Rearrangements of Allylic Sulfinates to Sulfones: A Mechanistic Study

ERIC Educational Resources Information Center

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

2010-01-01

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

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

PubMed

Walker, Susan

2012-01-01

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

Mechanistic-empirical Pavement Design Guide Implementation

DOT National Transportation Integrated Search

2010-06-01

The recently introduced Mechanistic-Empirical Pavement Design Guide (MEPDG) and associated computer software provides a state-of-practice mechanistic-empirical highway pavement design methodology. The MEPDG methodology is based on pavement responses ...

Assessing uncertainty in mechanistic models

Treesearch

Edwin J. Green; David W. MacFarlane; Harry T. Valentine

2000-01-01

Concern over potential global change has led to increased interest in the use of mechanistic models for predicting forest growth. The rationale for this interest is that empirical models may be of limited usefulness if environmental conditions change. Intuitively, we expect that mechanistic models, grounded as far as possible in an understanding of the biology of tree...

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

PubMed

Otaki, Joji M

2008-07-01

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

Rational and mechanistic perspectives on reinforcement learning.

PubMed

Chater, Nick

2009-12-01

This special issue describes important recent developments in applying reinforcement learning models to capture neural and cognitive function. But reinforcement learning, as a theoretical framework, can apply at two very different levels of description: mechanistic and rational. Reinforcement learning is often viewed in mechanistic terms--as describing the operation of aspects of an agent's cognitive and neural machinery. Yet it can also be viewed as a rational level of description, specifically, as describing a class of methods for learning from experience, using minimal background knowledge. This paper considers how rational and mechanistic perspectives differ, and what types of evidence distinguish between them. Reinforcement learning research in the cognitive and brain sciences is often implicitly committed to the mechanistic interpretation. Here the opposite view is put forward: that accounts of reinforcement learning should apply at the rational level, unless there is strong evidence for a mechanistic interpretation. Implications of this viewpoint for reinforcement-based theories in the cognitive and brain sciences are discussed.

MECHANISTIC INDICATORS OF CHILDHOOD ASTHMA (MICA)

EPA Science Inventory

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

A climate-driven mechanistic population model of Aedes albopictus with diapause.

PubMed

Jia, Pengfei; Lu, Liang; Chen, Xiang; Chen, Jin; Guo, Li; Yu, Xiao; Liu, Qiyong

2016-03-24

will benefit studying the transmission and the spatiotemporal distribution of mosquito-borne epidemics and eventually facilitating the early warning and control of the diseases.

Laboratory study of concrete properties to support implementation of the new AASHTO mechanistic-empirical pavement design guide.

DOT National Transportation Integrated Search

2012-09-01

Properties of concrete embodying materials typically used in Wisconsin paving projects were evaluated in support of future : implementation of the AASHTO Mechanistic-Empirical Pavement Design Guide (MEPDG). The primary concrete : properties studied w...

Laboratory study of concrete properties to support implementation of the new AASHTO mechanistic empirical pavement design guide.

DOT National Transportation Integrated Search

2012-09-01

Properties of concrete embodying materials typically used in Wisconsin paving projects were evaluated in support of future : implementation of the AASHTO Mechanistic-Empirical Pavement Design Guide (MEPDG). The primary concrete : properties studied w...

Mechanistic Studies of Oligonucleotide Aptamers With Potent Antiproliferative and Pro-Apoptotic Activity Against Prostate Cancer Cells

DTIC Science & Technology

2007-05-01

AD_________________ Award Number: W81XWH-04-1-0183 TITLE: Mechanistic Studies of Oligonucleotide...Ph.D. CONTRACTING ORGANIZATION: University of Louisville...Louisville, KY 40292-0001 REPORT DATE: May 2007 TYPE OF REPORT: Final PREPARED FOR: U.S. Army Medical Research and Materiel Command

Copper-facilitated Suzuki reactions: application to 2-heterocyclic boronates.

PubMed

Deng, James Z; Paone, Daniel V; Ginnetti, Anthony T; Kurihara, Hideki; Dreher, Spencer D; Weissman, Steven A; Stauffer, Shaun R; Burgey, Christopher S

2009-01-15

The palladium-catalyzed Suzuki-Miyaura reaction has been utilized as one of the most powerful methods for C-C bond formation. However, Suzuki reactions of electron-deficient 2-heterocyclic boronates generally give low conversions and remain challenging. The successful copper(I) facilitated Suzuki coupling of 2-heterocyclic boronates that is broad in scope is reported. Use of this methodology affords greatly enhanced yields of these notoriously difficult couplings. Furthermore, mechanistic investigations suggest a possible role of copper in the catalytic cycle.

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

PubMed Central

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

2009-01-01

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

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

DOE PAGES

Grossmann, Nina; Vakkasoglu, Ahmet S.; Hulpke, Sabine; ...

2014-11-07

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

Thermochemical and mechanistic studies of electrocatalytic hydrogen production by cobalt complexes containing pendant amines.

PubMed

Wiedner, Eric S; Appel, Aaron M; DuBois, Daniel L; Bullock, R Morris

2013-12-16

Two cobalt(tetraphosphine) complexes [Co(P(nC-PPh2)2N(Ph)2)(CH3CN)](BF4)2 with a tetradentate phosphine ligand (P(nC-PPh2)2N(Ph)2 = 1,5-diphenyl-3,7-bis((diphenylphosphino)alkyl)-1,5-diaza-3,7-diphosphacyclooctane; alkyl = (CH2)2, n = 2 (L2); (CH2)3, n = 3 (L3)) have been studied for electrocatalytic hydrogen production using 1:1 [(DMF)H](+):DMF. A turnover frequency (TOF) of 980 s(-1) with an overpotential at Ecat/2 of 1210 mV was measured for [Co(II)(L2)(CH3CN)](2+), and a TOF of 980 s(-1) with an overpotential at Ecat/2 of 930 mV was measured for [Co(II)(L3)(CH3CN)](2+). Addition of water increases the TOF of [Co(II)(L2)(CH3CN)](2+) to 18,000 s(-1). The catalytic wave for each of these complexes occurs at the reduction potential of the corresponding HCo(III) complex. Comprehensive thermochemical studies of [Co(II)(L2)(CH3CN)](2+) and [Co(II)(L3)(CH3CN)](2+) and species derived from them by addition/removal of protons/electrons were carried out using values measured experimentally and calculated using density functional theory (DFT). Notably, HCo(I)(L2) and HCo(I)(L3) were found to be remarkably strong hydride donors, with HCo(I)(L2) being a better hydride donor than BH4(-). Mechanistic studies of these catalysts reveal that H2 formation can occur by protonation of a HCo(II) intermediate, and that the pendant amines of these complexes facilitate proton delivery to the cobalt center. The rate-limiting step for catalysis is a net intramolecular isomerization of the protonated pendant amine from the nonproductive exoisomer to the productive endo isomer.

Generative mechanistic explanation building in undergraduate molecular and cellular biology

NASA Astrophysics Data System (ADS)

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

2017-09-01

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

Safety, Efficacy, and Mechanistic Studies Regarding Citrus aurantium (Bitter Orange) Extract and p‐Synephrine

PubMed Central

2017-01-01

Citrus aurantium L. (bitter orange) extracts that contain p‐synephrine as the primary protoalkaloid are widely used for weight loss/weight management, sports performance, appetite control, energy, and mental focus and cognition. Questions have been raised about the safety of p‐synephrine because it has some structural similarity to ephedrine. This review focuses on current human, animal, in vitro, and mechanistic studies that address the safety, efficacy, and mechanisms of action of bitter orange extracts and p‐synephrine. Numerous studies have been conducted with respect to p‐synephrine and bitter orange extract because ephedra and ephedrine were banned from use in dietary supplements in 2004. Approximately 30 human studies indicate that p‐synephrine and bitter orange extracts do not result in cardiovascular effects and do not act as stimulants at commonly used doses. Mechanistic studies suggest that p‐synephrine exerts its effects through multiple actions, which are discussed. Because p‐synephrine exhibits greater adrenergic receptor binding in rodents than humans, data from animals cannot be directly extrapolated to humans. This review, as well as several other assessments published in recent years, has concluded that bitter orange extract and p‐synephrine are safe for use in dietary supplements and foods at the commonly used doses. Copyright © 2017 The Authors Phytotherapy Research Published by John Wiley & Sons Ltd. PMID:28752649

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

PubMed

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

2015-01-01

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

Rational and Mechanistic Perspectives on Reinforcement Learning

ERIC Educational Resources Information Center

Chater, Nick

2009-01-01

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

Intriguing mechanistic labyrinths in gold(i) catalysis

PubMed Central

Obradors, Carla

2014-01-01

Many mechanistically intriguing reactions have been developed in the last decade using gold(i) as catalyst. Here we review the main mechanistic proposals in gold-catalysed activation of alkynes and allenes, in which this metal plays a central role by stabilising a variety of complex cationic intermediates. PMID:24176910

Transitioning from AOP to IATA - Exploiting mechanistic ...

EPA Pesticide Factsheets

Slide presentation at satellite meeting of the QSAR2016 Meeting on How to Transition from AOP to IATA-Exploiting mechanistic insight for practical decision making. . Slide presentation at satellite meeting of the QSAR2016 Meeting on How to Transition from AOP to IATA-Exploiting mechanistic insight for practical decision making. .

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

PubMed

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

2017-10-01

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

The physicochemical process of bacterial attachment to abiotic surfaces: Challenges for mechanistic studies, predictability and the development of control strategies.

PubMed

Wang, Yi; Lee, Sui Mae; Dykes, Gary

2015-01-01

Bacterial attachment to abiotic surfaces can be explained as a physicochemical process. Mechanisms of the process have been widely studied but are not yet well understood due to their complexity. Physicochemical processes can be influenced by various interactions and factors in attachment systems, including, but not limited to, hydrophobic interactions, electrostatic interactions and substratum surface roughness. Mechanistic models and control strategies for bacterial attachment to abiotic surfaces have been established based on the current understanding of the attachment process and the interactions involved. Due to a lack of process control and standardization in the methodologies used to study the mechanisms of bacterial attachment, however, various challenges are apparent in the development of models and control strategies. In this review, the physicochemical mechanisms, interactions and factors affecting the process of bacterial attachment to abiotic surfaces are described. Mechanistic models established based on these parameters are discussed in terms of their limitations. Currently employed methods to study these parameters and bacterial attachment are critically compared. The roles of these parameters in the development of control strategies for bacterial attachment are reviewed, and the challenges that arise in developing mechanistic models and control strategies are assessed.

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

PubMed

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

2014-01-01

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

Mindfulness & Self-Compassion Meditation for Combat Posttraumatic Stress Disorder: Randomized Controlled Trial and Mechanistic Study

DTIC Science & Technology

2013-10-01

VA Ann Arbor PTSD clinic; and c.) conducting a translational neuroimaging mechanistic study with pre- and post fMRI and neurocognitive testing . 15...might be helpful – both in terms of the psychological characteristics of change, and in terms of neural mechanisms in the brain. Mindfulness...neurocognitive testing . Our novel 16 week Mindfulness and Self-compassion group intervention, “Mindfulness-based Exposure therapy” (MBET), was developed

Mechanistic analysis of challenge-response experiments.

PubMed

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

2013-09-01

We present an application of mechanistic modeling and nonlinear longitudinal regression in the context of biomedical response-to-challenge experiments, a field where these methods are underutilized. In this type of experiment, a system is studied by imposing an experimental challenge, and then observing its response. The combination of mechanistic modeling and nonlinear longitudinal regression has brought new insight, and revealed an unexpected opportunity for optimal design. Specifically, the mechanistic aspect of our approach enables the optimal design of experimental challenge characteristics (e.g., intensity, duration). This article lays some groundwork for this approach. We consider a series of experiments wherein an isolated rabbit heart is challenged with intermittent anoxia. The heart responds to the challenge onset, and recovers when the challenge ends. The mean response is modeled by a system of differential equations that describe a candidate mechanism for cardiac response to anoxia challenge. The cardiac system behaves more variably when challenged than when at rest. Hence, observations arising from this experiment exhibit complex heteroscedasticity and sharp changes in central tendency. We present evidence that an asymptotic statistical inference strategy may fail to adequately account for statistical uncertainty. Two alternative methods are critiqued qualitatively (i.e., for utility in the current context), and quantitatively using an innovative Monte-Carlo method. We conclude with a discussion of the exciting opportunities in optimal design of response-to-challenge experiments. © 2013, The International Biometric Society.

Mechanistic Investigations into the Application of Sulfoxides in Carbohydrate Synthesis

PubMed Central

Brabham, Robin

2016-01-01

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

Why did Jacques Monod make the choice of mechanistic determinism?

PubMed

Loison, Laurent

2015-06-01

The development of molecular biology placed in the foreground a mechanistic and deterministic conception of the functioning of macromolecules. In this article, I show that this conception was neither obvious, nor necessary. Taking Jacques Monod as a case study, I detail the way he gradually came loose from a statistical understanding of determinism to finally support a mechanistic understanding. The reasons of the choice made by Monod at the beginning of the 1950s can be understood only in the light of the general theoretical schema supported by the concept of mechanistic determinism. This schema articulates three fundamental notions for Monod, namely that of the rigidity of the sequence of the genetic program, that of the intrinsic stability of macromolecules (DNA and proteins), and that of the specificity of molecular interactions. Copyright © 2015 Académie des sciences. Published by Elsevier SAS. All rights reserved.

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

PubMed Central

2017-01-01

Purpose Mechanistic case diagram (MCD) was recommended for increasing the depth of understanding of disease, but with few articles on its specific methods. We address the experience of making MCD in the fullest depth to identify the pros and cons of using MCDs in such ways. Methods During problem-based learning, we gave guidelines of MCD for its mechanistic exploration from subcellular processes to clinical features, being laid out in as much detail as possible. To understand the students’ attitudes and depth of study using MCDs, we analyzed the results of a questionnaire in an open format about experiencing MCDs and examined the resulting products. Results Through the responses to questionnaire, we found several favorable outcomes, major of which was deeper insight and comprehensive understanding of disease facilitated by the process of making well-organized diagram. The main disadvantages of these guidelines were the feeling of too much workload and difficulty of finding mechanisms. Students gave suggestions to overcome these problems: cautious reading of comprehensive texts, additional guidance from staff about depth and focus of mechanisms, and cooperative group work. From the analysis of maps, we recognized there should be allowance of diversities in the appearance of maps and many hypothetical connections, which could be related to an insufficient understanding of mechanisms in nature. Conclusion The more detailed an MCD task is, the better students can become acquainted with deep knowledges. However, this advantage should be balanced by the results that there are many ensuing difficulties for the work and deliberate help plans should be prepared. PMID:28870018

Testing mechanistic models of growth in insects.

PubMed

Maino, James L; Kearney, Michael R

2015-11-22

Insects are typified by their small size, large numbers, impressive reproductive output and rapid growth. However, insect growth is not simply rapid; rather, insects follow a qualitatively distinct trajectory to many other animals. Here we present a mechanistic growth model for insects and show that increasing specific assimilation during the growth phase can explain the near-exponential growth trajectory of insects. The presented model is tested against growth data on 50 insects, and compared against other mechanistic growth models. Unlike the other mechanistic models, our growth model predicts energy reserves per biomass to increase with age, which implies a higher production efficiency and energy density of biomass in later instars. These predictions are tested against data compiled from the literature whereby it is confirmed that insects increase their production efficiency (by 24 percentage points) and energy density (by 4 J mg(-1)) between hatching and the attainment of full size. The model suggests that insects achieve greater production efficiencies and enhanced growth rates by increasing specific assimilation and increasing energy reserves per biomass, which are less costly to maintain than structural biomass. Our findings illustrate how the explanatory and predictive power of mechanistic growth models comes from their grounding in underlying biological processes. © 2015 The Author(s).

Mechanistic studies of systemic immune responses induced by laser-nanotechnology

NASA Astrophysics Data System (ADS)

Chen, Wei R.; Zhou, Feifan; Henderson, Brock; Vasquez, Bailey; Liu, Hong; Hode, Tomas; Nordquist, Robert E.

2014-02-01

With the help of the specific absorption spectrum of carbon nanotubes, we achieved selective photothermal tumor cell destruction, particularly using a near-infrared laser to reduce potential damage to untargeted tissues. Combined with immunological stimulation, using a novel adjuvant, we also observed the anti-tumor immune responses when treating animal tumors using the laser-nano treatment. In fact, the local application of laser-nano-immunotherapy appeared to result in a systemic curative effect. In our mechanistic study, we found that the laser-nano-immuno treatment can activate antigen-presenting cells, such as dendritic cells (DCs). More importantly, the uptake and presentation of antigens by these antigen presenting cells were significantly enhanced, as shown by the strong binding of tumor cells and DCs as well as the proliferation of T cells caused by the DCs after the DCs had been incubated with laser-nano-immuno treated tumors. These cellular observations provide evidence that a systemic anti-tumor immune response was induced by the combination of laser and nanotechnology.

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

ERIC Educational Resources Information Center

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

2017-01-01

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

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

ERIC Educational Resources Information Center

Suzuki, Tasuma

2009-01-01

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

Characterizing Students' Mechanistic Reasoning about London Dispersion Forces

ERIC Educational Resources Information Center

Becker, Nicole; Noyes, Keenan; Cooper, Melanie

2016-01-01

Characterizing how students construct causal mechanistic explanations for chemical phenomena can provide us with important insights into the ways that students develop understanding of chemistry concepts. Here, we present two qualitative studies of undergraduate general chemistry students' reasoning about the causes of London dispersion forces in…

High-throughput identification of off-targets for the mechanistic study of severe adverse drug reactions induced by analgesics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pan, Jian-Bo; Ji, Nan; Pan, Wen

2014-01-01

Drugs may induce adverse drug reactions (ADRs) when they unexpectedly bind to proteins other than their therapeutic targets. Identification of these undesired protein binding partners, called off-targets, can facilitate toxicity assessment in the early stages of drug development. In this study, a computational framework was introduced for the exploration of idiosyncratic mechanisms underlying analgesic-induced severe adverse drug reactions (SADRs). The putative analgesic-target interactions were predicted by performing reverse docking of analgesics or their active metabolites against human/mammal protein structures in a high-throughput manner. Subsequently, bioinformatics analyses were undertaken to identify ADR-associated proteins (ADRAPs) and pathways. Using the pathways and ADRAPsmore » that this analysis identified, the mechanisms of SADRs such as cardiac disorders were explored. For instance, 53 putative ADRAPs and 24 pathways were linked with cardiac disorders, of which 10 ADRAPs were confirmed by previous experiments. Moreover, it was inferred that pathways such as base excision repair, glycolysis/glyconeogenesis, ErbB signaling, calcium signaling, and phosphatidyl inositol signaling likely play pivotal roles in drug-induced cardiac disorders. In conclusion, our framework offers an opportunity to globally understand SADRs at the molecular level, which has been difficult to realize through experiments. It also provides some valuable clues for drug repurposing. - Highlights: • A novel computational framework was developed for mechanistic study of SADRs. • Off-targets of drugs were identified in large scale and in a high-throughput manner. • SADRs like cardiac disorders were systematically explored in molecular networks. • A number of ADR-associated proteins were identified.« less

Mechanistic studies related to the safety of Li/SOCl2 cells

NASA Technical Reports Server (NTRS)

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

1985-01-01

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

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

EPA Science Inventory

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

Four Mechanistic Models of Peer Influence on Adolescent Cannabis Use.

PubMed

Caouette, Justin D; Feldstein Ewing, Sarah W

2017-06-01

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

Tear gas: an epidemiological and mechanistic reassessment

PubMed Central

Rothenberg, Craig; Achanta, Satyanarayana; Svendsen, Erik R.

2016-01-01

Deployments of tear gas and pepper spray have rapidly increased worldwide. Large amounts of tear gas have been used in densely populated cities, including Cairo, Istanbul, Rio de Janeiro, Manama (Bahrain), and Hong Kong. In the United States, tear gas was used extensively during recent riots in Ferguson, Missouri. Whereas tear gas deployment systems have rapidly improved—with aerial drone systems tested and requested by law enforcement—epidemiological and mechanistic research have lagged behind and have received little attention. Case studies and recent epidemiological studies revealed that tear gas agents can cause lung, cutaneous, and ocular injuries, with individuals affected by chronic morbidities at high risk for complications. Mechanistic studies identified the ion channels TRPV1 and TRPA1 as targets of capsaicin in pepper spray, and of the tear gas agents chloroacetophenone, CS, and CR. TRPV1 and TRPA1 localize to pain‐sensing peripheral sensory neurons and have been linked to acute and chronic pain, cough, asthma, lung injury, dermatitis, itch, and neurodegeneration. In animal models, transient receptor potential inhibitors show promising effects as potential countermeasures against tear gas injuries. On the basis of the available data, a reassessment of the health risks of tear gas exposures in the civilian population is advised, and development of new countermeasures is proposed. PMID:27391380

Facilitators of Survivorship Care Among Underserved Breast Cancer Survivors: a Qualitative Study.

PubMed

Ustjanauskas, Amy E; Quinn, Gwendolyn P; Pan, Tonya M; Rivera, Maria; Vázquez-Otero, Coralia; Ung, Danielle; Roetzheim, Richard G; Laronga, Christine; Johnson, Kenneth; Norton, Marilyn; Carrizosa, Claudia; Muñoz, Dariana; Goldenstein, Marissa; Nuhaily, Sumayah; Wells, Kristen J

2017-12-01

Research investigating facilitators of survivorship care among underserved breast cancer survivors (BCS) is sparse. This study aimed to explore facilitators of survivorship care among underserved BCS within the first 5 years following chemotherapy, radiation, or surgery for breast cancer. In-depth interviews were conducted, using a semi-structured interview guide, with underserved BCS exploring survivorship care experiences. Content analysis of the verbatim transcripts was applied, and results were summarized according to themes related to facilitators of breast cancer survivorship care. Interviews were conducted with 25 BCS. Eight main themes were identified: coordination of care; positive perceptions of health care providers; communication between patient and health care providers; financial and insurance facilitators; information, classes, and programs provided; assistance provided by organizations and health care professionals; transportation facilitators; and job flexibility. This study provides a comprehensive look at facilitators of survivorship care among underserved BCS. BCS endorsed several facilitators of their survivorship care, mainly at the interpersonal, organizational, and societal level. This study adds to the research literature on catalysts of care among underserved BCS. Results from this study are currently being used to inform a patient navigation intervention to facilitate care among this population.

A Cycloaromatization Protocol for Synthesis of Polysubstituted Phenol Derivatives: Method Development and Mechanistic Studies

PubMed Central

Spencer, William T.

2012-01-01

The scope of the cycloaromatization of propargylic ethers was explored using operationally simple air- and moisture-insensitive conditions. Highly substituted phenol derivatives were obtained in high yields. Mechanistic experiments indicate that the reaction occurs by an electrocyclization followed by 1,3-proton transfer. PMID:22891882

Putting the psychology back into psychological models: mechanistic versus rational approaches.

PubMed

Sakamoto, Yasuaki; Jones, Mattr; Love, Bradley C

2008-09-01

Two basic approaches to explaining the nature of the mind are the rational and the mechanistic approaches. Rational analyses attempt to characterize the environment and the behavioral outcomes that humans seek to optimize, whereas mechanistic models attempt to simulate human behavior using processes and representations analogous to those used by humans. We compared these approaches with regard to their accounts of how humans learn the variability of categories. The mechanistic model departs in subtle ways from rational principles. In particular, the mechanistic model incrementally updates its estimates of category means and variances through error-driven learning, based on discrepancies between new category members and the current representation of each category. The model yields a prediction, which we verify, regarding the effects of order manipulations that the rational approach does not anticipate. Although both rational and mechanistic models can successfully postdict known findings, we suggest that psychological advances are driven primarily by consideration of process and representation and that rational accounts trail these breakthroughs.

Mathematical Description and Mechanistic Reasoning: A Pathway toward STEM Integration

ERIC Educational Resources Information Center

Weinberg, Paul J.

2017-01-01

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

Facilitating classroom based interprofessional learning: a grounded theory study of university educators' perceptions of their role adequacy as facilitators.

PubMed

Derbyshire, Julie A; Machin, Alison I; Crozier, Suzanne

2015-01-01

The provision of inter professional learning (IPL) within undergraduate programmes is now well established within many Higher Education Institutions (HEIs). IPL aims to better equip nurses and other health professionals with effective collaborative working skills and knowledge to improve the quality of patient care. Although there is still ambiguity in relation to the optimum timing and method for delivering IPL, effective facilitation is seen as essential. This paper reports on a grounded theory study of university educators' perceptions of the knowledge and skills needed for their role adequacy as IPL facilitators. Data was collected using semi structured interviews with nine participants who were theoretically sampled from a range of professional backgrounds, with varied experiences of education and involvement in facilitating IPL. Constant comparative analysis was used to generate four data categories: creating and sustaining an IPL group culture through transformational IPL leadership (core category), readiness for IPL facilitation, drawing on past interprofessional learning and working experiences and role modelling an interprofessional approach. The grounded theory generated from this study, although propositional, suggests that role adequacy for IPL facilitation is dependent on facilitator engagement in a process of 'transformational interprofessional learning leadership' to create and sustain a group culture. Copyright © 2014 Elsevier Ltd. All rights reserved.

Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids

PubMed Central

Gunduz-Cinar, Ozge; Flynn, Shaun; Brockway, Emma; Kaugars, Katherine; Baldi, Rita; Ramikie, Teniel S; Cinar, Resat; Kunos, George; Patel, Sachin; Holmes, Andrew

2016-01-01

Pharmacologically elevating brain endocannabinoids (eCBs) share anxiolytic and fear extinction-facilitating properties with classical therapeutics, including the selective serotonin reuptake inhibitor, fluoxetine. There are also known functional interactions between the eCB and serotonin systems and preliminary evidence that antidepressants cause alterations in brain eCBs. However, the potential role of eCBs in mediating the facilitatory effects of fluoxetine on fear extinction has not been established. Here, to test for a possible mechanistic contribution of eCBs to fluoxetine's proextinction effects, we integrated biochemical, electrophysiological, pharmacological, and behavioral techniques, using the extinction-impaired 129S1/Sv1mJ mouse strain. Chronic fluoxetine treatment produced a significant and selective increase in levels of anandamide in the BLA, and an associated decrease in activity of the anandamide-catabolizing enzyme, fatty acid amide hydrolase. Slice electrophysiological recordings showed that fluoxetine-induced increases in anandamide were associated with the amplification of eCB-mediated tonic constraint of inhibitory, but not excitatory, transmission in the BLA. Behaviorally, chronic fluoxetine facilitated extinction retrieval in a manner that was prevented by systemic or BLA-specific blockade of CB1 receptors. In contrast to fluoxetine, citalopram treatment did not increase BLA eCBs or facilitate extinction. Taken together, these findings reveal a novel, obligatory role for amygdala eCBs in the proextinction effects of a major pharmacotherapy for trauma- and stressor-related disorders and anxiety disorders. PMID:26514583

Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids.

PubMed

Gunduz-Cinar, Ozge; Flynn, Shaun; Brockway, Emma; Kaugars, Katherine; Baldi, Rita; Ramikie, Teniel S; Cinar, Resat; Kunos, George; Patel, Sachin; Holmes, Andrew

2016-05-01

Pharmacologically elevating brain endocannabinoids (eCBs) share anxiolytic and fear extinction-facilitating properties with classical therapeutics, including the selective serotonin reuptake inhibitor, fluoxetine. There are also known functional interactions between the eCB and serotonin systems and preliminary evidence that antidepressants cause alterations in brain eCBs. However, the potential role of eCBs in mediating the facilitatory effects of fluoxetine on fear extinction has not been established. Here, to test for a possible mechanistic contribution of eCBs to fluoxetine's proextinction effects, we integrated biochemical, electrophysiological, pharmacological, and behavioral techniques, using the extinction-impaired 129S1/Sv1mJ mouse strain. Chronic fluoxetine treatment produced a significant and selective increase in levels of anandamide in the BLA, and an associated decrease in activity of the anandamide-catabolizing enzyme, fatty acid amide hydrolase. Slice electrophysiological recordings showed that fluoxetine-induced increases in anandamide were associated with the amplification of eCB-mediated tonic constraint of inhibitory, but not excitatory, transmission in the BLA. Behaviorally, chronic fluoxetine facilitated extinction retrieval in a manner that was prevented by systemic or BLA-specific blockade of CB1 receptors. In contrast to fluoxetine, citalopram treatment did not increase BLA eCBs or facilitate extinction. Taken together, these findings reveal a novel, obligatory role for amygdala eCBs in the proextinction effects of a major pharmacotherapy for trauma- and stressor-related disorders and anxiety disorders.

Identification of key characteristics of male reproductive toxicants as an approach for screening and sorting mechanistic evidence.

EPA Science Inventory

The application of systematic review practices in human health assessment includes integration of multi-disciplinary evidence from epidemiological, experimental, and mechanistic studies. Although mode of action analysis relies on the evaluation of mechanistic and toxicological ou...

Combining correlative and mechanistic habitat suitability models to improve ecological compensation.

PubMed

Meineri, Eric; Deville, Anne-Sophie; Grémillet, David; Gauthier-Clerc, Michel; Béchet, Arnaud

2015-02-01

Only a few studies have shown positive impacts of ecological compensation on species dynamics affected by human activities. We argue that this is due to inappropriate methods used to forecast required compensation in environmental impact assessments. These assessments are mostly descriptive and only valid at limited spatial and temporal scales. However, habitat suitability models developed to predict the impacts of environmental changes on potential species' distributions should provide rigorous science-based tools for compensation planning. Here we describe the two main classes of predictive models: correlative models and individual-based mechanistic models. We show how these models can be used alone or synoptically to improve compensation planning. While correlative models are easier to implement, they tend to ignore underlying ecological processes and lack accuracy. On the contrary, individual-based mechanistic models can integrate biological interactions, dispersal ability and adaptation. Moreover, among mechanistic models, those considering animal energy balance are particularly efficient at predicting the impact of foraging habitat loss. However, mechanistic models require more field data compared to correlative models. Hence we present two approaches which combine both methods for compensation planning, especially in relation to the spatial scale considered. We show how the availability of biological databases and software enabling fast and accurate population projections could be advantageously used to assess ecological compensation requirement efficiently in environmental impact assessments. © 2014 The Authors. Biological Reviews © 2014 Cambridge Philosophical Society.

Stuxnet Facilitates the Degradation of Polycomb Protein during Development.

PubMed

Du, Juan; Zhang, Junzheng; He, Tao; Li, Yajuan; Su, Ying; Tie, Feng; Liu, Min; Harte, Peter J; Zhu, Alan Jian

2016-06-20

Polycomb-group (PcG) proteins function to ensure correct deployment of developmental programs by epigenetically repressing target gene expression. Despite the importance, few studies have been focused on the regulation of PcG activity itself. Here, we report a Drosophila gene, stuxnet (stx), that controls Pc protein stability. We find that heightened stx activity leads to homeotic transformation, reduced Pc activity, and de-repression of PcG targets. Conversely, stx mutants, which can be rescued by decreased Pc expression, display developmental defects resembling hyperactivation of Pc. Our biochemical analyses provide a mechanistic basis for the interaction between stx and Pc; Stx facilitates Pc degradation in the proteasome, independent of ubiquitin modification. Furthermore, this mode of regulation is conserved in vertebrates. Mouse stx promotes degradation of Cbx4, an orthologous Pc protein, in vertebrate cells and induces homeotic transformation in Drosophila. Our results highlight an evolutionarily conserved mechanism of regulated protein degradation on PcG homeostasis and epigenetic activity. Copyright © 2016 Elsevier Inc. All rights reserved.

Unraveling molecular mechanistic differences in liver metabolism between lean and fat lines of Pekin duck (Anas platyrhynchos domestica): a proteomic study.

PubMed

Zheng, Aijuan; Chang, Wenhuan; Hou, Shuisheng; Zhang, Shu; Cai, Huiyi; Chen, Guilan; Lou, Ruiying; Liu, Guohua

2014-02-26

Duck is one of the major poultry meat sources for human consumption. To satisfy different eating habits, lean and fat strains of Pekin ducks have been developed. The objective of this study was to determine the molecular mechanistic differences in liver metabolism between two duck strains. The liver proteome of the Pekin duck lines was compared on days 1, 14, 28, and 42 posthatching using 2-DE based proteomics. There was a different abundance of 76 proteins in the livers of the two duck lines. Fat ducks strongly expressed proteins related to pathways of glycolysis, ATP synthesis, and protein catabolism, suggesting enhanced fat deposition rather than protein retention. In contrast, highly expressed proteins in lean ducks improved protein anabolism and reduced protein catabolism, resulting in an enhancement of lean meat deposition. Along with the decrease in fat deposition, the immune system of the lean duck strain may be enhanced by enhanced expression of proteins involved in stress response, immune defense, and antioxidant functions. These results indicate that selection pressure has shaped the two duck lines differently resulting in different liver metabolic capacities. These observed variations between the two strains at the molecular level are matched with physiological changes in growth performance and meat production. This information may have beneficial impacts in areas such as genetic modification through the manipulation of target proteins or genes in specific pathways to improve the efficiency of duck meat production. The objective of this study was to unravel molecular mechanistic differences in liver metabolism between lean and fat Pekin duck (Anas platyrhynchos domestica) strains. There was a different abundance of 76 proteins in the livers of the two duck lines. Enhanced protein expression in the fat ducks related to pathways of glycolysis, ATP synthesis and protein catabolism suggesting increased fat deposition rather than protein retention. In

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matheis, Katja A., E-mail: katja.matheis@boehringer-ingelheim.com; Com, Emmanuelle; High-Throughput Proteomics Core Facility OUEST-genopole

2011-04-15

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

Mechanistic modeling of pesticide exposure: The missing keystone of honey bee toxicology.

PubMed

Sponsler, Douglas B; Johnson, Reed M

2017-04-01

The role of pesticides in recent honey bee losses is controversial, partly because field studies often fail to detect effects predicted by laboratory studies. This dissonance highlights a critical gap in the field of honey bee toxicology: there exists little mechanistic understanding of the patterns and processes of exposure that link honey bees to pesticides in their environment. The authors submit that 2 key processes underlie honey bee pesticide exposure: 1) the acquisition of pesticide by foraging bees, and 2) the in-hive distribution of pesticide returned by foragers. The acquisition of pesticide by foraging bees must be understood as the spatiotemporal intersection between environmental contamination and honey bee foraging activity. This implies that exposure is distributional, not discrete, and that a subset of foragers may acquire harmful doses of pesticide while the mean colony exposure would appear safe. The in-hive distribution of pesticide is a complex process driven principally by food transfer interactions between colony members, and this process differs importantly between pollen and nectar. High priority should be placed on applying the extensive literature on honey bee biology to the development of more rigorously mechanistic models of honey bee pesticide exposure. In combination with mechanistic effects modeling, mechanistic exposure modeling has the potential to integrate the field of honey bee toxicology, advancing both risk assessment and basic research. Environ Toxicol Chem 2017;36:871-881. © 2016 SETAC. © 2016 SETAC.

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

PubMed

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

2017-11-15

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

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

ERIC Educational Resources Information Center

Aviles, Natalie B.; Reed, Isaac Ariail

2017-01-01

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

Evolutionary and mechanistic theories of aging.

PubMed

Hughes, Kimberly A; Reynolds, Rose M

2005-01-01

Senescence (aging) is defined as a decline in performance and fitness with advancing age. Senescence is a nearly universal feature of multicellular organisms, and understanding why it occurs is a long-standing problem in biology. Here we present a concise review of both evolutionary and mechanistic theories of aging. We describe the development of the general evolutionary theory, along with the mutation accumulation, antagonistic pleiotropy, and disposable soma versions of the evolutionary model. The review of the mechanistic theories focuses on the oxidative stress resistance, cellular signaling, and dietary control mechanisms of life span extension. We close with a discussion of how an approach that makes use of both evolutionary and molecular analyses can address a critical question: Which of the mechanisms that can cause variation in aging actually do cause variation in natural populations?

Spatially confined photoinactivation of bacteria: towards novel tools for detailed mechanistic studies

NASA Astrophysics Data System (ADS)

Thomsen, Hanna; James, Jeemol; Farewell, Anne; Ericson, Marica B.

2018-02-01

Antimicrobial resistance is a serious global threat fueling an accelerated field of research aimed at developing novel antimicrobial therapies. A particular challenge is the treatment of microbial biofilms formed upon bacterial growth and often associated with chronic infections. Biofilms comprise bacteria that have adhered to a surface and formed 3D microcolonies, and demonstrate significantly increased antimicrobial resistance compared to the planktonic counterpart. A challenge in developing novel strategies for fighting these chronic infections is a lack of mechanistic understanding of what primarily contributes to enhanced drug resistance. Tools for noninvasive study of live biofilms are necessary to begin to understand these mechanisms on both a single cell and 3D level. Herein, a method by which multiphoton microscopy is implemented to study a biofilm model of Staphylococcus epidermidis to noninvasively visualize and measure penetration of compounds in 3D biofilm structure and two photon excitation was exploited for spatially confined photoinactivation and microscopy optimized for evaluation of microbiological viability at a microscopic level. Future studies are aimed at future development of the proposed techniques for detailed studies of, e.g., quorum sensing and mechanisms contributing to antimicrobial resistance.

Impact of social relationships on Alzheimer's memory impairment: mechanistic studies.

PubMed

Hsiao, Ya-Hsin; Chang, Chih-Hua; Gean, Po-Wu

2018-01-11

Alzheimer's disease (AD) is characterized by progressive memory and neuronal loss culminating in cognitive impairment that not only affects a person's living ability but also becomes a society's as well as a family's economic burden. AD is the most common form of dementia in older persons. It is expected that the number of people with AD dementia will increase dramatically in the next 30 years, projecting to 75 million in 2030 and 131.5 million in 2050 worldwide. So far, no sufficient evidence is available to support that any medicine is able to prevent or reverse the progression of the disease. Early studies have shown that social environment, particularly social relationships, can affect one's behavior and mental health. A study analyzing the correlation between loneliness and risk of developing AD revealed that lonely persons had higher risk of AD compared with persons who were not lonely. On the other hand, it has been reported that we can prevent cognitive decline and delay the onset of AD if we keep mentally active and frequently participate in social activities. In this review, we focus on the impact of social behaviors on the progression of cognitive deficit in animal models of AD with a particular emphasis on a mechanistic scheme that explains how social isolation exacerbates cognitive impairment and how social interaction with conspecifics rescues AD patients' memory deficit.

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

PubMed

Lombrozo, Tania; Gwynne, Nicholas Z

2014-01-01

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

Mechanistic studies of the radical SAM enzyme spore photoproduct lyase (SPL).

PubMed

Li, Lei

2012-11-01

Spore photoproduct lyase (SPL) repairs a special thymine dimer 5-thyminyl-5,6-dihydrothymine, which is commonly called spore photoproduct or SP at the bacterial early germination phase. SP is the exclusive DNA photo-damage product in bacterial endospores; its generation and swift repair by SPL are responsible for the spores' extremely high UV resistance. The early in vivo studies suggested that SPL utilizes a direct reversal strategy to repair the SP in the absence of light. The research in the past decade further established SPL as a radical SAM enzyme, which utilizes a tri-cysteine CXXXCXXC motif to harbor a [4Fe-4S] cluster. At the 1+ oxidation state, the cluster provides an electron to the S-adenosylmethionine (SAM), which binds to the cluster in a bidentate manner as the fourth and fifth ligands, to reductively cleave the CS bond associated with the sulfonium ion in SAM, generating a reactive 5'-deoxyadenosyl (5'-dA) radical. This 5'-dA radical abstracts the proR hydrogen atom from the C6 carbon of SP to initiate the repair process; the resulting SP radical subsequently fragments to generate a putative thymine methyl radical, which accepts a back-donated H atom to yield the repaired TpT. SAM is suggested to be regenerated at the end of each catalytic cycle; and only a catalytic amount of SAM is needed in the SPL reaction. The H atom source for the back donation step is suggested to be a cysteine residue (C141 in Bacillus subtilis SPL), and the H-atom transfer reaction leaves a thiyl radical behind on the protein. This thiyl radical thus must participate in the SAM regeneration process; however how the thiyl radical abstracts an H atom from the 5'-dA to regenerate SAM is unknown. This paper reviews and discusses the history and the latest progress in the mechanistic elucidation of SPL. Despite some recent breakthroughs, more questions are raised in the mechanistic understanding of this intriguing DNA repair enzyme. This article is part of a Special Issue

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

DOT National Transportation Integrated Search

2009-02-01

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

Four Mechanistic Models of Peer Influence on Adolescent Cannabis Use

PubMed Central

Caouette, Justin D.; Feldstein Ewing, Sarah W.

2017-01-01

Purpose of review Most adolescents begin exploring cannabis in peer contexts, but the neural mechanisms that underlie peer influence on adolescent cannabis use are still unknown. This theoretical overview elucidates the intersecting roles of neural function and peer factors in cannabis use in adolescents. Recent findings Novel paradigms using functional magnetic resonance imaging (fMRI) in adolescents have identified distinct neural mechanisms of risk decision-making and incentive processing in peer contexts, centered on reward-motivation and affect regulatory neural networks; these findings inform a theoretical model of peer-driven cannabis use decisions in adolescents. Summary We propose four “mechanistic profiles” of social facilitation of cannabis use in adolescents: (1) peer influence as the primary driver of use; (2) cannabis exploration as the primary driver, which may be enhanced in peer contexts; (3) social anxiety; and (4) negative peer experiences. Identification of “neural targets” involved in motivating cannabis use may inform clinicians about which treatment strategies work best in adolescents with cannabis use problems, and via which social and neurocognitive processes. PMID:29104847

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

PubMed

Mahmood, Abda; Roberts, Ian; Shakur, Haleema

2017-07-17

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

Generative Mechanistic Explanation Building in Undergraduate Molecular and Cellular Biology

ERIC Educational Resources Information Center

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

2017-01-01

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

Imaging approach to mechanistic study of nanoparticle interactions with the blood-brain barrier.

PubMed

Bramini, Mattia; Ye, Dong; Hallerbach, Anna; Nic Raghnaill, Michelle; Salvati, Anna; Aberg, Christoffer; Dawson, Kenneth A

2014-05-27

Understanding nanoparticle interactions with the central nervous system, in particular the blood-brain barrier, is key to advances in therapeutics, as well as assessing the safety of nanoparticles. Challenges in achieving insights have been significant, even for relatively simple models. Here we use a combination of live cell imaging and computational analysis to directly study nanoparticle translocation across a human in vitro blood-brain barrier model. This approach allows us to identify and avoid problems in more conventional inferential in vitro measurements by identifying the catalogue of events of barrier internalization and translocation as they occur. Potentially this approach opens up the window of applicability of in vitro models, thereby enabling in depth mechanistic studies in the future. Model nanoparticles are used to illustrate the method. For those, we find that translocation, though rare, appears to take place. On the other hand, barrier uptake is efficient, and since barrier export is small, there is significant accumulation within the barrier.

Planarians as models of cadmium-induced neoplasia provide measurable benchmarks for mechanistic studies.

PubMed

Voura, Evelyn B; Montalvo, Melissa J; Dela Roca, Kevin T; Fisher, Julia M; Defamie, Virginie; Narala, Swami R; Khokha, Rama; Mulligan, Margaret E; Evans, Colleen A

2017-08-01

Bioassays of planarian neoplasia highlight the potential of these organisms as useful standards to assess whether environmental toxins such as cadmium promote tumorigenesis. These studies complement other investigations into the exceptional healing and regeneration of planarians - processes that are driven by a population of active stem cells, or neoblasts, which are likely transformed during planarian tumor growth. Our goal was to determine if planarian tumorigenesis assays are amenable to mechanistic studies of cadmium carcinogenesis. To that end we demonstrate, by examining both counts of cell populations by size, and instances of mitosis, that the activity of the stem cell population can be monitored. We also provide evidence that specific biomodulators can affect the potential of planarian neoplastic growth, in that an inhibitor of metalloproteinases effectively blocked the development of the lesions. From these results, we infer that neoblast activity does respond to cadmium-induced tumor growth, and that metalloproteinases are required for the progression of cancer in the planarian. Copyright © 2017 Elsevier Inc. All rights reserved.

Managing mechanistic and organic structure in health care organizations.

PubMed

Olden, Peter C

2012-01-01

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

Cognitive science as an interface between rational and mechanistic explanation.

PubMed

Chater, Nick

2014-04-01

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

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

PubMed Central

Fitzpatrick, Paul F.

2014-01-01

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

Revisiting sesquiterpene biosynthetic pathways leading to santalene and its analogues: a comprehensive mechanistic study.

PubMed

Jindal, Garima; Sunoj, Raghavan B

2012-10-21

Santalene and bergamotene are the major olefinic sesquiterpenes responsible for the fragrance of sandalwood oil. Herein we report the details of density functional theory investigations on the biosynthetic pathway of this important class of terpenes. The mechanistic study has been found to be effective toward gaining significant new insight into different possibilities for the formation of the key intermediates involved in santalene and bergamotene biosynthesis. The stereoelectronic features of the transition states and intermediates for (i) ring closure of the initial bisabolyl cation, and (ii) skeletal rearrangements in the ensuing bicyclic carbocationic intermediates leading to (-)-epi-β-santalene, (-)-β-santalene, (-)-α-santalene, (+)-epi-β-santalene, exo-β-bergamotene, endo-β-bergamotene, exo-α-bergamotene, and endo-α-bergamotene are presented. Interesting structural features pertaining to certain new carbocationic intermediates (such as b) resulting from the ring closure of bisabolyl cation are discussed. Extensive conformational sampling of all key intermediates along the biosynthetic pathway offered new insight into the role of the isoprenyl side chain conformation in the formation of santalene and its analogues. Although the major bicyclic products in Santalum album appear to arise from the right or left handed helical form of farnesyl pyrophosphate (FPP), different alternatives for their formation are found to be energetically feasible. The interconversion of the exo and endo isomers of bisabolyl cation and a likely epimerization, both with interesting mechanistic implications, are presented. The exo to endo conversion is identified to be energetically more favorable than another pathway emanating from the left handed helical FPP. The role of pyrophosphate (OPP(-)) in the penultimate deprotonation step leading to olefinic sesquiterpenes is also examined.

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

PubMed

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

2015-09-01

A novel class of benzoheterocyclic analogues of amodiaquine designed to avoid toxic reactive metabolite formation was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant) and NF54 (sensitive) strains of the malaria parasite Plasmodium falciparum. Structure-activity relationship studies led to the identification of highly promising analogues, the most potent of which had IC50s in the nanomolar range against both strains. The compounds further demonstrated good in vitro microsomal metabolic stability while those subjected to in vivo pharmacokinetic studies had desirable pharmacokinetic profiles. In vivo antimalarial efficacy in Plasmodium berghei infected mice was evaluated for four compounds, all of which showed good activity following oral administration. In particular, compound 19 completely cured treated mice at a low multiple dose of 4×10mg/kg. Mechanistic and bioactivation studies suggest hemozoin formation inhibition and a low likelihood of forming quinone-imine reactive metabolites, respectively. Copyright © 2015 Elsevier Ltd. All rights reserved.

Development of Alabama traffic factors for use in mechanistic-empirical pavement design.

DOT National Transportation Integrated Search

2015-02-01

The pavement engineering community is moving toward design practices that use mechanistic-empirical (M-E) approaches to the design and analysis of pavement structures. This effort is : embodied in the Mechanistic-Empirical Pavement Design Guide (MEPD...

Kinetic Profiling of Catalytic Organic Reactions as a Mechanistic Tool.

PubMed

Blackmond, Donna G

2015-09-02

The use of modern kinetic tools to obtain virtually continuous reaction progress data over the course of a catalytic reaction opens up a vista that provides mechanistic insights into both simple and complex catalytic networks. Reaction profiles offer a rate/concentration scan that tells the story of a batch reaction time course in a qualitative "fingerprinting" manner as well as in quantitative detail. Reaction progress experiments may be mathematically designed to elucidate catalytic rate laws from only a fraction of the number of experiments required in classical kinetic measurements. The information gained from kinetic profiles provides clues to direct further mechanistic analysis by other approaches. Examples from a variety of catalytic reactions spanning two decades of the author's work help to delineate nuances on a central mechanistic theme.

Mechanistic materials modeling for nuclear fuel performance

DOE PAGES

Tonks, Michael R.; Andersson, David; Phillpot, Simon R.; ...

2017-03-15

Fuel performance codes are critical tools for the design, certification, and safety analysis of nuclear reactors. However, their ability to predict fuel behavior under abnormal conditions is severely limited by their considerable reliance on empirical materials models correlated to burn-up (a measure of the number of fission events that have occurred, but not a unique measure of the history of the material). In this paper, we propose a different paradigm for fuel performance codes to employ mechanistic materials models that are based on the current state of the evolving microstructure rather than burn-up. In this approach, a series of statemore » variables are stored at material points and define the current state of the microstructure. The evolution of these state variables is defined by mechanistic models that are functions of fuel conditions and other state variables. The material properties of the fuel and cladding are determined from microstructure/property relationships that are functions of the state variables and the current fuel conditions. Multiscale modeling and simulation is being used in conjunction with experimental data to inform the development of these models. Finally, this mechanistic, microstructure-based approach has the potential to provide a more predictive fuel performance capability, but will require a team of researchers to complete the required development and to validate the approach.« less

Planning for climate change: the need for mechanistic systems-based approaches to study climate change impacts on diarrheal diseases

PubMed Central

Levy, Karen; Zimmerman, Julie; Elliott, Mark; Bartram, Jamie; Carlton, Elizabeth; Clasen, Thomas; Dillingham, Rebecca; Eisenberg, Joseph; Guerrant, Richard; Lantagne, Daniele; Mihelcic, James; Nelson, Kara

2016-01-01

Increased precipitation and temperature variability as well as extreme events related to climate change are predicted to affect the availability and quality of water globally. Already heavily burdened with diarrheal diseases due to poor access to water, sanitation and hygiene facilities, communities throughout the developing world lack the adaptive capacity to sufficiently respond to the additional adversity caused by climate change. Studies suggest that diarrhea rates are positively correlated with increased temperature, and show a complex relationship with precipitation. Although climate change will likely increase rates of diarrheal diseases on average, there is a poor mechanistic understanding of the underlying disease transmission processes and substantial uncertainty surrounding current estimates. This makes it difficult to recommend appropriate adaptation strategies. We review the relevant climate-related mechanisms behind transmission of diarrheal disease pathogens and argue that systems-based mechanistic approaches incorporating human, engineered and environmental components are urgently needed. We then review successful systems-based approaches used in other environmental health fields and detail one modeling framework to predict climate change impacts on diarrheal diseases and design adaptation strategies. PMID:26799810

Barriers and Facilitators to Central Venous Catheter Insertion: A Qualitative Study.

PubMed

Cameron, Kenzie A; Cohen, Elaine R; Hertz, Joelle R; Wayne, Diane B; Mitra, Debi; Barsuk, Jeffrey H

2018-03-14

The aims of the study were to identify perceived barriers and facilitators to central venous catheter (CVC) insertion among healthcare providers and to understand the extent to which an existing Simulation-Based Mastery Learning (SBML) program may address barriers and leverage facilitators. Providers participating in a CVC insertion SBML train-the-trainer program, in addition to intensive care unit nurse managers, were purposively sampled from Veterans Administration Medical Centers located in geographically diverse areas. We conducted semistructured interviews to assess perceptions of barriers and facilitators to CVC insertion. Deidentified transcripts were analyzed using a grounded theory approach and the constant comparative method. We subsequently mapped identified barriers and facilitators to our SBML curriculum to determine whether or not the curriculum addresses these factors. We interviewed 28 providers at six Veterans Administration Medical Centers, identifying the following five overarching factors of perceived barriers to CVC insertion: (1) equipment, (2) personnel/staff, (3) setting or organizational context, (4) patient or provider, and (5) time-related barriers. Three overarching factors of facilitators emerged: (1) equipment, (2) personnel, and (3) setting or organizational context facilitators. The SBML curriculum seems to address most identified barriers, while leveraging many facilitators; building on the commonly identified facilitator of nursing staff contribution by expanding the curriculum to explicitly include nurse involvement could improve team efficiency and organizational culture of safety. Many identified facilitators (e.g., ability to use ultrasound, personnel confidence/competence) were also identified as barriers. Evidence-based SBML programs have the potential to amplify these facilitators while addressing the barriers by providing an opportunity to practice and master CVC insertion skills.

