusive nutrient transport, multiple microbial biomass dynamics, and equilibrium and kinetic chemical reactions. TOUGHREACT-N was calibrated and tested against field measurements to assess pathways of N loss as either gas emission or solute leachate following fertilization and irrigation in a Central Valley, California, agricultural field as functions of fertilizer application rate and depth, and irrigation water volume. Our results, relative to the period before plants emerge, show that an increase in fertilizer rate produced a nonlinear response in terms of N losses. An increase of irrigation volume produced NO{sub 2}{sup -} and NO{sub 3}{sup -} leaching, whereas an increase in fertilization depth mainly increased leaching of all N solutes. In addition, nitrifying bacteria largely increased in mass with increasing fertilizer rate. Increases in water application caused nitrifiers and denitrifiers to decrease and increase their mass, respectively, while nitrifiers and denitrifiers reversed their spatial stratification when fertilizer was applied below 15 cm depth. Coupling aqueous advection and diffusion, and gaseous diffusion with biological processes, closely captured actual conditions and, in the system explored here, significantly clarified interpretation of field measurements.

  18. MESMO 2: a mechanistic marine silica cycle and coupling to a simple terrestrial scheme

    Directory of Open Access Journals (Sweden)

    K. Matsumoto

    2012-09-01

    Full Text Available Here we describe the second version of Minnesota Earth System Model for Ocean biogeochemistry (MESMO 2, an earth system model of intermediate complexity, which consists of a dynamical ocean, dynamic-thermodynamic sea ice, and energy moisture balanced atmosphere. The new version has more realistic land ice masks and is driven by seasonal winds. A major aim in version 2 is representing the marine silica cycle mechanistically in order to investigate climate-carbon feedbacks involving diatoms, a critically important class of phytoplankton in terms of carbon export production. This is achieved in part by including iron, on which phytoplankton uptake of silicic acid depends. Also, MESMO 2 is coupled to an existing terrestrial model, which allows for the exchange of carbon, water, and energy between land and the atmosphere. The coupled model, called MESMO 2E, is appropriate for more complete earth system simulations. The new version was calibrated with the goal of preserving reasonable interior ocean ventilation and various biological production rates in the ocean and land, while simulating key features of the marine silica cycle.

  19. 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.

  20. Chemopreventive and therapeutic potentials of thymoquinone in HepG2 cells: mechanistic perspectives.

    Science.gov (United States)

    ElKhoely, Abeer; Hafez, Hafez F; Ashmawy, Abeer M; Badary, Osama; Abdelaziz, Ahmed; Mostafa, Adel; Shouman, Samia A

    2015-07-01

    Liver cancer is the fifth commonest malignancy worldwide and the third leading cause of death. Identifying novel curative and preventive therapy may improve its prognosis. In this study, thymoquinone (TQ), the most active biological ingredient of Nigella sativa Linn, was investigated for its antitumor activity. Mechanistic perspectives underlying this antitumor activity were explored by testing its effect on cell cycle, apoptosis, and angiogenesis. In addition, the chemopreventive effect of TQ was carried out by measuring its effect on phase I CYP1A1 and phase II glutathione S-transferase (GST) drug-metabolizing enzymes. The results of the present study revealed the effectiveness of TQ as an antitumor agent against different types of cancer including brain, colon, cervix and liver at both a time- and concentration-dependent manner. In HepG2 cells, it induced G2/M phase cell cycle arrest and a concentration-dependent increase in the percentage of apoptotic cells with an increase in the ratio of Bax/BCL-2. Moreover, the expression of mRNA and protein level of vascular endothelial growth factor decreased as the concentration of TQ increased. Our data showed a significant inhibition of induced phase I CYP1A1 enzyme, and elevation in the content of glutathione and activity of phase II enzyme GST, in HepG2 cells. Our results provide support for the beneficial use of TQ as a therapeutic and chemopreventive agent against liver cancer. PMID:25796541

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

    International Nuclear Information System (INIS)

    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)

  2. Mechanistic investigations of unsaturated glucuronyl hydrolase from Clostridium perfringens.

    Science.gov (United States)

    Jongkees, Seino A K; Yoo, Hayoung; Withers, Stephen G

    2014-04-18

    Experiments were carried out to probe the details of the hydration-initiated hydrolysis catalyzed by the Clostridium perfringens unsaturated glucuronyl hydrolase of glycoside hydrolase family 88 in the CAZy classification system. Direct (1)H NMR monitoring of the enzymatic reaction detected no accumulated reaction intermediates in solution, suggesting that rearrangement of the initial hydration product occurs on-enzyme. An attempt at mechanism-based trapping of on-enzyme intermediates using a 1,1-difluoro-substrate was unsuccessful because the probe was too deactivated to be turned over by the enzyme. Kinetic isotope effects arising from deuterium-for-hydrogen substitution at carbons 1 and 4 provide evidence for separate first-irreversible and overall rate-determining steps in the hydration reaction, with two potential mechanisms proposed to explain these results. Based on the positioning of catalytic residues in the enzyme active site, the lack of efficient turnover of a 2-deoxy-2-fluoro-substrate, and several unsuccessful attempts at confirmation of a simpler mechanism involving a covalent glycosyl-enzyme intermediate, the most plausible mechanism is one involving an intermediate bearing an epoxide on carbons 1 and 2. PMID:24573682

  3. Sensitivity of Anopheles gambiae population dynamics to meteo-hydrological variability: a mechanistic approach

    Directory of Open Access Journals (Sweden)

    Gilioli Gianni

    2011-10-01

    Full Text Available Abstract Background Mechanistic models play an important role in many biological disciplines, and they can effectively contribute to evaluate the spatial-temporal evolution of mosquito populations, in the light of the increasing knowledge of the crucial driving role on vector dynamics played by meteo-climatic features as well as other physical-biological characteristics of the landscape. Methods In malaria eco-epidemiology landscape components (atmosphere, water bodies, land use interact with the epidemiological system (interacting populations of vector, human, and parasite. In the background of the eco-epidemiological approach, a mosquito population model is here proposed to evaluate the sensitivity of An. gambiae s.s. population to some peculiar thermal-pluviometric scenarios. The scenarios are obtained perturbing meteorological time series data referred to four Kenyan sites (Nairobi, Nyabondo, Kibwesi, and Malindi representing four different eco-epidemiological settings. Results Simulations highlight a strong dependence of mosquito population abundance on temperature variation with well-defined site-specific patterns. The upper extreme of thermal perturbation interval (+ 3°C gives rise to an increase in adult population abundance at Nairobi (+111% and Nyabondo (+61%, and a decrease at Kibwezi (-2% and Malindi (-36%. At the lower extreme perturbation (-3°C is observed a reduction in both immature and adult mosquito population in three sites (Nairobi -74%, Nyabondo -66%, Kibwezi -39%, and an increase in Malindi (+11%. A coherent non-linear pattern of population variation emerges. The maximum rate of variation is +30% population abundance for +1°C of temperature change, but also almost null and negative values are obtained. Mosquitoes are less sensitive to rainfall and both adults and immature populations display a positive quasi-linear response pattern to rainfall variation. Conclusions The non-linear temperature-dependent response is in

  4. Quantum Biology

    Directory of Open Access Journals (Sweden)

    Alessandro Sergi

    2009-06-01

    Full Text Available A critical assessment of the recent developmentsof molecular biology is presented.The thesis that they do not lead to a conceptualunderstanding of life and biological systems is defended.Maturana and Varela's concept of autopoiesis is briefly sketchedand its logical circularity avoided by postulatingthe existence of underlying living processes,entailing amplification from the microscopic to the macroscopic scale,with increasing complexity in the passage from one scale to the other.Following such a line of thought, the currently accepted model of condensed matter, which is based on electrostatics and short-ranged forces,is criticized. It is suggested that the correct interpretationof quantum dispersion forces (van der Waals, hydrogen bonding, and so onas quantum coherence effects hints at the necessity of includinglong-ranged forces (or mechanisms for them incondensed matter theories of biological processes.Some quantum effects in biology are reviewedand quantum mechanics is acknowledged as conceptually important to biology since withoutit most (if not all of the biological structuresand signalling processes would not even exist. Moreover, it is suggested that long-rangequantum coherent dynamics, including electron polarization,may be invoked to explain signal amplificationprocess in biological systems in general.

  5. Inhalation toxicity of propineb. Part II: Results of mechanistic studies in rats.

    Science.gov (United States)

    Pauluhn, Jürgen; Emura, M; Mohr, U; Rosenbruch, Martin

    2003-04-25

    Previous repeated inhalation exposure studies revealed two independent organotropic effects of inhaled propineb dust: One was restricted to the lung, the other to muscle weakness of hindlimbs. These effects were believed to be causally related to the principle decomposition products of this type of dithiocarbamate in the biological milieu and related to zinc and carbon disulfide. Two mechanistic 1-wk inhalation studies were performed, each focusing on one of these findings. The 7 x 6-h/day repeated-exposure inhalation study analyzed whether the nature of the response occurring at the alveolar level is "adaptive" or "early adverse" and whether soluble zinc is the causative agent. Groups of 18 female rats were exposed nose-only to mean concentrations of 0, 1.1, 5.5, and 25.8 mg propineb/m(3) and 6.9 mg ZnO/m(3). On postexposure days 1, 3, and 15 the time course of responses was analyzed by bronchoalveolar lavage (BAL), including quantification of Zn and metallothionein (MT) in BAL cells. Clinical evidence of muscular weakness was investigated separately in 20 female Wistar rats exposed to 70 mg propineb/m(3) on 5 consecutive days (6 h/day), followed by a 2-wk postexposure period. Clinical signs, body weights, and feed and water consumption were recorded as frequently as technically feasible. Fifty percent of rats received an oral cysteine supplementation to verify/refute the hypothesis that the incapacitation observed in previous studies is the cause of emaciation and associated impairment of CS(2) detoxification. The findings of the first study are consistent with this hypothesis, namely, that soluble Zn triggers a series of pulmonary events that is consistent with the homeostasis of this essential metal. It is concluded, accordingly, that the adjusted maximal workplace level for ZnO is also valid for propineb to preclude Zn-mediated responses to occur in the lung. With respect to muscular effects, this mechanistic study demonstrates further that the increased

  6. Mechanistic approaches to the study of evolution: the functional synthesis

    OpenAIRE

    Dean, Antony M; Joseph W Thornton

    2007-01-01

    An emerging synthesis of evolutionary biology and experimental molecular biology is providing much stronger and deeper inferences about the dynamics and mechanisms of evolution than were possible in the past. The new approach combines statistical analyses of gene sequences with manipulative molecular experiments to reveal how ancient mutations altered biochemical processes and produced novel phenotypes. This functional synthesis has set the stage for major advances in our understanding of fun...

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

    Science.gov (United States)

    Shaver, Dillon R.

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

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

    Science.gov (United States)

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

    2016-04-01

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

  9. Quantum Biology

    CERN Document Server

    Sergi, Alessandro

    2009-01-01

    A critical assessment of the recent developments of molecular biology is presented. The thesis that they do not lead to a conceptual understanding of life and biological systems is defended. Maturana and Varela's concept of autopoiesis is briefly sketched and its logical circularity avoided by postulating the existence of underlying {\\it living processes}, entailing amplification from the microscopic to the macroscopic scale, with increasing complexity in the passage from one scale to the other. Following such a line of thought, the currently accepted model of condensed matter, which is based on electrostatics and short-ranged forces, is criticized. It is suggested that the correct interpretation of quantum dispersion forces (van der Waals, hydrogen bonding, and so on) as quantum coherence effects hints at the necessity of including long-ranged forces (or mechanisms for them) in condensed matter theories of biological processes. Some quantum effects in biology are reviewed and quantum mechanics is acknowledge...

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

    International Nuclear Information System (INIS)

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

  11. Mechanistic studies of ethylene biosynthesis in higher plants

    International Nuclear Information System (INIS)

    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. 13C 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

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

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Julian C.-H., E-mail: chen@chemie.uni-frankfurt.de [Institute of Biophysical Chemistry, Goethe University Frankfurt, Max-von-Laue-Strasse 9, 60438 Frankfurt (Germany); Mustyakimov, Marat; Schoenborn, Benno P. [Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545 (United States); Langan, Paul [Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545 (United States); Department of Chemistry, University of Toledo, Toledo, OH 53606 (United States); Blum, Marc-Michael [Institute of Biophysical Chemistry, Goethe University Frankfurt, Max-von-Laue-Strasse 9, 60438 Frankfurt (Germany); Blum Scientific Services, Ledererstrasse 23, 80331 Munich (Germany)

    2010-11-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

  14. Circadian rhythms and addiction: mechanistic insights and future directions.

    Science.gov (United States)

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

    2014-06-01

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

  15. Mechanistic evaluation of virus clearance by depth filtration.

    Science.gov (United States)

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

    2015-01-01

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

  16. A global scale mechanistic model of the photosynthetic capacity

    Science.gov (United States)

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

    2015-08-01

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

  17. Mechanistic study of aerosols dry deposition onto vegetated canopies

    International Nuclear Information System (INIS)

    Aerosols dry deposition onto agricultural and forest areas is investigated. A special attention is given to highly rough surfaces and sub-micron aerosols, for which the estimation of the deposition is still uncertain. In fact the models used in radiological risk or air quality assessment studies are highly empirical and fail to reproduce the results of the most recent measurement campaigns. Therefore a theoretical framework, based on a mechanistic description, has been developed. The proposed approach consists in two steps. First, the interaction between aerosols and foliar surface is formulated by using a set of parameters, which are defined on the local scale of one foliar element. In the second step, the collective effect of the foliage is taken into account through statistical distribution of these parameters. The model integrates the three main aspects of aerosol dry deposition. These are the local aerodynamic characteristics of the flow within the canopy, the aerosol mechanisms governing the deposition, and the structural and morphological properties of the canopy. The physical processes considered in the study are inertial impaction, gravitational settling, brownian and turbulent diffusion, interception and turbulent impaction. The canopy characteristics considered are the spatial distribution, orientation and micro-structure of the foliar surfaces. The applicability of this framework is demonstrated in a realistic situation: for a given canopy and aerodynamic conditions, the spatial distribution of the aerosol captation by the foliage can be quantified. It enables to simulate numerically the distribution of aerosol concentration within the canopy and the overall deposition flux. (author)

  18. DNB analysis with mechanistic models for PWR fuel assemblies

    International Nuclear Information System (INIS)

    In order to predict the DNB heat flux of PWR fuel assemblies and the critical power of BWR fuel bundles, the Boiling Transition Analysis Code CAPE' has been developed in the IMPACT project. The CAPE code for PWR includes three analysis modules, subchannel analysis module, three-dimensional two-phase flow analysis module, and DNB evaluation module. The subchannel module uses drift-flux model to identify the hottest subchannel. The three-dimensional two-phase flow analysis module uses nonhomogeneous and nonequilibrium two fluid model to analyze the detailed three-dimensional two-phase flow behaviors such as void distribution. For DNB heat flux prediction, the DNB evaluation module uses the Weisman model in which is a mechanistic DNB evaluation model. This paper describes the analysis models, analysis techniques and the results of validation by rod bundle test analysis. To date, the average difference between calculated and 11 measured values was -0.6% with a standard deviation of 7.0%. (author)

  19. A mechanistic approach to postirradiation spoilage kinetics of fish

    International Nuclear Information System (INIS)

    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 +2oC 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

  20. A global scale mechanistic model of the photosynthetic capacity

    Science.gov (United States)

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

    2015-12-01

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

  1. A global scale mechanistic model of the photosynthetic capacity

    Directory of Open Access Journals (Sweden)

    A. A. Ali

    2015-08-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

  4. A Mechanistic Model of a Passive Autocatalytic Hydrogen Recombiner

    Directory of Open Access Journals (Sweden)

    Rożeń Antoni

    2015-03-01

    Full Text Available : A passive autocatalytic hydrogen recombiner (PAR is a self-starting device, without operator action or external power input, installed in nuclear power plants to remove hydrogen from the containment building of a nuclear reactor. A new mechanistic model of PAR has been presented and validated by experimental data and results of Computational Fluid Dynamics (CFD simulations. The model allows to quickly and accurately predict gas temperature and composition, catalyst temperature and hydrogen recombination rate. It is assumed in the model that an exothermic recombination reaction of hydrogen and oxygen proceeds at the catalyst surface only, while processes of heat and mass transport occur by assisted natural and forced convection in non-isothermal and laminar gas flow conditions in vertical channels between catalyst plates. The model accounts for heat radiation from a hot catalyst surface and has no adjustable parameters. It can be combined with an equation of chimney draft and become a useful engineering tool for selection and optimisation of catalytic recombiner geometry.

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

    Science.gov (United States)

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

    2015-03-31

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

  6. [Medical and biological consequences of nuclear disasters].

    Science.gov (United States)

    Stalpers, Lukas J A; van Dullemen, Simon; Franken, N A P Klaas

    2012-01-01

    Medical risks of radiation exaggerated; psychological risks underestimated. The discussion about atomic energy has become topical again following the nuclear accident in Fukushima. There is some argument about the gravity of medical and biological consequences of prolonged exposure to radiation. The risk of cancer following a low dose of radiation is usually estimated by linear extrapolation of the incidence of cancer among survivors of the atomic bombs dropped on Hiroshima and Nagasaki in 1945. The radiobiological linear-quadratic model (LQ-model) gives a more accurate description of observed data, is radiobiologically more plausible and is better supported by experimental and clinical data. On the basis of this model there is less risk of cancer being induced following radiation exposure. The gravest consequence of Chernobyl and Fukushima is not the medical and biological damage, but the psychological and economical impact on rescue workers and former inhabitants. PMID:22607840

  7. Trimethylamine-N-oxide switches from stabilizing nature: A mechanistic outlook through experimental techniques and molecular dynamics simulation.

    Science.gov (United States)

    Rani, Anjeeta; Jayaraj, Abhilash; Jayaram, B; Pannuru, Venkatesu

    2016-01-01

    In adaptation biology of the discovery of the intracellular osmolytes, the osmolytes are found to play a central role in cellular homeostasis and stress response. A number of models using these molecules are now poised to address a wide range of problems in biology. Here, a combination of biophysical measurements and molecular dynamics (MD) simulation method is used to examine the effect of trimethylamine-N-oxide (TMAO) on stem bromelain (BM) structure, stability and function. From the analysis of our results, we found that TMAO destabilizes BM hydrophobic pockets and active site as a result of concerted polar and non-polar interactions which is strongly evidenced by MD simulation carried out for 250 ns. This destabilization is enthalpically favourable at higher concentrations of TMAO while entropically unfavourable. However, to the best of our knowledge, the results constitute first detailed unambiguous proof of destabilizing effect of most commonly addressed TMAO on the interactions governing stability of BM and present plausible mechanism of protein unfolding by TMAO. PMID:27025561

  8. A computational approach to mechanistic and predictive toxicology of pesticides

    DEFF Research Database (Denmark)

    Kongsbak, Kristine Grønning; Vinggaard, Anne Marie; Hadrup, Niels;

    2014-01-01

    Emerging challenges of managing and interpreting large amounts of complex biological data have given rise to the growing field of computational biology. We investigated the applicability of an integrated systems toxicology approach on five selected pesticides to get an overview of their modes...... protein interactome. Then, we explored modes of action of the chemicals, by integrating protein-disease information to the resulting protein networks. The dominating human adverse effects affected were reproductive disorders followed by adrenal diseases. Our results indicated that prochloraz, tebuconazole...

  9. Mechanistic, mathematical model to predict the dynamics of tissue genesis in bone defects via mechanical feedback and mediation of biochemical factors.

    Directory of Open Access Journals (Sweden)

    Shannon R Moore

    2014-06-01

    Full Text Available The link between mechanics and biology in the generation and the adaptation of bone has been well studied in context of skeletal development and fracture healing. Yet, the prediction of tissue genesis within - and the spatiotemporal healing of - postnatal defects, necessitates a quantitative evaluation of mechano-biological interactions using experimental and clinical parameters. To address this current gap in knowledge, this study aims to develop a mechanistic mathematical model of tissue genesis using bone morphogenetic protein (BMP to represent of a class of factors that may coordinate bone healing. Specifically, we developed a mechanistic, mathematical model to predict the dynamics of tissue genesis by periosteal progenitor cells within a long bone defect surrounded by periosteum and stabilized via an intramedullary nail. The emergent material properties and mechanical environment associated with nascent tissue genesis influence the strain stimulus sensed by progenitor cells within the periosteum. Using a mechanical finite element model, periosteal surface strains are predicted as a function of emergent, nascent tissue properties. Strains are then input to a mechanistic mathematical model, where mechanical regulation of BMP-2 production mediates rates of cellular proliferation, differentiation and tissue production, to predict healing outcomes. A parametric approach enables the spatial and temporal prediction of endochondral tissue regeneration, assessed as areas of cartilage and mineralized bone, as functions of radial distance from the periosteum and time. Comparing model results to histological outcomes from two previous studies of periosteum-mediated bone regeneration in a common ovine model, it was shown that mechanistic models incorporating mechanical feedback successfully predict patterns (spatial and trends (temporal of bone tissue regeneration. The novel model framework presented here integrates a mechanistic feedback system based

  10. Biological Oceanography

    Science.gov (United States)

    Abbott, M. R.

    1984-01-01

    Within the framework of global biogeochemical cycles and ocean productivity, there are two areas that will be of particular interest to biological oceanography in the 1990s. The first is the mapping in space time of the biomass and productivity of phytoplankton in the world ocean. The second area is the coupling of biological and physical processes as it affects the distribution and growth rate of phytoplankton biomass. Certainly other areas will be of interest to biological oceanographers, but these two areas are amenable to observations from satellites. Temporal and spatial variability is a regular feature of marine ecosystems. The temporal and spatial variability of phytoplankton biomass and productivity which is ubiquitous at all time and space scales in the ocean must be characterized. Remote sensing from satellites addresses these problems with global observations of mesocale (2 to 20 days, 10 to 200 km) features over a long period of time.

  11. Biological preconcentrator

    Science.gov (United States)

    Manginell, Ronald P.; Bunker, Bruce C.; Huber, Dale L.

    2008-09-09

    A biological preconcentrator comprises a stimulus-responsive active film on a stimulus-producing microfabricated platform. The active film can comprise a thermally switchable polymer film that can be used to selectively absorb and desorb proteins from a protein mixture. The biological microfabricated platform can comprise a thin membrane suspended on a substrate with an integral resistive heater and/or thermoelectric cooler for thermal switching of the active polymer film disposed on the membrane. The active polymer film can comprise hydrogel-like polymers, such as poly(ethylene oxide) or poly(n-isopropylacrylamide), that are tethered to the membrane. The biological preconcentrator can be fabricated with semiconductor materials and technologies.

  12. 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

  13. 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.

  14. A partial mechanistic understanding of the North American monsoon

    Science.gov (United States)

    Erfani, Ehsan; Mitchell, David

    2014-12-01

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

  15. A mechanistic view of mitochondrial death decision pores

    Directory of Open Access Journals (Sweden)

    J.E. Belizário

    2007-08-01

    Full Text Available Mitochondria increase their outer and inner membrane permeability to solutes, protons and metabolites in response to a variety of extrinsic and intrinsic signaling events. The maintenance of cellular and intraorganelle ionic homeostasis, particularly for Ca2+, can determine cell survival or death. Mitochondrial death decision is centered on two processes: inner membrane permeabilization, such as that promoted by the mitochondrial permeability transition pore, formed across inner membranes when Ca2+ reaches a critical threshold, and mitochondrial outer membrane permeabilization, in which the pro-apoptotic proteins BID, BAX, and BAK play active roles. Membrane permeabilization leads to the release of apoptogenic proteins: cytochrome c, apoptosis-inducing factor, Smac/Diablo, HtrA2/Omi, and endonuclease G. Cytochrome c initiates the proteolytic activation of caspases, which in turn cleave hundreds of proteins to produce the morphological and biochemical changes of apoptosis. Voltage-dependent anion channel, cyclophilin D, adenine nucleotide translocase, and the pro-apoptotic proteins BID, BAX, and BAK may be part of the molecular composition of membrane pores leading to mitochondrial permeabilization, but this remains a central question to be resolved. Other transporting pores and channels, including the ceramide channel, the mitochondrial apoptosis-induced channel, as well as a non-specific outer membrane rupture may also be potential release pathways for these apoptogenic factors. In this review, we discuss the mechanistic models by which reactive oxygen species and caspases, via structural and conformational changes of membrane lipids and proteins, promote conditions for inner/outer membrane permeabilization, which may be followed by either opening of pores or a rupture of the outer mitochondrial membrane.

  16. Mechanistic Insights into Homogeneous and Heterogeneous Asymmetric Iron Catalysis

    Science.gov (United States)

    Sonnenberg, Jessica

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

  17. 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.

