BioAge: Toward A Multi-Determined, Mechanistic Account of Cognitive Aging

PubMed Central

DeCarlo, Correne A.; Tuokko, Holly A.; Williams, Dorothy; Dixon, Roger A.; MacDonald, Stuart W.S.

2014-01-01

The search for reliable early indicators of age-related cognitive decline represents a critical avenue for progress in aging research. Chronological age is a commonly used developmental index; however, it offers little insight into the mechanisms underlying cognitive decline. In contrast, biological age (BioAge), reflecting the vitality of essential biological systems, represents a promising operationalization of developmental time. Current BioAge models have successfully predicted age-related cognitive deficits. Research on aging-related cognitive function indicates that the interaction of multiple risk and protective factors across the human lifespan confers individual risk for late-life cognitive decline, implicating a multi-causal explanation. In this review, we explore current BioAge models, describe three broad yet pathologically relevant biological processes linked to cognitive decline, and propose a novel operationalization of BioAge accounting for both moderating and causal mechanisms of cognitive decline and dementia. We argue that a multivariate and mechanistic BioAge approach will lead to a greater understanding of disease pathology as well as more accurate prediction and early identification of late-life cognitive decline. PMID:25278166

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...

Supporting Mechanistic Reasoning in Domain-Specific Contexts

ERIC Educational Resources Information Center

Weinberg, Paul J.

2017-01-01

Mechanistic reasoning is an epistemic practice central within science, technology, engineering, and mathematics disciplines. Although there has been some work on mechanistic reasoning in the research literature and standards documents, much of this work targets domain-general characterizations of mechanistic reasoning; this study provides…

Overlapping 16p13.11 Deletion and Gain of Copies Variations Associated with Childhood Onset Psychosis Include Genes with Mechanistic Implications for Autism Associated Pathways: Two Case Reports

PubMed Central

Brownstein, Catherine A.; Kleiman, Robin J.; Engle, Elizabeth C.; Towne, Meghan C.; D’Angelo, Eugene J.; Yu, Timothy W.; Beggs, Alan H.; Picker, Jonathan; Fogler, Jason M.; Carroll, Devon; Schmitt, Rachel C. O.; Wolff, Robert R.; Shen, Yiping; Lip, Va; Bilguvar, Kaya; Kim, April; Tembulkar, Sahil; O’Donnell, Kyle; Gonzalez-Heydrich, Joseph

2016-01-01

Copy number variability at 16p13.11 has been associated with intellectual disability, autism, schizophrenia, epilepsy and attention-deficit hyperactivity disorder. Adolescent/adult- onset psychosis has been reported in a subset of these cases. Here, we report on two children with CNVs in 16p13.11 that developed psychosis before the age of 7. The genotype and neuropsychiatric abnormalities of these patients highlight several overlapping genes that have possible mechanistic relevance to pathways previously implicated in Autism Spectrum Disorders, including the mTOR signaling and the ubiquitin-proteasome cascades. A careful screening of the 16p13.11 region is warranted in patients with childhood onset psychosis. PMID:26887912

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 ...

From the exposome to mechanistic understanding of chemical ...

EPA Pesticide Factsheets

BACKGROUND: Current definitions of the exposome expand beyond the initial idea to consider the totality of exposure and aim to relate to biological effects. While the exposome has been established for human health, its principles can be extended to include broader ecological issues. The assessment of exposure is tightly interlinked with hazard assessment. OBJECTIVES: We explore if mechanistic understanding of the causal links between exposure and adverse effects on human health and the environment can be improved by integrating the exposome approach with the adverse outcome pathway (AOP) concept - a framework to structure and organize the sequence of toxicological events from an initial molecular interaction of a chemical to an adverse outcome.METHODS: This review was informed by a Workshop organized by the Integrated Project EXPOSOME at the UFZ Helmholtz Centre for Environmental Research in Leipzig, Germany. DISCUSSION: The exposome encompasses all chemicals, including exogenous chemicals and endogenous compounds that are produced in response to external factors. By complementing the exposome research with the AOP concept, we can achieve a better mechanistic understanding, weigh the importance of various components of the exposome, and determine primary risk drivers. The ability to interpret multiple exposures and mixture effects at the mechanistic level requires a more holistic approach facilitated by the exposome concept.CONCLUSION: Incorporating the AOP conc

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

NASA Astrophysics Data System (ADS)

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

2018-03-01

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

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.

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...

Minnesota logging utilization factors, 1975-1976--development, use, implications.

Treesearch

James E. Blyth; W. Brad Smith

1979-01-01

Discusses Minnesota saw log and pulpwood logging utilization factors developed during 1975-1976 and their implications. Compares factors for several species groups and shows their use in estimating growing stock cut for pulpwood and saw logs.

Overlapping 16p13.11 deletion and gain of copies variations associated with childhood onset psychosis include genes with mechanistic implications for autism associated pathways: Two case reports.

PubMed

Brownstein, Catherine A; Kleiman, Robin J; Engle, Elizabeth C; Towne, Meghan C; D'Angelo, Eugene J; Yu, Timothy W; Beggs, Alan H; Picker, Jonathan; Fogler, Jason M; Carroll, Devon; Schmitt, Rachel C O; Wolff, Robert R; Shen, Yiping; Lip, Va; Bilguvar, Kaya; Kim, April; Tembulkar, Sahil; O'Donnell, Kyle; Gonzalez-Heydrich, Joseph

2016-05-01

Copy number variability at 16p13.11 has been associated with intellectual disability, autism, schizophrenia, epilepsy, and attention-deficit hyperactivity disorder. Adolescent/adult- onset psychosis has been reported in a subset of these cases. Here, we report on two children with CNVs in 16p13.11 that developed psychosis before the age of 7. The genotype and neuropsychiatric abnormalities of these patients highlight several overlapping genes that have possible mechanistic relevance to pathways previously implicated in Autism Spectrum Disorders, including the mTOR signaling and the ubiquitin-proteasome cascades. A careful screening of the 16p13.11 region is warranted in patients with childhood onset psychosis. © 2016 Wiley Periodicals, Inc.

BioAge: toward a multi-determined, mechanistic account of cognitive aging.

PubMed

DeCarlo, Correne A; Tuokko, Holly A; Williams, Dorothy; Dixon, Roger A; MacDonald, Stuart W S

2014-11-01

The search for reliable early indicators of age-related cognitive decline represents a critical avenue for progress in aging research. Chronological age is a commonly used developmental index; however, it offers little insight into the mechanisms underlying cognitive decline. In contrast, biological age (BioAge), reflecting the vitality of essential biological systems, represents a promising operationalization of developmental time. Current BioAge models have successfully predicted age-related cognitive deficits. Research on aging-related cognitive function indicates that the interaction of multiple risk and protective factors across the human lifespan confers individual risk for late-life cognitive decline, implicating a multi-causal explanation. In this review, we explore current BioAge models, describe three broad yet pathologically relevant biological processes linked to cognitive decline, and propose a novel operationalization of BioAge accounting for both moderating and causal mechanisms of cognitive decline and dementia. We argue that a multivariate and mechanistic BioAge approach will lead to a greater understanding of disease pathology as well as more accurate prediction and early identification of late-life cognitive decline. Copyright © 2014 Elsevier B.V. All rights reserved.

Determining the Involvement and Therapeutic Implications of Host Cellular Factors in Hepatitis C Virus Cell-to-Cell Spread

PubMed Central

Barretto, Naina; Sainz, Bruno; Hussain, Snawar

2014-01-01

ABSTRACT Hepatitis C virus (HCV) infects 180 million people worldwide and is a leading cause of liver diseases such as fibrosis, cirrhosis, and hepatocellular carcinoma. It has been shown that HCV can spread to naive cells using two distinct entry mechanisms, “cell-free” entry of infectious extracellular virions that have been released by infected cells and direct “cell-to-cell” transmission. Here, we examined host cell requirements for HCV spread and found that the cholesterol uptake receptor NPC1L1, which we recently identified as being an antiviral target involved in HCV cell-free entry/spread, is also required for the cell-to-cell spread. In contrast, the very low density lipoprotein (VLDL) pathway, which is required for the secretion of cell-free infectious virus and thus has been identified as an antiviral target for blocking cell-free virus secretion/spread, is not required for cell-to-cell spread. Noting that HCV cell-free and cell-to-cell spread share some common factors but not others, we tested the therapeutic implications of these observations and demonstrate that inhibitors that target cell factors required for both forms of HCV spread exhibit synergy when used in combination with interferon (a representative inhibitor of intracellular HCV production), while inhibitors that block only cell-free spread do not. This provides insight into the mechanistic basis of synergy between interferon and HCV entry inhibitors and highlights the broader, previously unappreciated impact blocking HCV cell-to-cell spread can have on the efficacy of HCV combination therapies. IMPORTANCE HCV can spread to naive cells using distinct mechanisms: “cell-free” entry of extracellular virus and direct “cell-to-cell” transmission. Herein, we identify the host cell HCV entry factor NPC1L1 as also being required for HCV cell-to-cell spread, while showing that the VLDL pathway, which is required for the secretion of cell-free infectious virus, is not required for cell

Resolution of growth-defense conflict: mechanistic insights from jasmonate signaling.

PubMed

Guo, Qiang; Major, Ian T; Howe, Gregg A

2018-03-16

Induced plant resistance depends on the production of specialized metabolites that repel attack by biotic aggressors and is often associated with reduced growth of vegetative tissues. Despite progress in understanding the signal transduction networks that control growth-defense tradeoffs, much remains to be learned about how growth rate is coordinated with changes in metabolism during growth-to-defense transitions. Here, we highlight recent advances in jasmonate research to suggest how a major branch of plant immunity is dynamically regulated to calibrate growth-defense balance with shifts in carbon availability. We review evidence that diminished growth, as an integral facet of induced resistance, may optimize the temporal and spatial expression of defense compounds without compromising other critical roles of central metabolism. New insights into the evolution of jasmonate signaling further suggest that opposing selective pressures associated with too much or too little defense may have shaped the emergence of a modular jasmonate pathway that integrates primary and specialized metabolism through the control of repressor-transcription factor complexes. A better understanding of the mechanistic basis of growth-defense balance has important implications for boosting plant productivity, including insights into how these tradeoffs may be uncoupled for agricultural improvement. Copyright © 2018 Elsevier Ltd. All rights reserved.

FACTORS IMPLICATED IN AMPHIBIAN POPULATION DECLINES IN THE UNITED STATES

EPA Science Inventory

Factors adversely affecting amphibian populations in the US were evaluated using information from species accounts written in a standardized format by multiple authors (Volume 2 of this book). For each species, factors implicated by the authors (i.e., known or suspected) as affec...

The effect of environmental factors on the implementation of the Mechanistic-empirical pavement design guide (MEPDG).

DOT National Transportation Integrated Search

2011-07-01

Current pavement design based on the AASHTO Design Guide uses an empirical approach from the results of the AASHO Road Test conducted in 1958. To address some of the limitations of the original design guide, AASHTO developed a new guide: Mechanistic ...

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…

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

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

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

The use of mechanistic evidence in drug approval.

PubMed

Aronson, Jeffrey K; La Caze, Adam; Kelly, Michael P; Parkkinen, Veli-Pekka; Williamson, Jon

2018-06-11

The role of mechanistic evidence tends to be under-appreciated in current evidence-based medicine (EBM), which focusses on clinical studies, tending to restrict attention to randomized controlled studies (RCTs) when they are available. The EBM+ programme seeks to redress this imbalance, by suggesting methods for evaluating mechanistic studies alongside clinical studies. Drug approval is a problematic case for the view that mechanistic evidence should be taken into account, because RCTs are almost always available. Nevertheless, we argue that mechanistic evidence is central to all the key tasks in the drug approval process: in drug discovery and development; assessing pharmaceutical quality; devising dosage regimens; assessing efficacy, harms, external validity, and cost-effectiveness; evaluating adherence; and extending product licences. We recommend that, when preparing for meetings in which any aspect of drug approval is to be discussed, mechanistic evidence should be systematically analysed and presented to the committee members alongside analyses of clinical studies. © 2018 The Authors Journal of Evaluation in Clinical Practice Published by John Wiley & Sons Ltd.

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. .

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

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...

Stress-induced EGFR trafficking: mechanisms, functions, and therapeutic implications

PubMed Central

Tan, Xiaojun; Lambert, Paul F.; Rapraeger, Alan C.; Anderson, Richard A.

2016-01-01

Epidermal growth factor receptor (EGFR) has fundamental roles in normal physiology and in cancer, making it a rational target for cancer therapy. Surprisingly, however, inhibitors that target canonical, ligand-stimulated EGFR signaling have proven to be largely ineffective in treating many EGFR-dependent cancers. Recent evidence indicates that both intrinsic and therapy-induced cellular stress triggers robust, non-canonical pathways of ligand-independent EGFR trafficking and signaling, which provides cancer cells with a survival advantage and resistance to therapeutics. Here we review the mechanistic regulation of non-canonical EGFR trafficking and signaling, the pathological and therapeutic stresses that activate it, and discuss the implications of this pathway in clinical treatment of EGFR-overexpressing cancers. PMID:26827089

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.

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.

Cognitive changes and dementia risk after traumatic brain injury: implications for aging military personnel.

PubMed

Vincent, Andrea S; Roebuck-Spencer, Tresa M; Cernich, Alison

2014-06-01

Traumatic brain injury (TBI) is recognized as an important risk factor for the long-term cognitive health of military personnel, particularly in light of growing evidence that TBI increases risk for Alzheimer's disease and other dementias. In this article, we review the neurocognitive and neuropathologic changes after TBI with particular focus on the potential risk for cognitive decline across the life span in military service members. Implications for monitoring and surveillance of cognition in the aging military population are discussed. Additional studies are needed to clarify the factors that increase risk for later life cognitive decline, define the mechanistic link between these factors and dementia, and provide empirically supported interventions to mitigate the impact of TBI on cognition across the life span. Copyright © 2014 The Alzheimer's Association. All rights reserved.

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).

Bridging paradigms: hybrid mechanistic-discriminative predictive models.

PubMed

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

2013-03-01

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

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

PubMed

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

2013-11-01

The ecological impacts of nighttime light pollution have been a longstanding source of concern, accentuated by realized and projected growth in electrical lighting. As human communities and lighting technologies develop, artificial light increasingly modifies natural light regimes by encroaching on dark refuges in space, in time, and across wavelengths. A wide variety of ecological implications of artificial light have been identified. However, the primary research to date is largely focused on the disruptive influence of nighttime light on higher vertebrates, and while comprehensive reviews have been compiled along taxonomic lines and within specific research domains, the subject is in need of synthesis within a common mechanistic framework. Here we propose such a framework that focuses on the cross-factoring of the ways in which artificial lighting alters natural light regimes (spatially, temporally, and spectrally), and the ways in which light influences biological systems, particularly the distinction between light as a resource and light as an information source. We review the evidence for each of the combinations of this cross-factoring. As artificial lighting alters natural patterns of light in space, time and across wavelengths, natural patterns of resource use and information flows may be disrupted, with downstream effects to the structure and function of ecosystems. This review highlights: (i) the potential influence of nighttime lighting at all levels of biological organisation (from cell to ecosystem); (ii) the significant impact that even low levels of nighttime light pollution can have; and (iii) the existence of major research gaps, particularly in terms of the impacts of light at population and ecosystem levels, identification of intensity thresholds, and the spatial extent of impacts in the vicinity of artificial lights. © 2013 The Authors. Biological Reviews © 2013 Cambridge Philosophical Society.

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.

Somatodendritic dopamine release: recent mechanistic insights

PubMed Central

Rice, Margaret E.; Patel, Jyoti C.

2015-01-01

Dopamine (DA) is a key transmitter in motor, reward and cogitative pathways, with DA dysfunction implicated in disorders including Parkinson's disease and addiction. Located in midbrain, DA neurons of the substantia nigra pars compacta project via the medial forebrain bundle to the dorsal striatum (caudate putamen), and DA neurons in the adjacent ventral tegmental area project to the ventral striatum (nucleus accumbens) and prefrontal cortex. In addition to classical vesicular release from axons, midbrain DA neurons exhibit DA release from their cell bodies and dendrites. Somatodendritic DA release leads to activation of D2 DA autoreceptors on DA neurons that inhibit their firing via G-protein-coupled inwardly rectifying K+ channels. This helps determine patterns of DA signalling at distant axonal release sites. Somatodendritically released DA also acts via volume transmission to extrasynaptic receptors that modulate local transmitter release and neuronal activity in the midbrain. Thus, somatodendritic release is a pivotal intrinsic feature of DA neurons that must be well defined in order to fully understand the physiology and pathophysiology of DA pathways. Here, we review recent mechanistic aspects of somatodendritic DA release, with particular emphasis on the Ca2+ dependence of release and the potential role of exocytotic proteins. PMID:26009764

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

EPA Science Inventory

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

Factors Implicated in Safety-related Firefighter Fatalities.

PubMed

Kahn, Steven A; Palmieri, Tina L; Sen, Soman; Woods, Jason; Gunter, Oliver L

Firefighting is wrought with risk, as 80-100 firefighters (FFs) die on the job each year in the United States. Many of the fatalities have been analyzed by the National Institute for Occupational Safety and Health (NIOSH) to determine contributing factors. The purpose of this study is to determine variables that put FFs at risk for potentially preventable workplace mortality such as use of personal protective equipment (PPE), seat belts, and appropriate training/fitness/clearance for duty. The NIOSH FF Fatality Database reports from 2009 to 2014 were analyzed. Data including age, gender, years on the job, weather, other calls on the same shift, and department type were compared between FFs who employed PPE, seat belts, or wellness/fitness and those who did not. A second group of FFs was determined by NIOSH to have inexperience, lack of training, or inappropriate clearance for duty implicated in their fatalities. Comparisons for the second group were between those whose department used training and safety-related standard operating protocols and those who did not. In 84/176 deaths, PPE/seat belts/fitness was implicated in the fatality. Lack of PPE was more likely on clear days (P = .03) but less likely on cloudy and windy days (P < .001). These FFs dying with lack of PPE had more time on the job in a single department, 18 vs 13 years (P = .03), and more time in a volunteer department, 17 vs 8 years (P < .01). Being deployed on another call during the same shift was associated with lack of PPE-34 vs 16% of those who had not been on another call (P = .005). Lack of training, experience, or medical clearance was implicated in fatalities for 100/176 FFs. FFs who worked in departments that lacked standard operating protocols for respirator fit testing, PPE, fitness testing, rapid intervention, medical clearance, safety/distress alarms, vehicle maintenance, or incident command were statistically more likely to have lack of experience/training/clearance implicated in the

Transcription factors as readers and effectors of DNA methylation.