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

DTIC Science & Technology

2015-10-01

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

Mechanistic studies of 1,3-dipolar cycloadditions of bicyclic thioisomünchnones with alkenes. A computational rationale focused on donor-acceptor interactions.

PubMed

García de la Concepción, Juan; Ávalos, Martín; Cintas, Pedro; Jiménez, José L; Light, Mark E

2018-05-09

This paper describes a mechanistic study, with the interplay of experiment and theory, on the cycloadditions of a bicyclic mesoionic 1,3-dipole versus a series of representative symmetrical (1-phenyl-1H-pyrrole-2,5-dione and dimethyl maleate) and asymmetrical [(E)-(2-nitrovinyl)benzene, acrylonitrile, and but-3-en-2-one] olefinic dipolarophiles. These results allow a comparative analysis with monocyclic dipoles and open further avenues to structurally diversified heteroatom-rich rings. The unichiral version of the bicyclic dipole leads to adducts containing up to five chiral centers, whose formation proceeds with high levels of facial stereoinduction in reactions involving bulky dipolarophiles. The second and largest part of this study provides a theoretical interrogation on the pericyclic mechanism with DFT-methods [M06-2X/6-311++G(d,p)]. In order to get further mechanistic insights, we have also explored charge transfers between reaction partners using NBO analysis, which satisfactorily justifies the stereochemical outcome.

The Newtonian Mechanistic Paradigm, Special Education, and Contours of Alternatives: An Overview.

ERIC Educational Resources Information Center

Heshusius, Lous

1989-01-01

The article examines theoretical reorientations in special education away from the Newtonian mechanistic paradigm toward an emerging holistic paradigm. Recent literature is critiqued for renaming theories as paradigms, thereby providing an illusion of change while leaving fundamental mechanistic assumptions in place. (Author/DB)

Antiprotozoal Nitazoxanide Derivatives: Synthesis, Bioassays and QSAR Study Combined with Docking for Mechanistic Insight

PubMed Central

Scior, Thomas; Lozano-Aponte, Jorge; Ajmani, Subhash; Hernández-Montero, Eduardo; Chávez-Silva, Fabiola; Hernández-Núñez, Emanuel; Moo-Puc, Rosa; Fraguela-Collar, Andres; Navarrete-Vázquez, Gabriel

2015-01-01

In view of the serious health problems concerning infectious diseases in heavily populated areas, we followed the strategy of lead compound diversification to evaluate the near-by chemical space for new organic compounds. To this end, twenty derivatives of nitazoxanide (NTZ) were synthesized and tested for activity against Entamoeba histolytica parasites. To ensure drug-likeliness and activity relatedness of the new compounds, the synthetic work was assisted by a quantitative structure-activity relationships study (QSAR). Many of the inherent downsides – well-known to QSAR practitioners – we circumvented thanks to workarounds which we proposed in prior QSAR publication. To gain further mechanistic insight on a molecular level, ligand-enzyme docking simulations were carried out since NTZ is known to inhibit the protozoal pyruvate ferredoxin oxidoreductase (PFOR) enzyme as its biomolecular target. PMID:25872791

Mechanistic-empirical evaluation of the Mn/ROAD low volume road test sections.

DOT National Transportation Integrated Search

1998-05-01

The purpose of this study was to use Mn/ROAD mainline flexible pavement data to verify, refine, and modify the Illinois Department of Transportation (IDOT) Mechanistic-Empirical (M-E) based flexible pavement design procedures and concepts.

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

NASA Astrophysics Data System (ADS)

Scherr, Rachel E.; Robertson, Amy D.

2015-06-01

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

Synthesis and mechanistic studies of curcumin analog-based oximes as potential anticancer agents.

PubMed

Qin, Hua-Li; Leng, Jing; Youssif, Bahaa G M; Amjad, Muhammad Wahab; Raja, Maria Abdul Ghafoor; Hussain, Muhammad Ajaz; Hussain, Zahid; Kazmi, Syeda Naveed; Bukhari, Syed Nasir Abbas

2017-09-01

The incidence of cancer can be decreased by chemoprevention using either natural or synthetic agents. Apart from synthetic compounds, numerous natural products have exhibited promising potential to inhibit carcinogenesis in vivo. In this study, α, β-unsaturated carbonyl-based anticancer compounds were used as starting materials to synthesize new oxime analogs. The findings from the antiproliferative assay using seven different human cancer cell lines provided a clear picture of structure-activity relationship. The oxime analogs namely 7a and 8a showed strong antiproliferative activity against the cell lines. The mechanistic effects of compounds on EGFR-TK kinases and tubulin polymerization and BRAF V 600E were investigated. In addition, the efficacy of compounds in reversing the efflux-mediated resistance developed by cancer cells was also studied. The compounds 5a and 6a displayed potent activity on various targets such as BRAF V 600E and EGFR-TK kinases and also exhibited strong antiproliferative activity against different cell lines hence showing potential of multifunctional anticancer agents. © 2017 John Wiley & Sons A/S.

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

PubMed

Revell, Christopher; Somveille, Marius

2017-08-29

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

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

PubMed Central

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

2017-01-01

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

Engineering properties of resin modified pavement (RMP) for mechanistic design

NASA Astrophysics Data System (ADS)

Anderton, Gary Lee

1997-11-01

The research study described in this report focuses on determining the engineering properties of the resin modified pavement (RMP) material relating to pavement performance, and then developing a rational mechanistic design procedure to replace the current empirical design procedure. A detailed description of RMP is provided, including a review of the available literature on this relatively new pavement technology. Field evaluations of four existing and two new RMP project sites were made to assess critical failure modes and to obtain pavement samples for subsequent laboratory testing. Various engineering properties of laboratory-produced and field-recovered samples of RMP were measured and analyzed. The engineering properties evaluated included those relating to the material's stiffness, strength, thermal properties, and traffic-related properties. Comparisons of these data to typical values for asphalt concrete and portland cement concrete were made to relate the physical nature of RMP to more common pavement surfacing materials. A mechanistic design procedure was developed to determine appropriate thickness profiles of RMP, using stiffness and fatigue properties determined by this study. The design procedure is based on the U.S. Army Corps of Engineers layered elastic method for airfield flexible pavements. The WESPAVE computer program was used to demonstrate the new design procedure for a hypothetical airfield apron design. The results of the study indicated that RMP is a relatively stiff, viscoelastic pavement surfacing material with many of its strength and stiffness properties falling between those of typical asphalt concrete and portland cement concrete. The RMP's thermal and traffic-related properties indicated favorable field performance. The layered elastic design approach appeared to be a reasonable and practical method for RMP mechanistic pavement design, and this design procedure was recommended for future use and development.

The evolution of honey bee dance communication: a mechanistic perspective.

PubMed

Barron, Andrew B; Plath, Jenny Aino

2017-12-01

Honey bee dance has been intensively studied as a communication system, and yet we still know very little about the neurobiological mechanisms supporting how dances are produced and interpreted. Here, we discuss how new information on the functions of the central complex (CX) of the insect brain might shed some light on possible neural mechanisms of dance behaviour. We summarise the features of dance communication across the species of the genus Apis We then propose that neural mechanisms of orientation and spatial processing found to be supported by the CX may function in dance communication also, and that this mechanistic link could explain some specific features of the dance form. This is purely a hypothesis, but in proposing this hypothesis, and how it might be investigated, we hope to stimulate new mechanistic analyses of dance communication. © 2017. Published by The Company of Biologists Ltd.

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

EPA Science Inventory

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

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

PubMed

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

2010-11-10

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

Mechanistic model for catalytic recombination during aerobraking maneuvers

NASA Technical Reports Server (NTRS)

Willey, Ronald J.

1989-01-01

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

Specialists without spirit: limitations of the mechanistic biomedical model.

PubMed

Hewa, S; Hetherington, R W

1995-06-01

This paper examines the origin and the development of the mechanistic model of the human body and health in terms of Max Weber's theory of rationalization. It is argued that the development of Western scientific medicine is a part of the broad process of rationalization that began in sixteenth century Europe as a result of the Reformation. The development of the mechanistic view of the human body in Western medicine is consistent with the ideas of calculability, predictability, and control-the major tenets of the process of rationalization as described by Weber. In recent years, however, the limitations of the mechanistic model have been the topic of many discussions. George Engel, a leading advocate of general systems theory, is one of the leading proponents of a new medical model which includes the general quality of life, clean environment, and psychological, or spiritual stability of life. The paper concludes with consideration of the potential of Engel's proposed new model in the context of the current state of rationalization in modern industrialized society.

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

ERIC Educational Resources Information Center

Scherr, Rachel E.; Robertson, Amy D.

2015-01-01

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

Barriers and facilitators of sports in Dutch Paralympic athletes: An explorative study.

PubMed

Jaarsma, E A; Geertzen, J H B; de Jong, R; Dijkstra, P U; Dekker, R

2014-10-01

The purpose of this study was to gain insight in barriers and facilitators of sports in paralympic athletes. An online questionnaire was distributed through the Netherlands Olympic Committee and National Sports Confederation to determine personal and environmental barriers and facilitators of sports participation. The International Classification of Functioning, Disability and Health model and theory of planned behavior were used to respectively categorize the results in environmental and personal factors, and attitude, subjective norm and perceived behavioral control. Seventy-six Dutch Paralympic athletes completed the questionnaire (51% response rate). Barriers and facilitators experienced by ambulant and wheelchair athletes were compared. Most frequently mentioned personal barrier was dependency of others (22%), while most frequently mentioned environmental barrier was lack of sports facilities (30%). Wheelchair athletes mentioned more barriers (median = 3, interquartile range: 0.5-6), than ambulant athletes (median = 1.0,interquartile range:0.0-3.0, P = 0.023). One-third of the athletes did not experience any barriers. Most frequently mentioned personal facilitators to initiate sports participation were fun (78%), health (61%), and competition (53%). Most frequently mentioned environmental facilitator was social support (40%). This study indicated that barriers of sport were mostly environmental, while facilitators were usually personal factors. Attitude and subjective norm were considered the most important components for intention to participation in sports. The facilitators outweighed the barriers and kept the athletes being active in sports. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

MECHANISTIC-BASED DISINFECTION AND DISINFECTION BYPRODUCT MODELS

EPA Science Inventory

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

Reduction of Carbon Dioxide by a Molybdenum-Containing Formate Dehydrogenase: A Kinetic and Mechanistic Study.

PubMed

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.

Mechanistic investigation of the formation of H2 from HCOOH with a dinuclear Ru model complex for formate hydrogen lyase.

PubMed

Tokunaga, Taisuke; Yatabe, Takeshi; Matsumoto, Takahiro; Ando, Tatsuya; Yoon, Ki-Seok; Ogo, Seiji

2017-01-01

We report the mechanistic investigation of catalytic H 2 evolution from formic acid in water using a formate-bridged dinuclear Ru complex as a formate hydrogen lyase model. The mechanistic study is based on isotope-labeling experiments involving hydrogen isotope exchange reaction.

Mechanistic Studies in Friction and Wear of Bulk Materials

NASA Astrophysics Data System (ADS)

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

2014-07-01

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

Planning for climate change: The need for mechanistic systems-based approaches to study climate change impacts on diarrheal diseases.

PubMed

Mellor, Jonathan E; Levy, Karen; Zimmerman, Julie; Elliott, Mark; Bartram, Jamie; Carlton, Elizabeth; Clasen, Thomas; Dillingham, Rebecca; Eisenberg, Joseph; Guerrant, Richard; Lantagne, Daniele; Mihelcic, James; Nelson, Kara

2016-04-01

Increased precipitation and temperature variability as well as extreme events related to climate change are predicted to affect the availability and quality of water globally. Already heavily burdened with diarrheal diseases due to poor access to water, sanitation and hygiene facilities, communities throughout the developing world lack the adaptive capacity to sufficiently respond to the additional adversity caused by climate change. Studies suggest that diarrhea rates are positively correlated with increased temperature, and show a complex relationship with precipitation. Although climate change will likely increase rates of diarrheal diseases on average, there is a poor mechanistic understanding of the underlying disease transmission processes and substantial uncertainty surrounding current estimates. This makes it difficult to recommend appropriate adaptation strategies. We review the relevant climate-related mechanisms behind transmission of diarrheal disease pathogens and argue that systems-based mechanistic approaches incorporating human, engineered and environmental components are urgently needed. We then review successful systems-based approaches used in other environmental health fields and detail one modeling framework to predict climate change impacts on diarrheal diseases and design adaptation strategies. Copyright © 2016 Elsevier B.V. All rights reserved.

Comparison of mechanistic transport cycle models of ABC exporters.

PubMed

Szöllősi, Dániel; Rose-Sperling, Dania; Hellmich, Ute A; Stockner, Thomas

2018-04-01

ABC (ATP binding cassette) transporters, ubiquitous in all kingdoms of life, carry out essential substrate transport reactions across cell membranes. Their transmembrane domains bind and translocate substrates and are connected to a pair of nucleotide binding domains, which bind and hydrolyze ATP to energize import or export of substrates. Over four decades of investigations into ABC transporters have revealed numerous details from atomic-level structural insights to their functional and physiological roles. Despite all these advances, a comprehensive understanding of the mechanistic principles of ABC transporter function remains elusive. The human multidrug resistance transporter ABCB1, also referred to as P-glycoprotein (P-gp), is one of the most intensively studied ABC exporters. Using ABCB1 as the reference point, we aim to compare the dominating mechanistic models of substrate transport and ATP hydrolysis for ABC exporters and to highlight the experimental and computational evidence in their support. In particular, we point out in silico studies that enhance and complement available biochemical data. "This article is part of a Special Issue entitled: Beyond the Structure-Function Horizon of Membrane Proteins edited by Ute Hellmich, Rupak Doshi and Benjamin McIlwain." Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Exploring Organic Mechanistic Puzzles with Molecular Modeling

ERIC Educational Resources Information Center

Horowitz, Gail; Schwartz, Gary

2004-01-01

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

Copper-free asymmetric allylic alkylation with a Grignard reagent: design of the ligand and mechanistic studies.

PubMed

Grassi, David; Dolka, Chrysanthi; Jackowski, Olivier; Alexakis, Alexandre

2013-01-21

The Cu-free asymmetric allylic alkylation, catalysed by NHC, with Grignard reagents is reported on allyl bromide derivatives with good results. The enantioselectivity was quite homogeneous (around 85% ee) on large and various substrates, regardless of the nature of the Grignard reagent. The formation of stereogenic quaternary centres was highly regioselective for both aliphatic and aromatic derivatives with good enantiomeric excess (up to 92% ee). The methodology developed was found to be complementary with the Cu-catalysed version. Several new NHCs were tested with improved efficiency. In addition, mechanistic studies, using NMR spectroscopy, led to the discovery of the catalytically active species. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Computational Glycobiology: Mechanistic Studies of Carbohydrate-Active Enzymes and Implication for Inhibitor Design.

PubMed

Montgomery, Andrew P; Xiao, Kela; Wang, Xingyong; Skropeta, Danielle; Yu, Haibo

2017-01-01

Carbohydrate-active enzymes (CAZymes) are families of essential and structurally related enzymes, which catalyze the creation, modification, and degradation of glycosidic bonds in carbohydrates to maintain essentially all kingdoms of life. CAZymes play a key role in many biological processes underpinning human health and diseases (e.g., cancer, diabetes, Alzheimer's diseases, AIDS) and have thus emerged as important drug targets in the fight against pathogenesis. The realization of the full potential of CAZymes remains a significant challenge, relying on a deeper understanding of the molecular mechanisms of catalysis. Considering numerous unsettled questions in the literature, while with a large amount of structural, kinetic, and mutagenesis data available for CAZymes, there is a pressing need and an abundant opportunity for collaborative computational and experimental investigations with the aim to unlock the secrets of CAZyme catalysis at an atomic level. In this review, we briefly survey key methodology development in computational studies of CAZyme catalysis. This is complemented by selected case studies highlighting mechanistic insights provided by computational glycobiology. Implication for inhibitor design by mimicking the transition state is also illustrated for both glycoside hydrolases and glycosyltransferases. The challenges for such studies will be noted and finally an outlook for future directions will be provided. © 2017 Elsevier Inc. All rights reserved.

Leucine facilitates the insulin-stimulated glucose uptake and insulin signaling in skeletal muscle cells: involving mTORC1 and mTORC2.

PubMed

Liu, Hui; Liu, Rui; Xiong, Yufang; Li, Xiang; Wang, Xiaolei; Ma, Yan; Guo, Huailan; Hao, Liping; Yao, Ping; Liu, Liegang; Wang, Di; Yang, Xuefeng

2014-08-01

Leucine, a branched-chain amino acid, has been shown to promote glucose uptake and increase insulin sensitivity in skeletal muscle, but the exact mechanism remains unestablished. We addressed this issue in cultured skeletal muscle cells in this study. Our results showed that leucine alone did not have an effect on glucose uptake or phosphorylation of protein kinase B (AKT), but facilitated the insulin-induced glucose uptake and AKT phosphorylation. The insulin-stimulated glucose uptake and AKT phosphorylation were inhibited by the phosphatidylinositol 3-kinase inhibitor, wortmannin, but the inhibition was partially reversed by leucine. The inhibitor of mammalian target of rapamycin complex 1 (mTORC1), rapamycin, had no effect on the insulin-stimulated glucose uptake, but eliminated the facilitating effect of leucine in the insulin-stimulated glucose uptake and AKT phosphorylation. In addition, leucine facilitation of the insulin-induced AKT phosphorylation was neutralized by knocking down the core component of the mammalian target of rapamycin complex 2 (mTORC2) with specific siRNA. Together, these findings show that leucine can facilitate the insulin-induced insulin signaling and glucose uptake in skeletal muscle cells through both mTORC1 and mTORC2, implicating the potential importance of this amino acid in glucose homeostasis and providing new mechanistic insights.

Food for Thought ... Mechanistic Validation

PubMed Central

Hartung, Thomas; Hoffmann, Sebastian; Stephens, Martin

2013-01-01

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

In-situ DRIFTS measurements for the mechanistic study of NO oxidation over a commercial Cu-CHA catalyst

DOE PAGES

Ruggeri, Maria Pia; Nova, Isabella; Tronconi, Enrico; ...

2014-11-03

We report a mechanistic DRIFTS in-situ study of NO 2, NO + O 2 and NO adsorption on a commercial Cu-CHA catalyst for NH 3-SCR of NO x. Both pre-reduced and pre-oxidized catalyst samples were investigated with the aim of clarifying mechanistic aspects of the NO oxidation to NO 2 as a preliminary step towards the study of the Standard SCR reaction mechanism at low temperatures. Nitrosonium cations (NO +, N formal oxidation state = +3) were identified as key surface intermediates in the process of NO (+2) oxidation to NO 2 (+4) and nitrates (+5). While NO + andmore » nitrates were formed simultaneously upon catalyst exposure to NO 2, nitrates evolved consecutively to NO + when the catalyst was exposed to NO + O 2, suggesting that nitrite-like species, and not NO 2, are formed as the primary products of the NO oxidative activation over Cu-CHA. Upon catalyst exposure to NO only, i.e. in the absence of gaseous O 2, NO + and then nitrates were formed on a pre-oxidized sample but not on a pre-reduced one, which demonstrates the red-ox nature of the NO oxidation mechanism. The negative effect of H 2O on NO + and nitrates formation was also clearly established. Assuming Cu dimers as the active sites for NO oxidation to NO 2, we propose a mechanism which reconciles all the experimental observations. Specifically, we show that such a mechanism also explains the observed kinetic effects of H 2O, O 2 and NO 2 on the NO oxidation activity of the investigated Cu zeolite catalyst.« less

Non-directed aromatic C–H amination: catalytic and mechanistic studies enabled by Pd catalyst and reagent design†

PubMed Central

Bandara, H. M. D.; Jin, D.; Mantell, M. A.; Field, K. D.; Wang, A.; Narayanan, R. P.; Deskins, N. A.; Emmert, M. H.

2016-01-01

This manuscript describes the systematic development of pyridine-type ligands, which promote the Pd catalyzed, non-directed amination of benzene in combination with novel, hydroxylamine-based electrophilic amination reagents. DFT calculations and mechanistic experiments provide insights into the factors influencing the arene C–H amination protocol. PMID:28066540

The Ca2+-ATPase pump facilitates bidirectional proton transport across the sarco/endoplasmic reticulum.

PubMed

Espinoza-Fonseca, L Michel

2017-03-28

Ca 2+ transport across the sarco/endoplasmic reticulum (SR) plays an essential role in intracellular Ca 2+ homeostasis, signalling, cell differentiation and muscle contractility. During SR Ca 2+ uptake and release, proton fluxes are required to balance the charge deficit generated by the exchange of Ca 2+ and other ions across the SR. During Ca 2+ uptake by the SR Ca 2+ -ATPase (SERCA), two protons are countertransported from the SR lumen to the cytosol, thus partially compensating for the charge moved by Ca 2+ transport. Studies have shown that protons are also transported from the cytosol to the lumen during Ca 2+ release, but a transporter that facilitates proton transport into the SR lumen has not been described. In this article we propose that SERCA forms pores that facilitate bidirectional proton transport across the SR. We describe the location and structure of water-filled pores in SERCA that form cytosolic and luminal pathways for protons to cross the SR membrane. Based on this structural information, we suggest mechanistic models for proton translocation to the cytosol during active Ca 2+ transport, and into the SR lumen during SERCA inhibition by endogenous regulatory proteins. Finally, we discuss the physiological consequences of SERCA-mediated bidirectional proton transport across the SR membrane of muscle and non-muscle cells.

Profiling Adult Literacy Facilitators in Development Contexts: An Ethnographic Study in Ethiopia

ERIC Educational Resources Information Center

Warkineh, Turuwark Zalalam; Rogers, Alan; Danki, Tolera Negassa

2018-01-01

Teachers/facilitators in adult literacy learning programmes are recognised as being vital to successful learning outcomes. But little is known about them as a group. This small-scale research project comprising ethnographic-style case studies of five adult literacy facilitators (ALFs) in Ethiopia seeks to throw some light on these teachers, their…

A mechanistic physicochemical model of carbon dioxide transport in blood.

PubMed

O'Neill, David P; Robbins, Peter A

2017-02-01

A number of mathematical models have been produced that, given the Pco 2 and Po 2 of blood, will calculate the total concentrations for CO 2 and O 2 in blood. However, all these models contain at least some empirical features, and thus do not represent all of the underlying physicochemical processes in an entirely mechanistic manner. The aim of this study was to develop a physicochemical model of CO 2 carriage by the blood to determine whether our understanding of the physical chemistry of the major chemical components of blood together with their interactions is sufficiently strong to predict the physiological properties of CO 2 carriage by whole blood. Standard values are used for the ionic composition of the blood, the plasma albumin concentration, and the hemoglobin concentration. All K m values required for the model are taken from the literature. The distribution of bicarbonate, chloride, and H + ions across the red blood cell membrane follows that of a Gibbs-Donnan equilibrium. The system of equations that results is solved numerically using constraints for mass balance and electroneutrality. The model reproduces the phenomena associated with CO 2 carriage, including the magnitude of the Haldane effect, very well. The structural nature of the model allows various hypothetical scenarios to be explored. Here we examine the effects of 1) removing the ability of hemoglobin to form carbamino compounds; 2) allowing a degree of Cl - binding to deoxygenated hemoglobin; and 3) removing the chloride (Hamburger) shift. The insights gained could not have been obtained from empirical models. This study is the first to incorporate a mechanistic model of chloride-bicarbonate exchange between the erythrocyte and plasma into a full physicochemical model of the carriage of carbon dioxide in blood. The mechanistic nature of the model allowed a theoretical study of the quantitative significance for carbon dioxide transport of carbamino compound formation; the putative binding

A mechanistic physicochemical model of carbon dioxide transport in blood

PubMed Central

O’Neill, David P.

2017-01-01

A number of mathematical models have been produced that, given the Pco2 and Po2 of blood, will calculate the total concentrations for CO2 and O2 in blood. However, all these models contain at least some empirical features, and thus do not represent all of the underlying physicochemical processes in an entirely mechanistic manner. The aim of this study was to develop a physicochemical model of CO2 carriage by the blood to determine whether our understanding of the physical chemistry of the major chemical components of blood together with their interactions is sufficiently strong to predict the physiological properties of CO2 carriage by whole blood. Standard values are used for the ionic composition of the blood, the plasma albumin concentration, and the hemoglobin concentration. All Km values required for the model are taken from the literature. The distribution of bicarbonate, chloride, and H+ ions across the red blood cell membrane follows that of a Gibbs-Donnan equilibrium. The system of equations that results is solved numerically using constraints for mass balance and electroneutrality. The model reproduces the phenomena associated with CO2 carriage, including the magnitude of the Haldane effect, very well. The structural nature of the model allows various hypothetical scenarios to be explored. Here we examine the effects of 1) removing the ability of hemoglobin to form carbamino compounds; 2) allowing a degree of Cl− binding to deoxygenated hemoglobin; and 3) removing the chloride (Hamburger) shift. The insights gained could not have been obtained from empirical models. NEW & NOTEWORTHY This study is the first to incorporate a mechanistic model of chloride-bicarbonate exchange between the erythrocyte and plasma into a full physicochemical model of the carriage of carbon dioxide in blood. The mechanistic nature of the model allowed a theoretical study of the quantitative significance for carbon dioxide transport of carbamino compound formation; the putative

Atopic Dermatitis According to GARP: New Mechanistic Insights in Disease Pathogenesis.

PubMed

Nousbeck, Janna; Irvine, Alan D

2016-12-01

In complex disease such as atopic dermatitis, the journey from identification of strong risk loci to profound functional and mechanistic insights can take several years. Here, Manz et al. have elegantly deciphered the mechanistic pathways in the well-established 11q13.5 atopic dermatitis risk locus. Their genetic and functional insights emphasize a role for T regulatory cells in atopic dermatitis pathogenesis. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

In Situ, Time-Resolved, and Mechanistic Studies of Metal–Organic Framework Nucleation and Growth

DOE Office of Scientific and Technical Information (OSTI.GOV)

Van Vleet, Mary J.; Weng, Tingting; Li, Xinyi

The vast chemical and structural diversity of metal–organic frameworks (MOFs) opens up the exciting possibility of “crystal engineering” MOFs tailored for particular catalytic or separation applications. Yet the process of reaction discovery, optimization, and scale-up of MOF synthesis remains extremely challenging, presenting significant obstacles to the synthetic realization of many otherwise promising MOF structures. Recently, significant new insights into the fundamental processes governing MOF nucleation and growth, as well as the relationship between reaction parameters and synthetic outcome, have been derived using powerful in situ, time-resolved and/or mechanistic studies of MOF crystallization. This Review provides a summary and associated criticalmore » analysis of the results of these and other related “direct” studies of MOF nucleation and growth, with a particular emphasis on the recent advances in instrument technologies that have enabled such studies and on the major hypotheses, theories, and models that have been used to explain MOF formation. We conclude with a summary of the major insights that have been gained from the work summarized in this Review, outlining our own perspective on potential fruitful new directions for investigation.« less

In Situ, Time-Resolved, and Mechanistic Studies of Metal–Organic Framework Nucleation and Growth

DOE PAGES

Van Vleet, Mary J.; Weng, Tingting; Li, Xinyi; ...

2018-03-07

The vast chemical and structural diversity of metal–organic frameworks (MOFs) opens up the exciting possibility of “crystal engineering” MOFs tailored for particular catalytic or separation applications. Yet the process of reaction discovery, optimization, and scale-up of MOF synthesis remains extremely challenging, presenting significant obstacles to the synthetic realization of many otherwise promising MOF structures. Recently, significant new insights into the fundamental processes governing MOF nucleation and growth, as well as the relationship between reaction parameters and synthetic outcome, have been derived using powerful in situ, time-resolved and/or mechanistic studies of MOF crystallization. This Review provides a summary and associated criticalmore » analysis of the results of these and other related “direct” studies of MOF nucleation and growth, with a particular emphasis on the recent advances in instrument technologies that have enabled such studies and on the major hypotheses, theories, and models that have been used to explain MOF formation. We conclude with a summary of the major insights that have been gained from the work summarized in this Review, outlining our own perspective on potential fruitful new directions for investigation.« less

Following a natural experiment of guideline adaptation and early implementation: a mixed-methods study of facilitation

PubMed Central

2012-01-01

Background Facilitation is emerging as an important strategy in the uptake of evidence. However, it is not entirely clear from a practical perspective how facilitation occurs to help move research evidence into nursing practice. The Canadian Partnership Against Cancer, also known as the 'Partnership,' is a Pan-Canadian initiative supporting knowledge translation activity for improved care through guideline use. In this case-series study, five self-identified groups volunteered to use a systematic methodology to adapt existing clinical practice guidelines for Canadian use. With 'Partnership' support, local and external facilitators provided assistance for groups to begin the process by adapting the guidelines and planning for implementation. Methods To gain a more comprehensive understanding of the nature of facilitation, we conducted a mixed-methods study. Specifically, we examined the role and skills of individuals actively engaged in facilitation as well as the actual facilitation activities occurring within the 'Partnership.' The study was driven by and builds upon a focused literature review published in 2010 that examined facilitation as a role and process in achieving evidence-based practice in nursing. An audit tool outlining 46 discrete facilitation activities based on results of this review was used to examine the facilitation noted in the documents (emails, meeting minutes, field notes) of three nursing-related cases participating in the 'Partnership' case-series study. To further examine the concept, six facilitators were interviewed about their practical experiences. The case-audit data were analyzed through a simple content analysis and triangulated with participant responses from the focus group interview to understand what occurred as these cases undertook guideline adaptation. Results The analysis of the three cases revealed that almost all of the 46 discrete, practical facilitation activities from the literature were evidenced. Additionally, case

A mechanistic model to study the thermal ecology of a southeastern pacific dominant intertidal mussel and implications for climate change.

PubMed

Finke, G R; Bozinovic, F; Navarrete, S A

2009-01-01

Developing mechanistic models to predict an organism's body temperature facilitates the study of physiological stresses caused by extreme climatic conditions the species might have faced in the past or making predictions about changes to come in the near future. Because the models combine empirical observation of different climatic variables with essential morphological attributes of the species, it is possible to examine specific aspects of predicted climatic changes. Here, we develop a model for the competitively dominant intertidal mussel Perumytilus purpuratus that estimates body temperature on the basis of meteorological and tidal data with an average difference (+/-SE) of 0.410 degrees +/- 0.0315 degrees C in comparison with a field-deployed temperature logger. Modeled body temperatures of P. purpuratus in central Chile regularly exceeded 30 degrees C in summer months, and values as high as 38 degrees C were found. These results suggest that the temperatures reached by mussels in the intertidal zone in central Chile are not sufficiently high to induce significant mortality on adults of this species; however, because body temperatures >40 degrees C can be lethal for this species, sublethal effects on physiological performance warrant further investigation. Body temperatures of mussels increased sigmoidally with increasing tidal height. Body temperatures of individuals from approximately 70% of the tidal range leveled off and did not increase any further with increasing tidal height. Finally, body size played an important role in determining body temperature. A hypothetical 5-cm-long mussel (only 1 cm longer than mussels found in nature) did reach potentially lethal body temperatures, suggesting that the biophysical environment may play a role in limiting the size of this small species.

A holistic approach to anesthesia-induced neurotoxicity and its implications for future mechanistic studies.

PubMed

Zanghi, Christine N; Jevtovic-Todorovic, Vesna

The year 2016 marked the 15th anniversary since anesthesia-induced developmental neurotoxicity and its resulting cognitive dysfunction were first described. Since that time, multiple scientific studies have supported these original findings and investigated possible mechanisms behind anesthesia-induced neurotoxicity. This paper reviews the existing mechanistic literature on anesthesia-induced neurotoxicity in the context of a holistic approach that emphasizes the importance of both neuronal and non-neuronal cells during early postnatal development. Sections are divided into key stages in early neural development; apoptosis, neurogenesis, migration, differentiation, synaptogenesis, gliogenesis, myelination and blood brain barrier/cerebrovasculature. In addition, the authors combine the established literature in the field of anesthesia-induced neurotoxicity with literature from other related scientific fields to speculate on the potential role of non-neuronal cells and to generate new future hypotheses for understanding anesthetic toxicity and its application to the practice of pediatric anesthesia. Copyright © 2017 Elsevier Inc. All rights reserved.

MECHANISTIC AND SOURCE UNDERSTANDING OF PCDD/F FORMATION

EPA Science Inventory

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

A Case Study: Follow-Up Assessment of Facilitated Communication.

ERIC Educational Resources Information Center

Simon, Elliott W.; And Others

1996-01-01

This study of an adolescent with multiple disabilities, including moderate mental retardation, who was reported to engage in validated facilitated communication (FC) found he did not engage in validated FC; performance was equivalent whether food or nonfood reinforcers were used; and the Picture Exchange Communication System was a valid and…

Mechanistic Studies on the Triggered Release of Liposomal Contents by Matrix Metalloproteinase-9

PubMed Central

Elegbede, Adekunle I.; Banerjee, Jayati; Hanson, Andrea J.; Tobwala, Shakila; Ganguli, Bratati; Wang, Rongying; Lu, Xiaoning; Srivastava, D. K.; Mallik, Sanku

2009-01-01

Matrix metalloproteinases (MMPs) are a class of extracellular matrix degrading enzymes over-expressed in many cancers and contribute to the metastatic ability of the cancer cells. We have recently demonstrated that liposomal contents can be released when triggered by the enzyme MMP-9. Herein, we report our results on the mechanistic studies of the MMP-9 triggered release of the liposomal contents. We synthesized peptides containing the cleavage site for MMP-9 and conjugated them with fatty acids to prepare the corresponding lipopeptides. By employing Circular Dichroism spectroscopy, we demonstrate that the lipopeptides, when incorporated in liposomes, are de-mixed in the lipid bilayers and generate triple helical structures. MMP-9 cleaves the triple helical peptides, leading to the release of the liposomal contents. Other MMPs, which cannot hydrolyze triple helical peptides, failed to release the contents from the liposomes. We also observed that the rate and the extent of release of the liposomal contents depend on the mismatch between acyl chains of the synthesized lipopeptide and phospholipid components of the liposomes. Circular Dichroism spectroscopic studies imply that the observed differences in the release reflect the ability of the liposomal membrane to anneal the defects following the enzymatic cleavage of the liposome-incorporated lipopeptides. PMID:18642903

Indole-3- carbinol enhances sorafenib cytotoxicity in hepatocellular carcinoma cells: A mechanistic study.

PubMed

Abdelmageed, Mai M; El-Naga, Reem N; El-Demerdash, Ebtehal; Elmazar, Mohamed M

2016-09-09

Sorafenib is the only chemotherapeutic agent currently approved for unresectable hepatocellular carcinoma (HCC). However, poor response rates have been widely reported. Indole-3-carbinol (I3C) is a potential chemopreventive phytochemical. The present study aimed to explore the potential chemomodulatory effects of I3C on sorafenib in HCC cells as well as the possible underlying mechanisms. I3C exhibited a greater cytotoxicity in HepG2 cells compared to Huh-7 cells (p < 0.0001). Moreover, the co-treatment of HepG2 cells with I3C and sorafenib was more effective (p = 0.002). Accordingly, subsequent mechanistic studies were carried on HepG2 cells. The results show that the ability of I3C to enhance sorafenib cytotoxicity in HCC cells could be partially attributed to increasing the apoptotic activity and decreasing the angiogenic potentials. The combination had a negative effect on epithelial-mesenchymal transition (EMT). Increased NOX-1 expression was also observed which may indicate the involvement of NOX-1 in I3C chemomodulatory effects. Additionally, the combination induced cell cycle arrest at the G0/G1 phase. In conclusion, these findings provide evidence that I3C enhances sorafenib anti-cancer activity in HCC cells.

Indole-3- carbinol enhances sorafenib cytotoxicity in hepatocellular carcinoma cells: A mechanistic study

PubMed Central

Abdelmageed, Mai M.; El-Naga, Reem N.; El-Demerdash, Ebtehal; Elmazar, Mohamed M.

2016-01-01

Sorafenib is the only chemotherapeutic agent currently approved for unresectable hepatocellular carcinoma (HCC). However, poor response rates have been widely reported. Indole-3-carbinol (I3C) is a potential chemopreventive phytochemical. The present study aimed to explore the potential chemomodulatory effects of I3C on sorafenib in HCC cells as well as the possible underlying mechanisms. I3C exhibited a greater cytotoxicity in HepG2 cells compared to Huh-7 cells (p < 0.0001). Moreover, the co-treatment of HepG2 cells with I3C and sorafenib was more effective (p = 0.002). Accordingly, subsequent mechanistic studies were carried on HepG2 cells. The results show that the ability of I3C to enhance sorafenib cytotoxicity in HCC cells could be partially attributed to increasing the apoptotic activity and decreasing the angiogenic potentials. The combination had a negative effect on epithelial-mesenchymal transition (EMT). Increased NOX-1 expression was also observed which may indicate the involvement of NOX-1 in I3C chemomodulatory effects. Additionally, the combination induced cell cycle arrest at the G0/G1 phase. In conclusion, these findings provide evidence that I3C enhances sorafenib anti-cancer activity in HCC cells. PMID:27612096

Pain facilitation and pain inhibition during conditioned pain modulation in fibromyalgia and in healthy controls.

PubMed

Potvin, Stéphane; Marchand, Serge

2016-08-01

Although fibromyalgia (FM) is associated with a deficit in inhibitory conditioned pain modulation (CPM), the discriminative power of CPM procedures is unknown. Moreover, the high intersubject heterogeneity in CPM responses in FM raises the possibility that a sizeable subgroup of these patients may experience pain facilitation during CPM, but the phenomenon has not been explicitly studied. To address these issues, 96 patients with FM and 71 healthy controls were recruited. Thermal stimuli were used to measure pain thresholds. Pain inhibition was elicited using a tonic thermal test (Peltier thermode) administered before and after activation of CPM mechanisms using a cold pressor test. Thermal pain thresholds were lower in patients with FM than in healthy controls. Pain ratings during the cold pressor test were higher in patients with FM, relative to controls. The CPM inhibitory efficacy was lower in patients with FM than in controls. The CPM procedure had good specificity (78.9%) but low sensitivity (45.7%), whereas a composite pain index had good sensitivity (75.0%) and specificity (78.9%). Finally, the rate of patients with FM who reported pain facilitation during the CPM procedure was found to be significantly increased compared with that of controls (41.7% vs 21.2%). The good discriminative power of the composite pain index highlights the need for further validation studies using mechanistically relevant psychophysical procedures in FM. The low sensitivity of the CPM procedure, combined with the large proportion of patients with FM experiencing pain facilitation during CPM, strongly suggests that endogenous pain inhibition mechanisms are deeply impaired in patients with FM, but only in a subgroup of them.

Characterization of truck traffic in Michigan for the new mechanistic empirical pavement design guide.

DOT National Transportation Integrated Search

2009-12-01

The purpose of this study is to characterize traffic inputs in support of the new Mechanistic- : Empirical Pavement Design Guide (M-E PDG) for the state of Michigan. These traffic : characteristics include monthly distribution factors (MDF), hourly d...

Discovery and Mechanistic Study of Benzamide Derivatives That Modulate Hepatitis B Virus Capsid Assembly.

PubMed

Wu, Shuo; Zhao, Qiong; Zhang, Pinghu; Kulp, John; Hu, Lydia; Hwang, Nicky; Zhang, Jiming; Block, Timothy M; Xu, Xiaodong; Du, Yanming; Chang, Jinhong; Guo, Ju-Tao

2017-08-15

Chronic hepatitis B virus (HBV) infection is a global public health problem. Although the currently approved medications can reliably reduce the viral load and prevent the progression of liver diseases, they fail to cure the viral infection. In an effort toward discovery of novel antiviral agents against HBV, a group of benzamide (BA) derivatives that significantly reduced the amount of cytoplasmic HBV DNA were discovered. The initial lead optimization efforts identified two BA derivatives with improved antiviral activity for further mechanistic studies. Interestingly, similar to our previously reported sulfamoylbenzamides (SBAs), the BAs promote the formation of empty capsids through specific interaction with HBV core protein but not other viral and host cellular components. Genetic evidence suggested that both SBAs and BAs inhibited HBV nucleocapsid assembly by binding to the heteroaryldihydropyrimidine (HAP) pocket between core protein dimer-dimer interfaces. However, unlike SBAs, BA compounds uniquely induced the formation of empty capsids that migrated more slowly in native agarose gel electrophoresis from A36V mutant than from the wild-type core protein. Moreover, we showed that the assembly of chimeric capsids from wild-type and drug-resistant core proteins was susceptible to multiple capsid assembly modulators. Hence, HBV core protein is a dominant antiviral target that may suppress the selection of drug-resistant viruses during core protein-targeting antiviral therapy. Our studies thus indicate that BAs are a chemically and mechanistically unique type of HBV capsid assembly modulators and warranted for further development as antiviral agents against HBV. IMPORTANCE HBV core protein plays essential roles in many steps of the viral replication cycle. In addition to packaging viral pregenomic RNA (pgRNA) and DNA polymerase complex into nucleocapsids for reverse transcriptional DNA replication to take place, the core protein dimers, existing in several

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

NASA Astrophysics Data System (ADS)

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

2003-03-01

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

Experiences of practice facilitators working on the Improved Delivery of Cardiovascular Care project: Retrospective case study.

PubMed

Liddy, Clare; Rowan, Margo; Valiquette-Tessier, Sophie-Claire; Drosinis, Paul; Crowe, Lois; Hogg, William

2018-01-01

To examine the barriers to and facilitators of practice facilitation experienced by participants in the Improving Delivery of Cardiovascular Care (IDOCC) project. Case studies of practice facilitators' narrative reports. Eastern Ontario. Primary care practices that participated in the IDOCC project. Cases were identified by calculating sum scores in order to determine practices' performance relative to their peers. Two case exemplars were selected that scored within ± 1 SD of the total mean score, and a qualitative analysis of practice facilitators' narrative reports was conducted using a 5-factor implementation framework to identify barriers and facilitators. Narratives were divided into 3 phases: planning, implementation, and sustainability. Barriers and facilitators fluctuated over the intervention's 3 phases. Site A reported more barriers (n = 47) than facilitators (n = 38), while site B reported a roughly equal number of barriers (n = 144) and facilitators (n = 136). In both sites, the most common barriers involved organizational and provider factors and the most common facilitators were associated with innovation and structural factors. Both practices encountered various barriers and facilitators throughout the IDOCC's 3 phases. The case studies reveal the complex interactions of these factors over time, and provide insight into the implementation of practice facilitation programs. Copyright© the College of Family Physicians of Canada.

Getting the Words Out: Case Studies in Facilitated Communication Training.

ERIC Educational Resources Information Center

Crossley, Rosemary

1992-01-01

Case studies are presented of three individuals with severe communication impairments who had been judged to be intellectually impaired but revealed unexpected achievements after training in nonspeech communication. The communication training used facilitation to circumvent hand function impairments. (JDD)

Facilitated versus Non-Facilitated Online Case Discussions: Comparing Differences in Problem Space Coverage

ERIC Educational Resources Information Center

Ertmer, Peggy A.; Koehler, Adrie A.

2015-01-01

The facilitator plays a key role in guiding students' efforts during case discussions. However, few studies have compared differences in learning outcomes for students participating in facilitated versus non-facilitated discussions. In this research, we used "problem space coverage" as a learning measure to compare outcomes between…

Calibrating the mechanistic-empirical pavement design guide for Kansas.

DOT National Transportation Integrated Search

2015-04-01

The Kansas Department of Transportation (KDOT) is moving toward the implementation of the new American : Association of State Highway and Transportation Officials (AASHTO) Mechanistic-Empirical Pavement Design Guide (MEPDG) : for pavement design. The...

Lateralization in motor facilitation during action observation: a TMS study.

PubMed

Aziz-Zadeh, Lisa; Maeda, Fumiko; Zaidel, Eran; Mazziotta, John; Iacoboni, Marco

2002-05-01

Action observation facilitates corticospinal excitability. This is presumably due to a premotor neural system that is active when we perform actions and when we observe actions performed by others. It has been speculated that this neural system is a precursor of neural systems subserving language. If this theory is true, we may expect hemispheric differences in the motor facilitation produced by action observation, with the language-dominant left hemisphere showing stronger facilitation than the right hemisphere. Furthermore, it has been suggested that body parts are recognized via cortical regions controlling sensory and motor processing associated with that body part. If this is true, then corticospinal facilitation during action observation should be modulated by the laterality of the observed body part. The present study addressed these two issues using TMS for each motor cortex separately as participants observed actions being performed by a left hand, a right hand, or a control stimulus on the computer screen. We found no overall difference between the right and left hemisphere for motor-evoked potential (MEP) size during action observation. However, when TMS was applied to the left motor cortex, MEPs were larger while observing right hand actions. Likewise, when TMS was applied to the right motor cortex, MEPs were larger while observing left hand actions. Our data do not suggest left hemisphere superiority in the facilitating effects of action observation on the motor system. However, they do support the notion of a sensory-motor loop according to which sensory stimulus properties (for example, the image of a left hand or a right hand) directly affect motor cortex activity, even when no motor output is required. The pattern of this effect is congruent with the pattern of motor representation in each hemisphere.

Facilitating an L2 Book Club: A Conversation-Analytic Study of Task Management

ERIC Educational Resources Information Center

Ro, Eunseok

2018-01-01

This study employs conversation analysis to examine a facilitator's interactional practices in the post-expansion phase of students' presentations in the context of a book club for second language learning. The analysis shows how the facilitator establishes intersubjectivity with regard to the ongoing task and manages students' task performance.…

Nonspecific immunomodulators for recurrent respiratory tract infections, wheezing and asthma in children: a systematic review of mechanistic and clinical evidence.

PubMed

Esposito, Susanna; Soto-Martinez, Manuel E; Feleszko, Wojciech; Jones, Marcus H; Shen, Kun-Ling; Schaad, Urs B

2018-06-01

To provide an overview of the mechanistic and clinical evidence for the use of nonspecific immunomodulators in paediatric respiratory tract infection (RTI) and wheezing/asthma prophylaxis. Nonspecific immunomodulators have a long history of empirical use for the prevention of RTIs in vulnerable populations, such as children. The past decade has seen an increase in both the number and quality of studies providing mechanistic and clinical evidence for the prophylactic potential of nonspecific immunomodulators against both respiratory infections and wheezing/asthma in the paediatric population. Orally administered immunomodulators result in the mounting of innate and adaptive immune responses to infection in the respiratory mucosa and anti-inflammatory effects in proinflammatory environments. Clinical data reflect these mechanistic effects in reductions in the recurrence of respiratory infections and wheezing events in high-risk paediatric populations. A new generation of clinical studies is currently underway with the power to position the nonspecific bacterial lysate immunomodulator OM-85 as a potential antiasthma prophylactic. An established mechanistic and clinical role for prophylaxis against paediatric respiratory infections by nonspecific immunomodulators exists. Clinical trials underway promise to provide high-quality data to establish whether a similar role exists in wheezing/asthma prevention.

Mechanistic-empirical pavement design guide calibration for pavement rehabilitation.

DOT National Transportation Integrated Search

2013-01-01

The Oregon Department of Transportation (ODOT) is in the process of implementing the recently introduced AASHTO : Mechanistic-Empirical Pavement Design Guide (MEPDG) for new pavement sections. The majority of pavement work : conducted by ODOT involve...

Draft user's guide for UDOT mechanistic-empirical pavement design.

DOT National Transportation Integrated Search

2009-10-01

Validation of the new AASHTO Mechanistic-Empirical Pavement Design Guides (MEPDG) nationally calibrated pavement distress and smoothness prediction models when applied under Utah conditions, and local calibration of the new hot-mix asphalt (HMA) p...

Latent memory facilitates relearning through molecular signaling mechanisms that are distinct from original learning.

PubMed

Menges, Steven A; Riepe, Joshua R; Philips, Gary T

2015-09-01

A highly conserved feature of memory is that it can exist in a latent, non-expressed state which is revealed during subsequent learning by its ability to significantly facilitate (savings) or inhibit (latent inhibition) subsequent memory formation. Despite the ubiquitous nature of latent memory, the mechanistic nature of the latent memory trace and its ability to influence subsequent learning remains unclear. The model organism Aplysia californica provides the unique opportunity to make strong links between behavior and underlying cellular and molecular mechanisms. Using Aplysia, we have studied the mechanisms of savings due to latent memory for a prior, forgotten experience. We previously reported savings in the induction of three distinct temporal domains of memory: short-term (10min), intermediate-term (2h) and long-term (24h). Here we report that savings memory formation utilizes molecular signaling pathways that are distinct from original learning: whereas the induction of both original intermediate- and long-term memory in naïve animals requires mitogen activated protein kinase (MAPK) activation and ongoing protein synthesis, 2h savings memory is not disrupted by inhibitors of MAPK or protein synthesis, and 24h savings memory is not dependent on MAPK activation. Collectively, these findings reveal that during forgetting, latent memory for the original experience can facilitate relearning through molecular signaling mechanisms that are distinct from original learning. Copyright © 2015 Elsevier Inc. All rights reserved.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grabaskas, David; Bucknor, Matthew; Jerden, James

2016-10-01

The potential release of radioactive material during a plant incident, referred to as the source term, is a vital design metric and will be a major focus of advanced reactor licensing. The U.S. Nuclear Regulatory Commission has stated an expectation for advanced reactor vendors to present a mechanistic assessment of the potential source term in their license applications. The mechanistic source term presents an opportunity for vendors to realistically assess the radiological consequences of an incident, and may allow reduced emergency planning zones and smaller plant sites. However, the development of a mechanistic source term for advanced reactors is notmore » without challenges, as there are often numerous phenomena impacting the transportation and retention of radionuclides. This project sought to evaluate U.S. capabilities regarding the mechanistic assessment of radionuclide release from core damage incidents at metal fueled, pool-type sodium fast reactors (SFRs). The purpose of the analysis was to identify, and prioritize, any gaps regarding computational tools or data necessary for the modeling of radionuclide transport and retention phenomena. To accomplish this task, a parallel-path analysis approach was utilized. One path, led by Argonne and Sandia National Laboratories, sought to perform a mechanistic source term assessment using available codes, data, and models, with the goal to identify gaps in the current knowledge base. The second path, performed by an independent contractor, performed sensitivity analyses to determine the importance of particular radionuclides and transport phenomena in regards to offsite consequences. The results of the two pathways were combined to prioritize gaps in current capabilities.« less

Regioselective, borinic acid-catalyzed monoacylation, sulfonylation and alkylation of diols and carbohydrates: expansion of substrate scope and mechanistic studies.

PubMed

Lee, Doris; Williamson, Caitlin L; Chan, Lina; Taylor, Mark S

2012-05-16

Synthetic and mechanistic aspects of the diarylborinic acid-catalyzed regioselective monofunctionalization of 1,2- and 1,3-diols are presented. Diarylborinic acid catalysis is shown to be an efficient and general method for monotosylation of pyranoside derivatives bearing three secondary hydroxyl groups (7 examples, 88% average yield). In addition, the scope of the selective acylation, sulfonylation, and alkylation is extended to 1,2- and 1,3-diols not derived from carbohydrates (28 examples); the efficiency, generality, and operational simplicity of this method are competitive with those of state-of-the-art protocols including the broadly applied organotin-catalyzed or -mediated reactions. Mechanistic details of the organoboron-catalyzed processes are explored using competition experiments, kinetics, and catalyst structure-activity relationships. These experiments are consistent with a mechanism in which a tetracoordinate borinate complex reacts with the electrophilic species in the turnover-limiting step of the catalytic cycle.