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

    Science.gov (United States)

    Jayasinghe, Saroj

    2011-01-01

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

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

    Science.gov (United States)

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

    2011-01-01

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

  20. Metabolic diseases and pro- and prebiotics: Mechanistic insights

    Directory of Open Access Journals (Sweden)

    Nakamura Yukiko K

    2012-06-01

    Full Text Available Abstract Metabolic diseases, such as obesity and type 2 diabetes, are world-wide health problems. The prevalence of metabolic diseases is associated with dynamic changes in dietary macronutrient intake during the past decades. Based on national statistics and from a public health viewpoint, traditional approaches, such as diet and physical activity, have been unsuccessful in decreasing the prevalence of metabolic diseases. Since the approaches strongly rely on individual’s behavior and motivation, novel science-based strategies should be considered for prevention and therapy for the diseases. Metabolism and immune system are linked. Both overnutrition and infection result in inflammation through nutrient and pathogen sensing systems which recognize compounds with structural similarities. Dietary macronutrients (fats and sugars can induce inflammation through activation of an innate immune receptor, Toll-like receptor 4 (TLR4. Long-term intake of diets high in fats and meats appear to induce chronic systemic low-grade inflammation, endotoxicity, and metabolic diseases. Recent investigations support the idea of the involvement of intestinal bacteria in host metabolism and preventative and therapeutic potentials of probiotic and prebiotic interventions for metabolic diseases. Specific intestinal bacteria seem to serve as lipopolysaccharide (LPS sources through LPS and/or bacterial translocation into the circulation due to a vulnerable microbial barrier and increased intestinal permeability and to play a role in systemic inflammation and progression of metabolic diseases. This review focuses on mechanistic links between metabolic diseases (mainly obesity and type 2 diabetes, chronic systemic low-grade inflammation, intestinal environment, and nutrition and prospective views of probiotic and prebiotic interventions for the diseases.

  1. Mechanistic Insights to the Cytotoxicity of Amaryllidaceae Alkaloids

    Czech Academy of Sciences Publication Activity Database

    Nair, J. J.; Rárová, L.; Strnad, Miroslav; Bastida, J.; van Staden, J.

    2015-01-01

    Roč. 10, č. 1 (2015), s. 171-182. ISSN 1934-578X Grant ostatní: GA MŠk(CZ) ED0007/01/01 Institutional support: RVO:61389030 Keywords : Alkaloid * Amaryllidaceae * Apoptosis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.906, year: 2014 http://www.ncbi.nlm.nih.gov/pubmed/25920242

  2. Marine Biology

    Science.gov (United States)

    Dewees, Christopher M.; Hooper, Jon K.

    1976-01-01

    A variety of informational material for a course in marine biology or oceanology at the secondary level is presented. Among the topics discussed are: food webs and pyramids, planktonic blooms, marine life, plankton nets, food chains, phytoplankton, zooplankton, larval plankton and filter feeders. (BT)

  3. Biology Notes.

    Science.gov (United States)

    School Science Review, 1983

    1983-01-01

    Describes laboratory procedures, demonstrations, and classroom activities/materials, including water relation exercise on auxin-treated artichoke tuber tissue; aerobic respiration in yeast; an improved potometer; use of mobiles in biological classification, and experiments on powdery mildews and banana polyphenol oxidase. Includes reading lists…

  4. Alterations in glucocorticoid negative feedback following maternal Pb, prenatal stress and the combination: A potential biological unifying mechanism for their corresponding disease profiles

    International Nuclear Information System (INIS)

    Combined exposures to maternal lead (Pb) and prenatal stress (PS) can act synergistically to enhance behavioral and neurochemical toxicity in offspring. Maternal Pb itself causes permanent dysfunction of the body's major stress system, the hypothalamic pituitary adrenal (HPA) axis. The current study sought to determine the potential involvement of altered negative glucocorticoid feedback as a mechanistic basis of the effects in rats of maternal Pb (0, 50 or 150 ppm in drinking water beginning 2 mo prior to breeding), prenatal stress (PS; restraint on gestational days 16-17) and combined maternal Pb + PS in 8 mo old male and female offspring. Corticosterone changes were measured over 24 h following an i.p. injection stress containing vehicle or 100 or 300 μg/kg (females) or 100 or 150 μg/kg (males) dexamethasone (DEX). Both Pb and PS prolonged the time course of corticosterone reduction following vehicle injection stress. Pb effects were non-monotonic, with a greater impact at 50 vs. 150 ppm, particularly in males, where further enhancement occurred with PS. In accord with these findings, the efficacy of DEX in suppressing corticosterone was reduced by Pb and Pb + PS in both genders, with Pb efficacy enhanced by PS in females, over the first 6 h post-administration. A marked prolongation of DEX effects was found in males. Thus, Pb, PS and Pb + PS, sometimes additively, produced hypercortisolism in both genders, followed by hypocortisolism in males, consistent with HPA axis dysfunction. These findings may provide a plausible unifying biological mechanism for the reported links between Pb exposure and stress-associated diseases and disorders mediated via the HPA axis, including obesity, hypertension, diabetes, anxiety, schizophrenia and depression. They also suggest broadening of Pb screening programs to pregnant women in high stress environments

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

    Energy Technology Data Exchange (ETDEWEB)

    Schwantes, Jon M.

    2009-06-01

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

  6. Mechanistic-empirical processor performance modeling for constructing CPI stacks on real hardware

    OpenAIRE

    Eyerman S.; Hoste K.; Eeckhout L.

    2011-01-01

    Analytical processor performance modeling has received increased interest over the past few years. There are basically two approaches to constructing an analytical model: mechanistic modeling and empirical modeling. Mechanistic modeling builds up an analytical model starting from a basic understanding of the underlying system - white-box approach - whereas empirical modeling constructs an analytical model through statistical inference and machine learning from training data, e.g., regression ...

  7. Reduction of dynamical biochemical reactions networks in computational biology

    OpenAIRE

    Radulescu, O.; Gorban, A.N.; Zinovyev, A.; Noel, V.

    2012-01-01

    Biochemical networks are used in computational biology, to model mechanistic details of systems involved in cell signaling, metabolism, and regulation of gene expression. Parametric and structural uncertainty, as well as combinatorial explosion are strong obstacles against analyzing the dynamics of large models of this type. Multiscaleness, an important property of these networks, can be used to get past some of these obstacles. Networks with many well separated time scales, can be reduced to...

  8. Biology of Human Papillomavirus–Related Oropharyngeal Cancer

    OpenAIRE

    Howard, Jason D.; Chung, Christine H.

    2012-01-01

    Recent data show that human papillomavirus–positive oropharyngeal cancer (OPC) has a distinct biological and clinical behavior compared with human papillomavirus–negative OPC. As this subset of head and neck cancer represents an increasing public health concern, a thorough understanding of the causative and mechanistic differences between these diseases and how these distinctions impact clinical treatment is required. In this review, we will summarize recent data in epidemiology, the mechanis...

  9. Cortically-controlled population stochastic facilitation as a plausible substrate for guiding sensory transfer across the thalamic gateway.

    Directory of Open Access Journals (Sweden)

    Sébastien Béhuret

    Full Text Available The thalamus is the primary gateway that relays sensory information to the cerebral cortex. While a single recipient cortical cell receives the convergence of many principal relay cells of the thalamus, each thalamic cell in turn integrates a dense and distributed synaptic feedback from the cortex. During sensory processing, the influence of this functional loop remains largely ignored. Using dynamic-clamp techniques in thalamic slices in vitro, we combined theoretical and experimental approaches to implement a realistic hybrid retino-thalamo-cortical pathway mixing biological cells and simulated circuits. The synaptic bombardment of cortical origin was mimicked through the injection of a stochastic mixture of excitatory and inhibitory conductances, resulting in a gradable correlation level of afferent activity shared by thalamic cells. The study of the impact of the simulated cortical input on the global retinocortical signal transfer efficiency revealed a novel control mechanism resulting from the collective resonance of all thalamic relay neurons. We show here that the transfer efficiency of sensory input transmission depends on three key features: i the number of thalamocortical cells involved in the many-to-one convergence from thalamus to cortex, ii the statistics of the corticothalamic synaptic bombardment and iii the level of correlation imposed between converging thalamic relay cells. In particular, our results demonstrate counterintuitively that the retinocortical signal transfer efficiency increases when the level of correlation across thalamic cells decreases. This suggests that the transfer efficiency of relay cells could be selectively amplified when they become simultaneously desynchronized by the cortical feedback. When applied to the intact brain, this network regulation mechanism could direct an attentional focus to specific thalamic subassemblies and select the appropriate input lines to the cortex according to the descending

  10. 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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-10-02

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

  12. Mechanistically distinct mouse models for CRX-associated retinopathy.

    Directory of Open Access Journals (Sweden)

    Nicholas M Tran

    2014-02-01

    Full Text Available Cone-rod homeobox (CRX protein is a "paired-like" homeodomain transcription factor that is essential for regulating rod and cone photoreceptor transcription. Mutations in human CRX are associated with the dominant retinopathies Retinitis Pigmentosa (RP, Cone-Rod Dystrophy (CoRD and Leber Congenital Amaurosis (LCA, with variable severity. Heterozygous Crx Knock-Out (KO mice ("+/-" have normal vision as adults and fail to model the dominant human disease. To investigate how different mutant CRX proteins produce distinct disease pathologies, we generated two Crx Knock-IN (K-IN mouse models: Crx(E168d2 ("E168d2" and Crx(R90W ("R90W". E168d2 mice carry a frameshift mutation in the CRX activation domain, Glu168del2, which is associated with severe dominant CoRD or LCA in humans. R90W mice carry a substitution mutation in the CRX homeodomain, Arg90Trp, which is associated with dominant mild late-onset CoRD and recessive LCA. As seen in human patients, heterozygous E168d2 ("E168d2/+" but not R90W ("R90W/+" mice show severely impaired retinal function, while mice homozygous for either mutation are blind and undergo rapid photoreceptor degeneration. E168d2/+ mice also display abnormal rod/cone morphology, greater impairment of CRX target gene expression than R90W/+ or +/- mice, and undergo progressive photoreceptor degeneration. Surprisingly, E168d2/+ mice express more mutant CRX protein than wild-type CRX. E168d2neo/+, a subline of E168d2 with reduced mutant allele expression, displays a much milder retinal phenotype, demonstrating the impact of Crx expression level on disease severity. Both CRX([E168d2] and CRX([R90W] proteins fail to activate transcription in vitro, but CRX([E168d2] interferes more strongly with the function of wild type (WT CRX, supporting an antimorphic mechanism. E168d2 and R90W are mechanistically distinct mouse models for CRX-associated disease that will allow the elucidation of molecular mechanisms and testing of novel

  13. Mesoscopic biology

    Indian Academy of Sciences (India)

    G V Shivashankar

    2002-02-01

    In this paper we present a qualitative outlook of mesoscopic biology where the typical length scale is of the order of nanometers and the energy scales comparable to thermal energy. Novel biomolecular machines, governed by coded information at the level of DNA and proteins, operate at these length scales in biological systems. In recent years advances in technology have led to the study of some of the design principles of these machines; in particular at the level of an individual molecule. For example, the forces that operate in molecular interactions, the stochasticity involved in these interactions and their spatio-temporal dynamics are beginning to be explored. Understanding such design principles is opening new possibilities in mesoscopic physics with potential applications.

  14. Testing for Plausibly Causal Links Between Parental Bereavement and Child Socio-Emotional and Academic Outcomes: A Propensity-Score Matching Model.

    Science.gov (United States)

    Williams, Leslie D; Lawrence Aber, J

    2016-05-01

    The extant literature on parentally bereaved children has focused almost exclusively on the presence of negative mental health and socio-emotional outcomes among these children. However, findings from this literature have been equivocal. While some authors have found support for the presence of higher levels of internalizing and externalizing problems or mental health problems among this population, others have not found such a relationship. Additionally, study designs in this body of literature have limited both the internal and external validity of the research on parentally bereaved children. The present study seeks to address these issues of internal and external validity by utilizing propensity-score matching analyses to make plausibly causal inferences about the relationship between bereavement and internalizing and externalizing problems among children from a nearly nationally representative sample. This study also extends examination of the influence of parental bereavement to other domains of child development: namely, to academic outcomes. Findings suggest a lack of support for causal relationships between parental bereavement and either socio-emotional or academic outcomes among U.S. children. The plausibility of assumptions necessary to draw causal inferences is discussed. PMID:26340883

  15. Biological programming

    OpenAIRE

    Ramsden, Jeremy J.; Bándi, Gergely

    2010-01-01

    Biology offers a tremendous set of concepts that are potentially very powerfully usable for the software engineer, but they have been barely exploited hitherto. In this position paper we propose a fresh attempt to create the building blocks of a programming technology that could be as successful as life. A key guiding principle is to develop and make use of unambiguous definitions of the essential features of life.

  16. Biological radioprotector

    International Nuclear Information System (INIS)

    According to the patent description, the biological radioprotector is deuterium depleted water, DDW, produced by vacuum distillation with an isotopic content lower than natural value. It appears as such or in a mixture with natural water and carbon dioxide. It can be used for preventing and reducing the ionizing radiation effects upon humans or animal organisms, exposed therapeutically, professionally or accidentally to radiation. The most significant advantage of using DDW as biological radioprotector results from its way of administration. Indeed no one of the radioprotectors currently used today can be orally administrated, what reduces the patients' compliance to prophylactic administrations. The biological radioprotector is an unnoxious product obtained from natural water, which can be administrated as food additive instead of drinking water. Dose modification factor is according to initial estimates around 1.9, what is a remarkable feature when one takes into account that the product is toxicity-free and side effect-free and can be administrated prophylactically as a food additive. A net radioprotective action of the deuterium depletion was evidenced experimentally in laboratory animals (rats) hydrated with DDW of 30 ppm D/(D+H) concentration as compared with normally hydrated control animals. Knowing the effects of irradiation and mechanisms of the acute radiation disease as well as the effects of administration of radiomimetic chemicals upon cellular lines of fast cell division, it appears that the effects of administrating DDW result from stimulation of the immunity system. In conclusion, the biological radioprotector DDW presents the following advantages: - it is obtained from natural products without toxicity; - it is easy to be administrated as a food additive, replacing the drinking water; - besides radioprotective effects, the product has also immunostimulative and antitumoral effects

  17. Marine biology

    International Nuclear Information System (INIS)

    This book discusses both taxonomic and ecological topics on marine biology. Full coverage of marine organisms of all five kingdoms is provided, along with interesting and thorough discussion of all major marine habitats. Organization into six major parts allows flexibility. It also provides insight into important topics such as disposal of nuclear waste at sea, the idea that life began on the ocean floor, and how whales, krill, and people interact. A full-color photo chapter reviews questions, and exercises. The contents are: an overview marine biology: fundamental concepts/investigating life in the ocean; the physical ocean, the ocean floor, the nature of water, the nature and motion of ocean water; general ecology, conditions for life in the sea, biological productivity and energy transfer; marine organisms; monera, protista, mycota and metaphyta; the smaller marine animals, the large animals marine habitats, the intertidal zone/benthos of the continental shelf, the photic zone, the deep ocean, the ocean under stress, marine pollution, appendix a: the metric system and conversion factors/ appendix b: prefixes and suffixes/ appendix c: taxonomic classification of common marine organisms, and glossary, and index

  18. Marine biology

    Energy Technology Data Exchange (ETDEWEB)

    Thurman, H.V.; Webber, H.H.

    1984-01-01

    This book discusses both taxonomic and ecological topics on marine biology. Full coverage of marine organisms of all five kingdoms is provided, along with interesting and thorough discussion of all major marine habitats. Organization into six major parts allows flexibility. It also provides insight into important topics such as disposal of nuclear waste at sea, the idea that life began on the ocean floor, and how whales, krill, and people interact. A full-color photo chapter reviews questions, and exercises. The contents are: an overview marine biology: fundamental concepts/investigating life in the ocean; the physical ocean, the ocean floor, the nature of water, the nature and motion of ocean water; general ecology, conditions for life in the sea, biological productivity and energy transfer; marine organisms; monera, protista, mycota and metaphyta; the smaller marine animals, the large animals marine habitats, the intertidal zone/benthos of the continental shelf, the photic zone, the deep ocean, the ocean under stress, marine pollution, appendix a: the metric system and conversion factors/ appendix b: prefixes and suffixes/ appendix c: taxonomic classification of common marine organisms, and glossary, and index.

  19. Biological effects of low-dose ionizing radiation exposure

    International Nuclear Information System (INIS)

    The report on the meeting of the Strahlenschutzkommission 2007 concerning biological effects of low-dose ionizing radiation exposure includes the following contributions: Adaptive response. The importance of DNA damage mechanisms for the biological efficiency of low-energy photons. Radiation effects in mammography: the relative biological radiation effects of low-energy photons. Radiation-induced cataracts. Carcinomas following prenatal radiation exposure. Intercellular apoptosis induction and low-dose irradiation: possible consequences for the oncogenesis control. Mechanistic models for the carcinogenesis with radiation-induced cell inactivation: application to all solid tumors in the Japanese atomic bomb survivors. Microarrays at low radiation doses. Mouse models for the analysis of biological effects of low-dose ionizing radiation. The bystander effect: observations, mechanisms and implications. Lung carcinoma risk of Majak workers - modeling of carcinogenesis and the bystander effect. Microbeam studies in radiation biology - an overview. Carcinogenesis models with radiation-induced genomic instability. Application to two epidemiological cohorts.

  20. Radioprotective and antioxidant action of caffeine: mechanistic considerations

    International Nuclear Information System (INIS)

    Caffeine, a major constituent of coffee and other beverages has significant abilities to scavenge highly reactive free radicals and excited states of oxygen and to protect crucial biological molecules against these species. This is one of the possible reasons why caffeine acts as a radioprotector against oxygen-dependent (oxic) pathway of radiation damage and as an anti mutagen/anti carcinogen under certain conditions. The possible physicochemical and molecular mechanisms of caffeine action are briefly reviewed in the light of the recent finding. (author). 69 refs., 1 fig

  1. Biological knowledge in the National Curriculum of High School: an historical and philosophical analysis from the statutes of biology

    Directory of Open Access Journals (Sweden)

    Antônio Fernandes Nascimento Júnior

    2011-10-01

    Full Text Available We analyzed the National Curriculum for Secondary Schools with respect to the ontological, epistemological, historical, social and conceptual biology. This study aims to bring information and thinking about the inclusion of history and philosophy of biology for secondary education and for teacher training. We performed an analysis of PCNEM, PCNEM+ and Curriculum Guidelines as a whole from established categories. The results indicate a predominance of the ontological view of mechanistic biology. Epistemologically, although acknowledged, the question of scientific method is rarely discussed. The historical approach and social scientific activity and scientific knowledge are recognized by the documents, but an instrumental view prevails. The conceptual aspects are comprehensive and take into account the theories of structural biology. A philosophical discussion on the biology is missing in the parameters, indicating the need for the inclusion of issues related to ideas of determinism, chance and teleology.

  2. Experimental investigation and mechanistic modelling of dilute bubbly bulk boiling

    International Nuclear Information System (INIS)

    During evaporation the geometric shape of the vapour is not described using thermodynamics. In bubbly flows the bubble shape is considered spheric with small diameters and changing into various shapes upon growth. The heat and mass transfer happens at the interfacial area. The forces acting on the bubbles depend on the bubble diameter and shape. In this work the prediction of the bubble diameter and/or bubble number density in bulk boiling was considered outside the vicinity of the heat input area. Thus the boiling effects that happened inside the nearly saturated bulk were under investigation. This situation is relevant for nuclear safety analysis concerning a stagnant coolant in the spent fuel pool. In this research project a new experimental set-up to investigate was built. The experimental set-up consists of an instrumented, partly transparent, high and slender boiling container for visual observation. The direct visual observation of the boiling phenomena is necessary for the identification of basic mechanisms, which should be incorporated in the simulation model. The boiling process has been recorded by means of video images and subsequently was evaluated by digital image processing methods, and by that data concerning the characteristics of the boiling process were generated for the model development and validation. Mechanistic modelling is based on the derivation of relevant mechanisms concluded from observation, which is in line with physical knowledge. In this context two mechanisms were identified; the growth/-shrink mechanism (GSM) of the vapour bubbles and sudden increases of the bubble number density. The GSM was implemented into the CFD-Code ANSYS-CFX using the CFX Expression Language (CEL) by calculation of the internal bubble pressure using the Young-Laplace-Equation. This way a hysteresis is realised as smaller bubbles have an increased internal pressure. The sudden increases of the bubble number density are explainable by liquid super

  3. Experimental investigation and mechanistic modelling of dilute bubbly bulk boiling

    Energy Technology Data Exchange (ETDEWEB)

    Kutnjak, Josip

    2013-06-27

    During evaporation the geometric shape of the vapour is not described using thermodynamics. In bubbly flows the bubble shape is considered spheric with small diameters and changing into various shapes upon growth. The heat and mass transfer happens at the interfacial area. The forces acting on the bubbles depend on the bubble diameter and shape. In this work the prediction of the bubble diameter and/or bubble number density in bulk boiling was considered outside the vicinity of the heat input area. Thus the boiling effects that happened inside the nearly saturated bulk were under investigation. This situation is relevant for nuclear safety analysis concerning a stagnant coolant in the spent fuel pool. In this research project a new experimental set-up to investigate was built. The experimental set-up consists of an instrumented, partly transparent, high and slender boiling container for visual observation. The direct visual observation of the boiling phenomena is necessary for the identification of basic mechanisms, which should be incorporated in the simulation model. The boiling process has been recorded by means of video images and subsequently was evaluated by digital image processing methods, and by that data concerning the characteristics of the boiling process were generated for the model development and validation. Mechanistic modelling is based on the derivation of relevant mechanisms concluded from observation, which is in line with physical knowledge. In this context two mechanisms were identified; the growth/-shrink mechanism (GSM) of the vapour bubbles and sudden increases of the bubble number density. The GSM was implemented into the CFD-Code ANSYS-CFX using the CFX Expression Language (CEL) by calculation of the internal bubble pressure using the Young-Laplace-Equation. This way a hysteresis is realised as smaller bubbles have an increased internal pressure. The sudden increases of the bubble number density are explainable by liquid super

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

    Science.gov (United States)

    Hilton, Robert J.

    2011-07-01

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

  5. Obesity and cancer: mechanistic insights from transdisciplinary studies.

    Science.gov (United States)

    Allott, Emma H; Hursting, Stephen D

    2015-12-01

    Obesity is associated with a range of health outcomes that are of clinical and public health significance, including cancer. Herein, we summarize epidemiologic and preclinical evidence for an association between obesity and increased risk of breast and prostate cancer incidence and mortality. Moreover, we describe data from observational studies of weight change in humans and from calorie-restriction studies in mouse models that support a potential role for weight loss in counteracting tumor-promoting properties of obesity in breast and prostate cancers. Given that weight loss is challenging to achieve and maintain, we also consider evidence linking treatments for obesity-associated co-morbidities, including metformin, statins and non-steroidal anti-inflammatory drugs, with reduced breast and prostate cancer incidence and mortality. Finally, we highlight several challenges that should be considered when conducting epidemiologic and preclinical research in the area of obesity and cancer, including the measurement of obesity in population-based studies, the timing of obesity and weight change in relation to tumor latency and cancer diagnosis, and the heterogeneous nature of obesity and its associated co-morbidities. Given that obesity is a complex trait, comprised of behavioral, epidemiologic and molecular/metabolic factors, we argue that a transdisciplinary approach is the key to understanding the mechanisms linking obesity and cancer. As such, this review highlights the critical need to integrate evidence from both epidemiologic and preclinical studies to gain insight into both biologic and non-biologic mechanisms contributing to the obesity-cancer link. PMID:26373570

  6. Biological Databases

    Directory of Open Access Journals (Sweden)

    Kaviena Baskaran

    2013-12-01

    Full Text Available Biology has entered a new era in distributing information based on database and this collection of database become primary in publishing information. This data publishing is done through Internet Gopher where information resources easy and affordable offered by powerful research tools. The more important thing now is the development of high quality and professionally operated electronic data publishing sites. To enhance the service and appropriate editorial and policies for electronic data publishing has been established and editors of article shoulder the responsibility.

  7. Anticipating and Communicating Plausible Environmental and Health Concerns Associated with Future Disasters: The ShakeOut and ARkStorm Scenarios as Examples

    Science.gov (United States)

    Plumlee, G. S.; Morman, S. A.; Alpers, C. N.; Hoefen, T. M.; Meeker, G. P.