PubMed

Zhu, Heng; Wang, Guohua; Qian, Jiang

2016-08-01

Recent technological advances have made it possible to decode DNA methylomes at single-base-pair resolution under various physiological conditions. Many aberrant or differentially methylated sites have been discovered, but the mechanisms by which changes in DNA methylation lead to observed phenotypes, such as cancer, remain elusive. The classical view of methylation-mediated protein-DNA interactions is that only proteins with a methyl-CpG binding domain (MBD) can interact with methylated DNA. However, evidence is emerging to suggest that transcription factors lacking a MBD can also interact with methylated DNA. The identification of these proteins and the elucidation of their characteristics and the biological consequences of methylation-dependent transcription factor-DNA interactions are important stepping stones towards a mechanistic understanding of methylation-mediated biological processes, which have crucial implications for human development and disease.

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.

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.

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

The mosquito Aedes albopitus is a competent vector for the transmission of many blood-borne pathogens. An important factor that affects the mosquitoes' development and spreading is climate, such as temperature, precipitation and photoperiod. Existing climate-driven mechanistic models overlook the seasonal pattern of diapause, referred to as the survival strategy of mosquito eggs being dormant and unable to hatch under extreme weather. With respect to diapause, several issues remain unaddressed, including identifying the time when diapause eggs are laid and hatched under different climatic conditions, demarcating the thresholds of diapause and non-diapause periods, and considering the mortality rate of diapause eggs. Here we propose a generic climate-driven mechanistic population model of Ae. albopitus applicable to most Ae. albopictus-colonized areas. The new model is an improvement over the previous work by incorporating the diapause behaviors with many modifications to the stage-specific mechanism of the mosquitoes' life-cycle. monthly Container Index (CI) of Ae. albopitus collected in two Chinese cities, Guangzhou and Shanghai is used for model validation. The simulation results by the proposed model is validated with entomological field data by the Pearson correlation coefficient r (2) in Guangzhou (r (2) = 0.84) and in Shanghai (r (2) = 0.90). In addition, by consolidating the effect of diapause-related adjustments and temperature-related parameters in the model, the improvement is significant over the basic model. The model highlights the importance of considering diapause in simulating Ae. albopitus population. It also corroborates that temperature and photoperiod are significant in affecting the population dynamics of the mosquito. By refining the relationship between Ae. albopitus population and climatic factors, the model serves to establish a mechanistic relation to the growth and decline of the species. Understanding this relationship in a better way

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.

Physiological constraints on organismal response to global warming: Mechanistic insights from clinally varying populations and implications for assessing endangerment.

PubMed

Bernardo, Joseph; Spotila, James R

2006-03-22

Recent syntheses indicate that global warming affects diverse biological processes, but also highlight the potential for some species to adapt behaviourally or evolutionarily to rapid climate change. Far less attention has addressed the alternative, that organisms lacking this ability may face extinction, a fate projected to befall one-quarter of global biodiversity. This conclusion is controversial, in part because there exist few mechanistic studies that show how climate change could precipitate extinction. We provide a concrete, mechanistic example of warming as a stressor of organisms that are closely adapted to cool climates from a comparative analysis of organismal tolerance among clinally varying populations along a natural thermal gradient. We found that two montane salamanders exhibit significant metabolic depression at temperatures within the natural thermal range experienced by low and middle elevation populations. Moreover, the magnitude of depression was inversely related to native elevation, suggesting that low elevation populations are already living near the limit of their physiological tolerances. If this finding generally applies to other montane specialists, the prognosis for biodiversity loss in typically diverse montane systems is sobering. We propose that indices of warming-induced stress tolerance may provide a critical new tool for quantitative assessments of endangerment due to anthropogenic climate change across diverse species.

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.

Antimicrobial peptides as a possible interlink between periodontal diseases and its risk factors: A systematic review.

PubMed

Li, S; Schmalz, G; Schmidt, J; Krause, F; Haak, R; Ziebolz, D

2018-04-01

Antimicrobial peptides (AMPs) play a critical role in controlling innate and acquired immune responses. Local dysregulation of AMP is implicated in the pathogenesis of periodontal diseases as a response to periodontal pathogen challenge. Changes in AMP expression also characterize tobacco smoking, diabetes mellitus, obesity and rheumatoid arthritis, which are established risk factors of periodontal diseases, suggesting AMP may act as putative mechanistic links between these. The aim was to evaluate and summarize critically the current evidence pertaining to interrelationships between AMPs, periodontal diseases and selected periodontal disease risk factors. General and theme specific keywords were used to search the PUBMED database for studies relevant to AMP, periodontal diseases, smoking, diabetes mellitus, obesity and rheumatoid arthritis and critically reviewed. A total of 131 abstracts and 119 full text articles were screened for relevance; 13 studies were selected for inclusion after critical review. Local AMP dysregulation characteristic to periodontal diseases appears to occur within a broader landscape of complex systemic immune perturbations independently induced by smoking, metabolic and rheumatoid disease. The nature of these interactions and mechanistic pathways involved are inadequately understood. AMPs could be possible mechanistic interlinks between periodontal diseases and its risk factors. However, such evidence is very limited and more in vivo and in vitro studies are necessary to clarify the nature of such relationships. A greater understanding of AMPs as shared mediators is essential for unraveling their value as therapeutic or biomarker candidates. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

"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?

Transcription factors as readers and effectors of DNA methylation

PubMed Central

Zhu, Heng; Wang, Guohua; Qian, Jiang

2017-01-01

Recent technological advances have made it possible to decode DNA methylomes at single-base-pair resolution under various physiological conditions. Many aberrant or differentially methylated sites have been discovered, but the mechanisms by which changes in DNA methylation lead to observed phenotypes, such as cancer, remain elusive. The classical view of methylation-mediated protein-DNA interactions is that only proteins with a methyl-CpG binding domain (MBD) can interact with methylated DNA. However, evidence is emerging to suggest that transcription factors lacking a MBD can also interact with methylated DNA. The identification of these proteins and the elucidation of their characteristics and the biological consequences of methylation-dependent transcription factor-DNA interactions are important stepping stones towards a mechanistic understanding of methylation-mediated biological processes, which have crucial implications for human development and disease. PMID:27479905

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.

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 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.

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

Minimum-noise production of translation factor eIF4G maps to a mechanistically determined optimal rate control window for protein synthesis

PubMed Central

Meng, Xiang; Firczuk, Helena; Pietroni, Paola; Westbrook, Richard; Dacheux, Estelle; Mendes, Pedro; McCarthy, John E.G.

2017-01-01

Gene expression noise influences organism evolution and fitness. The mechanisms determining the relationship between stochasticity and the functional role of translation machinery components are critical to viability. eIF4G is an essential translation factor that exerts strong control over protein synthesis. We observe an asymmetric, approximately bell-shaped, relationship between the average intracellular abundance of eIF4G and rates of cell population growth and global mRNA translation, with peak rates occurring at normal physiological abundance. This relationship fits a computational model in which eIF4G is at the core of a multi-component–complex assembly pathway. This model also correctly predicts a plateau-like response of translation to super-physiological increases in abundance of the other cap-complex factors, eIF4E and eIF4A. Engineered changes in eIF4G abundance amplify noise, demonstrating that minimum stochasticity coincides with physiological abundance of this factor. Noise is not increased when eIF4E is overproduced. Plasmid-mediated synthesis of eIF4G imposes increased global gene expression stochasticity and reduced viability because the intrinsic noise for this factor influences total cellular gene noise. The naturally evolved eIF4G gene expression noise minimum maps within the optimal activity zone dictated by eIF4G's mechanistic role. Rate control and noise are therefore interdependent and have co-evolved to share an optimal physiological abundance point. PMID:27928055

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.

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

Network-based discovery through mechanistic systems biology. Implications for applications--SMEs and drug discovery: where the action is.

PubMed

Benson, Neil

2015-08-01

Phase II attrition remains the most important challenge for drug discovery. Tackling the problem requires improved understanding of the complexity of disease biology. Systems biology approaches to this problem can, in principle, deliver this. This article reviews the reports of the application of mechanistic systems models to drug discovery questions and discusses the added value. Although we are on the journey to the virtual human, the length, path and rate of learning from this remain an open question. Success will be dependent on the will to invest and make the most of the insight generated along the way. Copyright © 2015 Elsevier Ltd. All rights reserved.

Mechanistic 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

Enhanced/Synthetic Vision Systems - Human factors research and implications for future systems

NASA Technical Reports Server (NTRS)

Foyle, David C.; Ahumada, Albert J.; Larimer, James; Sweet, Barbara T.

1992-01-01

This paper reviews recent human factors research studies conducted in the Aerospace Human Factors Research Division at NASA Ames Research Center related to the development and usage of Enhanced or Synthetic Vision Systems. Research discussed includes studies of field of view (FOV), representational differences of infrared (IR) imagery, head-up display (HUD) symbology, HUD advanced concept designs, sensor fusion, and sensor/database fusion and evaluation. Implications for the design and usage of Enhanced or Synthetic Vision Systems are discussed.

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)

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

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 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.

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.

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...

Stress fracture risk factors in female football players and their clinical implications

PubMed Central

Warden, Stuart J; Creaby, Mark W; Bryant, Adam L; Crossley, Kay M

2007-01-01

A stress fracture represents the inability of the skeleton to withstand repetitive bouts of mechanical loading, which results in structural fatigue, and resultant signs and symptoms of localised pain and tenderness. Reports of stress fractures in female football players are not prevalent; however, they are probably under‐reported and their importance lies in the morbidity that they cause in terms of time lost from participation. By considering risk factors for stress fractures in female football players it may be possible to reduce the impact of these troublesome injuries. Risk factors for stress fractures in female football players include intrinsic risk factors such as gender, endocrine, nutritional, physical fitness and neuromusculoskeletal factors, as well as extrinsic risk factors such as training programme, equipment and environmental factors. This paper discusses these risk factors and their implications in terms of developing prevention and management strategies for stress fractures in female football players. PMID:17584950

Stress fracture risk factors in female football players and their clinical implications.

PubMed

Warden, Stuart J; Creaby, Mark W; Bryant, Adam L; Crossley, Kay M

2007-08-01

A stress fracture represents the inability of the skeleton to withstand repetitive bouts of mechanical loading, which results in structural fatigue, and resultant signs and symptoms of localised pain and tenderness. Reports of stress fractures in female football players are not prevalent; however, they are probably under-reported and their importance lies in the morbidity that they cause in terms of time lost from participation. By considering risk factors for stress fractures in female football players it may be possible to reduce the impact of these troublesome injuries. Risk factors for stress fractures in female football players include intrinsic risk factors such as gender, endocrine, nutritional, physical fitness and neuromusculoskeletal factors, as well as extrinsic risk factors such as training programme, equipment and environmental factors. This paper discusses these risk factors and their implications in terms of developing prevention and management strategies for stress fractures in female football players.

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.

Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases.

PubMed

Perl, Andras

2016-03-01

Mechanistic target of rapamycin (mTOR, also known as mammalian target of rapamycin) is a ubiquitous serine/threonine kinase that regulates cell growth, proliferation and survival. These effects are cell-type-specific, and are elicited in response to stimulation by growth factors, hormones and cytokines, as well as to internal and external metabolic cues. Rapamycin was initially developed as an inhibitor of T-cell proliferation and allograft rejection in the organ transplant setting. Subsequently, its molecular target (mTOR) was identified as a component of two interacting complexes, mTORC1 and mTORC2, that regulate T-cell lineage specification and macrophage differentiation. mTORC1 drives the proinflammatory expansion of T helper (TH) type 1, TH17, and CD4(-)CD8(-) (double-negative, DN) T cells. Both mTORC1 and mTORC2 inhibit the development of CD4(+)CD25(+)FoxP3(+) T regulatory (TREG) cells and, indirectly, mTORC2 favours the expansion of T follicular helper (TFH) cells which, similarly to DN T cells, promote B-cell activation and autoantibody production. In contrast to this proinflammatory effect of mTORC2, mTORC1 favours, to some extent, an anti-inflammatory macrophage polarization that is protective against infections and tissue inflammation. Outside the immune system, mTORC1 controls fibroblast proliferation and chondrocyte survival, with implications for tissue fibrosis and osteoarthritis, respectively. Rapamycin (which primarily inhibits mTORC1), ATP-competitive, dual mTORC1/mTORC2 inhibitors and upstream regulators of the mTOR pathway are being developed to treat autoimmune, hyperproliferative and degenerative diseases. In this regard, mTOR blockade promises to increase life expectancy through treatment and prevention of rheumatic diseases.

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

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

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

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.

Generation Y Student-Teachers' Motivational Factors: Retention Implications for K-12 Educational Leaders

ERIC Educational Resources Information Center

Bontempo, Brian

2010-01-01

Generation Y represents a growing number of student-teachers who will impact the future of educational practice, yet little research has been conducted for this demographic group. The purpose of this mixed-method study was to identify motivational factors of neophyte teachers and the retention implications these findings had on Kindergarten…

Infection control implications of heterogeneous resistance mechanisms in carbapenem-resistant Enterobacteriaceae (CRE).

PubMed

Goodman, K E; Simner, P J; Tamma, P D; Milstone, A M

2016-01-01

The Centers for Disease Control and Prevention (CDC) defines carbapenem-resistant Enterobacteriaceae (CRE) based upon a phenotypic demonstration of carbapenem resistance. However, considerable heterogeneity exists within this definitional umbrella. CRE may mechanistically differ by whether they do or do not produce carbapenemases. Moreover, patients can acquire CRE through multiple pathways: endogenously through antibiotic selective pressure on intestinal microbiota, exogenously through horizontal transmission or through a combination of these factors. Some evidence suggests that non-carbapenemase-producing CRE may be more frequently acquired by antibiotic exposure and carbapenemase-producing CRE via horizontal transmission, but definitive data are lacking. This review examines types of CRE resistance mechanisms, antibiotic exposure and horizontal transmission pathways of CRE acquisition, and the implications of these heterogeneities to the development of evidence-based CRE healthcare epidemiology policies. In our Expert Commentary & Five-Year View, we outline specific nosocomial CRE knowledge gaps and potential methodological approaches for their resolution.

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.

AASHTO mechanistic-empirical pavement design guide parametric study.

DOT National Transportation Integrated Search

2012-03-01

This study focuses on assessing the robustness of the AASHTO Mechanistic-Empirical Pavement Design Guide (MEPDG v 1.1) for rigid pavement : design projects in Wisconsin. The primary tasks conducted in this study included performing sensitivity analys...

Implications of Our Developing Understanding of Risk and Protective Factors in the Treatment of Adult Male Sexual Offenders

ERIC Educational Resources Information Center

Thornton, David

2013-01-01

This paper summarizes our developing knowledge of factors that contribute added risk of sexual recidivism (risk factors) and factors that are associated with a reduced risk of sexual recidivism (protective factors). Specific implications for the design of future treatment programs are drawn. This information is contrasted with the common foci of…

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.

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.

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...

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.

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.

Biomarker Discovery and Mechanistic Studies of Prostate Cancer Using Targeted Proteomic Approaches

DTIC Science & Technology

2010-07-01

1-0431 TITLE: Biomarker Discovery and Mechanistic Studies of Prostate Cancer Using Targeted Proteomic Approaches PRINCIPAL INVESTIGATOR...June 2010 4. TITLE AND SUBTITLE Biomarker Discovery and Mechanistic Studies of Prostate Cancer Using Targeted Proteomic 5a. CONTRACT NUMBER...1-0430; W81XWH-08-1-0431; Grant sponsor: NIH/NCRR COBRE Grant; Grant number: 1P20RR020171; Grant sponsor: NIH/NIDDK Grant; Grant number: R01DK053525

Integrating mechanistic and polymorphism data to characterize human genetic susceptibility for environmental chemical risk assessment in the 21st century

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

Mortensen, Holly M., E-mail: mortensen.holly@epa.gov; Euling, Susan Y.

Response to environmental chemicals can vary widely among individuals and between population groups. In human health risk assessment, data on susceptibility can be utilized by deriving risk levels based on a study of a susceptible population and/or an uncertainty factor may be applied to account for the lack of information about susceptibility. Defining genetic susceptibility in response to environmental chemicals across human populations is an area of interest in the NAS' new paradigm of toxicity pathway-based risk assessment. Data from high-throughput/high content (HT/HC), including -omics (e.g., genomics, transcriptomics, proteomics, metabolomics) technologies, have been integral to the identification and characterization ofmore » drug target and disease loci, and have been successfully utilized to inform the mechanism of action for numerous environmental chemicals. Large-scale population genotyping studies may help to characterize levels of variability across human populations at identified target loci implicated in response to environmental chemicals. By combining mechanistic data for a given environmental chemical with next generation sequencing data that provides human population variation information, one can begin to characterize differential susceptibility due to genetic variability to environmental chemicals within and across genetically heterogeneous human populations. The integration of such data sources will be informative to human health risk assessment.« less

Cardiac implications of hypoglycaemia in patients with diabetes – a systematic review

PubMed Central

2013-01-01

Background Hypoglycaemia has been associated with increased cardiovascular (CV) risk and mortality in a number of recent multicentre trials, but the mechanistic links driving this association remain ill defined. This review aims to summarize the available data on how hypoglycaemia may affect CV risk in patients with diabetes. Methods This was a systematic review of available mechanistic and clinical studies on the relationship between hypoglycaemia and cardiovascular risk. Study outcomes were compiled from relevant articles, and factors contributing to hypoglycaemia-mediated CVD and its complications are discussed. Results Six recent comprehensive clinical trials have reinforced the critical importance of understanding the link between hypoglycaemia and the CV system. In addition, 88 studies have indicated that hypoglycaemia mechanistically contributes to CV risk by increasing thrombotic tendency, causing abnormal cardiac repolarization, inducing inflammation, and contributing to the development of atherosclerosis. These hypoglycaemia-associated risk factors are conducive to events such as unstable angina, non-fatal and fatal myocardial infarction, sudden death, and stroke in patients with diabetes. Conclusions Emerging data suggest that there is an impact of hypoglycaemia on CV function and mechanistic link is multifactorial. Further research will be needed to ascertain the full impact of hypoglycaemia on the CV system and its complications. PMID:24053606

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...