Synthesis, Photoluminescence Behavior of Green Light Emitting Tb(III) Complexes and Mechanistic Investigation of Energy Transfer Process.

PubMed

Bala, Manju; Kumar, Satish; Devi, Rekha; Khatkar, Avni; Taxak, V B; Boora, Priti; Khatkar, S P

2018-06-04

A series of five new terbium(III) ion complexes with 4,4-difluoro-1-phenylbutane-1,3-dione (HDPBD) and anciliary ligands was synthesized. The composition and properties of complexes were analyzed by elemental analysis, IR, NMR, powder X-ray diffaraction, TG-DTG and photoluminescence spectroscopy. These complexes exhibited ligand sensitized green emission at 546 nm associated with 5 D 4  →  7 F 5 transitions of terbium ion in the emission spectra. The photoluminescence study manifested that the organic ligands act as antenna and facilitate the absorbed energy to emitting levels of Tb(III) ion efficiently. The enhanced luminescence intensity and decay time of ternary C2-C5 complexes observed due to synergistic effect of anciliary ligands. The CIE color coordinates of complexes came under the green region of chromaticity diagram. The mechanistic investigation of intramolecular energy transfer in the complexes was discussed in detail. These terbium(III) complexes can be thrivingly used as one of the green component in light emitting material and in display devices. Graphical Abstract Illustrate the sensitization process of the Tb ion and intramolecular energy transfer process in the Tb 3+ complex.

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

PubMed

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

2014-01-01

The chlorinated solvent trichloroethylene (TCE) is a ubiquitous environmental pollutant. The carcinogenic hazard of TCE was the subject of a 2012 evaluation by a Working Group of the International Agency for Research on Cancer (IARC). Information on exposures, relevant data from epidemiologic studies, bioassays in experimental animals, and toxicity and mechanism of action studies was used to conclude that TCE is carcinogenic to humans (Group 1). This article summarizes the key evidence forming the scientific bases for the IARC classification. Exposure to TCE from environmental sources (including hazardous waste sites and contaminated water) is common throughout the world. While workplace use of TCE has been declining, occupational exposures remain of concern, especially in developing countries. The strongest human evidence is from studies of occupational TCE exposure and kidney cancer. Positive, although less consistent, associations were reported for liver cancer and non-Hodgkin lymphoma. TCE is carcinogenic at multiple sites in multiple species and strains of experimental animals. The mechanistic evidence includes extensive data on the toxicokinetics and genotoxicity of TCE and its metabolites. Together, available evidence provided a cohesive database supporting the human cancer hazard of TCE, particularly in the kidney. For other target sites of carcinogenicity, mechanistic and other data were found to be more limited. Important sources of susceptibility to TCE toxicity and carcinogenicity were also reviewed by the Working Group. In all, consideration of the multiple evidence streams presented herein informed the IARC conclusions regarding the carcinogenicity of TCE. © 2013.

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

PubMed Central

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

2013-01-01

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

Application of Mechanistic Toxicology Data to Ecological Risk Assessments

EPA Science Inventory

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

Implementation of mechanistic pavement design : field and laboratory implementation.

DOT National Transportation Integrated Search

2006-12-01

One of the most important parameters needed for 2002 Mechanistic Pavement Design Guide is the dynamic modulus (E*). : The dynamic modulus (E*) describes the relationship between stress and strain for a linear viscoelastic material. The E* is the : pr...

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

EPA Science Inventory

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

Chitosan Improves Anti-Biofilm Efficacy of Gentamicin through Facilitating Antibiotic Penetration

PubMed Central

Mu, Haibo; Guo, Fan; Niu, Hong; Liu, Qianjin; Wang, Shunchun; Duan, Jinyou

2014-01-01

Antibiotic overuse is one of the major drivers in the generation of antibiotic resistant “super bugs” that can potentially cause serious effects on health. In this study, we reported that the polycationic polysaccharide, chitosan could improve the efficacy of a given antibiotic (gentamicin) to combat bacterial biofilms, the universal lifestyle of microbes in the world. Short- or long-term treatment with the mixture of chitosan and gentamicin resulted in the dispersal of Listeria monocytogenes (L. monocytogenes) biofilms. In this combination, chitosan with a moderate molecular mass (~13 kDa) and high N-deacetylation degree (~88% DD) elicited an optimal anti-biofilm and bactericidal activity. Mechanistic insights indicated that chitosan facilitated the entry of gentamicin into the architecture of L. monocytogenes biofilms. Finally, we showed that this combination was also effective in the eradication of biofilms built by two other Listeria species, Listeria welshimeri and Listeria innocua. Thus, our findings pointed out that chitosan supplementation might overcome the resistance of Listeria biofilms to gentamicin, which might be helpful in prevention of gentamicin overuse in case of combating Listeria biofilms when this specific antibiotic was recommended. PMID:25479075

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

PubMed

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

2015-01-01

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

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

PubMed Central

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

2015-01-01

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

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

PubMed

Wiper, Mallory L

2017-11-01

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

Treatment, Time, and Achievement: Do Searching Modes of Study Facilitate Learning?

ERIC Educational Resources Information Center

Rice, Marion J.

This report is a synthesis of five research studies comparing the facilitative effects on learning of searching and reception modes of study. The following five studies are discussed: (1) J.R. Dale, the effects on achievement of using the forced inferential response mode in an intermediate grade population-geography unit; (2) D.D. Dumbleton, the…

ASSORTATIVE MATING CAN IMPEDE OR FACILITATE FIXATION OF UNDERDOMINANT ALLELES

PubMed Central

NEWBERRY, MITCHELL G; MCCANDLISH, DAVID M; PLOTKIN, JOSHUA B

2017-01-01

Underdominant mutations have fixed between divergent species, yet classical models suggest that rare underdominant alleles are purged quickly except in small or subdivided populations. We predict that underdominant alleles that also influence mate choice, such as those affecting coloration patterns visible to mates and predators alike, can fix more readily. We analyze a mechanistic model of positive assortative mating in which individuals have n chances to sample compatible mates. This one-parameter model naturally spans random mating (n =1) and complete assortment (n → ∞), yet it produces sexual selection whose strength depends non-monotonically on n. This sexual selection interacts with viability selection to either inhibit or facilitate fixation. As mating opportunities increase, underdominant alleles fix as frequently as neutral mutations, even though sexual selection and underdominance independently each suppress rare alleles. This mechanism allows underdominant alleles to fix in large populations and illustrates how life history can affect evolutionary change. PMID:27497738

Assortative mating can impede or facilitate fixation of underdominant alleles.

PubMed

Newberry, Mitchell G; McCandlish, David M; Plotkin, Joshua B

2016-12-01

Underdominant mutations have fixed between divergent species, yet classical models suggest that rare underdominant alleles are purged quickly except in small or subdivided populations. We predict that underdominant alleles that also influence mate choice, such as those affecting coloration patterns visible to mates and predators alike, can fix more readily. We analyze a mechanistic model of positive assortative mating in which individuals have n chances to sample compatible mates. This one-parameter model naturally spans random mating (n=1) and complete assortment (n→∞), yet it produces sexual selection whose strength depends non-monotonically on n. This sexual selection interacts with viability selection to either inhibit or facilitate fixation. As mating opportunities increase, underdominant alleles fix as frequently as neutral mutations, even though sexual selection and underdominance independently each suppress rare alleles. This mechanism allows underdominant alleles to fix in large populations and illustrates how life history can affect evolutionary change. Copyright © 2016 Elsevier Inc. All rights reserved.

Regulatory T Cells in Skin Facilitate Epithelial Stem Cell Differentiation.

PubMed

Ali, Niwa; Zirak, Bahar; Rodriguez, Robert Sanchez; Pauli, Mariela L; Truong, Hong-An; Lai, Kevin; Ahn, Richard; Corbin, Kaitlin; Lowe, Margaret M; Scharschmidt, Tiffany C; Taravati, Keyon; Tan, Madeleine R; Ricardo-Gonzalez, Roberto R; Nosbaum, Audrey; Bertolini, Marta; Liao, Wilson; Nestle, Frank O; Paus, Ralf; Cotsarelis, George; Abbas, Abul K; Rosenblum, Michael D

2017-06-01

The maintenance of tissue homeostasis is critically dependent on the function of tissue-resident immune cells and the differentiation capacity of tissue-resident stem cells (SCs). How immune cells influence the function of SCs is largely unknown. Regulatory T cells (Tregs) in skin preferentially localize to hair follicles (HFs), which house a major subset of skin SCs (HFSCs). Here, we mechanistically dissect the role of Tregs in HF and HFSC biology. Lineage-specific cell depletion revealed that Tregs promote HF regeneration by augmenting HFSC proliferation and differentiation. Transcriptional and phenotypic profiling of T regs and HFSCs revealed that skin-resident Tregs preferentially express high levels of the Notch ligand family member, Jagged 1 (Jag1). Expression of Jag1 on Tregs facilitated HFSC function and efficient HF regeneration. Taken together, our work demonstrates that Tregs in skin play a major role in HF biology by promoting the function of HFSCs. Copyright © 2017 Elsevier Inc. All rights reserved.

Model-Based Analysis of Biopharmaceutic Experiments To Improve Mechanistic Oral Absorption Modeling: An Integrated in Vitro in Vivo Extrapolation Perspective Using Ketoconazole as a Model Drug.

PubMed

Pathak, Shriram M; Ruff, Aaron; Kostewicz, Edmund S; Patel, Nikunjkumar; Turner, David B; Jamei, Masoud

2017-12-04

Mechanistic modeling of in vitro data generated from metabolic enzyme systems (viz., liver microsomes, hepatocytes, rCYP enzymes, etc.) facilitates in vitro-in vivo extrapolation (IVIV_E) of metabolic clearance which plays a key role in the successful prediction of clearance in vivo within physiologically-based pharmacokinetic (PBPK) modeling. A similar concept can be applied to solubility and dissolution experiments whereby mechanistic modeling can be used to estimate intrinsic parameters required for mechanistic oral absorption simulation in vivo. However, this approach has not widely been applied within an integrated workflow. We present a stepwise modeling approach where relevant biopharmaceutics parameters for ketoconazole (KTZ) are determined and/or confirmed from the modeling of in vitro experiments before being directly used within a PBPK model. Modeling was applied to various in vitro experiments, namely: (a) aqueous solubility profiles to determine intrinsic solubility, salt limiting solubility factors and to verify pK a ; (b) biorelevant solubility measurements to estimate bile-micelle partition coefficients; (c) fasted state simulated gastric fluid (FaSSGF) dissolution for formulation disintegration profiling; and (d) transfer experiments to estimate supersaturation and precipitation parameters. These parameters were then used within a PBPK model to predict the dissolved and total (i.e., including the precipitated fraction) concentrations of KTZ in the duodenum of a virtual population and compared against observed clinical data. The developed model well characterized the intraluminal dissolution, supersaturation, and precipitation behavior of KTZ. The mean simulated AUC 0-t of the total and dissolved concentrations of KTZ were comparable to (within 2-fold of) the corresponding observed profile. Moreover, the developed PBPK model of KTZ successfully described the impact of supersaturation and precipitation on the systemic plasma concentration profiles of

Mechanistic Study of the Oxidative Coupling of Styrene with 2-Phenylpyridine Derivatives Catalyzed by Cationic Rhodium( III) via C–H Activation

PubMed Central

Brasse, Mikaël; Cámpora, Juan; Ellman, Jonathan A.; Bergman, Robert G.

2013-01-01

The Rh(III) catalyzed oxidative coupling of alkenes with arenes provides a greener alternative to the classical Heck reaction for the synthesis of arene-functionalized alkenes. The present mechanistic study gives insights for the rational development of this key transformation. The catalyst resting states and the rate law of the reaction have been identified. The reaction rate is solely dependent on catalyst and alkene concentrations and the rate determining step is the migratory insertion of alkene into a Rh–C(aryl) bond. PMID:23590843

Facilitating Facilitators: Enhancing PBL through a Structured Facilitator Development Program

ERIC Educational Resources Information Center

Salinitri, Francine D.; Wilhelm, Sheila M.; Crabtree, Brian L.

2015-01-01

With increasing adoption of the problem-based learning (PBL) model, creative approaches to enhancing facilitator training and optimizing resources to maintain effective learning in small groups is essential. We describe a theoretical framework for the development of a PBL facilitator training program that uses the constructivist approach as the…

Toward a Mechanistic Understanding of Environmentally Forced Zoonotic Disease Emergence: Sin Nombre Hantavirus

PubMed Central

Carver, Scott; Mills, James N.; Parmenter, Cheryl A.; Parmenter, Robert R.; Richardson, Kyle S.; Harris, Rachel L.; Douglass, Richard J.; Kuenzi, Amy J.; Luis, Angela D.

2015-01-01

Understanding the environmental drivers of zoonotic reservoir and human interactions is crucial to understanding disease risk, but these drivers are poorly predicted. We propose a mechanistic understanding of human–reservoir interactions, using hantavirus pulmonary syndrome as a case study. Crucial processes underpinning the disease's incidence remain poorly studied, including the connectivity among natural and peridomestic deer mouse host activity, virus transmission, and human exposure. We found that disease cases were greatest in arid states and declined exponentially with increasing precipitation. Within arid environments, relatively rare climatic conditions (e.g., El Niño) are associated with increased rainfall and reservoir abundance, producing more frequent virus transmission and host dispersal. We suggest that deer mice increase their occupancy of peridomestic structures during spring–summer, amplifying intraspecific transmission and human infection risk. Disease incidence in arid states may increase with predicted climatic changes. Mechanistic approaches incorporating reservoir behavior, reservoir–human interactions, and pathogen spillover could enhance our understanding of global hantavirus ecology, with applications to other directly transmitted zoonoses. PMID:26955081

Mechanistic models versus machine learning, a fight worth fighting for the biological community?

PubMed

Baker, Ruth E; Peña, Jose-Maria; Jayamohan, Jayaratnam; Jérusalem, Antoine

2018-05-01

Ninety per cent of the world's data have been generated in the last 5 years ( Machine learning: the power and promise of computers that learn by example Report no. DES4702. Issued April 2017. Royal Society). A small fraction of these data is collected with the aim of validating specific hypotheses. These studies are led by the development of mechanistic models focused on the causality of input-output relationships. However, the vast majority is aimed at supporting statistical or correlation studies that bypass the need for causality and focus exclusively on prediction. Along these lines, there has been a vast increase in the use of machine learning models, in particular in the biomedical and clinical sciences, to try and keep pace with the rate of data generation. Recent successes now beg the question of whether mechanistic models are still relevant in this area. Said otherwise, why should we try to understand the mechanisms of disease progression when we can use machine learning tools to directly predict disease outcome? © 2018 The Author(s).

Mechanistic Explanations for Restricted Evolutionary Paths That Emerge from Gene Regulatory Networks

PubMed Central

Cotterell, James; Sharpe, James

2013-01-01

The extent and the nature of the constraints to evolutionary trajectories are central issues in biology. Constraints can be the result of systems dynamics causing a non-linear mapping between genotype and phenotype. How prevalent are these developmental constraints and what is their mechanistic basis? Although this has been extensively explored at the level of epistatic interactions between nucleotides within a gene, or amino acids within a protein, selection acts at the level of the whole organism, and therefore epistasis between disparate genes in the genome is expected due to their functional interactions within gene regulatory networks (GRNs) which are responsible for many aspects of organismal phenotype. Here we explore epistasis within GRNs capable of performing a common developmental function – converting a continuous morphogen input into discrete spatial domains. By exploring the full complement of GRN wiring designs that are able to perform this function, we analyzed all possible mutational routes between functional GRNs. Through this study we demonstrate that mechanistic constraints are common for GRNs that perform even a simple function. We demonstrate a common mechanistic cause for such a constraint involving complementation between counter-balanced gene-gene interactions. Furthermore we show how such constraints can be bypassed by means of “permissive” mutations that buffer changes in a direct route between two GRN topologies that would normally be unviable. We show that such bypasses are common and thus we suggest that unlike what was observed in protein sequence-function relationships, the “tape of life” is less reproducible when one considers higher levels of biological organization. PMID:23613807

DEVELOPMENT AND VALIDATION OF A MECHANISTIC GROUND SPRAYER MODEL

EPA Science Inventory

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

From patterns to emerging processes in mechanistic urban ecology.

PubMed

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

2006-04-01

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

From parent to 'peer facilitator': a qualitative study of a peer-led parenting programme.

PubMed

Thomson, S; Michelson, D; Day, C

2015-01-01

Peer-led interventions are increasingly common in community health settings. Although peer-led approaches have proven benefits for service users, relatively little is known about the process and outcomes of participation for peer leaders. This study investigated experiences of parents who had participated as 'peer facilitators' in Empowering Parents, Empowering Communities (EPEC), a peer-led programme designed to improve access to evidence-based parenting support in socially disadvantaged communities. A qualitative cross-sectional design was used. Semi-structured interviews were conducted with 14 peer facilitators and scrutinized using thematic analysis. Peer facilitators developed their knowledge and skills through personal experience of receiving parenting support, participation in formal training and supervised practice, access to an intervention manual, and peer modelling. Peer facilitators described positive changes in their own families, confidence and social status. Transformative personal gains reinforced peer facilitators' role commitment and contributed to a cohesive 'family' identity among EPEC staff and service users. Peer facilitators' enthusiasm, openness and mutual identification with families were seen as critical to EPEC's effectiveness and sustainability. Peer facilitators also found the training emotionally and intellectually demanding. There were particular difficulties around logistical issues (e.g. finding convenient supervision times), managing psychosocial complexity and child safeguarding. The successful delivery and sustained implementation of peer-led interventions requires careful attention to the personal qualities and support of peer leaders. Based on the findings of this study, support should include training, access to intervention manuals, regular and responsive supervision, and logistical/administrative assistance. Further research is required to elaborate and extend these findings to other peer-led programmes. © 2014 John Wiley

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

NASA Astrophysics Data System (ADS)

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.

Analysis of Virginia-specific traffic data inputs for use with the mechanistic-empirical pavement design guide.

DOT National Transportation Integrated Search

2010-02-01

This study developed traffic inputs for use with the Guide for the Mechanistic-Empirical Design of New & Rehabilitated Pavement Structures (MEPDG) in Virginia and sought to determine if the predicted distresses showed differences between site-specifi...

Mechanistic ecohydrological modeling with Tethys-Chloris: an attempt to unravel complexity

NASA Astrophysics Data System (ADS)

Fatichi, S.; Ivanov, V. Y.; Caporali, E.

2010-12-01

The role of vegetation in controlling and mediating hydrological states and fluxes at the level of individual processes has been largely explored, which has lead to the improvement of our understanding of mechanisms and patterns in ecohydrological systems. Nonetheless, relatively few efforts have been directed toward the development of continuous, complex, mechanistic ecohydrological models operating at the watershed-scale. This study presents a novel ecohydrological model Tethys-Chloris (T&C) and aims to discuss current limitations and perspectives of the mechanistic approach in ecohydrology. The model attempts to synthesize the state-of-the-art knowledge on individual processes and mechanisms drawn from various disciplines such as hydrology, plant physiology, ecology, and biogeochemistry. The model reproduces all essential components of hydrological cycle resolving the mass and energy budgets at the hourly scale; it includes energy and mass exchanges in the atmospheric boundary layer; a module of saturated and unsaturated soil water dynamics; two layers of vegetation, and a module of snowpack evolution. The vegetation component parsimoniously parameterizes essential plant life-cycle processes, including photosynthesis, phenology, carbon allocation, tissues turnover, and soil biogeochemistry. Quantitative metrics of model performance are discussed and highlight the capabilities of T&C in reproducing ecohydrological dynamics. The simulated patterns mimic the outcome of hydrological dynamics with high realism, given the uncertainty of imposed boundary conditions and limited data availability. Furthermore, highly satisfactory results are obtained without significant (e.g., automated) calibration efforts despite the large phase-space dimensionality of the model. A significant investment into model design and development leads to such desirable behavior. This suggests that while using the presented tool for high-precision predictions can be still problematic, the

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

PubMed

MacLeod, Miles; Nersessian, Nancy J

2015-02-01

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

Facilitating the Development of Study Skills through a Blended Learning Approach

ERIC Educational Resources Information Center

Smith, Julian; Groves, Mark; Bowd, Belinda; Barber, Alison

2012-01-01

This study examined the effectiveness of a Blended Learning (BL) environment designed to facilitate the learning of study skills with a large (over 200) and diverse undergraduate student cohort in a Higher Education (HE) institution in the UK. A BL environment was designed using the model provided by Kerres & De Witt (2003), and was also…

Radical-molecule reaction C3H+H2O: a mechanistic study.

PubMed

Dong, Hao; Ding, Yi-Hong; Sun, Chia-Chung

2005-02-08

Despite the importance of the C(3)H radical in both combustion and interstellar space, the reactions of C(3)H toward stable molecules have never been studied. In this paper, we report our detailed mechanistic study on the radical-molecule reaction C(3)H+H(2)O at the Becke's three parameter Lee-Yang-Parr-B3LYP6-311G(d,p) and coupled cluster with single, double, and triple excitations-CCSD(T)6-311G(2d,p) (single-point) levels. It is shown that the C(3)H+H(2)O reaction initially favors formation of the carbene-insertion intermediates HCCCHOH (1a,1b) rather than the direct H- or OH-abstraction process. Subsequently, the isomers (1a,1b) can undergo a direct H- extrusion to form the well-known product propynal HCCCHO (P(5)). Highly competitively, (1a,1b) can take the successive 1,4- and 1,2-H-shift interconversion to isomer H(2)CCCHO(2a,2b) and then to isomer H(2)CCHCO(3a,3b), which can finally take a direct C-C bond cleavage to give product C(2)H(3) and CO (P(1)). The other products are kinetically much less feasible. With the overall entrance barrier 10.6 kcal/mol, the title reaction can be important in postburning processes. Particularly, our calculations suggest that the title reaction may play a role in the formation of the intriguing interstellar molecule, propynal HCCCHO. The calculated results will also be useful for the analogous C(3)H reactions such as with ammonia and alkanes.

Investigation of mechanistic deterioration modeling for bridge design and management.

DOT National Transportation Integrated Search

2017-04-01

The ongoing deterioration of highway bridges in Colorado dictates that an effective method for allocating limited management resources be developed. In order to predict bridge deterioration in advance, mechanistic models that analyze the physical pro...

A comprehensive mechanistic model for upward two-phase flow in wellbores

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sylvester, N.D.; Sarica, C.; Shoham, O.

1994-05-01

A comprehensive model is formulated to predict the flow behavior for upward two-phase flow. This model is composed of a model for flow-pattern prediction and a set of independent mechanistic models for predicting such flow characteristics as holdup and pressure drop in bubble, slug, and annular flow. The comprehensive model is evaluated by using a well data bank made up of 1,712 well cases covering a wide variety of field data. Model performance is also compared with six commonly used empirical correlations and the Hasan-Kabir mechanistic model. Overall model performance is in good agreement with the data. In comparison withmore » other methods, the comprehensive model performed the best.« less

MECHANISTIC DOSIMETRY MODELS OF NANOMATERIAL DEPOSITION IN THE RESPIRATORY TRACT

EPA Science Inventory

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

Online interprofessional education facilitation: A scoping review.

PubMed

Evans, Sherryn Maree; Ward, Catherine; Reeves, Scott

2018-04-22

The use of online media to deliver interprofessional education (IPE) is becoming more prevalent across health professions education settings. Facilitation of IPE activities is known to be critical to the effective delivery of IPE, however, specifics about the nature of online IPE facilitation remains unclear. To explore the health professions education literature to understand the extent, range and nature of research on online IPE facilitation. Scoping review methodology was used to guide a search of four electronic databases for relevant papers. Of the 2095 abstracts initially identified, after screening of both abstracts and full-text papers, 10 studies were selected for inclusion in this review. Following abstraction of key information from each study, a thematic analysis was undertaken. Three key themes emerged to describe the nature of the IPE facilitation literature: (1) types of online IPE facilitation contributions, (2) the experience of online IPE facilitation and (3) personal outcomes of online IPE facilitation. These IPE facilitation themes were particularly focused on facilitation of interprofessional student teams on an asynchronous basis. While the included studies provide some insight into the nature of online IPE facilitation, future research is needed to better understand facilitator contributions, and the facilitation experience and associated outcomes, both relating to synchronous and asynchronous online environments.

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

ERIC Educational Resources Information Center

Allen, Sue; And Others

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

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

PubMed

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

2007-07-01

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

Facilitators and barriers to exercising among people with osteoarthritis: a phenomenological study.

PubMed

Petursdottir, Unnur; Arnadottir, Solveig A; Halldorsdottir, Sigridur

2010-07-01

Evidence indicates that regular exercise improves the well-being of individuals with osteoarthritis (OA). However, these individuals seem to exercise less frequently than the general population and seem to have limited adherence to exercising. The purposes of this study were: (1) to increase knowledge and understanding of the experience of exercising among individuals with OA and (2) to determine what they perceive as facilitators and barriers to exercising. This study used a qualitative method, based on the Vancouver School of doing phenomenology, involving purposive sampling of 12 individuals and 16 interviews. The participants, 9 women and 3 men, were 50 to 82 years of age. Extended information on exercise behavior among people with OA is presented in a model in which internal and external facilitators and barriers to exercising are delineated. Based on this model, a checklist is proposed for physical therapists' assessment of these factors. Internal factors include individual attributes and personal experience of exercising, whereas external factors include the social and physical environment. The participants expressed how each of these internal and external factors could act both as a facilitator and a barrier to exercise participation and the pattern of exercising; for example, the presence of pain was an important aspect concerning internal barriers to exercising, whereas the hope of less pain was one of the main facilitators. Increased knowledge and understanding of the factors influencing exercise behavior in people with OA can help physical therapists and other health care professionals support them in initiating and maintaining a healthy exercise routine and, consequently, achieving a better quality of life.

Lewis acid-Lewis acid heterobimetallic cooperative catalysis: mechanistic studies and application in enantioselective aza-Michael reaction.

PubMed

Yamagiwa, Noriyuki; Qin, Hongbo; Matsunaga, Shigeki; Shibasaki, Masakatsu

2005-09-28

The full details of a catalytic asymmetric aza-Michael reaction of methoxylamine promoted by rare earth-alkali metal heterobimetallic complexes are described, demonstrating the effectiveness of Lewis acid-Lewis acid cooperative catalysis. First, enones were used as substrates, and the 1,4-adducts were obtained in good yield (57-98%) and high ee (81-96%). Catalyst loading was successfully reduced to 0.3-3 mol % with enones. To broaden the substrate scope of the reaction to carboxylic acid derivatives, alpha,beta-unsaturated N-acylpyrroles were used as monodentate, carboxylic acid derivatives. With beta-alkyl-substituted N-acylpyrroles, the reaction proceeded smoothly and the products were obtained in high yield and good ee. Transformation of the 1,4-adducts from enones and alpha,beta-unsaturated N-acylpyrroles afforded corresponding chiral aziridines and beta-amino acids. Detailed mechanistic studies, including kinetics, NMR analysis, nonlinear effects, and rare earth metal effects, are also described. The Lewis acid-Lewis acid cooperative mechanism, including the substrate coordination mode, is discussed in detail.

Mechanistic systems modeling to guide drug discovery and development

PubMed Central

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

2013-01-01

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

Facilitation of an end-of-life care programme into practice within UK nursing care homes: A mixed-methods study.

PubMed

Kinley, Julie; Preston, Nancy; Froggatt, Katherine

2018-06-01

The predicted demographic changes internationally have implications for the nature of care that older people receive and place of care as they age. Healthcare policy now promotes the implementation of end-of-life care interventions to improve care delivery within different settings. The Gold Standards Framework in Care Homes (GSFCH) programme is one end-of-life care initiative recommended by the English Department of Health. Only a small number of care homes that start the programme complete it, which raises questions about the implementation process. To identify the type, role, impact and cost of facilitation when implementing the GSFCH programme into nursing care home practice. A mixed-methods study. Nursing care homes in south-east England. Staff from 38 nursing care homes undertaking the GSFCH programme. Staff in 24 nursing care homes received high facilitation. Of those, 12 also received action learning. The remaining 14 nursing care homes received usual local facilitation of the GSFCH programme. Study data were collected from staff employed within nursing care homes (home managers and GSFCH coordinators) and external facilitators associated with the homes. Data collection included interviews, surveys and facilitator activity logs. Following separate quantitative (descriptive statistics) and qualitative (template) data analysis the data sets were integrated by 'following a thread'. This paper reports study data in relation to facilitation. Three facilitation approaches were provided to nursing home staff when implementing the GSFCH programme: 'fitting it in' facilitation; 'as requested' facilitation; and 'being present' facilitation. 'Being present' facilitation most effectively enabled the completion of the programme, through to accreditation. However, it was not sufficient to just be present. Without mastery and commitment, from all participants, including the external facilitator, learning and initiation of change failed to occur. Implementation of the

Mechanistic and Evolutionary Insights from Comparative Enzymology of Phosphomonoesterases and Phosphodiesterases across the Alkaline Phosphatase Superfamily

PubMed Central

2016-01-01

Naively one might have expected an early division between phosphate monoesterases and diesterases of the alkaline phosphatase (AP) superfamily. On the contrary, prior results and our structural and biochemical analyses of phosphate monoesterase PafA, from Chryseobacterium meningosepticum, indicate similarities to a superfamily phosphate diesterase [Xanthomonas citri nucleotide pyrophosphatase/phosphodiesterase (NPP)] and distinct differences from the three metal ion AP superfamily monoesterase, from Escherichia coli AP (EcAP). We carried out a series of experiments to map out and learn from the differences and similarities between these enzymes. First, we asked why there would be independent instances of monoesterases in the AP superfamily? PafA has a much weaker product inhibition and slightly higher activity relative to EcAP, suggesting that different metabolic evolutionary pressures favored distinct active-site architectures. Next, we addressed the preferential phosphate monoester and diester catalysis of PafA and NPP, respectively. We asked whether the >80% sequence differences throughout these scaffolds provide functional specialization for each enzyme’s cognate reaction. In contrast to expectations from this model, PafA and NPP mutants with the common subset of active-site groups embedded in each native scaffold had the same monoesterase:diesterase specificities; thus, the >107-fold difference in native specificities appears to arise from distinct interactions at a single phosphoryl substituent. We also uncovered striking mechanistic similarities between the PafA and EcAP monoesterases, including evidence for ground-state destabilization and functional active-site networks that involve different active-site groups but may play analogous catalytic roles. Discovering common network functions may reveal active-site architectural connections that are critical for function, and identifying regions of functional modularity may facilitate the design of new enzymes

Exploring Facilitators of Post-traumatic Growth in Patients with Spinal Cord Injury: A Qualitative Study

PubMed Central

Khanjani, Mohammad Saeed; Younesi, Seyed Jalal; Khankeh, Hamid Reza; Azkhosh, Manouchehr

2017-01-01

Introduction There is increasing evidence regarding people’s reactions to life stressors in which people also may show positive experiences following a traumatic event. The aim of the present study was to explain the facilitators of post-traumatic growth based on the experiences of patients with a spinal cord injury. Methods This was a qualitative study conducted on 16 Iranian patients with a spinal cord injury using semistructured, in-depth interviews, and content analysis in 2015. These participants, despite their spinal cord injury, were successful in their lives and were considered successful members of society. A purposive sampling method was used until reaching data saturation, and then the collected data were analyzed using a content analysis method. Results The study revealed several factors as facilitators of post-traumatic growth in the patients. The extracted facilitators were put into seven categories of main concepts, including existence of support resources, contact with spinal cord injury associations, spiritual beliefs, positive attitude toward injury, access to proper facilities, enhancement of knowledge and awareness, and active presence in society. Conclusion Different factors may facilitate post-traumatic growth in patients with a spinal cord injury. Understanding these facilitators may help us in designing educational, support, and consulting programs for patients and their families as well as to the correct the support programs. PMID:28243405

Exercise in patients with Type 2 diabetes: Facilitators and barriers - A qualitative study.

PubMed

Advika, T S; Idiculla, Jyothi; Kumari, S Jaya

2017-01-01

Diabetes is a major noncommunicable disease affecting more than 65 million Indians. Although treatment algorithms suggest lifestyle measures (diet and exercise) along with medications data regarding adherence to exercise as well as facilitators and barriers to the practice of physical activity in such patients are limited. Hence, this qualitative study was conducted. The objective of this study is to describe the factors which (1) Facilitated and (2) hindered the practice of regular exercise in patients with Type 2 diabetes. The study was conducted on 13 diabetic patients admitted to a tertiary care center in Bengaluru - St. John's Medical College Hospital, to explore factors that acted as facilitators and barriers to physical activity. Data saturation with the coded themes was achieved on interviewing 13 patients, after which, thematic analysis was done, and final themes reported. The age of the study participants (7 males, 6 females) ranged from 40 to 80 years. Among those who did exercise, factors such as awareness regarding the benefits of exercise and complications linked with diabetes, positive family support, and emphasis by nursing staff emerged as facilitators. Lack of time, obligations to others, inability to link exercise with blood sugar control, lack of perception of obesity as a health issue, inadequate emphasis by physicians, social/cultural issues, lack of infrastructure, and physical restriction were the factors that acted as barriers to physical activity. In addition to the above, a clear lack of adherence to standard guidelines, while advising patients by physicians was also noted. A comprehensive approach by both doctors and nurses, based on standard guidelines, could help in implementing adherence to exercise in patients with diabetes.

Composite Nanomechanics: A Mechanistic Properties Prediction

NASA Technical Reports Server (NTRS)

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

2007-01-01

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

Mechanistic modelling of the inhibitory effect of pH on microbial growth.

PubMed

Akkermans, Simen; Van Impe, Jan F

2018-06-01

Modelling and simulation of microbial dynamics as a function of processing, transportation and storage conditions is a useful tool to improve microbial food safety and quality. The goal of this research is to improve an existing methodology for building mechanistic predictive models based on the environmental conditions. The effect of environmental conditions on microbial dynamics is often described by combining the separate effects in a multiplicative way (gamma concept). This idea was extended further in this work by including the effects of the lag and stationary growth phases on microbial growth rate as independent gamma factors. A mechanistic description of the stationary phase as a function of pH was included, based on a novel class of models that consider product inhibition. Experimental results on Escherichia coli growth dynamics indicated that also the parameters of the product inhibition equations can be modelled with the gamma approach. This work has extended a modelling methodology, resulting in predictive models that are (i) mechanistically inspired, (ii) easily identifiable with a limited work load and (iii) easily extended to additional environmental conditions. Copyright © 2017. Published by Elsevier Ltd.

TFIIB-facilitated recruitment of preinitiation complexes by a TAF-independent mechanism.

PubMed

Hori, Roderick T; Xu, Shuping; Hu, Xianyuan; Pyo, Sung

2004-01-01

Gene activators contain activation domains that are thought to recruit limiting components of the transcription machinery to a core promoter. VP16, a viral gene activator, has served as a model for studying the mechanistic aspects of transcriptional activation from yeast to human. The VP16 activation domain can be divided into two modules--an N-terminal subdomain (VPN) and a C-terminal subdomain (VPC). This study demonstrates that VPC stimulates core promoters that are either independent or dependent on TAFs (TATA-box Binding Protein-Associated Factors). In contrast, VPN only activates the TAF-independent core promoter and this activity increases in a synergistic fashion when VPN is dimerized (VPN2). Compared to one copy of VPN (VPN1), VPN2 also displays a highly cooperative increase in binding hTFIIB. The increased TFIIB binding correlates with VPN2's increased ability to recruit a complex containing TFIID, TFIIA and TFIIB. However, VPN1 and VPN2 do not increase the assembly of a complex containing only TFIID and TFIIA. The VPN subdomain also facilitates assembly of a complex containing TBP:TFIIA:TFIIB, which lacks TAFs, and provides a mechanism that could function at TAF-independent promoters. Taken together, these results suggest the interaction between VPN and TFIIB potentially initiate a network of contacts allowing the activator to indirectly tether TFIID or TBP to DNA.

TFIIB-facilitated recruitment of preinitiation complexes by a TAF-independent mechanism

PubMed Central

Hori, Roderick T.; Xu, Shuping; Hu, Xianyuan; Pyo, Sung

2004-01-01

Gene activators contain activation domains that are thought to recruit limiting components of the transcription machinery to a core promoter. VP16, a viral gene activator, has served as a model for studying the mechanistic aspects of transcriptional activation from yeast to human. The VP16 activation domain can be divided into two modules—an N-terminal subdomain (VPN) and a C-terminal subdomain (VPC). This study demonstrates that VPC stimulates core promoters that are either independent or dependent on TAFs (TATA-box Binding Protein-Associated Factors). In contrast, VPN only activates the TAF-independent core promoter and this activity increases in a synergistic fashion when VPN is dimerized (VPN2). Compared to one copy of VPN (VPN1), VPN2 also displays a highly cooperative increase in binding hTFIIB. The increased TFIIB binding correlates with VPN2's increased ability to recruit a complex containing TFIID, TFIIA and TFIIB. However, VPN1 and VPN2 do not increase the assembly of a complex containing only TFIID and TFIIA. The VPN subdomain also facilitates assembly of a complex containing TBP:TFIIA:TFIIB, which lacks TAFs, and provides a mechanism that could function at TAF-independent promoters. Taken together, these results suggest the interaction between VPN and TFIIB potentially initiate a network of contacts allowing the activator to indirectly tether TFIID or TBP to DNA. PMID:15272087

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

EPA Science Inventory

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

Does Mechanistic Thinking Improve Student Success in Organic Chemistry?

ERIC Educational Resources Information Center

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

2012-01-01

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

Medical students' and facilitators' experiences of an Early Professional Contact course: active and motivated students, strained facilitators.

PubMed

von Below, Bernhard; Hellquist, Gunilla; Rödjer, Stig; Gunnarsson, Ronny; Björkelund, Cecilia; Wahlqvist, Mats

2008-12-02

Today, medical students are introduced to patient contact, communication skills, and clinical examination in the preclinical years of the curriculum with the purpose of gaining clinical experience. These courses are often evaluated from the student perspective. Reports with an additional emphasis on the facilitator perspective are scarce. According to constructive alignment, an influential concept from research in higher education, the learning climate between students and teachers is also of great importance. In this paper, we approach the learning climate by studying both students' and facilitators' course experiences.In 2001, a new "Early Professional Contact" longitudinal strand through term 1-4, was introduced at the Sahlgrenska Academy, University of Gothenburg, Sweden. General practitioners and hospital specialists were facilitators.The aim of this study was to assess and analyse students' and clinical facilitators' experiences of the Early Professional Contact course and to illuminate facilitators' working conditions. Inspired by a Swedish adaptation of the Course Experience Questionnaire, an Early Professional Contact Questionnaire was constructed. In 2003, on the completion of the first longitudinal strand, a student and facilitator version was distributed to 86 students and 21 facilitators. In the analysis, both Chi-square and the Mann-Whitney tests were used. Sixty students (70%) and 15 facilitators (71%) completed the questionnaire. Both students and facilitators were satisfied with the course. Students reported gaining iiration for their future work as doctors along with increased confidence in meeting patients. They also reported increased motivation for biomedical studies. Differences in attitudes between facilitators and students were found. Facilitators experienced a greater workload, less reasonable demands and less support, than students. In this project, a new Early Professional Contact course was analysed from both student and facilitator

Exploring factors facilitating adults with spinal cord injury rejoining the workforce: a pilot study.

PubMed

Wilbanks, Susan R; Ivankova, Nataliya V

2015-01-01

Return-to-work (RTW) rates after spinal cord injury (SCI) in the USA are very low and are continuing to decline. Previous research has attempted to identify factors facilitating RTW; however, the phenomenon of RTW involves many personal factors and predicting RTW success remains difficult. The purpose of this pilot study was to explore the factors facilitating adults with SCI rejoining the workforce in an urban area in order to identify items that may be emphasized in the rehabilitation process. The study was completed using qualitative methods. Four adults who had acquired a traumatic SCI in adulthood and were currently employed participated. Their experiences in RTW after injury were collected via semi-structured interviews and photography of assistive devices. The most common facilitating factor was motivation, with family and rehabilitation professionals serving as extrinsic motivators. Other facilitators were resources and perceived benefits. Motivation and resources were important facilitators, including rehabilitation professional's personal influence and therapies, and resource assistance from state agencies. The results indicate that practitioners can play an important role in influencing RTW, and resources from state agencies are helpful when individuals know how to access and utilize them. Assistive technology supports successful return to work after SCI. Motivation strongly influences return to work after SCI and can be influenced by rehabilitation professionals, family and community members. Patients should be well informed about how to access assistance programs such as vocational rehabilitation.

Social facilitation maintenance treatment for adults with obesity: study protocol for a randomised-controlled feasibility study (SFM study).

PubMed

Hilbert, Anja

2016-08-31

The long-term success of non-surgical weight loss treatment in adults with obesity is limited by substantial relapse, and only a few evidence-based weight loss maintenance treatments exist. This clinical trial investigates the feasibility and efficacy of a social facilitation maintenance programme for weight loss maintenance, tailored to meet the needs of obese adults who have undergone a lifestyle weight loss intervention. In a single-centre, open feasibility trial, 72 adults currently or previously obese or overweight who have undergone a lifestyle weight loss intervention are centrally randomised to 4 months of social facilitation maintenance treatment or treatment as a usual control condition. In 16 outpatient group sessions, the social facilitation maintenance treatment, based on a socioecological model and on evidence supporting social facilitation as a key process in maintaining weight loss, focuses on promoting interpersonal relationships to build up a healthy lifestyle for long-term weight loss maintenance. Primary outcome is the amount of weight regain at 6-month follow-up, compared with pre-treatment weight, derived from measured body weight. Secondary outcomes address feasibility, including recruitment, attrition, assessment non-completion, compliance and patients' programme evaluation; and in comparison with pre-weight loss maintenance, social and interpersonal functioning, eating behaviour and physical activity, psychological and physical symptoms, body composition and risk of comorbidity, and quality of life at post-treatment and follow-up assessments. The study was approved by the Ethical Committee at the University of Leipzig (165-13-15072013). The study results will be disseminated through peer-reviewed publications. DRKS00005182. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Mechanistic-empirical design concepts for continuously reinforced concrete pavements in Illinois.

DOT National Transportation Integrated Search

2009-04-01

The Illinois Department of Transportation (IDOT) currently has an existing jointed plain concrete pavement : (JPCP) design based on mechanistic-empirical (M-E) principles. However, their continuously reinforced concrete : pavement (CRCP) design proce...

Copper-Catalysed Aminoboration of Vinylarenes with Hydroxylamine Esters-A Computational Mechanistic Study.

PubMed

Tobisch, Sven

2017-12-14

An in-depth computational probe of the copper-mediated formal aminoboration of β-alkylstyrenes with bis(pinacolato)diboron B 2 pin 2 and an archetype hydroxylamine ester by a dppbz-ligated {P^P}Cu I boryl catalyst (dppbz≡{P^P}≡1,2-bis(diphenylphosphino)benzene) is presented. This first comprehensive computational study of the copper-mediated formal aminoboration utilising an electrophilic strategy has identified the most accessible pathway for productive catalysis. The mechanistic picture derived from smooth energy profiles acquired by employing a reliable computational protocol applied to a realistic catalyst model conforms to all available experimental data. The high degree of regio- and stereoselectivity achieved in syn-borylcupration and Umpolung electrophilic amination is instrumental to the exclusive generation of the (syn)-β-aminoalkylborane product. On the one hand, syn-borylcupration furnishes exclusively β-borylalkylcopper nucleophile upon boryl addition onto the vinylarene β-carbon. Its subsequent approach by the hydroxylamine electrophile to deliver the product with the release of {P^P}Cu I benzoate favours a stepwise stereoretentive S N 2-type oxidative addition/N-C bond-forming reductive elimination sequence. The copper benzoate species represents the catalyst resting state, and its transformation into the catalytically active borylcopper species upon salt metathesis with Li(OtBu) base and transmetallation with B 2 pin 2 is turnover limiting. Electronically modified β-alkylstyrenes featuring a para-CF 3 substituted phenyl ring render the borylcupration faster, and more electron-rich hydroxylamine agents decelerate the electrophilic amination. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

The Resourceful Facilitator: Teacher Leaders Constructing Identities as Facilitators of Teacher Peer Groups

ERIC Educational Resources Information Center

Allen, David

2016-01-01

The use of teacher peer groups is a prevalent strategy for school-based professional development and instructional improvement. Facilitation of such groups is an increasingly vital dimension of teacher leadership as a component of school improvement efforts. Drawing on a qualitative study of facilitation of teacher peer groups, the article…

How obstacles and facilitators predict academic performance: the mediating role of study burnout and engagement.

PubMed

Salanova, Marisa; Schaufeli, Wilmar; Martinez, Isabel; Breso, Edgar

2010-01-01

Most people would agree with the maxim that "success breeds success." However, this is not the whole story. The current study investigated the additional impact of psychosocial factors (i.e., performance obstacles and facilitators) as well as psychological well-being (i.e., burnout and engagement) on success (i.e., academic performance). More specifically, our purpose was to show that, instead of directly affecting future performance, obstacles and facilitators exert an indirect effect via well-being. A total of 527 university students comprised the sample and filled out a questionnaire. We obtained their previous and future academic performance Grade Point Average (GPA) from the university's records. Structural equations modeling showed that the best predictor of future performance was the students' previous performance. As expected, study engagement mediated the relationship between performance obstacles and facilitators on the one hand, and future performance on the other. Contrary to expectations, burnout did not predict future performance, although, it is significantly associated with the presence of obstacles and the absence of facilitators. Our results illustrate that, although "success breeds success" (i.e., the best predictor of future performance is past performance), positive psychological states like study engagement are also important in explaining future performance, at least more so than negative states like study burnout.

Study of Factors Which Facilitate Increase of Effectiveness of University Education

ERIC Educational Resources Information Center

Albekov, Adam; Romanova, Tatyana; Vovchenko, Natalya; Epifanova, Tatyana

2017-01-01

Purpose: The purpose of this paper is to study the factors which facilitate the increase of effectiveness of university education and determination of perspectives of their management for provision of maximization of effectiveness of university education by the example of modern Russia. Design/methodology/approach: The authors define the notion…

Calibrating the mechanistic-empirical pavement design guide for Kansas : [technical summary].

DOT National Transportation Integrated Search

2015-04-01

The Kansas Department of Transportation (KDOT) is moving toward the implementation : of the new American Association of State Highway and Transportation Officials : (AASHTO) Mechanistic-Empirical Pavement Design Guide (MEPDG) for pavement : design. T...

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

NASA Technical Reports Server (NTRS)

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

2010-01-01

migratory shorebirds in the central fly ways of North America. We demonstrated the phenotypic plasticity of a migratory population of Pectoral sandpipers consisting of an ensemble of 10,000 individual birds in response to changes in stopover locations using an individual based migration model driven by remotely sensed land surface data, climate data and biological field data. With the advent of new computing capabilities enabled hy recent GPU-GP computing paradigms and commodity hardware, it now is possible to simulate both larger ensemble populations and to incorporate more realistic mechanistic factors into migration models. Here, we take our first steps use these tools to study the impact of long-term drought variability on shorebird survival.

Mechanistic modeling of reactive soil nitrogen emissions across agricultural management practices

NASA Astrophysics Data System (ADS)

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

2017-12-01

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

Improvements In AF Ablation Outcome Will Be Based More On Technological Advancement Versus Mechanistic Understanding.

PubMed

Jiang Md, Chen-Yang; Jiang Ms, Ru-Hong

2014-01-01

Atrial fibrillation (AF) is one of the most common cardiac arrhythmias. Catheter ablation has proven more effective than antiarrhythmic drugs in preventing clinical recurrence of AF, however long-term outcome remains unsatisfactory. Ablation strategies have evolved based on progress in mechanistic understanding, and technologies have advanced continuously. This article reviews current mechanistic concepts and technological advancements in AF treatment, and summarizes their impact on improvement of AF ablation outcome.

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

EPA Pesticide Factsheets

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

Mechanistic systems modeling to guide drug discovery and development.

PubMed

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

2013-02-01

A crucial question that must be addressed in the drug development process is whether the proposed therapeutic target will yield the desired effect in the clinical population. Pharmaceutical and biotechnology companies place a large investment on research and development, long before confirmatory data are available from human trials. Basic science has greatly expanded the computable knowledge of disease processes, both through the generation of large omics data sets and a compendium of studies assessing cellular and systemic responses to physiologic and pathophysiologic stimuli. Given inherent uncertainties in drug development, mechanistic systems models can better inform target selection and the decision process for advancing compounds through preclinical and clinical research. Copyright © 2012 Elsevier Ltd. All rights reserved.

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

NASA Astrophysics Data System (ADS)

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.

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

PubMed Central

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

2017-01-01

On May 19, 2016, the US Food and Drug Administration (FDA) hosted a public workshop, entitled “Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation.”1 The topic of mechanistic oral absorption modeling, which is one of the major applications of physiologically based pharmacokinetic (PBPK) modeling and simulation, focuses on predicting oral absorption by mechanistically integrating gastrointestinal transit, dissolution, and permeation processes, incorporating systems, active pharmaceutical ingredient (API), and the drug product information, into a systemic mathematical whole‐body framework.2 PMID:28571121

Results of a feasibility study: barriers and facilitators in implementing the Sherbrooke model in France.

PubMed

Fassier, Jean-Baptiste; Durand, Marie-José; Caillard, Jean-François; Roquelaure, Yves; Loisel, Patrick

2015-05-01

Return-to-work interventions associated with the workplace environment are often more effective than conventional care. The Sherbrooke model is an integrated intervention that has proved successful in preventing work disability due to low-back pain. Implementation, however, runs up against many obstacles, and failure has been reported in many countries. The present study sought to identify barriers to and facilitators of the implementation of the Sherbrooke model within the French health system. A multiple case study with nested levels of analysis was performed in two regions of France. A conceptual framework was designed and refined to identify barriers and facilitators at the individual, organizational and contextual levels. Qualitative data were collected via semi-structured interview (N=22), focus groups (N=7), and observation and from the gray literature. Participants (N=61) belonged to three fields: healthcare, social insurance, and the workplace. Numerous barriers and facilitators were identified in each field and at each level, some specific and others common to workers in all fields. Individual and organizational barriers comprised lack of time and resources, discordant professional values, and perceived risk. Legal barriers comprised medical confidentiality, legal complexity, and priority given to primary prevention. Individual-level facilitators comprised needs and perceived benefits. Some organizations had concordant values and practices. Legal facilitators comprised possibilities of collaboration and gradual return to work. The present feasibility analysis of implementing the Sherbrooke model revealed numerous barriers and facilitators suggesting a new implementation strategy be drawn up if failure is to be avoided.

Assessment of glycemic response to an oral glucokinase activator in a proof of concept study: application of a semi-mechanistic, integrated glucose-insulin-glucagon model.

PubMed

Schneck, Karen B; Zhang, Xin; Bauer, Robert; Karlsson, Mats O; Sinha, Vikram P

2013-02-01

A proof of concept study was conducted to investigate the safety and tolerability of a novel oral glucokinase activator, LY2599506, during multiple dose administration to healthy volunteers and subjects with Type 2 diabetes mellitus (T2DM). To analyze the study data, a previously established semi-mechanistic integrated glucose-insulin model was extended to include characterization of glucagon dynamics. The model captured endogenous glucose and insulin dynamics, including the amplifying effects of glucose on insulin production and of insulin on glucose elimination, as well as the inhibitory influence of glucose and insulin on hepatic glucose production. The hepatic glucose production in the model was increased by glucagon and glucagon production was inhibited by elevated glucose concentrations. The contribution of exogenous factors to glycemic response, such as ingestion of carbohydrates in meals, was also included in the model. The effect of LY2599506 on glucose homeostasis in subjects with T2DM was investigated by linking a one-compartment, pharmacokinetic model to the semi-mechanistic, integrated glucose-insulin-glucagon system. Drug effects were included on pancreatic insulin secretion and hepatic glucose production. The relationships between LY2599506, glucose, insulin, and glucagon concentrations were described quantitatively and consequently, the improved understanding of the drug-response system could be used to support further clinical study planning during drug development, such as dose selection.