    2010-12-01

    Disasters commonly pose immediate threats to human safety, but can also produce hazardous materials (HM) that pose short- and long-term environmental-health threats. The U.S. Geological Survey (USGS) has helped assess potential environmental health characteristics of HM produced by various natural and anthropogenic disasters, such as the 2001 World Trade Center collapse, 2005 hurricanes Katrina and Rita, 2007-2009 southern California wildfires, various volcanic eruptions, and others. Building upon experience gained from these responses, we are now developing methods to anticipate plausible environmental and health implications of the 2008 Great Southern California ShakeOut scenario (which modeled the impacts of a 7.8 magnitude earthquake on the southern San Andreas fault, http://urbanearth.gps.caltech.edu/scenario08/), and the recent ARkStorm scenario (modeling the impacts of a major, weeks-long winter storm hitting nearly all of California, http://urbanearth.gps.caltech.edu/winter-storm/). Environmental-health impacts of various past earthquakes and extreme storms are first used to identify plausible impacts that could be associated with the disaster scenarios. Substantial insights can then be gleaned using a Geographic Information Systems (GIS) approach to link ShakeOut and ARkStorm effects maps with data extracted from diverse database sources containing geologic, hazards, and environmental information. This type of analysis helps constrain where potential geogenic (natural) and anthropogenic sources of HM (and their likely types of contaminants or pathogens) fall within areas of predicted ShakeOut-related shaking, firestorms, and landslides, and predicted ARkStorm-related precipitation, flooding, and winds. Because of uncertainties in the event models and many uncertainties in the databases used (e.g., incorrect location information, lack of detailed information on specific facilities, etc.) this approach should only be considered as the first of multiple steps

  8. THYROID FOLLICULAR CELL CARCINOGENESIS: MECHANISTIC AND SCIENCE POLICY CONSIDERATIONS (SAB REVIEW DRAFT)

    Science.gov (United States)

    A Technical Panel of EPA's Risk Assessment Forum investigated the potential mechanisms of action of agents that cause thyroid follicular tumors in animals and potentially in humans in an effort to develop a scientifically plausible approach for assessing risk due to exposure to t...

  9. Biological biomaterials

    Energy Technology Data Exchange (ETDEWEB)

    Jorge-Herrero, E. [Servicio de Cirugia Experimental. Clinica Puerta de Hierro, Madrid (Spain)

    1997-05-01

    There are a number of situations in which substances of biological origin are employed as biomaterials. Most of them are macromolecules derived from isolated connective tissue or the connective tissue itself in membrane form, in both cases, the tissue can be used in its natural form or be chemically treated. In other cases, certain blood vessels can be chemically pretreated and used as vascular prostheses. Proteins such as albumin, collagen and fibrinogen are employed to coat vascular prostheses. Certain polysaccharides have also been tested for use in controlled drug release systems. Likewise, a number of tissues, such as dura mater, bovine pericardium, procine valves and human valves, are used in the preparation of cardiac prostheses. We also use veins from animals or humans in arterial replacement. In none of these cases are the tissues employed dissimilar to the native tissues as they have been chemically modified, becoming a new bio material with different physical and biochemical properties. In short, we find that natural products are being utilized as biomaterials and must be considered as such; thus, it is necessary to study both their chemicobiological and physicomechanical properties. In the present report, we review the current applications, problems and future prospects of some of these biological biomaterials. (Author) 84 refs.

  10. Regulated expression of pH sensing G protein-coupled receptor-68 identified through chemical biology defines a new drug target for ischemic heart disease

    OpenAIRE

    Russell, Jamie L; Goetsch, Sean C.; Aguilar, Hector R.; Coe, Helen; Luo, Xiang; Liu, Ning; Van Rooij, Eva; Frantz, Doug E.; Schneider, Jay W.

    2012-01-01

    Chemical biology promises discovery of new and unexpected mechanistic pathways, protein functions and disease targets. Here, we probed the mechanism-of-action and protein targets of 3,5-disubstituted isoxazoles (Isx), cardiomyogenic small-molecules that target Notch-activated epicardium-derived cells (NECs) in vivo and promote functional recovery after myocardial infarction (MI). Mechanistic studies in NECs led to an Isx-activated Gq protein-coupled receptor (GqPCR) hypothesis tested in a cel...

  11. Mechanistic DNB model for an advanced sub-channel analysis of rod-bundle

    International Nuclear Information System (INIS)

    A mechanistic model that counts the cross-sectional void distribution in predicting departure from nucleate boiling (DNB) was introduced in a sub-channel analysis code. The prediction of the DNB heat flux was important for design and safety analysis of the pressurized water reactor (PWR). So far, several empirical correlations for the DNB heat flux had been developed, however the applicability was limited within the experimental condition of the database. To improve the applicability, some mechanistic models had been proposed. In this study, as a first step, a mechanistic model that illustrated the DNB as bubble congestion in a bubbly layer close to the heated wall was picked up and applied to a sub-channel analysis code. Local flow parameters, such as mass flux, void fraction was calculated by the sub-channel analysis code. In our preliminary study, the local flow parameters depended on the heat flux, and we chose an iterative method, where the sub-channel analysis was iterated until the local heat flux reached the DNB heat flux. This method was applied to an analysis of DNB tests for a rod bundle, and the result showed good agreement with the experiment. Here, the predictability for the tests with different fluids was compared with that of an empirical correlation. The mechanistic model was able to reproduce the experimental result for different fluid whereas the empirical correlation was not. This indicated that the present mechanistic model could represent a similarity in DNB phenomenon between different fluids. (author)

  12. Applying mechanistic models to reliability evaluation of mechanical components - An illustration

    International Nuclear Information System (INIS)

    Highlights: → The mechanistic model approach can be used to handle multi state problems. → The mechanistic model approach is based on the first principles of science and engineering. → A general methodology for performing analysis has been highlighted. → A case study on reliability analysis of control valve and feed water system has been discussed. - Abstract: The traditional reliability analyses, considers components to be in binary state, either functional or faulty, and does not consider the concept of multi state or intermediate states between these two binary states. However, there are several components, which need to be operated in different states and their failure criterion also depend on these states. Hence, when dealing with these types of components one should use multi state concept. This can be achieved by modeling the components with mechanistic models, which can give a new dimension for reliability analysis for multiple states. The mechanistic model approach is based on the first principles of science and engineering which provides details about the various failure mechanisms and thereby improved understanding of the associated root causes of the failure and driving forces responsible for component failures. In this paper a general methodology for modeling the components with mechanistic models has been explained and is further illustrated with an example component. A case study on feed water system (consisting of control valves and other mechanical components) of a typical nuclear reactor has been presented.

  13. Mechanistic basis of infertility of mouse intersubspecific hybrids

    Czech Academy of Sciences Publication Activity Database

    Bhattacharyya, Tanmoy; Gregorová, Soňa; Mihola, Ondřej; Anger, Martin; Šebestová, J.; Denny, P.; Šimeček, Petr; Forejt, Jiří

    2013-01-01

    Roč. 110, č. 6 (2013), E468-E477. ISSN 0027-8424 R&D Projects: GA MŠk(CZ) LD11079; GA MŠk(CZ) 1M0520; GA MŠk ED1.1.00/02.0109; GA ČR(CZ) GPP305/11/P630; GA ČR GA523/09/0743 Grant ostatní: AV ČR(CZ) Premium Academiae of the Academy of Sciences of the Czech Republic; GA MŠk(CZ) ED1.1.00/02.0068 Institutional research plan: CEZ:AV0Z50520514 Institutional support: RVO:68378050 ; RVO:67985904 Keywords : meiosis * meiotic sex chromosome inactivation * Prdm9 * chromosome substitution strains * Haldane's rule Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 9.809, year: 2013 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3568299/

  14. Insertion of O-H Bond of Rh(Ⅱ)-methylene Carbene into Alcohols: A Stepwise Mechanism More Plausible than a Concerted Mechanism

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The mechanisms of insertion of O-H bond of Rh( Ⅱ ) -methylene carbene into methanol and ethanol were studied by using B3LYP functional both in gas phase and in CH2Cl2. The formation of free alcoholic oxonium ylides is found to be impossible. Alcoholic oxonium ylide are formed as the intermediates before both the stepwise and the concerted transition states of insertion of O-H bond of Rh( Ⅱ ) -methylene carbene into methanol and ethanol. With regard to the mechanisms of insertion of O-H of Rh( Ⅱ ) -methylene carbene into alcohols, analysis of the energy barriers of the two mechanisms indicate that the stepwise mechanism is more plausible than the concerted mechanism.

  15. An Italian population-based case-control study on the association between farming and cancer: Are pesticides a plausible risk factor?

    Science.gov (United States)

    Salerno, Christian; Carcagnì, Antonella; Sacco, Sara; Palin, Lucio Antonio; Vanhaecht, Kris; Panella, Massimiliano; Guido, Davide

    2016-05-01

    This population-based case-control study investigated the association between farming (a proxy for pesticide exposure) and cancer in the Vercelli suburban area (northwest Italy). The residents, aged 25 to 79 years, in the above-mentioned area during the period 2002-2009 were considered. Cases were all the first hospital admissions for cancer. Controls were all the subjects not included in the cases and not excluded from the study. Cases and controls were classified according to whether they occupationally resulted farmers or nonfarmers during the period 1965-2009. Cancer odds ratios (ORs) between farmers and nonfarmers were calculated with generalized linear mixed models adjusted by gender and age. Farmers showed higher odds for all cancers (OR=1.459; p < .001), nonmelanoma skin cancer, colorectal cancer, and breast cancer. The results suggest a plausible association between pesticide exposure and cancer occurrence. PMID:25942634

  16. Biological effects

    International Nuclear Information System (INIS)

    Following an introduction into the field of cellular radiation effect considering the most important experimental results, the biological significance of the colony formation ability is brought out. The inactivation concept of stem cells does not only prove to be good, according to the present results, in the interpretation of the pathogenesis of acute radiation effects on moult tissue, it also enables chronicle radiation injuries to be interpreted through changes in the fibrous part of the organs. Radiation therapy of tumours can also be explained to a large extent by the radiation effect on the unlimited reproductiveness of tumour cells. The more or less similar dose effect curves for healthy and tumour tissue in practice lead to intermittent irradiation. The dependence of the intermittent doses and intervals on factors such as Elkind recovery, synchronisation, redistribution, reoxygenation, repopulation and regeneration are reviewed. (ORU/LH)

  17. Creating biological nanomaterials using synthetic biology

    International Nuclear Information System (INIS)

    Synthetic biology is a new discipline that combines science and engineering approaches to precisely control biological networks. These signaling networks are especially important in fields such as biomedicine and biochemical engineering. Additionally, biological networks can also be critical to the production of naturally occurring biological nanomaterials, and as a result, synthetic biology holds tremendous potential in creating new materials. This review introduces the field of synthetic biology, discusses how biological systems naturally produce materials, and then presents examples and strategies for incorporating synthetic biology approaches in the development of new materials. In particular, strategies for using synthetic biology to produce both organic and inorganic nanomaterials are discussed. Ultimately, synthetic biology holds the potential to dramatically impact biological materials science with significant potential applications in medical systems. (review)

  18. Creating biological nanomaterials using synthetic biology

    Directory of Open Access Journals (Sweden)

    MaryJoe K Rice

    2014-01-01

    Full Text Available Synthetic biology is a new discipline that combines science and engineering approaches to precisely control biological networks. These signaling networks are especially important in fields such as biomedicine and biochemical engineering. Additionally, biological networks can also be critical to the production of naturally occurring biological nanomaterials, and as a result, synthetic biology holds tremendous potential in creating new materials. This review introduces the field of synthetic biology, discusses how biological systems naturally produce materials, and then presents examples and strategies for incorporating synthetic biology approaches in the development of new materials. In particular, strategies for using synthetic biology to produce both organic and inorganic nanomaterials are discussed. Ultimately, synthetic biology holds the potential to dramatically impact biological materials science with significant potential applications in medical systems.

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

    International Nuclear Information System (INIS)

    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

  20. Structural Biology Fact Sheet

    Science.gov (United States)

    ... Home > Science Education > Structural Biology Fact Sheet Structural Biology Fact Sheet Tagline (Optional) Middle/Main Content Area What is structural biology? Structural biology is a field of science focused ...

  1. Glycosphingolipid Modification: Structural Diversity, Functional and Mechanistic Integration of Diabetes

    Directory of Open Access Journals (Sweden)

    Tadashi Yamashita

    2011-08-01

    Full Text Available Glycosphingolipids (GSLs are present in all mammalian cell plasma membranes and intracellular membrane structures. They are especially concentrated in plasma membrane lipid domains that are specialized for cell signaling. Plasma membranes have typical structures called rafts and caveola domain structures, with large amounts of sphingolipids, cholesterol, and sphingomyelin. GSLs are usually observed in many organs ubiquitously. However, GSLs, including over 400 derivatives, participate in diverse cellular functions. Several studies indicate that GSLs might have an effect on signal transduction related to insulin receptors and epidermal growth factor receptors. GSLs may modulate immune responses by transmitting signals from the exterior to the interior of the cell. Guillain-Barré syndrome is one of the autoimmune disorders characterized by symmetrical weakness in the muscles of the legs. The targets of the immune response are thought to be gangliosides, which are one group of GSLs. Other GSLs may serve as second messengers in several signaling pathways that are important to cell survival or programmed cell death. In the search for clear evidence that GSLs may play critical roles in various biological functions, many researchers have made genetically engineered mice. Before the era of gene manipulation, spontaneous animal models or chemical-induced disease models were used.

  2. Management of Inflammation by Natural Polyphenols: A Comprehensive Mechanistic Update.

    Science.gov (United States)

    Sarkar, Souvik; Mazumder, Somnath; Saha, Shubhra J; Bandyopadhyay, Uday

    2016-05-27

    Inflammation generates a systemic response against injury or infection from bacteria, viruses, and other pathogens. The welfare of host is the primary target of this process. However, uncontrolled or inadequate regulation of the inflammatory response produces detrimental effects leading to the generation of various chronic disorders including atherosclerosis, type-2 diabetes, neurodegenerative disease, cancer and Alzheimer's disease with severe tissue damage. The exact identity of the inflammatory stimuli is still elusive as they function in multiple pathways; therefore targeting a particular pathway does not resolve the problem. Existing therapeutics targeting the inflammatory responses include steroidal antiinflammatory drugs (SAIDs) and nonsteroidal antiinflammatory drugs (NSAIDs). In spite of their numerous beneficial effects, both SAIDs as well as NSAIDs have their independent, unavoidable side effects, which discourage their prolonged therapeutic applications. Since the management of uncontrolled inflammation is critical for the general wellbeing, therefore an alternative source of multi-targeted non-toxic therapeutic intervention is mandatory. Plant-derived phenols constitute such a group of molecules that can be utilised to manage inflammation. They synergistically modulate several important components involved in multiple signalling pathways that regulate uncontrolled inflammation to exhibit their beneficial health effects. This review discusses the recent advances in structure-function activity of some antiinflammatory polyphenols, their bioavailability enhancement, clinical/ preclinical findings with a view to provide knowledge for developing novel antiinflammatory drugs by following system biology of proinflammatory responses with minimal side effects. PMID:27087243

  3. Inhibition of insulin fibrillation by osmolytes: Mechanistic insights.

    Science.gov (United States)

    Choudhary, Sinjan; Kishore, Nand; Hosur, Ramakrishna V

    2015-01-01

    We have studied here using a number of biophysical tools the effects of osmolytes, betaine, citrulline, proline and sorbitol which differ significantly in terms of their physical characteristics such as, charge distribution, polarity, H-bonding abilities etc, on the fibrillation of insulin. Among these, betaine, citrulline, and proline are very effective in decreasing the extent of fibrillation. Proline also causes a substantial delay in the onset of fibrillation in the concentration range (50-250 mM) whereas such an effect is seen for citrulline only at 250 mM, and in case of betaine this effect is not seen at all in the whole concentration range. The enthalpies of interaction at various stages of fibrillation process have suggested that the preferential exclusion of the osmolyte and its polar interaction with the protein are important in inhibition. The results indicate that the osmolytes are most effective when added prior to the elongation stage of fibrillation. These observations have significant biological implications, since insulin fibrillation is known to cause injection amyloidosis and our data may help in designing lead drug molecules and development of potential therapeutic strategies. PMID:26616401

  4. Inhibition of insulin fibrillation by osmolytes: Mechanistic Insights

    Science.gov (United States)

    Choudhary, Sinjan; Kishore, Nand; Hosur, Ramakrishna V.

    2015-11-01

    We have studied here using a number of biophysical tools the effects of osmolytes, betaine, citrulline, proline and sorbitol which differ significantly in terms of their physical characteristics such as, charge distribution, polarity, H-bonding abilities etc, on the fibrillation of insulin. Among these, betaine, citrulline, and proline are very effective in decreasing the extent of fibrillation. Proline also causes a substantial delay in the onset of fibrillation in the concentration range (50-250 mM) whereas such an effect is seen for citrulline only at 250 mM, and in case of betaine this effect is not seen at all in the whole concentration range. The enthalpies of interaction at various stages of fibrillation process have suggested that the preferential exclusion of the osmolyte and its polar interaction with the protein are important in inhibition. The results indicate that the osmolytes are most effective when added prior to the elongation stage of fibrillation. These observations have significant biological implications, since insulin fibrillation is known to cause injection amyloidosis and our data may help in designing lead drug molecules and development of potential therapeutic strategies.

  5. A mechanistic model for droplet deposition heat transfer in dispersed flow film boiling

    International Nuclear Information System (INIS)

    A mechanistic droplet deposition model has been developed to quantify the direct contact heat transfer present in dispersed flow film boiling. Lagrangian subscale trajectory calculations utilizing realistic velocity and temperature distributions in the momentum boundary layer are used to determine the number of dispersed droplets able to achieve contact with the heated wall. Coupling the droplet deposition model with a physical direct contact heat transfer coefficient model allows the total direct contact heat transfer to be determined based upon the local vapor mass flux, wall superheat, and vapor superheat. Comparisons to the existing models highlight the more mechanistic nature of the proposed model. (author)

  6. Mechanistic model for cuttings removal from solid bed in inclined channels

    Energy Technology Data Exchange (ETDEWEB)

    Ramadan, A.; Skalle, P. [Department of Petroleum Engineering and Applied Geophysics, NTNU, S.P. Andersens vei 15 A, N-7491 Trondheim (Norway); Johansen, S.T. [SINTEF Material Technology, Trondheim (Norway); Svein, J. [SINTEF Industrial Management, Trondheim (Norway); Saasen, A. [Statoil Drilling and Well Fluids, N-4035 Stavanger (Norway)

    2001-09-01

    This paper presents the results and analysis of a set of erosion rate experiments, designed to investigate the removal rate of stationary sand bed particles in an inclined channel. The erosion rate tests of three beds with different bed particle-size ranges show that beds with intermediate average particle size have the maximum erosion rate. The theoretical analysis using a mechanistic model supports this observation. The instantaneous acceleration of bed particles at the beginning of transportation is correlated with particle removal rate. It is shown that the mechanistic model can predict optimum operating parameters to improve the efficiency of hole cleaning.

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

    Science.gov (United States)

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

    2015-01-01

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

  8. Simulating Biological and Non-Biological Motion

    Science.gov (United States)

    Bruzzo, Angela; Gesierich, Benno; Wohlschlager, Andreas

    2008-01-01

    It is widely accepted that the brain processes biological and non-biological movements in distinct neural circuits. Biological motion, in contrast to non-biological motion, refers to active movements of living beings. Aim of our experiment was to investigate the mechanisms underlying mental simulation of these two movement types. Subjects had to…

  9. A Brief Introduction to Chinese Biological Biological

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    Chinese Biological Abstracts sponsored by the Library, the Shanghai Institutes for Biological Sciences, the Biological Documentation and Information Network, all of the Chinese Academy of Sciences, commenced publication in 1987 and was initiated to provide access to the Chinese information in the field of biology.

  10. Mechanistic simulation of radiation damage to DNA and its repair: On the track towards systems radiation biology modelling

    International Nuclear Information System (INIS)

    The biophysical simulation code PARTRAC enables, by combining track structure calculations with DNA models on diverse genomic scales, prediction of DNA damage yields and patterns for various radiation qualities. To extend its applicability to later endpoints such as mutagenesis or cell killing, a continuative model for repair of radiation-induced double-strand break (DSB) via non-homologous end-joining has complemented the PARTRAC code by about 12 orders of magnitude on a temporal scale. The repair model describes step-by-step by the Monte Carlo method the attachment and dissociation of involved repair enzymes and diffusion motion of DNA ends. The complexity of initial DNA lesion patterns influences the repair kinetics and outcome via additional cleaning steps required for dirty DNA ends. Model parameters have been taken from measured attachment kinetics of repair enzymes and adaptation to DSB rejoining kinetics after gamma irradiation. Application of the DNA repair model to damage patterns following nitrogen ion irradiation and comparison with experimental results reveal the need for further model refinements. Nevertheless, already the present model represents a promising step towards systems modelling of cellular response to radiation. (authors)

  11. Creating biological nanomaterials using synthetic biology

    OpenAIRE

    MaryJoe K Rice; Ruder, Warren C.

    2014-01-01

    Synthetic biology is a new discipline that combines science and engineering approaches to precisely control biological networks. These signaling networks are especially important in fields such as biomedicine and biochemical engineering. Additionally, biological networks can also be critical to the production of naturally occurring biological nanomaterials, and as a result, synthetic biology holds tremendous potential in creating new materials. This review introduces the field of synthetic bi...

  12. Toward synthesizing executable models in biology.

    Science.gov (United States)

    Fisher, Jasmin; Piterman, Nir; Bodik, Rastislav

    2014-01-01

    Over the last decade, executable models of biological behaviors have repeatedly provided new scientific discoveries, uncovered novel insights, and directed new experimental avenues. These models are computer programs whose execution mechanistically simulates aspects of the cell's behaviors. If the observed behavior of the program agrees with the observed biological behavior, then the program explains the phenomena. This approach has proven beneficial for gaining new biological insights and directing new experimental avenues. One advantage of this approach is that techniques for analysis of computer programs can be applied to the analysis of executable models. For example, one can confirm that a model agrees with experiments for all possible executions of the model (corresponding to all environmental conditions), even if there are a huge number of executions. Various formal methods have been adapted for this context, for example, model checking or symbolic analysis of state spaces. To avoid manual construction of executable models, one can apply synthesis, a method to produce programs automatically from high-level specifications. In the context of biological modeling, synthesis would correspond to extracting executable models from experimental data. We survey recent results about the usage of the techniques underlying synthesis of computer programs for the inference of biological models from experimental data. We describe synthesis of biological models from curated mutation experiment data, inferring network connectivity models from phosphoproteomic data, and synthesis of Boolean networks from gene expression data. While much work has been done on automated analysis of similar datasets using machine learning and artificial intelligence, using synthesis techniques provides new opportunities such as efficient computation of disambiguating experiments, as well as the ability to produce different kinds of models automatically from biological data. PMID:25566538

  13. Towards Synthesizing Executable Models in Biology

    Directory of Open Access Journals (Sweden)

    Jasmin eFisher

    2014-12-01

    Full Text Available Over the last decade, executable models of biological behaviors have repeatedly provided new scientific discoveries, uncovered novel insights, and directed new experimental avenues. These models are computer programs whose execution mechanistically simulates aspects of the cell’s behaviors. If the observed behavior of the program agrees with the observed biological behavior, then the program explains the phenomena. This approach has proven beneficial for gaining new biological insights and directing new experimental avenues. One advantage of this approach is that techniques for analysis of computer programs can be applied to the analysis of executable models. For example, one can confirm that a model agrees with experiments for all possible executions of the model (corresponding to all environmental conditions, even if there are a huge number of executions. Various formal methods have been adapted for this context, for example, model checking or symbolic analysis of state spaces. To avoid manual construction of executable models, one can apply synthesis, a method to produce programs automatically from high-level specifications. In the context of biological modelling, synthesis would correspond to extracting executable models from experimental data. We survey recent results about the usage of the techniques underlying synthesis of computer programs for the inference of biological models from experimental data. We describe synthesis of biological models from curated mutation experiment data, inferring network connectivity models from phosphoproteomic data, and synthesis of Boolean networks from gene expression data. While much work has been done on automated analysis of similar datasets using machine learning and artificial intelligence, using synthesis techniques provides new opportunities such as efficient computation of disambiguating experiments, as well as the ability to produce different kinds of models automatically from biological data.

  14. More on Grandmother Cells and the Biological Implausibility of PDP Models of Cognition: A Reply to Plaut and McClelland (2010) and Quian Quiroga and Kreiman (2010)

    Science.gov (United States)

    Bowers, Jeffrey S.

    2010-01-01

    Plaut and McClelland (2010) and Quian Quiroga and Kreiman both challenged my characterization of localist and distributed representations. They also challenged the biological plausibility of grandmother cells on conceptual and empirical grounds. This reply addresses these issues in turn. The premise of my argument is that grandmother cells in…

  15. A Mechanistic Neural Field Theory of How Anesthesia Suppresses Consciousness: Synaptic Drive Dynamics, Bifurcations, Attractors, and Partial State Equipartitioning.