Quantitative analysis of intrinsic and extrinsic factors in the aggregation mechanism of Alzheimer-associated Aβ-peptide

NASA Astrophysics Data System (ADS)

Meisl, Georg; Yang, Xiaoting; Frohm, Birgitta; Knowles, Tuomas P. J.; Linse, Sara

2016-01-01

Disease related mutations and environmental factors are key determinants of the aggregation mechanism of the amyloid-β peptide implicated in Alzheimer's disease. Here we present an approach to investigate these factors through acquisition of highly reproducible data and global kinetic analysis to determine the mechanistic influence of intrinsic and extrinsic factors on the Aβ aggregation network. This allows us to translate the shift in macroscopic aggregation behaviour into effects on the individual underlying microscopic steps. We apply this work-flow to the disease-associated Aβ42-A2V variant, and to a variation in pH as examples of an intrinsic and an extrinsic perturbation. In both cases, our data reveal a shift towards a mechanism in which a larger fraction of the reactive flux goes via a pathway that generates potentially toxic oligomeric species in a fibril-catalyzed reaction. This is in agreement with the finding that Aβ42-A2V leads to early-onset Alzheimer’s disease and enhances neurotoxicity.

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…

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...

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

Biomarker Discovery and Mechanistic Studies of Prostate Cancer Using Targeted Proteomic Approaches

DTIC Science & Technology

2012-07-01

1-0431 TITLE: Biomarker Discovery and Mechanistic Studies of Prostate Cancer Using Targeted Proteomic Approaches PRINCIPAL INVESTIGATOR...July 2012 2. REPORT TYPE Final 3. DATES COVERED (From - To) 1 July 2008 – 30 June 2012 4. TITLE AND SUBTITLE Biomarker Discovery and Mechanistic...Department of Defense Synergistic Idea Development Award W81XWH-08-1-0430 (to H.Z) and W81XWH-08-1-0431 (to N.K.), an NIH/NCRR COBRE grant 1P20RR020171 (to

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...

Kinetic Model Facilitates Analysis of Fibrin Generation and Its Modulation by Clotting Factors: Implications for Hemostasis-Enhancing Therapies

DTIC Science & Technology

2014-01-01

facilitates analysis of fibrin generation and its modulation by clotting factors : implications for hemostasis-enhancing therapies† Alexander Y...investigate the ability of fibrinogen and a recently proposed prothrombin complex concentrate composition, PCC-AT (a combination of the clotting factors II...kinetics. Moreover, the model qualitatively predicted the impact of tissue factor and tPA/tenecteplase level variations on the fibrin output. In the

Kinetic and Mechanistic Examination of Acid–Base Bifunctional Aminosilica Catalysts in Aldol and Nitroaldol Condensations

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

Collier, Virginia E.; Ellebracht, Nathan C.; Lindy, George I.

The kinetic and mechanistic understanding of cooperatively catalyzed aldol and nitroaldol condensations is probed using a series of mesoporous silicas functionalized with aminosilanes to provide bifunctional acid–base character. Mechanistically, a Hammett analysis is performed to determine the effects of electron-donating and electron-withdrawing groups of para-substituted benzaldehyde derivatives on the catalytic activity of each condensation reaction. This information is also used to discuss the validity of previously proposed catalytic mechanisms and to propose a revised mechanism with plausible reaction intermediates. For both reactions, electron-withdrawing groups increase the observed rates of reaction, though resonance effects play an important, yet subtle, role inmore » the nitroaldol condensation, in which a p-methoxy electron-donating group is also able to stabilize the proposed carbocation intermediate. Additionally, activation energies and pre-exponential factors are calculated via the Arrhenius analysis of two catalysts with similar amine loadings: one catalyst had silanols available for cooperative interactions (acid–base catalysis), while the other was treated with a silanol-capping reagent to prevent such cooperativity (base-only catalysis). The values obtained for activation energies and pre-exponential factors in each reaction are discussed in the context of the proposed mechanisms and the importance of cooperative interactions in each reaction. The catalytic activity decreases for all reactions when the silanols are capped with trimethylsilyl groups, and higher temperatures are required to make accurate rate measurements, emphasizing the vital role the weakly acidic silanols play in the catalytic cycles. The results indicate that loss of acid sites is more detrimental to the catalytic activity of the aldol condensation than the nitroaldol condensation, as evidenced by the significant decrease in the pre-exponential factor for the aldol

Kinetic and Mechanistic Examination of Acid–Base Bifunctional Aminosilica Catalysts in Aldol and Nitroaldol Condensations

DOE PAGES

Collier, Virginia E.; Ellebracht, Nathan C.; Lindy, George I.; ...

2015-12-09

The kinetic and mechanistic understanding of cooperatively catalyzed aldol and nitroaldol condensations is probed using a series of mesoporous silicas functionalized with aminosilanes to provide bifunctional acid–base character. Mechanistically, a Hammett analysis is performed to determine the effects of electron-donating and electron-withdrawing groups of para-substituted benzaldehyde derivatives on the catalytic activity of each condensation reaction. This information is also used to discuss the validity of previously proposed catalytic mechanisms and to propose a revised mechanism with plausible reaction intermediates. For both reactions, electron-withdrawing groups increase the observed rates of reaction, though resonance effects play an important, yet subtle, role inmore » the nitroaldol condensation, in which a p-methoxy electron-donating group is also able to stabilize the proposed carbocation intermediate. Additionally, activation energies and pre-exponential factors are calculated via the Arrhenius analysis of two catalysts with similar amine loadings: one catalyst had silanols available for cooperative interactions (acid–base catalysis), while the other was treated with a silanol-capping reagent to prevent such cooperativity (base-only catalysis). The values obtained for activation energies and pre-exponential factors in each reaction are discussed in the context of the proposed mechanisms and the importance of cooperative interactions in each reaction. The catalytic activity decreases for all reactions when the silanols are capped with trimethylsilyl groups, and higher temperatures are required to make accurate rate measurements, emphasizing the vital role the weakly acidic silanols play in the catalytic cycles. The results indicate that loss of acid sites is more detrimental to the catalytic activity of the aldol condensation than the nitroaldol condensation, as evidenced by the significant decrease in the pre-exponential factor for the aldol

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.

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 ...

Integration of biotic ligand models (BLM) and bioaccumulation kinetics into a mechanistic framework for metal uptake in aquatic organisms.

PubMed

Veltman, Karin; Huijbregts, Mark A J; Hendriks, A Jan

2010-07-01

Both biotic ligand models (BLM) and bioaccumulation models aim to quantify metal exposure based on mechanistic knowledge, but key factors included in the description of metal uptake differ between the two approaches. Here, we present a quantitative comparison of both approaches and show that BLM and bioaccumulation kinetics can be merged into a common mechanistic framework for metal uptake in aquatic organisms. Our results show that metal-specific absorption efficiencies calculated from BLM-parameters for freshwater fish are highly comparable, i.e. within a factor of 2.4 for silver, cadmium, copper, and zinc, to bioaccumulation-absorption efficiencies for predominantly marine fish. Conditional affinity constants are significantly related to the metal-specific covalent index. Additionally, the affinity constants of calcium, cadmium, copper, sodium, and zinc are significantly comparable across aquatic species, including molluscs, daphnids, and fish. This suggests that affinity constants can be estimated from the covalent index, and constants can be extrapolated across species. A new model is proposed that integrates the combined effect of metal chemodynamics, as speciation, competition, and ligand affinity, and species characteristics, as size, on metal uptake by aquatic organisms. An important direction for further research is the quantitative comparison of the proposed model with acute toxicity values for organisms belonging to different size classes.

Evidence of Second-Order Factor Structure in a Diagnostic Problem Space: Implications for Medical Education.

ERIC Educational Resources Information Center

Papa, Frank J.; And Others

1997-01-01

Chest pain was identified as a specific medical problem space, and disease classes were modeled to define it. Results from a test taken by 628 medical residents indicate a second-order factor structure that suggests that chest pain is a multidimensional problem space. Implications for medical education are discussed. (SLD)

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

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.

NUCLEAR FACTOR-Y: still complex after all these years?

PubMed

Myers, Zachary A; Holt, Ben F

2018-06-11

The NUCLEAR FACTOR-Y (NF-Y) families of transcription factors are important regulators of plant development and physiology. Though NF-Y regulatory roles have recently been suggested for numerous aspects of plant biology, their roles in flowering time, early seedling development, stress responses, hormone signaling, and nodulation are the best characterized. The past few years have also seen significant advances in our understanding of the mechanistic function of the NF-Y, and as such, increasingly complex and interesting questions are now more approachable. This review will primarily focus on these developmental, physiological, and mechanistic roles of the NF-Y in recent research. Copyright © 2018 Elsevier Ltd. All rights reserved.

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...

Design, synthesis and biological evaluation of pyrazolylaminoquinazoline derivatives as highly potent pan-fibroblast growth factor receptor inhibitors.

PubMed

Fan, Jun; Dai, Yang; Shao, Jingwei; Peng, Xia; Wang, Chen; Cao, Sufen; Zhao, Bin; Ai, Jing; Geng, Meiyu; Duan, Wenhu

2016-06-01

Fibroblast growth factor receptors (FGFRs) are important oncology targets due to the dysregulation of this signaling pathway in a wide variety of human cancers. We identified a series of pyrazolylaminoquinazoline derivatives as potent FGFR inhibitors with low nanomolar potency. The representative compound 29 strongly inhibited FGFR1-3 kinase activity and suppressed FGFR signaling transduction in FGFR-addicted cancer cells; FGFRs-driven cell proliferation was also strongly inhibited regardless of mechanistic complexity implicated in FGFR activation, which further confirmed that 29 was a potent pan-FGFR inhibitor. The flexibility of our structure offered the potential to preserve good affinity for mutant FGFR, which is important for developing TKIs with long-term efficacy. Copyright © 2016 Elsevier Ltd. All rights reserved.

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.

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

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.

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...

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...

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

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.

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…

Phosphine-alkene ligands as mechanistic probes in the Pauson-Khand reaction.

PubMed

Ferrer, Catalina; Benet-Buchholz, Jordi; Riera, Antoni; Verdaguer, Xavier

2010-07-26

An alkyne tetracarbonyl dicobalt complex with a chelated phosphine-alkene ligand, in which the phosphorus atom and the alkene from the ligand are attached to the same cobalt atom has been prepared, isolated, and characterized by X-ray crystallography. The complex serves as a mechanistic model for an intermediate of the Pauson-Khand (PK) reaction. Although the alkene fragment is located in an equatorial coordination site with an appropriate orientation, and, therefore, should undergo insertion, it failed to give the PK product upon either thermal or N-methylmorpholine N-oxide activation. However, a phosphine-alkene complex that contains a terminal alkene readily provided the corresponding PK product. We attribute this change in reactivity to the different ability of each olefin to undergo 1,2-insertion. These results provide further insights into the factors that govern a crucial step in the PK reaction, the olefin insertion.

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.

A perspective on reagent diversity and non-covalent binding of reactive carbonyl species (RCS) and effector reagents in nonenzymatic glycation (NEG): Mechanistic considerations and implications for future research

NASA Astrophysics Data System (ADS)

Rodnick, Kenneth J.; Holman, R. W.; Ropski, Pamela S.; Huang, Mingdong; Swislocki, Arthur L. M.

2017-06-01

This perspective focuses on illustrating the underappreciated connections between reactive carbonyl species (RCS), initial binding in the nonenzymatic glycation (NEG) process, and nonenzymatic covalent protein modification (here termed NECPM). While glucose is the central species involved in NEG, recent studies indicate that the initially-bound glucose species in the NEG of human hemoglobin (HbA) and human serum albumin (HSA) are non-RCS ring-closed isomers. The ring-opened glucose, an RCS structure that reacts in the NEG process, is most likely generated from previously-bound ring-closed isomers undergoing concerted acid/base reactions while bound to protein. The generation of the glucose RCS can involve concomitantly-bound physiological species (e.g., inorganic phosphate, water, etc.); here termed effector reagents. Extant NEG schemes do not account for these recent findings. In addition, effector reagent reactions with glucose in the serum and erythrocyte cytosol can generate RCS (e.g., glyoxal, glyceraldehyde, etc.). Recent research has shown that these RCS covalently modify proteins in vivo via NECPM mechanisms. A general scheme that reflects both the reagent and mechanistic diversity that can lead to NEG and NECPM is presented here. A perspective that accounts for the relationships between RCS, NEG, and NECPM can facilitate the understanding of site selectivity, may help explain overall glycation rates, and may have implications for the clinical assessment/control of diabetes mellitus. In view of this perspective, concentrations of ribose, fructose, Pi, bicarbonate, counter ions, and the resulting RCS generated within intracellular and extracellular compartments may be of importance and of clinical relevance. Future research is also proposed.

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…

Theoretical Analysis of Cobalt Hangman Porphyrins: Ligand Dearomatization and Mechanistic Implications for Hydrogen Evolution

DOE PAGES

Solis, Brian H.; Maher, Andrew G.; Honda, Tatsuhiko; ...

2014-11-06

The design of molecular electrocatalysts for hydrogen evolution has been targeted as a strategy for the conversion of solar energy to chemical fuels. In cobalt hangman porphyrins, a carboxylic acid group on a xanthene backbone is positioned over a metalloporphyrin to serve as a proton relay. A key proton-coupled electron transfer (PCET) step along the hydrogen evolution pathway occurs via a sequential ET-PT mechanism in which electron transfer (ET) is followed by proton transfer (PT). Herein theoretical calculations are employed to investigate the mechanistic pathways of these hangman metalloporphyrins. The calculations confirm the ET-PT mechanism by illustrating that the calculatedmore » reduction potentials for this mechanism are consistent with experimental data. Under strong-acid conditions, the calculations indicate that this catalyst evolves H 2 by protonation of a formally Co(II) hydride intermediate, as suggested by previous experiments. Under weak-acid conditions, however, the calculations reveal a mechanism that proceeds via a phlorin intermediate, in which the meso carbon of the porphyrin is protonated. In the first electrochemical reduction, the neutral Co(II) species is reduced to a monoanionic singlet Co(I) species. Subsequent reduction leads to a dianionic doublet, formally a Co(0) complex in which substantial mixing of Co and porphyrin orbitals indicates ligand redox noninnocence. The partial reduction of the ligand disrupts the aromaticity in the porphyrin ring. As a result of this ligand dearomatization, protonation of the dianionic species is significantly more thermodynamically favorable at the meso carbon than at the metal center, and the ET-PT mechanism leads to a dianionic phlorin species. According to the proposed mechanism, the carboxylate group of this dianionic phlorin species is reprotonated, the species is reduced again, and H 2 is evolved from the protonated carboxylate and the protonated carbon. This proposed mechanism is a

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...

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.

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...

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...

Equation-free mechanistic ecosystem forecasting using empirical dynamic modeling

PubMed Central

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

2015-01-01

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

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.

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…

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.

Mechanistic modeling of microbial interactions at pore to profile scale resolve methane emission dynamics from permafrost soil

NASA Astrophysics Data System (ADS)

Ebrahimi, Ali; Or, Dani

2017-05-01

The sensitivity of polar regions to raising global temperatures is reflected in rapidly changing hydrological processes associated with pronounced seasonal thawing of permafrost soil and increased biological activity. Of particular concern is the potential release of large amounts of soil carbon and stimulation of other soil-borne greenhouse gas emissions such as methane. Soil methanotrophic and methanogenic microbial communities rapidly adjust their activity and spatial organization in response to permafrost thawing and other environmental factors. Soil structural elements such as aggregates and layering affect oxygen and nutrient diffusion processes thereby contributing to methanogenic activity within temporal anoxic niches (hot spots). We developed a mechanistic individual-based model to quantify microbial activity dynamics in soil pore networks considering transport processes and enzymatic activity associated with methane production in soil. The model was upscaled from single aggregates to the soil profile where freezing/thawing provides macroscopic boundary conditions for microbial activity at different soil depths. The model distinguishes microbial activity in aerate bulk soil from aggregates (or submerged profile) for resolving methane production and oxidation rates. Methane transport pathways by diffusion and ebullition of bubbles vary with hydration dynamics. The model links seasonal thermal and hydrologic dynamics with evolution of microbial community composition and function affecting net methane emissions in good agreement with experimental data. The mechanistic model enables systematic evaluation of key controlling factors in thawing permafrost and microbial response (e.g., nutrient availability and enzyme activity) on long-term methane emissions and carbon decomposition rates in the rapidly changing polar regions.

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

Structural and Mechanistic Roles of Novel Chemical Ligands on the SdiA Quorum-Sensing Transcription Regulator

DOE PAGES

Nguyen, Y.; Nguyen, Nam X.; Rogers, Jamie L.; ...