USE OF MECHANISTIC DATA TO HELP DEFINE DOSE-RESPONSE CURVES

EPA Science Inventory

Use of Mechanistic Data to Help Define Dose-Response Curves

The cancer risk assessment process described by the U.S. EPA necessitates a description of the dose-response curve for tumors in humans at low (environmental) exposures. This description can either be a default l...

Base course resilient modulus for the mechanistic-empirical pavement design guide.

DOT National Transportation Integrated Search

2011-11-01

The Mechanistic-Empirical Pavement Design Guidelines (MEPDG) recommend use of modulus in lieu of structural number for base layer thickness design. Modulus is nonlinear with respect to effective confinement stress, loading strain, and moisture. For d...

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

EPA Science Inventory

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

Implementation of the AASHTO mechanistic-empirical pavement design guide for Colorado.

DOT National Transportation Integrated Search

2000-01-01

The objective of this project was to integrate the American Association of State Highway and Transportation Officials (AASHTO) Mechanistic-Empirical Pavement Design Guide, Interim Edition: A Manual of Practice and its accompanying software into the d...

Mechanistic equivalent circuit modelling of a commercial polymer electrolyte membrane fuel cell

NASA Astrophysics Data System (ADS)

Giner-Sanz, J. J.; Ortega, E. M.; Pérez-Herranz, V.

2018-03-01

Electrochemical impedance spectroscopy (EIS) has been widely used in the fuel cell field since it allows deconvolving the different physic-chemical processes that affect the fuel cell performance. Typically, EIS spectra are modelled using electric equivalent circuits. In this work, EIS spectra of an individual cell of a commercial PEM fuel cell stack were obtained experimentally. The goal was to obtain a mechanistic electric equivalent circuit in order to model the experimental EIS spectra. A mechanistic electric equivalent circuit is a semiempirical modelling technique which is based on obtaining an equivalent circuit that does not only correctly fit the experimental spectra, but which elements have a mechanistic physical meaning. In order to obtain the aforementioned electric equivalent circuit, 12 different models with defined physical meanings were proposed. These equivalent circuits were fitted to the obtained EIS spectra. A 2 step selection process was performed. In the first step, a group of 4 circuits were preselected out of the initial list of 12, based on general fitting indicators as the determination coefficient and the fitted parameter uncertainty. In the second step, one of the 4 preselected circuits was selected on account of the consistency of the fitted parameter values with the physical meaning of each parameter.

Specialist nurses' perceptions of inviting patients to participate in clinical research studies: a qualitative descriptive study of barriers and facilitators.

PubMed

French, Caroline; Stavropoulou, Charitini

2016-08-11

Increasing the number of patients participating in research studies is a current priority in the National Health Service (NHS) in the United Kingdom. The role of specialist nurses in inviting patients to participate is important, yet little is known about their experiences of doing so. The aim of this study was to explore the perceptions of barriers and facilitators held by specialist nurses with experience of inviting adult NHS patients to a wide variety of research studies. A cross-sectional qualitative descriptive study was conducted between March and July 2015. Participants were 12 specialist nurses representing 7 different clinical specialties and 7 different NHS Trusts. We collected data using individual semi-structured interviews, and analysed transcripts using the Framework method to inductively gain a descriptive overview of barriers and facilitators. Barriers and facilitators were complex and interdependent. Perceptions varied among individuals, however barriers and facilitators centred on five main themes: i) assessing patient suitability, ii) teamwork, iii) valuing research, iv) the invitation process and v) understanding the study. Facilitators to inviting patients to participate in research often stemmed from specialist nurses' attitudes, skills and experience. Positive research cultures, effective teamwork and strong relationships between research and clinical teams at the local clinical team level were similarly important. Barriers were reported when specialist nurses felt they were providing patients with insufficient information during the invitation process, and when specialist nurses felt they did not understand studies to their satisfaction. Our study offers several new insights regarding the role of specialist nurses in recruiting patients for research. It shows that strong local research culture and teamwork overcome some wider organisational and workload barriers reported in previous studies. In addition, and in contrast to common practice

Profiling adult literacy facilitators in development contexts: An ethnographic study in Ethiopia

NASA Astrophysics Data System (ADS)

Warkineh, Turuwark Zalalam; Rogers, Alan; Danki, Tolera Negassa

2018-02-01

Teachers/facilitators in adult literacy learning programmes are recognised as being vital to successful learning outcomes. But little is known about them as a group. This small-scale research project comprising ethnographic-style case studies of five adult literacy facilitators (ALFs) in Ethiopia seeks to throw some light on these teachers, their backgrounds and what they bring to their teaching, with a view to improving the effectiveness of their work. The researchers found that all of the ALFs had high levels of commitment, but none of the ALFs received much in the way of training, and professional support for their role was in some cases missing. The degree (and their perception) of their own literacy practices varied greatly among them, even in their common use of mobile phones. It also emerged that while they had all fought very hard for their own education, one of the main reasons all of them stated for going into literacy teaching was not a general belief in the value of education but their priority need of a regular income. Another insight is that the female ALFs struggled more than their male counterparts in engaging learners; the women were criticised more excessively than the men. This research reveals something of the diversity of facilitators, and concludes that further such studies are needed in different contexts.

Facilitating Intercultural Development during Study Abroad: A Case Study of CIEE's Seminar on Living and Learning Abroad

ERIC Educational Resources Information Center

Harvey, Tara Alicia

2013-01-01

This study examines a relatively new phenomenon in study abroad: the practice of intervening in students' intercultural learning during their experience abroad. In this paper, I refer to this type of intentional and focused action taken by educators to facilitate student learning abroad as a "study abroad intervention." This study…

Mechanistic insight into prolonged electromechanical delay in dyssynchronous heart failure: a computational study

PubMed Central

Constantino, Jason; Hu, Yuxuan; Lardo, Albert C.

2013-01-01

In addition to the left bundle branch block type of electrical activation, there are further remodeling aspects associated with dyssynchronous heart failure (HF) that affect the electromechanical behavior of the heart. Among the most important are altered ventricular structure (both geometry and fiber/sheet orientation), abnormal Ca2+ handling, slowed conduction, and reduced wall stiffness. In dyssynchronous HF, the electromechanical delay (EMD), the time interval between local myocyte depolarization and myofiber shortening onset, is prolonged. However, the contributions of the four major HF remodeling aspects in extending EMD in the dyssynchronous failing heart remain unknown. The goal of this study was to determine the individual and combined contributions of HF-induced remodeling aspects to EMD prolongation. We used MRI-based models of dyssynchronous nonfailing and HF canine electromechanics and constructed additional models in which varying combinations of the four remodeling aspects were represented. A left bundle branch block electrical activation sequence was simulated in all models. The simulation results revealed that deranged Ca2+ handling is the primary culprit in extending EMD in dyssynchronous HF, with the other aspects of remodeling contributing insignificantly. Mechanistically, we found that abnormal Ca2+ handling in dyssynchronous HF slows myofiber shortening velocity at the early-activated septum and depresses both myofiber shortening and stretch rate at the late-activated lateral wall. These changes in myofiber dynamics delay the onset of myofiber shortening, thus giving rise to prolonged EMD in dyssynchronous HF. PMID:23934857

A mechanistic and kinetic study on the formation of PBDD/Fs from PBDEs.

PubMed

Altarawneh, Mohammednoor; Dlugogorski, Bogdan Z

2013-05-21

This study presents a detailed mechanistic and kinetic investigation that explains the experimentally observed high yields of formation of polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs) from the polybrominated diphenyl ethers (PBDEs), commonly deployed in brominated flame retardants (BFRs). Theoretical calculations involved the accurate meta hybrid functional of M05-2X. The previously suggested pathways of debromination and generation of bromophenols/bromophenoxys/bromobenzenes were found to be unimportant corridors for the formation of PBDD/Fs. A loss of an ortho Br or H atom from PBDEs, followed by a ring-closure reaction, is the most accessible pathway for the production of PBDFs via modest reaction barriers. The initially formed peroxy-type adduct (RO₂) is found to evolve in a complex, nevertheless very exoergic, mechanism to produce PBDDs. Results indicate that, degree and pattern of bromination, in the vicinity of the ether oxygen bridge, has a minor influence on governing mechanisms and that even fully brominated isomers of BFRs are capable of forming PBDD/Fs. We thoroughly discuss bimolecular reactions of PBDEs with Br and H, as well as the Br-displacement reaction by triplet oxygen. The rate of the Br-displacement reaction significantly exceeds that of the unimolecular inititiation reactions due to loss of ortho Br or H. Results presented herein address conclusively the intriguing question of how PBDEs form PBDD/Fs, a matter that has been in the center of much debate among environmental chemists.

Mechanistic Insights into the Efficacy of Sodium Bicarbonate Supplementation to Improve Athletic Performance.

PubMed

Siegler, Jason C; Marshall, Paul W M; Bishop, David; Shaw, Greg; Green, Simon

2016-12-01

A large proportion of empirical research and reviews investigating the ergogenic potential of sodium bicarbonate (NaHCO 3 ) supplementation have focused predominately on performance outcomes and only speculate about underlying mechanisms responsible for any benefit. The aim of this review was to critically evaluate the influence of NaHCO 3 supplementation on mechanisms associated with skeletal muscle fatigue as it translates directly to exercise performance. Mechanistic links between skeletal muscle fatigue, proton accumulation (or metabolic acidosis) and NaHCO 3 supplementation have been identified to provide a more targeted, evidence-based approach to direct future research, as well as provide practitioners with a contemporary perspective on the potential applications and limitations of this supplement. The mechanisms identified have been broadly categorised under the sections 'Whole-body Metabolism', 'Muscle Physiology' and 'Motor Pathways', and when possible, the performance outcomes of these studies contextualized within an integrative framework of whole-body exercise where other factors such as task demand (e.g. large vs. small muscle groups), cardio-pulmonary and neural control mechanisms may outweigh any localised influence of NaHCO 3 . Finally, the 'Performance Applications' section provides further interpretation for the practitioner founded on the mechanistic evidence provided in this review and other relevant, applied NaHCO 3 performance-related studies.

Mechanistic Study of Human Glucose Transport Mediated by GLUT1.

PubMed

Fu, Xuegang; Zhang, Gang; Liu, Ran; Wei, Jing; Zhang-Negrerie, Daisy; Jian, Xiaodong; Gao, Qingzhi

2016-03-28

The glucose transporter 1 (GLUT1) belongs to the major facilitator superfamily (MFS) and is responsible for the constant uptake of glucose. However, the molecular mechanism of sugar transport remains obscure. In this study, homology modeling and molecular dynamics (MD) simulations in lipid bilayers were performed to investigate the combination of the alternate and multisite transport mechanism of glucose with GLUT1 in atomic detail. To explore the substrate recognition mechanism, the outward-open state human GLUT1 homology model was generated based on the template of xylose transporter XylE (PDB ID: 4GBZ), which shares up to 29% sequence identity and 49% similarity with GLUT1. Through the MD simulation study of glucose across lipid bilayer with both the outward-open GLUT1 and the GLUT1 inward-open crystal structure, we investigated six different conformational states and identified four key binding sites in both exofacial and endofacial loops that are essential for glucose recognition and transport. The study further revealed that four flexible gates consisting of W65/Y292/Y293-M420/TM10b-W388 might play important roles in the transport cycle. The study showed that some side chains close to the central ligand binding site underwent larger position changes. These conformational interchanges formed gated networks within an S-shaped central channel that permitted staged ligand diffusion across the transporter. This study provides new inroads for the understanding of GLUT1 ligand recognition paradigm and configurational features which are important for molecular, structural, and physiological research of the MFS members, especially for GLUT1-targeted drug design and discovery.

A Critical Evaluation of Studies Employing Alkenyl Halide ’Mechanistic Probe’ as Indicators of Single Electron Transfer Processes.

DTIC Science & Technology

1987-07-07

College Station, TX 77843 Pittsburgh, PA 15260 Introduction: Chemical reactions come about through the reorganization of valence electrons. The notion...Contmnue on reverie of necessary and odentify 0)’ Wooc ,7umor r) Recently it has been suggested that many reaction traditionally classed in polar terms may...evaluates the utility of these alkenyl halide probes as mechanistic probes for SET. Reactions which interfere with the standard analysis ~ include the

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

PubMed

Weissgerber, Tracey L

2014-11-01

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

A semi-mechanistic model of dead fine fuel moisture for Temperate and Mediterranean ecosystems

NASA Astrophysics Data System (ADS)

Resco de Dios, Víctor; Fellows, Aaron; Boer, Matthias; Bradstock, Ross; Nolan, Rachel; Goulden, Michel

2014-05-01

Fire is a major disturbance in terrestrial ecosystems globally. It has an enormous economic and social cost, and leads to fatalities in the worst cases. The moisture content of the vegetation (fuel moisture) is one of the main determinants of fire risk. Predicting the moisture content of dead and fine fuel (< 2.5 cm in diameter) is particularly important, as this is often the most important component of the fuel complex for fire propagation. A variety of drought indices, empirical and mechanistic models have been proposed to model fuel moisture. A commonality across these different approaches is that they have been neither validated across large temporal datasets nor validated across broadly different vegetation types. Here, we present the results of a study performed at 6 locations in California, USA (5 sites) and New South Wales, Australia (1 site), where 10-hours fuel moisture content was continuously measured every 30 minutes during one full year at each site. We observed that drought indices did not accurately predict fuel moisture, and that empirical and mechanistic models both needed site-specific calibrations, which hinders their global application as indices of fuel moisture. We developed a novel, single equation and semi-mechanistic model, based on atmospheric vapor-pressure deficit. Across sites and years, mean absolute error (MAE) of predicted fuel moisture was 4.7%. MAE dropped <1% in the critical range of fuel moisture <10%. The high simplicity, accuracy and precision of our model makes it suitable for a wide range of applications: from operational purposes, to global vegetation models.

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

PubMed

Soriano, Elena; Marco-Contelles, José

2009-08-18

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

Evaluation of Eight Case Studies of Facilitated Communication.

ERIC Educational Resources Information Center

Moore, Susan; And Others

1993-01-01

The ability of eight adults with mental retardation (and in some cases cerebral palsy) to communicate using facilitated communication was assessed by a multidisciplinary team. Not one of the subjects demonstrated an ability to communicate using the technique. (JDD)

Minorities with lupus nephritis and medications: a study of facilitators to medication decision-making.

PubMed

Singh, Jasvinder A; Qu, Haiyan; Yazdany, Jinoos; Chatham, Winn; Shewchuk, Richard

2015-12-17

Medication decision-making poses a challenge for a significant proportion of patients. This is an even more challenging for patients who have complex, rare, immune conditions that affect them at a young age and are associated with the use of life-long treatment, perceived by some as having significant risk of side effects and toxicity. The aim of our study was to examine the perspectives of women with lupus nephritis on facilitators to medication decision-making. We used the nominal group technique (NGT), a structured formative process to elicit patient perspectives. An NGT expert moderated eight patient group meetings. Participants (n = 52) responded to the question "What sorts of things make it easier for people to decide to take the medicines that doctors prescribe for treating their lupus kidney disease?" Patients nominated, discussed, and prioritized facilitators to medication decisional processes. Fifty-two women with lupus nephritis participated in eight NGT meetings (27 African-American, 13 Hispanic, and 12 Caucasian). Average age was 40.6 years (standard deviation (SD) = 13.3), and disease duration was 11.8 years (SD = 8.3); 36.5 % obtained at least a college education, and 55.8 % had difficulty in reading health materials. Patients generated 280 decision-making facilitators (range of 26 to 42 per panel). Of these, 102 (36 %) facilitators were perceived by patients as having relatively more influence in decision-making processes than others. Prioritized facilitators included effective patient-physician communication regarding benefits/harms, patient desire to live a normal life and improve quality of life, concern for their dependents, experiencing benefits and few/infrequent/no harms with lupus medications, and their affordability. Relative to African-Americans, Caucasian and Hispanic patients endorsed a smaller percentage of facilitators as influential. Level of agreement with which patients within panels independently agreed in their

The Facilitators and Barriers to Nurses’ Participation in Continuing Education Programs: A Mixed Method Explanatory Sequential Study

PubMed Central

Shahhosseini, Zohreh; Hamzehgardeshi, Zeinab

2015-01-01

Background: Since several factors affect nurses’ participation in Continuing Education, and that nurses’ Continuing Education affects patients’ and community health status, it is essential to know facilitators and barriers of participation in Continuing Education programs and plan accordingly. This mixed approach study aimed to investigate the facilitators and barriers of nurses’ participation, to explore nurses’ perception of the most common facilitators and barriers. Methods: An explanatory sequential mixed methods design with follow up explanations variant were used, and it involved collecting quantitative data (361 nurses) first and then explaining the quantitative results with in-depth interviews during a qualitative study. Results: The results showed that the mean score of facilitators to nurses’ participation in Continuing Education was significantly higher than the mean score of barriers (61.99±10.85 versus 51.17±12.83; p<0.001, t=12.23). The highest mean score of facilitators of nurses’ participation in Continuing Education was related to “Update my knowledge”. By reviewing the handwritings in qualitative phase, two main levels of updating information and professional skills were extracted as the most common facilitators and lack of support as the most common barrier to nurses’ participation in continuing education program. Conclusion: According to important role Continuing Education on professional skills, nurse managers should facilitate the nurse’ participation in the Continues Education. PMID:25948439

The facilitators and barriers to nurses' participation in continuing education programs: a mixed method explanatory sequential study.

PubMed

Shahhosseini, Zohreh; Hamzehgardeshi, Zeinab

2014-11-30

Since several factors affect nurses' participation in Continuing Education, and that nurses' Continuing Education affects patients' and community health status, it is essential to know facilitators and barriers of participation in Continuing Education programs and plan accordingly. This mixed approach study aimed to investigate the facilitators and barriers of nurses' participation, to explore nurses' perception of the most common facilitators and barriers. An explanatory sequential mixed methods design with follow up explanations variant were used, and it involved collecting quantitative data (361 nurses) first and then explaining the quantitative results with in-depth interviews during a qualitative study. The results showed that the mean score of facilitators to nurses' participation in Continuing Education was significantly higher than the mean score of barriers (61.99 ± 10.85 versus 51.17 ± 12.83; p<0.001, t=12.23). The highest mean score of facilitators of nurses' participation in Continuing Education was related to "Update my knowledge". By reviewing the handwritings in qualitative phase, two main levels of updating information and professional skills were extracted as the most common facilitators and lack of support as the most common barrier to nurses' participation in continuing education program. According to important role Continuing Education on professional skills, nurse managers should facilitate the nurse' participation in the Continues Education.

Barriers to and Facilitators of Antiretroviral Therapy Adherence in Nepal: A Qualitative Study

PubMed Central

Simkhada, Padam; Randall, Julian; Freeman, Jennifer V; van Teijlingen, Edwin

2012-01-01

Patient's adherence is crucial to get the best out of antiretroviral therapy (ART). This study explores in-depth the barriers to and facilitators of ART adherence among Nepalese patients and service providers prescribing ART. Face-to-face semi-structured interviews were conducted with 34 participants. Interviews were audio-taped, transcribed, and translated into English before being analyzed thematically. ART-prescribed patients described a range of barriers for failing to adhere to ART. Financial difficulties, access to healthcare services, frequent transport blockades, religious/ritual obstacles, stigma and discrimination, and side-effects were the most-frequently discussed barriers whereas trustworthy health workers, perceived health benefits, and family support were the most-reported facilitators. Understanding barriers and facilitators can help in the design of an appropriate and targeted intervention. Healthcare providers should address some of the practical and cultural issues around ART whilst policy-makers should develop appropriate social policy to promote adherence among ART-prescribed patients. PMID:23304907

Facilitators and Barriers to Implementing Clinical Governance: A Qualitative Study among Senior Managers in Iran.

PubMed

Ravaghi, Hamid; Rafiei, Sima; Heidarpour, Peigham; Mohseni, Maryam

2014-09-01

Health care systems should assign quality improvement as their main mission. Clinical governance (CG) is a key strategy to improve quality of health care services. The Iranian Ministry of Health and Medical Education (MOHME) has promoted CG as a framework for safeguarding quality and safety in all hospitals since 2009. The purpose of this study was to explore perceived facilitators and barriers to implementing CG by deputies for curative affairs of Iranian medical universities. A qualitative study was conducted using face to face interviews with a purposeful sample of 43 deputies for curative affairs of Iranian Medical Universities and documents review. Thematic analysis was used to analyze the data. Five themes were explored including: knowledge and attitude toward CG, culture, organizational factors, managerial factors and barriers. The main perceived facilitating factors were adequate knowledge and positive attitude toward CG, supporting culture, managers' commitment, effective communication and well designed incentives. Pe rceived barriers were the reverse of facilitators noted above in addition to insufficient resources, legal challenges, workload and parallel quality programs. Successful implementation of CG in Iran will require identifying barriers and challenges existing in the way of CG implementation and try to mitigate them by using appropriate facilitators.

Transporter-Enzyme Interplay: Deconvoluting Effects of Hepatic Transporters and Enzymes on Drug Disposition Using Static and Dynamic Mechanistic Models.

PubMed

Varma, Manthena V; El-Kattan, Ayman F

2016-07-01

A large body of evidence suggests hepatic uptake transporters, organic anion-transporting polypeptides (OATPs), are of high clinical relevance in determining the pharmacokinetics of substrate drugs, based on which recent regulatory guidances to industry recommend appropriate assessment of investigational drugs for the potential drug interactions. We recently proposed an extended clearance classification system (ECCS) framework in which the systemic clearance of class 1B and 3B drugs is likely determined by hepatic uptake. The ECCS framework therefore predicts the possibility of drug-drug interactions (DDIs) involving OATPs and the effects of genetic variants of SLCO1B1 early in the discovery and facilitates decision making in the candidate selection and progression. Although OATP-mediated uptake is often the rate-determining process in the hepatic clearance of substrate drugs, metabolic and/or biliary components also contribute to the overall hepatic disposition and, more importantly, to liver exposure. Clinical evidence suggests that alteration in biliary efflux transport or metabolic enzymes associated with genetic polymorphism leads to change in the pharmacodynamic response of statins, for which the pharmacological target resides in the liver. Perpetrator drugs may show inhibitory and/or induction effects on transporters and enzymes simultaneously. It is therefore important to adopt models that frame these multiple processes in a mechanistic sense for quantitative DDI predictions and to deconvolute the effects of individual processes on the plasma and hepatic exposure. In vitro data-informed mechanistic static and physiologically based pharmacokinetic models are proven useful in rationalizing and predicting transporter-mediated DDIs and the complex DDIs involving transporter-enzyme interplay. © 2016, The American College of Clinical Pharmacology.

Business-IT Alignment in Trade Facilitation: A Case Study

NASA Astrophysics Data System (ADS)

Adaba, Godfried; Rusu, Lazar; El-Mekawy, Mohamed

In the information age, no organization can thrive without harnessing the power of IT. The effective deployment of IT to achieve business goals and gain competitive advantage requires the alignment of business and IT strategies of organizations. Using the Strategic Alignment Maturity model, this paper evaluates strategic alignment maturity of Customs Excise Preventive service, a frontline public organization charged with trade facilitation in Ghana. Strategic alignment maturity is at level 3; which implies the existence of an established process to leverage IT for efficiency and effectiveness. Efforts are required to strengthen alignment and fully harness the potential of IT to facilitate trade in Ghana.

Facilitated Communication: An Experimental Evaluation.

ERIC Educational Resources Information Center

Regal, Robert A.; And Others

1994-01-01

Nineteen adults with developmental disabilities, judged competent in facilitated communication, participated in a validation study using an information passing design requiring short-term recall of stimulus cards with shapes, colors, and numbers. Results failed to validate facilitated communication for the group as a whole, any individual…

Virtual OD: Facilitating Groups Online

ERIC Educational Resources Information Center

Milton, Judy; Watkins, Karen E.; Daley, Barbara J.

2005-01-01

This study examined the role of facilitators in nine virtual action learning groups. A qualitative analysis of the facilitators' interventions across all groups resulted in a typology that included group management, group process, and support interventions. A model showing the relationship among these categories proposes that effective…

Validation of a Mechanistic Model for Non-Invasive Study of Ecological Energetics in an Endangered Wading Bird with Counter-Current Heat Exchange in its Legs.

PubMed

Fitzpatrick, Megan J; Mathewson, Paul D; Porter, Warren P

2015-01-01

Mechanistic models provide a powerful, minimally invasive tool for gaining a deeper understanding of the ecology of animals across geographic space and time. In this paper, we modified and validated the accuracy of the mechanistic model Niche Mapper for simulating heat exchanges of animals with counter-current heat exchange mechanisms in their legs and animals that wade in water. We then used Niche Mapper to explore the effects of wading and counter-current heat exchange on the energy expenditures of Whooping Cranes, a long-legged wading bird. We validated model accuracy against the energy expenditure of two captive Whooping Cranes measured using the doubly-labeled water method and time energy budgets. Energy expenditure values modeled by Niche Mapper were similar to values measured by the doubly-labeled water method and values estimated from time-energy budgets. Future studies will be able to use Niche Mapper as a non-invasive tool to explore energy-based limits to the fundamental niche of Whooping Cranes and apply this knowledge to management decisions. Basic questions about the importance of counter-current exchange and wading to animal physiological tolerances can also now be explored with the model.

Validation of a Mechanistic Model for Non-Invasive Study of Ecological Energetics in an Endangered Wading Bird with Counter-Current Heat Exchange in its Legs

PubMed Central

Fitzpatrick, Megan J.; Mathewson, Paul D.; Porter, Warren P.

2015-01-01

Mechanistic models provide a powerful, minimally invasive tool for gaining a deeper understanding of the ecology of animals across geographic space and time. In this paper, we modified and validated the accuracy of the mechanistic model Niche Mapper for simulating heat exchanges of animals with counter-current heat exchange mechanisms in their legs and animals that wade in water. We then used Niche Mapper to explore the effects of wading and counter-current heat exchange on the energy expenditures of Whooping Cranes, a long-legged wading bird. We validated model accuracy against the energy expenditure of two captive Whooping Cranes measured using the doubly-labeled water method and time energy budgets. Energy expenditure values modeled by Niche Mapper were similar to values measured by the doubly-labeled water method and values estimated from time-energy budgets. Future studies will be able to use Niche Mapper as a non-invasive tool to explore energy-based limits to the fundamental niche of Whooping Cranes and apply this knowledge to management decisions. Basic questions about the importance of counter-current exchange and wading to animal physiological tolerances can also now be explored with the model. PMID:26308207

Structure of the apoptosome: mechanistic insights into activation of an initiator caspase from Drosophila

PubMed Central

Pang, Yuxuan; Bai, Xiao-chen; Yan, Chuangye; Hao, Qi; Chen, Zheqin; Wang, Jia-Wei

2015-01-01

Apoptosis is executed by a cascade of caspase activation. The autocatalytic activation of an initiator caspase, exemplified by caspase-9 in mammals or its ortholog, Dronc, in fruit flies, is facilitated by a multimeric adaptor complex known as the apoptosome. The underlying mechanism by which caspase-9 or Dronc is activated by the apoptosome remains unknown. Here we report the electron cryomicroscopic (cryo-EM) structure of the intact apoptosome from Drosophila melanogaster at 4.0 Å resolution. Analysis of the Drosophila apoptosome, which comprises 16 molecules of the Dark protein (Apaf-1 ortholog), reveals molecular determinants that support the assembly of the 2.5-MDa complex. In the absence of dATP or ATP, Dronc zymogen potently induces formation of the Dark apoptosome, within which Dronc is efficiently activated. At 4.1 Å resolution, the cryo-EM structure of the Dark apoptosome bound to the caspase recruitment domain (CARD) of Dronc (Dronc-CARD) reveals two stacked rings of Dronc-CARD that are sandwiched between two octameric rings of the Dark protein. The specific interactions between Dronc-CARD and both the CARD and the WD40 repeats of a nearby Dark protomer are indispensable for Dronc activation. These findings reveal important mechanistic insights into the activation of initiator caspase by the apoptosome. PMID:25644603

The informativity of sound modulates crossmodal facilitation of visual discrimination: a fMRI study.

PubMed

Li, Qi; Yu, Hongtao; Li, Xiujun; Sun, Hongzan; Yang, Jingjing; Li, Chunlin

2017-01-18

Many studies have investigated behavioral crossmodal facilitation when a visual stimulus is accompanied by a concurrent task-irrelevant sound. Lippert and colleagues reported that a concurrent task-irrelevant sound reduced the uncertainty of the timing of the visual display and improved perceptional responses (informative sound). However, the neural mechanism by which the informativity of sound affected crossmodal facilitation of visual discrimination remained unclear. In this study, we used event-related functional MRI to investigate the neural mechanisms underlying the role of informativity of sound in crossmodal facilitation of visual discrimination. Significantly faster reaction times were observed when there was an informative relationship between auditory and visual stimuli. The functional MRI results showed sound informativity-induced activation enhancement including the left fusiform gyrus and the right lateral occipital complex. Further correlation analysis showed that the right lateral occipital complex was significantly correlated with the behavioral benefit in reaction times. This suggests that this region was modulated by the informative relationship within audiovisual stimuli that was learnt during the experiment, resulting in late-stage multisensory integration and enhanced behavioral responses.

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

EPA Science Inventory

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

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

INCORPORATION OF MECHANISTIC INFORMATION IN THE ARSENIC PBPK MODEL DEVELOPMENT PROCESS

EPA Science Inventory

INCORPORATING MECHANISTIC INSIGHTS IN A PBPK MODEL FOR ARSENIC

Elaina M. Kenyon, Michael F. Hughes, Marina V. Evans, David J. Thomas, U.S. EPA; Miroslav Styblo, University of North Carolina; Michael Easterling, Analytical Sciences, Inc.

A physiologically based phar...

Practice Facilitators' and Leaders' Perspectives on a Facilitated Quality Improvement Program.

PubMed

McHugh, Megan; Brown, Tiffany; Liss, David T; Walunas, Theresa L; Persell, Stephen D

2018-04-01

Practice facilitation is a promising approach to helping practices implement quality improvements. Our purpose was to describe practice facilitators' and practice leaders' perspectives on implementation of a practice facilitator-supported quality improvement program and describe where their perspectives aligned and diverged. We conducted interviews with practice leaders and practice facilitators who participated in a program that included 35 improvement strategies aimed at the ABCS of heart health (aspirin use in high-risk individuals, blood pressure control, cholesterol management, and smoking cessation). Rapid qualitative analysis was used to collect, organize, and analyze the data. We interviewed 17 of the 33 eligible practice leaders, and the 10 practice facilitators assigned to those practices. Practice leaders and practice facilitators both reported value in the program's ability to bring needed, high-quality resources to practices. Practice leaders appreciated being able to set the schedule for facilitation and select among the 35 interventions. According to practice facilitators, however, relying on practice leaders to set the pace of the intervention resulted in a lower level of program intensity than intended. Practice leaders preferred targeted assistance, particularly electronic health record documentation guidance and linkages to state smoking cessation programs. Practice facilitators reported that the easiest interventions were those that did not alter care practices. The dual perspectives of practice leaders and practice facilitators provide a more holistic picture of enablers and barriers to program implementation. There may be greater opportunities to assist small practices through simple, targeted practice facilitator-supported efforts rather than larger, comprehensive quality improvement projects. © 2018 Annals of Family Medicine, Inc.

Understanding the barriers and facilitators to dietary guidelines adherence: The HEALTH study

USDA-ARS?s Scientific Manuscript database

The majority of the U.S. population does not meet recommendations for consumption of dairy, whole grain, fruit, and vegetables. The goal of this study was to understand barriers and facilitators to adherence to the Dietary Guidelines for Americans for four nutrient-rich food groups in fifth grade c...

Integration of QSAR and SAR methods for the mechanistic interpretation of predictive models for carcinogenicity

PubMed Central

Fjodorova, Natalja; Novič, Marjana

2012-01-01

The knowledge-based Toxtree expert system (SAR approach) was integrated with the statistically based counter propagation artificial neural network (CP ANN) model (QSAR approach) to contribute to a better mechanistic understanding of a carcinogenicity model for non-congeneric chemicals using Dragon descriptors and carcinogenic potency for rats as a response. The transparency of the CP ANN algorithm was demonstrated using intrinsic mapping technique specifically Kohonen maps. Chemical structures were represented by Dragon descriptors that express the structural and electronic features of molecules such as their shape and electronic surrounding related to reactivity of molecules. It was illustrated how the descriptors are correlated with particular structural alerts (SAs) for carcinogenicity with recognized mechanistic link to carcinogenic activity. Moreover, the Kohonen mapping technique enables one to examine the separation of carcinogens and non-carcinogens (for rats) within a family of chemicals with a particular SA for carcinogenicity. The mechanistic interpretation of models is important for the evaluation of safety of chemicals. PMID:24688639

Viscoelastic Emulsion Improved the Bioaccessibility and Oral Bioavailability of Crystalline Compound: A Mechanistic Study Using in Vitro and in Vivo Models.

PubMed

Ting, Yuwen; Jiang, Yike; Lan, Yaqi; Xia, Chunxin; Lin, Zhenyu; Rogers, Michael A; Huang, Qingrong

2015-07-06

The oral bioavailability of hydrophobic compound is usually limited by the poor aqueous solubility in the gastrointestinal (GI) tract. Various oral formulations were developed to enhance the systemic concentration of such molecules. Moreover, compounds with high melting temperature that appear as insoluble crystals imposed a great challenge to the development of oral vehicle. Polymethoxyflavone, an emerging category of bioactive compounds with potent therapeutic efficacies, were characterized as having a hydrophobic and highly crystalline chemical structure. To enhance the oral dosing efficiency of polymethoxyflavone, a viscoelastic emulsion system with a high static viscosity was developed and optimized using tangeretin, one of the most abundant polymethoxyflavones found in natural sources, as a modeling compound. In the present study, different in vitro and in vivo models were used to mechanistically evaluate the effect of emulsification on oral bioavailability of tangeretin. In vitro lipolysis revealed that emulsified tangeretin was digested and became bioaccessible much faster than unprocessed tangeretin oil suspension. By simulating the entire human GI tract, TNO's gastrointestinal model (TIM-1) is a valuable tool to mechanistically study the effect of emulsification on the digestion events that lead to a better oral bioavailability of tangeretin. TIM-1 result indicated that tangeretin was absorbed in the upper GI tract. Thus, a higher oral bioavailability can be expected if the compound becomes bioaccessible in the intestinal lumen soon after dosing. In vivo pharmacokinetics analysis on mice again confirmed that the oral bioavailability of tangeretin increased 2.3 fold when incorporated in the viscoelastic emulsion than unformulated oil suspension. By using the combination of in vitro and in vivo models introduced in this work, the mechanism that underlie the effect of viscoelastic emulsion on the oral bioavailability of tangeretin was well-elucidated.

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

PubMed

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

2017-08-01

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

Flow-mediated Dilation: Can New Approaches Provide Greater Mechanistic Insight into Vascular Dysfunction in Preeclampsia and Other Diseases?

PubMed Central

Weissgerber, Tracey L.

2015-01-01

Endothelial dysfunction is a key feature of preeclampsia, and may contribute to increased cardiovascular disease risk years after pregnancy. Flow-mediated dilation (FMD) is a non-invasive endothelial function test that predicts cardiovascular event risk. New protocols allow researchers to measure three components of the FMD response: FMD, low flow-mediated constriction and the shear stimulus. This review encourages researchers to think beyond “low FMD” by examining how these three components may provide additional insights into the mechanisms and location of vascular dysfunction. The review then examines what FMD studies reveal about vascular dysfunction in preeclampsia, while highlighting opportunities to gain greater mechanistic insight from new protocols. Studies using traditional protocols show that FMD is low in mid-pregnancy prior to preeclampsia, at diagnosis, and for three years post-partum. However, FMD returns to normal by ten years post-partum. Studies using new protocols are needed to gain more mechanistic insight. PMID:25182159

Base course resilient modulus for the mechanistic-empirical pavement design guide : [summary].

DOT National Transportation Integrated Search

2011-01-01

Elastic modulus determination is often used in designing pavements and evaluating pavement performance. The Mechanistic-Empirical Pavement Design Guide (MEPDG) has become an important source of guidance for pavement design and rehabilitation. MEPDG r...

Mechanistic species distribution modeling reveals a niche shift during invasion.

PubMed

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

2017-06-01

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

Understanding the facilitators and barriers of antiretroviral adherence in Peru: A qualitative study

PubMed Central

2010-01-01

Background Antiretroviral scale-up is increasing in resource-constrained settings. To date, few studies have explored the barriers and facilitators of adherence to ART in these settings. Facilitators and barriers of antiretroviral adherence in Peru are not completely understood. Methods At two clinics that serve a large number of HIV-positive individuals in Lima, Peru, 31 in-depth interviews were carried out in 2006 with adult HIV-positive individuals receiving ART. Purposive sampling was used to recruit the participants. Interviews were transcribed and coded using two Spanish-speaking researchers and a content analysis approach to identify themes in the data. Results Among the participants, 28/31 (90%) were male, 25/31 (81%) were self-identified as mestizo, and 19/31 (61%) had an education above high school. The most frequently discussed barriers to adherence included side effects, simply forgetting, inconvenience, dietary requirements, being away from home, and fear of disclosure/stigma. The most frequently discussed facilitators to adherence included having a fixed routine, understanding the need for compliance, seeing positive results, treatment knowledge, and faith in treatment. Conclusions Overall, these findings were similar to the facilitators and challenges experienced by individuals on ART in other resource constrained settings. Further treatment support tools and networks should be developed to decrease the challenges of ART adherence for HIV-positive individuals in Lima, Peru. PMID:20070889

Climatic impact of Amazon deforestation - a mechanistic model study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ning Zeng; Dickinson, R.E.; Xubin Zeng

1996-04-01

Recent general circulation model (GCM) experiments suggest a drastic change in the regional climate, especially the hydrological cycle, after hypothesized Amazon basinwide deforestation. To facilitate the theoretical understanding os such a change, we develop an intermediate-level model for tropical climatology, including atmosphere-land-ocean interaction. The model consists of linearized steady-state primitive equations with simplified thermodynamics. A simple hydrological cycle is also included. Special attention has been paid to land-surface processes. It generally better simulates tropical climatology and the ENSO anomaly than do many of the previous simple models. The climatic impact of Amazon deforestation is studied in the context of thismore » model. Model results show a much weakened Atlantic Walker-Hadley circulation as a result of the existence of a strong positive feedback loop in the atmospheric circulation system and the hydrological cycle. The regional climate is highly sensitive to albedo change and sensitive to evapotranspiration change. The pure dynamical effect of surface roughness length on convergence is small, but the surface flow anomaly displays intriguing features. Analysis of the thermodynamic equation reveals that the balance between convective heating, adiabatic cooling, and radiation largely determines the deforestation response. Studies of the consequences of hypothetical continuous deforestation suggest that the replacement of forest by desert may be able to sustain a dry climate. Scaling analysis motivated by our modeling efforts also helps to interpret the common results of many GCM simulations. When a simple mixed-layer ocean model is coupled with the atmospheric model, the results suggest a 1{degrees}C decrease in SST gradient across the equatorial Atlantic Ocean in response to Amazon deforestation. The magnitude depends on the coupling strength. 66 refs., 16 figs., 4 tabs.« less

Birth environment facilitation by midwives assisting in non-hospital births: a qualitative interview study.

PubMed

Igarashi, Toshiko; Wakita, Mariko; Miyazaki, Kikuko; Nakayama, Takeo

2014-07-01

midwifery homes (similar to birth centres) are rich in midwifery wisdom and skills that differ from those in hospital obstetrical departments, and a certain percentage of pregnant women prefer birth in these settings. This study aimed to understand the organisation of the perinatal environment considered important by independent midwives in non-hospital settings and to clarify the processes involved. semi-structured qualitative interview study and constant comparative analysis. 14 independent midwives assisting at births in midwifery homes in Japan, and six independent midwives assisting at home births. Osaka, Kyoto, Nara, and Shiga, Japan. midwives assisting at non-hospital births organised the birth environment based on the following four categories: 'an environment where the mother and family are autonomous'; 'a physical environment that facilitates birth'; 'an environment that facilitates the movement of the mother for birth'; and 'scrupulous safety preparation'. These, along with their sub-categories, are presented in this paper. independent midwives considered it important to create a candid relationship between the midwife and the woman/family from the period of pregnancy to facilitate birth in which the woman and her family were autonomous. They also organised a distinctive environment for non-hospital birth, with preparations to guarantee safety. Experiential knowledge and skills played a major part in creating an environment to facilitate birth, and the effectiveness of this needs to be investigated objectively in future research. Copyright © 2014 Elsevier Ltd. All rights reserved.

Barriers and Facilitators Affecting Patient Portal Implementation from an Organizational Perspective: Qualitative Study.

PubMed

Kooij, Laura; Groen, Wim G; van Harten, Wim H

2018-05-11

The number of patient portals is rising, and although portals can have positive effects, their implementation has major impacts on the providing health care institutions. However, little is known about the organizational factors affecting successful implementation. Knowledge of the specific barriers to and facilitators of various stakeholders is likely to be useful for future implementations. The objective of this study was to identify the barriers to and facilitators of patient portal implementation facing various stakeholders within hospital organizations in the Netherlands. Purposive sampling was used to select hospitals of various types. A total of 2 university medical centers, 3 teaching hospitals, and 2 general hospitals were included. For each, 3 stakeholders were interviewed: (1) medical professionals, (2) managers, and (3) information technology employees. In total, 21 semistructured interviews were conducted using the Grol and Wensing model, which describes barriers to and facilitators of change in health care practice at 6 levels: (1) innovation; (2) individual professional; (3) patient; (4) social context; (5) organizational context; and (6) economic and political context. Two researchers independently selected and coded quotes by applying this model using a (deductive) directed content approach. Additional factors related to technical and portal characteristics were added using the model of McGinn et al, developed for implementation of electronic health records. In total, we identified 376 quotes, 26 barriers, and 28 facilitators. Thirteen barriers and 12 facilitators were common for all stakeholder groups. The facilitators' perceived usefulness (especially less paperwork) was mentioned by all the stakeholders, followed by subjects' positive attitude. The main barriers were lack of resources (namely, lack of staff and materials), financial difficulties (especially complying with high costs, lack of reimbursements), and guaranteeing privacy and security

A mechanistic study of limonene oxidation products and pathways following cleaning activities

NASA Astrophysics Data System (ADS)

Carslaw, Nicola

2013-12-01

Indoor air pollution has caused increasing concern since the 1970s, when the advent of stricter energy efficiency measures lead to increased reports of building related symptoms. Cleaning activities have been linked to adverse health effects indoors, although it is unclear which of the components of cleaning products cause these reported health effects. This paper uses a detailed chemical model for indoor air chemistry, to identify the species formed at the highest concentrations following use of a limonene-based cleaning product. The explicit nature of the chemical mechanism also permits the key pathways to their formation to be identified. The results show that the key species in terms of gas-phase concentration are multi-functional carbonyl species including limonaldehyde, 4-acetyl-1-methyl-1-cyclohexene and other dicarbonyl species. The particle-phase was dominated by peroxide species. The predicted gas-phase concentrations for three limonene-oxidation products were compared to recently published human reference values, but found not to be high enough to cause concern for typical indoor conditions, or under high indoor ozone conditions. However, cleaning products contain a range of terpenes other than limonene, which could also produce some of the secondary products identified here, as well as more common species such as formaldehyde, glyoxal and hydrogen peroxide. A mechanistic pathway analysis shows that the secondary products formed through limonene oxidation indoors depend critically on the competition between ozone and hydroxyl radicals, such that indoor pollutant concentrations and composition could vary widely in different locations for a nominally similar residence and indoor activities. Future studies should focus on aiming to measure multi-functional carbonyl species indoors to help validate models, whilst human reference values are needed for many more relevant species indoors.

Facilitators and Barriers to Implementing Clinical Governance: A Qualitative Study among Senior Managers in Iran

PubMed Central

RAVAGHI, Hamid; RAFIEI, Sima; HEIDARPOUR, Peigham; MOHSENI, Maryam

2014-01-01

Abstract Background Health care systems should assign quality improvement as their main mission. Clinical governance (CG) is a key strategy to improve quality of health care services. The Iranian Ministry of Health and Medical Education (MOHME) has promoted CG as a framework for safeguarding quality and safety in all hospitals since 2009. The purpose of this study was to explore perceived facilitators and barriers to implementing CG by deputies for curative affairs of Iranian medical universities. Methods A qualitative study was conducted using face to face interviews with a purposeful sample of 43 deputies for curative affairs of Iranian Medical Universities and documents review. Thematic analysis was used to analyze the data Results Five themes were explored including: knowledge and attitude toward CG, culture, organizational factors, managerial factors and barriers. The main perceived facilitating factors were adequate knowledge and positive attitude toward CG, supporting culture, managers’ commitment, effective communication and well designed incentives. Pe rceived barriers were the reverse of facilitators noted above in addition to insufficient resources, legal challenges, workload and parallel quality programs. Conclusions Successful implementation of CG in Iran will require identifying barriers and challenges existing in the way of CG implementation and try to mitigate them by using appropriate facilitators. PMID:26175981

Predicting phenolic acid absorption in Caco-2 cells: a theoretical permeability model and mechanistic study.

PubMed

Farrell, Tracy L; Poquet, Laure; Dew, Tristan P; Barber, Stuart; Williamson, Gary

2012-02-01

There is a considerable need to rationalize the membrane permeability and mechanism of transport for potential nutraceuticals. The aim of this investigation was to develop a theoretical permeability equation, based on a reported descriptive absorption model, enabling calculation of the transcellular component of absorption across Caco-2 monolayers. Published data for Caco-2 permeability of 30 drugs transported by the transcellular route were correlated with the descriptors 1-octanol/water distribution coefficient (log D, pH 7.4) and size, based on molecular mass. Nonlinear regression analysis was used to derive a set of model parameters a', β', and b' with an integrated molecular mass function. The new theoretical transcellular permeability (TTP) model obtained a good fit of the published data (R² = 0.93) and predicted reasonably well (R² = 0.86) the experimental apparent permeability coefficient (P(app)) for nine non-training set compounds reportedly transported by the transcellular route. For the first time, the TTP model was used to predict the absorption characteristics of six phenolic acids, and this original investigation was supported by in vitro Caco-2 cell mechanistic studies, which suggested that deviation of the P(app) value from the predicted transcellular permeability (P(app)(trans)) may be attributed to involvement of active uptake, efflux transporters, or paracellular flux.

Learning to Lead, Leading to Learn: How Facilitators Learn to Lead Lesson Study

ERIC Educational Resources Information Center

Lewis, Jennifer M.

2016-01-01

This article presents research on how teacher developers in the United States learn to conduct lesson study. Although the practice of lesson study is expanding rapidly in the US, high-quality implementation requires skilled facilitation. In contexts such as the United States where this form of professional development is relatively novel, few…

Interactions between Kar2p and Its Nucleotide Exchange Factors Sil1p and Lhs1p Are Mechanistically Distinct*

PubMed Central

Hale, Sarah J.; Lovell, Simon C.; de Keyzer, Jeanine; Stirling, Colin J.

2010-01-01

Kar2p, an essential Hsp70 chaperone in the endoplasmic reticulum of Saccharomyces cerevisiae, facilitates the transport and folding of nascent polypeptides within the endoplasmic reticulum lumen. The chaperone activity of Kar2p is regulated by its intrinsic ATPase activity that can be stimulated by two different nucleotide exchange factors, namely Sil1p and Lhs1p. Here, we demonstrate that the binding requirements for Lhs1p are complex, requiring both the nucleotide binding domain plus the linker domain of Kar2p. In contrast, the IIB domain of Kar2p is sufficient for binding of Sil1p, and point mutations within IIB specifically blocked Sil1p-dependent activation while remaining competent for activation by Lhs1p. Taken together, these results demonstrate that the interactions between Kar2p and its two nucleotide exchange factors can be functionally resolved and are thus mechanistically distinct. PMID:20430899

Barriers to and factors facilitating breast cancer screening among Iranian women: a qualitative study.

PubMed

Lamyian, M; Hydarnia, A; Ahmadi, F; Faghihzadeh, S; Aguilar-Vafaie, M E

2007-01-01

This study used qualitative methodology to understand Iranian women's views about barriers to and factors facilitating screening for early detection of breast cancer. Using grounded theory with in-depth interviews of 31 participants, themes emerged from the data in 2 main categories (internal and external) with 3 sub-categories: women's attitudes, feelings and beliefs; women's social network experiences; and accessibility. Facilitating factors for screening were self-care, fear, proactive coping, state of mind and advocacy. Barriers were negligence, cancer-related fear, low self-efficacy, fatalism, misinformation, ineffective health communication and competing priorities.

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

PubMed

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

2014-11-01

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

Validation of pavement performance curves for the mechanistic-empirical pavement design guide.

DOT National Transportation Integrated Search

2009-02-01

The objective of this research is to determine whether the nationally calibrated performance models used in the Mechanistic-Empirical : Pavement Design Guide (MEPDG) provide a reasonable prediction of actual field performance, and if the desired accu...

An exploration of tutors' experiences of facilitating problem-based learning. Part 2--implications for the facilitation of problem based learning.

PubMed

Haith-Cooper, Melanie

2003-01-01

This paper is the second of two parts exploring a study that was undertaken to investigate the role of the tutor in facilitating problem-based learning (PBL). The first part focussed on the methodological underpinnings of the study. This paper aims to focus on the findings of the study and their implications for the facilitation of PBL. Six essential themes emerged from the findings that described the facilitation role. The tutors believed that their facilitation role was essentially structured around the decision of when to intervene and how to intervene in the PBL process. Modelling and non-verbal communication were seen as essential strategies for the facilitator. Underpinning these decisions was the need to trust in the philosophy of PBL. However, within many of the themes, there was a divergence of opinion as to how the role should actually be undertaken. Despite this, these findings have implications for the future role of PBL facilitators in Health Professional Education.

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

PubMed Central

Alexanian, Erik J.; Hartwig, John F.

2010-01-01

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 β-hydrogen elimination from alkyl complexes. The rates of reactions of the enolates were inversely dependent on the concentration of added phosphine, indicating that β-hydrogen elimination from the enolate complexes occurs after reversible dissociation of a phosphine. A normal, primary kinetic isotope effect was measured, and this effect was consistent with rate-limiting β-hydrogen elimination or C-H bond-forming reductive elimination to form methane. Reactions of substituted enolate complexes were also studied to determine the effect of the steric and electronic properties of the enolate complexes on the rates of β-hydrogen elimination. These studies showed that reactions of the alkylplatinum enolate complexes were retarded by electron-withdrawing substituents on the enolate and that reactions of enolate complexes possessing alkyl substituents at the β-position occurred at rates that were similar to those of complexes lacking alkyl substituents at this position. Despite the trend in electronic effects on the rates of reactions of enolate complexes and the substantial electronic differences between an enolate and an alkyl ligand, the rates of decomposition of the enolate complexes were similar to those of the analogous alkyl complexes. To the extent that the rates of reaction of the two types of complex are different, those involving β-hydrogen elimination from the enolate ligand were faster. A difference between the identity of the rate-determining step for

Mechanistic, Mathematical Model to Predict the Dynamics of Tissue Genesis in Bone Defects via Mechanical Feedback and Mediation of Biochemical Factors

PubMed Central

Moore, Shannon R.; Saidel, Gerald M.; Knothe, Ulf; Knothe Tate, Melissa L.

2014-01-01

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 on the

Characteristics of genomic signatures derived using univariate methods and mechanistically anchored functional descriptors for predicting drug- and xenobiotic-induced nephrotoxicity.