    Science.gov (United States)

    Hou, Saing Paul; Haddad, Wassim M; Meskin, Nader; Bailey, James M

    2015-12-01

    With the advances in biochemistry, molecular biology, and neurochemistry there has been impressive progress in understanding the molecular properties of anesthetic agents. However, there has been little focus on how the molecular properties of anesthetic agents lead to the observed macroscopic property that defines the anesthetic state, that is, lack of responsiveness to noxious stimuli. In this paper, we use dynamical system theory to develop a mechanistic mean field model for neural activity to study the abrupt transition from consciousness to unconsciousness as the concentration of the anesthetic agent increases. The proposed synaptic drive firing-rate model predicts the conscious-unconscious transition as the applied anesthetic concentration increases, where excitatory neural activity is characterized by a Poincaré-Andronov-Hopf bifurcation with the awake state transitioning to a stable limit cycle and then subsequently to an asymptotically stable unconscious equilibrium state. Furthermore, we address the more general question of synchronization and partial state equipartitioning of neural activity without mean field assumptions. This is done by focusing on a postulated subset of inhibitory neurons that are not themselves connected to other inhibitory neurons. Finally, several numerical experiments are presented to illustrate the different aspects of the proposed theory. PMID:26438186

  16. Hydroxyl and one-electron oxidation mediated reactions of the purine bases of DNA and model compounds: Mechanistic aspects

    Energy Technology Data Exchange (ETDEWEB)

    Cadet, J.; Berger, M.; Buchko, G.W.; Joshi, P.C.; Morin, B.; Raoul, S.; Ravanat, J.L. [CEA/DRFMC/SESAM/LAN, Grenoble (France)

    1995-12-31

    A large body of information is now available on the early events involved in the radiation-induced decomposition of DNA and related compounds in both aqueous solutions and in the solid state. However, despite many efforts devoted to the identification of radiation-induced DNA modifications in the past two decades there is still a paucity of data on the final decomposition products which arise form the fate of initially generated DNA purine radicals, at least, in aqueous aerated solutions. One major exception deals with the characterization of 7,8-dihydro-8-oxo-2{prime}-deoxyguanosine (8-oxodG) within isolated and nuclear DNA upon exposure to ionizing radiation. It should be noted that the biological significance of 8-oxodG 6 as inferred from comprehensive DNA repair and mutagenic studies has been recently assessed. The present survey focuses on recent mechanistic aspects of the decomposition of the guanine moiety of DNA and model compounds as the result of hydroxyl radical and one-electron oxidation reactions in aerated aqueous solutions. In addition, a model system aimed at explaining the radiation-induced formation of DNA-protein crosslinks in aerated aqueous solution is presented.

  17. 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.

  18. Building phenomenological models of complex biological processes

    Science.gov (United States)

    Daniels, Bryan; Nemenman, Ilya

    2009-11-01

    A central goal of any modeling effort is to make predictions regarding experimental conditions that have not yet been observed. Overly simple models will not be able to fit the original data well, but overly complex models are likely to overfit the data and thus produce bad predictions. Modern quantitative biology modeling efforts often err on the complexity side of this balance, using myriads of microscopic biochemical reaction processes with a priori unknown kinetic parameters to model relatively simple biological phenomena. In this work, we show how Bayesian model selection (which is mathematically similar to low temperature expansion in statistical physics) can be used to build coarse-grained, phenomenological models of complex dynamical biological processes, which have better predictive powers than microscopically correct, but poorely constrained mechanistic molecular models. We illustrate this on the example of a multiply-modifiable protein molecule, which is a simplified description of multiple biological systems, such as an immune receptors and an RNA polymerase complex. Our approach is similar in spirit to the phenomenological Landau expansion for the free energy in the theory of critical phenomena.

  19. Plausible Speech Translation in Literature%论文学作品中似是而非的辞格翻译

    Institute of Scientific and Technical Information of China (English)

    廖巧云

    2011-01-01

    辞格是一种语言变体,是各种语言共有的现象。由于各种原因,辞格的误译现象在翻译活动中并不鲜见。然而,辞格误译却有很大一部分呈现出似是而非的特征。辞格中似是而非的翻译,表面看来完全正确,并且在两种语言中具有形式上完全对等的特征,这使得它们更容易被译文读者接受,使其无意识中被迫接受错误信息。本文借用奈达的翻译功能对等理论,通过对文学作品中出现的似是而非的辞格译文进行案例分析,从而尽可能地为译者在今后的辞格翻译活动提供借鉴,减少辞格翻译中似是而非的现象。%Speech is a language variant,is the common phenomenon to all languages.For various reasons,the phenomenon of a mistranslation of speech activities in the translation is not uncommon.However,there is a huge misinterpretation of speech as part of showing a paradoxical character.Speech translation in the paradoxical,seemingly completely correct,and in the two languages have formal characteristics of full reciprocity,which makes them more likely to be asked readers to accept,it was forced to accept the error message unconscious.This paper uses Nida's translation functional equivalence theory,through the literary works that ap-pear plausible case analysis of the translation of speech,which as much as possible for the translators in the future of speech trans-lation activities provide a reference,to reduce the plausible translation of speech phenomenon.

  20. Estimating enteric methane emissions from Chilean beef fattening systems using a mechanistic model

    NARCIS (Netherlands)

    Arias, R.A.; Catrileo, A.; Larraín, R.; Vera, R.; Velásquez, A.; Toneatti, M.; France, J.; Dijkstra, J.; Kebreab, E.

    2015-01-01

    A mechanistic model (COWPOLL) was used to estimate enteric methane (CH4) emissions from beef production systems in Chile. The results expressed as a proportion of gross energy intake (GEI) were compared with enteric fermentation data reported in the last Chilean greenhouse gases inventory, which uti

  1. A dynamic mechanistic model of lactic acid metabolism in the rumen

    NARCIS (Netherlands)

    Mills, J.A.N.; Crompton, L.A.; Ellis, J.L.; Dijkstra, J.; Bannink, A.; Hook, S.E.; Benchaar, C.; France, J.

    2014-01-01

    Current feed evaluation systems for ruminants are too imprecise to describe diets in terms of their acidosis risk. The dynamic mechanistic model described herein arises from the integration of a lactic acid (La) metabolism module into an extant model of whole-rumen function. The model was evaluated

  2. 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…

  3. 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…

  4. Reactions of functionalized alkenes with sulfur trioxide; mechanistic and synthetic aspects. Doctoral thesis

    Energy Technology Data Exchange (ETDEWEB)

    Schonk, R.M.

    1993-01-07

    In the thesis mechanistic studies on the sulfonation of mono-functionalized alkenes, viz. phenylalkenes, naphthylalkenes, alkenoic acids, alkadienes and cycloalkylidenes, mainly with sulfur trioxide are described. The main objective of the studies is to determine the effect of the substituents at the alkene moiety on the formation of the beta-sultones and carbyl sulfates and on their chemistry.

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

    Science.gov (United States)

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

    2008-01-01

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

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

    Science.gov (United States)

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

    2014-05-01

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

  7. Mechanistic modelling of fluidized bed drying processes of wet porous granules

    DEFF Research Database (Denmark)

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

    2011-01-01

    Fluidized bed dryers are frequently used in industrial applications and also in the pharmaceutical industry. The general incentives to develop mechanistic models for pharmaceutical processes are listed, and our vision on how this can particularly be done for fluidized bed drying processes of wet...

  8. A Central Theory of Biology

    Science.gov (United States)

    Torday, John S.

    2015-01-01

    The history of physiologic cellular–molecular interrelationships can be traced all the way back to the unicellular state by following the pathway formed by lipids ubiquitously accommodating calcium homeostasis, and its consequent adaptive effects on oxygen uptake by cells, tissues and organs. As a result, a cohesive, mechanistically integrated view of physiology can be formulated by recognizing the continuum comprising conception, development, physiologic homeostasis and death mediated by soluble growth factor signaling. Seeing such seemingly disparate processes as embryogenesis, chronic disease and dying as the gain and subsequent loss of cell–cell signaling provides a novel perspective for physiology and medicine. It is emblematic of the self-organizing, self-referential nature of life, starting from its origins. Such organizing principles obviate the pitfalls of teleologic evolution, conversely providing a way of resolving such seeming dichotomies as holism and reductionism, genotype and phenotype, emergence and contingence, proximate and ultimate causation in evolution, cells and organisms. The proposed approach is scale-free and predictive, offering a Central Theory of Biology. PMID:25911556

  9. Multi-scale observation and cross-scale mechanistic modeling on terrestrial ecosystem carbon cycle

    Institute of Scientific and Technical Information of China (English)

    CAO Mingkui; YU Guirui; LIU Jiyuan; LI Kerang

    2005-01-01

    To predict global climate change and to implement the Kyoto Protocol for stabilizing atmospheric greenhouse gases concentrations require quantifying spatio-temporal variations in the terrestrial carbon sink accurately. During the past decade multi-scale ecological experiment and observation networks have been established using various new technologies (e.g. controlled environmental facilities, eddy covariance techniques and quantitative remote sensing), and have obtained a large amount of data about terrestrial ecosystem carbon cycle. However, uncertainties in the magnitude and spatio-temporal variations of the terrestrial carbon sink and in understanding the underlying mechanisms have not been reduced significantly. One of the major reasons is that the observations and experiments were conducted at individual scales independently, but it is the interactions of factors and processes at different scales that determine the dynamics of the terrestrial carbon sink. Since experiments and observations are always conducted at specific scales, to understand cross-scale interactions requires mechanistic analysis that is best to be achieved by mechanistic modeling. However, mechanistic ecosystem models are mainly based on data from single-scale experiments and observations and hence have no capacity to simulate mechanistic cross-scale interconnection and interactions of ecosystem processes. New-generation mechanistic ecosystem models based on new ecological theoretical framework are needed to quantify the mechanisms from micro-level fast eco-physiological responses to macro-level slow acclimation in the pattern and structure in disturbed ecosystems. Multi-scale data-model fusion is a recently emerging approach to assimilate multi-scale observational data into mechanistic, dynamic modeling, in which the structure and parameters of mechanistic models for simulating cross-scale interactions are optimized using multi-scale observational data. The models are validated and

  10. Observational evidence for the plausible linkage of Equatorial Electrojet (EEJ) electric field variations with the post sunset F-region electrodynamics

    Science.gov (United States)

    Sreeja, V.; Devasia, C. V.; Ravindran, Sudha; Pant, Tarun Kumar

    2009-11-01

    The paper is based on a detailed observational study of the Equatorial Spread F (ESF) events on geomagnetically quiet (Ap≤20) days of the solar maximum (2001), moderate (2004) and minimum (2006) years using the ionograms and magnetograms from the magnetic equatorial location of Trivandrum (8.5° N; 77° E; dip lat ~0.5° N) in India. The study brings out some interesting aspects of the daytime Equatorial Electrojet (EEJ) related electric field variations and the post sunset F-region electrodynamics governing the nature of seasonal characteristics of the ESF phenomena during these years. The observed results seem to indicate a plausible linkage of daytime EEJ related electric field variations with pre-reversal enhancement which in turn is related to the occurrence of ESF. These electric field variations are shown to be better represented through a parameter, termed as "E", in the context of possible coupling between the E- and F-regions of the ionosphere. The observed similarities in the gross features of the variations in the parameter "E" and the F-region vertical drift (Vz) point towards the potential usage of the EEJ related parameter "E" as an useful index for the assessment of Vz prior to the occurrence of ESF.

  11. The most plausible explanation of the cyclical period changes in close binaries: the case of the RS CVn-type binary WW Dra

    CERN Document Server

    Liao, W -P

    2010-01-01

    We searched the orbital period changes in 182 EA-type (including the 101 Algol systems used by \\cite{hal89}), 43 EB-type and 53 EW-type binaries with known both the mass ratio and the spectral type of their secondary components. We reproduced and improved the same diagram as Hall's (1989) according to the new collected data. Our plots do not support the conclusion derived by \\cite{hal89} that all cases of cyclical period changes are restricted to binaries having the secondary component with spectral types later than F5. The presence of period changes also among stars with secondary component of early type indicates that the magnetic activity is one cause, but not the only one, for the period variation. It is discovered that cyclic period changes, likely due to the presence of a third body are more frequent in EW-type binaries among close binaries. Therefore, the most plausible explanation of the cyclical period changes is the LTTE via the presence of a third body. By using the century-long historical record o...

  12. Observational evidence for the plausible linkage of Equatorial Electrojet (EEJ electric field variations with the post sunset F-region electrodynamics

    Directory of Open Access Journals (Sweden)

    V. Sreeja

    2009-11-01

    Full Text Available The paper is based on a detailed observational study of the Equatorial Spread F (ESF events on geomagnetically quiet (Ap≤20 days of the solar maximum (2001, moderate (2004 and minimum (2006 years using the ionograms and magnetograms from the magnetic equatorial location of Trivandrum (8.5° N; 77° E; dip lat ~0.5° N in India. The study brings out some interesting aspects of the daytime Equatorial Electrojet (EEJ related electric field variations and the post sunset F-region electrodynamics governing the nature of seasonal characteristics of the ESF phenomena during these years. The observed results seem to indicate a plausible linkage of daytime EEJ related electric field variations with pre-reversal enhancement which in turn is related to the occurrence of ESF. These electric field variations are shown to be better represented through a parameter, termed as "E", in the context of possible coupling between the E- and F-regions of the ionosphere. The observed similarities in the gross features of the variations in the parameter "E" and the F-region vertical drift (Vz point towards the potential usage of the EEJ related parameter "E" as an useful index for the assessment of Vz prior to the occurrence of ESF.

  13. Biological effects of radiation

    International Nuclear Information System (INIS)

    This fourth chapter presents: cell structure and metabolism; radiation interaction with biological tissues; steps of the production of biological effect of radiation; radiosensitivity of tissues; classification of biological effects; reversibility, transmissivity and influence factors; pre-natal biological effects; biological effects in therapy and syndrome of acute irradiation

  14. Cellular and molecular mechanistic insight into the DNA-damaging potential of few-layer graphene in human primary endothelial cells.

    Science.gov (United States)

    Sasidharan, Abhilash; Swaroop, Siddharth; Chandran, Parwathy; Nair, Shantikumar; Koyakutty, Manzoor

    2016-07-01

    Despite graphene being proposed for a multitude of biomedical applications, there is a dearth in the fundamental cellular and molecular level understanding of how few-layer graphene (FLG) interacts with human primary cells. Herein, using human primary umbilical vein endothelial cells as model of vascular transport, we investigated the basic mechanism underlying the biological behavior of graphene. Mechanistic toxicity studies using a battery of cell based assays revealed an organized oxidative stress paradigm involving cytosolic reactive oxygen stress, mitochondrial superoxide generation, lipid peroxidation, glutathione oxidation, mitochondrial membrane depolarization, enhanced calcium efflux, all leading to cell death by apoptosis/necrosis. We further investigated the effect of graphene interactions using cDNA microarray analysis and identified potential adverse effects by down regulating key genes involved in DNA damage response and repair mechanisms. Single cell gel electrophoresis assay/Comet assay confirmed the DNA damaging potential of graphene towards human primary cells. PMID:26970024

  15. Radiation physics, biophysics, and radiation biology

    International Nuclear Information System (INIS)

    Research at the Radiological Research Laboratory is a blend of physics, chemistry, and biology, involving research at the basic level with the admixture of a small proportion of pragmatic or applied research in support of radiation protection and/or radiotherapy. Current research topics include: oncogenic transformation assays, mutation studies involving interactions between radiation and environmental contaminants, isolation, characterization and sequencing of a human repair gene, characterization of a dominant transforming gene found in C3H 10T1/2 cells, characterize ab initio the interaction of DNA and radiation, refine estimates of the radiation quality factor Q, a new mechanistic model of oncogenesis showing the role of long-term low dose medium LET radiation, and time dependent modeling of radiation induced chromosome damage and subsequent repair or misrepair

  16. Biological activities and medicinal properties of Gokhru (Pedalium murex L.)

    Institute of Scientific and Technical Information of China (English)

    V Rajashekar; E Upender Rao; Srinivas P

    2012-01-01

    Bada Gokhru (Pedalium murex L.) is perhaps the most useful traditional medicinal plant in India. Each part of the neem tree has some medicinal property and is thus commercially exploitable. During the last five decades, apart from the chemistry of the Pedalium murex compounds, considerable progress has been achieved regarding the biological activity and medicinal applications of this plant. It is now considered as a valuable source of unique natural products for development of medicines against various diseases and also for the development of industrial products. This review gives a bird’s eye view mainly on the biological activities of some of this compounds isolated, pharmacological actions of the extracts, clinical studies and plausible medicinal applications of gokharu along with their safety evaluation.

  17. Follicular-fluid anti-Mullerian hormone (FF AMH is a plausible biochemical indicator of functional viability of oocyte in conventional in vitro fertilization (IVF cycles

    Directory of Open Access Journals (Sweden)

    Bindu N Mehta

    2013-01-01

    Full Text Available Context: Oocyte quality may be a governing factor in influencing in vitro fertilization (IVF outcomes. However, morphological evaluation of oocyte quality is difficult in conventional IVF cycles. Follicular-fluid (FF, the site for oocyte growth and development, has not yet been sufficiently explored to obtain a marker indicative of oocyte quality. Anti-Mullerian hormone (AMH is produced by granulosa cells of preantral and early-antral follicles and is released in FF. Aim: To investigate AMH as a biochemical indicator of functional viability/quality of oocyte produced in the FF micro-environmental milieu. Settings and Design: Prospective study involving 132 cycles of conventional IVF-embryo transfer (ET in infertile women. Subjects and Methods: AMH concentration was estimated in pooled FF on day of oocyte pickup. Cycles were sorted into low and high groups according to median (50 th centile values of measurement. Main outcome measure was oocyte viability, which included morphological assessment of oocyte quality, fertilization rate, clinical pregnancy, and implantation rates. Statistical Analysis: Graph-pad Prism 5 statistical package. Results: Low FF AMH group shows significantly higher percentage of top-quality oocytes (65.08 ± 24.88 vs. 50.18 ± 25.01%, P =0.0126, fertilization (83.65 ± 18.38 vs. 75.78 ± 21.02%, P =0.0171, clinical pregnancy (57.57 vs. 16.67%, P <0.0001, and embryo implantation rates (29.79 vs. 7.69%, P <0.0001 compared to high FF AMH group. FF AMH shares an inverse correlation with FF E2 (Pearson r = −0.43, r 2 = 0.18 and clinical pregnancy (Pearson r = −0.46, r 2 = 0.21. Threshold value of FF AMH for pregnancy is <1.750 ng/mg protein. Conclusion: FF AMH is a plausible biochemical indicator of functional viability of oocyte in conventional IVF cycles.

  18. From provocative narrative scenarios to quantitative biophysical model results: Simulating plausible futures to 2070 in an urbanizing agricultural watershed in Wisconsin, USA

    Science.gov (United States)

    Booth, E.; Chen, X.; Motew, M.; Qiu, J.; Zipper, S. C.; Carpenter, S. R.; Kucharik, C. J.; Steven, L. I.

    2015-12-01

    Scenario analysis is a powerful tool for envisioning future social-ecological change and its consequences on human well-being. Scenarios that integrate qualitative storylines and quantitative biophysical models can create a vivid picture of these potential futures but the integration process is not straightforward. We present - using the Yahara Watershed in southern Wisconsin (USA) as a case study - a method for developing quantitative inputs (climate, land use/cover, and land management) to drive a biophysical modeling suite based on four provocative and contrasting narrative scenarios that describe plausible futures of the watershed to 2070. The modeling suite consists of an agroecosystem model (AgroIBIS-VSF), hydrologic routing model (THMB), and empirical lake water quality model and estimates several biophysical indicators to evaluate the watershed system under each scenario. These indicators include water supply, lake flooding, agricultural production, and lake water quality. Climate (daily precipitation and air temperature) for each scenario was determined using statistics from 210 different downscaled future climate projections for two 20-year time periods (2046-2065 and 2081-2100) and modified using a stochastic weather generator to allow flexibility for matching specific climate events within the scenario narratives. Land use/cover for each scenario was determined first by quantifying changes in areal extent every decade for 15 categories at the watershed scale to be consistent with the storyline events and theme. Next, these changes were spatially distributed using a rule-based framework based on land suitability metrics that determine transition probabilities. Finally, agricultural inputs including manure and fertilizer application rates were determined for each scenario based on the prevalence of livestock, water quality regulations, and technological innovations. Each scenario is compared using model inputs (maps and time-series of land use/cover and

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

    Science.gov (United States)

    Wooldridge, Scott A.

    2014-12-01

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

  20. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-05-23

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

  2. 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)

  3. Mechanistic studies of magnetically recyclable Pd - Fe3O4 heterodimeric nanocrystal-catalyzed organic reactions.

    Science.gov (United States)

    Byun, Sangmoon; Chung, Jooyoung; Kwon, Jungmin; Moon Kim, B

    2015-04-01

    Recently, we have reported several catalytic applications of new Pd - Fe3 O4 heterodimeric nanocrystals as magnetically separable catalysts. Successful applications of the nanocrystals towards various useful organic reactions such as Suzuki, Heck, and Sonogashira coupling reactions, direct C - H arylation, and Wacker oxidation have been recorded. However, detailed mechanistic courses of the reactions have not been delineated, and it was not clear whether these processes proceeded through a homogeneous or heterogeneous mechanism. Here, we report detailed mechanistic investigations of the reactions employing the Pd - Fe3 O4 nanoparticle catalysts. Suzuki coupling and Wacker oxidation reactions were chosen as two representative heterogeneous reactions employing the Pd - Fe3 O4 catalysts, and general kinetic studies, hot filtration tests, and three-phase tests were carried out for the two reactions. The studies showed that the reactions most probably proceed via a solution-phase mechanism. PMID:25620124

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

    Science.gov (United States)

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

    2016-03-01

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

  5. Synthesis, Cytotoxicity and Mechanistic Evaluation of 4-Oxoquinoline-3-carboxamide Derivatives: Finding New Potential Anticancer Drugs

    Directory of Open Access Journals (Sweden)

    Luana da S. M. Forezi

    2014-05-01

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

  6. A mechanistic model of the effects of light and temperature on algal primary productivity

    OpenAIRE

    Duarte, Pedro

    1995-01-01

    In this work a model of algal primary productivity combining a mechanistic light function with a temperature Arrhenius function is presented. Data on primary productivity obtained with algae acclimated to different environmental conditions was used to test the model. A simple method for model parameter estimation based on regression analysis is described. The parameter estimates can be improved by a non-linear least-squares method (e.g. the Gauss-Newton method) resulting in a s...

  7. Mars mechanistic film-splitting and dryout model in annulus geometry

    International Nuclear Information System (INIS)

    Annular flow in annulus geometry is characterized as two liquid films flowing along the inner heated rod and outer unheated walls. Critical heat flux (CHF) occurs when the liquid film on the inner heated wall dries out, while there still exists the liquid film on the outer cold wall. In the MARS code, film dryout is calculated by a mechanistic model or CHF table look-up method. The mechanistic film dryout is modeled using a complex function of film flow rate, applied heat flux and entrainment/deposition rate, etc. and is determined by the hydrodynamic solution. The table look-up method interpolates the AECL-UO CHF table. However, both models were not able to distinguish the liquid films on the cold and hot surfaces in a calculation cell, that is, the cold wall effect. This resulted in over-estimation of the calculated CHF in the single-channel modeling of annulus geometry, which necessitated a new model that could consider the cold wall effect mechanistically in the single-channel modeling. In order to consider the cold wall effect, a mechanistic film splitting model has been developed for MARS implementation, in which the inner and outer liquid film fractions are solved analytically by introducing a maximum velocity plane concept in the vapor core. In addition, the droplet entrainment and deposition models and the transition criterion for the annular flow regime are improved in order to enhance code accuracy. The new MARS version has been assessed using the KAERI annulus CHF tests and the results shows enhanced agreement with the experimental data

  8. A mechanistic description of the formation and evolution of vegetation patterns

    OpenAIRE

    R. Foti; Ramírez, J. A.

    2013-01-01

    Vegetation patterns are a common and well-defined characteristic of many landscapes. In this paper we explore some of the physical mechanisms responsible for the establishment of self-organized, non-random vegetation patterns that arise at the hillslope scale in many areas of the world, especially in arid and semi-arid regions. In doing so, we provide a fundamental mechanistic understanding of the dynamics of vegetation pattern formation and development. Reciprocal effects of vegetation on th...

  9. Pt-Mechanistic Study of the β-Hydrogen Elimination from Organoplatinum(II) Enolate Complexes

    OpenAIRE

    Alexanian, Erik J.; Hartwig, John F.

    2008-01-01

    A detailed mechanistic investigation of the thermal reactions of a series of bisphosphine alkylplatinum(II) enolate complexes is reported. The reactions of methylplatinum enolate complexes in the presence of added phosphine form methane and either free or coordinated enone, depending on the steric properties of the enone. Kinetic studies were conducted to determine the relationship between the rates and mechanism of β-hydrogen elimination from enolate complexes and the rates and mechanism of ...

  10. Telomere extension by telomerase and ALT generates variant repeats by mechanistically distinct processes

    OpenAIRE

    Lee, Michael; Hills, Mark; Conomos, Dimitri; Stutz, Michael D.; Dagg, Rebecca A.; Lau, Loretta M. S.; Reddel, Roger R; Hilda A Pickett

    2013-01-01

    Telomeres are terminal repetitive DNA sequences on chromosomes, and are considered to comprise almost exclusively hexameric TTAGGG repeats. We have evaluated telomere sequence content in human cells using whole-genome sequencing followed by telomere read extraction in a panel of mortal cell strains and immortal cell lines. We identified a wide range of telomere variant repeats in human cells, and found evidence that variant repeats are generated by mechanistically distinct processes during te...