2015-05-19

Bacteria engage in chemical signaling, termed quorum sensing (QS), to mediate intercellular communication, mimicking multicellular organisms. The LuxR family of QS transcription factors regulates gene expression, coordinating population behavior by sensing endogenous acyl homoserine lactones (AHLs). However, some bacteria (such as Escherichia coli) do not produce AHLs. These LuxR orphans sense exogenous AHLs but also regulate transcription in the absence of AHLs. Importantly, this AHL-independent regulatory mechanism is still largely unknown. Here we present several structures of one such orphan LuxR-type protein, SdiA, from enterohemorrhagic E. coli (EHEC), in the presence and absence of AHL. SdiA is actually not inmore » an apo state without AHL but is regulated by a previously unknown endogenous ligand, 1-octanoyl-rac-glycerol (OCL), which is ubiquitously found throughout the tree of life and serves as an energy source, signaling molecule, and substrate for membrane biogenesis. While exogenous AHL renders to SdiA higher stability and DNA binding affinity, OCL may function as a chemical chaperone placeholder that stabilizes SdiA, allowing for basal activity. Structural comparison between SdiA-AHL and SdiA-OCL complexes provides crucial mechanistic insights into the ligand regulation of AHL-dependent and -independent function of LuxR-type proteins. Importantly, in addition to its contribution to basic science, this work has implications for public health, inasmuch as the SdiA signaling system aids the deadly human pathogen EHEC to adapt to a commensal lifestyle in the gastrointestinal (GI) tract of cattle, its main reservoir. These studies open exciting and novel avenues to control shedding of this human pathogen in the environment. IMPORTANCE Quorum sensing refers to bacterial chemical signaling. The QS acyl homoserine lactone (AHL) signals are recognized by LuxR-type receptors that regulate gene transcription. However, some bacteria have orphan Lux

Redox-based epigenetic status in drug addiction: a potential contributor to gene priming and a mechanistic rationale for metabolic intervention

PubMed Central

Trivedi, Malav S.; Deth, Richard

2015-01-01

Alcohol and other drugs of abuse, including psychostimulants and opioids, can induce epigenetic changes: a contributing factor for drug addiction, tolerance, and associated withdrawal symptoms. DNA methylation is a major epigenetic mechanism and it is one of more than 200 methylation reactions supported by methyl donor S-adenosylmethionine (SAM). Levels of SAM are controlled by cellular redox status via the folate and vitamin B12-dependent enzyme methionine synthase (MS). For example, under oxidative conditions MS is inhibited, diverting its substrate homocysteine (HCY) to the trans sulfuration pathway. Alcohol, dopamine, and morphine, can alter intracellular levels of glutathione (GSH)-based cellular redox status, subsequently affecting SAM levels and DNA methylation status. Here, existing evidence is presented in a coherent manner to propose a novel hypothesis implicating the involvement of redox-based epigenetic changes in drug addiction. Further, we discuss how a “gene priming” phenomenon can contribute to the maintenance of redox and methylation status homeostasis under various stimuli including drugs of abuse. Additionally, a new mechanistic rationale for the use of metabolic interventions/redox-replenishers as symptomatic treatment of alcohol and other drug addiction and associated withdrawal symptoms is also provided. Hence, the current review article strengthens the hypothesis that neuronal metabolism has a critical bidirectional coupling with epigenetic changes in drug addiction exemplified by the link between redox-based metabolic changes and resultant epigenetic consequences under the effect of drugs of abuse. PMID:25657617

Redox-based epigenetic status in drug addiction: a potential contributor to gene priming and a mechanistic rationale for metabolic intervention.

PubMed

Trivedi, Malav S; Deth, Richard

2014-01-01

Alcohol and other drugs of abuse, including psychostimulants and opioids, can induce epigenetic changes: a contributing factor for drug addiction, tolerance, and associated withdrawal symptoms. DNA methylation is a major epigenetic mechanism and it is one of more than 200 methylation reactions supported by methyl donor S-adenosylmethionine (SAM). Levels of SAM are controlled by cellular redox status via the folate and vitamin B12-dependent enzyme methionine synthase (MS). For example, under oxidative conditions MS is inhibited, diverting its substrate homocysteine (HCY) to the trans sulfuration pathway. Alcohol, dopamine, and morphine, can alter intracellular levels of glutathione (GSH)-based cellular redox status, subsequently affecting SAM levels and DNA methylation status. Here, existing evidence is presented in a coherent manner to propose a novel hypothesis implicating the involvement of redox-based epigenetic changes in drug addiction. Further, we discuss how a "gene priming" phenomenon can contribute to the maintenance of redox and methylation status homeostasis under various stimuli including drugs of abuse. Additionally, a new mechanistic rationale for the use of metabolic interventions/redox-replenishers as symptomatic treatment of alcohol and other drug addiction and associated withdrawal symptoms is also provided. Hence, the current review article strengthens the hypothesis that neuronal metabolism has a critical bidirectional coupling with epigenetic changes in drug addiction exemplified by the link between redox-based metabolic changes and resultant epigenetic consequences under the effect of drugs of abuse.

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.

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

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

Implications of direct protective factors for public health research and prevention strategies to reduce youth violence.

PubMed

Hall, Jeffrey E; Simon, Thomas R; Lee, Rosalyn D; Mercy, James A

2012-08-01

The development of work on direct protective factors for youth violence has been delayed by conceptual and methodologic problems that have constrained the design, execution, and interpretation of prevention research. These problems are described in detail and actively addressed in review and analytic papers developed by the CDC's Expert Panel on Protective Factors for youth violence. The present paper synthesizes findings from these papers, specifies their implications for public health research and prevention strategies to reduce youth violence, and suggests directions for future research. Published by Elsevier Inc.

The role of prostaglandins E1 and E2, dinoprostone, and misoprostol in cervical ripening and the induction of labor: a mechanistic approach.

PubMed

Bakker, Ronan; Pierce, Stephanie; Myers, Dean

2017-08-01

Prostaglandins play a critical role in cervical ripening by increasing inflammatory mediators in the cervix and inducing cervical remodeling. Prostaglandin E1 (PGE1) and prostaglandin E2 (PGE2) exert different effects on these processes and on myometrial contractility. These mechanistic differences may affect outcomes in women treated with dinoprostone, a formulation identical to endogenous PGE2, compared with misoprostol, a PGE1 analog. The objective of this review is to evaluate existing evidence regarding mechanistic differences between PGE1 and PGE2, and consider the clinical implications of these differences in patients requiring cervical ripening for labor induction. We conducted a critical narrative review of peer-reviewed articles identified using PubMed and other online databases. While both dinoprostone and misoprostol are effective in cervical ripening and labor induction, they differ in their clinical and pharmacological profiles. PGE2 has been shown to stimulate interleukin-8, an inflammatory cytokine that promotes the influx of neutrophils and induces remodeling of the cervical extracellular matrix, and to induce functional progesterone withdrawal. Misoprostol has been shown to elicit a dose-dependent effect on myometrial contractility, which may affect rates of uterine tachysystole in clinical practice. Differences in the mechanism of action between misoprostol and PGE2 may contribute to their variable effects in the cervix and myometrium, and should be considered to optimize outcomes.

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…

FACTORS IMPLICATED IN AMPHIBIAN POPULATION DECLINES IN THE US, AND AN EVALUATION OF THE CASE FOR INVASIVE SPECIES

EPA Science Inventory

Factors known or suspected to be adversely affecting native amphibian populations in the US were identified using information from 267 species accounts written in a standardized format by multiple authors in a forthcoming book. Land use was the most frequently implicated adverse ...

Factors affecting choice of a healthy lifestyle: implications for nurses.

PubMed

Ochieng, Bertha M N

2006-02-01

Living a healthy lifestyle still remains a challenge to a wide section of the population. This article argues that since a healthy lifestyle is associated with other aspects of economic and social life, it should be examined within this context. This perspective suggests that participation in a healthy lifestyle, with its behavioural emphasis, which typically involves decisions about food, exercise, smoking, alcohol, drug use, risk of infection and accidents, is not necessarily up to the individual. Socioeconomic status, level of education, family, kin and social networks, gender, age and interpersonal influences all affect the choice of lifestyle. This has implications for community practitioners working in the field of health promotion, in particular to promote healthy lifestyle. A correlation model is presented that can be used by practitioners to identity factors that should be taken into consideration when working with clients to enable them to make a healthy lifestyle the easier option.

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

PubMed

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

2015-07-01

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

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...

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

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.

Ethanol potentiates the genotoxicity of the food-derived mammary carcinogen PhIP in human estrogen receptor-positive mammary cells: mechanistic support for lifestyle factors (cooked red meat and ethanol) associated with mammary cancer.

PubMed

Malik, Durr-E-Shahwar; David, Rhiannon M; Gooderham, Nigel J

2018-04-01

Consumption of cooked/processed meat and ethanol are lifestyle risk factors in the aetiology of breast cancer. Cooking meat generates heterocyclic amines such as 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Epidemiology, mechanistic and animal studies indicate that PhIP is a mammary carcinogen that could be causally linked to breast cancer incidence; PhIP is DNA damaging, mutagenic and oestrogenic. PhIP toxicity involves cytochrome P450 (CYP1 family)-mediated metabolic activation to DNA-damaging species, and transcriptional responses through Aryl hydrocarbon receptor (AhR) and estrogen-receptor-α (ER-α). Ethanol consumption is a modifiable lifestyle factor strongly associated with breast cancer risk. Ethanol toxicity involves alcohol dehydrogenase metabolism to reactive acetaldehyde, and is also a substrate for CYP2E1, which when uncoupled generates reactive oxygen species (ROS) and DNA damage. Here, using human mammary cells that differ in estrogen-receptor status, we explore genotoxicity of PhIP and ethanol and mechanisms behind this toxicity. Treatment with PhIP (10 -7 -10 -4 M) significantly induced genotoxicity (micronuclei formation) preferentially in ER-α positive human mammary cell lines (MCF-7, ER-α+) compared to MDA-MB-231 (ER-α-) cells. PhIP-induced CYP1A2 in both cell lines but CYP1B1 was selectively induced in ER-α(+) cells. ER-α inhibition in MCF-7 cells attenuated PhIP-mediated micronuclei formation and CYP1B1 induction. PhIP-induced CYP2E1 and ROS via ER-α-STAT-3 pathway, but only in ER-α (+) MCF-7 cells. Importantly, simultaneous treatments of physiological concentrations ethanol (10 -3 -10 -1 M) with PhIP (10 -7 -10 -4 M) increased oxidative stress and genotoxicity in MCF-7 cells, compared to the individual chemicals. Collectively, these data offer a mechanistic basis for the increased risk of breast cancer associated with dietary cooked meat and ethanol lifestyle choices.

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...

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.

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

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.

Siderophilic Cyanobacteria: Implications for Early Earth.

NASA Technical Reports Server (NTRS)

Brown, I. I.; Mummey, D.; Sarkisova, S.; Shen, G.; Bryant, D. A.; Lindsay, J.; Garrison, D.; McKay, D. S.

2006-01-01

Of all extant environs, iron-depositing hot springs (IDHS) may exhibit the greatest similarity to late Precambrian shallow warm oceans in regards to temperature, O2 gradients and dissolved iron and H2S concentrations. Despite the insights into the ecology, evolutionary biology, paleogeobiochemistry, and astrobiology examination of IDHS could potentially provide, very few studies dedicated to the physiology and diversity of cyanobacteria (CB) inhabiting IDHS have been conducted. Results. Here we describe the phylogeny, physiology, ultrastructure and biogeochemical activity of several recent CB isolates from two different greater Yellowstone area IDHS, LaDuke and Chocolate Pots. Phylogenetic analysis of 16S rRNA genes indicated that 6 of 12 new isolates examined couldn't be placed within established CB genera. Some of the isolates exhibited pronounced requirements for elevated iron concentrations, with maximum growth rates observed when 0.4-1 mM Fe(3+) was present in the media. In light of "typical" CB iron requirements, our results indicate that elevated iron likely represents a salient factor selecting for "siderophilicM CB species in IDHS. A universal feature of our new isolates is their ability to produce thick EPS layers in which iron accumulates resulting in the generation of well preserved signatures. In parallel, siderophilic CB show enhanced ability to etch the analogs of iron-rich lunar regolith minerals and impact glasses. Despite that iron deposition by CB is not well understood mechanistically, we recently obtained evidence that the PS I:PS II ratio is higher in one of our isolates than for other CB. Although still preliminary, this finding is in direct support of the Y. Cohen hypothesis that PSI can directly oxidize Fe(2+). Conclusion. Our results may have implications for factors driving CB evolutionary relationships and biogeochemical processes on early Earth and probably Mars.

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.

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...

Serine phosphorylation by SYK is critical for nuclear localization and transcription factor function of Ikaros

PubMed Central

Uckun, Fatih M.; Ma, Hong; Zhang, Jian; Ozer, Zahide; Dovat, Sinisa; Mao, Cheney; Ishkhanian, Rita; Goodman, Patricia; Qazi, Sanjive

2012-01-01

Ikaros is a zinc finger-containing DNA-binding protein that plays a pivotal role in immune homeostasis through transcriptional regulation of the earliest stages of lymphocyte ontogeny and differentiation. Functional deficiency of Ikaros has been implicated in the pathogenesis of acute lymphoblastic leukemia, the most common form of childhood cancer. Therefore, a stringent regulation of Ikaros activity is considered of paramount importance, but the operative molecular mechanisms responsible for its regulation remain largely unknown. Here we provide multifaceted genetic and biochemical evidence for a previously unknown function of spleen tyrosine kinase (SYK) as a partner and posttranslational regulator of Ikaros. We demonstrate that SYK phoshorylates Ikaros at unique C-terminal serine phosphorylation sites S358 and S361, thereby augmenting its nuclear localization and sequence-specific DNA binding activity. Mechanistically, we establish that SYK-induced Ikaros activation is essential for its nuclear localization and optimal transcription factor function. PMID:23071339

The role of angiogenic factors in fibroid pathogenesis: potential implications for future therapy

PubMed Central

Tal, Reshef; Segars, James H.

2014-01-01

Background It is well established that tumors are dependent on angiogenesis for their growth and survival. Although uterine fibroids are known to be benign tumors with reduced vascularization, recent work demonstrates that the vasculature of fibroids is grossly and microscopically abnormal. Accumulating evidence suggests that angiogenic growth factor dysregulation may be implicated in these vascular and other features of fibroid pathophysiology. Methods Literature searches were performed in PubMed and Google Scholar for articles with content related to angiogenic growth factors and myometrium/leiomyoma. The findings are hereby reviewed and discussed. Results Multiple growth factors involved in angiogenesis are differentially expressed in leiomyoma compared with myometrium. These include epidermal growth factor (EGF), heparin-binding-EGF, vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived growth factor, transforming growth factor-β and adrenomedullin. An important paradox is that although leiomyoma tissues are hypoxic, leiomyoma feature down-regulation of key molecular regulators of the hypoxia response. Furthermore, the hypoxic milieu of leiomyoma may contribute to fibroid development and growth. Notably, common treatments for fibroids such as GnRH agonists and uterine artery embolization (UAE) are shown to work at least partly via anti-angiogenic mechanisms. Conclusions Angiogenic growth factors play an important role in mechanisms of fibroid pathophysiology, including abnormal vasculature and fibroid growth and survival. Moreover, the fibroid's abnormal vasculature together with its aberrant hypoxic and angiogenic response may make it especially vulnerable to disruption of its vascular supply, a feature which could be exploited for treatment. Further experimental studies are required in order to gain a better understanding of the growth factors that are involved in normal and pathological myometrial angiogenesis, and to assess

Organizational (role structuring) and personal (organizational commitment and job involvement) factors: do they predict interprofessional team effectiveness?

PubMed

Freund, Anat; Drach-Zahavy, Anat

2007-06-01

Teamwork in community clinics was examined to propose and test a model that views the different kinds of commitment (job involvement and organizational commitment) and the potential conflict between them, as mediators between personal and organizational factors (mechanistic structuring and organic structuring) and the effectiveness of interprofessional teamwork. Differences among the professional groups became evident with regard to their views of the goals of teamwork and the ways to achieve them. As for mechanistic structuring, although the clinic members saw their mechanistic structuring in a more bureaucratic sense, the combination of mechanistic structuring and organic structuring led to effective teamwork. In terms of commitment, while staff members were committed primarily to their job and not the organization, commitment to the organization produced effective teamwork in the clinics.

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...

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...

Homing of mesenchymal stem cells: mechanistic or stochastic? Implications for targeted delivery in arthritis.

PubMed

Eseonu, Onyedikachi I; De Bari, Cosimo

2015-02-01

Mesenchymal stem cells (MSCs) are multipotent cells with the capacity to undergo chondrogenic differentiation. Systemically administered MSCs have been shown to preferentially accumulate at sites of tissue damage and inflammation, thus MSC-based therapy holds great promise for the treatment of inflammatory diseases such as RA. Modulation of MSC homing may allow targeted delivery of systemically administered MSCs to damaged articular cartilage, where they can suppress immune-mediated cartilage destruction and contribute to cartilage repair via a combination of chondrogenic differentiation and paracrine stimulation of intrinsic residual repair. To harness the potential of MSC homing, a thorough understanding of the mechanism is key. This review discusses current knowledge of the mechanism of MSC homing to injured/inflamed tissue and its implications for targeted MSC-based therapy in arthritis. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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.

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

In SilicoModel-driven Assessment of the Effects of Brain-derived Neurotrophic Factor Deficiency on Glutamate and Gamma-Aminobutyric Acid: Implications for Understanding Schizophrenia Pathophysiology.

PubMed

Agrawal, Rimjhim; Kalmady, Sunil Vasu; Venkatasubramanian, Ganesan

2017-05-31

Deficient brain-derived neurotrophic factor (BDNF) is one of the important mechanisms underlying the neuroplasticity abnormalities in schizophrenia. Aberration in BDNF signaling pathways directly or circuitously influences neurotransmitters like glutamate and gamma-aminobutyric acid (GABA). For the first time, this study attempts to construct and simulate the BDNF-neurotransmitter network in order to assess the effects of BDNF deficiency on glutamate and GABA. Using CellDesigner, we modeled BDNF interactions with calcium influx via N-methyl-D-aspartate receptor (NMDAR)- Calmodulin activation; synthesis of GABA via cell cycle regulators protein kinase B, glycogen synthase kinase and β-catenin; transportation of glutamate and GABA. Steady state stability, perturbation time-course simulation and sensitivity analysis were performed in COPASI after assigning the kinetic functions, optimizing the unknown parameters using random search and genetic algorithm. Study observations suggest that increased glutamate in hippocampus, similar to that seen in schizophrenia, could potentially be contributed by indirect pathway originated from BDNF. Deficient BDNF could suppress Glutamate decarboxylase 67-mediated GABA synthesis. Further, deficient BDNF corresponded to impaired transport via vesicular glutamate transporter, thereby further increasing the intracellular glutamate in GABAergic and glutamatergic cells. BDNF also altered calcium dependent neuroplasticity via NMDAR modulation. Sensitivity analysis showed that Calmodulin, cAMP response element-binding protein (CREB) and CREB regulated transcription coactivator-1 played significant role in this network. The study presents in silico quantitative model of biochemical network constituting the key signaling molecules implicated in schizophrenia pathogenesis. It provides mechanistic insights into putative contribution of deficient BNDF towards alterations in neurotransmitters and neuroplasticity that are consistent with current

In Silico Model-driven Assessment of the Effects of Brain-derived Neurotrophic Factor Deficiency on Glutamate and Gamma-Aminobutyric Acid: Implications for Understanding Schizophrenia Pathophysiology

PubMed Central

Agrawal, Rimjhim; Kalmady, Sunil Vasu; Venkatasubramanian, Ganesan

2017-01-01

Objective Deficient brain-derived neurotrophic factor (BDNF) is one of the important mechanisms underlying the neuroplasticity abnormalities in schizophrenia. Aberration in BDNF signaling pathways directly or circuitously influences neurotransmitters like glutamate and gamma-aminobutyric acid (GABA). For the first time, this study attempts to construct and simulate the BDNF-neurotransmitter network in order to assess the effects of BDNF deficiency on glutamate and GABA. Methods Using CellDesigner, we modeled BDNF interactions with calcium influx via N-methyl-D-aspartate receptor (NMDAR)-Calmodulin activation; synthesis of GABA via cell cycle regulators protein kinase B, glycogen synthase kinase and β-catenin; transportation of glutamate and GABA. Steady state stability, perturbation time-course simulation and sensitivity analysis were performed in COPASI after assigning the kinetic functions, optimizing the unknown parameters using random search and genetic algorithm. Results Study observations suggest that increased glutamate in hippocampus, similar to that seen in schizophrenia, could potentially be contributed by indirect pathway originated from BDNF. Deficient BDNF could suppress Glutamate decarboxylase 67-mediated GABA synthesis. Further, deficient BDNF corresponded to impaired transport via vesicular glutamate transporter, thereby further increasing the intracellular glutamate in GABAergic and glutamatergic cells. BDNF also altered calcium dependent neuroplasticity via NMDAR modulation. Sensitivity analysis showed that Calmodulin, cAMP response element-binding protein (CREB) and CREB regulated transcription coactivator-1 played significant role in this network. Conclusion The study presents in silico quantitative model of biochemical network constituting the key signaling molecules implicated in schizophrenia pathogenesis. It provides mechanistic insights into putative contribution of deficient BNDF towards alterations in neurotransmitters and

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...