PubMed

Shi, Weiwei; Bugrim, Andrej; Nikolsky, Yuri; Nikolskya, Tatiana; Brennan, Richard J

2008-01-01

ABSTRACT The ideal toxicity biomarker is composed of the properties of prediction (is detected prior to traditional pathological signs of injury), accuracy (high sensitivity and specificity), and mechanistic relationships to the endpoint measured (biological relevance). Gene expression-based toxicity biomarkers ("signatures") have shown good predictive power and accuracy, but are difficult to interpret biologically. We have compared different statistical methods of feature selection with knowledge-based approaches, using GeneGo's database of canonical pathway maps, to generate gene sets for the classification of renal tubule toxicity. The gene set selection algorithms include four univariate analyses: t-statistics, fold-change, B-statistics, and RankProd, and their combination and overlap for the identification of differentially expressed probes. Enrichment analysis following the results of the four univariate analyses, Hotelling T-square test, and, finally out-of-bag selection, a variant of cross-validation, were used to identify canonical pathway maps-sets of genes coordinately involved in key biological processes-with classification power. Differentially expressed genes identified by the different statistical univariate analyses all generated reasonably performing classifiers of tubule toxicity. Maps identified by enrichment analysis or Hotelling T-square had lower classification power, but highlighted perturbed lipid homeostasis as a common discriminator of nephrotoxic treatments. The out-of-bag method yielded the best functionally integrated classifier. The map "ephrins signaling" performed comparably to a classifier derived using sparse linear programming, a machine learning algorithm, and represents a signaling network specifically involved in renal tubule development and integrity. Such functional descriptors of toxicity promise to better integrate predictive toxicogenomics with mechanistic analysis, facilitating the interpretation and risk assessment of

Contextual Facilitators and Maintaining of Compassion-Based Care: An Ethnographic Study.

PubMed

Babaei, Sima; Taleghani, Fariba; Keyvanara, Mahmoud

2017-01-01

Compassion is an important part of nursing. It fosters better relationships between nurses and their patients. Moreover, it gives patients more confidence in the care they receive. Determining facilitators of compassion are essential to holistic care. The purpose of this study was to explore these facilitators. This ethnographic study was conducted in 2014-2015 with 20 nurses, 12 patients, and 4 family members in the medical and surgical wards. Data collection was done through observations and in-depth semi-structured interviews with purposive sampling. The study was carried out in 15 months. Data analysis was performed using constant comparison based on Strauss and Corbin. Data analysis defined three main themes and eight subthemes as the fundamentals of compassion-based care. Nurses' personal factors with subcategories of personality, attitudes, and values and holistic view; and socio-cultural factors with subcategories of kindness role model, religious, and cultural values are needed to elicit compassionate behaviors. Initiator factors, with subcategories of patient suffering, patient communication demands, and patient emotional and psychological necessity are also needed to start compassionate behaviors. The findings of this study showed that nurses' communication with patients is nurse's duty in order to understand and respect the needs of patients. Attention should be paid to issues relating to compassion in nursing and practice educational programs. Indeed, creating a care environment with compassion, regardless of any shortcomings in the work condition, would help in the development of effective nursing.

Characterization of unbound materials (soils/aggregates) for mechanistic-empirical pavement design guide.

DOT National Transportation Integrated Search

2009-02-01

The resilient modulus (MR) input parameters in the Mechanistic-Empirical Pavement Design Guide (MEPDG) program have a significant effect on the projected pavement performance. The MEPDG program uses three different levels of inputs depending on the d...

Mechanistic-empirical design, implementation, and monitoring for flexible pavements : a project summary.

DOT National Transportation Integrated Search

2014-05-01

This document is a summary of tasks performed for Project ICT-R27-060. : Mechanistic-empirical (M-E)based flexible pavement design concepts and procedures were : developed in previous Illinois Cooperative Highway Research Program projects (IHR-510...

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

NASA Astrophysics Data System (ADS)

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

2016-12-01

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

In vitro solubility, dissolution and permeability studies combined with semi-mechanistic modeling to investigate the intestinal absorption of desvenlafaxine from an immediate- and extended release formulation.

PubMed

Franek, F; Jarlfors, A; Larsen, F; Holm, P; Steffansen, B

2015-09-18

Desvenlafaxine is a biopharmaceutics classification system (BCS) class 1 (high solubility, high permeability) and biopharmaceutical drug disposition classification system (BDDCS) class 3, (high solubility, poor metabolism; implying low permeability) compound. Thus the rate-limiting step for desvenlafaxine absorption (i.e. intestinal dissolution or permeation) is not fully clarified. The aim of this study was to investigate whether dissolution and/or intestinal permeability rate-limit desvenlafaxine absorption from an immediate-release formulation (IRF) and Pristiq(®), an extended release formulation (ERF). Semi-mechanistic models of desvenlafaxine were built (using SimCyp(®)) by combining in vitro data on dissolution and permeation (mechanistic part of model) with clinical data (obtained from literature) on distribution and clearance (non-mechanistic part of model). The model predictions of desvenlafaxine pharmacokinetics after IRF and ERF administration were compared with published clinical data from 14 trials. Desvenlafaxine in vivo dissolution from the IRF and ERF was predicted from in vitro solubility studies and biorelevant dissolution studies (using the USP3 dissolution apparatus), respectively. Desvenlafaxine apparent permeability (Papp) at varying apical pH was investigated using the Caco-2 cell line and extrapolated to effective intestinal permeability (Peff) in human duodenum, jejunum, ileum and colon. Desvenlafaxine pKa-values and octanol-water partition coefficients (Do:w) were determined experimentally. Due to predicted rapid dissolution after IRF administration, desvenlafaxine was predicted to be available for permeation in the duodenum. Desvenlafaxine Do:w and Papp increased approximately 13-fold when increasing apical pH from 5.5 to 7.4. Desvenlafaxine Peff thus increased with pH down the small intestine. Consequently, desvenlafaxine absorption from an IRF appears rate-limited by low Peff in the upper small intestine, which "delays" the predicted

Can Supported Reduced Vanadium Oxides form H2 from CH3OH? A Computational Gas-Phase Mechanistic Study.

PubMed

González-Navarrete, Patricio; Andrés, Juan; Calatayud, Monica

2018-02-01

A detailed density functional theory study is presented to clarify the mechanistic aspects of the methanol (CH 3 OH) dehydrogenation process to yield hydrogen (H 2 ) and formaldehyde (CH 2 O). A gas-phase vanadium oxide cluster is used as a model system to represent reduced V(III) oxides supported on TiO 2 catalyst. The theoretical results provide a complete scenario, involving several reaction pathways in which different methanol adsorption sites are considered, with presence of hydride and methoxide intermediates. Methanol dissociative adsorption process is both kinetically and thermodynamically feasible on V-O-Ti and V═O sites, and it might lead to form hydride species with interesting catalytic reactivity. The formation of H 2 and CH 2 O on reduced vanadium sites, V(III), is found to be more favorable than for oxidized vanadium species, V(V), taking place along energy barriers of 29.9 and 41.0 kcal/mol, respectively.

Mechanistic models of biofilm growth in porous media

NASA Astrophysics Data System (ADS)

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

2014-07-01

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

The Influence of Facilitator and Facilitation Characteristics on Participants' Ratings of Stepfamily Education

ERIC Educational Resources Information Center

Higginbotham, Brian J.; Myler, Cory

2010-01-01

We examine the relative importance of facilitator and facilitation characteristics on participant ratings of a stepfamily education program. Data from 48 facilitators and 598 participants suggest that quality facilitation is more meaningful to participants than whether facilitators have comparable demographic characteristics or life experiences.…

Mechanistic elucidation of the antitumor properties of withaferin A in breast cancer

PubMed Central

Nagalingam, Arumugam; Kuppusamy, Panjamurthy; Singh, Shivendra V.; Sharma, Dipali; Saxena, Neeraj K.

2014-01-01

Withaferin A (WFA) is a steroidal lactone with antitumor effects manifested at multiple levels which are mechanistically obscure. Using a phospho-kinase screening array, we discovered that WFA activated phosphorylation of the S6 kinase RSK in breast cancer cells. Pursuing this observation, we defined activation of ERK-RSK and Elk1-CHOP kinase pathways in upregulating transcription of the death receptor DR5. Through this route, WFA acted as an effective DR5 activator capable of potentiating the biological effects of celecoxib, etoposide and TRAIL. Accordingly, WFA treatment inhibited breast tumor formation in xenograft and MMTV-neu mouse models in a manner associated with activation of the ERK/RSK axis, DR5 upregulation and elevated nuclear accumulation of Elk1 and CHOP. Together, our results offer mechanistic insight into how WFA inhibits breast tumor growth. PMID:24732433

MECHANISTIC DATA & CANCER RISK ASSESSMENT: THE NEED FOR QUANTITATIVE MOLECULAR ENDPOINTS

EPA Science Inventory

The cancer risk assessment process as currently proposed by the U.S. Environmental Protection Agency allows for the use of mechanistic data to inform the low dose tumor response in humans and in laboratory animals. The aim is to reduce the reliance on defaults that introduce a re...

A mechanistic assessment of nutrient flushing at the catchment scale

Treesearch

Willem J. van Verseveld; Jeffrey J. McDonnell; Kate Lajtha

2008-01-01

This paper mechanistically assesses the flushing mechanism of DOC, DON, and DIN at the hillslope and catchment scales during two storm events, in a small catchment (WS10), H.J. Andrews Experimental Forest in the western Cascade Mountains of Oregon. Using a combination of natural tracer and hydrometric data, and end-member mixing analysis, we were able to describe the...

Predictive and mechanistic multivariate linear regression models for reaction development

PubMed Central

Santiago, Celine B.; Guo, Jing-Yao

2018-01-01

Multivariate Linear Regression (MLR) models utilizing computationally-derived and empirically-derived physical organic molecular descriptors are described in this review. Several reports demonstrating the effectiveness of this methodological approach towards reaction optimization and mechanistic interrogation are discussed. A detailed protocol to access quantitative and predictive MLR models is provided as a guide for model development and parameter analysis. PMID:29719711

School Administrator Perceptions of Cyberbullying Facilitators and Barriers to Preventive Action: A Qualitative Study.

PubMed

Young, Rachel; Tully, Melissa; Ramirez, Marizen

2017-06-01

Schools are often held responsible for preventing or addressing cyberbullying, yet little is known about school administrator perceptions of cyberbullying and the challenges they face in addressing this public health issue. The goal of this study is to examine school administrators' perceptions of the facilitators of cyberbullying and barriers to primary and secondary prevention strategies. Public school administrators ( N = 36) participated in in-depth interviews about bullying and discussed their experiences with cyberbullying and their perceptions of cyberbullying facilitators and barriers to prevention. Three main themes arose from the analysis: (1) cyberbullying as a major challenge; (2) facilitators of cyberbullying and barriers to preventive action, including parents and technology; and (3) prevention efforts, including unclear jurisdiction for action, primary versus secondary prevention efforts, and technology attributes that facilitate school response to bullying. Although administrators perceive cyberbullying as a major challenge facing their schools, they are often unsure about appropriate primary and secondary prevention efforts. Relationships with parents and police complicate response and prevention as schools attempt to navigate unclear jurisdiction. Additionally, technology presents a challenge to schools because it is seen as an enabler of cyberbullying, a facilitator of prevention, and a necessary part of education efforts. Lack of research on prevention strategies, parents' knowledge and attitudes, and confusion about responsibility for addressing cyberbullying are barriers to action. Findings suggest administrators could benefit from additional clarity on which strategies are most effective for primary prevention of cyberbullying, and that prevention strategies should proactively involve parents to promote effective collaboration with schools.

Classical autophagy proteins LC3B and ATG4B facilitate melanosome movement on cytoskeletal tracks.

PubMed

Ramkumar, Amrita; Murthy, Divya; Raja, Desingu Ayyappa; Singh, Archana; Krishnan, Anusha; Khanna, Sangeeta; Vats, Archana; Thukral, Lipi; Sharma, Pushkar; Sivasubbu, Sridhar; Rani, Rajni; Natarajan, Vivek T; Gokhale, Rajesh S

2017-08-03

Macroautophagy/autophagy is a dynamic and inducible catabolic process that responds to a variety of hormonal and environmental cues. Recent studies highlight the interplay of this central pathway in a variety of pathophysiological diseases. Although defective autophagy is implicated in melanocyte proliferation and pigmentary disorders, the mechanistic relationship between the 2 pathways has not been elucidated. In this study, we show that autophagic proteins LC3B and ATG4B mediate melanosome trafficking on cytoskeletal tracks. While studying melanogenesis, we observed spatial segregation of LC3B-labeled melanosomes with preferential absence at the dendritic ends of melanocytes. This LC3B labeling of melanosomes did not impact the steady-state levels of these organelles but instead facilitated their intracellular positioning. Melanosomes primarily traverse on microtubule and actin cytoskeletal tracks and our studies reveal that LC3B enables the assembly of microtubule translocon complex. At the microtubule-actin crossover junction, ATG4B detaches LC3B from melanosomal membranes by enzymatic delipidation. Further, by live-imaging we show that melanosomes transferred to keratinocytes lack melanocyte-specific LC3B. Our study thus elucidates a new role for autophagy proteins in directing melanosome movement and reveal the unconventional use of these proteins in cellular trafficking pathways. Such crosstalk between the central cellular function and housekeeping pathway may be a crucial mechanism to balance melanocyte bioenergetics and homeostasis.

Using learning theory, interprofessional facilitation competencies, and behavioral indicators to evaluate facilitator training.

PubMed

LeGros, Theresa A; Amerongen, Helen M; Cooley, Janet H; Schloss, Ernest P

2015-01-01

Despite the increasing need for faculty and preceptors skilled in interprofessional facilitation (IPF), the relative novelty of the field poses a challenge to the development and evaluation of IPF programs. We use learning theory and IPF competencies with associated behavioral indicators to develop and evaluate six key messages in IPF training and experience. Our mixed methods approach included two phases: quantitative data collection with embedded qualitative data, followed by qualitative data collection in explanatory sequential fashion. This enabled triangulated analyses of both data types and of facilitation behaviors from facilitator and student perspectives. Results indicate the competency-based training was effective. Facilitators felt comfortable performing behaviors associated with IPF competencies; student observations of those behaviors supported facilitator self-reported performance. Overall, students perceived more facilitation opportunities than facilitators. Findings corroborate the importance of recruiting seasoned facilitators and establishing IPF guidelines that acknowledge variable team dynamics and help facilitators recognize teachable moments.

Selection criteria and facilitation training for the study of groupware

NASA Technical Reports Server (NTRS)

Robichaux, Barry P.

1993-01-01

Computer support for planning and decision making groups is a growing trend in the 90s. Groupware is a name often applied to group software and has been defined as 'computer-based systems that support groups engaged in a common task (or goal) and that provide an interface to a shared environment'. Unlike most single-user software, groupware assists user groups in their collaboration, coordination, and communication efforts. This paper focuses on groupware to support the meeting process. These systems are often called group decision support systems (GDSS), electronic meeting systems (EMS), or group support systems (GSS). The term 'meeting support groupware' is used here to include any computer-based system to support meetings. In order to understand this technology, one must first understand groups, what they do and the problems they face, and groupware, a wide range of technology to support group work. Guidelines for selecting groups for study as part of an overall research plan are provided in this document. These were taken from the literature and from persons for whom the information in this paper was targeted. Also, guidelines for facilitation training are discussed. Familiarity with known and accepted techniques are the principle duties of the facilitator and any form of training must include practice in using these techniques.

Factors related to the nursing student-patient relationship: the students' perspective.

PubMed

Suikkala, Arja; Leino-Kilpi, Helena; Katajisto, Jouko

2008-07-01

The aim of this study was to describe nursing students' perceptions of factors related to three types of student-patient relationship identified in an earlier study: mechanistic, authoritative and facilitative. Another aim was to identify which factors predict the type of relationship. A convenience sample of 310 Bachelor of Health Care students was recruited. The data were collected by using a questionnaire especially designed for this study. Data analysis used the chi-square test, Fisher's exact test, one-way analysis of variance and multinomial logistic regression. Older age was the only significant predictor of a facilitative relationship, whereas fourth-year studies and support received from a person other than supervisor predicted an authoritative relationship. Furthermore, students in authoritative and facilitative relationships had a more positive perception of the patient's attributes as a patient and of patient's improved health and commitment to self-care than students in a mechanistic relationship. A positive perception of the atmosphere during collaboration was more common among students in an authoritative relationship than in a mechanistic relationship. The findings of this study offer useful clues for developing nursing education and empowering patients with a view to improving the quality of nursing care.

Mechanistic Studies of Hafnium-Pyridyl Amido-Catalyzed 1-Octene Polymerization and Chain Transfer Using Quench-Labeling Methods.

PubMed

Cueny, Eric S; Johnson, Heather C; Anding, Bernie J; Landis, Clark R

2017-08-30

Chromophore quench-labeling applied to 1-octene polymerization as catalyzed by hafnium-pyridyl amido precursors enables quantification of the amount of active catalyst and observation of the molecular weight distribution (MWD) of Hf-bound polymers via UV-GPC analysis. Comparison of the UV-detected MWD with the MWD of the "bulk" (all polymers, from RI-GPC analysis) provides important mechanistic information. The time evolution of the dual-detection GPC data, concentration of active catalyst, and monomer consumption suggests optimal activation conditions for the Hf pre-catalyst in the presence of the activator [Ph 3 C][B(C 6 F 5 ) 4 ]. The chromophore quench-labeling agents do not react with the chain-transfer agent ZnEt 2 under the reaction conditions. Thus, Hf-bound polymeryls are selectively labeled in the presence of zinc-polymeryls. Quench-labeling studies in the presence of ZnEt 2 reveal that ZnEt 2 does not influence the rate of propagation at the Hf center, and chain transfer of Hf-bound polymers to ZnEt 2 is fast and quasi-irreversible. The quench-label techniques represent a means to study commercial polymerization catalysts that operate with high efficiency at low catalyst concentrations without the need for specialized equipment.

The lens of the eye: exposures in the UK medical sector and mechanistic studies of radiation effects.

PubMed

Bouffler, S D; Peters, S; Gilvin, P; Slack, K; Markiewicz, E; Quinlan, R A; Gillan, J; Coster, M; Barnard, S; Rothkamm, K; Ainsbury, E

2015-06-01

The recommendation from the International Commission on Radiological Protection that the occupational equivalent dose limit for the lens of the eye should be reduced to 20 mSv year(-1), averaged over 5 years with no year exceeding 50 mSv, has stimulated a discussion on the practicalities of implementation of this revised dose limit, and the most appropriate risk and protection framework to adopt. This brief paper provides an overview of some of the drivers behind the move to a lower recommended dose limit. The issue of implementation in the medical sector in the UK has been addressed through a small-scale survey of doses to the lens of the eye amongst interventional cardiologists and radiologists. In addition, a mechanistic study of early and late post-irradiation changes in the lens of the eye in in-vivo-exposed mice is outlined. Surveys and studies such as those described can contribute to a deeper understanding of fundamental and practical issues, and therefore contribute to a robust evidence base for ensuring adequate protection of the eye while avoiding undesirable restrictions to working practices. © The International Society for Prosthetics and Orthotics Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

3,4-Methylenedioxymethamphetamine facilitates fear extinction learning.

PubMed

Young, M B; Andero, R; Ressler, K J; Howell, L L

2015-09-15

Acutely administered 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') has been proposed to have long-term positive effects on post-traumatic stress disorder (PTSD) symptoms when combined with psychotherapy. No preclinical data support a mechanistic basis for these claims. Given the persistent nature of psychotherapeutic gains facilitated by MDMA, we hypothesized that MDMA improves fear extinction learning, a key process in exposure-based therapies for PTSD. In these experiments, mice were first exposed to cued fear conditioning and treated with drug vehicle or MDMA before extinction training 2 days later. MDMA was administered systemically and also directly targeted to brain structures known to contribute to extinction. In addition to behavioral measures of extinction, changes in mRNA levels of brain-derived neurotrophic factor (Bdnf) and Fos were measured after MDMA treatment and extinction. MDMA (7.8 mg kg(-1)) persistently and robustly enhanced long-term extinction when administered before extinction training. MDMA increased the expression of Fos in the amygdala and medial prefrontal cortex (mPFC), whereas increases in Bdnf expression were observed only in the amygdala after extinction training. Extinction enhancements were recapitulated when MDMA (1 μg) was infused directly into the basolateral complex of the amygdala (BLA), and enhancement was abolished when BDNF signaling was inhibited before extinction. These findings suggest that MDMA enhances fear memory extinction through a BDNF-dependent mechanism, and that MDMA may be a useful adjunct to exposure-based therapies for PTSD and other anxiety disorders characterized by altered fear learning.

Functional and mechanistic diversity of distal transcription enhancers

PubMed Central

Bulger, Michael; Groudine, Mark

2013-01-01

Biological differences among metazoans, and between cell types in a given organism, arise in large part due to differences in gene expression patterns. The sequencing of multiple metazoan genomes, coupled with recent advances in genome-wide analysis of histone modifications and transcription factor binding, has revealed that among regulatory DNA sequences, gene-distal enhancers appear to exhibit the greatest diversity and cell-type specificity. Moreover, such elements are emerging as important targets for mutations that can give rise to disease and to genetic variability that underlies evolutionary change. Studies of long-range interactions between distal genomic sequences in the nucleus indicate that enhancers are often important determinants of nuclear organization, contributing to a general model for enhancer function that involves direct enhancer-promoter contact. In a number of systems, however, mechanisms for enhancer function are emerging that do not fit solely within such a model, suggesting that enhancers as a class of DNA regulatory element may be functionally and mechanistically diverse. PMID:21295696

The coefficient of restitution of pressurized balls: a mechanistic model

NASA Astrophysics Data System (ADS)

Georgallas, Alex; Landry, Gaëtan

2016-01-01

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

Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry: Mechanistic Studies and Methods for Improving the Structural Identification of Carbohydrates

PubMed Central

Lai, Yin-Hung; Wang, Yi-Sheng

2017-01-01

Although matrix-assisted laser desorption/ionization (MALDI) mass spectrometry is one of the most widely used soft ionization methods for biomolecules, the lack of detailed understanding of ionization mechanisms restricts its application in the analysis of carbohydrates. Structural identification of carbohydrates achieved by MALDI mass spectrometry helps us to gain insights into biological functions and pathogenesis of disease. In this review, we highlight mechanistic details of MALDI, including both ionization and desorption. Strategies to improve the ion yield of carbohydrates are also reviewed. Furthermore, commonly used fragmentation methods to identify the structure are discussed. PMID:28959517

Mechanistic Studies of Combustion and Structure Formation During Synthesis of Advanced Materials

NASA Technical Reports Server (NTRS)

Varma, A.; Lau, C.; Mukasyan, A. S.

2001-01-01

reactants occurs within each particle, and mixtures of elemental powders, where interparticle contacts are important for the reaction; and 3) Mechanistic Studies of Phase Separation in Combustion of Thermite Systems. Studies are devoted to experiments on thermite systems (metal oxide-reducing metal) where phase separation processes occur to produce alloys with tailored compositions and properties. The separation may be either gravity-driven or due to surface forces, and systematic studies to elucidate the true mechanism are being conducted. The knowledge obtained will be used to find the most promising ways of controlling the microstructure and properties of combustion-synthesized materials. Low-gravity experiments are essential to create idealized an environment for insights into the physics and chemistry of advanced material synthesis processes.

Mechanistic Physiologically Based Pharmacokinetic Modeling of the Dissolution and Food Effect of a Biopharmaceutics Classification System IV Compound-The Venetoclax Story.

PubMed

Emami Riedmaier, Arian; Lindley, David J; Hall, Jeffrey A; Castleberry, Steven; Slade, Russell T; Stuart, Patricia; Carr, Robert A; Borchardt, Thomas B; Bow, Daniel A J; Nijsen, Marjoleen

2018-01-01

Venetoclax, a selective B-cell lymphoma-2 inhibitor, is a biopharmaceutics classification system class IV compound. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to mechanistically describe absorption and disposition of an amorphous solid dispersion formulation of venetoclax in humans. A mechanistic PBPK model was developed incorporating measured amorphous solubility, dissolution, metabolism, and plasma protein binding. A middle-out approach was used to define permeability. Model predictions of oral venetoclax pharmacokinetics were verified against clinical studies of fed and fasted healthy volunteers, and clinical drug interaction studies with strong CYP3A inhibitor (ketoconazole) and inducer (rifampicin). Model verification demonstrated accurate prediction of the observed food effect following a low-fat diet. Ratios of predicted versus observed C max and area under the curve of venetoclax were within 0.8- to 1.25-fold of observed ratios for strong CYP3A inhibitor and inducer interactions, indicating that the venetoclax elimination pathway was correctly specified. The verified venetoclax PBPK model is one of the first examples mechanistically capturing absorption, food effect, and exposure of an amorphous solid dispersion formulated compound. This model allows evaluation of untested drug-drug interactions, especially those primarily occurring in the intestine, and paves the way for future modeling of biopharmaceutics classification system IV compounds. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Barriers and facilitators experienced in collaborative prospective research in orthopaedic oncology: A qualitative study.

PubMed

Rendon, J S; Swinton, M; Bernthal, N; Boffano, M; Damron, T; Evaniew, N; Ferguson, P; Galli Serra, M; Hettwer, W; McKay, P; Miller, B; Nystrom, L; Parizzia, W; Schneider, P; Spiguel, A; Vélez, R; Weiss, K; Zumárraga, J P; Ghert, M

2017-05-01

As tumours of bone and soft tissue are rare, multicentre prospective collaboration is essential for meaningful research and evidence-based advances in patient care. The aim of this study was to identify barriers and facilitators encountered in large-scale collaborative research by orthopaedic oncological surgeons involved or interested in prospective multicentre collaboration. All surgeons who were involved, or had expressed an interest, in the ongoing Prophylactic Antibiotic Regimens in Tumour Surgery (PARITY) trial were invited to participate in a focus group to discuss their experiences with collaborative research in this area. The discussion was digitally recorded, transcribed and anonymised. The transcript was analysed qualitatively, using an analytic approach which aims to organise the data in the language of the participants with little theoretical interpretation. The 13 surgeons who participated in the discussion represented orthopaedic oncology practices from seven countries (Argentina, Brazil, Italy, Spain, Denmark, United States and Canada). Four categories and associated themes emerged from the discussion: the need for collaboration in the field of orthopaedic oncology due to the rarity of the tumours and the need for high level evidence to guide treatment; motivational factors for participating in collaborative research including establishing proof of principle, learning opportunity, answering a relevant research question and being part of a collaborative research community; barriers to participation including funding, personal barriers, institutional barriers, trial barriers, and administrative barriers and facilitators for participation including institutional facilitators, leadership, authorship, trial set-up, and the support of centralised study coordination. Orthopaedic surgeons involved in an ongoing international randomised controlled trial (RCT) were motivated by many factors to participate. There were a number of barriers to and facilitators

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

NASA Astrophysics Data System (ADS)

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.

Motivators, Facilitators, and Barriers to Physical Activity in Older Adults: A Qualitative Study.

PubMed

Miller, Wendy; Brown, Patrick R

In this descriptive, qualitative research study, the researchers used semistructured interviews with older adults who engaged in regular physical activity to identify common motivators, facilitators, and barriers to participating in regular exercise. The authors used these interviews to identify major themes and discuss implications for population health.

Barriers and Facilitators Affecting Patient Portal Implementation from an Organizational Perspective: Qualitative Study.

PubMed Central

Kooij, Laura; Groen, Wim G

2018-01-01

Background The number of patient portals is rising, and although portals can have positive effects, their implementation has major impacts on the providing health care institutions. However, little is known about the organizational factors affecting successful implementation. Knowledge of the specific barriers to and facilitators of various stakeholders is likely to be useful for future implementations. Objective The objective of this study was to identify the barriers to and facilitators of patient portal implementation facing various stakeholders within hospital organizations in the Netherlands. Methods Purposive sampling was used to select hospitals of various types. A total of 2 university medical centers, 3 teaching hospitals, and 2 general hospitals were included. For each, 3 stakeholders were interviewed: (1) medical professionals, (2) managers, and (3) information technology employees. In total, 21 semistructured interviews were conducted using the Grol and Wensing model, which describes barriers to and facilitators of change in health care practice at 6 levels: (1) innovation; (2) individual professional; (3) patient; (4) social context; (5) organizational context; and (6) economic and political context. Two researchers independently selected and coded quotes by applying this model using a (deductive) directed content approach. Additional factors related to technical and portal characteristics were added using the model of McGinn et al, developed for implementation of electronic health records. Results In total, we identified 376 quotes, 26 barriers, and 28 facilitators. Thirteen barriers and 12 facilitators were common for all stakeholder groups. The facilitators’ perceived usefulness (especially less paperwork) was mentioned by all the stakeholders, followed by subjects’ positive attitude. The main barriers were lack of resources (namely, lack of staff and materials), financial difficulties (especially complying with high costs, lack of

User's perspectives of barriers and facilitators to implementing quality colonoscopy services in Canada: a study protocol.

PubMed

Jobin, Gilles; Gagnon, Marie Pierre; Candas, Bernard; Dubé, Catherine; Ben Abdeljelil, Anis; Grenier, Sonya

2010-11-02

Colorectal cancer (CRC) represents a serious and growing health problem in Canada. Colonoscopy is used for screening and diagnosis of symptomatic or high CRC risk individuals. Although a number of countries are now implementing quality colonoscopy services, knowledge synthesis of barriers and facilitators perceived by healthcare professionals and patients during implementation has not been carried out. In addition, the perspectives of various stakeholders towards the implementation of quality colonoscopy services and the need of an efficient organisation of such services have been reported in the literature but have not been synthesised yet. The present study aims to produce a comprehensive synthesis of actual knowledge on the barriers and facilitators perceived by all stakeholders to the implementation of quality colonoscopy services in Canada. First, we will conduct a comprehensive review of the scientific literature and other published documentation on the barriers and facilitators to implementing quality colonoscopy services. Standardised literature searches and data extraction methods will be used. The quality of the studies and their relevance to informing decisions on colonoscopy services implementation will be assessed. For each group of users identified, barriers and facilitators will be categorised and compiled using narrative synthesis and meta-analytical techniques. The principle factors identified for each group of users will then be validated for its applicability to various Canadian contexts using the Delphi study method. Following this study, a set of strategies will be identified to inform decision makers involved in the implementation of quality colonoscopy services across Canadian jurisdictions. This study will be the first to systematically summarise the barriers and facilitators to implementation of quality colonoscopy services perceived by different groups and to consider the local contexts in order to ensure the applicability of this

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

ERIC Educational Resources Information Center

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

2017-01-01

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

Supervision of Facilitators in a Multisite Study: Goals, Process, and Outcomes

PubMed Central

2010-01-01

Objective To describe the aims, implementation, and desired outcomes of facilitator supervision for both interventions (treatment and control) in Project Eban and to present the Eban Theoretical Framework for Supervision that guided the facilitators’ supervision. The qualifications and training of supervisors and facilitators are also described. Design This article provides a detailed description of supervision in a multisite behavioral intervention trial. The Eban Theoretical Framework for Supervision is guided by 3 theories: cognitive behavior therapy, the Life-long Model of Supervision, and “Empowering supervisees to empower others: a culturally responsive supervision model.” Methods Supervision is based on the Eban Theoretical Framework for Supervision, which provides guidelines for implementing both interventions using goals, process, and outcomes. Results Because of effective supervision, the interventions were implemented with fidelity to the protocol and were standard across the multiple sites. Conclusions Supervision of facilitators is a crucial aspect of multisite intervention research quality assurance. It provides them with expert advice, optimizes the effectiveness of facilitators, and increases adherence to the protocol across multiple sites. Based on the experience in this trial, some of the challenges that arise when conducting a multisite randomized control trial and how they can be handled by implementing the Eban Theoretical Framework for Supervision are described. PMID:18724192

New mechanistic insights in the NH 3-SCR reactions at low temperature

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ruggeri, Maria Pia; Selleri, Tomasso; Nova, Isabella

2016-05-06

The present study is focused on the investigation of the low temperature Standard SCR reaction mechanism over Fe- and Cu-promoted zeolites. Different techniques are employed, including in situ DRIFTS, transient reaction analysis and chemical trapping techniques. The results present strong evidence of nitrite formation in the oxidative activation of NO and of their role in SCR reactions. These elements lead to a deeper understanding of the standard SCR chemistry at low temperature and can potentially improve the consistency of mechanistic mathematical models. Furthermore, comprehension of the mechanism on a fundamental level can contribute to the development of improved SCR catalysts.

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

EPA Science Inventory

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

Characterization of material properties for mechanistic-empirical pavement design in Wyoming : final report.

DOT National Transportation Integrated Search

2016-12-01

The Wyoming Department of Transportation (WYDOT) recently transitioned from the empirical AASHTO Design for Design of Pavement Structures to the Mechanistic Empirical Pavement Design Guide (MEPDG) as their standard pavement design procedure. A compre...

Iranian Nurses' Views on Barriers and Facilitators in Patient Education: A Cross-Sectional Study.

PubMed

Ramezanli, Somayeh; Badiyepeymaie Jahromi, Zohreh

2015-03-18

As a major factor in patient-centered care, patient education has a great impact on the quality of care provided by nurses; however, clinical nurses' performance with regard to patient education is not satisfactory. This study is an attempt to investigate barriers and facilitators in patient education from nurses' point of view. 122 nurses at Jahrom University of Medical Sciences participated in this descriptive-cross sectional study. Sampling was based on the census method. The questionnaire used to collect data included questions about nurses' demography, barriers (10 questions), and facilitators (10 questions) in patient education. The questionnaire was designed to be completed independently. To analyze the data, the researchers used descriptive statistics, including frequency, mean and standard deviation. The highest scores related to barriers to patient education were: nurses' insufficient knowledge, patients' physical and emotional unpreparedness, and lack of a proper environment for education. The most important facilitators, on the other hand, were: enhancement of instructing nurses' knowledge and skills, motivating nurses, and a step-by-step approach to patient education. It is important that nurses be prepared and motivated to train their patients. By satisfactory patient education on the part of nurses, patients will be more willing to cooperate in the treatment process.

Iranian Nurses’ Views on Barriers and Facilitators in Patient Education: A Cross-Sectional Study

PubMed Central

Ramezanli, Somayeh; Jahromi, Zohreh Badiyepeymaie

2015-01-01

Background: As a major factor in patient-centered care, patient education has a great impact on the quality of care provided by nurses; however, clinical nurses’ performance with regard to patient education is not satisfactory. This study is an attempt to investigate barriers and facilitators in patient education from nurses’ point of view. Methods: 122 nurses at Jahrom University of Medical Sciences participated in this descriptive-cross sectional study. Sampling was based on the census method. The questionnaire used to collect data included questions about nurses’ demography, barriers (10 questions), and facilitators (10 questions) in patient education. The questionnaire was designed to be completed independently. To analyze the data, the researchers used descriptive statistics, including frequency, mean and standard deviation. Results: The highest scores related to barriers to patient education were: nurses’ insufficient knowledge, patients’ physical and emotional unpreparedness, and lack of a proper environment for education. The most important facilitators, on the other hand, were: enhancement of instructing nurses’ knowledge and skills, motivating nurses, and a step-by-step approach to patient education. Conclusion: It is important that nurses be prepared and motivated to train their patients. By satisfactory patient education on the part of nurses, patients will be more willing to cooperate in the treatment process. PMID:26156926

Analysis of Initial Cell Spreading Using Mechanistic Contact Formulations for a Deformable Cell Model

PubMed Central

Odenthal, Tim; Smeets, Bart; Van Liedekerke, Paul; Tijskens, Engelbert; Van Oosterwyck, Hans; Ramon, Herman

2013-01-01

Adhesion governs to a large extent the mechanical interaction between a cell and its microenvironment. As initial cell spreading is purely adhesion driven, understanding this phenomenon leads to profound insight in both cell adhesion and cell-substrate interaction. It has been found that across a wide variety of cell types, initial spreading behavior universally follows the same power laws. The simplest cell type providing this scaling of the radius of the spreading area with time are modified red blood cells (RBCs), whose elastic responses are well characterized. Using a mechanistic description of the contact interaction between a cell and its substrate in combination with a deformable RBC model, we are now able to investigate in detail the mechanisms behind this universal power law. The presented model suggests that the initial slope of the spreading curve with time results from a purely geometrical effect facilitated mainly by dissipation upon contact. Later on, the spreading rate decreases due to increasing tension and dissipation in the cell's cortex as the cell spreads more and more. To reproduce this observed initial spreading, no irreversible deformations are required. Since the model created in this effort is extensible to more complex cell types and can cope with arbitrarily shaped, smooth mechanical microenvironments of the cells, it can be useful for a wide range of investigations where forces at the cell boundary play a decisive role. PMID:24146605

A traffic data plan for mechanistic-empirical pavement designs (2002 pavement design guide).

DOT National Transportation Integrated Search

2003-01-01

The Virginia Department of Transportation (VDOT) is preparing to implement the mechanistic-empirical pavement design methodology being developed under the National Cooperative Research Program's Project 1-37A, commonly referred to as the 2002 Pavemen...

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

PubMed

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

2014-11-20

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

Mechanistic studies on reduced exercise performance and cardiac deconditioning with simulated zero gravity

NASA Technical Reports Server (NTRS)

Tipton, Charles M.

1991-01-01

The primary purpose of this research is to study the physiological mechanisms associated with the exercise performance of rats subjected to conditions of simulated weightlessness. A secondary purpose is to study related physiological changes associated with other systems. To facilitate these goals, a rodent suspension model was developed (Overton-Tipton) and a VO2 max testing procedure was perfected. Three methodological developments occurred during this past year deserving of mention. The first was the refinement of the tail suspension model so that (1) the heat dissipation functions of the caudal artery can be better utilized, and (2) the blood flow distribution to the tail would have less external constriction. The second was the development on a one-leg weight bearing model for use in simulated weightlessness studies concerned with change in muscle mass, muscle enzyme activity, and hind limb blood flow. The chemical body composition of 30 rats was determined and used to develop a prediction equation for percent fat using underwater weighing procedures to measure carcass specific gravity and to calculate body density, body fat, and fat free mass.

Field verification of KDOT's Superpave mixture properties to be used as inputs in the NCHRP mechanistic-empirical pavement design guide.

DOT National Transportation Integrated Search

2009-01-01

In the MechanisticEmpirical Pavement Design Guide (M-EPDG), prediction of flexible pavement response and performance needs an input of dynamic modulus of hot-mix asphalt (HMA) at all three levels of hierarchical inputs. This study was intended to ...

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

ERIC Educational Resources Information Center

Bhattacharyya, Gautam

2013-01-01

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

A new mechanistic framework to predict OCS fluxes in soils

NASA Astrophysics Data System (ADS)

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

2015-04-01

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

Mechanistic Insights of Ethanol Steam Reforming over Ni–CeO x (111): The Importance of Hydroxyl Groups for Suppressing Coke Formation

DOE PAGES

Liu, Zongyuan; Duchoň, Tomáš; Wang, Huanru; ...

2015-07-30

We have studied the reaction of ethanol and water over Ni–CeO 2-x(111) model surfaces to elucidate the mechanistic steps associated with the ethanol steam reforming (ESR) reaction. Our results provide insights about the importance of hydroxyl groups to the ESR reaction over Ni-based catalysts. Systematically, we have investigated the reaction of ethanol on Ni–CeO 2-x(111) at varying Ce³⁺ concentrations (CeO 1.8–2.0) with absence/presence of water using a combination of soft X-ray photoelectron spectroscopy (sXPS) and temperature-programmed desorption (TPD). Consistent with previous reports, upon annealing, metallic Ni formed on reduced ceria while NiO was the main component on fully oxidized ceria.more » Ni⁰ is the active phase leading to both the C–C and C–H cleavage of ethanol but is also responsible for carbon accumulation or coking. We have identified a Ni₃C phase that formed prior to the formation of coke. At temperatures above 600K, the lattice oxygen from ceria and the hydroxyl groups from water interact cooperatively in the removal of coke, likely through a strong metal–support interaction between nickel and ceria that facilitates oxygen transfer.« less

Development of traffic data input resources for the mechanistic empirical pavement design process.

DOT National Transportation Integrated Search

2011-12-12

The Mechanistic-Empirical Pavement Design Guide (MEPDG) for New and Rehabilitated Pavement Structures uses : nationally based data traffic inputs and recommends that state DOTs develop their own site-specific and regional : values. To support the MEP...

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

NASA Astrophysics Data System (ADS)

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

2016-07-01

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

Perceived Barriers and Facilitators to School Social Work Practice: A Mixed-Methods Study

ERIC Educational Resources Information Center

Teasley, Martell; Canifield, James P.; Archuleta, Adrian J.; Crutchfield, Jandel; Chavis, Annie McCullough

2012-01-01

Understanding barriers to practice is a growing area within school social work research. Using a convenience sample of 284 school social workers, this study replicates the efforts of a mixed-method investigation designed to identify barriers and facilitators to school social work practice within different geographic locations. Time constraints and…

Toward Facilitative Mentoring and Catalytic Interventions

ERIC Educational Resources Information Center

Smith, Melissa K.; Lewis, Marilyn

2015-01-01

In TESOL teacher mentoring, giving advice can be conceptualized as a continuum, ranging from directive to facilitative feedback. The goal, over time, is to lead toward the facilitative end of the continuum and specifically to catalytic interventions that encourage self-reflection and autonomous learning. This study begins by examining research on…

Barriers and facilitators of adherence to antidepressants among outpatients with major depressive disorder: A qualitative study.

PubMed

Ho, Siew Ching; Jacob, Sabrina Anne; Tangiisuran, Balamurugan

2017-01-01

One of the major challenges in treating major depressive disorder (MDD) is patients' non-adherence to medication. This study aimed to explore the barriers and facilitators of patients' adherence to antidepressants among outpatients with MDD. Semi-structured and individual in-depth interviews were conducted among patients with MDD who were taking antidepressants, in the psychiatric clinic of a government-run hospital in Malaysia. Participants were purposively sampled from different genders and ethnicities. Interviews were conducted using a validated topic guide, and responses were audio-recorded, transcribed verbatim, checked, and analyzed using the grounded theory approach. A total of 30 patients were interviewed. Forty different themes and sub-themes were identified which were conceptually divided into two distinct categories related to barriers and facilitators to adherence. The barriers were: patient-specific, medication-specific, healthcare provision and system, social-cultural, and logistics. The facilitators were: having insight, perceived health benefits, regular activities, patient-provider relationship, reminders, and social support networks. Patient-specific barriers and medication side effects were the major challenges for adhering to treatment. Perceived health benefits and having insight on the need for treatment were the most frequently cited facilitators. Targeted interventions should be developed to address the key barriers, and promote measures to facilitate adherence in this group of patients.

Modeling Bird Migration under Climate Change: A Mechanistic Approach

NASA Technical Reports Server (NTRS)

Smith, James A.

2009-01-01

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

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

DOT National Transportation Integrated Search

2018-06-01

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

Facilitators and barriers to healthy eating in a worksite cafeteria: a qualitative study from Nepal.

PubMed

Shrestha, Archana; Pyakurel, Prajjwal; Shrestha, Abha; Gautam, Rabin; Manandhar, Nisha; Rhodes, Elizabeth; Tamrakar, Dipesh; Karmacharya, Biraj Man; Malik, Vasanti; Mattei, Josiemer; Spiegelman, Donna

2017-01-01

Worksite interventions can serve as a potential platform for translating existing knowledge of diabetes prevention and facilitate healthy food choices. The study explored perceptions about healthy eating as well as potential facilitators and barriers to healthy eating among employees in a wire manufacturing factory in Nepal. We conducted a cross-sectional exploratory qualitative study in a wire manufacturing industry in eastern Nepal. We conducted three focus group discussions (FGDs) with a total of 26 employees and four in-depth interviews (IDIs) with cafeteria operators/managers from a wire manufacturing factory in eastern Nepal. FGDs and IDIs were audio-recorded, transcribed verbatim and analysed using the thematic method. Most employees defined healthy eating as the consumption of food prepared and maintained using hygienic practices and fresh foods in general. Major barriers to healthy eating included unavailability of healthy foods, difficulty in changing eating habits, the preference for fried foods in Nepali culture and the high costs of some healthy foods. The most commonly reported facilitator of healthy eating was the availability of affordable healthy food options in worksite cafeterias. Availability of healthy food options at an affordable price could lead to healthier food choices in the worksite.

Mechanistic study of intertypic nucleoprotein complex formation and its inhibitory effect toward influenza A virus.

PubMed

Narkpuk, Jaraspim; Jaru-Ampornpan, Peera; Subali, Theressa; Bertulfo, Fatima Carla T; Wongthida, Phonphimon; Jongkaewwattana, Anan

2015-11-01

Co-infection of influenza A and B viruses (IAV and IBV) results in marked decreases in IAV replication. Multiple mechanisms have been proposed for this phenomenon. Recently, we reported that IBV nucleoprotein (BNP) alone can suppress IAV replication and proposed an inhibition model in which BNP binds IAV nucleoprotein (ANP) and disrupts IAV polymerase complexes. Here, using mutagenesis and co-immunoprecipitation, we determined the protein motifs mediating the intertypic ANP-BNP complex and showed that it specifically interferes with ANP׳s interaction with the PB2 subunit of the IAV polymerase but not with the other subunit PB1. We further demonstrated that BNP only suppresses growth of IAVs but not other RNA viruses. However, different IAV strains display varied sensitivity toward the BNP׳s inhibitory effect. Together, our data provide mechanistic insights into intertypic nucleoprotein complex formation and highlight the role of BNP as a potential broad-spectrum anti-IAV agent. Copyright © 2015 Elsevier Inc. All rights reserved.

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

PubMed

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

2012-12-01

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

Studying and Facilitating Dialogue in Select Online Management Courses

ERIC Educational Resources Information Center

Ivancevich, John M.; Gilbert, Jacqueline A.; Konopaske, Robert

2009-01-01

Dialogue is arguably one of the most significant elements of learning in higher education. The premise of this article is that online instructors can creatively facilitate dialogue for effectively teaching online management courses. This article presents a dialogue-focused framework for addressing significant behavioral, structural, and…

Mechanistic failure mode investigation and resolution of parvovirus retentive filters.

PubMed

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

2016-07-08

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

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

PubMed Central

2013-01-01

Summary 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. PMID:24367437

A mechanistic investigation of the algae growth "Droop" model.

PubMed

Lemesle, V; Mailleret, L

2008-06-01

In this work a mechanistic explanation of the classical algae growth model built by M. R. Droop in the late sixties is proposed. We first recall the history of the construction of the "predictive" variable yield Droop model as well as the meaning of the introduced cell quota. We then introduce some theoretical hypotheses on the biological phenomena involved in nutrient storage by the algae that lead us to a "conceptual" model. Though more complex than Droop's one, our model remains accessible to a complete mathematical study: its confrontation to the Droop model shows both have the same asymptotic behavior. However, while Droop's cell quota comes from experimental bio-chemical measurements not related to intra-cellular biological phenomena, its analogous in our model directly follows our theoretical hypotheses. This new model should then be looked at as a re-interpretation of Droop's work from a theoretical biologist's point of view.

Modeling of Mn/Road test sections with the CRREL mechanistic pavement design procedure

DOT National Transportation Integrated Search

1996-09-01

The U.S. Army Cold Regions Research and Engineering Laboratory is developing a mechanistic pavement design procedure for use in seasonal frost areas. The procedure was used to predict pavement performance of some test sections under construction at t...

Mechanistic aspects of protein corona formation: insulin adsorption onto gold nanoparticle surfaces

NASA Astrophysics Data System (ADS)

Grass, Stefan; Treuel, Lennart

2014-02-01

In biological fluids, an adsorption layer of proteins, a "protein corona" forms around nanoparticles (NPs) largely determining their biological identity. In many interactions with NPs proteins can undergo structural changes. Here, we study the adsorption of insulin onto gold NPs (mean hydrodynamic particle diameter 80 ± 18 nm), focusing on the structural consequences of the adsorption process for the protein. We use surface enhanced Raman scattering (SERS) spectroscopy to study changes in the protein's secondary structure as well as the impact on integrity and conformations of disulfide bonds immediately on the NP surface. A detailed comparison to SERS spectra of cysteine and cystine provides first mechanistic insights into the causes for these conformational changes. Potential biological and toxicological implications of these findings are also discussed.

Modeling of batch sorber system: kinetic, mechanistic, and thermodynamic modeling

NASA Astrophysics Data System (ADS)

Mishra, Vishal

2017-10-01

The present investigation has dealt with the biosorption of copper and zinc ions on the surface of egg-shell particles in the liquid phase. Various rate models were evaluated to elucidate the kinetics of copper and zinc biosorptions, and the results indicated that the pseudo-second-order model was more appropriate than the pseudo-first-order model. The curve of the initial sorption rate versus the initial concentration of copper and zinc ions also complemented the results of the pseudo-second-order model. Models used for the mechanistic modeling were the intra-particle model of pore diffusion and Bangham's model of film diffusion. The results of the mechanistic modeling together with the values of pore and film diffusivities indicated that the preferential mode of the biosorption of copper and zinc ions on the surface of egg-shell particles in the liquid phase was film diffusion. The results of the intra-particle model showed that the biosorption of the copper and zinc ions was not dominated by the pore diffusion, which was due to macro-pores with open-void spaces present on the surface of egg-shell particles. The thermodynamic modeling reproduced the fact that the sorption of copper and zinc was spontaneous, exothermic with the increased order of the randomness at the solid-liquid interface.

Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach.

PubMed

Anderson, Gail D

2005-01-01

Observational studies have documented that women take a variety of medications during pregnancy. It is well known that pregnancy can induce changes in the plasma concentrations of some drugs. The use of mechanistic-based approaches to drug interactions has significantly increased our ability to predict clinically significant drug interactions and improve clinical care. This same method can also be used to improve our understanding regarding the effect of pregnancy on pharmacokinetics of drugs. Limited studies suggest bioavailability of drugs is not altered during pregnancy. Increased plasma volume and protein binding changes can alter the apparent volume of distribution (Vd) of drugs. Through changes in Vd and clearance, pregnancy can cause increases or decreases in the terminal elimination half-life of drugs. Depending on whether a drug is excreted unchanged by the kidneys or which metabolic isoenzyme is involved in the metabolism of a drug can determine whether or not a change in dosage is needed during pregnancy. The renal excretion of unchanged drugs is increased during pregnancy. The metabolism of drugs catalysed by select cytochrome P450 (CYP) isoenzymes (i.e. CYP3A4, CYP2D6 and CYP2C9) and uridine diphosphate glucuronosyltransferase (UGT) isoenzymes (i.e. UGT1A4 and UGT2B7) are increased during pregnancy. Dosages of drugs predominantly metabolised by these isoenzymes or excreted by the kidneys unchanged may need to be increased during pregnancy in order to avoid loss of efficacy. In contrast, CYP1A2 and CYP2C19 activity is decreased during pregnancy, suggesting that dosage reductions may be needed to minimise potential toxicity of their substrates. There are limitations to the available data. This analysis is based primarily on observational studies, many including small numbers of women. For some isoenzymes, the effect of pregnancy on only one drug has been evaluated. The full-time course of pharmacokinetic changes during pregnancy is often not studied. The

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

PubMed

Fawzy, Ahmed

2016-03-15

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

A COMPUTATIONAL AND EXPERIMENTAL STUDY OF MERCURY SPECIATION AS FACILITATED BY THE DEACON PROCESS

EPA Science Inventory

The paper gives results of a computational and experimental study of mercury (Hg) speciation as facilitated by the Deacon process. Fly ashes that contain trace cupric or ferric oxide are effective catalysts for elemental mercury (Hg) conversion to mercuric chloride in the presenc...

Fine particulate matter air pollution and atherosclerosis: Mechanistic insights.