  11. 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 ostatní: 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: 5.636, year: 2014

  12. Mechanistic insights on immunosenescence and chronic immune activation in HIV-tuberculosis co-infection

    OpenAIRE

    Esaki M Shankar; Velu, Vijayakumar; Kamarulzaman, Adeeba; Larsson, Marie

    2015-01-01

    Immunosenescence is marked by accelerated degradation of host immune responses leading to the onset of opportunistic infections, where senescent T cells show remarkably higher ontogenic defects as compared to healthy T cells. The mechanistic association between T-cell immunosenescence and human immunodeficiency virus (HIV) disease progression, and functional T-cell responses in HIV-tuberculosis (HIV-TB) co-infection remains to be elaborately discussed. Here, we discussed the association of im...

  13. Studies on the interaction of isocyanides with imines: reaction scope and mechanistic variations.

    Science.gov (United States)

    Ghashghaei, Ouldouz; Manna, Consiglia Annamaria; Vicente-García, Esther; Revés, Marc; Lavilla, Rodolfo

    2014-01-01

    The interaction of imines with isocyanides has been studied. The main product results from a sequential process involving the attack of two units of isocyanide, under Lewis acid catalysis, upon the carbon-nitrogen double bond of the imine to form the 4-membered ring system. The scope of the reaction regarding the imine and isocyanide ranges has been determined, and also some mechanistic variations and structural features have been described. PMID:24454559

  14. Mechanistic Modeling Reveals the Critical Knowledge Gaps in Bile Acid–Mediated DILI

    OpenAIRE

    Woodhead, J L; Yang, K.; Brouwer, K L R; Siler, S. Q.; Stahl, S H; Ambroso, J L; Baker, D; Watkins, P B; Howell, B A

    2014-01-01

    Bile salt export pump (BSEP) inhibition has been proposed to be an important mechanism for drug-induced liver injury (DILI). Modeling can prioritize knowledge gaps concerning bile acid (BA) homeostasis and thus help guide experimentation. A submodel of BA homeostasis in rats and humans was constructed within DILIsym, a mechanistic model of DILI. In vivo experiments in rats with glibenclamide were conducted, and data from these experiments were used to validate the model. The behavior of DILIs...

  15. Estimating enteric methane emissions from Chilean beef fattening systems using a mechanistic model

    OpenAIRE

    Arias, RA; Catrileo, A; Larraín, R; Vera, R; Velásquez, A.; Toneatti, M; France, J; Dijkstra, J.; Kebreab, E.

    2015-01-01

    Copyright © 2014 Cambridge University Press. A mechanistic model (COWPOLL) was used to estimate enteric methane (CH4) emissions from beef production systems in Chile. The results expressed as a proportion of gross energy intake (GEI) were compared with enteric fermentation data reported in the last Chilean greenhouse gases inventory, which utilized an earlier the Intergovernmental Panel on Climate Change Tier 2 approach. The simulation analysis was based on information from feedstuffs, dry ma...

  16. Asphalt Materials Characterization in Support of Implementation of the Proposed Mechanistic-Empirical Pavement Design Guide

    OpenAIRE

    Flintsch, Gerardo W.; Loulizi, Amara; Stacey D. Diefenderfer; Khaled A. Galal; Diefenderfer, Brian K.

    2007-01-01

    The proposed Mechanistic-Empirical Pavement Design Guide (MEPDG) procedure is an improved methodology for pavement design and evaluation of paving materials. Since this new procedure depends heavily on the characterization of the fundamental engineering properties of paving materials, a thorough material characterization of mixes used in Virginia is needed to use the MEPDG to design new and rehabilitated flexible pavements. The primary objective of this project was to perform a full hot-mix a...

  17. Model Discrimination and Mechanistic Interpretation of Kinetic Data in Protein Aggregation Studies

    OpenAIRE

    Bernacki, Joseph P.; Murphy, Regina M.

    2009-01-01

    Given the importance of protein aggregation in amyloid diseases and in the manufacture of protein pharmaceuticals, there has been increased interest in measuring and modeling the kinetics of protein aggregation. Several groups have analyzed aggregation data quantitatively, typically measuring aggregation kinetics by following the loss of protein monomer over time and invoking a nucleated growth mechanism. Such analysis has led to mechanistic conclusions about the size and nature of the nucleu...

  18. Studies on the interaction of isocyanides with imines: reaction scope and mechanistic variations

    Directory of Open Access Journals (Sweden)

    Ouldouz Ghashghaei

    2014-01-01

    Full Text Available The interaction of imines with isocyanides has been studied. The main product results from a sequential process involving the attack of two units of isocyanide, under Lewis acid catalysis, upon the carbon–nitrogen double bond of the imine to form the 4-membered ring system. The scope of the reaction regarding the imine and isocyanide ranges has been determined, and also some mechanistic variations and structural features have been described.

  19. 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 ostatní: 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: 5.636, year: 2014

  20. Technology Advances and Mechanistic Modelling in Freeze-drying and Dehydration of Food

    OpenAIRE

    Wanren Chen; Xiang Gui; Hua Li

    2015-01-01

    Aim of study is to introduce some advanced freeze-drying technology and mechanistic modelling in freeze-drying and dehydration of food, freeze-drying is based on the dehydration by sublimation of a frozen product, due to very low temperature, all the deterioration activity and microbiological activity are stopped and provide better quality to the final product. Meanwhile the main problems of the freeze-dried food were proposed and its prospect and outlook was also analyzed, expecting to obtai...

  1. Epithelial apoptosis in mechanistically distinct methods of injury in the murine small intestine

    OpenAIRE

    Vyas, D.; Robertson, C M; Stromberg, P.E.; J. R. Martin; Dunne, W. M.; Houchen, C.W.; Barrett, T A; Ayala, A; Perl, M.; Buchman, T G; Coopersmith, C.M.

    2007-01-01

    Gut epithelial apoptosis is involved in the pathophysiology of multiple diseases. This study characterized intestinal apoptosis in three mechanistically distinct injuries with different kinetics of cell death. FVB/N mice were subjected to gamma radiation, Pseudomonas aeruginosa pneumonia or injection of monoclonal anti-CD3 antibody and sacrificed 4, 12, or 24 hours post-injury (n=10/time point). Apoptosis was quantified in the jejunum by hematoxylin and eosin (H&E), active caspase-3, terminal...

  2. Sensitivity analysis of a mechanistic model for the ammonia emission of dairy cow houses

    OpenAIRE

    Snoek, J W; Ogink, N.W.M.; Stigter, J.D.; Groot Koerkamp, P.W.G.

    2012-01-01

    Emission of ammonia (NH3) from animal husbandry, and specially from the dairy sector, contributes significantly to acidification and eutrophication, and affects sensitive natural areas. In the nineties Monteny (1998) introduced a mechanistic model to understand and predict the NH3 emissions from cubicle dairy cow houses. Although a limited sensitivity analysis was carried out, we still lack information that essential for further development of the model. Our aim is that the model can predict ...

  3. Complexity, Post-genomic Biology and Gene Expression Programs

    Science.gov (United States)

    Williams, Rohan B. H.; Luo, Oscar Junhong

    Gene expression represents the fundamental phenomenon by which information encoded in a genome is utilised for the overall biological objectives of the organism. Understanding this level of information transfer is therefore essential for dissecting the mechanistic basis of form and function of organisms. We survey recent developments in the methodology of the life sciences that is relevant for understanding the organisation and function of the genome and review our current understanding of the regulation of gene expression, and finally, outline some new approaches that may be useful in understanding the organisation of gene regulatory systems.

  4. Mechanistic analytical models for long-distance seed dispersal by wind.

    Science.gov (United States)

    Katul, G G; Porporato, A; Nathan, R; Siqueira, M; Soons, M B; Poggi, D; Horn, H S; Levin, S A

    2005-09-01

    We introduce an analytical model, the Wald analytical long-distance dispersal (WALD) model, for estimating dispersal kernels of wind-dispersed seeds and their escape probability from the canopy. The model is based on simplifications to well-established three-dimensional Lagrangian stochastic approaches for turbulent scalar transport resulting in a two-parameter Wald (or inverse Gaussian) distribution. Unlike commonly used phenomenological models, WALD's parameters can be estimated from the key factors affecting wind dispersal--wind statistics, seed release height, and seed terminal velocity--determined independently of dispersal data. WALD's asymptotic power-law tail has an exponent of -3/2, a limiting value verified by a meta-analysis for a wide variety of measured dispersal kernels and larger than the exponent of the bivariate Student t-test (2Dt). We tested WALD using three dispersal data sets on forest trees, heathland shrubs, and grassland forbs and compared WALD's performance with that of other analytical mechanistic models (revised versions of the tilted Gaussian Plume model and the advection-diffusion equation), revealing fairest agreement between WALD predictions and measurements. Analytical mechanistic models, such as WALD, combine the advantages of simplicity and mechanistic understanding and are valuable tools for modeling large-scale, long-term plant population dynamics. PMID:16224691

  5. A reconciliation of empirical and mechanistic models of the air-sea gas transfer velocity

    Science.gov (United States)

    Goddijn-Murphy, Lonneke; Woolf, David K.; Callaghan, Adrian H.; Nightingale, Philip D.; Shutler, Jamie D.

    2016-01-01

    Models of the air-sea transfer velocity of gases may be either empirical or mechanistic. Extrapolations of empirical models to an unmeasured gas or to another water temperature can be erroneous if the basis of that extrapolation is flawed. This issue is readily demonstrated for the most well-known empirical gas transfer velocity models where the influence of bubble-mediated transfer, which can vary between gases, is not explicitly accounted for. Mechanistic models are hindered by an incomplete knowledge of the mechanisms of air-sea gas transfer. We describe a hybrid model that incorporates a simple mechanistic view—strictly enforcing a distinction between direct and bubble-mediated transfer—but also uses parameterizations based on data from eddy flux measurements of dimethyl sulphide (DMS) to calibrate the model together with dual tracer results to evaluate the model. This model underpins simple algorithms that can be easily applied within schemes to calculate local, regional, or global air-sea fluxes of gases.

  6. Mechanistic insight into gramicidin-based detection of protein-ligand interactions via sensitized photoinactivation

    Energy Technology Data Exchange (ETDEWEB)

    Rokitskaya, Tatyana I; Kotova, Elena A; Antonenko, Yuri N [Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119991 (Russian Federation); Macrae, Michael X; Blake, Steven; Yang, Jerry [Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, MC 0358, La Jolla, CA 92093-0358 (United States); Egorova, Natalya S, E-mail: jerryyang@ucsd.ed, E-mail: antonen@genebee.msu.s [Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117871 Moscow (Russian Federation)

    2010-11-17

    Among the many challenges for the development of ion channel-based sensors is the poor understanding of how to engineer modified transmembrane pores with tailored functionality that can respond to external stimuli. Here, we use the method of sensitized photoinactivation of gramicidin A (gA) channels in planar bilayer lipid membranes to help elucidate the underlying mechanistic details for changes in macroscopic transmembrane ionic current observed upon interaction of C-terminally attached gA ligands with specific proteins in solution. Three different systems were studied: (i) carbonic anhydrase (CA) and gA-sulfonamide, (ii) PSD-95 protein (belonging to the 'PDZ domain-containing protein') and a gA analog carrying the KGGHRRSARYLESSV peptide sequence at the C-terminus, and (iii) an anti-biotin antibody and gA-biotin. The results challenge a previously proposed mechanistic hypothesis suggesting that protein-induced current suppression is due to steric blockage of the ion passage through gA channels, while they reveal new insight for consideration in alternative mechanistic models. Additionally, we demonstrate that the length of a linker between the ligand and the gA channel may be less important for gramicidin-based detection of monovalent compared to multivalent protein-ligand interactions. These studies collectively shed new light on the mechanism of protein-induced current alterations in bilayer recordings of gA derivatives, which may be important in the design of new gramicidin-based sensors.

  7. Mechanistic insight into gramicidin-based detection of protein-ligand interactions via sensitized photoinactivation

    Science.gov (United States)

    Rokitskaya, Tatyana I.; Macrae, Michael X.; Blake, Steven; Egorova, Natalya S.; Kotova, Elena A.; Yang, Jerry; Antonenko, Yuri N.

    2010-11-01

    Among the many challenges for the development of ion channel-based sensors is the poor understanding of how to engineer modified transmembrane pores with tailored functionality that can respond to external stimuli. Here, we use the method of sensitized photoinactivation of gramicidin A (gA) channels in planar bilayer lipid membranes to help elucidate the underlying mechanistic details for changes in macroscopic transmembrane ionic current observed upon interaction of C-terminally attached gA ligands with specific proteins in solution. Three different systems were studied: (i) carbonic anhydrase (CA) and gA-sulfonamide, (ii) PSD-95 protein (belonging to the 'PDZ domain-containing protein') and a gA analog carrying the KGGHRRSARYLESSV peptide sequence at the C-terminus, and (iii) an anti-biotin antibody and gA-biotin. The results challenge a previously proposed mechanistic hypothesis suggesting that protein-induced current suppression is due to steric blockage of the ion passage through gA channels, while they reveal new insight for consideration in alternative mechanistic models. Additionally, we demonstrate that the length of a linker between the ligand and the gA channel may be less important for gramicidin-based detection of monovalent compared to multivalent protein-ligand interactions. These studies collectively shed new light on the mechanism of protein-induced current alterations in bilayer recordings of gA derivatives, which may be important in the design of new gramicidin-based sensors.

  8. Comparative Evaluation of Statistical and Mechanistic Models of Escherichia coli at Beaches in Southern Lake Michigan.

    Science.gov (United States)

    Safaie, Ammar; Wendzel, Aaron; Ge, Zhongfu; Nevers, Meredith B; Whitman, Richard L; Corsi, Steven R; Phanikumar, Mantha S

    2016-03-01

    Statistical and mechanistic models are popular tools for predicting the levels of indicator bacteria at recreational beaches. Researchers tend to use one class of model or the other, and it is difficult to generalize statements about their relative performance due to differences in how the models are developed, tested, and used. We describe a cooperative modeling approach for freshwater beaches impacted by point sources in which insights derived from mechanistic modeling were used to further improve the statistical models and vice versa. The statistical models provided a basis for assessing the mechanistic models which were further improved using probability distributions to generate high-resolution time series data at the source, long-term "tracer" transport modeling based on observed electrical conductivity, better assimilation of meteorological data, and the use of unstructured-grids to better resolve nearshore features. This approach resulted in improved models of comparable performance for both classes including a parsimonious statistical model suitable for real-time predictions based on an easily measurable environmental variable (turbidity). The modeling approach outlined here can be used at other sites impacted by point sources and has the potential to improve water quality predictions resulting in more accurate estimates of beach closures. PMID:26825142

  9. Comparative evaluation of statistical and mechanistic models of Escherichia coli at beaches in southern Lake Michigan

    Science.gov (United States)

    Safaie, Ammar; Wendzel, Aaron; Ge, Zhongfu; Nevers, Meredith; Whitman, Richard L.; Corsi, Steven R.; Phanikumar, Mantha S.

    2016-01-01

    Statistical and mechanistic models are popular tools for predicting the levels of indicator bacteria at recreational beaches. Researchers tend to use one class of model or the other, and it is difficult to generalize statements about their relative performance due to differences in how the models are developed, tested, and used. We describe a cooperative modeling approach for freshwater beaches impacted by point sources in which insights derived from mechanistic modeling were used to further improve the statistical models and vice versa. The statistical models provided a basis for assessing the mechanistic models which were further improved using probability distributions to generate high-resolution time series data at the source, long-term “tracer” transport modeling based on observed electrical conductivity, better assimilation of meteorological data, and the use of unstructured-grids to better resolve nearshore features. This approach resulted in improved models of comparable performance for both classes including a parsimonious statistical model suitable for real-time predictions based on an easily measurable environmental variable (turbidity). The modeling approach outlined here can be used at other sites impacted by point sources and has the potential to improve water quality predictions resulting in more accurate estimates of beach closures.

  10. Biological conversion system

    Science.gov (United States)

    Scott, C.D.

    A system for bioconversion of organic material comprises a primary bioreactor column wherein a biological active agent (zymomonas mobilis) converts the organic material (sugar) to a product (alcohol), a rejuvenator column wherein the biological activity of said biological active agent is enhanced, and means for circulating said biological active agent between said primary bioreactor column and said rejuvenator column.

  11. Synthetic biology: insights into biological computation.

    Science.gov (United States)

    Manzoni, Romilde; Urrios, Arturo; Velazquez-Garcia, Silvia; de Nadal, Eulàlia; Posas, Francesc

    2016-04-18

    Organisms have evolved a broad array of complex signaling mechanisms that allow them to survive in a wide range of environmental conditions. They are able to sense external inputs and produce an output response by computing the information. Synthetic biology attempts to rationally engineer biological systems in order to perform desired functions. Our increasing understanding of biological systems guides this rational design, while the huge background in electronics for building circuits defines the methodology. In this context, biocomputation is the branch of synthetic biology aimed at implementing artificial computational devices using engineered biological motifs as building blocks. Biocomputational devices are defined as biological systems that are able to integrate inputs and return outputs following pre-determined rules. Over the last decade the number of available synthetic engineered devices has increased exponentially; simple and complex circuits have been built in bacteria, yeast and mammalian cells. These devices can manage and store information, take decisions based on past and present inputs, and even convert a transient signal into a sustained response. The field is experiencing a fast growth and every day it is easier to implement more complex biological functions. This is mainly due to advances in in vitro DNA synthesis, new genome editing tools, novel molecular cloning techniques, continuously growing part libraries as well as other technological advances. This allows that digital computation can now be engineered and implemented in biological systems. Simple logic gates can be implemented and connected to perform novel desired functions or to better understand and redesign biological processes. Synthetic biological digital circuits could lead to new therapeutic approaches, as well as new and efficient ways to produce complex molecules such as antibiotics, bioplastics or biofuels. Biological computation not only provides possible biomedical and

  12. Toward a mechanistic understanding of patterns in biomineralization and new insights for old dogmas in geological settings (Invited)

    Science.gov (United States)

    Dove, P. M.; Hamm, L.; Giuffre, A. J.; Han, N.; De Yoreo, J. J.

    2013-12-01

    The ability of organisms to mineralize tissues into skeletons and other functional structures is a remarkable achievement of biology. Yet, the physical basis for how macromolecules regulate the placement and onset of mineral formation is not well established. Efforts to understand nucleation onto organic substrates have produced two, seemingly contradictory, lines of thought: The biomineralization community widely assumes the organic matrix promotes nucleation through stereochemical matching to guide the organization of solute ions, while materials synthesis groups use simple binding assays to correlate high binding strength with good promoters of nucleation. This study reconciles the two views and provides a mechanistic explanation for template-directed nucleation by correlating heterogeneous nucleation barriers with crystal-substrate binding free energies. Using surface assembled monolayers (SAM) as simple model systems, we first measure the kinetics of calcite nucleation onto model substrates that present different functional group chemistries (carboxyl, thiol, phosphate, hydroxyl) and conformations (C11, C16 chain lengths). We find rates are substrate-specific and obey predictions of classical nucleation theory at supersaturations that extend above the solubility of amorphous calcium carbonate (ACC). Analysis of the kinetic data shows the thermodynamic barrier to nucleation is reduced by minimizing the interfacial free energy of the system, γ. We then use dynamic force spectroscopy to independently measure calcite-substrate binding free energies, ΔGb. Moreover, we show that within the classical theory of nucleation, γ and ΔGb should be linearly related. The results bear out this prediction and demonstrate that low energy barriers to nucleation correlate with strong crystal-substrate binding. This relationship is general to all functional group chemistries and conformations. These findings reconcile the long-standing concept of templated nucleation through

  13. Computational Systems Chemical Biology

    OpenAIRE

    Oprea, Tudor I.; May, Elebeoba E.; Leitão, Andrei; Tropsha, Alexander

    2011-01-01

    There is a critical need for improving the level of chemistry awareness in systems biology. The data and information related to modulation of genes and proteins by small molecules continue to accumulate at the same time as simulation tools in systems biology and whole body physiologically-based pharmacokinetics (PBPK) continue to evolve. We called this emerging area at the interface between chemical biology and systems biology systems chemical biology, SCB (Oprea et al., 2007).

  14. Pictures of Synthetic Biology

    OpenAIRE

    Cserer, Amelie; Seiringer, Alexandra

    2009-01-01

    This article is concerned with the representation of Synthetic Biology in the media and by biotechnology experts. An analysis was made of German-language media articles published between 2004 and 2008, and interviews with biotechnology-experts at the Synthetic Biology conference SB 3.0 in Zurich 2007. The results have been reflected in terms of the definition of Synthetic Biology, applications of Synthetic Biology and the perspectives of opportunities and risks. In the media, Synthetic Biolog...

  15. Regulated Extracellular Choline Acetyltransferase Activity- The Plausible Missing Link of the Distant Action of Acetylcholine in the Cholinergic Anti-Inflammatory Pathway.

    Directory of Open Access Journals (Sweden)

    Swetha Vijayaraghavan

    Full Text Available Acetylcholine (ACh, the classical neurotransmitter, also affects a variety of nonexcitable cells, such as endothelia, microglia, astrocytes and lymphocytes in both the nervous system and secondary lymphoid organs. Most of these cells are very distant from cholinergic synapses. The action of ACh on these distant cells is unlikely to occur through diffusion, given that ACh is very short-lived in the presence of acetylcholinesterase (AChE and butyrylcholinesterase (BuChE, two extremely efficient ACh-degrading enzymes abundantly present in extracellular fluids. In this study, we show compelling evidence for presence of a high concentration and activity of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT in human cerebrospinal fluid (CSF and plasma. We show that ChAT levels are physiologically balanced to the levels of its counteracting enzymes, AChE and BuChE in the human plasma and CSF. Equilibrium analyses show that soluble ChAT maintains a steady-state ACh level in the presence of physiological levels of fully active ACh-degrading enzymes. We show that ChAT is secreted by cultured human-brain astrocytes, and that activated spleen lymphocytes release ChAT itself rather than ACh. We further report differential CSF levels of ChAT in relation to Alzheimer's disease risk genotypes, as well as in patients with multiple sclerosis, a chronic neuroinflammatory disease, compared to controls. Interestingly, soluble CSF ChAT levels show strong correlation with soluble complement factor levels, supporting a role in inflammatory regulation. This study provides a plausible explanation for the long-distance action of ACh through continuous renewal of ACh in extracellular fluids by the soluble ChAT and thereby maintenance of steady-state equilibrium between hydrolysis and synthesis of this ubiquitous cholinergic signal substance in the brain and peripheral compartments. These findings may have important implications for the role of cholinergic

  16. Effects of sex-sorting and sperm dosage on conception rates of Holstein heifers: is comparable fertility of sex-sorted and conventional semen plausible?

    Science.gov (United States)

    Dejarnette, J M; Leach, M A; Nebel, R L; Marshall, C E; McCleary, C R; Moreno, J F

    2011-07-01

    plausibility of comparable conception rates to conventional semen in the absence of major technological advances in efficiency of sperm sorting or cryopreservation. PMID:21700034

  17. Radiation physics, biophysics and radiation biology. Progress report, October 1, 1982-November 1983

    International Nuclear Information System (INIS)

    A wide range of research is carried out at the Radiological Research Laboratory, from computer simulation of particle tracks to the determination of oncogenic transformation in mammalian cells. Mechanistic studies remain the central mission in an attempt to understand the biological action of ionizing radiations. Collaborative research is carried out on the use of radiosensitizers on chemosensitizers on the effect of hormones on oncogenic transformation and on cataractogenesis

  18. Developing optimal input design strategies in cancer systems biology with applications to microfluidic device engineering

    OpenAIRE

    Maiwald Thomas; Bellomo Domenico; Menolascina Filippo; Bevilacqua Vitoantonio; Ciminelli Caterina; Paradiso Angelo; Tommasi Stefania

    2009-01-01

    Abstract Background Mechanistic models are becoming more and more popular in Systems Biology; identification and control of models underlying biochemical pathways of interest in oncology is a primary goal in this field. Unfortunately the scarce availability of data still limits our understanding of the intrinsic characteristics of complex pathologies like cancer: acquiring information for a system understanding of complex reaction networks is time consuming and expensive. Stimulus response ex...