Millifluidics for Chemical Synthesis and Time-resolved Mechanistic Studies

PubMed Central

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

2013-01-01

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

Labor Inhibits Placental Mechanistic Target of Rapamycin Complex 1 Signaling

PubMed Central

LAGER, Susanne; AYE, Irving L.M.H.; GACCIOLI, Francesca; RAMIREZ, Vanessa I.; JANSSON, Thomas; POWELL, Theresa L.

2014-01-01

Introduction Labor induces a myriad of changes in placental gene expression. These changes may represent a physiological adaptation inhibiting placental cellular processes associated with a high demand for oxygen and energy (e.g., protein synthesis and active transport) thereby promoting oxygen and glucose transfer to the fetus. We hypothesized that mechanistic target of rapamycin complex 1 (mTORC1) signaling, a positive regulator of trophoblast protein synthesis and amino acid transport, is inhibited by labor. Methods Placental tissue was collected from healthy, term pregnancies (n=15 no-labor; n=12 labor). Activation of Caspase-1, IRS1/Akt, STAT, mTOR, and inflammatory signaling pathways was determined by Western blot. NFκB p65 and PPARγ DNA binding activity was measured in isolated nuclei. Results Labor increased Caspase-1 activation and mTOR complex 2 signaling, as measured by phosphorylation of Akt (S473). However, mTORC1 signaling was inhibited in response to labor as evidenced by decreased phosphorylation of mTOR (S2448) and 4EBP1 (T37/46 and T70). Labor also decreased NFκB and PPARγ DNA binding activity, while having no effect on IRS1 or STAT signaling pathway. Discussion and conclusion Several placental signaling pathways are affected by labor, which has implications for experimental design in studies of placental signaling. Inhibition of placental mTORC1 signaling in response to labor may serve to down-regulate protein synthesis and amino acid transport, processes that account for a large share of placental oxygen and glucose consumption. We speculate that this response preserves glucose and oxygen for transfer to the fetus during the stressful events of labor. PMID:25454472

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

Factors Influencing Mini-CEX Rater Judgments and Their Practical Implications: A Systematic Literature Review.

PubMed

Lee, Victor; Brain, Keira; Martin, Jenepher

2017-06-01

At present, little is known about how mini-clinical evaluation exercise (mini-CEX) raters translate their observations into judgments and ratings. The authors of this systematic literature review aim both to identify the factors influencing mini-CEX rater judgments in the medical education setting and to translate these findings into practical implications for clinician assessors. The authors searched for internal and external factors influencing mini-CEX rater judgments in the medical education setting from 1980 to 2015 using the Ovid MEDLINE, PsycINFO, ERIC, PubMed, and Scopus databases. They extracted the following information from each study: country of origin, educational level, study design and setting, type of observation, occurrence of rater training, provision of feedback to the trainee, research question, and identified factors influencing rater judgments. The authors also conducted a quality assessment for each study. Seventeen articles met the inclusion criteria. The authors identified both internal and external factors that influence mini-CEX rater judgments. They subcategorized the internal factors into intrinsic rater factors, judgment-making factors (conceptualization, interpretation, attention, and impressions), and scoring factors (scoring integration and domain differentiation). The current theories of rater-based judgment have not helped clinicians resolve the issues of rater idiosyncrasy, bias, gestalt, and conflicting contextual factors; therefore, the authors believe the most important solution is to increase the justification of rater judgments through the use of specific narrative and contextual comments, which are more informative for trainees. Finally, more real-world research is required to bridge the gap between the theory and practice of rater cognition.

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.

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.

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.

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

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…

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...

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

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

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

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...

The role of non-need factors in individual GP utilisation analysis and their implications for the pursuance of equity: a cross-country comparison.

PubMed

McGregor, P; McKee, P; O'Neill, C

2008-05-01

A substantial amount of health care resources is allocated within the UK using formulae that relate funding to measures of population need. The aim of this paper is to demonstrate the importance of non-need factors in determining utilisation of services at an individual level and explore the implications inclusion of such factors has in the consideration of equity. In the paper we develop a utility model that accords a role to non-health factors in the determination of service use. A series of functions incorporating non-health factors as explanatory variables in GP utilisation functions are estimated using data from the British Household Panel Survey. The functions are decomposed to ascertain the role of service structure and examine the role of income across the four countries of the UK in explaining utilisation. The implications of our findings for the pursuance of equity in the NHS when individual choice has an explicit role are discussed.

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

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

PubMed Central

Upadhyaya, Indu; Kollanoor-Johny, Anup

2014-01-01

The emergence of antibiotic resistance in pathogenic bacteria has led to renewed interest in exploring the potential of plant-derived antimicrobials (PDAs) as an alternative therapeutic strategy to combat microbial infections. Historically, plant extracts have been used as a safe, effective, and natural remedy for ailments and diseases in traditional medicine. Extensive research in the last two decades has identified a plethora of PDAs with a wide spectrum of activity against a variety of fungal and bacterial pathogens causing infections in humans and animals. Active components of many plant extracts have been characterized and are commercially available; however, research delineating the mechanistic basis of their antimicrobial action is scanty. This review highlights the potential of various plant-derived compounds to control pathogenic bacteria, especially the diverse effects exerted by plant compounds on various virulence factors that are critical for pathogenicity inside the host. In addition, the potential effect of PDAs on gut microbiota is discussed. PMID:25298964

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…

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

Magnetophoresis for enhancing transdermal drug delivery: Mechanistic studies and patch design

PubMed Central

Murthy, S. Narasimha; Sammeta, Srinivasa M.; Bower, C.

2017-01-01

Magnetophoresis is a method of enhancement of drug permeation across the biological barriers by application of magnetic field. The present study investigated the mechanistic aspects of magnetophoretic transdermal drug delivery and also assessed the feasibility of designing a magnetophoretic transdermal patch system for the delivery of lidocaine. In vitro drug permeation studies were carried out across the porcine epidermis at different magnetic field strengths. The magnetophoretic drug permeation “flux enhancement factor” was found to increase with the applied magnetic field strength. The mechanistic studies revealed that the magnetic field applied in this study did not modulate permeability of the stratum corneum barrier. The predominant mechanism responsible for magnetically mediated drug permeation enhancement was found to be “magnetokinesis”. The octanol/water partition coefficient of drugs was also found to increase when exposed to the magnetic field. A reservoir type transdermal patch system with a magnetic backing was designed for in vivo studies. The dermal bioavailability (AUC0–6 h) from the magnetophoretic patch system in vivo, in rats was significantly higher than the similarly designed nonmagnetic control patch. PMID:20728484

Genetic framework for GATA factor function in vascular biology.

PubMed

Linnemann, Amelia K; O'Geen, Henriette; Keles, Sunduz; Farnham, Peggy J; Bresnick, Emery H

2011-08-16

Vascular endothelial dysfunction underlies the genesis and progression of numerous diseases. Although the GATA transcription factor GATA-2 is expressed in endothelial cells and is implicated in coronary heart disease, it has been studied predominantly as a master regulator of hematopoiesis. Because many questions regarding GATA-2 function in the vascular biology realm remain unanswered, we used ChIP sequencing and loss-of-function strategies to define the GATA-2-instigated genetic network in human endothelial cells. In contrast to erythroid cells, GATA-2 occupied a unique target gene ensemble consisting of genes encoding key determinants of endothelial cell identity and inflammation. GATA-2-occupied sites characteristically contained motifs that bind activator protein-1 (AP-1), a pivotal regulator of inflammatory genes. GATA-2 frequently occupied the same chromatin sites as c-JUN and c-FOS, heterodimeric components of AP-1. Although all three components were required for maximal AP-1 target gene expression, GATA-2 was not required for AP-1 chromatin occupancy. GATA-2 conferred maximal phosphorylation of chromatin-bound c-JUN at Ser-73, which stimulates AP-1-dependent transactivation, in a chromosomal context-dependent manner. This work establishes a link between a GATA factor and inflammatory genes, mechanistic insights underlying GATA-2-AP-1 cooperativity and a rigorous genetic framework for understanding GATA-2 function in normal and pathophysiological vascular states.

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...

Structural and mechanistic insights into human splicing factor SF3b complex derived using an integrated approach guided by the cryo-EM density maps

PubMed Central

Rakesh, Ramachandran; Joseph, Agnel Praveen; Bhaskara, Ramachandra M.; Srinivasan, Narayanaswamy

2016-01-01

ABSTRACT Pre-mRNA splicing in eukaryotes is performed by the spliceosome, a highly complex macromolecular machine. SF3b is a multi-protein complex which recognizes the branch point adenosine of pre-mRNA as part of a larger U2 snRNP or U11/U12 di-snRNP in the dynamic spliceosome machinery. Although a cryo-EM map is available for human SF3b complex, the structure and relative spatial arrangement of all components in the complex are not yet known. We have recognized folds of domains in various proteins in the assembly and generated comparative models. Using an integrative approach involving structural and other experimental data, guided by the available cryo-EM density map, we deciphered a pseudo-atomic model of the closed form of SF3b which is found to be a “fuzzy complex” with highly flexible components and multiplicity of folds. Further, the model provides structural information for 5 proteins (SF3b10, SF3b155, SF3b145, SF3b130 and SF3b14b) and localization information for 4 proteins (SF3b10, SF3b145, SF3b130 and SF3b14b) in the assembly for the first time. Integration of this model with the available U11/U12 di-snRNP cryo-EM map enabled elucidation of an open form. This now provides new insights on the mechanistic features involved in the transition between closed and open forms pivoted by a hinge region in the SF3b155 protein that also harbors cancer causing mutations. Moreover, the open form guided model of the 5′ end of U12 snRNA, which includes the branch point duplex, shows that the architecture of SF3b acts as a scaffold for U12 snRNA: pre-mRNA branch point duplex formation with potential implications for branch point adenosine recognition fidelity. PMID:27618338

Polymer Film Dewetting by Water/Surfactant/Good-Solvent Mixtures: A Mechanistic Insight and Its Implications for the Conservation of Cultural Heritage.

PubMed

Baglioni, Michele; Montis, Costanza; Chelazzi, David; Giorgi, Rodorico; Berti, Debora; Baglioni, Piero

2018-06-18

Aqueous nanostructured fluids (NSFs) have been proposed to remove polymer coatings from the surface of works of art; this process usually involves film dewetting. The NSF cleaning mechanism was studied using several techniques that were employed to obtain mechanistic insight on the interaction of a methacrylic/acrylic copolymer (Paraloid B72) film laid on glass surfaces and several NSFs, based on two solvents and two surfactants. The experimental results provide a detailed picture of the dewetting process. The gyration radius and the reduction of the T g of Paraloid B72 fully swollen in the two solvents is larger for propylene carbonate than for methyl ethyl ketone, suggesting higher mobility of polymer chains for the former, while a nonionic alcohol ethoxylate surfactant was more effective than sodium dodecylsulfate in favoring the dewetting process. FTIR 2D imaging showed that the dewetting patterns observed on model samples are also present on polymer-coated mortar tiles when exposed to NSFs. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Incidence, Risk Factors, and Clinical Implications of Pneumonia Following Total Hip and Knee Arthroplasty.

PubMed

Bohl, Daniel D; Saltzman, Bryan M; Sershon, Robert A; Darrith, Brian; Okroj, Kamil T; Della Valle, Craig J

2017-06-01

The purpose of this study is to determine the incidence, risk factors, and clinical implications of pneumonia following total joint arthroplasty (TJA). The American College of Surgeons National Surgical Quality Improvement Program was used to conduct a retrospective cohort study of patients undergoing TJA. Independent risk factors for the development of pneumonia within 30 days of TJA were identified using multivariate regression. Mortality and readmission rates were compared between patients who did and did not develop pneumonia. Multivariate regression was used to adjust for all demographic, comorbidity, and procedural characteristics. In total, 171,200 patients met inclusion criteria, of whom 66,493 (38.8%) underwent THA and 104,707 (61.2%) underwent TKA. Of the 171,200 patients, 590 developed pneumonia, yielding a rate of 0.34% (95% confidence interval = 0.32%-0.37%). Independent risk factors for pneumonia were chronic obstructive pulmonary disease, diabetes mellitus, greater age (most notably ≥80 years), dyspnea on exertion, dependent functional status, lower body mass index, hypertension, current smoker status, and male sex. The subset of patients who developed pneumonia following discharge had a higher readmission rate (82.1% vs 3.4%, adjusted relative risk [RR] = 16.6, P < .001) and a higher mortality rate (3.7% vs 0.1%, adjusted RR = 19.4, P < .001). Among 124 total mortalities, 22 (17.7%) occurred in patients who had developed pneumonia. Pneumonia is a serious complication following TJA that occurs in approximately 1 in 300 patients. Approximately 4 in 5 patients who develop pneumonia are subsequently readmitted, and approximately 1 in 25 die. Given the serious implications of this complication, evidence-based pneumonia prevention programs including oral hygiene with chlorhexidine, sitting upright for meals, elevation of the head of the bed to at least 30°, aggressive incentive spirometry, and early ambulation should be considered for patients at

Direct Spectroscopic Detection of ATP Turnover Reveals Mechanistic Divergence of ABC Exporters.

PubMed

Collauto, Alberto; Mishra, Smriti; Litvinov, Aleksei; Mchaourab, Hassane S; Goldfarb, Daniella

2017-08-01

We have applied high-field (W-band) pulse electron-nuclear double resonance (ENDOR) and electron-electron double resonance (ELDOR)-detected nuclear magnetic resonance (EDNMR) to characterize the coordination sphere of the Mn 2+ co-factor in the nucleotide binding sites (NBSs) of ABC transporters. MsbA and BmrCD are two efflux transporters hypothesized to represent divergent catalytic mechanisms. Our results reveal distinct coordination of Mn 2+ to ATP and transporter residues in the consensus and degenerate NBSs of BmrCD. In contrast, the coordination of Mn 2+ at the two NBSs of MsbA is similar, which provides a mechanistic rationale for its higher rate constant of ATP hydrolysis relative to BmrCD. Direct detection of vanadate ion, trapped in a high-energy post-hydrolysis intermediate, further supports the notion of asymmetric hydrolysis by the two NBSs of BmrCD. The integrated spectroscopic approach presented here, which link energy input to conformational dynamics, can be applied to a variety of systems powered by ATP turnover. Copyright © 2017 Elsevier Ltd. All rights reserved.

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-...

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.

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...

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.

Metabolic syndrome and its components after liver transplantation: incidence, prevalence, risk factors, and implications.

PubMed

Anastácio, Lucilene Rezende; Lima, Agnaldo Soares; Toulson Davisson Correia, Maria Isabel

2010-04-01

Metabolic syndrome is defined as the mutual existence of obesity, impaired fasting glucose levels, insulin resistance, hypertension, and dyslipidemia. After liver transplantation, patients typically develop these disorders, and even though there has been minimal research focused on the chronic impact of this syndrome on post-liver transplant patients, studies point to an association with major vascular events and fibrosis. The aim of the current work is to review data on the incidence, prevalence, risk factors, and implications of metabolic syndrome and its components in patients who have undergone liver transplantation. Copyright 2009 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Sociocultural factors and breast cancer in sub-Saharan Africa: implications for diagnosis and management.

PubMed

Tetteh, Dinah A; Faulkner, Sandra L

2016-01-01

The incidence of breast cancer is on the rise in sub-Saharan Africa (SSA) and efforts at early diagnosis have not been very successful because the public has scant knowledge about the disease, a large percentage of breast cancer cases are diagnosed late and mainly rural SSA women's practice of breast self-examination is poor. In this paper, we argue that an examination of the social and cultural contexts of SSA that influence breast cancer diagnosis and management in the region is needed. We discuss the implications of sociocultural factors, such as gender roles and spirituality, on breast cancer diagnosis and management in SSA.

Mechanistic Studies at the Interface Between Organometallic Chemistry and Homogeneous Catalysis

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

Casey, Charles P

Mechanistic Studies at the Interface Between Organometallic Chemistry and Homogeneous Catalysis Charles P. Casey, Principal Investigator Department of Chemistry, University of Wisconsin - Madison, Madison, Wisconsin 53706 Phone 608-262-0584 FAX: 608-262-7144 Email: casey@chem.wisc.edu http://www.chem.wisc.edu/main/people/faculty/casey.html Executive Summary. Our goal was to learn the intimate mechanistic details of reactions involved in homogeneous catalysis and to use the insight we gain to develop new and improved catalysts. Our work centered on the hydrogenation of polar functional groups such as aldehydes and ketones and on hydroformylation. Specifically, we concentrated on catalysts capable of simultaneously transferring hydride from a metal center and a proton frommore » an acidic oxygen or nitrogen center to an aldehyde or ketone. An economical iron based catalyst was developed and patented. Better understanding of fundamental organometallic reactions and catalytic processes enabled design of energy and material efficient chemical processes. Our work contributed to the development of catalysts for the selective and mild hydrogenation of ketones and aldehydes; this will provide a modern green alternative to reductions by LiAlH4 and NaBH4, which require extensive work-up procedures and produce waste streams. (C5R4OH)Ru(CO)2H Hydrogenation Catalysts. Youval Shvo described a remarkable catalytic system in which the key intermediate (C5R4OH)Ru(CO)2H (1) has an electronically coupled acidic OH unit and a hydridic RuH unit. Our efforts centered on understanding and improving upon this important catalyst for reduction of aldehydes and ketones. Our mechanistic studies established that the reduction of aldehydes by 1 to produce alcohols and a diruthenium bridging hydride species occurs much more rapidly than regeneration of the ruthenium hydride from the diruthenium bridging hydride species. Our mechanistic studies require simultaneous transfer of hydride from

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.