PubMed

Bai, Yuntao; Sun, Qinghua

2016-12-01

Atherosclerosis is a progressive disease characterized by the accumulation of lipids and fibrous plaque in the arteries. Its etiology is very complicated and its risk factors primarily include genetic defects, smoking, hyperlipidemia, hypertension, lack of exercise, and infection. Recent studies suggest that fine particulate matter (PM2.5) air pollution may also contribute to the development of atherosclerosis. The present review integrates current experimental evidence with mechanistic pathways whereby PM2.5 exposure can promote the development of atherosclerosis. PM2.5-mediated enhancement of atherosclerosis is likely due to its pro-oxidant and pro-inflammatory effects, involving multiple organs, different cell types, and various molecular mediators. Studies about the effects of PM2.5inhalation on atherosclerosis may yield a better understanding of the link between air pollution and major cardiovascular diseases, and provide useful information for policy makers to determine acceptable levels of PM2.5 air quality. This article is part of a Special Issue entitled Air Pollution, edited by Wenjun Ding, Andrew J. Ghio and Weidong Wu. Copyright © 2016 Elsevier B.V. All rights reserved.

Neural mechanisms underlying the facilitation of naming in aphasia using a semantic task: an fMRI study

PubMed Central

2012-01-01

Background Previous attempts to investigate the effects of semantic tasks on picture naming in both healthy controls and people with aphasia have typically been confounded by inclusion of the phonological word form of the target item. As a result, it is difficult to isolate any facilitatory effects of a semantically-focused task to either lexical-semantic or phonological processing. This functional magnetic resonance imaging (fMRI) study examined the neurological mechanisms underlying short-term (within minutes) and long-term (within days) facilitation of naming from a semantic task that did not include the phonological word form, in both participants with aphasia and age-matched controls. Results Behavioral results showed that a semantic task that did not include the phonological word form can successfully facilitate subsequent picture naming in both healthy controls and individuals with aphasia. The whole brain neuroimaging results for control participants identified a repetition enhancement effect in the short-term, with modulation of activity found in regions that have not traditionally been associated with semantic processing, such as the right lingual gyrus (extending to the precuneus) and the left inferior occipital gyrus (extending to the fusiform gyrus). In contrast, the participants with aphasia showed significant differences in activation over both the short- and the long-term for facilitated items, predominantly within either left hemisphere regions linked to semantic processing or their right hemisphere homologues. Conclusions For control participants in this study, the short-lived facilitation effects of a prior semantic task that did not include the phonological word form were primarily driven by object priming and episodic memory mechanisms. However, facilitation effects appeared to engage a predominantly semantic network in participants with aphasia over both the short- and the long-term. The findings of the present study also suggest that right

Facilitators in Ambivalence

ERIC Educational Resources Information Center

Karlsson, Mikael R.; Erlandson, Peter

2018-01-01

This is part of a larger ethnographical study concerning how school development in a local educational context sets cultural and social life in motion. The main data "in this article" consists of semi-structural interviews with teachers (facilitators) who have the responsibility of carrying out a project about formative assessment in…

Emergent Global Patterns of Ecosystem Structure and Function from a Mechanistic General Ecosystem Model

PubMed Central

Emmott, Stephen; Hutton, Jon; Lyutsarev, Vassily; Smith, Matthew J.; Scharlemann, Jörn P. W.; Purves, Drew W.

2014-01-01

Anthropogenic activities are causing widespread degradation of ecosystems worldwide, threatening the ecosystem services upon which all human life depends. Improved understanding of this degradation is urgently needed to improve avoidance and mitigation measures. One tool to assist these efforts is predictive models of ecosystem structure and function that are mechanistic: based on fundamental ecological principles. Here we present the first mechanistic General Ecosystem Model (GEM) of ecosystem structure and function that is both global and applies in all terrestrial and marine environments. Functional forms and parameter values were derived from the theoretical and empirical literature where possible. Simulations of the fate of all organisms with body masses between 10 µg and 150,000 kg (a range of 14 orders of magnitude) across the globe led to emergent properties at individual (e.g., growth rate), community (e.g., biomass turnover rates), ecosystem (e.g., trophic pyramids), and macroecological scales (e.g., global patterns of trophic structure) that are in general agreement with current data and theory. These properties emerged from our encoding of the biology of, and interactions among, individual organisms without any direct constraints on the properties themselves. Our results indicate that ecologists have gathered sufficient information to begin to build realistic, global, and mechanistic models of ecosystems, capable of predicting a diverse range of ecosystem properties and their response to human pressures. PMID:24756001

Emergent global patterns of ecosystem structure and function from a mechanistic general ecosystem model.

PubMed

Harfoot, Michael B J; Newbold, Tim; Tittensor, Derek P; Emmott, Stephen; Hutton, Jon; Lyutsarev, Vassily; Smith, Matthew J; Scharlemann, Jörn P W; Purves, Drew W

2014-04-01

Anthropogenic activities are causing widespread degradation of ecosystems worldwide, threatening the ecosystem services upon which all human life depends. Improved understanding of this degradation is urgently needed to improve avoidance and mitigation measures. One tool to assist these efforts is predictive models of ecosystem structure and function that are mechanistic: based on fundamental ecological principles. Here we present the first mechanistic General Ecosystem Model (GEM) of ecosystem structure and function that is both global and applies in all terrestrial and marine environments. Functional forms and parameter values were derived from the theoretical and empirical literature where possible. Simulations of the fate of all organisms with body masses between 10 µg and 150,000 kg (a range of 14 orders of magnitude) across the globe led to emergent properties at individual (e.g., growth rate), community (e.g., biomass turnover rates), ecosystem (e.g., trophic pyramids), and macroecological scales (e.g., global patterns of trophic structure) that are in general agreement with current data and theory. These properties emerged from our encoding of the biology of, and interactions among, individual organisms without any direct constraints on the properties themselves. Our results indicate that ecologists have gathered sufficient information to begin to build realistic, global, and mechanistic models of ecosystems, capable of predicting a diverse range of ecosystem properties and their response to human pressures.

Semi-mechanistic autoinduction model of midazolam in critically ill patients: population pharmacokinetic analysis.

PubMed

Aoyama, T; Hirata, K; Yamamoto, Y; Yokota, H; Hayashi, H; Aoyama, Y; Matsumoto, Y

2016-08-01

Midazolam (MDZ) is commonly used for sedating critically ill patients. The daily dose required for adequate sedation increases in increments over 100 h after administration. The objectives of this study were to characterize the MDZ pharmacokinetics in critically ill patients and to describe the phenomenon of increasing daily dose by means of population pharmacokinetic analysis. Data were obtained from 30 patients treated in an intensive care unit. The patients received MDZ intravenously as a combination of bolus and continuous infusion. Serum MDZ concentration was assayed by high-performance liquid chromatography. Population pharmacokinetic analysis was performed using the NONMEM software package. The alteration of clearance unexplained by demographic factors and clinical laboratory data was described as an autoinduction of MDZ clearance using a semi-mechanistic pharmacokinetic-enzyme turnover model. The final population pharmacokinetic model was a one-compartment model estimated by incorporating a semi-mechanistic pharmacokinetic-enzyme turnover model for clearance, taking autoinduction into account. A significant covariate for MDZ clearance was total bilirubin. An increase in total bilirubin indicated a reduction in MDZ clearance. From simulation using the population pharmacokinetic parameters obtained in this study, MDZ clearance increased 2·3 times compared with pre-induced clearance 100 h after the start of 12·5 mg/h continuous infusion. Autoinduction and total bilirubin were significant predictors of the clearance of MDZ in this population. Step-by-step dosage adjustment using this population pharmacokinetic model may be useful for establishing a MDZ dosage regimen in critically ill patients. © 2016 John Wiley & Sons Ltd.

Barriers and facilitators of adherence to antidepressants among outpatients with major depressive disorder: A qualitative study

PubMed Central

Jacob, Sabrina Anne; Tangiisuran, Balamurugan

2017-01-01

Background One of the major challenges in treating major depressive disorder (MDD) is patients’ non-adherence to medication. This study aimed to explore the barriers and facilitators of patients’ adherence to antidepressants among outpatients with MDD. Methods Semi-structured and individual in-depth interviews were conducted among patients with MDD who were taking antidepressants, in the psychiatric clinic of a government-run hospital in Malaysia. Participants were purposively sampled from different genders and ethnicities. Interviews were conducted using a validated topic guide, and responses were audio-recorded, transcribed verbatim, checked, and analyzed using the grounded theory approach. Results A total of 30 patients were interviewed. Forty different themes and sub-themes were identified which were conceptually divided into two distinct categories related to barriers and facilitators to adherence. The barriers were: patient-specific, medication-specific, healthcare provision and system, social-cultural, and logistics. The facilitators were: having insight, perceived health benefits, regular activities, patient-provider relationship, reminders, and social support networks. Conclusions Patient-specific barriers and medication side effects were the major challenges for adhering to treatment. Perceived health benefits and having insight on the need for treatment were the most frequently cited facilitators. Targeted interventions should be developed to address the key barriers, and promote measures to facilitate adherence in this group of patients. PMID:28614368

Understanding Facilitation: Theory and Principles.

ERIC Educational Resources Information Center

Hogan, Christine

This book introduces newcomers to the concept of facilitation, and it presents a critical analysis of established and current theory on facilitation for existing practitioners. The following are among the topics discussed: (1) emergence of the field of facilitation; (2) development of facilitation in management; (3) development of facilitation in…

A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors. | Office of Cancer Genomics

Cancer.gov

We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract.

Producing Gestures Facilitates Route Learning

PubMed Central

So, Wing Chee; Ching, Terence Han-Wei; Lim, Phoebe Elizabeth; Cheng, Xiaoqin; Ip, Kit Yee

2014-01-01

The present study investigates whether producing gestures would facilitate route learning in a navigation task and whether its facilitation effect is comparable to that of hand movements that leave physical visible traces. In two experiments, we focused on gestures produced without accompanying speech, i.e., co-thought gestures (e.g., an index finger traces the spatial sequence of a route in the air). Adult participants were asked to study routes shown in four diagrams, one at a time. Participants reproduced the routes (verbally in Experiment 1 and non-verbally in Experiment 2) without rehearsal or after rehearsal by mentally simulating the route, by drawing it, or by gesturing (either in the air or on paper). Participants who moved their hands (either in the form of gestures or drawing) recalled better than those who mentally simulated the routes and those who did not rehearse, suggesting that hand movements produced during rehearsal facilitate route learning. Interestingly, participants who gestured the routes in the air or on paper recalled better than those who drew them on paper in both experiments, suggesting that the facilitation effect of co-thought gesture holds for both verbal and nonverbal recall modalities. It is possibly because, co-thought gesture, as a kind of representational action, consolidates spatial sequence better than drawing and thus exerting more powerful influence on spatial representation. PMID:25426624

3,4-Methylenedioxymethamphetamine facilitates fear extinction learning

PubMed Central

Young, M B; Andero, R; Ressler, K J; Howell, L L

2015-01-01

Acutely administered 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy') has been proposed to have long-term positive effects on post-traumatic stress disorder (PTSD) symptoms when combined with psychotherapy. No preclinical data support a mechanistic basis for these claims. Given the persistent nature of psychotherapeutic gains facilitated by MDMA, we hypothesized that MDMA improves fear extinction learning, a key process in exposure-based therapies for PTSD. In these experiments, mice were first exposed to cued fear conditioning and treated with drug vehicle or MDMA before extinction training 2 days later. MDMA was administered systemically and also directly targeted to brain structures known to contribute to extinction. In addition to behavioral measures of extinction, changes in mRNA levels of brain-derived neurotrophic factor (Bdnf) and Fos were measured after MDMA treatment and extinction. MDMA (7.8 mg kg−1) persistently and robustly enhanced long-term extinction when administered before extinction training. MDMA increased the expression of Fos in the amygdala and medial prefrontal cortex (mPFC), whereas increases in Bdnf expression were observed only in the amygdala after extinction training. Extinction enhancements were recapitulated when MDMA (1  μg) was infused directly into the basolateral complex of the amygdala (BLA), and enhancement was abolished when BDNF signaling was inhibited before extinction. These findings suggest that MDMA enhances fear memory extinction through a BDNF-dependent mechanism, and that MDMA may be a useful adjunct to exposure-based therapies for PTSD and other anxiety disorders characterized by altered fear learning. PMID:26371762

Thermal degradation events as health hazards: Particle vs gas phase effects, mechanistic studies with particles

NASA Astrophysics Data System (ADS)

Oberdörster, G.; Ferin, J.; Finkelstein, J.; Soderholm, S.

the highly acute toxicity of fumes. Future studies will include adsorption of typical gas phase components (HCl, HF) on surrogate particles to differentiate between gas and particle phase effects and to perform mechanistic studies aimed at introducing therapeutic/preventive measures. These studies will be complemented by a comparison with actual thermal degradation products.

Mechanistic understanding of monosaccharide-air flow battery electrochemistry

NASA Astrophysics Data System (ADS)

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

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

Development of local calibration factors and design criteria values for mechanistic-empirical pavement design.

DOT National Transportation Integrated Search

2015-08-01

A mechanistic-empirical (ME) pavement design procedure allows for analyzing and selecting pavement structures based : on predicted distress progression resulting from stresses and strains within the pavement over its design life. The Virginia : Depar...

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

NASA Astrophysics Data System (ADS)

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

2016-03-01

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

Ultrasound and Microbubble Guided Drug Delivery: Mechanistic Understanding and Clinical Implications

PubMed Central

Wang, Tzu-Yin; Wilson, Katheryne E.; Machtaler, Steven; Willmann, Jürgen K.

2014-01-01

Ultrasound mediated drug delivery using microbubbles is a safe and noninvasive approach for spatially localized drug administration. This approach can create temporary and reversible openings on cellular membranes and vessel walls (a process called “sonoporation”), allowing for enhanced transport of therapeutic agents across these natural barriers. It is generally believed that the sonoporation process is highly associated with the energetic cavitation activities (volumetric expansion, contraction, fragmentation, and collapse) of the microbubble. However, a thorough understanding of the process was unavailable until recently. Important progress on the mechanistic understanding of sonoporation and the corresponding physiological responses in vitro and in vivo has been made. Specifically, recent research shed light on the cavitation process of microbubbles and fluid motion during insonation of ultrasound, on the spatio-temporal interactions between microbubbles and cells or vessel walls, as well as on the temporal course of the subsequent biological effects. These findings have significant clinical implications on the development of optimal treatment strategies for effective drug delivery. In this article, current progress in the mechanistic understanding of ultrasound and microbubble mediated drug delivery and its implications for clinical translation is discussed. PMID:24372231

Streptococcus pneumoniae Endohexosaminidase D, Structural and Mechanistic Insight into Substrate-Assisted Catalysis in Family 85 Glycoside Hydrolases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abbott, D.; Macauley, M; Vocadlo, D

2009-01-01

Endo-?-d-glucosaminidases from family 85 of glycoside hydrolases (GH85 endohexosaminidases) act to cleave the glycosidic linkage between the two N-acetylglucosamine units that make up the chitobiose core of N-glycans. Endohexosaminidase D (Endo-D), produced by Streptococcus pneumoniae, is believed to contribute to the virulence of this organism by playing a role in the deglycosylation of IgG antibodies. Endohexosaminidases have received significant attention for this reason and, moreover, because they are powerful tools for chemoenzymatic synthesis of proteins having defined glycoforms. Here we describe mechanistic and structural studies of the catalytic domain (SpGH85) of Endo-D that provide compelling support for GH85 enzymes usingmore » a catalytic mechanism involving substrate-assisted catalysis. Furthermore, the structure of SpGH85 in complex with the mechanism-based competitive inhibitor NAG-thiazoline (Kd = 28 ?m) provides a coherent rationale for previous mutagenesis studies of Endo-D and other related GH85 enzymes. We also find GH85, GH56, and GH18 enzymes have a similar configuration of catalytic residues. Notably, GH85 enzymes have an asparagine in place of the aspartate residue found in these other families of glycosidases. We propose that this residue, as the imidic acid tautomer, acts analogously to the key catalytic aspartate of GH56 and GH18 enzymes. This topographically conserved arrangement of the asparagine residue and a conserved glutamic acid, coupled with previous kinetic studies, suggests these enzymes may use an unusual proton shuttle to coordinate effective general acid and base catalysis to aid cleavage of the glycosidic bond. These results collectively provide a blueprint that may be used to facilitate protein engineering of these enzymes to improve their function as biocatalysts for synthesizing glycoproteins having defined glycoforms and also may serve as a guide for generating inhibitors of GH85 enzymes.« less

A Qualitative Study of Facilitators and Barriers Related to Comprehensive and Integrated School Psychological Services

ERIC Educational Resources Information Center

Castillo, Jose M.; Wolgemuth, Jennifer R.; Barclay, Chris; Mattison, Amira; Tan, Sim Yin; Sabnis, Sujay; Brundage, Amber; Marshall, Leslie

2016-01-01

Recent studies indicate that the majority of school psychologists' time continues to be dedicated to SPED related activities. Despite ongoing calls for school psychologists to expand their roles, why many practitioners do not deliver more comprehensive services is not well understood. This qualitative study investigated facilitators of and…

Bacterial Diterpene Synthases: New Opportunities for Mechanistic Enzymology and Engineered Biosynthesis

PubMed Central

Smanski, Michael J.; Peterson, Ryan M.; Huang, Sheng-Xiong; Shen, Ben

2012-01-01

Diterpenoid biosynthesis has been extensively studied in plants and fungi, yet cloning and engineering diterpenoid pathways in these organisms remain challenging. Bacteria are emerging as prolific producers of diterpenoid natural products, and bacterial diterpene synthases are poised to make significant contributions to our understanding of terpenoid biosynthesis. Here we will first survey diterpenoid natural products of bacterial origin and briefly review their biosynthesis with emphasis on diterpene synthases (DTSs) that channel geranylgeranyl diphosphate to various diterpenoid scaffolds. We will then highlight differences of DTSs of bacterial and higher organism origins and discuss the challenges in discovering novel bacterial DTSs. We will conclude by discussing new opportunities for DTS mechanistic enzymology and applications of bacterial DTS in biocatalysis and metabolic pathway engineering. PMID:22445175

Rationale and design of the East-West late lumen loss study: Comparison of late lumen loss between Eastern and Western drug-eluting stent study cohorts.

PubMed

Harrison, Robert W; Radhakrishnan, Vaishnavi; Lam, Peter S; Allocco, Dominic J; Brar, Sandeep; Fahy, Martin; Fisher, Rebecca; Ikeno, Fumiaki; Généreux, Philippe; Kimura, Takeshi; Liu, Minglei; Lye, Weng Kit; Mintz, Gary S; Nagai, Hirofumi; Suzuki, Yuka; White, Roseann; Allen, John C; Krucoff, Mitchell W

2016-12-01

The contemporary evaluation of novel drug-eluting stents (DES) includes mechanistic observations that characterize postdeployment stent behavior. Quantification of late lumen loss due to neointimal hyperplasia 8-13 months after stent implantation, via quantitative coronary angiography (QCA), constitutes such an observation and is required by most regulatory authorities. Late lumen loss, as determined by QCA, has been validated as a surrogate for clinical endpoints such as target vessel revascularization. The mechanistic response to DES has not been directly compared across predominantly Asian or Western populations, whereas understanding their comparability across geographic populations could enhance global DES evaluation. The East-West late lumen loss study is designed to demonstrate whether the residual differences in late lumen loss, as assessed by QCA, is different between Eastern and Western DES recipients from studies with protocol angiography at 8-13 months of follow-up. Data from independent core laboratories that have characterized angiographic late lumen loss in DES clinical trials with protocol follow-up angiography will be compiled and dichotomized into Eastern and Western populations. A prospectively developed propensity score model incorporating clinical and anatomic variables affecting late lumen loss will be used to adjust comparisons of QCA measurements. Documentation of whether there are clinically meaningful differences in mechanistic response to DES implantation across genetically unique geographies could facilitate both the quality and efficiency of global device evaluation requiring invasive follow-up for novel stent designs. Copyright © 2016 Elsevier Inc. All rights reserved.

Station Blackout: A case study in the interaction of mechanistic and probabilistic safety analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Curtis Smith; Diego Mandelli; Cristian Rabiti

2013-11-01

The ability to better characterize and quantify safety margins is important to improved decision making about nuclear power plant design, operation, and plant life extension. As research and development (R&D) in the light-water reactor (LWR) Sustainability (LWRS) Program and other collaborative efforts yield new data, sensors, and improved scientific understanding of physical processes that govern the aging and degradation of plant SSCs needs and opportunities to better optimize plant safety and performance will become known. The purpose of the Risk Informed Safety Margin Characterization (RISMC) Pathway R&D is to support plant decisions for risk-informed margin management with the aim tomore » improve economics, reliability, and sustain safety of current NPPs. In this paper, we describe the RISMC analysis process illustrating how mechanistic and probabilistic approaches are combined in order to estimate a safety margin. We use the scenario of a “station blackout” wherein offsite power and onsite power is lost, thereby causing a challenge to plant safety systems. We describe the RISMC approach, illustrate the station blackout modeling, and contrast this with traditional risk analysis modeling for this type of accident scenario.« less

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

PubMed

Magnusson, Rasmus; Mariotti, Guido Pio; Köpsén, Mattias; Lövfors, William; Gawel, Danuta R; Jörnsten, Rebecka; Linde, Jörg; Nordling, Torbjörn E M; Nyman, Elin; Schulze, Sylvie; Nestor, Colm E; Zhang, Huan; Cedersund, Gunnar; Benson, Mikael; Tjärnberg, Andreas; Gustafsson, Mika

2017-06-01

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

Facilitators and barriers to healthy eating in a worksite cafeteria: a qualitative study from Nepal

PubMed Central

Shrestha, Archana; Pyakurel, Prajjwal; Shrestha, Abha; Gautam, Rabin; Manandhar, Nisha; Rhodes, Elizabeth; Tamrakar, Dipesh; Karmacharya, Biraj Man; Malik, Vasanti; Mattei, Josiemer; Spiegelman, Donna

2017-01-01

Objective Worksite interventions can serve as a potential platform for translating existing knowledge of diabetes prevention and facilitate healthy food choices. The study explored perceptions about healthy eating as well as potential facilitators and barriers to healthy eating among employees in a wire manufacturing factory in Nepal. Methods and materials We conducted a cross-sectional exploratory qualitative study in a wire manufacturing industry in eastern Nepal. We conducted three focus group discussions (FGDs) with a total of 26 employees and four in-depth interviews (IDIs) with cafeteria operators/managers from a wire manufacturing factory in eastern Nepal. FGDs and IDIs were audio-recorded, transcribed verbatim and analysed using the thematic method. Results Most employees defined healthy eating as the consumption of food prepared and maintained using hygienic practices and fresh foods in general. Major barriers to healthy eating included unavailability of healthy foods, difficulty in changing eating habits, the preference for fried foods in Nepali culture and the high costs of some healthy foods. The most commonly reported facilitator of healthy eating was the availability of affordable healthy food options in worksite cafeterias. Conclusion Availability of healthy food options at an affordable price could lead to healthier food choices in the worksite. PMID:29225703

Corticotomy-facilitated orthodontics using piezosurgery versus rotary instruments: an experimental study.

PubMed

Farid, Karim A; Mostafa, Yehya A; Kaddah, Mohammed A; El-Sharaby, Fouad Aly

2014-10-01

The aim of this study was to evaluate corticotomy-facilitated orthodontics (CFO) using piezosurgery versus conventional rotary instruments. Ten healthy adult male mongrel dogs of comparable age with a complete set of permanent dentition with average weights between 13-17 kilograms were used. CFO using conventional rotary instruments versus piezosurgery was performed on each dog in a split mouth design. For every dog, mandibular 2nd premolar retraction on each side was attempted after extracting 3rd premolars followed by corticotomy-facilitated orthodontics using conventional rotary surgical burs on the left side and an ultrasonic piezosurgery system on the right side of the same animal. Intraoral measurements of the rate of tooth movement were taken with a sliding caliper. Measurements were performed by the same operator at the time of surgery (appliance delivery) and every month for six months. The dogs were sacrificed after six months from initiation of tooth movement to evaluate the amount of tooth movement for both conventional rotary and piezosurgery corticotomy techniques. A statistically significantly higher mean amount of tooth movement for conventional rotary instrument versus the piezosurgery corticotomy technique was observed at all time intervals. Tooth movement was 1.6 times faster when CFO was done using conventional rotary instruments as compared to a piezosurgery device.

Questioning skills of clinical facilitators supporting undergraduate nursing students.

PubMed

Phillips, Nicole M; Duke, Maxine M; Weerasuriya, Rona

2017-12-01

To report on a study investigating questioning skills of clinical facilitators who support the learning of undergraduate nursing students. The ability to think critically is integral to decision-making and the provision of safe and quality patient care. Developing students' critical thinking skills is expected of those who supervise and facilitate student learning in the clinical setting. Models used to facilitate student learning in the clinical setting have changed over the years with clinicians having dual responsibility for patient care and facilitating student learning. Many of these nurses have no preparation for the educative role. This study adapted a comparative study conducted over fifteen years ago. Descriptive online survey including three acute care patient scenarios involving an undergraduate nursing student. Participants were required to identify the questions they would ask the student in relation to the scenario. A total of 133 clinical facilitators including clinical teachers, clinical educators and preceptors from five large partner healthcare organisations of one Australian university participated. The majority of questions asked were knowledge questions, the lowest category in the cognitive domain requiring only simple recall of information. Facilitators who had undertaken an education-related course/workshop or formal qualification asked significantly more questions from the higher cognitive level. The study provides some evidence that nursing facilitators in the clinical setting ask students predominantly low-level questions. Further research is needed to identify strategies that develop the capacity of facilitators to ask higher level cognitive questions. Clinical facilitators should undertake targeted education that focuses on how to frame questions for students that demand application, analysis, synthesis and evaluation. © 2017 John Wiley & Sons Ltd.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mamoon, A.; Gamal-Eldeen, A; Ruppel, M

2009-01-01

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

Mechanistic characterization of chloride interferences in electrothermal atomization systems

USGS Publications Warehouse

Shekiro, J.M.; Skogerboe, R.K.; Taylor, Howard E.

1988-01-01

A computer-controlled spectrometer with a photodiode array detector has been used for wavelength and temperature resolved characterization of the vapor produced by an electrothermal atomizer. The system has been used to study the chloride matrix interference on the atomic absorption spectrometric determination of manganese and copper. The suppression of manganese and copper atom populations by matrix chlorides such as those of calcium and magnesium is due to the gas-phase formation of an analyte chloride species followed by the diffusion of significant fractions of these species from the atom cell prior to completion of the atomization process. The analyte chloride species cannot be formed when matrix chlorides with metal-chloride bond dissociation energies above those of the analyte chlorides are the principal entitles present. The results indicate that multiple wavelength spectrometry used to obtain temperature-resolved spectra is a viable tool in the mechanistic characterization of interference effects observed with electrothermal atomization systems. ?? 1988 American Chemical Society.

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

PubMed

2018-02-01

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

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

USGS Publications Warehouse

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.

Continually emerging mechanistic complexity of the multi-enzyme cellulosome complex.

PubMed

Smith, Steven P; Bayer, Edward A; Czjzek, Mirjam

2017-06-01

The robust plant cell wall polysaccharide-degrading properties of anaerobic bacteria are harnessed within elegant, marcomolecular assemblages called cellulosomes, in which proteins of complementary activities amass on scaffold protein networks. Research efforts have focused and continue to focus on providing detailed mechanistic insights into cellulosomal complex assembly, topology, and function. The accumulated information is expanding our fundamental understanding of the lignocellulosic biomass decomposition process and enhancing the potential of engineered cellulosomal systems for biotechnological purposes. Ongoing biochemical studies continue to reveal unexpected functional diversity within traditional cellulase families. Genomic, proteomic, and functional analyses have uncovered unanticipated cellulosomal proteins that augment the function of the native and designer cellulosomes. In addition, complementary structural and computational methods are continuing to provide much needed insights on the influence of cellulosomal interdomain linker regions on cellulosomal assembly and activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Improved characterization of truck traffic volumes and axle loads for mechanistic-empirical pavement design.

DOT National Transportation Integrated Search

2012-12-01

The recently developed mechanistic-empirical pavement design guide (MEPDG) requires a multitude of traffic : inputs to be defined for the design of pavement structures, including the initial two-way annual average daily truck : traffic (AADTT), direc...

Layer moduli of Nebraska pavements for the new Mechanistic-Empirical Pavement Design Guide (MEPDG).

DOT National Transportation Integrated Search

2010-12-01

As a step-wise implementation effort of the Mechanistic-Empirical Pavement Design Guide (MEPDG) for the design : and analysis of Nebraska flexible pavement systems, this research developed a database of layer moduli dynamic : modulus, creep compl...

Pre-synaptic kainate receptor-mediated facilitation of glutamate release involves PKA and Ca(2+) -calmodulin at thalamocortical synapses.

PubMed

Andrade-Talavera, Yuniesky; Duque-Feria, Paloma; Sihra, Talvinder S; Rodríguez-Moreno, Antonio

2013-09-01

We have investigated the mechanisms underlying the facilitatory modulation mediated by kainate receptor (KAR) activation in the cortex, using isolated nerve terminals (synaptosomes) and slice preparations. In cortical nerve terminals, kainate (KA, 100 μM) produced an increase in 4-aminopyridine (4-AP)-evoked glutamate release. In thalamocortical slices, KA (1 μM) produced an increase in the amplitude of evoked excitatory post-synaptic currents (eEPSCs) at synapses established between thalamic axon terminals from the ventrobasal nucleus onto stellate neurons of L4 of the somatosensory cortex. In both, synaptosomes and slices, the effect of KA was antagonized by 6-cyano-7-nitroquinoxaline-2,3-dione, and persisted after pre-treatment with a cocktail of antagonists of other receptors whose activation could potentially have produced facilitation of release indirectly. Mechanistically, the observed effects of KA appear to be congruent in synaptosomal and slice preparations. Thus, the facilitation by KA of synaptosomal glutamate release and thalamocortical synaptic transmission were suppressed by the inhibition of protein kinase A and occluded by the stimulation of adenylyl cyclase. Dissecting this G-protein-independent regulation further in thalamocortical slices, the KAR-mediated facilitation of synaptic transmission was found to be sensitive to the block of Ca(2+) permeant KARs by philanthotoxin. Intriguingly, the synaptic facilitation was abrogated by depletion of intracellular Ca(2+) stores by thapsigargin, or inhibition of Ca(2+) -induced Ca(2+) -release by ryanodine. Thus, the KA-mediated modulation was contingent on both Ca(2+) entry through Ca(2+) -permeable KARs and liberation of intracellular Ca(2+) stores. Finally, sensitivity to W-7 indicated that the increased cytosolic [Ca(2+) ] underpinning KAR-mediated regulation of synaptic transmission at thalamocortical synapses, requires downstream activation of calmodulin. We conclude that neocortical pre

Molecular Signaling Network Motifs Provide a Mechanistic Basis for Cellular Threshold Responses

PubMed Central

Bhattacharya, Sudin; Conolly, Rory B.; Clewell, Harvey J.; Kaminski, Norbert E.; Andersen, Melvin E.

2014-01-01

Background: Increasingly, there is a move toward using in vitro toxicity testing to assess human health risk due to chemical exposure. As with in vivo toxicity testing, an important question for in vitro results is whether there are thresholds for adverse cellular responses. Empirical evaluations may show consistency with thresholds, but the main evidence has to come from mechanistic considerations. Objectives: Cellular response behaviors depend on the molecular pathway and circuitry in the cell and the manner in which chemicals perturb these circuits. Understanding circuit structures that are inherently capable of resisting small perturbations and producing threshold responses is an important step towards mechanistically interpreting in vitro testing data. Methods: Here we have examined dose–response characteristics for several biochemical network motifs. These network motifs are basic building blocks of molecular circuits underpinning a variety of cellular functions, including adaptation, homeostasis, proliferation, differentiation, and apoptosis. For each motif, we present biological examples and models to illustrate how thresholds arise from specific network structures. Discussion and Conclusion: Integral feedback, feedforward, and transcritical bifurcation motifs can generate thresholds. Other motifs (e.g., proportional feedback and ultrasensitivity)produce responses where the slope in the low-dose region is small and stays close to the baseline. Feedforward control may lead to nonmonotonic or hormetic responses. We conclude that network motifs provide a basis for understanding thresholds for cellular responses. Computational pathway modeling of these motifs and their combinations occurring in molecular signaling networks will be a key element in new risk assessment approaches based on in vitro cellular assays. Citation: Zhang Q, Bhattacharya S, Conolly RB, Clewell HJ III, Kaminski NE, Andersen ME. 2014. Molecular signaling network motifs provide a

School Administrator Perceptions of Cyberbullying Facilitators and Barriers to Preventive Action: A Qualitative Study

ERIC Educational Resources Information Center

Young, Rachel; Tully, Melissa; Ramirez, Marizen

2017-01-01

Background: Schools are often held responsible for preventing or addressing cyberbullying, yet little is known about school administrator perceptions of cyberbullying and the challenges they face in addressing this public health issue. Aims: The goal of this study is to examine school administrators' perceptions of the facilitators of…

Facilitation of contrast detection in near-peripheral vision.

PubMed

Giorgi, Robert G; Soong, Grace P; Woods, Russell L; Peli, Eli

2004-12-01

Foveal detection of a Gabor patch (target) is facilitated by collinear, displaced high-contrast flankers. Polat and Sagi reported that the same phenomenon occurred in the periphery, but no data were presented [Proc. Natl. Acad. Sci. 91 (1994) 1206]. Others have found no facilitation in a limited number of conditions tested. To resolve this apparent conflict, we measured lateral facilitation in the near-periphery using a range of stimulus parameters. We found facilitation for a range of target-flanker distances for peripheral eccentricities up to 6 degrees , but the magnitude of the effect was less than found in central vision. Facilitation varied across subjects and with spatial frequency. Flanker contrast had no effect over the range evaluated (10-80%). Equal facilitation was found for two global arrangements of the stimulus pattern. Facilitation was found using a temporal, but not a spatial two-alternative forced-choice paradigm, accounting for the different results among previous studies. This finding supports previous indications of the role of attention in altering such facilitation. The value of facilitation from lateral interactions for persons with central vision impairment, who have to shift their attention to a peripheral locus constantly, needs to be examined.

Hierarchical Modeling of Activation Mechanisms in the ABL and EGFR Kinase Domains: Thermodynamic and Mechanistic Catalysts of Kinase Activation by Cancer Mutations

PubMed Central

Dixit, Anshuman; Verkhivker, Gennady M.

2009-01-01

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

Physiologic, demographic and mechanistic factors predicting New Injury Severity Score (NISS) in motor vehicle accident victims.

PubMed

Staff, T; Eken, T; Wik, L; Røislien, J; Søvik, S

2014-01-01

Current literature on motor vehicle accidents (MVAs) has few reports regarding field factors that predict the degree of injury. Also, studies of mechanistic factors rarely consider concurrent predictive effects of on-scene patient physiology. The New Injury Severity Score (NISS) has previously been found to correlate with mortality, need for ICU admission, length of hospital stay, and functional recovery after trauma. To potentially increase future precision of trauma triage, we assessed how the NISS is associated with physiologic, demographic and mechanistic variables from the accident site. Using mixed-model linear regression analyses, we explored the association between NISS and pre-hospital Glasgow Coma Scale (GCS) score, Revised Trauma Score (RTS) categories of respiratory rate (RR) and systolic blood pressure (SBP), gender, age, subject position in the vehicle, seatbelt use, airbag deployment, and the estimated squared change in vehicle velocity on impact ((Δv)(2)). Missing values were handled with multiple imputation. We included 190 accidents with 353 dead or injured subjects (mean NISS 17, median NISS 8, IQR 1-27). For the 307 subjects in front-impact MVAs, the mean increase in NISS was -2.58 per GCS point, -2.52 per RR category level, -2.77 per SBP category level, -1.08 for male gender, 0.18 per year of age, 4.98 for driver vs. rear passengers, 4.83 for no seatbelt use, 13.52 for indeterminable seatbelt use, 5.07 for no airbag deployment, and 0.0003 per (km/h)(2) velocity change (all p<0.002). This study in victims of MVAs demonstrated that injury severity (NISS) was concurrently and independently predicted by poor pre-hospital physiologic status, increasing age and female gender, and several mechanistic measures of localised and generalised trauma energy. Our findings underscore the need for precise information from the site of trauma, to reduce undertriage, target diagnostic efforts, and anticipate need for high-level care and rehabilitative resources

Adolescents' perspectives on the barriers and facilitators of physical activity: a systematic review of qualitative studies.

PubMed

Martins, João; Marques, Adilson; Sarmento, Hugo; Carreiro da Costa, Francisco

2015-10-01

This article examined qualitative studies of adolescents' perspectives about the facilitators and barriers of physical activity, published from 2007 to 2014. A systematic review of 'Web of Science', 'EBSCO', 'Psychinfo' and 'ERIC' databases was performed according to Preferred Reporting Items for Systematic reviews and Meta-analyses guidelines. The following keywords were used: 'physical activity' and 'physical education', each one individually associated with 'correlate', 'determinant', 'facilitator', 'barrier', 'factor influen*', and with 'qualitative', 'focus group', 'interview', "narrative'. Out of 3815 studies initially identified, due to inclusion and quality criteria, only 12 were fully reviewed. Studies' outcomes were analyzed through thematic analysis. The majority of these reported research with young adolescent girls. Few studies have considered the socioeconomic status influence. According to young people's perspectives, the main facilitators and hampering factors to their participation in physical activity were the following: attitude toward physical activity; motivation; perceptions of competence and body image; fun; influence of friends, family and physical education teachers and environmental physical activity opportunities. Specific life transition periods were referred only as a barrier to physical activity. Strategies of pedagogical actions and for developing physical activity intervention programs were discussed, in order to effectively promote the adoption of active lifestyles among youth. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Parent Involvement Facilitators: Unlocking Social Capital Wealth

ERIC Educational Resources Information Center

Ferrara, Margaret M.

2015-01-01

This case study provides an overview of a family outreach intervention that supports student retention in school through a school-home communication link. This intervention structure, which employs staff appropriately called parent involvement facilitators (PIFs), is one that school districts have employed to facilitate family engagement in…

Facilitators for practice change in Spanish community pharmacy.

PubMed

Gastelurrutia, Miguel A; Benrimoj, S I Charlie; Castrillon, Carla C; de Amezua, María J Casado; Fernandez-Llimos, Fernando; Faus, Maria J

2009-02-01

To identify and prioritise facilitators for practice change in Spanish community pharmacy. Spanish community pharmacies. Qualitative study. Thirty-three semi-structured interviews were conducted with community pharmacists (n = 15) and pharmacy strategists (n = 18), and the results were examined using the content analysis method. In addition, two nominal groups (seven community pharmacists and seven strategists) were formed to identify and prioritise facilitators. Results of both techniques were then triangulated. Facilitators for practice change. Twelve facilitators were identified and grouped into four domains (D1: Pharmacist; D2: Pharmacy as an organisation; D3: Pharmaceutical profession; D4: Miscellaneous). Facilitators identified in D1 include: the need for more clinical education at both pre- and post-graduate levels; the need for clearer and unequivocal messages from professional leaders about the future of the professional practice; and the need for a change in pharmacists' attitudes. Facilitators in D2 are: the need to change the reimbursement system to accommodate cognitive service delivery as well as dispensing; and the need to change the front office of pharmacies. Facilitators identified in D3 are: the need for the Spanish National Professional Association to take a leadership role in the implementation of cognitive services; the need to reduce administrative workload; and the need for universities to reduce the gap between education and research. Other facilitators identified in this study include: the need to increase patients' demand for cognitive services at pharmacies; the need to improve pharmacist-physician relationships; the need for support from health care authorities; and the need for improved marketing of cognitive services and their benefits to society, including physicians and health care authorities. Twelve facilitators were identified. Strategists considered clinical education and pharmacists' attitude as the most important, and

The autism puzzle: challenging a mechanistic model on conceptual and historical grounds

PubMed Central

2013-01-01

Although clinicians and researchers working in the field of autism are generally not concerned with philosophical categories of kinds, a model for understanding the nature of autism is important for guiding research and clinical practice. Contemporary research in the field of autism is guided by the depiction of autism as a scientific object that can be identified with systematic neuroscientific investigation. This image of autism is compatible with a permissive account of natural kinds: the mechanistic property cluster (MPC) account of natural kinds, recently proposed as the model for understanding psychiatric disorders. Despite the heterogeneity, multicausality and fuzzy boundaries that complicate autism research, a permissive account of natural kinds (MPC kinds) provides prescriptive guidance for the investigation of objective causal mechanisms that should inform nosologists in their attempt to carve autism’s boundaries at its natural joints. However, this essay will argue that a mechanistic model of autism is limited since it disregards the way in which autism relates to ideas about what kind of behavior is abnormal. As historical studies and definitions of autism show, normative issues concerning disability, impairment and societal needs have been and still are inextricably linked to how we recognize and understand autism. The current search for autism’s unity in neurobiological mechanisms ignores the values, social norms and various perspectives on mental pathology that play a significant role in 'the thing called autism’. Autism research needs to engage with these issues in order to achieve more success in the effort to become clinically valuable. PMID:24207065

Superhydrophobic photosensitizers. Mechanistic studies of (1)O2 generation in the plastron and solid/liquid droplet interface.

PubMed

Aebisher, David; Bartusik, Dorota; Liu, Yang; Zhao, Yuanyuan; Barahman, Mark; Xu, QianFeng; Lyons, Alan M; Greer, Alexander

2013-12-18

We describe here a physical-organic study of the first triphasic superhydrophobic sensitizer for photooxidations in water droplets. Control of synthetic parameters enables the mechanistic study of "borderline" two- and three-phase superhydrophobic sensitizer surfaces where (1)O2 is generated in compartments that are wetted, partially wetted, or remain dry in the plastron (i.e., air layer beneath the droplet). The superhydrophobic surface is synthesized by partially embedding silicon phthalocyanine (Pc) sensitizing particles to specific locations on polydimethylsiloxane (PDMS) posts printed in a square array (1 mm tall posts on 0.5 mm pitch). In the presence of red light and oxygen, singlet oxygen is formed on the superhydrophobic surface and reacts with 9,10-anthracene dipropionate dianion (1) within a freestanding water droplet to produce an endoperoxide in 54-72% yields. Control of the (1)O2 chemistry was achieved by the synthesis of superhydrophobic surfaces enriched with Pc particles either at the PDMS end-tips or at PDMS post bases. Much of the (1)O2 that reacts with anthracene 1 in the droplets was generated by the sensitizer "wetted" at the Pc particle/water droplet interface and gave the highest endoperoxide yields. About 20% of the (1)O2 can be introduced into the droplet from the plastron. The results indicate that the superhydrophobic sensitizer surface offers a unique system to study (1)O2 transfer routes where a balance of gas and liquid contributions of (1)O2 is tunable within the same superhydrophobic surface.

Kinetic and mechanistic reactivity. Isoprene impact on ozone levels in an urban area near Tijuca Forest, Rio de Janeiro.

PubMed

da Silva, Cleyton Martins; da Silva, Luane Lima; Corrêa, Sergio Machado; Arbilla, Graciela

2016-12-01

Volatile organic compounds (VOCs) play a central role in atmospheric chemistry. In this work, the kinetic and mechanistic reactivities of VOCs are analyzed, and the contribution of the organic compounds emitted by anthropogenic and natural sources is estimated. VOCs react with hydroxyl radicals and other photochemical oxidants, such as ozone and nitrate radicals, which cause the conversion of NO to NO 2 in various potential reaction paths, including photolysis, to form oxygen atoms, which generate ozone. The kinetic reactivity was evaluated based on the reaction coefficients for hydroxyl radicals with VOCs. The mechanistic reactivity was estimated using a detailed mechanism and the incremental reactivity scale that Carter proposed. Different scenarios were proposed and discussed, and a minimum set of compounds, which may describe the tropospheric reactivity in the studied area, was determined. The role of isoprene was analyzed in terms of its contribution to ozone formation.

The Role of Touch in Facilitated Communication.

ERIC Educational Resources Information Center

Kezuka, Emiko

1997-01-01

A study investigated the role of touch in the use of facilitated communication with Japanese individuals with autism. Five experiments were conducted involving a "telepathy game" using a rod with an attached strain gauge. Results found the facilitator's contact controlled the motor responses of the subjects. (Author/CR)

A Model of Small Group Facilitator Competencies

ERIC Educational Resources Information Center

Kolb, Judith A.; Jin, Sungmi; Song, Ji Hoon

2008-01-01

This study used small group theory, quantitative and qualitative data collected from experienced practicing facilitators at three points of time, and a building block process of collection, analysis, further collection, and consolidation to develop a model of small group facilitator competencies. The proposed model has five components:…

Mechanistic Studies of Human Spermine Oxidase: Kinetic Mechanism and pH Effects†

PubMed Central

Adachi, Maria S.; Juarez, Paul R.; Fitzpatrick, Paul F.

2009-01-01

In mammalian cells, the flavoprotein spermine oxidase (SMO) catalyzes the oxidation of spermine to spermidine and 3-aminopropanal. Mechanistic studies have been carried out with the recombinant human enzyme. The initial velocity pattern when the ratio between the concentrations of spermine and oxygen is kept constant establishes the steady-state kinetic pattern as ping-pong. Reduction of SMO by spermine in the absence of oxygen is biphasic. The rate constant for the rapid phase varies with the substrate concentration, with a limiting value (k3) of 49 s−1 and an apparent Kd value of 48 µM at pH 8.3. The rate constant for the slow step is independent of the spermine concentration, with a value of 5.5 s−1, comparable to the kcat value of 6.6 s−1. The kinetics of the oxidative half-reaction depend on the aging time after spermine and enzyme are mixed in a double mixing experiment. At an aging time of 6 s the reaction is monophasic with a second order rate constant of 4.2 mM−1 s−1. At an aging time of 0.3 s the reaction is biphasic with two second order constants equal to 4.0 and 40 mM−1 s−1. Neither is equal to the kcat/KO2 value of 13 mM−1s−1. These results establish the existence of more than one pathway for the reaction of the reduced flavin intermediate with oxygen. The kcat/KM value for spermine exhibits a bell-shaped pH-profile, with an average pKa value of 8.3. This profile is consistent with the active form of spermine having three charged nitrogens. The pH profile for k3 shows a pKa value of 7.4 for a group that must be unprotonated. The pKi-pH profiles for the competitive inhibitors N,N’-dibenzylbutane-1,4-diamine and spermidine show that the fully protonated forms of the inhibitors and the unprotonated form of an amino acid residue with a pKa of about 7.4 in the active site are preferred for binding. PMID:20000632

A Physical Education Teacher's Journey: From District Coordinator to Facilitator

ERIC Educational Resources Information Center

Hunuk, Deniz

2017-01-01

Background: Despite the accumulating evidence highlighting the significant roles of an effective facilitator and appropriate pedagogies that a facilitator employs in shaping the professional learning environment, there is a paucity of research that explores how facilitators learn to facilitate. Purpose: The overall purpose of this study was to…

Barriers, facilitators and attitudes influencing health promotion activities in general practice: an explorative pilot study

PubMed Central

2013-01-01

Background The number of chronically ill patients increases every year. This is partly due to an unhealthy lifestyle. However, the frequency and quality of (evidence-based) health promotion activities conducted by Dutch general practitioners (GPs) and practice nurses (PNs) are limited. The aim of this pilot study was to explore which lifestyle interventions Dutch GPs and PNs carry out in primary care, which barriers and facilitators can be identified and what main topics are with respect to attitudes towards health promoting activities. These topic areas will be identified for a future, larger scale study. Method This qualitative study consisted of 25 semi-structured interviews with sixteen GPs and nine PNs. ATLAS.ti was used to analyse the transcripts of the interviews. Results All GPs and PNs said they discuss lifestyle with their patients. Next to this, GPs and PNs counsel patients, and/or refer them to other disciplines. Only few said they refer patients to specific lifestyle programs or interventions in their own practice or in the neighbourhood. Several barriers and facilitators were identified. The main topics as barriers are: a lack of patients’ motivation to make lifestyle changes, insufficient reimbursement, a lack of proven effectiveness of interventions and a lack of overview of health promoting programs in their neighbourhood. The most cited facilitators are availability of a PN, collaboration with other disciplines and availability of interventions in their own practice. With respect to attitudes, six different types of GPs were identified reflecting the main topics that relate to attitudes, varying from ‘ignorer’ to ‘nurturer’. The topics relating to PNs attitudes towards health promotion activities, were almost unanimously positive. Conclusion GPs and PNs all say they discuss lifestyle issues with their patients, but the health promotion activities that are organized in their practice vary. Main topics that hinder or facilitate

Managing treatment for end-stage renal disease--a qualitative study exploring cultural perspectives on facilitators and barriers to treatment adherence.

PubMed

Griva, K; Ng, H J; Loei, J; Mooppil, N; McBain, H; Newman, S P

2013-01-01

Although adherence to hemodialysis (HD) regimes is important to maximise good clinical outcomes, it remains suboptimal and not well understood, particularly for those in non-Western settings and patients from Asian cultures. This qualitative study sought to explore cultural perspectives on facilitators and barriers to treatment adherence in HD patients. A descriptive exploratory design was used for the study, incorporating individual semi-structured interviews (n = 17) and three focus groups (n = 20). Each interview/focus group was audio-taped and transcribed verbatim, and coding was conducted by two coders using an iterative process. Study participants identified personal and social/contextual factors as major barriers or facilitators of treatment adherence. Barriers include time consumption, forgetfulness, concerns about safety, poor knowledge/understanding, poor communication and lack of control/social pressure. Participants also identified facilitators, both internal (self-initiated) and external (initiated by family, health care professional and peers) to ensure treatment adherence. These included support from family members and social obligation towards others, risk perception, establishment of routines and peer support. Internal and external factors can hinder or facilitate adherence to diet, fluid and medications in the context of dialysis. Several of these barriers/facilitators can be effectively addressed in the context of interventions and psycho-educational programmes.

Barriers and facilitators to disease-modifying antirheumatic drug use in patients with inflammatory rheumatic diseases: a qualitative theory-based study.

PubMed

Voshaar, Marieke; Vriezekolk, Johanna; van Dulmen, Sandra; van den Bemt, Bart; van de Laar, Mart

2016-10-21

Although disease-modifying anti-rheumatic drugs (DMARDs) are the cornerstone of treatment for inflammatory rheumatic diseases, medication adherence to DMARDs is often suboptimal. Effective interventions to improve adherence to DMARDs are lacking, and new targets are needed to improve adherence. The aim of the present study was to explore patients' barriers and facilitators of optimal DMARD use. These factors might be used as targets for adherence interventions. In a mixed method study design, patients (n = 120) with inflammatory arthritis (IA) completed a questionnaire based on an existing adapted Theoretical Domains Framework (TDF) to identify facilitators and barriers of DMARD use. A subgroup of these patients (n = 21) participated in focus groups to provide insights into their facilitators and barriers. The answers to the questionnaires and responses of the focus groups were thematically coded by three researchers independently and subsequently categorized. The barriers and facilitators that were reported by IA patients presented large inter-individual variations. The identified barriers and facilitators could be captured in the following domains based on an adapted TDF: (i) knowledge, (ii) emotions, (iii) attention, memory, and decision processes, (iv) social influences, (v) beliefs about capability, (vi) beliefs about consequences, (vii) motivation and goals, (viii) goal conflict, (ix) environmental context and resources, and (x) skills. Patients with IA have a variety of barriers and facilitators with regard to their DMARD use. All of these barriers and facilitators could be categorized into adapted domains of the TDF. Interventions that address individual facilitators and barriers, based on capability, opportunity, and motivation, are needed to develop strategies for medication adherence that are tailored to individual patient needs.

Barriers and Facilitators of Physical Education Participation for Students with Disabilities: An Exploratory Study

ERIC Educational Resources Information Center

Haegele, Justin; Zhu, Xihe; Davis, Summer

2018-01-01

The purpose of this study was to explore the barriers and facilitators to participation in physical education (PE) for students with disabilities (SWD) from the perspectives of in-service physical educators. A convenience sample of 168 physical educators (72% female, 94% Caucasian) from the United States completed a short questionnaire. After data…

Facilitating LOS Debriefings: A Training Manual

NASA Technical Reports Server (NTRS)

McDonnell, Lori K.; Jobe, Kimberly K.; Dismukes, R. Key

1997-01-01

This manual is a practical guide to help airline instructors effectively facilitate debriefings of Line Oriented Simulations (LOS). It is based on a recently completed study of Line Oriented Flight Training (LOFT) debriefings at several U.S. airlines. This manual presents specific facilitation tools instructors can use to achieve debriefing objectives. The approach of the manual is to be flexible so it can be tailored to the individual needs of each airline. Part One clarifies the purpose and objectives of facilitation in the LOS setting. Part Two provides recommendations for clarifying roles and expectations and presents a model for organizing discussion. Part Tree suggests techniques for eliciting active crew participation and in-depth analysis and evaluation. Finally, in Part Four, these techniques are organized according to the facilitation model. Examples of how to effectively use the techniques are provided throughout, including strategies to try when the debriefing objectives are not being fully achieved.