  19. Biologic relativity: Who is the observer and what is observed?

    Science.gov (United States)

    Torday, John S; Miller, William B

    2016-05-01

    When quantum physics and biological phenomena are analogously explored, it emerges that biologic causation must also be understood independently of its overt appearance. This is similar to the manner in which Bohm characterized the explicate versus the implicate order as overlapping frames of ambiguity. Placed in this context, the variables affecting epigenetic inheritance can be properly assessed as a key mechanistic principle of evolution that significantly alters our understanding of homeostasis, pleiotropy, and heterochrony, and the purposes of sexual reproduction. Each of these become differing manifestations of a new biological relativity in which biologic space-time becomes its own frame. In such relativistic cellular contexts, it is proper to question exactly who has observer status, and who and what are being observed. Consideration within this frame reduces biology to cellular information sharing through cell-cell communication to resolve ambiguities at every scope and scale. In consequence, it becomes implicit that eukaryotic evolution derives from the unicellular state, remaining consistently adherent to it in a continuous evolutionary arc based upon elemental, non-stochastic physiologic first principles. Furthermore, the entire cell including its cytoskeletal apparatus and membranes that participate in the resolution of biological uncertainties must be considered as having equivalent primacy with genomes in evolutionary terms. PMID:26980522

  20. Household ownership and use of insecticide treated nets among target groups after implementation of a national voucher programme in the United Republic of Tanzania: plausibility study using three annual cross sectional household surveys

    OpenAIRE

    Hanson, Kara; Marchant, Tanya; Nathan, Rose; Mponda, Hadji; Jones, Caroline; Bruce, Jane; Mshinda, Hassan; Schellenberg, Joanna Armstrong

    2009-01-01

    Objectives To evaluate the impact of the Tanzania National Voucher Scheme on the coverage and equitable distribution of insecticide treated nets, used to prevent malaria, to pregnant women and their infants. Design Plausibility study using three nationally representative cross sectional household and health facility surveys, timed to take place early, mid-way, and at the end of the roll out of the national programme. Setting The Tanzania National Voucher Scheme was implemented in antenatal se...

  1. 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.

  2. Validating Mechanistic Sorption Model Parameters and Processes for Reactive Transport in Alluvium

    Energy Technology Data Exchange (ETDEWEB)

    Zavarin, M; Roberts, S K; Rose, T P; Phinney, D L

    2002-05-02

    The laboratory batch and flow-through experiments presented in this report provide a basis for validating the mechanistic surface complexation and ion exchange model we use in our hydrologic source term (HST) simulations. Batch sorption experiments were used to examine the effect of solution composition on sorption. Flow-through experiments provided for an analysis of the transport behavior of sorbing elements and tracers which includes dispersion and fluid accessibility effects. Analysis of downstream flow-through column fluids allowed for evaluation of weakly-sorbing element transport. Secondary Ion Mass Spectrometry (SIMS) analysis of the core after completion of the flow-through experiments permitted the evaluation of transport of strongly sorbing elements. A comparison between these data and model predictions provides additional constraints to our model and improves our confidence in near-field HST model parameters. In general, cesium, strontium, samarium, europium, neptunium, and uranium behavior could be accurately predicted using our mechanistic approach but only after some adjustment was made to the model parameters. The required adjustments included a reduction in strontium affinity for smectite, an increase in cesium affinity for smectite and illite, a reduction in iron oxide and calcite reactive surface area, and a change in clinoptilolite reaction constants to reflect a more recently published set of data. In general, these adjustments are justifiable because they fall within a range consistent with our understanding of the parameter uncertainties. These modeling results suggest that the uncertainty in the sorption model parameters must be accounted for to validate the mechanistic approach. The uncertainties in predicting the sorptive behavior of U-1a and UE-5n alluvium also suggest that these uncertainties must be propagated to nearfield HST and large-scale corrective action unit (CAU) models.

  3. Mechanistic investigation of the endo-alpha-N-acetylgalactosaminidase from Streptococcus pneumoniae R6.

    Science.gov (United States)

    Willis, Lisa M; Zhang, Ran; Reid, Anne; Withers, Stephen G; Wakarchuk, Warren W

    2009-11-01

    The large (1767-amino acid) endo-alpha-N-acetylgalactosaminidase from Streptococcus pneumoniae (SpGH101) specifically removes an O-linked disaccharide Gal-beta-1,3-GalNAc-alpha from glycoproteins. While the enzyme from natural sources has been used as a reagent for many years, very few mechanistic studies have been performed. Using the recently determined three-dimensional structure of the recombinant protein as a background, we report here a mechanistic investigation of the SpGH101 retaining alpha-glycoside hydrolase using a combination of synthetic and natural substrates. On the basis of a model of the substrate complex of SpGH101, we propose D764 and E796 as the nucleophile and general acid-base residues, respectively. These roles were confirmed by kinetic and mechanistic analysis of mutants at those positions using synthetic substrates and anion rescue experiments. pK(a) values of 5.3 and 7.2 were assigned to D764 and E796 on the basis of the pK(a) values derived from the bell-shaped dependence of k(cat)/K(m) upon pH. The enzyme contains several putative carbohydrate binding modules whose glycan binding specificities were probed using the printed glycan array of the Consortium for Functional Glycomics using the inactive D764A and D764F mutants that had been labeled with Alexafluor 488. These studies revealed binding to galacto-N-biose, consistent with a role for these domains in localizing the enzyme near its substrates. PMID:19788271

  4. Advances in Biological Science.

    Science.gov (United States)

    Oppenheimer, Steven B.; And Others

    1988-01-01

    Reviews major developments in areas that are at the cutting edge of biological research. Areas include: human anti-cancer gene, recombinant DNA techniques for the detection of Huntington disease carriers, and marine biology. (CW)

  5. Biology of Blood

    Science.gov (United States)

    ... Mail Facebook TwitterTitle Google+ LinkedIn Home Blood Disorders Biology of Blood Overview of Blood Medical Dictionary Also ... Version. DOCTORS: Click here for the Professional Version Biology of Blood Overview of Blood Components of Blood ...

  6. Neuronal nicotinic receptors as novel targets for inflammation and neuroprotection:mechanistic considerations and clinical relevance

    Institute of Scientific and Technical Information of China (English)

    Merouane BENGHEKIF

    2009-01-01

    A number of studies have confirmed the potential for neuronal nicotinic acetylcholine receptor (NNR)-mediated neuro- protection and, more recently, its anti-inflammatory effects. The mechanistic overlap between these pathways and the ubiquitous effects observed following diverse insults suggest that NNRs modulate fundamental pathways involved in cell survival. These results have wide-reaching implications for the design of experimental therapeutics that regulate inflamma- tory and anti-apoptotic responses through NNRs and represent an initial step toward understanding the benefits of novel therapeutic strategies for the management of central nervous system disorders that target neuronal survival and associated inflammatory processes.

  7. Combined experimental and theoretical mechanistic investigation of the Barbier allylation in aqueous media

    DEFF Research Database (Denmark)

    Dam, Johan Hygum; Fristrup, Peter; Madsen, Robert

    2008-01-01

    The Barbier allylation of a series of para-substituted benzaldehydes with allylbromide in the presence of Zn, In, Sn, Sb, Bi, and Mg was investigated using competition experiments. In all cases, the slope of the Hammett plots indicated a build-up of negative charge in the selectivity-determining ...... effect of solvent described by a polarized continuum model. The calculated secondary deuterium isotope effects based on this mechanism were found to be in good agreement with experimental values, thus adding further support to this mechanistic scenario....

  8. Problems in mechanistic theoretical models for cell transformation by ionizing radiation

    International Nuclear Information System (INIS)

    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)

  9. Mechanistic modeling of thermal-mechanical deformation of CANDU pressure tube under localized high temperature condition

    International Nuclear Information System (INIS)

    Thermal strain deformation is a pressure tube failure mechanism. The main objective of this paper is to develop mechanistic models to evaluate local thermal-mechanical deformation of a pressure tube in CANDU reactor and to investigate fuel channel integrity under localized contact between fuel elements and pressure tube. The consequence of concern is potential creep strain failure of a pressure tube and calandria tube. The initial focus will be on the case where a fuel rod contacts the pressure tube at full power with highly cooling condition

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

    OpenAIRE

    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 ju...

  11. Symmetry Analysis in Mechanistic Studies of Nucleophilic Substitution and β-Elimination Reactions

    OpenAIRE

    Xiaoping Sun

    2010-01-01

    A mechanistic study of the bimolecular nucleophilic substitution (SN2) reaction for halomethane CH3X (X = Cl, Br, or I) is approached by using symmetry principles and molecular orbital theory. The electrophilicity of the functionalized sp3–carbon is attributable to a 2p-orbital-based antibonding MO along the C–X bond. This antibonding MO, upon accepting an electron pair from a nucleophile, gives rise to dissociation of the C–X bond and formation of a new Nuc–C bond. Correlations are made betw...

  12. Advancements in the mechanistic understanding of the copper-catalyzed azide–alkyne cycloaddition

    OpenAIRE

    Regina Berg; Straub, Bernd F.

    2013-01-01

    The copper-catalyzed azide–alkyne cycloaddition (CuAAC) is one of the most broadly applicable and easy-to-handle reactions in the arsenal of organic chemistry. However, the mechanistic understanding of this reaction has lagged behind the plethora of its applications for a long time. As reagent mixtures of copper salts and additives are commonly used in CuAAC reactions, the structure of the catalytically active species itself has remained subject to speculation, which can be attributed to the ...

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

    OpenAIRE

    Woodhead, Jeffrey L; Kyunghee eYang; Siler, Scott Q.; Paul Brent Watkins; Brouwer, Kim L.R.; Barton, Hugh A.; Howell, Brett A.

    2014-01-01

    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 ex...

  14. Exploring BSEP inhibition-mediated toxicity with a mechanistic model of drug-induced liver injury

    OpenAIRE

    Woodhead, Jeffrey L; Yang, Kyunghee; Siler, Scott Q.; Watkins, Paul B.; Brouwer, Kim L.R.; Barton, Hugh A.; Howell, Brett A.

    2014-01-01

    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 ex...

  15. GLUT, SGLT, and SWEET: Structural and mechanistic investigations of the glucose transporters.

    Science.gov (United States)

    Deng, Dong; Yan, Nieng

    2016-03-01

    Glucose is the primary fuel to life on earth. Cellular uptake of glucose is a fundamental process for metabolism, growth, and homeostasis. Three families of secondary glucose transporters have been identified in human, including the major facilitator superfamily glucose facilitators GLUTs, the sodium-driven glucose symporters SGLTs, and the recently identified SWEETs. Structures of representative members or their prokaryotic homologs of all three families were obtained. This review focuses on the recent advances in the structural elucidation of the glucose transporters and the mechanistic insights derived from these structures, including the molecular basis for substrate recognition, alternating access, and stoichiometric coupling of co-transport. PMID:26650681

  16. 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.

  17. Deterministic chaos in government debt dynamics with mechanistic primary balance rules

    CERN Document Server

    Lindgren, Jussi Ilmari

    2011-01-01

    This paper shows that with mechanistic primary budget rules and with some simple assumptions on interest rates the well-known debt dynamics equation transforms into the infamous logistic map. The logistic map has very peculiar and rich nonlinear behaviour and it can exhibit deterministic chaos with certain parameter regimes. Deterministic chaos means the existence of the butterfly effect which in turn is qualitatively very important, as it shows that even deterministic budget rules produce unpredictable behaviour of the debt-to-GDP ratio, as chaotic systems are extremely sensitive to initial conditions.

  18. Synthetic and Mechanistic Studies of Strained Heterocycle Opening Reactions Mediated by Zirconium(IV) Imido Complexes

    OpenAIRE

    Blum, Suzanne A.; Rivera, Vicki A.; Ruck, Rebecca T.; Michael, Forrest E.; Bergman, Robert G.

    2005-01-01

    The reactions of the bis(cyclopentadienyl)(tert-butylimido)zirconium complex (Cp2Zr=N-t-Bu)(THF) (1) with epoxides, aziridines, and episulfides were investigated. Heterocycles without accessible β-hydrogens undergo insertion/protonation of the C–X bond to produce 1,2-amino alcohols (X = O) and 1,2-diamines (X = NR), whereas heterocycles with accessible β-hydrogens undergo elimination/protonation to produce allylic alcohols (X = O) and allylic sulfides (X = S). Mechanistic investigations suppo...

  19. Technology Advances and Mechanistic Modelling in Freeze-drying and Dehydration of Food

    Directory of Open Access Journals (Sweden)

    Wanren Chen

    2015-08-01

    Full Text Available Aim of study is to introduce some advanced freeze-drying technology and mechanistic modelling in freeze-drying and dehydration of food, freeze-drying is based on the dehydration by sublimation of a frozen product, due to very low temperature, all the deterioration activity and microbiological activity are stopped and provide better quality to the final product. Meanwhile the main problems of the freeze-dried food were proposed and its prospect and outlook was also analyzed, expecting to obtain technical and theoretical support for the production of freeze-drying food.

  20. Comparison of mechanistic models in the initial rate enzymatic hydrolysis of AFEX-treated wheat straw

    Directory of Open Access Journals (Sweden)

    Agbogbo Frank K

    2010-03-01

    Full Text Available Abstract Background Different mechanistic models have been used in the literature to describe the enzymatic hydrolysis of pretreated biomass. Although these different models have been applied to different substrates, most of these mechanistic models fit into two- and three-parameter mechanistic models. The purpose of this study is to compare the models and determine the activation energy and the enthalpy of adsorption of Trichoderma reesei enzymes on ammonia fibre explosion (AFEX-treated wheat straw. Experimental enzymatic hydrolysis data from AFEX-treated wheat straw were modelled with two- and three-parameter mechanistic models from the literature. In order to discriminate between the models, initial rate data at 49°C were subjected to statistical analysis (analysis of variance and scatter plots. Results For three-parameter models, the HCH-1 model best fitted the experimental data; for two-parameter models Michaelis-Menten (M-M best fitted the experimental data. All the three-parameter models fitted the data better than the two-parameter models. The best three models at 49°C (HCH-1, Huang and M-M were compared using initial rate data at three temperatures (35°, 42° and 49°C. The HCH-1 model provided the best fit based on the F values, the scatter plot and the residual sum of squares. Also, its kinetic parameters were linear in Arrhenius/van't Hoff's plots, unlike the other models. The activation energy (Ea is 47.6 kJ/mol and the enthalpy change of adsorption (ΔH is -118 kJ/mol for T. reesei enzymes on AFEX-treated wheat straw. Conclusion Among the two-parameter models, Michaelis-Menten model provided the best fit compared to models proposed by Humphrey and Wald. For the three-parameter models, HCH-1 provided the best fit because the model includes a fractional coverage parameter (ϕ which accounts for the number of reactive sites covered by the enzymes.

  1. IGF-I/IGFBP- 3 ratio: a mechanistic insight into the metabolic syndrome

    OpenAIRE

    Sierra-Johnson, Justo; Romero-Corral, Abel; Somers, Virend K.; Lopez-Jimenez, Francisco; Mälarstig, Anders; Brismar, Kerstin; Hamsten, Anders; Fisher, Rachel M; Héllenius, Mai-Lis

    2009-01-01

    Abstract Recent reports suggest that insulin-like growth factor 1 (IGF-I) and insulin-like growth factor binding protein 3 (IGFBP-3) have independent and opposing mechanistic effects on insulin. Our aim was to assess the relationship between the IGF-I/IGFBP-3 ratio and the metabolic syndrome. We examined 3,281 subjects (1,463 men; 1,818 women aged 20 to 49 years), otherwise healthy adults, who participated in the Third National Health and Nutrition Examination Survey (NHANES III) a...

  2. Engineering scalable biological systems

    OpenAIRE

    Lu, Timothy K.

    2010-01-01

    Synthetic biology is focused on engineering biological organisms to study natural systems and to provide new solutions for pressing medical, industrial, and environmental problems. At the core of engineered organisms are synthetic biological circuits that execute the tasks of sensing inputs, processing logic, and performing output functions. In the last decade, significant progress has been made in developing basic designs for a wide range of biological circuits in bacteria, yeast, and mammal...

  3. Systems interface biology

    OpenAIRE

    Francis J Doyle; Stelling, Jörg

    2006-01-01

    The field of systems biology has attracted the attention of biologists, engineers, mathematicians, physicists, chemists and others in an endeavour to create systems-level understanding of complex biological networks. In particular, systems engineering methods are finding unique opportunities in characterizing the rich behaviour exhibited by biological systems. In the same manner, these new classes of biological problems are motivating novel developments in theoretical systems approaches. Henc...

  4. Biological Races in Humans

    OpenAIRE

    Templeton, Alan R.

    2013-01-01

    Races may exist in humans in a cultural sense, but biological concepts of race are needed to access their reality in a non-species-specific manner and to see if cultural categories correspond to biological categories within humans. Modern biological concepts of race can be implemented objectively with molecular genetic data through hypothesis-testing. Genetic data sets are used to see if biological races exist in humans and in our closest evolutionary relative, the chimpanzee. Using the two m...

  5. Upgrading Undergraduate Biology Education

    Science.gov (United States)

    Musante, Susan

    2011-01-01

    On many campuses throughout the country, undergraduate biology education is in serious need of an upgrade. During the past few decades, the body of biological knowledge has grown exponentially, and as a research endeavor, the practice of biology has evolved. Education research has also made great strides, revealing many new insights into how…

  6. Biology Myth-Killers

    Science.gov (United States)

    Lampert, Evan

    2014-01-01

    "Biology Myth-Killers" is an activity designed to identify and correct common misconceptions for high school and college introductory biology courses. Students identify common myths, which double as biology misconceptions, and use appropriate sources to share the "truth" about the myths. This learner-centered activity is a fun…

  7. Designing synthetic biology.

    Science.gov (United States)

    Agapakis, Christina M

    2014-03-21

    Synthetic biology is frequently defined as the application of engineering design principles to biology. Such principles are intended to streamline the practice of biological engineering, to shorten the time required to design, build, and test synthetic gene networks. This streamlining of iterative design cycles can facilitate the future construction of biological systems for a range of applications in the production of fuels, foods, materials, and medicines. The promise of these potential applications as well as the emphasis on design has prompted critical reflection on synthetic biology from design theorists and practicing designers from many fields, who can bring valuable perspectives to the discipline. While interdisciplinary connections between biologists and engineers have built synthetic biology via the science and the technology of biology, interdisciplinary collaboration with artists, designers, and social theorists can provide insight on the connections between technology and society. Such collaborations can open up new avenues and new principles for research and design, as well as shed new light on the challenging context-dependence-both biological and social-that face living technologies at many scales. This review is inspired by the session titled "Design and Synthetic Biology: Connecting People and Technology" at Synthetic Biology 6.0 and covers a range of literature on design practice in synthetic biology and beyond. Critical engagement with how design is used to shape the discipline opens up new possibilities for how we might design the future of synthetic biology. PMID:24156739

  8. Biological Water or Rather Water in Biology?

    Czech Academy of Sciences Publication Activity Database

    Jungwirth, Pavel

    2015-01-01

    Roč. 6, č. 13 (2015), s. 2449-2451. ISSN 1948-7185 Institutional support: RVO:61388963 Keywords : biological water * protein * interface Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 7.458, year: 2014

  9. Synthetic biological networks

    International Nuclear Information System (INIS)

    Despite their obvious relationship and overlap, the field of physics is blessed with many insightful laws, while such laws are sadly absent in biology. Here we aim to discuss how the rise of a more recent field known as synthetic biology may allow us to more directly test hypotheses regarding the possible design principles of natural biological networks and systems. In particular, this review focuses on synthetic gene regulatory networks engineered to perform specific functions or exhibit particular dynamic behaviors. Advances in synthetic biology may set the stage to uncover the relationship of potential biological principles to those developed in physics. (review article)

  10. Construction of the Core of Pseudolaric Acid A and Mechanistic Studies on Intramolecular [4+3] Cycloaddition

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    This paper describes the construction of hemiacetal 2, the core of pseudolaric acid A via oxidative cleavage of acetonide 6 or 7 and enolization-hemiacetalization of aldehyde 8. A plausible general mechanism for the intramolecular [4+3] cycloaddition of sulfoxide 4 to adduct 3 is suggested.

  11. Divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease.

    Science.gov (United States)

    Allison, Beth J; Kaandorp, Joepe J; Kane, Andrew D; Camm, Emily J; Lusby, Ciara; Cross, Christine M; Nevin-Dolan, Rhianon; Thakor, Avnesh S; Derks, Jan B; Tarry-Adkins, Jane L; Ozanne, Susan E; Giussani, Dino A

    2016-05-01

    Aging and developmental programming are both associated with oxidative stress and endothelial dysfunction, suggesting common mechanistic origins. However, their interrelationship has been little explored. In a rodent model of programmed cardiovascular dysfunction we determined endothelial function and vascular telomere length in young (4 mo) and aged (15 mo) adult offspring of normoxic or hypoxic pregnancy with or without maternal antioxidant treatment. We show loss of endothelial function [maximal arterial relaxation to acetylcholine (71 ± 3 vs. 55 ± 3%) and increased vascular short telomere abundance (4.2-1.3 kb) 43.0 ± 1.5 vs. 55.1 ± 3.8%) in aged vs. young offspring of normoxic pregnancy (P compared with aged offspring of untreated hypoxic pregnancy had lower levels of short telomeres (vascular short telomere length abundance 35.1 ± 2.5 vs. 48.2 ± 2.6%) and of plasma proinflammatory chemokine (24.6 ± 2.8 vs. 36.8 ± 5.5 pg/ml, P cardiovascular aging and developmental programming of cardiovascular disease, and aging being decelerated by antioxidants even prior to birth.-Allison, B. J., Kaandorp, J. J., Kane, A. D., Camm, E. J., Lusby, C., Cross, C. M., Nevin-Dolan, R., Thakor, A. S., Derks, J. B., Tarry-Adkins, J. L., Ozanne, S. E., Giussani, D. A. Divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease. PMID:26932929

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

    International Nuclear Information System (INIS)

    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 Ca2+, Cl-, and HCO3- 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 Kd 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

  13. 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.

  14. 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.

  15. A mechanistic description of the formation and evolution of vegetation patterns

    Directory of Open Access Journals (Sweden)

    R. Foti

    2012-07-01

    Full Text Available Vegetation patterns are a common and well-defined characteristic of many landscapes. In this paper we explore some of the physical mechanisms responsible for the establishment of self-organized, non-random vegetation patterns that arise at the hillslope scale in many areas of the world, especially in arid and semi-arid regions. In doing so, we provide a fundamental mechanistic understanding of the dynamics of vegetation pattern formation and development. Reciprocal effects of vegetation on the hillslope thermodynamics, runoff production and run-on infiltration, root density, surface albedo and soil moisture content are analyzed. In particular, we: (1 present a physically based mechanistic description of processes leading to vegetation pattern formation; (2 quantify the relative impact of each process on pattern formation; and (3 describe the relationships between vegetation patterns and the climatic, hydraulic and topographic characteristics of the system. We validate the model by comparing simulations with observed natural patterns in the areas of Niger near Niamey and Somalia near Garoowe. Our analyses suggest that the phenomenon of pattern formation is primarily driven by run-on infiltration and mechanisms of facilitation/inhibition among adjacent vegetation groups mediated by vegetation effects on soil properties and controls on soil moisture and albedo. Nonetheless, even in presence of those mechanisms, patterns arise only when the climatic conditions, particularly annual precipitation and net radiation, are favorable.

  16. A mechanistic description of the formation and evolution of vegetation patterns

    Directory of Open Access Journals (Sweden)

    R. Foti

    2013-01-01

    Full Text Available Vegetation patterns are a common and well-defined characteristic of many landscapes. In this paper we explore some of the physical mechanisms responsible for the establishment of self-organized, non-random vegetation patterns that arise at the hillslope scale in many areas of the world, especially in arid and semi-arid regions. In doing so, we provide a fundamental mechanistic understanding of the dynamics of vegetation pattern formation and development. Reciprocal effects of vegetation on the hillslope thermodynamics, runoff production and run-on infiltration, root density, surface albedo and soil moisture content are analyzed. In particular, we: (1 present a physically based mechanistic description of processes leading to vegetation pattern formation; (2 quantify the relative impact of each process on pattern formation; and (3 describe the relationships between vegetation patterns and the climatic, hydraulic and topographic characteristics of the system. We validate the model by comparing simulations with observed natural patterns in the areas of Niger near Niamey and Somalia near Garoowe. Our analyses suggest that the phenomenon of pattern formation is primarily driven by run-on infiltration and mechanisms of facilitation/inhibition among adjacent vegetation groups, mediated by vegetation effects on soil properties and controls on soil moisture and albedo. Nonetheless, even in presence of those mechanisms, patterns arise only when the climatic conditions, particularly annual precipitation and net radiation, are favorable.

  17. 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.