A zinc finger transcription factor ART1 regulates multiple genes implicated in aluminum tolerance in rice.

PubMed

Yamaji, Naoki; Huang, Chao Feng; Nagao, Sakiko; Yano, Masahiro; Sato, Yutaka; Nagamura, Yoshiaki; Ma, Jian Feng

2009-10-01

Aluminum (Al) toxicity is the major limiting factor of crop production on acid soils, but some plant species have evolved ways of detoxifying Al. Here, we report a C2H2-type zinc finger transcription factor ART1 (for Al resistance transcription factor 1), which specifically regulates the expression of genes related to Al tolerance in rice (Oryza sativa). ART1 is constitutively expressed in the root, and the expression level is not affected by Al treatment. ART1 is localized in the nucleus of all root cells. A yeast one-hybrid assay showed that ART1 has a transcriptional activation potential and interacts with the promoter region of STAR1, an important factor in rice Al tolerance. Microarray analysis revealed 31 downstream transcripts regulated by ART1, including STAR1 and 2 and a couple of homologs of Al tolerance genes in other plants. Some of these genes were implicated in both internal and external detoxification of Al at different cellular levels. Our findings shed light on comprehensively understanding how plants detoxify aluminum to survive in an acidic environment.

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

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.

A mechanistic pharmacokinetic model to assess modified oral drug bioavailability post bariatric surgery in morbidly obese patients: interplay between CYP3A gut wall metabolism, permeability and dissolution.

PubMed

Darwich, Adam S; Pade, Devendra; Ammori, Basil J; Jamei, Masoud; Ashcroft, Darren M; Rostami-Hodjegan, Amin

2012-07-01

Due to the multi-factorial physiological implications of bariatric surgery, attempts to explain trends in oral bioavailability following bariatric surgery using singular attributes of drugs or simplified categorisations such as the biopharmaceutics classification system have been unsuccessful. So we have attempted to use mechanistic models to assess changes to bioavailability of model drugs. Pharmacokinetic post bariatric surgery models were created for Roux-en-Y gastric bypass, biliopancreatic diversion with duodenal switch, sleeve gastrectomy and jejunoileal bypass, through altering the 'Advanced Dissolution Absorption and Metabolism' (ADAM) model incorporated into the Simcyp® Simulator. Post to pre surgical simulations were carried out for five drugs with varying characteristics regarding their gut wall metabolism, dissolution and permeability (simvastatin, omeprazole, diclofenac, fluconazole and ciprofloxacin). The trends in oral bioavailability pre to post surgery were found to be dependent on a combination of drug parameters, including solubility, permeability and gastrointestinal metabolism as well as the surgical procedure carried out. In the absence of clinical studies, the ability to project the direction and the magnitude of changes in bioavailability of drug therapy, using evidence-based mechanistic pharmacokinetic in silico models would be of significant value in guiding prescribers to make the necessary adjustments to dosage regimens for an increasing population of patients who are undergoing bariatric surgery. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

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.

Fox transcription factors: from development to disease.

PubMed

Golson, Maria L; Kaestner, Klaus H

2016-12-15

Forkhead box (Fox) transcription factors are evolutionarily conserved in organisms ranging from yeast to humans. They regulate diverse biological processes both during development and throughout adult life. Mutations in many Fox genes are associated with human disease and, as such, various animal models have been generated to study the function of these transcription factors in mechanistic detail. In many cases, the absence of even a single Fox transcription factor is lethal. In this Primer, we provide an overview of the Fox family, highlighting several key Fox transcription factor families that are important for mammalian development. © 2016. Published by The Company of Biologists Ltd.

Localization and roles of Ski8p protein in Sordaria meiosis and delineation of three mechanistically distinct steps of meiotic homolog juxtaposition.

PubMed

Tessé, Sophie; Storlazzi, Aurora; Kleckner, Nancy; Gargano, Silvana; Zickler, Denise

2003-10-28

Ski8p is implicated in degradation of non-poly(A) and double-stranded RNA, and in meiotic DNA recombination. We have identified the Sordaria macrospora SKI8 gene. Ski8p is cytoplasmically localized in all vegetative and sexual cycle cells, and is nuclear localized, specifically in early-mid-meiotic prophase, in temporal correlation with Spo11p, the meiotic double-strand break (DSB) transesterase. Localizations of Ski8p and Spo11p are mutually interdependent. ski8 mutants exhibit defects in vegetative growth, entry into the sexual program, and sporulation. Diverse meiotic defects, also seen in spo11 mutants, are diagnostic of DSB absence, and they are restored by exogenous DSBs. These results suggest that Ski8p promotes meiotic DSB formation by acting directly within meiotic prophase chromosomes. Mutant phenotypes also divide meiotic homolog juxtaposition into three successive, mechanistically distinct steps; recognition, presynaptic alignment, and synapsis, which are distinguished by their differential dependence on DSBs.

Localization and roles of Ski8p protein in Sordaria meiosis and delineation of three mechanistically distinct steps of meiotic homolog juxtaposition

PubMed Central

Tessé, Sophie; Storlazzi, Aurora; Kleckner, Nancy; Gargano, Silvana; Zickler, Denise

2003-01-01

Ski8p is implicated in degradation of non-poly(A) and double-stranded RNA, and in meiotic DNA recombination. We have identified the Sordaria macrospora SKI8 gene. Ski8p is cytoplasmically localized in all vegetative and sexual cycle cells, and is nuclear localized, specifically in early-mid-meiotic prophase, in temporal correlation with Spo11p, the meiotic double-strand break (DSB) transesterase. Localizations of Ski8p and Spo11p are mutually interdependent. ski8 mutants exhibit defects in vegetative growth, entry into the sexual program, and sporulation. Diverse meiotic defects, also seen in spo11 mutants, are diagnostic of DSB absence, and they are restored by exogenous DSBs. These results suggest that Ski8p promotes meiotic DSB formation by acting directly within meiotic prophase chromosomes. Mutant phenotypes also divide meiotic homolog juxtaposition into three successive, mechanistically distinct steps; recognition, presynaptic alignment, and synapsis, which are distinguished by their differential dependence on DSBs. PMID:14563920

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.

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...

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

The role of risk factors and trigger factors in cerebrovascular events after mitral valve replacement: implications for antithrombotic management.

PubMed

Butchart, E G; Moreno de la Santa, P; Rooney, S J; Lewis, P A

1994-03-01

To determine the effect of risk factors and trigger factors on cerebrovascular events, 622 patients who survived mitral valve replacement between December 1979 and December 1992 were analyzed. Ninety-six patients suffered 139 nonhemorrhagic cerebrovascular events. Data were available on 138 events in 95 patients. There were 32 transient ischemic attacks (TIAs), 57 reversible ischemic neurological deficits (RINDs), and 49 strokes. Age, sex, atrial fibrillation, left atrial size, systemic hypertension, and abnormal body mass index did not discriminate between patients who suffered events and those who did not. In contrast, smoking status differed significantly between patients who suffered events and those who did not. Among current or recent ex-smokers, the risk of stroke or RIND was significantly higher than in non-smokers (p < < 0.001). The odds ratio of suffering any type of event in patients who smoked at any time postoperatively versus those who did not smoke was 2.9 (95% confidence interval: 1.8 to 4.6). Of 61 patients contacted directly, 30% recalled an infective episode immediately prior to their event. A diurnal and seasonal influence on events was also detected with peaks in the morning and in the winter months, respectively (both p < 0.001). It is concluded that there is persuasive evidence for the involvement of several nonprosthetic factors in the incidence of cerebrovascular events after mitral valve replacement. This has implications for patient management and for future analysis of prosthetic heart valve series.

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

NASA Astrophysics Data System (ADS)

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

2015-12-01

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

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.

A review of factors explaining variability in fentanyl pharmacokinetics; focus on implications for cancer patients

PubMed Central

Zandvliet, Maarten L.; Koolen, Stijn L. W.; Mathijssen, Ron H. J.; van der Rijt, Carin C. D.

2016-01-01

Fentanyl is a strong opioid that is available for various administration routes, and which is widely used to treat cancer‐related pain. Many factors influence the fentanyl pharmacokinetics leading to a wide inter‐ and intrapatient variability. This systematic review summarizes multiple studied factors that potentially influence fentanyl pharmacokinetics with a focus on implications for cancer patients. The use of CYP3A4 inhibitors and inducers, impaired liver function, and heating of the patch potentially influence fentanyl pharmacokinetics in a clinically relevant way. In elderly patients, current data suggest that we should carefully dose fentanyl due to alterations in absorption and metabolism. The influence of BMI and gender on fentanyl pharmacokinetics is questionable, most probably due to a large heterogeneity in the published studies. Pharmacogenetics, e.g. the CYP3A5*3 gene polymorphism, may influence fentanyl pharmacokinetics as well, although further study is warranted. Several other factors have been studied but did not show significant and clinically relevant effects on fentanyl pharmacokinetics. Unfortunately, most of the published papers that studied factors influencing fentanyl pharmacokinetics describe healthy volunteers instead of cancer patients. Results from the studies in volunteers may not be simply extrapolated to cancer patients because of multiple confounding factors. To handle fentanyl treatment in a population of cancer patients, it is essential that physicians recognize factors that influence fentanyl pharmacokinetics, thereby preventing potential side‐effects and increasing its efficacy. PMID:27619152

NASH is an Inflammatory Disorder: Pathogenic, Prognostic and Therapeutic Implications

PubMed Central

van Rooyen, Derrick; Gan, Lay; Chitturi, Shivrakumar

2012-01-01

While non-alcoholic fatty liver disease (NAFLD) is highly prevalent (15% to 45%) in modern societies, only 10% to 25% of cases develop hepatic fibrosis leading to cirrhosis, end-stage liver disease or hepatocellular carcinoma. Apart from pre-existing fibrosis, the strongest predictor of fibrotic progression in NAFLD is steatohepatitis or non-alcoholic steatohepatitis (NASH). The critical features other than steatosis are hepatocellular degeneration (ballooning, Mallory hyaline) and mixed inflammatory cell infiltration. While much is understood about the relationship of steatosis to metabolic factors (over-nutrition, insulin resistance, hyperglycemia, metabolic syndrome, hypoadiponectinemia), less is known about inflammatory recruitment, despite its importance for the perpetuation of liver injury and fibrogenesis. In this review, we present evidence that liver inflammation has prognostic significance in NAFLD. We then consider the origins and components of liver inflammation in NASH. Hepatocytes injured by toxic lipid molecules (lipotoxicity) play a central role in the recruitment of innate immunity involving Toll-like receptors (TLRs), Kupffer cells (KCs), lymphocytes and neutrophils and possibly inflammasome. The key pro-inflammatory signaling pathways in NASH are nuclear factor-kappa B (NF-κB) and c-Jun N-terminal kinase (JNK). The downstream effectors include adhesion molecules, chemokines, cytokines and the activation of cell death pathways leading to apoptosis. The upstream activators of NF-κB and JNK are more contentious and may depend on the experimental model used. TLRs are strong contenders. It remains possible that inflammation in NASH originates outside the liver and in the gut microbiota that prime KC/TLR responses, inflamed adipose tissue and circulating inflammatory cells. We briefly review these mechanistic considerations and project their implications for the effective treatment of NASH. PMID:22570745

Corticotropin-releasing factor receptor-1 antagonism mitigates beta amyloid pathology and cognitive and synaptic deficits in a mouse model of Alzheimer's disease.

PubMed

Zhang, Cheng; Kuo, Ching-Chang; Moghadam, Setareh H; Monte, Louise; Campbell, Shannon N; Rice, Kenner C; Sawchenko, Paul E; Masliah, Eliezer; Rissman, Robert A

2016-05-01

Stress and corticotropin-releasing factor (CRF) have been implicated as mechanistically involved in Alzheimer's disease (AD), but agents that impact CRF signaling have not been carefully tested for therapeutic efficacy or long-term safety in animal models. To test whether antagonism of the type-1 corticotropin-releasing factor receptor (CRFR1) could be used as a disease-modifying treatment for AD, we used a preclinical prevention paradigm and treated 30-day-old AD transgenic mice with the small-molecule, CRFR1-selective antagonist, R121919, for 5 months, and examined AD pathologic and behavioral end points. R121919 significantly prevented the onset of cognitive impairment in female mice and reduced cellular and synaptic deficits and beta amyloid and C-terminal fragment-β levels in both genders. We observed no tolerability or toxicity issues in mice treated with R121919. CRFR1 antagonism presents a viable disease-modifying therapy for AD, recommending its advancement to early-phase human safety trials. Copyright © 2015 Alzheimer's Association. All rights reserved.

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…

Mechanistic insights into the role of mTOR signaling in neuronal differentiation.

PubMed

Bateman, Joseph M

2015-01-01

Temporal control of neuronal differentiation is critical to produce a complete and fully functional nervous system. Loss of the precise temporal control of neuronal cell fate can lead to defects in cognitive development and to disorders such as epilepsy and autism. Mechanistic target of rapamycin (mTOR) is a large serine/threonine kinase that acts as a crucial sensor of cellular homeostasis. mTOR signaling has recently emerged as a key regulator of neurogenesis. However, the mechanism by which mTOR regulates neurogenesis is poorly understood. In constrast to other functions of the pathway, 'neurogenic mTOR pathway factors' have not previously been identified. We have very recently used Drosophila as a model system to identify the gene unkempt as the first component of the mTOR pathway regulating neuronal differentiation. Our study demonstrates that specific adaptor proteins exist that channel mTOR signaling toward the regulation of neuronal cell fate. In this Commentary we discuss the role of mTOR signaling in neurogenesis and the significance of these findings in advancing our understanding of the mechanism by which mTOR signaling controls neuronal differentiation.

On the evolution of specialization with a mechanistic underpinning in structured metapopulations.

PubMed

Nurmi, Tuomas; Parvinen, Kalle

2008-03-01

We analyze the evolution of specialization in resource utilization in a discrete-time metapopulation model using the adaptive dynamics approach. The local dynamics in the metapopulation are based on the Beverton-Holt model with mechanistic underpinnings. The consumer faces a trade-off in the abilities to consume two resources that are spatially heterogeneously distributed to patches that are prone to local catastrophes. We explore the factors favoring the spread of generalist or specialist strategies. Increasing fecundity or decreasing catastrophe probability favors the spread of the generalist strategy and increasing environmental heterogeneity enlarges the parameter domain where the evolutionary branching is possible. When there are no catastrophes, increasing emigration diminishes the parameter domain where the evolutionary branching may occur. Otherwise, the effect of emigration on evolutionary dynamics is non-monotonous: both small and large values of emigration probability favor the spread of the specialist strategies whereas the parameter domain where evolutionary branching may occur is largest when the emigration probability has intermediate values. We compare how different forms of spatial heterogeneity and different models of local growth affect the evolutionary dynamics. We show that even small changes in the resource dynamics may have outstanding evolutionary effects to the consumers.

Mechanistic modeling of thermo-hydrological processes and microbial interactions at pore to profile scales resolve methane emission dynamics from permafrost soil

NASA Astrophysics Data System (ADS)

Ebrahimi, Ali; Or, Dani

2017-04-01

The sensitivity of the Earth's polar regions to raising global temperatures is reflected in rapidly changing hydrological processes with pronounced seasonal thawing of permafrost soil and increased biological activity. Of particular concern is the potential release of large amounts of soil carbon and the stimulation of other soil-borne GHG emissions such as methane. Soil methanotrophic and methanogenic microbial communities rapidly adjust their activity and spatial organization in response to permafrost thawing and a host of other environmental factors. Soil structural elements such as aggregates and layering and hydration status affect oxygen and nutrient diffusion processes thereby contributing to methanogenic activity within temporal anoxic niches (hotspots or hot-layers). We developed a mechanistic individual based model to quantify microbial activity dynamics within soil pore networks considering, hydration, temperature, transport processes and enzymatic activity associated with methane production in soil. The model was the upscaled from single aggregates (or hotspots) to quantifying emissions from soil profiles in which freezing/thawing processes provide macroscopic boundary conditions for microbial activity at different soil depths. The model distinguishes microbial activity in aerate bulk soil from aggregates (or submerged parts of the profile) for resolving methane production and oxidation rates. Methane transport pathways through soil by diffusion and ebullition of bubbles vary with hydration dynamics and affect emission patterns. The model links seasonal thermal and hydrologic dynamics with evolution of microbial community composition and function affecting net methane emissions in good agreement with experimental data. The mechanistic model enables systematic evaluation of key controlling factors in thawing permafrost and microbial response (e.g., nutrient availability, enzyme activity, PH) on long term methane emissions and carbon decomposition rates

Promyelocytic Leukemia Protein Is a Cell-Intrinsic Factor Inhibiting Parvovirus DNA Replication

PubMed Central

Mitchell, Angela M.; Hirsch, Matthew L.; Li, Chengwen

2014-01-01

Tripartite motif proteins are important viral restriction factors and affect processes ranging from uncoating to transcription to immune signaling. Specifically, the promyelocytic leukemia protein (TRIM19; also called PML) is a viral restriction factor inhibiting processes from uncoating to transcription to cell survival. Here we investigated PML's effect on adeno-associated virus (AAV), a parvovirus used for gene delivery. Although dependovirus (AAV) and autonomous parvovirus (minute virus of mice) replication centers can colocalize with PML, PML's functional effect on parvoviruses is unknown. Using PML knockout mice, we determined that PML knockout enhances recombinant AAV2 (rAAV2) transduction at a range of vector doses in both male and female mice. In fact, male and female PML knockout mice exhibited up to 56-fold and 28-fold increases in transduction, respectively. PML inhibited several rAAV serotypes, suggesting a conserved mechanism, and organ specificity correlated with PML expression. Mechanistically, PML inhibited rAAV second-strand DNA synthesis, precluding inhibition of self-complementary rAAV, and did not affect the prior steps in transduction. Furthermore, we confirmed the effect of human PML on rAAV transduction through small interfering RNA (siRNA)-mediated knockdown in HuH7 cells and determined that the highest level of inhibition was due to effects of PML isoform II (PMLII). Overexpression of PMLII resulted in inhibition of second-strand synthesis, vector production, and genome replication. Moreover, wild-type AAV2 production and infectivity were also inhibited by PMLII, demonstrating a PML interaction with wild-type AAV. These data have important implications for AAV-mediated gene therapy. Additionally, PMLII inhibition of AAV second-strand synthesis and replication, which are processes necessary for all parvoviruses, suggests implications for replication of other parvoviruses. PMID:24198403

Promyelocytic leukemia protein is a cell-intrinsic factor inhibiting parvovirus DNA replication.