Perspectives on Research Participation and Facilitation Among Dialysis Patients, Clinic Personnel, and Medical Providers: A Focus Group Study.

PubMed

Flythe, Jennifer E; Narendra, Julia H; Dorough, Adeline; Oberlander, Jonathan; Ordish, Antoinette; Wilkie, Caroline; Dember, Laura M

2017-12-19

Most prospective studies involving individuals receiving maintenance dialysis have been small, and many have had poor clinical translatability. Research relevance can be enhanced through stakeholder engagement. However, little is known about dialysis clinic stakeholders' perceptions of research participation and facilitation. The objective of this study was to characterize the perspectives of dialysis clinic stakeholders (patients, clinic personnel, and medical providers) on: (1) research participation by patients and (2) research facilitation by clinic personnel and medical providers. We also sought to elucidate stakeholder preferences for research communication. Qualitative study. 7 focus groups (59 participants: 8 clinic managers, 14 nurses/patient care technicians, 8 social workers/dietitians, 11 nephrologists/advanced practice providers, and 18 patients/care partners) from 7 North Carolina dialysis clinics. Clinics and participants were purposively sampled. Focus groups were recorded and transcribed. Thematic analysis. We identified 11 themes that captured barriers to and facilitators of research participation by patients and research facilitation by clinic personnel and medical providers. We collapsed these themes into 4 categories to create an organizational framework for considering stakeholder (narrow research understanding, competing personal priorities, and low patient literacy and education levels), relationship (trust, buy-in, and altruistic motivations), research design (convenience, follow-up, and patient incentives), and dialysis clinic (professional demands, teamwork, and communication) aspects that may affect stakeholder interest in participating in or facilitating research. These themes appear to shape the degree of research readiness of a dialysis clinic environment. Participants preferred short research communications delivered in multiple formats. Potential selection bias and inclusion of English-speaking participants only. Our findings

Mechanistic and clinical insights at the scleroderma-cancer interface

PubMed Central

Shah, Ami A.; Casciola-Rosen, Livia

2017-01-01

Emerging data suggest tantalizing links between cancer and systemic inflammatory rheumatic syndromes. In scleroderma, patients may have an increased risk of cancer secondary to chronic inflammation and damage from the disease, malignant transformation promoted by immunosuppressive therapies, a shared susceptibility to both cancer and autoimmunity, or a common inciting exposure. However, it is increasingly recognized that a subset of patients develop cancer around the time that scleroderma clinically manifests, raising the question of cancer-induced autoimmunity. In this review, we discuss data suggesting a mechanistic link between cancer and the development of scleroderma, and the clinical implications of these findings. PMID:29264402

How mechanisms explain interfield cooperation: biological-chemical study of plant growth hormones in Utrecht and Pasadena, 1930-1938.

PubMed

Schürch, Caterina

2017-09-01

This article examines to what extent a particular case of cross-disciplinary research in the 1930s was structured by mechanistic reasoning. For this purpose, it identifies the interfield theories that allowed biologists and chemists to use each other's techniques and findings, and that provided the basis for the experiments performed to identify plant growth hormones and to learn more about their role in the mechanism of plant growth. In 1930, chemists and biologists in Utrecht and Pasadena began to cooperatively study plant growth. I will argue that these researchers decided to join forces because they believed to rely on each other's findings and methods to solve their research problems adequately. In the course of the cooperation, organic chemists arrived at isolating plant growth hormones by using a test method developed in plant physiology. This achievement, in turn, facilitated biologists' investigation of the mechanism of plant growth. Researchers eventually believed to have the means to study the relation between a substance's molecular structure and its physiological activity. The way they conceptualized the problem of identifying hormones and unraveling the mechanism of plant growth, as well as their actual research actions are compatible with the new mechanists' account of mechanism research. The study illustrates that focusing on researchers' mechanistic reasoning can contribute considerably to explaining the structure of cross-disciplinary research projects.

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

NASA Astrophysics Data System (ADS)

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

2016-07-01

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

A structural and mechanistic study of π-clamp-mediated cysteine perfluoroarylation.

PubMed

Dai, Peng; Williams, Jonathan K; Zhang, Chi; Welborn, Matthew; Shepherd, James J; Zhu, Tianyu; Van Voorhis, Troy; Hong, Mei; Pentelute, Bradley L

2017-08-11

Natural enzymes use local environments to tune the reactivity of amino acid side chains. In searching for small peptides with similar properties, we discovered a four-residue π-clamp motif (Phe-Cys-Pro-Phe) for regio- and chemoselective arylation of cysteine in ribosomally produced proteins. Here we report mutational, computational, and structural findings directed toward elucidating the molecular factors that drive π-clamp-mediated arylation. We show the significance of a trans conformation prolyl amide bond for the π-clamp reactivity. The π-clamp cysteine arylation reaction enthalpy of activation (ΔH ‡ ) is significantly lower than a non-π-clamp cysteine. Solid-state NMR chemical shifts indicate the prolyl amide bond in the π-clamp motif adopts a 1:1 ratio of the cis and trans conformation, while in the reaction product Pro3 was exclusively in trans. In two structural models of the perfluoroarylated product, distinct interactions at 4.7 Å between Phe1 side chain and perfluoroaryl electrophile moiety are observed. Further, solution 19 F NMR and isothermal titration calorimetry measurements suggest interactions between hydrophobic side chains in a π-clamp mutant and the perfluoroaryl probe. These studies led us to design a π-clamp mutant with an 85-fold rate enhancement. These findings will guide us toward the discovery of small reactive peptides to facilitate abiotic chemistry in water.

A Pilot Study: Facilitating Cross-Cultural Understanding with Project-Based Collaborative Learning in an Online Environment

ERIC Educational Resources Information Center

Shadiev, Rustam; Hwang, Wu-Yuin; Huang, Yueh-Min

2015-01-01

This study investigated three aspects: how project-based collaborative learning facilitates cross-cultural understanding; how students perceive project-based collaborative learning implementation in a collaborative cyber community (3C) online environment; and what types of communication among students are used. A qualitative case study approach…

Mechanistic Biomarkers in Acetaminophen-induced Hepatotoxicity and Acute Liver Failure: From Preclinical Models to Patients

PubMed Central

McGill, Mitchell R.; Jaeschke, Hartmut

2015-01-01

SUMMARY Introduction Drug hepatotoxicity is a major clinical issue. Acetaminophen (APAP) overdose is especially common. Serum biomarkers used to follow patient progress reflect either liver injury or function, but focus on biomarkers that can provide insight into the basic mechanisms of hepatotoxicity is increasing and enabling us to translate mechanisms of toxicity from animal models to humans. Areas covered We review recent advances in mechanistic serum biomarker research in drug hepatotoxicity. Specifically, biomarkers for reactive drug intermdiates, mitochondrial dysfunction, nuclear DNA damage, mode of cell death and inflammation are discussed, as well as microRNAs. Emphasis is placed on APAP-induced liver injury. Expert Opinion Several serum biomarkers of reactive drug intermediates, mitochondrial damage, nuclear DNA damage, apoptosis and necrosis, and inflammation have been described. These studies have provided evidence that mitochondrial damage is critical in APAP hepatotoxicity in humans, while apoptosis has only a minor role, and inflammation is important for recovery and regeneration after APAP overdose. Additionally, mechanistic serum biomarkers have been shown to predict outcome as well as, or better than, some clinical scores. In the future, such biomarkers will help determine the need for liver transplantation and, with improved understanding of the human pathophysiology, identify novel therapeutic targets. PMID:24836926

Barriers and facilitators to cooking from 'scratch' using basic or raw ingredients: A qualitative interview study.

PubMed

Lavelle, Fiona; McGowan, Laura; Spence, Michelle; Caraher, Martin; Raats, Monique M; Hollywood, Lynsey; McDowell, Dawn; McCloat, Amanda; Mooney, Elaine; Dean, Moira

2016-12-01

Previous research has highlighted an ambiguity in understanding cooking related terminology and a number of barriers and facilitators to home meal preparation. However, meals prepared in the home still include convenience products (typically high in sugars, fats and sodium) which can have negative effects on health. Therefore, this study aimed to qualitatively explore: (1) how individuals define cooking from 'scratch', and (2) their barriers and facilitators to cooking with basic ingredients. 27 semi-structured interviews were conducted with participants (aged 18-58 years) living on the island of Ireland, eliciting definitions of 'cooking from scratch' and exploring the reasons participants cook in a particular way. The interviews were professionally transcribed verbatim and Nvivo 10 was used for an inductive thematic analysis. Our results highlighted that although cooking from 'scratch' lacks a single definition, participants viewed it as optimal cooking. Barriers to cooking with raw ingredients included: 1) time pressures; (2) desire to save money; (3) desire for effortless meals; (4) family food preferences; and (5) effect of kitchen disasters. Facilitators included: 1) desire to eat for health and well-being; (2) creative inspiration; (3) ability to plan and prepare meals ahead of time; and (4) greater self-efficacy in one's cooking ability. Our findings contribute to understanding how individuals define cooking from 'scratch', and barriers and facilitators to cooking with raw ingredients. Interventions should focus on practical sessions to increase cooking self-efficacy; highlight the importance of planning ahead and teach methods such as batch cooking and freezing to facilitate cooking from scratch. Copyright © 2016 Elsevier Ltd. All rights reserved.

Ecological Forecasting in Chesapeake Bay: Using a Mechanistic-Empirical Modelling Approach

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brown, C. W.; Hood, Raleigh R.; Long, Wen

The Chesapeake Bay Ecological Prediction System (CBEPS) automatically generates daily nowcasts and three-day forecasts of several environmental variables, such as sea-surface temperature and salinity, the concentrations of chlorophyll, nitrate, and dissolved oxygen, and the likelihood of encountering several noxious species, including harmful algal blooms and water-borne pathogens, for the purpose of monitoring the Bay's ecosystem. While the physical and biogeochemical variables are forecast mechanistically using the Regional Ocean Modeling System configured for the Chesapeake Bay, the species predictions are generated using a novel mechanistic empirical approach, whereby real-time output from the coupled physical biogeochemical model drives multivariate empirical habitat modelsmore » of the target species. The predictions, in the form of digital images, are available via the World Wide Web to interested groups to guide recreational, management, and research activities. Though full validation of the integrated forecasts for all species is still a work in progress, we argue that the mechanistic–empirical approach can be used to generate a wide variety of short-term ecological forecasts, and that it can be applied in any marine system where sufficient data exist to develop empirical habitat models. This paper provides an overview of this system, its predictions, and the approach taken.« less

Barriers and facilitators to antiretroviral therapy adherence among Peruvian adolescents living with HIV: A qualitative study

PubMed Central

Wong, Milagros; Muñoz, Maribel; Valle, Emiliano; Leon, Segundo R.; Díaz Perez, Dayana; Kolevic, Lenka; Franke, Molly

2018-01-01

AIDS deaths among adolescents are increasing globally. This qualitative study investigated the barriers and facilitators to cART adherence among Peruvian adolescents living with HIV. Guided by a social ecological model, we analyzed transcripts from 24 psychosocial support groups for HIV-positive adolescents aged 13–17 years and 15 individual, in-depth interviews with cART providers and caregivers to identify the barriers and facilitators to cART adherence at the individual, family/caregiver and hospital levels. Most barriers and facilitators to cART adherence clustered at the individual and family/caregiver levels, centering on support provided to adolescents; history of declining health due to suboptimal cART adherence; side effects from antiretroviral drugs; and cART misinformation. Interventions to support adolescent HIV cART adherence should begin at the individual and family/caregiver levels and include an educational component. No adolescent living with HIV should die from AIDS in an era of accessible cART. PMID:29447226

Enzymatic hydrolysis of p-nitroacetanilide: mechanistic studies of the aryl acylamidase from Pseudomonas fluorescens.

PubMed

Stein, Ross L

2002-01-22

Aryl acylamidase (EC 3.1.5.13; AAA) catalyzes the hydrolysis of p-nitroacetanilide (PNAA) via the standard three-step mechanism of serine hydrolases: binding of substrate (K(s)), acylation of active-site serine (k(acyl)), and hydrolytic deacylation (k(deacyl)). Key mechanistic findings that emerged from this study include that (1) AAA requires a deprotonated base with a pK(a) of 8.3 for expression of full activity toward PNAA. Limiting values of kinetic parameters at high pH are k(c) = 7 s(-1), K(m) = 20 microM, and k(c)/K(m) = 340 000 M(-1) s(-1). (2) At pH 10, where all the isotope effects were conducted, k(c) is equally rate-limited by k(acyl) and k(deacyl). (3) The following isotope effects were determined: (D)()2(O)(k(c)/K(m)) = 1.7 +/- 0.2, (D)()2(O)k(c) = 3.5 +/- 0.3, and (beta)(D)(k(c)/K(m)) = 0.83 +/- 0.04, (beta)(D)k(c) = 0.96 +/- 0.01. These values, together with proton inventories for k(c)/K(m) and k(c), suggest the following mechanism: (i) The initial binding of substrate to enzyme to form the Michaelis complex is accompanied by solvation changes that generate solvent deuterium isotope effects originating from hydrogen ion fractionation at multiple sites on the enzyme surface. (ii) From within the Michaelis complex, the active site serine attacks the carbonyl carbon of PNAA with general-base catalysis to form a substantially tetrahedral transition state enroute to the acyl-enzyme. (iii) Finally, deacylation occurs through a process involving a rate-limiting solvent isotope effect, generating conformational change of the acyl-enzyme that positions the carbonyl bond in a polarizing environment that is optimal for attack by water.

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

PubMed

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

2017-03-01

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

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

USGS Publications Warehouse

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

2017-01-01

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

Asphalt materials characterization in support of implementation of the proposed mechanistic-empirical pavement design guide.

DOT National Transportation Integrated Search

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 engineer...

Stereoselective rhodium-catalysed [2+2+2] cycloaddition of linear allene-ene/yne-allene substrates: reactivity and theoretical mechanistic studies.

PubMed

Haraburda, Ewelina; Torres, Óscar; Parella, Teodor; Solà, Miquel; Pla-Quintana, Anna

2014-04-22

Allene-ene-allene (2 and 5) and allene-yne-allene (3 and 7) N-tosyl and O-linked substrates were satisfactorily synthesised. The [2+2+2] cycloaddition reaction catalysed by the Wilkinson catalyst [RhCl(PPh3 )3 ] was evaluated. Substrates 2 and 5, which bear a double bond in the central position, gave a tricyclic structure in a reaction in which four contiguous stereogenic centres were formed as a single diastereomer. The reaction of substrates 3 and 7, which bear a triple bond in the central position, gave a tricyclic structure with a cyclohexenic ring core, again in a diastereoselective manner. All cycloadducts were formed by a regioselective reaction of the inner allene double bond and, therefore, feature an exocyclic diene motif. A Diels-Alder reaction on N-tosyl linked cycloadducts 8 and 10 allowed pentacyclic scaffolds to be diastereoselectively constructed. The reactivity of the allenes on [2+2+2] cycloaddition reactions was studied for the first time by density functional theory calculations. This mechanistic study rationalizes the order in which the unsaturations take part in the catalytic cycle, the reactivity of the two double bonds of the allene towards the [2+2+2] cycloaddition reaction, and the diastereoselectivity of the reaction. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

m6A demethylase FTO facilitates tumor progression in lung squamous cell carcinoma by regulating MZF1 expression.

PubMed

Liu, Jiqin; Ren, Dangli; Du, Zhenhua; Wang, Hekong; Zhang, Hua; Jin, Ying

2018-08-25

N 6 -Methyladenosine (m 6 A) represents the most prevalent internal modification in mammalian mRNAs. Emerging evidences suggest that m 6 A modification is profoundly implicated in many biological processes, including cancer development. However, limited knowledge is available about the functional importance of m 6 A in lung cancer. In this study, by data mining The Cancer Genome Atlas (TCGA) database, we first identified fat mass- and obesity-associated protein (FTO) as a prognostic factor for lung squamous cell carcinoma (LUSC). Then we showed that FTO, but not other m 6 A modification genes including METTL3, METTL14 and ALKBH5, was the major dysregulated factor responsible for aberrant m 6 A modification in LUSC. Loss-of-function studies suggested that FTO knockdown effectively inhibited cell proliferation and invasion, while promoted cell apoptosis of L78 and NCI-H520 cells. Furthermore, overexpression of FTO, but not its mutant form, facilitated the malignant phenotypes of CHLH-1 cells. Mechanistically, FTO enhanced MZF1 expression by reducing m 6 A levels and mRNA stability in MZF1 mRNA transcript, leading to oncogenic functions. Taken together, our study demonstrates the functional importance of FTO in the tumor progression of LUSC and provides a potential therapeutic target for LUSC treatment. Copyright © 2018 Elsevier Inc. All rights reserved.

Systematic Review and Meta-study Synthesis of Qualitative Studies Evaluating Facilitators and Barriers to Participation in Colorectal Cancer Screening.

PubMed

Honein-AbouHaidar, Gladys N; Kastner, Monika; Vuong, Vincent; Perrier, Laure; Daly, Corinne; Rabeneck, Linda; Straus, Sharon; Baxter, Nancy N

2016-06-01

Screening reduces the incidence, morbidity, and mortality of colorectal cancer, yet participation tends to be low. We undertook a systematic review and meta-study synthesis of qualitative studies to identify facilitators and barriers to colorectal cancer screening participation. We searched major bibliographic databases for records published in all languages from inception to February 2015. Included primary studies that elicited views and perceptions towards colorectal cancer screening were appraised for relevance and quality. We used a two-stage synthesis to create an interpretation of colorectal cancer screening decisions grounded in primary studies; a thematic analysis to group themes and systematically compare studies and a meta-synthesis to generate an expanded theory of colorectal cancer screening participation. Ninety-four studies were included. The decision to participate in colorectal cancer screening depended on an individual's awareness of colorectal cancer screening. Awareness affected views of cancer, attitudes towards colorectal cancer screening modalities, and motivation for screening. Factors mediating awareness included public education to address misconceptions, primary care physician efforts to recommend screening, and the influence of friends and family. Specific barriers to participation in populations with lower participation rates included language barriers, logistical challenges to attending screening tests, and cultural beliefs. This study identifies key barriers, facilitators, and mediators to colorectal cancer screening participation. Cancer Epidemiol Biomarkers Prev; 25(6); 907-17. ©2016 AACR. ©2016 American Association for Cancer Research.

Nurse as a Facilitator to Professional Communication: A Qualitative Study

PubMed Central

Ghiyasvandian, Shahrzad; Zakerimoghadam, Masoumeh; Peyravi, Hamid

2015-01-01

Nurses need to establish communication with other healthcare professionals to facilitate the process of care. Healthcare professionals have complementary roles in providing care to patients. As the key members of the healthcare team, nurses also have an important role in establishing communication among other healthcare professionals. The final outcome of professional communication is effective care and improved patient outcomes. The aim of this study was to explore nurses’ role in establishing professional communications with other healthcare professionals. This was a descriptive qualitative study. The study was conducted by using the content analysis approach. A purposive sample of sixteen healthcare professionals was recruited from six teaching hospitals affiliated to Tehran University of Medical Sciences, Tehran, Iran. Study data were gathered by conducting personal face-to-face semi-structured interviews and were analyzed by using the qualitative content analysis approach. The three main themes of the study were ‘Nurse as the mediator of communication’, ‘Nurse as the executor of others’ duties, and ‘Nurse as a scapegoat’. Study findings can be used by nurses, managers, and health policy-makers to develop effective strategies for exactly determining and clarifying nurses and other healthcare professionals’ roles as well as for informing the public and other healthcare professionals about nurses’ roles and importance. PMID:25716406

Zscan4 Inhibits Maintenance DNA Methylation to Facilitate Telomere Elongation in Mouse Embryonic Stem Cells.

PubMed

Dan, Jiameng; Rousseau, Philippe; Hardikar, Swanand; Veland, Nicolas; Wong, Jiemin; Autexier, Chantal; Chen, Taiping

2017-08-22

Proper telomere length is essential for embryonic stem cell (ESC) self-renewal and pluripotency. Mouse ESCs (mESCs) sporadically convert to a transient totipotent state similar to that of two-cell (2C) embryos to recover shortened telomeres. Zscan4, which exhibits a burst of expression in 2C-like mESCs, is required for telomere extension in these cells. However, the mechanism by which Zscan4 extends telomeres remains elusive. Here, we show that Zscan4 facilitates telomere elongation by inducing global DNA demethylation through downregulation of Uhrf1 and Dnmt1, major components of the maintenance DNA methylation machinery. Mechanistically, Zscan4 recruits Uhrf1 and Dnmt1 and promotes their degradation, which depends on the E3 ubiquitin ligase activity of Uhrf1. Blocking DNA demethylation prevents telomere elongation associated with Zscan4 expression, suggesting that DNA demethylation mediates the effect of Zscan4. Our results define a molecular pathway that contributes to the maintenance of telomere length homeostasis in mESCs. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

How can clinical practice guidelines be adapted to facilitate shared decision making? A qualitative key-informant study.

PubMed

van der Weijden, Trudy; Pieterse, Arwen H; Koelewijn-van Loon, Marije S; Knaapen, Loes; Légaré, France; Boivin, Antoine; Burgers, Jako S; Stiggelbout, Anne M; Faber, Marjan; Elwyn, Glyn

2013-10-01

To explore how clinical practice guidelines can be adapted to facilitate shared decision making. This was a qualitative key-informant study with group discussions and semi-structured interviews. First, 75 experts in guideline development or shared decision making participated in group discussions at two international conferences. Next, health professionals known as experts in depression or breast cancer, experts on clinical practice guidelines and/or shared decision making, and patient representatives were interviewed (N=20). Using illustrative treatment decisions on depression or breast cancer, we asked the interviewees to indicate as specifically as they could how guidelines could be used to facilitate shared decision making. Interviewees suggested some generic strategies, namely to include a separate chapter on the importance of shared decision making, to use language that encourages patient involvement, and to develop patient versions of guidelines. Recommendation-specific strategies, related to specific decision points in the guideline, were also suggested: These include structuring the presentation of healthcare options to increase professionals' option awareness; structuring the deliberation process between professionals and patients; and providing relevant patient support tools embedded at important decision points in the guideline. This study resulted in an overview of strategies to adapt clinical practice guidelines to facilitate shared decision making. Some strategies seemed more contentious than others. Future research should assess the feasibility and impact of these strategies to make clinical practice guidelines more conducive to facilitate shared decision making.

Regulating the chromatin landscape: structural and mechanistic perspectives.

PubMed

Bartholomew, Blaine

2014-01-01

A large family of chromatin remodelers that noncovalently modify chromatin is crucial in cell development and differentiation. They are often the targets of cancer, neurological disorders, and other human diseases. These complexes alter nucleosome positioning, higher-order chromatin structure, and nuclear organization. They also assemble chromatin, exchange out histone variants, and disassemble chromatin at defined locations. We review aspects of the structural organization of these complexes, the functional properties of their protein domains, and variation between complexes. We also address the mechanistic details of these complexes in mobilizing nucleosomes and altering chromatin structure. A better understanding of these issues will be vital for further analyses of subunits of these chromatin remodelers, which are being identified as targets in human diseases by NGS (next-generation sequencing).

An exploration of teaching presence in online interprofessional education facilitation.

PubMed

Evans, Sherryn Maree; Ward, Catherine; Reeves, Scott

2017-07-01

Although the prevalence of online asynchronous interprofessional education (IPE) has increased in the last decade, little is known about the processes of facilitation in this environment. The teaching presence element of the Community of Inquiry Framework offers an approach to analyze the contributions of online facilitators, however, to date it has only been used on a limited basis in health professions education literature. Using an exploratory case study design, we explored the types of contributions made by IPE facilitators to asynchronous interprofessional team discussions by applying the notion of teaching presence. Using a purposeful sampling approach, we analyzed 14 facilitators' contributions to asynchronous team discussion boards in an online IPE course. We analyzed data using directed content analysis based on the key indicators of teaching presence. The online IPE facilitators undertook the three critical pedagogical functions identified in teaching presence: facilitating discourse, direct instruction, and instructional design and organization. While our data fitted well with a number of key activities embedded in these three functions, further modification of the teaching presence concept was needed to describe our facilitators' teaching presence. This study provides an initial insight into the key elements of online asynchronous IPE facilitation. Further research is required to continue to illuminate the complexity of online asynchronous IPE facilitation.

Traffic load spectra for implementing and using the mechanistic-empirical pavement design guide in Georgia.

DOT National Transportation Integrated Search

2014-02-01

The GDOT is preparing for implementation of the Mechanistic-Empirical Pavement Design : Guide (MEPDG). As part of this preparation, a statewide traffic load spectra program is being : developed for gathering truck axle loading data. This final report...

Facilitating Grant Proposal Writing in Health Behaviors for University Faculty: A Descriptive Study

PubMed Central

Stein, L. A. R.; Clair, M.; Lebeau, R.; Prochaska, J. O.; Rossi, J. S.; Swift, J.

2015-01-01

Grant proposal writing in the behavioral sciences is important for fiscal reasons and scientific reasons at many universities. This report describes a grant proposal–writing seminar series provided to University faculty (N = 20) and explores factors facilitating and impeding writing. Summary statistics are provided for quantitative data. Free responses were sorted by independent raters into meaningful categories. As a consequence of the training, 45% planned to submit within 18 months; 80% of grant proposals targeted NIH. At 1-year follow-up, 40% actually submitted grants. Factors impeding grant proposal writing included competing professional demands; factors facilitating writing included regularly scheduled feedback on written proposal sections and access to expert collaborators. Obtaining grants generates financial resources, facilitates training experiences, and vastly contributes to the growth and dissemination of the knowledge base in an area. PMID:21444921

Barriers and facilitators to learn and improve through morbidity and mortality conferences: a qualitative study.

PubMed

de Vos, Marit S; Hamming, Jaap F; Marang-van de Mheen, Perla J

2017-11-12

To explore barriers and facilitators to successful morbidity and mortality conferences (M&M), driving learning and improvement. This is a qualitative study with semistructured interviews. Inductive, thematic content analysis was used to identify barriers and facilitators, which were structured across a pre-existing framework for change in healthcare. Dutch academic surgical department with a long tradition of M&M. An interview sample of surgeons, residents and physician assistants (n=12). A total of 57 barriers and facilitators to successful M&M, covering 18 themes, varying from 'case type' to 'leadership', were perceived by surgical staff. While some factors related to M&M organisation, others concerned individual or social aspects. Eight factors, of which four were at the social level, had simultaneous positive and negative effects (eg, 'hierarchy' and 'team spirit'). Mediating pathways for M&M success were found to relate to available information , staff motivation and realisation processes. This study provides leads for improvement of M&M practice, as well as for further research on key elements of successful M&M. Various factors were perceived to affect M&M success, of which many were individual and social rather than organisational factors, affecting information and realisation processes but also staff motivation. Based on these findings, practical recommendations were formulated to guide efforts towards best practices for M&M. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease

PubMed Central

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.

2016-01-01

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 < 0.05). Hypoxic pregnancy in young offspring accelerated endothelial dysfunction (maximal arterial relaxation to acetylcholine: 42 ± 1%, P < 0.05) but this was dissociated from increased vascular short telomere length abundance. Maternal allopurinol rescued maximal arterial relaxation to acetylcholine in aged offspring of normoxic or hypoxic pregnancy but not in young offspring of hypoxic pregnancy. Aged offspring of hypoxic allopurinol pregnancy 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 < 0.05). These data provide evidence for divergence of mechanistic pathways mediating 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

Divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease.

PubMed

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 < 0.05). Hypoxic pregnancy in young offspring accelerated endothelial dysfunction (maximal arterial relaxation to acetylcholine: 42 ± 1%, P < 0.05) but this was dissociated from increased vascular short telomere length abundance. Maternal allopurinol rescued maximal arterial relaxation to acetylcholine in aged offspring of normoxic or hypoxic pregnancy but not in young offspring of hypoxic pregnancy. Aged offspring of hypoxic allopurinol pregnancy 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 < 0.05). These data provide evidence for divergence of mechanistic pathways mediating 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. © FASEB.

Mechanistic Analysis of the C-H Amination Reaction of Menthol by CuBr2 and Selectfluor.

PubMed

Sathyamoorthi, Shyam; Lai, Yin-Hung; Bain, Ryan M; Zare, Richard N

2018-05-18

The mechanism of the Ritter-type C-H amination reaction of menthol with acetonitrile using CuBr 2 , Selectfluor, and Zn(OTf) 2 , first disclosed by Baran and coworkers in 2012, was studied using a combination of online electrospray ionization mass spectrometry, continuous UV/vis spectrometric monitoring, and density functional theory calculations. In addition to corroborating Baran's original mechanistic proposal, these studies uncovered a second pathway to product formation, which likely only occurs in microdroplets. DFT calculations show that neither pathway has a barrier that is greater than 6.8 kcal/mol, suggesting that both mechanisms are potentially operative under ambient conditions.

Supporting Online AP Students: The Rural Facilitator and Considerations for Training

ERIC Educational Resources Information Center

Hendrix, Nicole; Degner, Katherine

2016-01-01

Online courses supplemented by on-site facilitators help many rural students pursue advanced coursework, but research is warranted to better understand facilitator role and training needs. This study examined facilitation experiences, demographic characteristics, and professional development activities of rural on-site facilitators associated with…

Mechanistic Insight of Probiotics Derived Anticancer Pharmaceuticals: A Road Forward for Cancer Therapeutics.

PubMed

Kumar, Raman; Dhanda, Suman

2017-04-01

Probiotics are living organisms that confer health benefits when administered in adequate amounts. Probiotics are continuously being explored for their different health beneficiary activities. Anticancer activity is one of the most important benefits both from a preventive and therapeutic point of view. Though not many studies have been conducted to date in this area, a number suggest using laboratory animal models and different cell lines that there may be a mechanistic basis for the anticancer effects of probiotics and require more scientific justification and clinical trials. Most studies of probiotics are conducted for colon cancer associated with inflammatory bowel disease. Studies are also being extended to other types of cancer in different cell lines. This review summarizes studied probiotics considered for treatment of colon cancer and some other cancers (in cancer cell lines) and also proposed mechanism how probiotics are inhibiting cancer growth along with some challenges and future perspectives.

Application of Pulse Radiolysis to Mechanistic Investigations of Catalysis Relevant to Artificial Photosynthesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fujita, Etsuko; Grills, David C.; Polyansky, Dmitry E.

Taking inspiration from natural photosystems, the goal of artificial photosynthesis is to harness solar energy to convert abundant materials, such as CO 2 and H 2O, into solar fuels. Catalysts are required to ensure that the necessary redox half-reactions proceed in the most energy-efficient manner. It is thus critical to gain a detailed mechanistic understanding of these catalytic reactions in order to develop new and improved catalysts. Many of the key catalytic intermediates are short-lived transient species, requiring time-resolved spectroscopic techniques for their observation. The two main methods for rapidly generating such species on the sub-microsecond timescale are laser flashmore » photolysis and pulse radiolysis. These methods complement one another, and both can provide important spectroscopic and kinetic information. However, pulse radiolysis proves to be superior in systems with significant spectroscopic overlap between photosensitizer and other species present during the reaction. In this paper, we review the pulse radiolysis technique and how it has been applied to mechanistic investigations of half-reactions relevant to artificial photosynthesis.« less

Application of Pulse Radiolysis to Mechanistic Investigations of Catalysis Relevant to Artificial Photosynthesis

DOE PAGES

Fujita, Etsuko; Grills, David C.; Polyansky, Dmitry E.

2017-09-12

Taking inspiration from natural photosystems, the goal of artificial photosynthesis is to harness solar energy to convert abundant materials, such as CO 2 and H 2O, into solar fuels. Catalysts are required to ensure that the necessary redox half-reactions proceed in the most energy-efficient manner. It is thus critical to gain a detailed mechanistic understanding of these catalytic reactions in order to develop new and improved catalysts. Many of the key catalytic intermediates are short-lived transient species, requiring time-resolved spectroscopic techniques for their observation. The two main methods for rapidly generating such species on the sub-microsecond timescale are laser flashmore » photolysis and pulse radiolysis. These methods complement one another, and both can provide important spectroscopic and kinetic information. However, pulse radiolysis proves to be superior in systems with significant spectroscopic overlap between photosensitizer and other species present during the reaction. In this paper, we review the pulse radiolysis technique and how it has been applied to mechanistic investigations of half-reactions relevant to artificial photosynthesis.« less

Assessing causal mechanistic interactions: a peril ratio index of synergy based on multiplicativity.

PubMed

Lee, Wen-Chung

2013-01-01

The assessments of interactions in epidemiology have traditionally been based on risk-ratio, odds-ratio or rate-ratio multiplicativity. However, many epidemiologists fail to recognize that this is mainly for statistical conveniences and often will misinterpret a statistically significant interaction as a genuine mechanistic interaction. The author adopts an alternative metric system for risk, the 'peril'. A peril is an exponentiated cumulative rate, or simply, the inverse of a survival (risk complement) or one plus an odds. The author proposes a new index based on multiplicativity of peril ratios, the 'peril ratio index of synergy based on multiplicativity' (PRISM). Under the assumption of no redundancy, PRISM can be used to assess synergisms in sufficient cause sense, i.e., causal co-actions or causal mechanistic interactions. It has a less stringent threshold to detect a synergy as compared to a previous index of 'relative excess risk due to interaction'. Using the new PRISM criterion, many situations in which there is not evidence of interaction judged by the traditional indices are in fact corresponding to bona fide positive or negative synergisms.

The Relationship of Facilitative Functioning to Effective Peer Supervision

ERIC Educational Resources Information Center

Seligman, Linda

1978-01-01

This study investigates peer supervision. The criterion used was counselor trainees' growth in facilitative functioning. The study sought to ascertain whether the facilitative counselor trainee was also the effective peer supervisor, to provide information on evaluating peer-supervisory experience, and to shed light on the most effective…

Barriers and Facilitators to Implementing Primary Stroke Center Policy in the United States: Results From 4 Case Study States

PubMed Central

Slade, Catherine P.; Brewer, Gene A.; Gase, Lauren N.

2011-01-01

Objectives. We identified barriers and facilitators to the state-level implementation of primary stroke center (PSC) policies, which encourage the certification or designation of specialized stroke treatment facilities and may address concerns such as transportation bypass, telemedicine, and treatment protocols. Methods. We studied the experiences of 4 states (Florida, Massachusetts, New Mexico, and New York) selected from the 18 states that had enacted PSC policies or were actively considering doing so. We conducted semistructured interviews during fieldwork in each case study state. Results. Our results showed that system fragmentation, gaps in human and financial resources, and complexity at the interorganizational and operational levels are common barriers and that policy champions, stakeholder support and communication, and operational adaptation are essential facilitators in the adoption and implementation of PSC policies. Conclusions. The identification of barriers and facilitators reveals the contextual elements that can help or hinder policy implementation and may be useful in informing policy formulation and implementation in other jurisdictions. Proactively identifying jurisdictional challenges and opportunities may help facilitate the policy process for PSC designation and allow jurisdictions to develop more effective stroke systems of care. PMID:21233430

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

PubMed

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

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

Disturbance-mediated facilitation by an intertidal ecosystem engineer.

PubMed

Wright, Jeffrey T; Gribben, Paul E

2017-09-01

Ecosystem engineers facilitate communities by providing a structural habitat that reduces abiotic stress or predation pressure for associated species. However, disturbance may damage or move the engineer to a more stressful environment, possibly increasing the importance of facilitation for associated communities. In this study, we determined how disturbance to intertidal boulders (i.e., flipping) and the subsequent movement of a structural ecosystem engineer, the tube-forming serpulid worm Galeolaria caespitosa, from the bottom (natural state, low abiotic stress) to the top (disturbed state, high abiotic stress) surface of boulders influenced the importance of facilitation for intertidal communities across two intertidal zones. Theory predicts stronger relative facilitation should occur in the harsher environments of the top of boulders and the high intertidal zone. To test this prediction, we experimentally positioned boulders with the serpulids either face up or face down for 12 months in low and high zones in an intertidal boulder field. There were very different communities associated with the different boulders and serpulids had the strongest facilitative effects on the more stressful top surface of boulders with approximately double the species richness compared to boulders lacking serpulids. Moreover, within the serpulid matrix itself there was also approximately double the species richness (both zones) and abundance (high zone only) of small invertebrates on the top of boulders compared to the bottom. The high relative facilitation on the top of boulders reflected a large reduction in temperature by the serpulid matrix on that surface (up to 10°C) highlighting a key role for modification of the abiotic environment in determining the community-wide facilitation. This study has demonstrated that disturbance and subsequent movement of an ecosystem engineer to a more stressful environment increased the importance of facilitation and allowed species to

Descriptive vs. mechanistic network models in plant development in the post-genomic era.

PubMed

Davila-Velderrain, J; Martinez-Garcia, J C; Alvarez-Buylla, E R

2015-01-01

Network modeling is now a widespread practice in systems biology, as well as in integrative genomics, and it constitutes a rich and diverse scientific research field. A conceptually clear understanding of the reasoning behind the main existing modeling approaches, and their associated technical terminologies, is required to avoid confusions and accelerate the transition towards an undeniable necessary more quantitative, multidisciplinary approach to biology. Herein, we focus on two main network-based modeling approaches that are commonly used depending on the information available and the intended goals: inference-based methods and system dynamics approaches. As far as data-based network inference methods are concerned, they enable the discovery of potential functional influences among molecular components. On the other hand, experimentally grounded network dynamical models have been shown to be perfectly suited for the mechanistic study of developmental processes. How do these two perspectives relate to each other? In this chapter, we describe and compare both approaches and then apply them to a given specific developmental module. Along with the step-by-step practical implementation of each approach, we also focus on discussing their respective goals, utility, assumptions, and associated limitations. We use the gene regulatory network (GRN) involved in Arabidopsis thaliana Root Stem Cell Niche patterning as our illustrative example. We show that descriptive models based on functional genomics data can provide important background information consistent with experimentally supported functional relationships integrated in mechanistic GRN models. The rationale of analysis and modeling can be applied to any other well-characterized functional developmental module in multicellular organisms, like plants and animals.

Barriers and facilitators to using NHS Direct: a qualitative study of 'users' and 'non-users'.

PubMed

Cook, Erica J; Randhawa, Gurch; Large, Shirley; Guppy, Andy; Chater, Angel M; Ali, Nasreen

2014-10-25

NHS Direct, introduced in 1998, has provided 24/7 telephone-based healthcare advice and information to the public in England and Wales. National studies have suggested variation in the uptake of this service amongst the UK's diverse population. This study provides the first exploration of the barriers and facilitators that impact upon the uptake of this service from the perspectives of both 'users' and 'non- users'. Focus groups were held with NHS Direct 'users' (N = 2) from Bedfordshire alongside 'non-users' from Manchester (N = 3) and Mendip, Somerset (N = 4). Each focus group had between five to eight participants. A total of eighty one people aged between 21 and 94 years old (M: 58.90, SD: 22.70) took part in this research. Each focus group discussion lasted approximately 90 minutes and was audiotape-recorded with participants' permission. The recordings were transcribed verbatim. A framework approach was used to analyse the transcripts. The findings from this research uncovered a range of barriers and facilitators that impact upon the uptake of NHS Direct. 'Non-users' were unaware of the range of services that NHS Direct provided. Furthermore, 'non-users' highlighted a preference for face-to face communication, identifying a lack of confidence in discussing healthcare over the telephone. This was particularly evident among older people with cognitive difficulties. The cost to telephone a '0845' number from a mobile was also viewed to be a barrier to access NHS Direct, expressed more often by 'non-users' from deprived communities. NHS Direct 'users' identified that awareness, ease of use and convenience were facilitators which influenced their decision to use the service. An understanding of the barriers and facilitators which impact on the access and uptake of telephone-based healthcare is essential to move patients towards the self-care model. This research has highlighted the need for telephone-based healthcare services to increase public awareness; through

Facilitating Facilitators to Facilitate, in Problem or Enquiry Based Learning Sessions

ERIC Educational Resources Information Center

Coelho, Catherine

2014-01-01

Problem based learning (PBL) has been used in dental education over the past 20 years and uses a patient case scenario to stimulate learning in a small group setting, where a trained facilitator does not teach but guides the group to bring about deep contextualized learning, to be empathetic to each other and to encourage fair and equitable…

Characterizing seasonal variations in pavement material properties for use in a mechanistic-empirical design procedure

DOT National Transportation Integrated Search

2000-12-01

Recent advances in flexible pavement design have prompted agencies to move toward the development and use of mechanistic-empirical (M-E) design procedures. This report analyzed seasonal trends in flexible pavement layer moduli to calibrate a M-E desi...

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

PubMed Central

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

2014-01-01

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

Mechanistic Parameters of Electrocatalytic Water Oxidation on LiMn2 O4 in Comparison to Natural Photosynthesis.

PubMed

Köhler, Lennart; Ebrahimizadeh Abrishami, Majid; Roddatis, Vladimir; Geppert, Janis; Risch, Marcel

2017-11-23

Targeted improvement of the low efficiency of water oxidation during the oxygen evolution reaction (OER) is severely hindered by insufficient knowledge of the electrocatalytic mechanism on heterogeneous surfaces. We chose LiMn 2 O 4 as a model system for mechanistic investigations as it shares the cubane structure with the active site of photosystem II and the valence of Mn 3.5+ with the dark-stable S1 state in the mechanism of natural photosynthesis. The investigated LiMn 2 O 4 nanoparticles are electrochemically stable in NaOH electrolytes and show respectable activity in any of the main metrics. At low overpotential, the key mechanistic parameters of Tafel slope, Nernst slope, and reaction order have constant values on the RHE scale of 62(1) mV dec -1 , 1(1) mV pH -1 , -0.04(2), respectively. These values are interpreted in the context of the well-studied mechanism of natural photosynthesis. The uncovered difference in the reaction sequence is important for the design of efficient bio-inspired electrocatalysts. © 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Air pollution, inflammation and preterm birth: a potential mechanistic link.

PubMed

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

2014-02-01

Preterm birth is a public health issue of global significance, which may result in mortality during the perinatal period or may lead to major health and financial consequences due to lifelong impacts. Even though several risk factors for preterm birth have been identified, prevention efforts have failed to halt the increasing rates of preterm birth. Epidemiological studies have identified air pollution as an emerging potential risk factor for preterm birth. However, many studies were limited by study design and inadequate exposure assessment. Due to the ubiquitous nature of ambient air pollution and the potential public health significance of any role in causing preterm birth, a novel focus investigating possible causal mechanisms influenced by air pollution is therefore a global health priority. We hypothesize that air pollution may act together with other biological factors to induce systemic inflammation and influence the duration of pregnancy. Evaluation and testing of this hypothesis is currently being conducted in a prospective cohort study in Mexico City and will provide an understanding of the pathways that mediate the effects of air pollution on preterm birth. The important public health implication is that crucial steps in this mechanistic pathway can potentially be acted on early in pregnancy to reduce the risk of preterm birth. Copyright © 2013 Elsevier Ltd. All rights reserved.

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

PubMed Central

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

2014-01-01

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

Facilitating Factors and Barriers to the Use of Emerging Technologies for Suicide Prevention in Europe: Multicountry Exploratory Study

PubMed Central

Delgado, Carmen; Sánchez-Prada, Andrés; Parra-Vidales, Esther; de Leo, Diego; Franco-Martín, Manuel

2018-01-01

Background This study provides an analysis on the use of emerging technologies for the prevention of suicide in 8 different European countries. Objective The objective of this study was to analyze the potentiality of using emerging technologies in the area of suicide prevention based on the opinion of different professionals involved in suicide prevention. Methods Opinions of 3 groups of stakeholders (ie, relevant professionals in suicide field) were gathered using a specifically designed questionnaire to explore dimensions underlying perceptions of facilitating factors and barriers in relation to the use of emerging technologies for suicide prevention. Results Goal 1 involved facilitating factors for the use of emerging technologies in suicide prevention. Northern European countries, except for Belgium, attach greater relevance to those that optimize implementation and benefits. On the other hand, Southern European countries attach greater importance to professionally oriented and user-centered facilitating factors. According to different stakeholders, the analysis of these facilitating factors suggest that professionals in the field of social work attach greater relevance to those that optimize implementation and benefits. However, professionals involved in the area of mental health, policy makers, and political decision makers give greater importance to professionally oriented and user-centered facilitating factors. Goal 2 was related to barriers to the usability of emerging technologies for suicide prevention. Both countries and stakeholders attach greater importance to barriers associated with resource constraints than to those centered on personal limitations. There are no differences between countries or between stakeholders. Nevertheless, there is a certain stakeholders-countries interaction that indicates that the opinions on resource constraints expressed by different stakeholders do not follow a uniform pattern in different countries, but they differ

Facilitating Factors and Barriers to the Use of Emerging Technologies for Suicide Prevention in Europe: Multicountry Exploratory Study.

PubMed

Muñoz-Sánchez, Juan-Luis; Delgado, Carmen; Parra-Vidales, Esther; Franco-Martín, Manuel

2018-01-24

This study provides an analysis on the use of emerging technologies for the prevention of suicide in 8 different European countries. The objective of this study was to analyze the potentiality of using emerging technologies in the area of suicide prevention based on the opinion of different professionals involved in suicide prevention. Opinions of 3 groups of stakeholders (ie, relevant professionals in suicide field) were gathered using a specifically designed questionnaire to explore dimensions underlying perceptions of facilitating factors and barriers in relation to the use of emerging technologies for suicide prevention. Goal 1 involved facilitating factors for the use of emerging technologies in suicide prevention. Northern European countries, except for Belgium, attach greater relevance to those that optimize implementation and benefits. On the other hand, Southern European countries attach greater importance to professionally oriented and user-centered facilitating factors. According to different stakeholders, the analysis of these facilitating factors suggest that professionals in the field of social work attach greater relevance to those that optimize implementation and benefits. However, professionals involved in the area of mental health, policy makers, and political decision makers give greater importance to professionally oriented and user-centered facilitating factors. Goal 2 was related to barriers to the usability of emerging technologies for suicide prevention. Both countries and stakeholders attach greater importance to barriers associated with resource constraints than to those centered on personal limitations. There are no differences between countries or between stakeholders. Nevertheless, there is a certain stakeholders-countries interaction that indicates that the opinions on resource constraints expressed by different stakeholders do not follow a uniform pattern in different countries, but they differ depending on the country. Although all

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

EPA Science Inventory

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

Perspectives on barriers and facilitators to self-care in Lebanese cardiac patients: A qualitative descriptive study.

PubMed

Dumit, Nuhad Yazbik; Noureddine, Samar Nayef; Magilvy, Joan Kathy

2016-08-01

Cardiovascular disease is the leading cause of mortality worldwide. Cardiac self-care practices are essential for managing cardiac illness and improving quality of life. However, these practices may be affected by factors that may hinder or facilitate self-care especially in countries that experience political and economic instabilities. The purpose of this study was to explore self-care practices among Lebanese cardiac patients. Another aim was to reveal factors that might influence these self-care practices. This is a qualitative descriptive study. Participants were recruited from a referral medical center in Beirut, Lebanon and interviews took place in their homes. Purposive sample of 15 adult participants, seven females and eight males, diagnosed with coronary artery disease at least a year ago and not in critical condition recruited from the cardiology clinics of the medical center. Data were collected through semi-structured audio-recorded interviews that took place in their places of residents. Three themes emerged from the data: I. The behaviors of cardiac patients demonstrated selected self-care practices; II. Patients identified barriers to self-care reflective of the Lebanese political and socio-economic situation; and, III. Patients described facilitators to self-care consistent with the Lebanese socio-cultural values and norms. The most common self-care practices included taking medications and eating properly. Participants emphasized avoiding stress and being upset as a self-protective measure for cardiac health. Health care costs, family responsibilities, psychological factors and the country's political situation impeded self-care practices whereas family support facilitated them. Lebanese patients reported select self-care practices in dealing with their cardiac illness. Barriers and facilitators to their self-care behaviors reflected the Lebanese context and culture. Thus health care providers must assess their patients' practices within their

Exploring reforms while learning to teach science: Facilitating exploration of theory-practice relationships in a teacher education study group

NASA Astrophysics Data System (ADS)

Foster, Jacob G.

This dissertation inserts a new view into an old problem in teacher education. The study explores the theory-practice gap, the large distance between what preservice science teachers experience in schools, are able to enact, and are told they should hold themselves to in their practice. It does so by narrowing the focus of analysis to a secondary science study group and examining how the facilitator uses sociocultural constructivism to promote discussion. The analysis surfaces key communicative moves made by the facilitator and preservice teachers that yield fruitful discussion of theory-practice relationships. Additionally, the study's use of discourse analysis as a methodology and intertextuality as a conceptual framework opens new directions for applied sociolinguistic research and scholarship in science teacher education. Findings from the study focus on what was discussed and how explorations of theory-practice relationships were facilitated. Preservice teachers in the study group engaged in meaningful conversations about constructivist theory and its application to their students and teaching of science. They discussed many science education topics such as planning science lessons that actively engage students, assessment of content understanding, and management of content-based activities. Discussions of broader science education goals, including implementation of inquiry or development of collaborative communities, were not promoted. Examination of the facilitation illuminates a number of strategies found to be helpful in supporting these explorations. This study shows that facilitation can successfully support preservice teachers to construct understanding of social constructivist assumptions underlying the National Science Education Standards (NSES), as well as a few components of the Standards themselves. The focus on the underlying assumptions suggests that science teacher education should focus on these so that preservice teachers can build a strong

Barriers and facilitators to mental health help-seeking for young elite athletes: a qualitative study

PubMed Central

2012-01-01

Background Adolescents and young adults experience a high level of mental disorders, yet tend not to seek help. Research indicates that there are many barriers and facilitators to help-seeking for young people in the general community. However there are limited data available for young elite athletes. This study aims to determine what young elite athletes perceive as the barriers and facilitators to help-seeking for common mental health problems. Methods Fifteen elite athletes aged 16–23 years each participated in one of three focus group discussions. In addition to written data, verbal responses were audio taped, transcribed and thematically analysed. Results Participants’ written and verbal data suggested that stigma was the most important perceived barrier to seeking help for young elite athletes. Other notable barriers were a lack of mental health literacy, and negative past experiences of help-seeking. Facilitators to help-seeking were encouragement from others, having an established relationship with a provider, pleasant previous interactions with providers, the positive attitudes of others, especially their coach, and access to the internet. Conclusions Intervention strategies for improving help-seeking in young elite athletes should focus on reducing stigma, increasing mental health literacy, and improving relations with potential providers. PMID:23009161

Application of comparative vibrational spectroscopic and mechanistic studies in analysis of fisetin structure

NASA Astrophysics Data System (ADS)

Dimitrić Marković, Jasmina M.; Marković, Zoran S.; Milenković, Dejan; Jeremić, Svetlana

2011-12-01

This paper addresses experimental and theoretical research in fisetin (2-(3,4-dihydroxyphenyl)-3,7-dihydroxychromen-4-one) structure by means of experimental IR and Raman spectroscopies and mechanistic calculations. Density Functional Theory calculations, with M05-2X functional and the 6-311+G (2df, p) basis set implemented in the Gaussian 09 package, are performed with the aim to support molecular structure, vibrational bands' positions and their intensities. Potential energy distribution (PED) values and the description of the largest vibrational contributions to the normal modes are calculated. The most intense bands appear in the 1650-1500 cm -1 wavenumber region. This region involves a combination of the C dbnd O, C2 dbnd C3 and C-C stretching vibrational modes. Most of the bands in the 1500-1000 cm -1 range involve C-C stretching, O-C stretching and in-plane C-C-H, C-O-H, C-C-O and C-C-C bending vibrations of the rings. The region below 1000 cm -1 is characteristic to the combination of in plane C-C-C-H, H-C-C-H, C-C-C-C, C-C-O-C and out of plane O-C-C-C, C-C-O-C, C-C-C-C torsional modes. The Raman spectra of baicalein and quercetin were used for qualitative comparison with fisetin spectrum and verification of band assignments. The applied detailed vibrational spectral analysis and the assignments of the bands, proposed on the basis of fundamentals, reproduced the experimental results with high degree of accuracy.