  18. Diverse evolutionary roots and mechanistic variations of the CRISPR-Cas systems.

    Science.gov (United States)

    Mohanraju, Prarthana; Makarova, Kira S; Zetsche, Bernd; Zhang, Feng; Koonin, Eugene V; van der Oost, John

    2016-08-01

    Adaptive immunity had been long thought of as an exclusive feature of animals. However, the discovery of the CRISPR-Cas defense system, present in almost half of prokaryotic genomes, proves otherwise. Because of the everlasting parasite-host arms race, CRISPR-Cas has rapidly evolved through horizontal transfer of complete loci or individual modules, resulting in extreme structural and functional diversity. CRISPR-Cas systems are divided into two distinct classes that each consist of three types and multiple subtypes. We discuss recent advances in CRISPR-Cas research that reveal elaborate molecular mechanisms and provide for a plausible scenario of CRISPR-Cas evolution. We also briefly describe the latest developments of a wide range of CRISPR-based applications. PMID:27493190

  19. Coupling of terminal alkynes and isonitriles by organo-actinide complexes: Scope and mechanistic insights

    International Nuclear Information System (INIS)

    The coupling reaction of terminal alkynes with several isonitriles, catalyzed by the neutral organo-actinide complexes Cp*2AnMe2 (Cp* = C5Me5, An = Th, U) or the cationic complex [(Et2N)3U][BPh4], yielded substituted α, β-acetylenic aldimines, in good to excellent yields. The reaction proceeded via a 1,1-insertion of the isonitrile carbon into a metal-acetylide bond, followed by a protonolysis by the acidic proton of the terminal alkyne. Additional insertion products were obtained by altering the catalyst and the reactant ratios. A plausible mechanism for the catalytic reaction is also presented, based on kinetics measurements and thermodynamic studies of the coupling reaction with Cp*2ThMe2 or [(Et2N)3U][BPh4] as catalysts. The reaction is first-order in catalyst and isonitrile and zero-order in alkyne. (authors)

  20. Quantum biological information theory

    CERN Document Server

    Djordjevic, Ivan B

    2016-01-01

    This book is a self-contained, tutorial-based introduction to quantum information theory and quantum biology. It serves as a single-source reference to the topic for researchers in bioengineering, communications engineering, electrical engineering, applied mathematics, biology, computer science, and physics. The book provides all the essential principles of the quantum biological information theory required to describe the quantum information transfer from DNA to proteins, the sources of genetic noise and genetic errors as well as their effects. Integrates quantum information and quantum biology concepts; Assumes only knowledge of basic concepts of vector algebra at undergraduate level; Provides a thorough introduction to basic concepts of quantum information processing, quantum information theory, and quantum biology; Includes in-depth discussion of the quantum biological channel modelling, quantum biological channel capacity calculation, quantum models of aging, quantum models of evolution, quantum models o...

  1. Mechanistic Studies at the Interface Between Organometallic Chemistry and Homogeneous Catalysis

    Energy Technology Data Exchange (ETDEWEB)

    Charles P. Casey

    2012-11-14

    Mechanistic Studies at the Interface Between Organometallic Chemistry and Homogeneous Catalysis Charles P. Casey, Principal Investigator Department of Chemistry, University of Wisconsin - Madison, Madison, Wisconsin 53706 Phone 608-262-0584 FAX: 608-262-7144 Email: casey@chem.wisc.edu http://www.chem.wisc.edu/main/people/faculty/casey.html Executive Summary. Our goal was to learn the intimate mechanistic details of reactions involved in homogeneous catalysis and to use the insight we gain to develop new and improved catalysts. Our work centered on the hydrogenation of polar functional groups such as aldehydes and ketones and on hydroformylation. Specifically, we concentrated on catalysts capable of simultaneously transferring hydride from a metal center and a proton from an acidic oxygen or nitrogen center to an aldehyde or ketone. An economical iron based catalyst was developed and patented. Better understanding of fundamental organometallic reactions and catalytic processes enabled design of energy and material efficient chemical processes. Our work contributed to the development of catalysts for the selective and mild hydrogenation of ketones and aldehydes; this will provide a modern green alternative to reductions by LiAlH4 and NaBH4, which require extensive work-up procedures and produce waste streams. (C5R4OH)Ru(CO)2H Hydrogenation Catalysts. Youval Shvo described a remarkable catalytic system in which the key intermediate (C5R4OH)Ru(CO)2H (1) has an electronically coupled acidic OH unit and a hydridic RuH unit. Our efforts centered on understanding and improving upon this important catalyst for reduction of aldehydes and ketones. Our mechanistic studies established that the reduction of aldehydes by 1 to produce alcohols and a diruthenium bridging hydride species occurs much more rapidly than regeneration of the ruthenium hydride from the diruthenium bridging hydride species. Our mechanistic studies require simultaneous transfer of hydride from ruthenium to

  2. Docking Screens for Novel Ligands Conferring New Biology.

    Science.gov (United States)

    Irwin, John J; Shoichet, Brian K

    2016-05-12

    It is now plausible to dock libraries of 10 million molecules against targets over several days or weeks. When the molecules screened are commercially available, they may be rapidly tested to find new leads. Although docking retains important liabilities (it cannot calculate affinities accurately nor even reliably rank order high-scoring molecules), it can often can distinguish likely from unlikely ligands, often with hit rates above 10%. Here we summarize the improvements in libraries, target quality, and methods that have supported these advances, and the open access resources that make docking accessible. Recent docking screens for new ligands are sketched, as are the binding, crystallographic, and in vivo assays that support them. Like any technique, controls are crucial, and key experimental ones are reviewed. With such controls, docking campaigns can find ligands with new chemotypes, often revealing the new biology that may be docking's greatest impact over the next few years. PMID:26913380

  3. Synthetic Biology and the Moral Significance of Artificial Life: A Reply to Douglas, Powell and Savulescu.

    Science.gov (United States)

    Christiansen, Andreas

    2016-06-01

    I discuss the moral significance of artificial life within synthetic biology via a discussion of Douglas, Powell and Savulescu's paper 'Is the creation of artificial life morally significant'. I argue that the definitions of 'artificial life' and of 'moral significance' are too narrow. Douglas, Powell and Savulescu's definition of artificial life does not capture all core projects of synthetic biology or the ethical concerns that have been voiced, and their definition of moral significance fails to take into account the possibility that creating artificial life is conditionally acceptable. Finally, I show how several important objections to synthetic biology are plausibly understood as arguing that creating artificial life in a wide sense is only conditionally acceptable. PMID:26833578

  4. Preconditioning is hormesis part II: How the conditioning dose mediates protection: Dose optimization within temporal and mechanistic frameworks.

    Science.gov (United States)

    Calabrese, Edward J

    2016-08-01

    In Part I, hormetic doses of a variety of agents stimulated adaptive responses that conditioned and protected cells against the subsequent toxicity resulting from a second, higher dose (called a challenging dose) of the same or different agents. Herein (Part II), the optimal conditioning (hormetic) doses of many agents are documented, cellular mechanisms and temporal profiles are examined from which the conditioning (hormetic) responses are elicited, and the optimal conditioning doses are compared to the levels at which optimal protection occurs in response to the toxic challenge dose. Entry criteria for study evaluation required a conditioning mechanism-induced endpoint response, an hormetic/biphasic dose response for the protective response following the challenging dose, and a mechanistic assessment of how the conditioning dose afforded protection against a toxic challenging dose. The conditioning dose that demonstrated the largest increase in a mechanism-related conditioning (hormetic) response (i.e., prior to administration of the challenging dose) was the same dose that was optimally protective following the challenging dose. Specific receptor antagonists and/or inhibitors of cell signaling pathways which blocked the induction of conditioning (hormetic) effects during the conditioning period abolished the protective effects following the application of a challenge dose, thus identifying a specific and essential component of the hormetic mechanism. Conditioning responses often had sufficient doses to assess the nature of the dose response. In each of the cases these mechanism-based endpoints displayed an hormetic dose response. The present analysis reveals that hormetic biphasic dose responses were associated with both the conditioning process and the protective effects elicited following the challenging dose. Furthermore, based on optimal dosage, temporal relationships and the known mediating actions of receptor-based and/or cell signaling-based mechanisms

  5. Determination of the upper and lower limits of the mechanistic stoichiometry of incompletely coupled fluxes. Stoichiometry of incompletely coupled reactions.

    Science.gov (United States)

    Beavis, A D; Lehninger, A L

    1986-07-15

    A rationale is formulated for the design of experiments to determine the upper and lower limits of the mechanistic stoichiometry of any two incompletely coupled fluxes J1 and J2. Incomplete coupling results when there is a branch at some point in the sequence of reactions or processes coupling the two fluxes. The upper limit of the mechanistic stoichiometry is given by the minimum value of dJ2/dJ1 obtained when the fluxes are systematically varied by changes in steps after the branch point. The lower limit is given by the maximum value of dJ2/dJ1 obtained when the fluxes are varied by changes in steps prior to the branch point. The rationale for determining these limits is developed from both a simple kinetic model and from a linear nonequilibrium thermodynamic treatment of coupled fluxes, using the mechanistic approach [Westerhoff, H. V. & van Dam, K. (1979) Curr. Top. Bioenerg. 9, 1-62]. The phenomenological stoichiometry, the flux ratio at level flow and the affinity ratio at static head of incompletely coupled fluxes are defined in terms of mechanistic conductances and their relationship to the mechanistic stoichiometry is discussed. From the rationale developed, experimental approaches to determine the mechanistic stoichiometry of mitochondrial oxidative phosphorylation are outlined. The principles employed do not require knowledge of the pathway or the rate of transmembrane leaks or slippage and may also be applied to analysis of the stoichiometry of other incompletely coupled systems, including vectorial H+/O and K+/O translocation coupled to mitochondrial electron transport. PMID:3015612

  6. A mechanistic code for intact and defective nuclear fuel element performance

    Science.gov (United States)

    Shaheen, Khaled

    During reactor operation, nuclear fuel elements experience an environment featuring high radiation, temperature, and pressure. Predicting in-reactor performance of nuclear fuel elements constitutes a complex multi-physics problem, one that requires numerical codes to be solved. Fuel element performance codes have been developed for different reactor and fuel designs. Most of these codes simulate fuel elements using one-or quasi-two-dimensional geometries, and some codes are only applicable to steady state but not transient behaviour and vice versa. Moreover, while many conceptual and empirical separate-effects models exist for defective fuel behaviour, wherein the sheath is breached allowing coolant ingress and fission gas escape, there have been few attempts to predict defective fuel behaviour in the context of a mechanistic fuel performance code. Therefore, a mechanistic fuel performance code, called FORCE (Fuel Operational peRformance Computations in an Element) is proposed for the time-dependent behaviour of intact and defective CANDU nuclear fuel elements. The code, which is implemented in the COMSOL Multiphysics commercial software package, simulates the fuel, sheath, and fuel-to-sheath gap in a radial-axial geometry. For intact fuel performance, the code couples models for heat transport, fission gas production and diffusion, and structural deformation of the fuel and sheath. The code is extended to defective fuel performance by integrating an adapted version of a previously developed fuel oxidation model, and a model for the release of radioactive fission product gases from the fuel to the coolant. The FORCE code has been verified against the ELESTRES-IST and ELESIM industrial code for its predictions of intact fuel performance. For defective fuel behaviour, the code has been validated against coulometric titration data for oxygen-to-metal ratio in defective fuel elements from commercial reactors, while also being compared to a conceptual oxidation model

  7. Prediction of a subcooled boiling flow with mechanistic wall boiling and bubble size models

    International Nuclear Information System (INIS)

    Subcooled boiling is one of the crucial phenomena for the design, operation and safety analysis of a nuclear power plant. In recent years, developers of multiphase CFD (Computational Fluid Dynamics) codes focused their development activity on the mechanistic prediction of DNB (Departure from Nucleate Boiling) in PWR. Wall boiling model is one of the key parameters for this purpose. In order to enhance prediction capability of the subcooled boiling flow, an advanced wall boiling model consisting of a mechanistic bubble departure model (Klausner et al., 1993), Hibiki et al.'s (2009) active nucleate site model and Cole's bubble departure frequency model was explored for the CFD code. To ensure a wide range applicability of the advanced wall boiling model, each model was evaluated separately according to the flow conditions such as pressure, temperature and flow rate. Finally, the advanced wall boiling model was implemented into the STAR-CD as a form of user FORTRAN file. One of the other important parameters for an accurate prediction of the subcooled boiling flow is bubble size which governs interfacial transfer terms between two phases. In this study, the S-gamma model, which was developed for the STAR-CD (Lo, 2006), was applied as a bubble size model. For the validation of the present wall boiling and bubble size models, benchmark calculations were carried out against SUBO and DEBORA subcooled boiling flow data. Working fluid of SUBO test is steam/water and its pressure condition is about 2 bars. In contrast to this, working fluid of DEBORA test is Refrigerant-12 (R-12) and phasic density ratio of the tests is equivalent to that of steam/water around 90 to 170 bars. Therefore, present benchmark calculation covers wide range pressure condition of steam/water. The calculation results confirms that the new mechanistic wall boiling and bubble size models follow well the tendency on the change of flow conditions and they can be applicable to the wide range of flow

  8. Branching processes in biology

    CERN Document Server

    Kimmel, Marek

    2015-01-01

    This book provides a theoretical background of branching processes and discusses their biological applications. Branching processes are a well-developed and powerful set of tools in the field of applied probability. The range of applications considered includes molecular biology, cellular biology, human evolution and medicine. The branching processes discussed include Galton-Watson, Markov, Bellman-Harris, Multitype, and General Processes. As an aid to understanding specific examples, two introductory chapters, and two glossaries are included that provide background material in mathematics and in biology. The book will be of interest to scientists who work in quantitative modeling of biological systems, particularly probabilists, mathematical biologists, biostatisticians, cell biologists, molecular biologists, and bioinformaticians. The authors are a mathematician and cell biologist who have collaborated for more than a decade in the field of branching processes in biology for this new edition. This second ex...

  9. Spectroscopy of biological nanocrystals

    OpenAIRE

    Ortac, Inanc; Severcan, Feride

    2007-01-01

    Nanocrystals have gained much interest in recent years, due to their unusual properties allowing interesting applications in physical and biological science. In this literature review, biological nanocrystals are discussed from the spectroscopic point of view. Firstly, the theory behind the outstanding abilities of the nanocrystals is described. Secondly, the spectroscopic properties of biological nanocrystals are mentioned. Lastly, the use of nanocrystals with various spectroscopic applicati...

  10. Biological detector and method

    Energy Technology Data Exchange (ETDEWEB)

    Sillerud, Laurel; Alam, Todd M; McDowell, Andrew F

    2014-04-15

    A biological detector includes a conduit for receiving a fluid containing one or more magnetic nanoparticle-labeled, biological objects to be detected and one or more permanent magnets or electromagnet for establishing a low magnetic field in which the conduit is disposed. A microcoil is disposed proximate the conduit for energization at a frequency that permits detection by NMR spectroscopy of whether the one or more magnetically-labeled biological objects is/are present in the fluid.

  11. Biological detector and method

    Energy Technology Data Exchange (ETDEWEB)

    Sillerud, Laurel; Alam, Todd M.; McDowell, Andrew F.

    2015-11-24

    A biological detector includes a conduit for receiving a fluid containing one or more magnetic nanoparticle-labeled, biological objects to be detected and one or more permanent magnets or electromagnet for establishing a low magnetic field in which the conduit is disposed. A microcoil is disposed proximate the conduit for energization at a frequency that permits detection by NMR spectroscopy of whether the one or more magnetically-labeled biological objects is/are present in the fluid.

  12. Introducing Aquatic Biology

    OpenAIRE

    Kinne, Otto; Browman, Howard I.; Seaman, Matthias

    2007-01-01

    The Inter-Research Science Center (IR) journals Marine Ecology Progress Series (MEPS) and Aquatic Microbial Ecology (AME) have been receiving increasing numbers of high-quality manuscripts that are principally biological, rather than ecological. With regret, we have had to turn these submissions away. Also, leading limnologists have for many years suggested that IR should provide an outlet for top quality articles on freshwater biology and ecology. Aquatic Biology (...

  13. Biological detector and method

    Science.gov (United States)

    Sillerud, Laurel; Alam, Todd M; McDowell, Andrew F

    2013-02-26

    A biological detector includes a conduit for receiving a fluid containing one or more magnetic nanoparticle-labeled, biological objects to be detected and one or more permanent magnets or electromagnet for establishing a low magnetic field in which the conduit is disposed. A microcoil is disposed proximate the conduit for energization at a frequency that permits detection by NMR spectroscopy of whether the one or more magnetically-labeled biological objects is/are present in the fluid.

  14. Glycobiology Current Molecular Biology

    OpenAIRE

    Sabire KARAÇALI

    2003-01-01

    Carbohydrate chemistry evolved into carbohydrate biochemistry and gradually into the biology of carbohydrates, or glycobiology, at the end of the last century. Glycobiology is the new research area of modern molecular biology, and it investigates the structure, biosynthesis and biological functions of glycans. The numbers, linkage types (a or b), positions, binding points and functional group differences of monosaccharides create microheterogeneity. Thus, numerous glycoforms with precise stru...

  15. Foundations of biology

    OpenAIRE

    Sikorav, Jean-Louis; Braslau, Alan; Goldar, Arach

    2014-01-01

    It is often stated that there are no laws in biology, where everything is contingent and could have been otherwise, being solely the result of historical accidents. Furthermore, the customary introduction of fundamental biological entities such as individual organisms, cells, genes, catalysts and motors remains largely descriptive; constructive approaches involving deductive reasoning appear, in comparison, almost absent. As a consequence, both the logical content and principles of biology ne...

  16. Does “quorum sensing” imply a new type of biological information?

    DEFF Research Database (Denmark)

    Bruni, Luis Emilio

    2002-01-01

    When dealing with biological communication and information, unifying concepts are necessary in order to couple the different “codes” that are being inductively “cracked” and defined at different emergent and “de-emergent” levels of the biological hierarchy. In this paper I compare the type of...... biological information implied by genetic information with that implied in the concept of “quorum sensing” (which refers to a prokaryotic cell-to-cell communication system) in order to explore if such integration is being achieved. I use the Lux operon paradigm and the Vibrio fischeri – Euprymna scolopes...... symbiotic partnership to exemplify the emergence of informational contexts along the biological hierarchy (from molecules to ecologies). I suggest that the biosemiotic epistemological framework can play an integra¬tive role to overcome the limits of dyadic mechanistic descriptions when relating the...

  17. Biological aerosol background characterization

    Science.gov (United States)

    Blatny, Janet; Fountain, Augustus W., III

    2011-05-01

    To provide useful information during military operations, or as part of other security situations, a biological aerosol detector has to respond within seconds or minutes to an attack by virulent biological agents, and with low false alarms. Within this time frame, measuring virulence of a known microorganism is extremely difficult, especially if the microorganism is of unknown antigenic or nucleic acid properties. Measuring "live" characteristics of an organism directly is not generally an option, yet only viable organisms are potentially infectious. Fluorescence based instruments have been designed to optically determine if aerosol particles have viability characteristics. Still, such commercially available biological aerosol detection equipment needs to be improved for their use in military and civil applications. Air has an endogenous population of microorganisms that may interfere with alarm software technologies. To design robust algorithms, a comprehensive knowledge of the airborne biological background content is essential. For this reason, there is a need to study ambient live bacterial populations in as many locations as possible. Doing so will permit collection of data to define diverse biological characteristics that in turn can be used to fine tune alarm algorithms. To avoid false alarms, improving software technologies for biological detectors is a crucial feature requiring considerations of various parameters that can be applied to suppress alarm triggers. This NATO Task Group will aim for developing reference methods for monitoring biological aerosol characteristics to improve alarm algorithms for biological detection. Additionally, they will focus on developing reference standard methodology for monitoring biological aerosol characteristics to reduce false alarm rates.

  18. Recent developments in using mechanistic cardiac modelling for drug safety evaluation.

    Science.gov (United States)

    Davies, Mark R; Wang, Ken; Mirams, Gary R; Caruso, Antonello; Noble, Denis; Walz, Antje; Lavé, Thierry; Schuler, Franz; Singer, Thomas; Polonchuk, Liudmila

    2016-06-01

    On the tenth anniversary of two key International Conference on Harmonisation (ICH) guidelines relating to cardiac proarrhythmic safety, an initiative aims to consider the implementation of a new paradigm that combines in vitro and in silico technologies to improve risk assessment. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative (co-sponsored by the Cardiac Safety Research Consortium, Health and Environmental Sciences Institute, Safety Pharmacology Society and FDA) is a bold and welcome step in using computational tools for regulatory decision making. This review compares and contrasts the state-of-the-art tools from empirical to mechanistic models of cardiac electrophysiology, and how they can and should be used in combination with experimental tests for compound decision making. PMID:26891981

  19. Mechanistic target of rapamycin (Mtor is essential for murine embryonic heart development and growth.

    Directory of Open Access Journals (Sweden)

    Yi Zhu

    Full Text Available Mechanistic target of rapamycin (Mtor is required for embryonic inner cell mass proliferation during early development. However, Mtor expression levels are very low in the mouse heart during embryogenesis. To determine if Mtor plays a role during mouse cardiac development, cardiomyocyte specific Mtor deletion was achieved using α myosin heavy chain (α-MHC driven Cre recombinase. Initial mosaic expression of Cre between embryonic day (E 10.5 and E11.5 eliminated a subset of cardiomyocytes with high Cre activity by apoptosis and reduced overall cardiac proliferative capacity. The remaining cardiomyocytes proliferated and expanded normally. However loss of 50% of cardiomyocytes defined a threshold that impairs the ability of the embryonic heart to sustain the embryo's circulatory requirements. As a result 92% of embryos with cardiomyocyte Mtor deficiency died by the end of gestation. Thus Mtor is required for survival and proliferation of cardiomyocytes in the developing heart.

  20. Reactions of Co(III)-nitrosyl complexes with superoxide and their mechanistic insights.

    Science.gov (United States)

    Kumar, Pankaj; Lee, Yong-Min; Park, Young Jun; Siegler, Maxime A; Karlin, Kenneth D; Nam, Wonwoo

    2015-04-01

    New Co(III)-nitrosyl complexes bearing N-tetramethylated cyclam (TMC) ligands, [(12-TMC)Co(III)(NO)](2+) (1) and [(13-TMC)Co(III)(NO)](2+) (2), were synthesized via [(TMC)Co(II)(CH3CN)](2+) + NO(g) reactions. Spectroscopic and structural characterization showed that these compounds bind the nitrosyl moiety in a bent end-on fashion. Complexes 1 and 2 reacted with KO2/2.2.2-cryptand to produce [(12-TMC)Co(II)(NO2)](+) (3) and [(13-TMC)Co(II)(NO2)](+) (4), respectively; these possess O,O'-chelated nitrito ligands. Mechanistic studies using (18)O-labeled superoxide ((18)O2(•-)) showed that one O atom in the nitrito ligand is derived from superoxide and the O2 produced comes from the other superoxide O atom. Evidence supporting the formation of a Co-peroxynitrite intermediate is also presented. PMID:25793706

  1. 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.

  2. Mechanistic Investigation of a Non-Heme Iron Enzyme Catalyzed Epoxidation in (-)-4'-Methoxycyclopenin Biosynthesis.

    Science.gov (United States)

    Chang, Wei-Chen; Li, Jikun; Lee, Justin L; Cronican, Andrea A; Guo, Yisong

    2016-08-24

    Mechanisms have been proposed for α-KG-dependent non-heme iron enzyme catalyzed oxygen atom insertion into an olefinic moiety in various natural products, but they have not been examined in detail. Using a combination of methods including transient kinetics, Mössbauer spectroscopy, and mass spectrometry, we demonstrate that AsqJ-catalyzed (-)-4'-methoxycyclopenin formation uses a high-spin Fe(IV)-oxo intermediate to carry out epoxidation. Furthermore, product analysis on (16)O/(18)O isotope incorporation from the reactions using the native substrate, 4'-methoxydehydrocyclopeptin, and a mechanistic probe, dehydrocyclopeptin, reveals evidence supporting oxo↔hydroxo tautomerism of the Fe(IV)-oxo species in the non-heme iron enzyme catalysis. PMID:27442345

  3. Dual effect of red wine on liver redox status: a concise and mechanistic review.

    Science.gov (United States)

    Silva, Paula; Fernandes, Eduarda; Carvalho, Félix

    2015-10-01

    Chronic ethanol consumption is a strong risk factor for the development of liver disease. Multiple mechanisms are involved in ethanol-mediated liver injury; oxidative stress being pointed has an important factor. However, it should be noted that moderate consumption of red wine has been associated with hepatoprotective effects, mainly due to the antioxidant effect of resveratrol, one of its polyphenolic compounds. In this paper, the potential molecular mechanisms through which the protective effects of resveratrol counteract the oxidative effect of ethanol and the way as this dual effect impacts liver oxidative stress are reviewed. Mechanistic evaluation of modulation of oxidative signaling pathways by ethanol and resveratrol may explain the pathogenesis of various liver diseases and ultimately to disclose possible pharmacological therapies. PMID:26026610

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

    International Nuclear Information System (INIS)

    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.)

  5. 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.