PubMed

Mitchell, Angela M; Hirsch, Matthew L; Li, Chengwen; Samulski, R Jude

2014-01-01

Tripartite motif proteins are important viral restriction factors and affect processes ranging from uncoating to transcription to immune signaling. Specifically, the promyelocytic leukemia protein (TRIM19; also called PML) is a viral restriction factor inhibiting processes from uncoating to transcription to cell survival. Here we investigated PML's effect on adeno-associated virus (AAV), a parvovirus used for gene delivery. Although dependovirus (AAV) and autonomous parvovirus (minute virus of mice) replication centers can colocalize with PML, PML's functional effect on parvoviruses is unknown. Using PML knockout mice, we determined that PML knockout enhances recombinant AAV2 (rAAV2) transduction at a range of vector doses in both male and female mice. In fact, male and female PML knockout mice exhibited up to 56-fold and 28-fold increases in transduction, respectively. PML inhibited several rAAV serotypes, suggesting a conserved mechanism, and organ specificity correlated with PML expression. Mechanistically, PML inhibited rAAV second-strand DNA synthesis, precluding inhibition of self-complementary rAAV, and did not affect the prior steps in transduction. Furthermore, we confirmed the effect of human PML on rAAV transduction through small interfering RNA (siRNA)-mediated knockdown in HuH7 cells and determined that the highest level of inhibition was due to effects of PML isoform II (PMLII). Overexpression of PMLII resulted in inhibition of second-strand synthesis, vector production, and genome replication. Moreover, wild-type AAV2 production and infectivity were also inhibited by PMLII, demonstrating a PML interaction with wild-type AAV. These data have important implications for AAV-mediated gene therapy. Additionally, PMLII inhibition of AAV second-strand synthesis and replication, which are processes necessary for all parvoviruses, suggests implications for replication of other parvoviruses.

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

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.

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...

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...

Expression of receptors for putative anabolic growth factors in human intervertebral disc: implications for repair and regeneration of the disc.

PubMed

Le Maitre, Christine L; Richardson, Stephen M A; Baird, Pauline; Freemont, Anthony J; Hoyland, Judith A

2005-12-01

Low back pain (LBP) is a common, debilitating and economically important disorder. Current evidence implicates loss of intervertebral disc (IVD) matrix consequent upon 'degeneration' as a major cause of LBP. Degeneration of the IVD involves increases in degradative enzymes and decreases in the extracellular matrix (ECM) component in a process that is controlled by a range of cytokines and growth factors. Studies have suggested using anabolic growth factors to regenerate the normal matrix of the IVD, hence restoring disc height and reversing degenerative disc disease. However, for such therapies to be successful it is vital that the target cells (i.e. the disc cells) express the appropriate receptors. This immunohistochemical study has for the first time investigated the expression and localization of four potentially beneficial growth factor receptors (i.e. TGFbetaRII, BMPRII, FGFR3 and IGFRI) in non-degenerate and degenerate human IVDs. Receptor expression was quantified across regions of the normal and degenerate disc and showed that cells of the nucleus pulposus (NP) and inner annulus fibrosus (IAF) expressed significantly higher levels of the four growth factor receptors investigated. There were no significant differences between the four growth factor expression in non-degenerate and degenerate biopsies. However, expression of TGFbetaRII, FGFR3 and IGFRI, but not BMP RII, were observed in the ingrowing blood vessels that characterize part of the disease aetiology. In conclusion, this study has demonstrated the expression of the four growth factor receptors at similar levels in the chondrocyte-like cells of the NP and IAF in both non-degenerate and degenerate discs, implicating a role in normal disc homeostasis and suggesting that the application of these growth factors to the degenerate human IVD would stimulate matrix production. However, the expression of some of the growth factor receptors on ingrowing blood vessels might be problematic in a therapeutic

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.

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

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

Influence of landscape-scale factors in limiting brook trout populations in Pennsylvania streams

USGS Publications Warehouse

Kocovsky, P.M.; Carline, R.F.

2006-01-01

Landscapes influence the capacity of streams to produce trout through their effect on water chemistry and other factors at the reach scale. Trout abundance also fluctuates over time; thus, to thoroughly understand how spatial factors at landscape scales affect trout populations, one must assess the changes in populations over time to provide a context for interpreting the importance of spatial factors. We used data from the Pennsylvania Fish and Boat Commission's fisheries management database to investigate spatial factors that affect the capacity of streams to support brook trout Salvelinus fontinalis and to provide models useful for their management. We assessed the relative importance of spatial and temporal variation by calculating variance components and comparing relative standard errors for spatial and temporal variation. We used binary logistic regression to predict the presence of harvestable-length brook trout and multiple linear regression to assess the mechanistic links between landscapes and trout populations and to predict population density. The variance in trout density among streams was equal to or greater than the temporal variation for several streams, indicating that differences among sites affect population density. Logistic regression models correctly predicted the absence of harvestable-length brook trout in 60% of validation samples. The r 2-value for the linear regression model predicting density was 0.3, indicating low predictive ability. Both logistic and linear regression models supported buffering capacity against acid episodes as an important mechanistic link between landscapes and trout populations. Although our models fail to predict trout densities precisely, their success at elucidating the mechanistic links between landscapes and trout populations, in concert with the importance of spatial variation, increases our understanding of factors affecting brook trout abundance and will help managers and private groups to protect and

Thermal relationships and exercise physiology in anuran amphibians: integration and evolutionary implications.

PubMed

Navas, Carlos A; Gomes, Fernando R; Carvalho, José Eduardo

2008-11-01

Thermal and water balance are coupled in anurans, and species with particularly permeable skin avoid overheating more effectively than minimizing variance of body temperature. In turn, temperature affects muscle performance in several ways, so documenting the mean and variance of body temperature of active frogs can help explain variation in behavioral performance. The two types of activities studied in most detail, jumping and calling, differ markedly in duration and intensity, and there are distinct differences in the metabolic profile and fiber type of the supporting muscles. Characteristics of jumping and calling also vary significantly among species, and these differences have a number of implications that we discuss in some detail throughout this paper. One question that emerges from this topic is whether anuran species exhibit activity temperatures that match the temperature range over which they perform best. Although this seems the case, thermal preferences are variable and may not necessarily reflect typical activity temperatures. The performance versus temperature curves and the thermal limits for anuran activity reflect the thermal ecology of species more than their systematic position. Anuran thermal physiology, therefore, seems to be phenotypically plastic and susceptible to adaptive evolution. Although generalizations regarding the mechanistic basis of such adjustments are not yet possible, recent attempts have been made to reveal the mechanistic basis of acclimation and acclimatization.

Unification and mechanistic detail as drivers of model construction: models of networks in economics and sociology.

PubMed

Kuorikoski, Jaakko; Marchionni, Caterina

2014-12-01

We examine the diversity of strategies of modelling networks in (micro) economics and (analytical) sociology. Field-specific conceptions of what explaining (with) networks amounts to or systematic preference for certain kinds of explanatory factors are not sufficient to account for differences in modelling methodologies. We argue that network models in both sociology and economics are abstract models of network mechanisms and that differences in their modelling strategies derive to a large extent from field-specific conceptions of the way in which a good model should be a general one. Whereas the economics models aim at unification, the sociological models aim at a set of mechanism schemas that are extrapolatable to the extent that the underlying psychological mechanisms are general. These conceptions of generality induce specific biases in mechanistic explanation and are related to different views of when knowledge from different fields should be seen as relevant.

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).

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.

Exposure to thermal degradation products arising from fire or smoke could be a major concern for manned space missions. Severe acute lung damage has been reported in people after accidental exposure to fumes from plastic materials, and animal studies revealed the extremely high toxicity of freshly generated fumes whereas a decrease in toxicity of aged fumes has been found. This and the fact that toxicity of the freshly generated fumes can be prevented with filters raises the question whether the toxicity may be due to the particulate rather than the gas phase components of the thermodegradation products. Indeed, results from recent studies implicate ultrafine particles (particle diameter in the nm range) as potential severe pulmonary toxicants. We have conducted a number of in vivo (inhalation and instillation studies in rats) and in vitro studies to test the hypothesis that ultrafine particles possess an increased potential to injure the lung compared to larger-sized particles. We used as surrogate particles ultrafine TiO 2 particles (12 and 20 nm diameter). Results in exposed rats showed that the ultrafine TiO 2 particles not only induce a greater acute inflammatory reaction in the lung than larger-sized TiO 2 particles, but can also lead to persistent chronic effects, as indicated by an adverse effect on alveolar macrophage mediated clearance function of particles. Release of mediators from alveolar macrophages during phagocytosis of the ultrafine particles and an increased access of the ultrafine particles to the pulmonary interstitium are likely factors contributing to their pulmonary toxicity. In vitro studies with lung cells (alveolar macrophages) showed, in addition, that ultrafine TiO 2 particles have a greater potential to induce cytokines than larger-sized particles. We conclude from our present studies that ultrafine particles have a significant potential to injure the lung and that their occurrence in thermal degradation events can play a major role in

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...

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.

A critical examination of the U.S. nursing shortage: contributing factors, public policy implications.

PubMed

Fox, Rebekah L; Abrahamson, Kathleen

2009-01-01

BACKGROUND. Despite short-lived periods of adequacy in nurse availability, the nursing shortage has endured. In order to better understand the myriad factors that influence the current shortage of nurses, as well as possible solutions, this project addresses the influence of social factors and government policy on nurse staffing inadequacy. When the government intervenes in a philosophically free-market economy, the assumption is that a problem, such as the current nursing shortage, could not be solved without such intervention. PURPOSE. Nursing care arguably falls into the realm of protecting the common good, and therefore requires government oversight. We provide a critical analysis of policy intervention efforts into the nursing shortage debate by examining the passage of legislation, the provision of educational assistance, and the establishment of minimum staffing requirements and minimum quality standards for reimbursement, which all impact nursing supply and demand. RESULTS. Arguments supporting and opposing policy intervention in general, and its impact on the overall provision of nursing care in the United States, were examined. Without policy incentive to place financial value on the quality of care provided by nurses, a simple increase in the number of available nurses is unlikely to solve the current problem. IMPLICATIONS. Important considerations that should be factored into policy creation include measurement and compensation for quality care, the nature of recruitment efforts of new nurses, and the complex nature of a nursing work.

Mechanistic kinetic models of enzymatic cellulose hydrolysis-A review.

PubMed

Jeoh, Tina; Cardona, Maria J; Karuna, Nardrapee; Mudinoor, Akshata R; Nill, Jennifer

2017-07-01

Bioconversion of lignocellulose forms the basis for renewable, advanced biofuels, and bioproducts. Mechanisms of hydrolysis of cellulose by cellulases have been actively studied for nearly 70 years with significant gains in understanding of the cellulolytic enzymes. Yet, a full mechanistic understanding of the hydrolysis reaction has been elusive. We present a review to highlight new insights gained since the most recent comprehensive review of cellulose hydrolysis kinetic models by Bansal et al. (2009) Biotechnol Adv 27:833-848. Recent models have taken a two-pronged approach to tackle the challenge of modeling the complex heterogeneous reaction-an enzyme-centric modeling approach centered on the molecularity of the cellulase-cellulose interactions to examine rate limiting elementary steps and a substrate-centric modeling approach aimed at capturing the limiting property of the insoluble cellulose substrate. Collectively, modeling results suggest that at the molecular-scale, how rapidly cellulases can bind productively (complexation) and release from cellulose (decomplexation) is limiting, while the overall hydrolysis rate is largely insensitive to the catalytic rate constant. The surface area of the insoluble substrate and the degrees of polymerization of the cellulose molecules in the reaction both limit initial hydrolysis rates only. Neither enzyme-centric models nor substrate-centric models can consistently capture hydrolysis time course at extended reaction times. Thus, questions of the true reaction limiting factors at extended reaction times and the role of complexation and decomplexation in rate limitation remain unresolved. Biotechnol. Bioeng. 2017;114: 1369-1385. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

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.

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

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).

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.

Mechanistic studies of high-density lipoproteins.

PubMed

Kashyap, M L

1998-12-17

There is increasing evidence that high-density lipoprotein (HDL) and its subfractions are protective against atherosclerotic cardiovascular disease. Physical exercise, weight reduction, smoking cessation, diabetes mellitus control, and specific drugs, including niacin, fibrates, and estrogens, are effective methods to increase HDL levels. Niacin is the oldest and most powerful clinical agent for raising HDL levels. Niaspan, an extended-release niacin formulation, is as potent as immediate-release niacin in increasing levels of HDL cholesterol; subfractions HDL2 and HDL3; apolipoprotein A-I, the major protein of HDL, and its cardioprotective subfraction lipoprotein A-I. Recent research from our laboratory suggests a novel mechanism by which niacin inhibits hepatic removal of HDL-apoprotein A-I without interfering with the removal of cholesterol carried by HDL, thus augmenting reverse cholesterol transport. Other mechanistic studies indicate that fibrates and estrogens stimulate the synthesis and production of HDL-apoprotein A-I. Because niacin decreases HDL-apoprotein A-I removal, and fibrates and estrogens increase HDL-apoprotein A-I production, combinations of niacin with these agents may raise HDL levels more than fibrates or estrogens alone.

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

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...

Application of response surface methodology and semi-mechanistic model to optimize fluoride removal using crushed concrete in a fixed-bed column.

PubMed

Gu, Bon-Wun; Lee, Chang-Gu; Park, Seong-Jik

2018-03-01

The aim of this study was to investigate the removal of fluoride from aqueous solutions by using crushed concrete fines as a filter medium under varying conditions of pH 3-7, flow rate of 0.3-0.7 mL/min, and filter depth of 10-20 cm. The performance of fixed-bed columns was evaluated on the basis of the removal ratio (Re), uptake capacity (qe), degree of sorbent used (DoSU), and sorbent usage rate (SUR) obtained from breakthrough curves (BTCs). Three widely used semi-mechanistic models, that is, Bohart-Adams, Thomas, and Yoon-Nelson models, were applied to simulate the BTCs and to derive the design parameters. The Box-Behnken design of response surface methodology (RSM) was used to elucidate the individual and interactive effects of the three operational parameters on the column performance and to optimize these parameters. The results demonstrated that pH is the most important factor in the performance of fluoride removal by a fixed-bed column. The flow rate had a significant negative influence on Re and DoSU, and the effect of filter depth was observed only in the regression model for DoSU. Statistical analysis indicated that the model attained from the RSM study is suitable for describing the semi-mechanistic model parameters.

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...

The CoFactor database: organic cofactors in enzyme catalysis.

PubMed

Fischer, Julia D; Holliday, Gemma L; Thornton, Janet M

2010-10-01

Organic enzyme cofactors are involved in many enzyme reactions. Therefore, the analysis of cofactors is crucial to gain a better understanding of enzyme catalysis. To aid this, we have created the CoFactor database. CoFactor provides a web interface to access hand-curated data extracted from the literature on organic enzyme cofactors in biocatalysis, as well as automatically collected information. CoFactor includes information on the conformational and solvent accessibility variation of the enzyme-bound cofactors, as well as mechanistic and structural information about the hosting enzymes. The database is publicly available and can be accessed at http://www.ebi.ac.uk/thornton-srv/databases/CoFactor.

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...

A review of factors that affect contact angle and implications for flotation practice.

PubMed

Chau, T T; Bruckard, W J; Koh, P T L; Nguyen, A V

2009-09-30

Contact angle and the wetting behaviour of solid particles are influenced by many physical and chemical factors such as surface roughness and heterogeneity as well as particle shape and size. A significant amount of effort has been invested in order to probe the correlation between these factors and surface wettability. Some of the key investigations reported in the literature are reviewed here. It is clear from the papers reviewed that, depending on many experimental conditions such as the size of the surface heterogeneities and asperities, surface cleanliness, and the resolution of measuring equipment and data interpretation, obtaining meaningful contact angle values is extremely difficult and such values are reliant on careful experimental control. Surface wetting behaviour depends on not only surface texture (roughness and particle shape), and surface chemistry (heterogeneity) but also on hydrodynamic conditions in the preparation route. The inability to distinguish the effects of each factor may be due to the interplay and/or overlap of two or more factors in each system. From this review, it was concluded that: Surface geometry (and surface roughness of different scales) can be used to tune the contact angle; with increasing surface roughness the apparent contact angle decreases for hydrophilic materials and increases for hydrophobic materials. For non-ideal surfaces, such as mineral surfaces in the flotation process, kinetics plays a more important role than thermodynamics in dictating wettability. Particle size encountered in flotation (10-200 microm) showed no significant effect on contact angle but has a strong effect on flotation rate constant. There is a lack of a rigid quantitative correlation between factors affecting wetting, wetting behaviour and contact angle on minerals; and hence their implication for flotation process. Specifically, universal correlation of contact angle to flotation recovery is still difficult to predict from first principles

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

Relationship between Audio-Visual Materials and Environmental Factors on Students Academic Performance in Senior Secondary Schools in Borno State: Implications for Counselling

ERIC Educational Resources Information Center

Bello, S.; Goni, Umar

2016-01-01

This is a survey study, designed to determine the relationship between audio-visual materials and environmental factors on students' academic performance in Senior Secondary Schools in Borno State: Implications for Counselling. The study set two research objectives, and tested two research hypotheses. The population of this study is 1,987 students…

Factors implicated in the initiation of human parturition in term and preterm labor: a review.