Understanding the challenges to facilitating active learning in the resident conferences: a qualitative study of internal medicine faculty and resident perspectives

PubMed Central

Sawatsky, Adam P.; Zickmund, Susan L.; Berlacher, Kathryn; Lesky, Dan; Granieri, Rosanne

2015-01-01

Background In the Next Accreditation System, the Accreditation Council for Graduate Medical Education outlines milestones for medical knowledge and requires regular didactic sessions in residency training. There are many challenges to facilitating active learning in resident conferences, and we need to better understand resident learning preferences and faculty perspectives on facilitating active learning. The goal of this study was to identify challenges to facilitating active learning in resident conferences, both through identifying specific implementation barriers and identifying differences in perspective between faculty and residents on effective teaching and learning strategies. Methods The investigators invited core residency faculty to participate in focus groups. The investigators used a semistructured guide to facilitate discussion about learning preferences and teaching perspectives in the conference setting and used an ‘editing approach’ within a grounded theory framework to qualitative analysis to code the transcripts and analyze the results. Data were compared to previously collected data from seven resident focus groups. Results Three focus groups with 20 core faculty were conducted. We identified three domains pertaining to facilitating active learning in resident conferences: barriers to facilitating active learning formats, similarities and differences in faculty and resident learning preferences, and divergence between faculty and resident opinions about effective teaching strategies. Faculty identified several setting, faculty, and resident barriers to facilitating active learning in resident conferences. When compared to residents, faculty expressed similar learning preferences; the main differences were in motivations for conference attendance and type of content. Resident preferences and faculty perspectives differed on the amount of information appropriate for lecture and the role of active participation in resident conferences

Understanding the challenges to facilitating active learning in the resident conferences: a qualitative study of internal medicine faculty and resident perspectives.

PubMed

Sawatsky, Adam P; Zickmund, Susan L; Berlacher, Kathryn; Lesky, Dan; Granieri, Rosanne

2015-01-01

Background In the Next Accreditation System, the Accreditation Council for Graduate Medical Education outlines milestones for medical knowledge and requires regular didactic sessions in residency training. There are many challenges to facilitating active learning in resident conferences, and we need to better understand resident learning preferences and faculty perspectives on facilitating active learning. The goal of this study was to identify challenges to facilitating active learning in resident conferences, both through identifying specific implementation barriers and identifying differences in perspective between faculty and residents on effective teaching and learning strategies. Methods The investigators invited core residency faculty to participate in focus groups. The investigators used a semistructured guide to facilitate discussion about learning preferences and teaching perspectives in the conference setting and used an 'editing approach' within a grounded theory framework to qualitative analysis to code the transcripts and analyze the results. Data were compared to previously collected data from seven resident focus groups. Results Three focus groups with 20 core faculty were conducted. We identified three domains pertaining to facilitating active learning in resident conferences: barriers to facilitating active learning formats, similarities and differences in faculty and resident learning preferences, and divergence between faculty and resident opinions about effective teaching strategies. Faculty identified several setting, faculty, and resident barriers to facilitating active learning in resident conferences. When compared to residents, faculty expressed similar learning preferences; the main differences were in motivations for conference attendance and type of content. Resident preferences and faculty perspectives differed on the amount of information appropriate for lecture and the role of active participation in resident conferences. Conclusion

Understanding the challenges to facilitating active learning in the resident conferences: a qualitative study of internal medicine faculty and resident perspectives.

PubMed

Sawatsky, Adam P; Zickmund, Susan L; Berlacher, Kathryn; Lesky, Dan; Granieri, Rosanne

2015-01-01

In the Next Accreditation System, the Accreditation Council for Graduate Medical Education outlines milestones for medical knowledge and requires regular didactic sessions in residency training. There are many challenges to facilitating active learning in resident conferences, and we need to better understand resident learning preferences and faculty perspectives on facilitating active learning. The goal of this study was to identify challenges to facilitating active learning in resident conferences, both through identifying specific implementation barriers and identifying differences in perspective between faculty and residents on effective teaching and learning strategies. The investigators invited core residency faculty to participate in focus groups. The investigators used a semistructured guide to facilitate discussion about learning preferences and teaching perspectives in the conference setting and used an 'editing approach' within a grounded theory framework to qualitative analysis to code the transcripts and analyze the results. Data were compared to previously collected data from seven resident focus groups. Three focus groups with 20 core faculty were conducted. We identified three domains pertaining to facilitating active learning in resident conferences: barriers to facilitating active learning formats, similarities and differences in faculty and resident learning preferences, and divergence between faculty and resident opinions about effective teaching strategies. Faculty identified several setting, faculty, and resident barriers to facilitating active learning in resident conferences. When compared to residents, faculty expressed similar learning preferences; the main differences were in motivations for conference attendance and type of content. Resident preferences and faculty perspectives differed on the amount of information appropriate for lecture and the role of active participation in resident conferences. This study highlights several

Development of an interprofessional lean facilitator assessment scale.

PubMed

Bravo-Sanchez, Cindy; Dorazio, Vincent; Denmark, Robert; Heuer, Albert J; Parrott, J Scott

2018-05-01

High reliability is important for optimising quality and safety in healthcare organisations. Reliability efforts include interprofessional collaborative practice (IPCP) and Lean quality/process improvement strategies, which require skilful facilitation. Currently, no validated Lean facilitator assessment tool for interprofessional collaboration exists. This article describes the development and pilot evaluation of such a tool; the Interprofessional Lean Facilitator Assessment Scale (ILFAS), which measures both technical and 'soft' skills, which have not been measured in other instruments. The ILFAS was developed using methodologies and principles from Lean/Shingo, IPCP, metacognition research and Bloom's Taxonomy of Learning Domains. A panel of experts confirmed the initial face validity of the instrument. Researchers independently assessed five facilitators, during six Lean sessions. Analysis included quantitative evaluation of rater agreement. Overall inter-rater agreement of the assessment of facilitator performance was high (92%), and discrepancies in the agreement statistics were analysed. Face and content validity were further established, and usability was evaluated, through primary stakeholder post-pilot feedback, uncovering minor concerns, leading to tool revision. The ILFAS appears comprehensive in the assessment of facilitator knowledge, skills, abilities, and may be useful in the discrimination between facilitators of different skill levels. Further study is needed to explore instrument performance and validity.

Barriers and facilitators to exchanging health information: a systematic review.

PubMed

Eden, Karen B; Totten, Annette M; Kassakian, Steven Z; Gorman, Paul N; McDonagh, Marian S; Devine, Beth; Pappas, Miranda; Daeges, Monica; Woods, Susan; Hersh, William R

2016-04-01

We conducted a systematic review of studies assessing facilitators and barriers to use of health information exchange (HIE). We searched MEDLINE, PsycINFO, CINAHL, and the Cochrane Library databases between January 1990 and February 2015 using terms related to HIE. English-language studies that identified barriers and facilitators of actual HIE were included. Data on study design, risk of bias, setting, geographic location, characteristics of the HIE, perceived barriers and facilitators to use were extracted and confirmed. Ten cross-sectional, seven multiple-site case studies, and two before-after studies that included data from several sources (surveys, interviews, focus groups, and observations of users) evaluated perceived barriers and facilitators to HIE use. The most commonly cited barriers to HIE use were incomplete information, inefficient workflow, and reports that the exchanged information that did not meet the needs of users. The review identified several facilitators to use. Incomplete patient information was consistently mentioned in the studies conducted in the US but not mentioned in the few studies conducted outside of the US that take a collective approach toward healthcare. Individual patients and practices in the US may exercise the right to participate (or not) in HIE which effects the completeness of patient information available to be exchanged. Workflow structure and user roles are key but understudied. We identified several facilitators in the studies that showed promise in promoting electronic health data exchange: obtaining more complete patient information; thoughtful workflow that folds in HIE; and inclusion of users early in implementation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Mechanistic studies of hydrogen evolution in aqueous solution catalyzed by a tertpyridine-amine cobalt complex

DOE PAGES

Lewandowska-Andralojc, Anna; Baine, Teera; Zhao, Xuan; ...

2015-04-22

The ability of cobalt-based transition metal complexes to catalyze electrochemical proton reduction to produce molecular hydrogen has resulted in a large number of mechanistic studies involving various cobalt complexes. In addition, while the basic mechanism of proton reduction promoted by cobalt species is well understood, the reactivity of certain reaction intermediates, such as Co I and Co III–H, is still relatively unknown owing to their transient nature, especially in aqueous media. In this work we investigate the properties of intermediates produced during catalytic proton reduction in aqueous solutions promoted by the [(DPA-Bpy)Co(OH₂)] n+ (DPA-Bpy = N,N-bis(2-pyridinylmethyl)-2,20-bipyridine-6-methanamine) complex ([Co(L)(OH₂)] n+ wheremore » L is the pentadentate DPA-Bpy ligand or [ Co(OH₂)] n+ as a shorthand). Experimental results based on transient pulse radiolysis and laser flash photolysis methods, together with electrochemical studies and supported by DFT calculations indicate that, while the water ligand is strongly coordinated to the metal center in the oxidation state 3+, one-electron reduction of the complex to form a Co II species results in weakening the Co–O bond. The further reduction to a Co I species leads to the loss of the aqua ligand and the formation of [ CoI–VS)]⁺ (VS = vacant site). Interestingly, DFT calculations also predict the existence of a [Co I(κ⁴-L)(OH₂)]⁺ species at least transiently, and its formation is consistent with the experimental Pourbaix diagram. Both electrochemical and kinetics results indicate that the Co I species must undergo some structural change prior to accepting the proton, and this transformation represents the rate-determining step (RDS) in the overall formation of [ CoIII–H]⁺. We propose that this RDS may originate from the slow removal of a solvent ligand in the intermediate [Co I(κ⁴-L)(OH₂)]⁺ in addition to the significant structural reorganization of the metal complex

hNaa10p contributes to tumorigenesis by facilitating DNMT1-mediated tumor suppressor gene silencing

PubMed Central

Lee, Chung-Fan; Ou, Derick S.-C.; Lee, Sung-Bau; Chang, Liang-Hao; Lin, Ruo-Kai; Li, Ying-Shiuan; Upadhyay, Anup K.; Cheng, Xiaodong; Wang, Yi-Ching; Hsu, Han-Shui; Hsiao, Michael; Wu, Cheng-Wen; Juan, Li-Jung

2010-01-01

Hypermethylation-mediated tumor suppressor gene silencing plays a crucial role in tumorigenesis. Understanding its underlying mechanism is essential for cancer treatment. Previous studies on human N-α-acetyltransferase 10, NatA catalytic subunit (hNaa10p; also known as human arrest-defective 1 [hARD1]), have generated conflicting results with regard to its role in tumorigenesis. Here we provide multiple lines of evidence indicating that it is oncogenic. We have shown that hNaa10p overexpression correlated with poor survival of human lung cancer patients. In vitro, enforced expression of hNaa10p was sufficient to cause cellular transformation, and siRNA-mediated depletion of hNaa10p impaired cancer cell proliferation in colony assays and xenograft studies. The oncogenic potential of hNaa10p depended on its interaction with DNA methyltransferase 1 (DNMT1). Mechanistically, hNaa10p positively regulated DNMT1 enzymatic activity by facilitating its binding to DNA in vitro and its recruitment to promoters of tumor suppressor genes, such as E-cadherin, in vivo. Consistent with this, interaction between hNaa10p and DNMT1 was required for E-cadherin silencing through promoter CpG methylation, and E-cadherin repression contributed to the oncogenic effects of hNaa10p. Together, our data not only establish hNaa10p as an oncoprotein, but also reveal that it contributes to oncogenesis through modulation of DNMT1 function. PMID:20592467

Adolescents' Perspectives on the Barriers and Facilitators of Physical Activity: A Systematic Review of Qualitative Studies

ERIC Educational Resources Information Center

Martins, João; Marques, Adilson; Sarmento, Hugo; Carreiro da Costa, Francisco

2015-01-01

This article examined qualitative studies of adolescents' perspectives about the facilitators and barriers of physical activity, published from 2007 to 2014. A systematic review of "Web of Science", "EBSCO", "Psychinfo" and "ERIC" databases was performed according to Preferred Reporting Items for Systematic…

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

PubMed Central

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

2010-01-01

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

Application of empirical and mechanistic-empirical pavement design procedures to Mn/ROAD concrete pavement test sections

DOT National Transportation Integrated Search

1997-05-01

Current pavement design procedures are based principally on empirical approaches. The current trend toward developing more mechanistic-empirical type pavement design methods led Minnesota to develop the Minnesota Road Research Project (Mn/ROAD), a lo...

Serpin Facilitates Tumor-Suppressive Cell Competition by Blocking Toll-Mediated Yki Activation in Drosophila.

PubMed

Katsukawa, Mitsuko; Ohsawa, Shizue; Zhang, Lina; Yan, Yan; Igaki, Tatsushi

2018-06-04

Normal epithelial tissue exerts an intrinsic tumor-suppressive effect against oncogenically transformed cells. In Drosophila imaginal epithelium, clones of oncogenic polarity-deficient cells mutant for scribble (scrib) or discs large (dlg) are eliminated by cell competition when surrounded by wild-type cells. Here, through a genetic screen in Drosophila, we identify Serpin5 (Spn5), a secreted negative regulator of Toll signaling, as a crucial factor for epithelial cells to eliminate scrib mutant clones from epithelium. Downregulation of Spn5 in wild-type cells leads to elevation of Toll signaling in neighboring scrib cells. Strikingly, forced activation of Toll signaling or Toll-related receptor (TRR) signaling in scrib clones transforms scrib cells from losers to supercompetitors, resulting in tumorous overgrowth of mutant clones. Mechanistically, Toll activation in scrib clones leads to c-Jun N-terminal kinase (JNK) activation and F-actin accumulation, which cause strong activation of the Hippo pathway effector Yorkie that blocks cell death and promotes cell proliferation. Our data suggest that Spn5 secreted from normal epithelial cells acts as a component of the extracellular surveillance system that facilitates elimination of pre-malignant cells from epithelium. Copyright © 2018 Elsevier Ltd. All rights reserved.

Mindfulness-Based Cognitive Therapy for Cancer Patients Delivered via Internet: Qualitative Study of Patient and Therapist Barriers and Facilitators

PubMed Central

Bisseling, Else M; Schellekens, Melanie PJ; Jansen, Ellen TM; van der Lee, Marije L; Speckens, Anne EM

2017-01-01

Background The number of patients living with cancer is growing, and a substantial number of patients suffer from psychological distress. Mindfulness-based interventions (MBIs) seem effective in alleviating psychological distress. Unfortunately, several cancer patients find it difficult, if not impossible, to attend a group-based course. Internet-based MBIs (eMBIs) such as Internet-based mindfulness-based cognitive therapy (eMBCT) may offer solutions. However, it is yet to be studied what facilitators and barriers cancer patients experience during eMBCT. Objective This study aimed to explore facilitators and barriers of individual asynchronous therapist-assisted eMBCT as experienced by both patients and therapists. Methods Patients with heterogeneous cancer diagnoses suffering from psychological distress were offered eMBCT. This 9-week intervention mirrored the group-based MBCT protocol and included weekly asynchronous written therapist feedback. Patients were granted access to a website that contained the eMBCT protocol and a secured inbox, and they were asked to practice and fill out diaries on which the therapist provided feedback. In total, 31 patients participated in an individual posttreatment interview on experienced facilitators and barriers during eMBCT. Moreover, eight therapists were interviewed. The data were analyzed with qualitative content analysis to identify barriers and facilitators in eMBCT. Results Both patients and therapists mentioned four overarching themes as facilitators and barriers: treatment setting (the individual and Internet-based nature of the treatment), treatment format (how the treatment and its guidance were organized and delivered), role of the therapist, and individual patient characteristics. Conclusions The eMBCT provided flexibility in when, where, and how patients and therapists engage in MBCT. Future studies should assess how different eMBCT designs could further improve barriers that were found. PMID:29254912

Implementing clinical guidelines in stroke: a qualitative study of perceived facilitators and barriers.

PubMed

Donnellan, Claire; Sweetman, S; Shelley, E

2013-08-01

Clinical guidelines are frequently used as a mechanism for implementing evidence-based practice. However research indicates that health professionals vary in the extent to which they adhere to these guidelines. This study aimed to study the perceptions of stakeholders and health professionals on the facilitators and barriers to implementing national stroke guidelines in Ireland. Qualitative interviews using focus groups were conducted with stakeholders (n=3) and multidisciplinary team members from hospitals involved in stroke care (n=7). All focus group interviews were semi-structured, using open-ended questions. Data was managed and analysed using NVivo 9 software. The main themes to emerge from the focus groups with stakeholders and hospital multidisciplinary teams were very similar in terms of topics discussed. These were resources, national stroke guidelines as a tool for change, characteristics of national stroke guidelines, advocacy at local level and community stroke care challenges. Facilitators perceived by stakeholders and health professionals included having dedicated resources, user-friendly guidelines relevant at local level and having supportive advocates on the ground. Barriers were inadequate resources, poor guideline characteristics and insufficient training and education. This study highlights health professionals' perspectives regarding many key concepts which may affect the implementation of stroke care guidelines. The introduction of stroke clinical guidelines at a national level is not sufficient to improve health care quality as they should be incorporated in a quality assurance cycle with education programmes and feedback from surveys of clinical practice. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Photoisomerization of ruthenium(ii) aquo complexes: mechanistic insights and application development.

PubMed

Hirahara, Masanari; Yagi, Masayuki

2017-03-21

Ruthenium(ii) complexes with polypyridyl ligands have been extensively studied as promising functional molecules due to their unique photochemical and photophysical properties as well as redox properties. In this context, we report the photoisomerization of distal-[Ru(tpy)(pynp)OH 2 ] 2+ (d-1) (tpy = 2,2';6',2''-terpyridine, pynp = 2-(2-pyridyl)-1,8-naphthyridine) to proximal-[Ru(tpy)(pynp)OH 2 ] 2+ (p-1), which has not been previously characterized for polypyridyl ruthenium(ii) aquo complexes. Herein, we review recent progress made by our group on the mechanistic insights and application developments related to the photoisomerization of polypyridyl ruthenium(ii) aquo complexes. We report a new strategic synthesis of dinuclear ruthenium(ii) complexes that can act as an active water oxidation catalyst, as well as the development of unique visible-light-responsive giant vesicles, both of which were achieved based on photoisomerization.

Perceived Barriers and Facilitators of Exercise and Healthy Dietary Choices: A Study of Employees and Managers within a Large Transport Organisation

ERIC Educational Resources Information Center

Donaldson-Feilder, Emma; Lewis, Rachel; Pavey, Louisa; Jones, Bethan; Green, Melanie; Webster, Angela

2017-01-01

Objective: The objective of this study was to examine employees' perceived barriers and facilitators of physical activity and healthy dietary choices, and managers' perceptions of how best to facilitate physical activity and healthy dietary choices among their team members. Design: Single time-point survey with categorical and open-ended…

Barriers and facilitators to health care professionals discussing child weight with parents: A meta-synthesis of qualitative studies.

PubMed

Bradbury, Daisy; Chisholm, Anna; Watson, Paula M; Bundy, Christine; Bradbury, Nicola; Birtwistle, Sarah

2018-04-26

Childhood obesity is one of the most serious global public health challenges. However, obesity and its consequences are largely preventable. As parents play an important role in their children's weight-related behaviours, good communication between parents and health care professionals (HCPs) is essential. This systematic review provides a meta-synthesis of qualitative studies exploring the barriers and facilitators experienced by HCPs when discussing child weight with parents. Searches were conducted using the following databases: MEDLINE (OVID), Psych INFO (OVID), EMBASE (OVID), Web of Knowledge and CINAHL. Thirteen full-text qualitative studies published in English language journals since 1985 were included. Included studies collected data from HCPs (e.g., nurses, doctors, dieticians, psychologists, and clinical managers) concerning their experiences of discussing child weight-related issues with parents. An inductive thematic analysis was employed to synthesize findings. Emerging subthemes were categorized using a socio-ecological framework into intra/interpersonal factors, organizational factors, and societal factors. Perceived barriers and facilitators most commonly related to intra/interpersonal level factors, that is, relating to staff factors, parental factors, or professional-parent interactions. HCPs also attributed a number of barriers, but not facilitators, at the organizational and societal levels. The findings of this review may help to inform the development of future weight-related communication interventions. Whilst intra/interpersonal interventions may go some way to improving health care practice, it is crucial that all stakeholders consider the wider organizational and societal context in which these interactions take place. Statement of contribution What is already known on the subject? Childhood obesity is one of the United Kingdom's most serious current public health challenges. Health care professionals are in a prime position to identify

Data-Driven Mechanistic Modeling of Influence of Microstructure on High-Cycle Fatigue Life of Nickel Titanium

NASA Astrophysics Data System (ADS)

Kafka, Orion L.; Yu, Cheng; Shakoor, Modesar; Liu, Zeliang; Wagner, Gregory J.; Liu, Wing Kam

2018-04-01

A data-driven mechanistic modeling technique is applied to a system representative of a broken-up inclusion ("stringer") within drawn nickel-titanium wire or tube, e.g., as used for arterial stents. The approach uses a decomposition of the problem into a training stage and a prediction stage. It is applied to compute the fatigue crack incubation life of a microstructure of interest under high-cycle fatigue. A parametric study of a matrix-inclusion-void microstructure is conducted. The results indicate that, within the range studied, a larger void between halves of the inclusion increases fatigue life, while larger inclusion diameter reduces fatigue life.

Developing facilitation skills--a narrative.

PubMed

Newton, Jennifer M

2003-07-01

Effective facilitation has been identified in the literature as one of three elements, along with context and evidence, that have a dynamic and coexisting relationship to enable the successful uptake of evidence into practice. This paper presents an overview of the concept of facilitation within the context of practice development, ahead of a personal and professional reflective account of a 'developing facilitator'. In the summer of 2001, the author was instrumental in organising the first Practice Development School in Melbourne. Thrown in at the deep end, she found herself co-facilitating with an experienced practice developer from the United Kingdom. Having never facilitated in the arena of an action learning group, nor worked in the field of practice development, there was initially a sense of impending overload and drowning in the new knowledge and skills that needed to be acquired. Drawing upon the work of narrative inquiry the author shares her experiences in the anticipation that in telling her story it will assist others in their journey of becoming a facilitator.

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

PubMed

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

2016-10-10

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

Enhancing the Transition to University by Facilitating Social and Study Networks: Results of a One-Day Workshop.

ERIC Educational Resources Information Center

Peat, Mary; Dalziel, James; Grant, Anthony M.

2000-01-01

Describes a one-day workshop developed at the University of Sydney (Australia) to facilitate social and study-related peer networks. Qualitative and quantitative analyses found that the workshops enhanced study, self-motivation, and general enjoyment of university life and were helpful in easing the transition of undergraduate students.…

Mechanistic insight into neurotoxicity induced by developmental insults

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tamm, Christoffer; Ceccatelli, Sandra

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

Facilitators and Barriers of Electronic Health Record Patient Portal Adoption by Older Adults: A Literature Study.

PubMed

Wildenbos, Gaby Anne; Peute, Linda; Jaspers, Monique

2017-01-01

Patient portal usage by older adults, patients aged 50 years old and above, is intended to improve their access and quality of care. Acceptance of patient portals by this target group is low. This paper discusses the results of a literature review to determine the facilitators and barriers that drive or inhibit older patients to adopt patient portals. Articles were included when they described an acceptance, adoption or usability evaluation study of a patient portal. From a total of 245 potentially relevant articles, 8 articles were finally included. We used the Unified Theory of Acceptance and Use of Technology (UTAUT) as a classification model to analyze factors influencing older adults' acceptance of patient portals. Main facilitators for acceptance were 'performance expectancy' and 'voluntariness of use' related to a higher level of education and experienced health. Main barriers were limited health literacy and motivation related to involuntariness to use a patient portal. Poor facilitation conditions (limited technology access and no prior knowledge on existence of a patient portal) hampered access to a portal. More thorough insight into the latter is needed to improve the reach and effectiveness of patient portals among older patients.

A cross-sectional study of facilitators and barriers of Iranian nurses' participation in continuing education programs.

PubMed

Hamzehgardeshi, Zeinab; Shahhosseini, Zohreh

2013-12-27

Continuing education is one of the modern strategies to maintain and elevate knowledge and professional skills of nurses which in turn elevate the health status of society. Since several factors affect nurses' participation in continuing education, it's essential to know promoters and obstacles in this issue and plan accordingly. In this cross-sectional study, 361 Iranian nurses who were recruited by convenience sampling method completed an anonymous, self-administered questionnaire from October 2012 to April 2013. Topics covered the participants' attitudes towards facilitators and barriers of their participation in continuing education. Mean and standard deviation of participants ' age were 37.14±7.58 years and 93.94% were female. The maximum score of facilitators and barriers to nurses' participation in continuing education were related to "Update my knowledge" and "Work commitments" respectively. The results showed among Iranian nurses, the mean score of personal and structural barriers was significantly higher than the mean score of interpersonal ones (F=2122.66, p<0.001). Results highlight policy makers and nursing managers' role on improving the accessibility to provided continuing education programs by enforcement of facilitators and reducing barriers focusing on the personal and structural barriers.

Assessing Causal Mechanistic Interactions: A Peril Ratio Index of Synergy Based on Multiplicativity

PubMed Central

Lee, Wen-Chung

2013-01-01

The assessments of interactions in epidemiology have traditionally been based on risk-ratio, odds-ratio or rate-ratio multiplicativity. However, many epidemiologists fail to recognize that this is mainly for statistical conveniences and often will misinterpret a statistically significant interaction as a genuine mechanistic interaction. The author adopts an alternative metric system for risk, the ‘peril’. A peril is an exponentiated cumulative rate, or simply, the inverse of a survival (risk complement) or one plus an odds. The author proposes a new index based on multiplicativity of peril ratios, the ‘peril ratio index of synergy based on multiplicativity’ (PRISM). Under the assumption of no redundancy, PRISM can be used to assess synergisms in sufficient cause sense, i.e., causal co-actions or causal mechanistic interactions. It has a less stringent threshold to detect a synergy as compared to a previous index of ‘relative excess risk due to interaction’. Using the new PRISM criterion, many situations in which there is not evidence of interaction judged by the traditional indices are in fact corresponding to bona fide positive or negative synergisms. PMID:23826299

Reporting to Improve Reproducibility and Facilitate Validity Assessment for Healthcare Database Studies V1.0.

PubMed

Wang, Shirley V; Schneeweiss, Sebastian; Berger, Marc L; Brown, Jeffrey; de Vries, Frank; Douglas, Ian; Gagne, Joshua J; Gini, Rosa; Klungel, Olaf; Mullins, C Daniel; Nguyen, Michael D; Rassen, Jeremy A; Smeeth, Liam; Sturkenboom, Miriam

2017-09-01

Defining a study population and creating an analytic dataset from longitudinal healthcare databases involves many decisions. Our objective was to catalogue scientific decisions underpinning study execution that should be reported to facilitate replication and enable assessment of validity of studies conducted in large healthcare databases. We reviewed key investigator decisions required to operate a sample of macros and software tools designed to create and analyze analytic cohorts from longitudinal streams of healthcare data. A panel of academic, regulatory, and industry experts in healthcare database analytics discussed and added to this list. Evidence generated from large healthcare encounter and reimbursement databases is increasingly being sought by decision-makers. Varied terminology is used around the world for the same concepts. Agreeing on terminology and which parameters from a large catalogue are the most essential to report for replicable research would improve transparency and facilitate assessment of validity. At a minimum, reporting for a database study should provide clarity regarding operational definitions for key temporal anchors and their relation to each other when creating the analytic dataset, accompanied by an attrition table and a design diagram. A substantial improvement in reproducibility, rigor and confidence in real world evidence generated from healthcare databases could be achieved with greater transparency about operational study parameters used to create analytic datasets from longitudinal healthcare databases. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.

Oxygen Reduction Reaction on Ag(111) in Alkaline Solution: A Combined Density Functional Theory and Kinetic Monte Carlo Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Shizhong; White, Michael G.; Liu, Ping

We reported a detailed mechanistic study of the oxygen reduction reaction (ORR) on the model Ag(111) surface in alkaline solution by using density functional theory (DFT) and Kinetic Monte Carlo (KMC) simulations, in which multiple pathways involving either 2 e - or 4 e - mechanisms were included. The theoretical modelling presented here is able to reproduce the experimentally measured polarization curves in both low and high potential regions. An electrochemical 4 e - network including both a chemisorbed water (*H 2O)-mediated 4 e - associative pathway and the conventional associative pathway was identified to dominate the ORR mechanism. Onmore » the basis of the mechanistic understanding derived from these calculations, the ways to promote the ORR on Ag(111) were provided, including facilitating *OH removal, **O 2 reduction by *H 2O, and suppressing **O 2 desorption. Finally, the origin of the different ORR behaviors of Ag(111) and Pt(111) was also discussed in detail.« less

Oxygen Reduction Reaction on Ag(111) in Alkaline Solution: A Combined Density Functional Theory and Kinetic Monte Carlo Study

DOE PAGES

Liu, Shizhong; White, Michael G.; Liu, Ping

2018-01-25

We reported a detailed mechanistic study of the oxygen reduction reaction (ORR) on the model Ag(111) surface in alkaline solution by using density functional theory (DFT) and Kinetic Monte Carlo (KMC) simulations, in which multiple pathways involving either 2 e - or 4 e - mechanisms were included. The theoretical modelling presented here is able to reproduce the experimentally measured polarization curves in both low and high potential regions. An electrochemical 4 e - network including both a chemisorbed water (*H 2O)-mediated 4 e - associative pathway and the conventional associative pathway was identified to dominate the ORR mechanism. Onmore » the basis of the mechanistic understanding derived from these calculations, the ways to promote the ORR on Ag(111) were provided, including facilitating *OH removal, **O 2 reduction by *H 2O, and suppressing **O 2 desorption. Finally, the origin of the different ORR behaviors of Ag(111) and Pt(111) was also discussed in detail.« less

Mechanistic investigation into sunlight-facilitated photodegradation of pyrene in seawater with oil dispersants.

PubMed

Fu, Jie; Gong, Yanyan; Cai, Zhengqing; O'Reilly, S E; Zhao, Dongye

2017-01-30

This study investigated the effects of 3 model oil dispersants (Corexit EC9500A, Corexit EC9527A and SPC 1000) on photodegradation of pyrene under simulated sunlight. Both Corexit dispersants enhanced photodegradation of pyrene, while SPC1000 slightly inhibited the reaction. Span 80 and Tween 85 were the key ingredients causing the effects, though the underlying mechanisms differed. Span 80 enriches pyrene in the upper layer of water column, whereas Tween 85 induces a photosensitization process. Two reactive oxygen species, 1 O 2 and O 2 - , were found responsible for pyrene photodegradation, though the presence of EC9500A suppressed the 1 O 2 pathway. In terms of photodegradation products, EC9500A enhanced generation of polyaromatic intermediates, i.e., phenaleno[1,9-cd][1,2]dioxine, 1-hydroxypyrene, and 1,8-pyrenequinone, but did not alter the classical photodegradation pathway. The Corexit dispersants were more prone to photochemical decomposition, with multiple by-products detected. The information aids in our understanding of the effects of dispersants on photochemical weathering of oil compositions. Copyright © 2016 Elsevier Ltd. All rights reserved.

Hepatic signaling by the mechanistic target of rapamycin complex 2 (mTORC2)

PubMed Central

Lamming, Dudley W.; Demirkan, Gokhan; Boylan, Joan M.; Mihaylova, Maria M.; Peng, Tao; Ferreira, Jonathan; Neretti, Nicola; Salomon, Arthur; Sabatini, David M.; Gruppuso, Philip A.

2014-01-01

The mechanistic target of rapamycin (mTOR) exists in two complexes that regulate diverse cellular processes. mTOR complex 1 (mTORC1), the canonical target of rapamycin, has been well studied, whereas the physiological role of mTORC2 remains relatively uncharacterized. In mice in which the mTORC2 component Rictor is deleted in liver [Rictor-knockout (RKO) mice], we used genomic and phosphoproteomic analyses to characterize the role of hepatic mTORC2 in vivo. Overnight food withdrawal followed by refeeding was used to activate mTOR signaling. Rapamycin was administered before refeeding to specify mTORC2-mediated events. Hepatic mTORC2 regulated a complex gene expression and post-translational network that affects intermediary metabolism, ribosomal biogenesis, and proteasomal biogenesis. Nearly all changes in genes related to intermediary metabolic regulation were replicated in cultured fetal hepatocytes, indicating a cell-autonomous effect of mTORC2 signaling. Phosphoproteomic profiling identified mTORC2-related signaling to 144 proteins, among which were metabolic enzymes and regulators. A reduction of p38 MAPK signaling in the RKO mice represents a link between our phosphoproteomic and gene expression results. We conclude that hepatic mTORC2 exerts a broad spectrum of biological effects under physiological conditions. Our findings provide a context for the development of targeted therapies to modulate mTORC2 signaling.—Lamming, D. W., Demirkan, G., Boylan, J. M., Mihaylova, M. M., Peng, T., Ferreira, J., Neretti, N., Salomon, A., Sabatini, D. M., Gruppuso, P. A. Hepatic signaling by the mechanistic target of rapamycin complex 2 (mTORC2). PMID:24072782

Motor resonance facilitates movement execution: an ERP and kinematic study

PubMed Central

Ménoret, Mathilde; Curie, Aurore; des Portes, Vincent; Nazir, Tatjana A.; Paulignan, Yves

2013-01-01

Action observation, simulation and execution share neural mechanisms that allow for a common motor representation. It is known that when these overlapping mechanisms are simultaneously activated by action observation and execution, motor performance is influenced by observation and vice versa. To understand the neural dynamics underlying this influence and to measure how variations in brain activity impact the precise kinematics of motor behavior, we coupled kinematics and electrophysiological recordings of participants while they performed and observed congruent or non-congruent actions or during action execution alone. We found that movement velocities and the trajectory deviations of the executed actions increased during the observation of congruent actions compared to the observation of non-congruent actions or action execution alone. This facilitation was also discernible in the motor-related potentials of the participants; the motor-related potentials were transiently more negative in the congruent condition around the onset of the executed movement, which occurred 300 ms after the onset of the observed movement. This facilitation seemed to depend not only on spatial congruency but also on the optimal temporal relationship of the observation and execution events. PMID:24133437

Task 4 : testing Iowa Portland cement concrete mixtures for the AASHTO mechanistic-empirical pavement design procedure.

DOT National Transportation Integrated Search

2008-05-01

The present research project was designed to identify the typical Iowa material input values that are required by the Mechanistic- : Empirical Pavement Design Guide (MEPDG) for the Level 3 concrete pavement design. It was also designed to investigate...

How work-self conflict/facilitation influences exhaustion and task performance: A three-wave study on the role of personal resources.

PubMed

Demerouti, Evangelia; Sanz-Vergel, Ana Isabel; Petrou, Paraskevas; van den Heuvel, Machteld

2016-10-01

Although work and family are undoubtedly important life domains, individuals are also active in other life roles which are also important to them (like pursuing personal interests). Building on identity theory and the resource perspective on work-home interface, we examined whether there is an indirect effect of work-self conflict/facilitation on exhaustion and task performance over time through personal resources (i.e., self-efficacy and optimism). The sample was composed of 368 Dutch police officers. Results of the 3-wave longitudinal study confirmed that work-self conflict was related to lower levels of self-efficacy, whereas work-self facilitation was related to improved optimism over time. In turn, self-efficacy was related to higher task performance, whereas optimism was related to diminished levels of exhaustion over time. Further analysis supported the negative, indirect effect of work-self facilitation on exhaustion through optimism over time, and only a few reversed causal effects emerged. The study contributes to the literature on interrole management by showing the role of personal resources in the process of conflict or facilitation over time. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Facilitating Wellness in Urban-Dwelling, Low-Income Older Adults Through Community Mobility: A Mixed-Methods Study.

PubMed

Mulry, Claire M; Papetti, Christina; De Martinis, Julian; Ravinsky, Mark

Community participation is integral to wellness. This study examined the outcomes of Let's Go, a program designed to facilitate community participation of urban-dwelling, low-income older adults. Fifty-two older adults participated in a mixed-methods, single-group pretest-posttest study. The Impact on Participation and Autonomy Questionnaire, participant surveys, and semistructured interviews were used to evaluate self-reported participation in community-based occupations, confidence, isolation, frequency of community trips, autonomy outdoors, and satisfaction with social life and relationships. Significant improvement was found in participation, confidence, frequency of community trips, autonomy outdoors, and satisfaction with social life and relationships at 4 wk and 6 mo. Qualitative themes were decreased isolation, importance of peer and community support, increased knowledge of mobility options, and a shift from fear to confidence. Community mobility programming can facilitate the participation of marginalized older adults in community-based occupations. Copyright © 2017 by the American Occupational Therapy Association, Inc.

Perceived barriers and facilitators to participation in physical activity for children with disability: a qualitative study.

PubMed

Shields, Nora; Synnot, Anneliese

2016-01-19

Children with disability engage in less physical activity compared to their typically developing peers. Our aim was to explore the barriers and facilitators to participation in physical activity for this group. Ten focus groups, involving 63 participants (23 children with disability, 20 parents of children with disability and 20 sport and recreation staff), were held to explore factors perceived as barriers and facilitators to participation in physical activity by children with disability. Data were analysed thematically by two researchers. Four themes were identified: (1) similarities and differences, (2) people make the difference, (3) one size does not fit all, and (4) communication and connections. Key facilitators identified were the need for inclusive pathways that encourage ongoing participation as children grow or as their skills develop, and for better partnerships between key stakeholders from the disability, sport, education and government sectors. Children with disabilities' need for the early attainment of motor and social skills and the integral role of their families in supporting them were considered to influence their participation in physical activity. Children with disability were thought to face additional barriers to participation compared to children with typical development including a lack of instructor skills and unwillingness to be inclusive, negative societal attitudes towards disability, and a lack of local opportunities. The perspectives gathered in this study are relevant to the many stakeholders involved in the design and implementation of effective interventions, strategies and policies to promote participation in physical activity for children with disability. We outline ten strategies for facilitating participation.

Facilitating interpersonal interaction and learning online: linking theory and practice.

PubMed

Sargeant, Joan; Curran, Vernon; Allen, Michael; Jarvis-Selinger, Sandra; Ho, Kendall

2006-01-01

An earlier study of physicians' perceptions of interactive online learning showed that these were shaped both by program design and quality and the quality and quantity of interpersonal interaction. We explore instructor roles in enhancing online learning through interpersonal interaction and the learning theories that inform these. This was a qualitative study using focus groups and interviews. Using purposive sampling, 50 physicians were recruited based on their experience with interactive online CME and face-to-face CME. Qualitative thematic and interpretive analysis was used. Two facilitation roles appeared key: creating a comfortable learning environment and enhancing the educational value of electronic discussions. Comfort developed gradually, and specific interventions like facilitating introductions and sharing experiences in a friendly, informative manner were helpful. As in facilitating effective small-group learning, instructors' thoughtful use of techniques that facilitated constructive interaction based on learner's needs and practice demands contributed to the educational value of interpersonal interactions. Facilitators require enhanced skills to engage learners in meaningful interaction and to overcome the transactional distance of online learning. The use of learning theories, including behavioral, cognitive, social, humanistic, and constructivist, can strengthen the educational design and facilitation of online programs. Preparation for online facilitation should include instruction in the roles and techniques required and the theories that inform them.

Metal-ligand cooperation in catalytic intramolecular hydroamination: a computational study of iridium-pyrazolato cooperative activation of aminoalkenes.

PubMed

Tobisch, Sven

2012-06-04

The present study comprehensively explores diverse mechanistic pathways for intramolecular hydroamination of prototype 2,2-dimethyl-4-penten-1-amine by Cp*Ir chloropyrazole (1; Cp*=pentamethylcyclopentadienyl) in the presence of KOtBu base with the aid of density functional theory (DFT) calculations. The most accessible mechanistic pathway for catalytic turnover commences from Cp*Ir pyrazolato (Pz) substrate adduct 2⋅S, representing the catalytically competent compound and proceeds via initial electrophilic activation of the olefin C=C bond by the metal centre. It entails 1) facile and reversible anti nucleophilic amine attack on the iridium-olefin linkage; 2) Ir-C bond protonolysis via stepwise transfer of the ammonium N-H proton at the zwitterionic [Cp*IrPz-alkyl] intermediate onto the metal that is linked to turnover-limiting, reductive, cycloamine elimination commencing from a high-energy, metastable [Cp*IrPz-hydrido-alkyl] species; and 3) subsequent facile cycloamine liberation to regenerate the active catalyst species. The amine-iridium bound 2 a⋅S likely corresponds to the catalyst resting state and the catalytic reaction is expected to proceed with a significant primary kinetic isotope. This study unveils the vital role of a supportive hydrogen-bonded network involving suitably aligned β-basic pyrazolato and cycloamido moieties together with an external amine molecule in facilitating metal protonation and reductive elimination. Cooperative hydrogen bonding thus appears pivotal for effective catalysis. The mechanistic scenario is consonant with catalyst performance data and furthermore accounts for the variation in performance for [Cp*IrPz] compounds featuring a β- or γ-basic pyrazolato unit. As far as the route that involves amine N-H bond activation is concerned, a thus far undocumented pathway for concerted amidoalkene → cycloamine conversion through olefin protonation by the pyrazole N-H concurrent with N-C ring closure is disclosed as a

Evolution of local facilitation in arid ecosystems.

PubMed

Kéfi, Sonia; van Baalen, Minus; Rietkerk, Max; Loreau, Michel

2008-07-01

In harsh environments, sessile organisms can make their habitat more hospitable by buffering environmental stress or increasing resource availability. Although the ecological significance of such local facilitation is widely established, the evolutionary aspects have been seldom investigated. Yet addressing the evolutionary aspects of local facilitation is important because theoretical studies show that systems with such positive interactions can exhibit alternative stable states and that such systems may suddenly become extinct when they evolve (evolutionary suicide). Arid ecosystems currently experience strong changes in climate and human pressures, but little is known about the effects of these changes on the selective pressures exerted on the vegetation. Here, we focus on the evolution of local facilitation in arid ecosystems, using a lattice-structured model explicitly considering local interactions among plants. We found that the evolution of local facilitation depends on the seed dispersal strategy. In systems characterized by short-distance seed dispersal, adaptation to a more stressful environment leads to high local facilitation, allowing the population to escape extinction. In contrast, systems characterized by long-distance seed dispersal become extinct under increased stress even when allowed to adapt. In this case, adaptation in response to climate change and human pressures could give the final push to the desertification of arid ecosystems.

Exploring Dimensions of Critical Reflection in Activist-Facilitator Practice

ERIC Educational Resources Information Center

Hanson, Cindy

2013-01-01

This article explores how 14 diverse, Canadian activist-facilitators working in international development experience and understand "critical reflection" as a component of participatory methodologies in facilitation practices. The findings, based on my doctoral study, demonstrate that although critical reflection is often discussed as…

Mechanistic Probes of Zeolitic Imidazolate Framework for Photocatalytic Application

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pattengale, Brian; Yang, Sizhuo; Lee, Sungsik

2017-11-07

In this work, we report a zeolitic imidazolate framework (ZIF-67) with remarkable activity for hydrogen evolution reaction (HER) of 40,500 μmol H2/g MOF, which is, to the best of our knowledge, the highest activity achieved by any MOF system. This result necessitated assessment of its atomic-scale mechanistic function for HER using advanced spectroscopy techniques including time-resolved optical (OTA) and in situ X-ray absorption (XAS) spectroscopy. Through the correlation of OTA results with catalytic performance, we demonstrated that the electron transfer (ET) rather than energy transfer (ENT) pathway between photosensitizer and ZIF-67 is the key factor that controls the efficiency ofmore » HER activity, as HER activity that undergoes ET pathway is 3 orders of magnitude higher than that of ENT process. Using in situ XAS, we unraveled the spectral features for key intermediate species which are likely responsible for the rate determining process under turn over conditions. This work represents an original approach to study porous ZIF materials at the molecular level using advanced spectroscopic techniques, providing unprecedented insights into the photoactive nature of ZIF frameworks.« less

Application of comparative vibrational spectroscopic and mechanistic studies in analysis of fisetin structure.

PubMed

Dimitrić Marković, Jasmina M; Marković, Zoran S; Milenković, Dejan; Jeremić, Svetlana

2011-12-01

This paper addresses experimental and theoretical research in fisetin (2-(3,4-dihydroxyphenyl)-3,7-dihydroxychromen-4-one) structure by means of experimental IR and Raman spectroscopies and mechanistic calculations. Density Functional Theory calculations, with M05-2X functional and the 6-311+G (2df, p) basis set implemented in the Gaussian 09 package, are performed with the aim to support molecular structure, vibrational bands' positions and their intensities. Potential energy distribution (PED) values and the description of the largest vibrational contributions to the normal modes are calculated. The most intense bands appear in the 1650-1500 cm(-1) wavenumber region. This region involves a combination of the CO, C2C3 and C-C stretching vibrational modes. Most of the bands in the 1500-1000 cm(-1) range involve C-C stretching, O-C stretching and in-plane C-C-H, C-O-H, C-C-O and C-C-C bending vibrations of the rings. The region below 1000 cm(-1) is characteristic to the combination of in plane C-C-C-H, H-C-C-H, C-C-C-C, C-C-O-C and out of plane O-C-C-C, C-C-O-C, C-C-C-C torsional modes. The Raman spectra of baicalein and quercetin were used for qualitative comparison with fisetin spectrum and verification of band assignments. The applied detailed vibrational spectral analysis and the assignments of the bands, proposed on the basis of fundamentals, reproduced the experimental results with high degree of accuracy. Copyright © 2011 Elsevier B.V. All rights reserved.

A kinetico-mechanistic study on the C-H bond activation of primary benzylamines; cooperative and solid-state cyclopalladation on dimeric complexes.

PubMed

Font, Helena; Font-Bardia, Mercè; Gómez, Kerman; González, Gabriel; Granell, Jaume; Macho, Israel; Martínez, Manuel

2014-09-28

The cyclometallation reactions of dinuclear μ-acetato complexes of the type [Pd(AcO)(μ-AcO)L]2 (L = 4-RC6H4CH2NH2, R = H, Cl, F, CF3), a process found to occur readily even in the solid state, have been studied from a kinetico-mechanistic perspective. Data indicate that the dinuclear acetato bridged derivatives are excellent starting materials to activate carbon-hydrogen bonds in a facile way. In all cases the established concerted ambiphilic proton abstraction by a coordinated acetato ligand has been proved. The metallation has also been found to occur in a cooperative manner, with the metallation of the first palladium unit of the dimeric complex being rate determining; no intermediate mono-metallated compounds are observed in any of the processes. The kinetically favoured bis-cyclopalladated compound obtained after complete C-H bond activation does not correspond to the final isolated XRD-characterized complexes. This species, bearing the classical open-book dimeric form, has a much more complex structure than the final isolated compound, with different types of acetato ligands.

A Mechanistic Understanding of Allosteric Immune Escape Pathways in the HIV-1 Envelope Glycoprotein

PubMed Central

Sethi, Anurag; Tian, Jianhui; Derdeyn, Cynthia A.; Korber, Bette; Gnanakaran, S.

2013-01-01

The HIV-1 envelope (Env) spike, which consists of a compact, heterodimeric trimer of the glycoproteins gp120 and gp41, is the target of neutralizing antibodies. However, the high mutation rate of HIV-1 and plasticity of Env facilitates viral evasion from neutralizing antibodies through various mechanisms. Mutations that are distant from the antibody binding site can lead to escape, probably by changing the conformation or dynamics of Env; however, these changes are difficult to identify and define mechanistically. Here we describe a network analysis-based approach to identify potential allosteric immune evasion mechanisms using three known HIV-1 Env gp120 protein structures from two different clades, B and C. First, correlation and principal component analyses of molecular dynamics (MD) simulations identified a high degree of long-distance coupled motions that exist between functionally distant regions within the intrinsic dynamics of the gp120 core, supporting the presence of long-distance communication in the protein. Then, by integrating MD simulations with network theory, we identified the optimal and suboptimal communication pathways and modules within the gp120 core. The results unveil both strain-dependent and -independent characteristics of the communication pathways in gp120. We show that within the context of three structurally homologous gp120 cores, the optimal pathway for communication is sequence sensitive, i.e. a suboptimal pathway in one strain becomes the optimal pathway in another strain. Yet the identification of conserved elements within these communication pathways, termed inter-modular hotspots, could present a new opportunity for immunogen design, as this could be an additional mechanism that HIV-1 uses to shield vulnerable antibody targets in Env that induce neutralizing antibody breadth. PMID:23696718

Parameter and uncertainty estimation for mechanistic, spatially explicit epidemiological models

NASA Astrophysics Data System (ADS)

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

2014-05-01

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

Downregulation of RBO-PI4KIIIα Facilitates Aβ42 Secretion and Ameliorates Neural Deficits in Aβ42-Expressing Drosophila.

PubMed

Zhang, Xiao; Wang, Wen-An; Jiang, Li-Xiang; Liu, Hai-Yan; Zhang, Bao-Zhu; Lim, Nastasia; Li, Qing-Yi; Huang, Fu-De

2017-05-10

Phosphoinositides and their metabolizing enzymes are involved in Aβ 42 metabolism and Alzheimer's disease pathogenesis. In yeast and mammals, Eighty-five requiring 3 (EFR3), whose Drosophila homolog is Rolling Blackout (RBO), forms a plasma membrane-localized protein complex with phosphatidylinositol-4-kinase Type IIIα (PI4KIIIα) and a scaffold protein to tightly control the level of plasmalemmal phosphatidylinositol-4-phosphate (PI 4 P). Here, we report that RBO binds to Drosophila PI4KIIIα, and that in an Aβ 42 -expressing Drosophila model, separate genetic reduction of PI4KIIIα and RBO, or pharmacological inhibition of PI4KIIIα ameliorated synaptic transmission deficit, climbing ability decline, premature death, and reduced neuronal accumulation of Aβ 42 Moreover, we found that RBO-PI4KIIIa downregulation increased neuronal Aβ 42 release and that PI4P facilitated the assembly or oligomerization of Aβ 42 in/on liposomes. These results indicate that RBO-PI4KIIIa downregulation facilitates neuronal Aβ 42 release and consequently reduces neuronal Aβ 42 accumulation likely via decreasing Aβ 42 assembly in/on plasma membrane. This study suggests the RBO-PI4KIIIα complex as a potential therapeutic target and PI4KIIIα inhibitors as drug candidates for Alzheimer's disease treatment. SIGNIFICANCE STATEMENT Phosphoinositides and their metabolizing enzymes are involved in Aβ 42 metabolism and Alzheimer's disease pathogenesis. Here, in an Aβ 42 -expressing Drosophila model, we discovered and studied the beneficial role of downregulating RBO or its interacting protein PI4KIIIα-a protein that tightly controls the plasmalemmal level of PI 4 P-against the defects caused by Aβ 42 expression. Mechanistically, RBO-PI4KIIIα downregulation reduced neuronal Aβ 42 accumulation, and interestingly increased neuronal Aβ 42 release. This study suggests the RBO-PI4KIIIα complex as a novel therapeutic target, and PI4KIIIα inhibitors as new drug candidates. Copyright �

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

EPA Science Inventory

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