  6. Mechanistic Modeling Reveals the Critical Knowledge Gaps in Bile Acid-Mediated DILI.

    Science.gov (United States)

    Woodhead, J L; Yang, K; Brouwer, K L R; Siler, S Q; Stahl, S H; Ambroso, J L; Baker, D; Watkins, P B; Howell, B A

    2014-01-01

    Bile salt export pump (BSEP) inhibition has been proposed to be an important mechanism for drug-induced liver injury (DILI). Modeling can prioritize knowledge gaps concerning bile acid (BA) homeostasis and thus help guide experimentation. A submodel of BA homeostasis in rats and humans was constructed within DILIsym, a mechanistic model of DILI. In vivo experiments in rats with glibenclamide were conducted, and data from these experiments were used to validate the model. The behavior of DILIsym was analyzed in the presence of a simulated theoretical BSEP inhibitor. BSEP inhibition in humans is predicted to increase liver concentrations of conjugated chenodeoxycholic acid (CDCA) and sulfate-conjugated lithocholic acid (LCA) while the concentration of other liver BAs remains constant or decreases. On the basis of a sensitivity analysis, the most important unknowns are the level of BSEP expression, the amount of intestinal synthesis of LCA, and the magnitude of farnesoid-X nuclear receptor (FXR)-mediated regulation. PMID:25006780

  7. Study of n-Butyl Acrylate Self-Initiation Reaction Experimentally and via Macroscopic Mechanistic Modeling

    Directory of Open Access Journals (Sweden)

    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.

  8. Mechanistic and genetic studies of radiation tumorigenesis in the mouse - implications for low dose risk estimation

    International Nuclear Information System (INIS)

    Radiation cancer risk estimates remain firmly based upon epidemiological data. Experimental validation of the fundamental aspects of these risk estimates relies on animal studies. In particular, animal model systems for radiation carcinogenesis can provide data for mechanistic modelling approaches to risk estimation. The accuracy and validity of risk estimation models developed will depend upon the extent of our understanding of the process of radiation carcinogenesis. The study of 'spontaneous' tumours in humans continues to provide a sound context in which to consider the mechanisms of radiation carcinogenesis. Several mouse radiation carcinogenesis systems are considered here with particular reference to the nature of the initiating event and the influence of genetic susceptibility on radiation-induced cancer. (author)

  9. From nitrogen enrichment to oxygen depletion: a mechanistic model of coastal marine ecosystems response

    DEFF Research Database (Denmark)

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

    oxygen (DO) consumption as a function of N input. Such indicator is the basis for an eXposure Factor (XF) applied in Life Cycle Impact Assessment (LCIA) to estimate impacts from N enrichment. The Large Marine Ecosystems (LME) biogeographical classification system was adopted to address the spatial...... variation of the modelled parameters and to characterise spatially differentiated N-emissions. Preliminary XF results range from 0.5 kgO2·kgN-1 in the Central Arctic Ocean to 16 kgO2·kgN-1 in the Baltic Sea, out of a total of 66 LME-dependent XFs. All the relevant processes were included in a mechanistic...

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

    Directory of Open Access Journals (Sweden)

    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.

  11. MECHANISTIC EVALUATION OF BUTEA MONOSPERMA USING IN VITRO AND IN VIVO MURINE MODELS OF BRONCHIAL ASTHMA

    Directory of Open Access Journals (Sweden)

    Shirole R. L.

    2013-06-01

    Full Text Available The present investigation aimed to elucidate the probable mechanism of antiasthmatic action of Butea monosperma. Bioactive fractionations of methanolic extract of B. monosperma (MBM were carried out to get, ethyl acetate fraction (EBM and butanolic fraction (BBM of Butea monosperma. All fractions were evaluated mechanistically for its antiasthmatic actions in vitro using lipoxygenase assay. The lipoxygenase inhibitory effect of the extract followed the order BBM > MBM > EBM. Based on in vitro lipoxygenase assay BBM was selected for in vitro compound 48/80 induced mast cell degranulation assay and in vivo lipopolysaccharide induced inflammation in rats. BBM 50, 100 and 200μg/ml inhibited compound 48/80 induced mast cell degranulation. BBM exhibited dose dependent (50, 100 and 200mg/kg i.p. inhibition of lipopolysaccharide-induced increased in total cell count, differential leukocyte count, nitrate-nitrite, total protein and albumin levels in bronchoalveolar fluid (BALF and myeloperoxidase (MPO levels in lungs homogenate.

  12. Mechanistic modelling of gaseous fission product behaviour in UO2 fuel by Rtop code

    International Nuclear Information System (INIS)

    The current status of a mechanistic modelling by the RTOP code of the fission product behaviour in polycrystalline UO2 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)

  13. 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. PMID:21249237

  14. 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.

  15. 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.

    2013-01-01

    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.

  16. TIMES-SS - A mechanistic evaluation of an external validation study using reaction chemistry principles

    DEFF Research Database (Denmark)

    Roberts, David W.; Patlewicz, Grace; Dimitrov, Sabcho D.; Low, Lawrence K.; Aptula, Aynur O.; Kern, Petra S.; Dimitrova, Gergana D.; Comber, Mike I.H.; Phillips, Richard D.; Niemela, Jay; Madsen, Charlotte Bernhard; Wedebye, Eva Bay; Bailey, Paul T.; Mekenyan, Ovanes G.

    2007-01-01

    The TImes MEtabolism Simulator platform used for predicting skin sensitization (TIMES-SS) is a hybrid expert system that was developed at Bourgas University using funding and data from a consortium comprised of industry and regulators. TIMES-SS encodes structure-toxicity and structure-skin metabo......The TImes MEtabolism Simulator platform used for predicting skin sensitization (TIMES-SS) is a hybrid expert system that was developed at Bourgas University using funding and data from a consortium comprised of industry and regulators. TIMES-SS encodes structure-toxicity and structure......-skin metabolism relationships through a number of transformations, some of which are underpinned by mechanistic three-dimensional quantitative structure-activity relationships. Here, we describe an external validation exercise that was recently carried out. As part of this exercise, data were generated for 40 new...

  17. Explicit kinetic heterogeneity: mechanistic models for interpretation of labeling data in heterogeneous populations

    Energy Technology Data Exchange (ETDEWEB)

    Ganusov, Vitaly V [Los Alamos National Laboratory

    2008-01-01

    Estimation of division and death rates of lymphocytes in different conditions is vital for quantitative understanding of the immune system. Deuterium, in the form of deuterated glucose or heavy water, can be used to measure rates of proliferation and death of lymphocytes in vivo. Inferring these rates from labeling and delabeling curves has been subject to considerable debate with different groups suggesting different mathematical models for that purpose. We show that the three models that are most commonly used are in fact mathematically identical and differ only in their interpretation of the estimated parameters. By extending these previous models, we here propose a more mechanistic approach for the analysis of data from deuterium labeling experiments. We construct a model of 'kinetic heterogeneity' in which the total cell population consists of many sub-populations with different rates of cell turnover. In this model, for a given distribution of the rates of turnover, the predicted fraction of labeled DNA accumulated and lost can be calculated. Our model reproduces several previously made experimental observations, such as a negative correlation between the length of the labeling period and the rate at which labeled DNA is lost after label cessation. We demonstrate the reliability of the new explicit kinetic heterogeneity model by applying it to artificially generated datasets, and illustrate its usefulness by fitting experimental data. In contrast to previous models, the explicit kinetic heterogeneity model (1) provides a mechanistic way of interpreting labeling data; (2) allows for a non-exponential loss of labeled cells during delabeling, and (3) can be used to describe data with variable labeling length.

  18. Advancements in the mechanistic understanding of the copper-catalyzed azide–alkyne cycloaddition

    Directory of Open Access Journals (Sweden)

    Regina Berg

    2013-12-01

    Full Text Available The copper-catalyzed azide–alkyne cycloaddition (CuAAC is one of the most broadly applicable and easy-to-handle reactions in the arsenal of organic chemistry. However, the mechanistic understanding of this reaction has lagged behind the plethora of its applications for a long time. As reagent mixtures of copper salts and additives are commonly used in CuAAC reactions, the structure of the catalytically active species itself has remained subject to speculation, which can be attributed to the multifaceted aggregation chemistry of copper(I alkyne and acetylide complexes. Following an introductory section on common catalyst systems in CuAAC reactions, this review will highlight experimental and computational studies from early proposals to very recent and more sophisticated investigations, which deliver more detailed insights into the CuAAC’s catalytic cycle and the species involved. As diverging mechanistic views are presented in articles, books and online resources, we intend to present the research efforts in this field during the past decade and finally give an up-to-date picture of the currently accepted dinuclear mechanism of CuAAC. Additionally, we hope to inspire research efforts on the development of molecularly defined copper(I catalysts with defined structural characteristics, whose main advantage in contrast to the regularly used precatalyst reagent mixtures is twofold: on the one hand, the characteristics of molecularly defined, well soluble catalysts can be tuned according to the particular requirements of the experiment; on the other hand, the understanding of the CuAAC reaction mechanism can be further advanced by kinetic studies and the isolation and characterization of key intermediates.

  19. 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.

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

    International Nuclear Information System (INIS)

    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 Kd 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 Kd values. The overall error in Kd is viewed as the best representation of model uncertainty in ISD model/database development. (author)

  1. Reduction of Carbon Dioxide by a Molybdenum-Containing Formate Dehydrogenase: A Kinetic and Mechanistic Study.

    Science.gov (United States)

    Maia, Luisa B; Fonseca, Luis; Moura, Isabel; Moura, José J G

    2016-07-20

    Carbon dioxide accumulation is a major concern for the ecosystems, but its abundance and low cost make it an interesting source for the production of chemical feedstocks and fuels. However, the thermodynamic and kinetic stability of the carbon dioxide molecule makes its activation a challenging task. Studying the chemistry used by nature to functionalize carbon dioxide should be helpful for the development of new efficient (bio)catalysts for atmospheric carbon dioxide utilization. In this work, the ability of Desulfovibrio desulfuricans formate dehydrogenase (Dd FDH) to reduce carbon dioxide was kinetically and mechanistically characterized. The Dd FDH is suggested to be purified in an inactive form that has to be activated through a reduction-dependent mechanism. A kinetic model of a hysteretic enzyme is proposed to interpret and predict the progress curves of the Dd FDH-catalyzed reactions (initial lag phase and subsequent faster phase). Once activated, Dd FDH is able to efficiently catalyze, not only the formate oxidation (kcat of 543 s(-1), Km of 57.1 μM), but also the carbon dioxide reduction (kcat of 46.6 s(-1), Km of 15.7 μM), in an overall reaction that is thermodynamically and kinetically reversible. Noteworthy, both Dd FDH-catalyzed formate oxidation and carbon dioxide reduction are completely inactivated by cyanide. Current FDH reaction mechanistic proposals are discussed and a different mechanism is here suggested: formate oxidation and carbon dioxide reduction are proposed to proceed through hydride transfer and the sulfo group of the oxidized and reduced molybdenum center, Mo(6+)═S and Mo(4+)-SH, are suggested to be the direct hydride acceptor and donor, respectively. PMID:27348246

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

    Directory of Open Access Journals (Sweden)

    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

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

    International Nuclear Information System (INIS)

    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.

  4. Systems Biology Graphical Notation: Process Description language Level 1 Version 1.3.

    Science.gov (United States)

    Moodie, Stuart; Le Novère, Nicolas; Demir, Emek; Mi, Huaiyu; Villéger, Alice

    2015-01-01

    The Systems Biological Graphical Notation (SBGN) is an international community effort for standardized graphical representations of biological pathways and networks. The goal of SBGN is to provide unambiguous pathway and network maps for readers with different scientific backgrounds as well as to support efficient and accurate exchange of biological knowledge between different research communities, industry, and other players in systems biology. Three SBGN languages, Process Description (PD), Entity Relationship (ER) and Activity Flow (AF), allow for the representation of different aspects of biological and biochemical systems at different levels of detail. The SBGN Process Description language represents biological entities and processes between these entities within a network. SBGN PD focuses on the mechanistic description and temporal dependencies of biological interactions and transformations. The nodes (elements) are split into entity nodes describing, e.g., metabolites, proteins, genes and complexes, and process nodes describing, e.g., reactions and associations. The edges (connections) provide descriptions of relationships (or influences) between the nodes, such as consumption, production, stimulation and inhibition. Among all three languages of SBGN, PD is the closest to metabolic and regulatory pathways in biological literature and textbooks, but its well-defined semantics offer a superior precision in expressing biological knowledge. PMID:26528561

  5. Low early-life social class leaves a biological residue manifested by decreased glucocorticoid and increased proinflammatory signaling

    OpenAIRE

    Miller, Gregory E.; Chen, Edith; Fok, Alexandra K.; Walker, Hope; Lim, Alvin; Nicholls, Erin F.; Cole, Steve; Kobor, Michael S.

    2009-01-01

    Children reared in unfavorable socioeconomic circumstances show increased susceptibility to the chronic diseases of aging when they reach the fifth and sixth decades of life. One mechanistic hypothesis for this phenomenon suggests that social adversity in early life programs biological systems in a manner that persists across decades and thereby accentuates vulnerability to disease. Here we examine the basic tenets of this hypothesis by performing genome-wide transcriptional profiling in heal...

  6. Harnessing the Power of Integrated Mitochondrial Biology and Physiology: A Special Report on the NHLBI Mitochondria in Heart Diseases Initiative

    OpenAIRE

    Ping, P.; Gustafsson, ÅB; Bers, DM; Blatter, LA; Cai, H; Jahangir, A; Kelly, D; Muoio, D; O'Rourke, B; Rabinovitch, P; Trayanova, N; van Eyk, J.; Weiss, JN; Wong, R; Longacre, LS

    2015-01-01

    © 2015 American Heart Association, Inc. Mitochondrial biology is the sum of diverse phenomena from molecular profiles to physiological functions. A mechanistic understanding of mitochondria in disease development, and hence the future prospect of clinical translations, relies on a systems-level integration of expertise from multiple fields of investigation. Upon the successful conclusion of a recent National Institutes of Health, National Heart, Lung, and Blood Institute initiative on integra...

  7. Biological Clocks & Circadian Rhythms

    Science.gov (United States)

    Robertson, Laura; Jones, M. Gail

    2009-01-01

    The study of biological clocks and circadian rhythms is an excellent way to address the inquiry strand in the National Science Education Standards (NSES) (NRC 1996). Students can study these everyday phenomena by designing experiments, gathering and analyzing data, and generating new experiments. As students explore biological clocks and circadian…

  8. Experimenting with Mathematical Biology

    Science.gov (United States)

    Sanft, Rebecca; Walter, Anne

    2016-01-01

    St. Olaf College recently added a Mathematical Biology concentration to its curriculum. The core course, Mathematics of Biology, was redesigned to include a wet laboratory. The lab classes required students to collect data and implement the essential modeling techniques of formulation, implementation, validation, and analysis. The four labs…

  9. Bioinformatics and School Biology

    Science.gov (United States)

    Dalpech, Roger

    2006-01-01

    The rapidly changing field of bioinformatics is fuelling the need for suitably trained personnel with skills in relevant biological "sub-disciplines" such as proteomics, transcriptomics and metabolomics, etc. But because of the complexity--and sheer weight of data--associated with these new areas of biology, many school teachers feel…

  10. Biological Macromolecule Crystallization Database

    Science.gov (United States)

    SRD 21 Biological Macromolecule Crystallization Database (Web, free access)   The Biological Macromolecule Crystallization Database and NASA Archive for Protein Crystal Growth Data (BMCD) contains the conditions reported for the crystallization of proteins and nucleic acids used in X-ray structure determinations and archives the results of microgravity macromolecule crystallization studies.

  11. Biological pretreatment sewages water

    OpenAIRE

    Veselý, Václav

    2009-01-01

    Bachelor's thesis deals with waste water purification at the stage of pre-inflow of water into the biological waste water treatment plants. It is divided into two parts, a theoretical and calculation. The theoretical part deals about sewage water and the method of biological treatment. Design proposal is part of the activation tank for quantity EO.

  12. Integrated Biological Control

    International Nuclear Information System (INIS)

    Biological control is any activity taken to prevent, limit, clean up, or remediate potential environmental, health and safety, or workplace quality impacts from plants, animals, or microorganisms. At Hanford the principal emphasis of biological control is to prevent the transport of radioactive contamination by biological vectors (plants, animals, or microorganisms), and where necessary, control and clean up resulting contamination. Other aspects of biological control at Hanford include industrial weed control (e.g.; tumbleweeds), noxious weed control (invasive, non-native plant species), and pest control (undesirable animals such as rodents and stinging insects; and microorganisms such as molds that adversely affect the quality of the workplace environment). Biological control activities may be either preventive (apriori) or in response to existing contamination spread (aposteriori). Surveillance activities, including ground, vegetation, flying insect, and other surveys, and apriori control actions, such as herbicide spraying and placing biological barriers, are important in preventing radioactive contamination spread. If surveillance discovers that biological vectors have spread radioactive contamination, aposteriori control measures, such as fixing contamination, followed by cleanup and removal of the contamination to an approved disposal location are typical response functions. In some cases remediation following the contamination cleanup and removal is necessary. Biological control activities for industrial weeds, noxious weeds and pests have similar modes of prevention and response

  13. Augmented telomerase activity, reduced telomere length and the presence of alternative lengthening of telomere in renal cell carcinoma: plausible predictive and diagnostic markers.

    Science.gov (United States)

    Pal, Deeksha; Sharma, Ujjawal; Khajuria, Ragini; Singh, Shrawan Kumar; Kakkar, Nandita; Prasad, Rajendra

    2015-05-15

    In this study, we analyzed 100 cases of renal cell carcinoma (RCC) for telomerase activity, telomere length and alternative lengthening of telomeres (ALT) using the TRAP assay, TeloTTAGGG assay kit and immunohistochemical analysis of ALT associated promyelocytic leukemia (PML) bodies respectively. A significantly higher (P=0.000) telomerase activity was observed in 81 cases of RCC which was correlated with clinicopathological features of tumor for instance, stage (P=0.008) and grades (P=0.000) but not with the subtypes of RCC (P = 0.355). Notwithstanding, no correlation was found between telomerase activity and subtypes of RCC. Strikingly, the telomere length was found to be significantly shorter in RCC (P=0.000) to that of corresponding normal renal tissues and it is well correlated with grades (P=0.016) but not with stages (P=0.202) and subtypes (P=0.669) of RCC. In this study, telomere length was also negatively correlated with the age of patients (r(2)=0.528; P=0.000) which supports the notion that it could be used as a marker for biological aging. ALT associated PML bodies containing PML protein was found in telomerase negative cases of RCC. It suggests the presence of an ALT pathway mechanism to maintain the telomere length in telomerase negative RCC tissues which was associated with high stages of RCC, suggesting a prevalent mechanism for telomere maintenance in high stages. In conclusion, the telomerase activity and telomere length can be used as a diagnostic as well as a predictive marker in RCC. The prevalence of ALT mechanism in high stages of RCC is warranted for the development of anti-ALT inhibitors along with telomerase inhibitor against RCC as a therapeutic approach. PMID:25769384

  14. Mechanistic Projection of First-in-Human Dose for Bispecific Immunomodulatory P-Cadherin LP-DART: An Integrated PK/PD Modeling Approach.

    Science.gov (United States)

    Chen, X; Haddish-Berhane, N; Moore, P; Clark, T; Yang, Y; Li, H; Xuan, D; Barton, H A; Betts, A M; Barletta, F

    2016-09-01

    A bispecific immunomodulatory biotherapeutic molecule (P-cadherin LP-DART) based on the Dual Affinity Re-Targeting (DART) scaffold has been developed as a potential antitumor treatment showing efficacy in preclinical testing. A minimal anticipated biological effect level (MABEL) approach was applied to project the first-in-human (FIH) dose, because of its immune agonistic properties following target engagement. The pharmacological activity of P-cadherin LP-DART is driven by binding to both P-cadherin on the tumor cells and CD3 on T cells. Therefore, the concentration of the tri-molecular synapse formed between drug, T cell, and tumor cell, rather than drug concentration, is responsible for efficacy. A mechanistic pharmacokinetic/pharmacodynamic (PK/PD)-driven approach was explored to understand the exposure-response relationship based on the synapse concentration to project the MABEL dose. Orthogonal approaches including PK-driven and receptor occupancy calculations were also investigated. This study showcases the application of PK/PD modeling in immune-oncology, and could potentially be implemented for other bispecific biotherapeutics. PMID:27170541

  15. A Multi-scale Computational Platform to Mechanistically Assess the Effect of Genetic Variation on Drug Responses in Human Erythrocyte Metabolism.

    Science.gov (United States)

    Mih, Nathan; Brunk, Elizabeth; Bordbar, Aarash; Palsson, Bernhard O

    2016-07-01

    Progress in systems medicine brings promise to addressing patient heterogeneity and individualized therapies. Recently, genome-scale models of metabolism have been shown to provide insight into the mechanistic link between drug therapies and systems-level off-target effects while being expanded to explicitly include the three-dimensional structure of proteins. The integration of these molecular-level details, such as the physical, structural, and dynamical properties of proteins, notably expands the computational description of biochemical network-level properties and the possibility of understanding and predicting whole cell phenotypes. In this study, we present a multi-scale modeling framework that describes biological processes which range in scale from atomistic details to an entire metabolic network. Using this approach, we can understand how genetic variation, which impacts the structure and reactivity of a protein, influences both native and drug-induced metabolic states. As a proof-of-concept, we study three enzymes (catechol-O-methyltransferase, glucose-6-phosphate dehydrogenase, and glyceraldehyde-3-phosphate dehydrogenase) and their respective genetic variants which have clinically relevant associations. Using all-atom molecular dynamic simulations enables the sampling of long timescale conformational dynamics of the proteins (and their mutant variants) in complex with their respective native metabolites or drug molecules. We find that changes in a protein's structure due to a mutation influences protein binding affinity to metabolites and/or drug molecules, and inflicts large-scale changes in metabolism. PMID:27467583

  16. Examining the Use of a Mechanistic Model to Generate an In Vivo/In Vitro Correlation: Journey Through a Thought Process.

    Science.gov (United States)

    Mistry, Bipin; Patel, Nikunjkumar; Jamei, Masoud; Rostami-Hodjegan, Amin; Martinez, Marilyn N

    2016-09-01

    The attention and interest in establishing in vivo/in vitro correlations (IVIVCs) is grounded in its tremendous utility as a prognostic tool. It can be used to support formulation optimization, predict in vivo drug exposure across a potential patient population, select a biologically relevant in vitro dissolution test condition, and support the use of in vitro dissolution data as a surrogate for in vivo bioequivalence trials. The pharmacological and statistical implications of this correlation are linked to the method by which the IVIVC was determined and to the assumptions and optimization approaches integrated into the estimation procedure. Using previously published data generated in normal healthy volunteers, an IVIVC for metoprolol was established using a mechanistic modeling approach. Within that framework, we explored the consequences of (1) our method of fitting a single Weibull function to the in vivo dissolution, (2) our selection of weighting scheme and optimization approaches, (3) the impact of applying a fixed versus fitted gastric emptying time, and 4) the importance of factoring population variability into our IVIVC estimation and profile reconvolution. We identified those factors found to be critical in terms of their influence on the accuracy of our predicted systemic metoprolol concentration-time profiles. We considered the strengths and weaknesses of our approach and discussed how the results of this study may impact efforts to generate IVIVCs with compounds presenting physicochemical characteristics different from that of metoprolol. PMID:27312260

  17. Biological sample collector

    Science.gov (United States)

    Murphy, Gloria A.

    2010-09-07

    A biological sample collector is adapted to a collect several biological samples in a plurality of filter wells. A biological sample collector may comprise a manifold plate for mounting a filter plate thereon, the filter plate having a plurality of filter wells therein; a hollow slider for engaging and positioning a tube that slides therethrough; and a slide case within which the hollow slider travels to allow the tube to be aligned with a selected filter well of the plurality of filter wells, wherein when the tube is aligned with the selected filter well, the tube is pushed through the hollow slider and into the selected filter well to sealingly engage the selected filter well and to allow the tube to deposit a biological sample onto a filter in the bottom of the selected filter well. The biological sample collector may be portable.

  18. Optics of Biological Particles

    CERN Document Server

    Hoekstra, Alfons; Videen, Gorden

    2007-01-01

    This book covers the optics of single biological particles, both theory and experiment, with emphasis on Elastic Light Scattering and Fluorescence. It deals with the optics of bacteria (bio-aerosols), marine particles (selected phytoplankton communities) and red and white blood cells. Moreover, there are dedicated chapters on a general theory for scattering by a cell, and modelling and simulation of scattering by inhomogeneous biological cells. Finally, one chapter is dedicated to astro-biological signatures, discussing the possibilities for detecting non-terrestrial biological material. The volume has up-to-date discussions on new experimental and numerical techniques, and many examples of applications of these techniques in real-life systems, as used to detect and characterize e.g. biological warfare agents or human blood cells.

  19. Frontiers in mathematical biology

    CERN Document Server

    1994-01-01

    Volume 100, which is the final volume of the LNBM series serves to commemorate the acievements in two decades of this influential collection of books in mathematical biology. The contributions, by the leading mathematical biologists, survey the state of the art in the subject, and offer speculative, philosophical and critical analyses of the key issues confronting the field. The papers address fundamental issues in cell and molecular biology, organismal biology, evolutionary biology, population ecology, community and ecosystem ecology, and applied biology, plus the explicit and implicit mathematical challenges. Cross-cuttting issues involve the problem of variation among units in nonlinear systems, and the related problems of the interactions among phenomena across scales of space, time and organizational complexity.

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

    International Nuclear Information System (INIS)

    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