PubMed

Ravanos, Konstantinos; Dagklis, Themistoklis; Petousis, Stamatios; Margioula-Siarkou, Chrysoula; Prapas, Yannis; Prapas, Nikolaos

2015-01-01

After accommodating the pregnancy for an average of 40 weeks, the uterus expels the fetus, the placenta and the membranes through the birth canal in a process named parturition. The absolute sequence of events that trigger and sustain human parturition are not yet fully clarified. Evidence suggests that spontaneous preterm and term labor seem to share a common inflammatory pathway. However, there are several other factors being involved in the initiation of human parturition. Placental corticotropin releasing hormone production seems to serve as a placental clock that might be set to ring earlier or later determining the duration of pregnancy and timing of labor. Estrogens do not cause contractions but their properties seem to capacitate uterus to coordinate and enhance contractions. Cytokines, prostaglandins, nitric oxide and steroids seem also to induce ripening by mediating remodeling of the extracellular matrix and collagen. Infection and microbe invasion resulting in chorioamnionitis also represents a common cause of early preterm labour. This review provides an overview of all these factors considered to be implicated in the initiation of human parturition.

The Microbiome and Complement Activation: A Mechanistic Model for Preterm Birth

PubMed Central

Dunn, Alexis B.; Dunlop, Anne L.; Hogue, Carol J.; Miller, Andrew; Corwin, Elizabeth J.

2018-01-01

Preterm Birth (PTB, < 37 completed weeks' gestation) is one of the leading obstetrical problems in the United States affecting approximately 1 of every 9 births. Even more concerning are the persistent racial disparities in PTB with particularly high rates in African Americans. There are several recognized pathophysiologic pathways to PTB, including infection and/or exaggerated systemic or local inflammation. Intrauterine infection is a causal factor linked to PTB, thought to result most commonly from inflammatory processes triggered by microbial invasion of bacteria ascending from the vaginal microbiome. Trials to treat various infections have shown limited efficacy in reducing PTB risk, suggesting that other complex mechanisms, including those associated with inflammation, may be involved in the relationship between microbes, infection, and PTB. A key mediator of the inflammatory response, and recently shown to be associated with PTB, is the complement system, an innate defense mechanism involved in both normal physiologic processes that occur during pregnancy implantation, as well as processes that promote the elimination of pathogenic microbes. The purpose of this paper is to present a mechanistic model of inflammation-associated PTB, which hypothesizes a relationship between the microbiome and dysregulation of the complement system. Exploring the relationships between the microbial environment and complement biomarkers may elucidate a potentially modifiable biological pathway to preterm birth. PMID:28073296

Mechanistic impact of outdoor air pollution on asthma and allergic diseases

PubMed Central

Zhang, Qingling; Qiu, Zhiming; Chung, Kian Fan

2015-01-01

Over the past decades, asthma and allergic diseases, such as allergic rhinitis and eczema, have become increasingly common, but the reason for this increased prevalence is still unclear. It has become apparent that genetic variation alone is not sufficient to account for the observed changes; rather, the changing environment, together with alterations in lifestyle and eating habits, are likely to have driven the increase in prevalence, and in some cases, severity of disease. This is particularly highlighted by recent awareness of, and concern about, the exposure to ubiquitous environmental pollutants, including chemicals with oxidant-generating capacities, and their impact on the human respiratory and immune systems. Indeed, several epidemiological studies have identified a variety of risk factors, including ambient pollutant gases and airborne particles, for the prevalence and the exacerbation of allergic diseases. However, the responsible pollutants remain unclear and the causal relationship has not been established. Recent studies of cellular and animal models have suggested several plausible mechanisms, with the most consistent observation being the direct effects of particle components on the generation of reactive oxygen species (ROS) and the resultant oxidative stress and inflammatory responses. This review attempts to highlight the experimental findings, with particular emphasis on several major mechanistic events initiated by exposure to particulate matters (PMs) in the exposure-disease relationship. PMID:25694815

Development of a Mechanistic-Based Healing Model for Self-Healing Glass Seals

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

Xu, Wei; Stephens, Elizabeth V.; Sun, Xin

Self-healing glass, a recent development of hermetic sealant materials, has the ability to effectively repair damage when heated to elevated temperatures; thus, able to extend its service life. Since crack healing morphological changes in the glass material are usually temperature and stress dependent, quantitative studies to determine the effects of thermo-mechanical conditions on the healing behavior of the self-healing glass sealants are extremely useful to accommodate the design and optimization of the sealing systems within SOFCs. The goal of this task is to develop a mechanistic-based healing model to quantify the stress and temperature dependent healing behavior. A two-step healingmore » mechanism was developed and implemented into finite element (FE) models through user-subroutines. Integrated experimental/kinetic Monte Carlo (kMC) simulation methodology was taken to calibrate the model parameters. The crack healing model is able to investigate the effects of various thermo-mechanical factors; therefore, able to determine the critical conditions under which the healing mechanism will be activated. Furthermore, the predicted results can be used to formulate the continuum damage-healing model and to assist the SOFC stack level simulations in predicting and evaluating the effectiveness and the performance of various engineering seal designs.« less

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...

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

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,…

Antimony photoresists for EUV lithography: mechanistic studies

NASA Astrophysics Data System (ADS)

Murphy, Michael; Narasimhan, Amrit; Grzeskowiak, Steven; Sitterly, Jacob; Schuler, Philip; Richards, Jeff; Denbeaux, Greg; Brainard, Robert L.

2017-03-01

We have developed a method to study the photomechanism of our antimony carboxylate platform R3Sb(COOR')2. A series of mechanistic studies followed the production of reaction byproducts by mass spectrometer, as they left the film during exposure to EUV photons and 80 eV electrons. We identified several prominent outgassing fragments and their rates of production as a function of ligand structure. The degree of outgassing appears to be well-correlated with the bond dissociation energy of the carboxylate ligand R' group. Furthermore, a deuterium labeling study was conducted to determine from which ligand hydrogen is abstracted to form benzene and phenol during exposure. Benzene and phenol were found to abstract hydrogen from opposing sites within the film, and with greater than 95% isotopic purity. Using the results of the outgassing studies alongside established mechanisms for electron-induced reactions; a series of reaction pathways were proposed to generate the aforementioned outgassing species and a possible nonvolatile negative-tone photoproduct.

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.

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.

Cadmium dynamics in the rhizosphere and Cd uptake of different plant species evaluated by a mechanistic model.

PubMed

Stritsis, Christos; Steingrobe, Bernd; Claassen, Norbert

2014-01-01

Maize, sunflower,flax, and spinach differed in the accumulation of Cd when grown on a Cd contaminated soil. This was mainly due to the different Cd net influx, In, that varied among species by a factor of up to 30. The objective of this study was to find possible reasons for the different Cd In by using a mechanistic model. After 14 days of Cd uptake the model calculated only a small Cd depletion at the root surface, e.g. from 0.22 mumol L(-1) down to 0.19 mumol L(-1) for maize and from 0.48 mumol L(-1) down to 0.35 mumol L(-1)for spinach. Even so the model always overestimated the Cd I(n), for spinach by a factor of 1.5 and for maize by a factor of 10. Only simulating a decrease of C(Li) or the root absorbing power, alpha, by 40% to 90% gave an agreement of calculated and measured I(n),. This may be interpreted as that about 40% in the case of spinach and 90% in the case of maize of the Cd in soil solution were not accessible for plant uptake. The high sensitivity to alpha also shows that not the Cd transport to the root but alpha was limiting the step for Cd uptake.

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

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...

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

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

Risk factors, causes, and the economic implications of unplanned readmissions following total hip arthroplasty.

PubMed

Clement, Rutledge Carter; Derman, Peter B; Graham, Danielle S; Speck, Rebecca M; Flynn, David N; Levin, Lawrence Scott; Fleisher, Lee A

2013-09-01

In order to identify risk factors for readmissions following total hip arthroplasty (THA) and the causes and financial implications of such readmissions, we analyzed clinical and administrative data on 1583 consecutive primary THAs performed at a single institution. The 30-day readmission rate was 6.51%. Increased age, length of stay, and body mass index were associated with significantly higher readmission rates. The most common re-admitting diagnoses were deep infection, pain, and hematoma. Average profit was lower for episodes of care with readmissions ($1548 vs. $2872, P=0.028). If Medicare stops reimbursing for THA readmissions, the institution under review would sustain an average net loss of $11,494 for episodes of care with readmissions and would need to maintain readmission rates below 23.6% in order to remain profitable. © 2013 Elsevier Inc. All rights reserved.

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...

Connective tissue growth factor and bone morphogenetic protein 2 are induced following myocardial ischemia in mice and humans.

PubMed

Rutkovskiy, Arkady; Sagave, Julia; Czibik, Gabor; Baysa, Anton; Zihlavnikova Enayati, Katarina; Hillestad, Vigdis; Dahl, Christen Peder; Fiane, Arnt; Gullestad, Lars; Gravning, Jørgen; Ahmed, Shakil; Attramadal, Håvard; Valen, Guro; Vaage, Jarle

2017-09-01

We aimed to study the cardiac expression of bone morphogenetic protein 2, its receptor 1 b, and connective tissue growth factor, factors implicated in cardiac embryogenesis, following ischemia/hypoxia, heart failure, and in remodeling hearts from humans and mice. Biopsies from the left ventricle of patients with end-stage heart failure due to dilated cardiomyopathy or coronary artery disease were compared with donor hearts and biopsies from patients with normal heart function undergoing coronary artery bypass grafting. Mouse model of post-infarction remodeling was made by permanent ligation of the left coronary artery. Hearts were analyzed by real-time polymerase chain reaction and Western blotting after 24 hours and after 2 and 4 weeks. Patients with dilated cardiomyopathy and mice post-infarction had increased cardiac expression of connective tissue growth factor. Bone morphogenetic protein 2 was increased in human hearts failing due to coronary artery disease and in mice post-infarction. Gene expression of bone morphogenetic protein receptor 1 beta was reduced in hearts of patients with failure, but increased two weeks following permanent ligation of the left coronary artery in mice. In conclusion, connective tissue growth factor is upregulated in hearts of humans with dilated cardiomyopathy, bone morphogenetic protein 2 is upregulated in remodeling due to myocardial infarction while its receptor 1 b in human failing hearts is downregulated. A potential explanation might be an attempt to engage regenerative processes, which should be addressed by further, mechanistic studies.

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

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...

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.

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...

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

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

Mechanistic approach to understanding the toxicity of the azole fungicide triadimefon to a nontarget aquatic insect and implications for exposure assessment.

PubMed

Kenneke, John F; Mazur, Christopher S; Kellock, Kristen A; Overmyer, Jay P

2009-07-15

Mechanistic and stereoselective based in vitro metabolism assays were utlilized to gain insight into the toxic mode of action of the 1,2,4-triazole fungicide, triadimefon, with black fly (Diptera: Simuliidae) larvae. Based on results from enzyme inhibitor studies, the metabolism of triadimefon in black fly larvae microsomes was found to occur predominantly via an oxidative P450-mediated pathway; triadimenol was formed via the stereoselective reduction of the prochiral carbonyl group of triadimefon. The relatively minor contribution of carbonyl reduction suggests that triadimefon may inhibit ecdysone 20-monooxygenase and disrupt insect molting hormone biosynthesis. 48-h LC50 tests for triadimefon and triadimenol with black fly larvae yielded median values (with 95% confidence intervals) of 6.1 (5.8-6.4) and 22.3 (20.3-24.1) mg/L respectively. The exposure of black fly larvae to sublethal concentrations of triadimefon resulted in increased microsomal P450 activity and affected the microsomal rates of both triadimefon depletion and triadimenol formation. In contrast to trout, black fly larvae produced a higher fraction of the more toxic triadimenol stereoisomers, which may explain in part why triadimefon exhibited a significantly greater toxicity with black fly larvae than trout. These results illustrate that while LC50 tests conducted with commercial triadimenol would presumably expose each organism to the same relative abundance of the four triadimenol stereoisomers, LC50 tests with triadimefon ultimately expose each organism to a unique set of triadimenol stereoisomers depending upon the organism's stereoselective metabolism.

Individual, employment and psychosocial factors influencing walking to work: Implications for intervention design

PubMed Central

Esliger, Dale W.; Taylor, Ian M.; Sherar, Lauren B.

2017-01-01

Background Promoting walking for the journey to and from work (commuter walking) is a potential strategy for increasing physical activity. Understanding the factors influencing commuter walking is important for identifying target groups and designing effective interventions. This study aimed to examine individual, employment-related and psychosocial factors associated with commuter walking and to discuss the implications for targeting and future design of interventions. Methods 1,544 employees completed a baseline survey as part of the ‘Walking Works’ intervention project (33.4% male; 36.3% aged <30 years). Multivariate logistic regression was used to examine the associations of individual (age, ethnic group, educational qualifications, number of children <16 and car ownership), employment-related (distance lived from work, free car parking at work, working hours, working pattern and occupation) and psychosocial factors (perceived behavioural control, intention, social norms and social support from work colleagues) with commuter walking. Results Almost half of respondents (n = 587, 49%) were classified as commuter walkers. Those who were aged <30 years, did not have a car, had no free car parking at work, were confident of including some walking or intended to walk to or from work on a regular basis, and had support from colleagues for walking were more likely to be commuter walkers. Those who perceived they lived too far away from work to walk, thought walking was less convenient than using a car for commuting, did not have time to walk, needed a car for work or had always travelled the same way were less likely to be commuter walkers. Conclusions A number of individual, employment-related and psychosocial factors were associated with commuter walking. Target groups for interventions to promote walking to and from work may include those in older age groups and those who own or have access to a car. Multi-level interventions targeting individual level behaviour

Individual, employment and psychosocial factors influencing walking to work: Implications for intervention design.

PubMed

Adams, Emma J; Esliger, Dale W; Taylor, Ian M; Sherar, Lauren B

2017-01-01

Promoting walking for the journey to and from work (commuter walking) is a potential strategy for increasing physical activity. Understanding the factors influencing commuter walking is important for identifying target groups and designing effective interventions. This study aimed to examine individual, employment-related and psychosocial factors associated with commuter walking and to discuss the implications for targeting and future design of interventions. 1,544 employees completed a baseline survey as part of the 'Walking Works' intervention project (33.4% male; 36.3% aged <30 years). Multivariate logistic regression was used to examine the associations of individual (age, ethnic group, educational qualifications, number of children <16 and car ownership), employment-related (distance lived from work, free car parking at work, working hours, working pattern and occupation) and psychosocial factors (perceived behavioural control, intention, social norms and social support from work colleagues) with commuter walking. Almost half of respondents (n = 587, 49%) were classified as commuter walkers. Those who were aged <30 years, did not have a car, had no free car parking at work, were confident of including some walking or intended to walk to or from work on a regular basis, and had support from colleagues for walking were more likely to be commuter walkers. Those who perceived they lived too far away from work to walk, thought walking was less convenient than using a car for commuting, did not have time to walk, needed a car for work or had always travelled the same way were less likely to be commuter walkers. A number of individual, employment-related and psychosocial factors were associated with commuter walking. Target groups for interventions to promote walking to and from work may include those in older age groups and those who own or have access to a car. Multi-level interventions targeting individual level behaviour change, social support within the

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

Toward a mechanistic understanding of vulnerability to hook-and-line fishing: Boldness as the basic target of angling-induced selection.

PubMed

Klefoth, Thomas; Skov, Christian; Kuparinen, Anna; Arlinghaus, Robert

2017-12-01

In passively operated fishing gear, boldness-related behaviors should fundamentally affect the vulnerability of individual fish and thus be under fisheries selection. To test this hypothesis, we used juvenile common-garden reared carp ( Cyprinus carpio ) within a narrow size range to investigate the mechanistic basis of behavioral selection caused by angling. We focused on one key personality trait (i.e., boldness), measured in groups within ponds, two morphological traits (body shape and head shape), and one life-history trait (juvenile growth capacity) and studied mean standardized selection gradients caused by angling. Carp behavior was highly repeatable within ponds. In the short term, over seven days of fishing, total length, not boldness, was the main predictor of angling vulnerability. However, after 20 days of fishing, boldness turned out to be the main trait under selection, followed by juvenile growth rate, while morphological traits were only weakly related to angling vulnerability. In addition, we found juvenile growth rate to be moderately correlated with boldness. Hence, direct selection on boldness will also induce indirect selection on juvenile growth and vice versa, but given that the two traits are not perfectly correlated, independent evolution of both traits is also possible. Our study is among the first to mechanistically reveal that energy-acquisition-related behaviors, and not growth rate per se, are key factors determining the probability of capture, and hence, behavioral traits appear to be the prime targets of angling selection. We predict an evolutionary response toward increased shyness in intensively angling-exploited fish stocks, possibly causing the emergence of a timidity syndrome.

How do various maize crop models vary in their responses to climate change factors?

USDA-ARS?s Scientific Manuscript database

Potential consequences of climate change on crop production can be studied using mechanistic crop simulation models. While a broad variety of maize simulation models exist, it is not known whether different models give similar grain yield responses to changes in climatic factors, or whether they agr...

Structural and mechanistic analysis of a β-glycoside phosphorylase identified by screening a metagenomic library.

PubMed

Macdonald, Spencer S; Patel, Ankoor; Larmour, Veronica L C; Morgan-Lang, Connor; Hallam, Steven J; Mark, Brian L; Withers, Stephen G

2018-03-02

Glycoside phosphorylases have considerable potential as catalysts for the assembly of useful glycans for products ranging from functional foods and prebiotics to novel materials. However, the substrate diversity of currently identified phosphorylases is relatively small, limiting their practical applications. To address this limitation, we developed a high-throughput screening approach using the activated substrate 2,4-dinitrophenyl β-d-glucoside (DNPGlc) and inorganic phosphate for identifying glycoside phosphorylase activity and used it to screen a large insert metagenomic library. The initial screen, based on release of 2,4-dinitrophenyl from DNPGlc in the presence of phosphate, identified the gene bglP, encoding a retaining β-glycoside phosphorylase from the CAZy GH3 family. Kinetic and mechanistic analysis of the gene product, BglP, confirmed a double displacement ping-pong mechanism involving a covalent glycosyl-enzyme intermediate. X-ray crystallographic analysis provided insights into the phosphate-binding mode and identified a key glutamine residue in the active site important for substrate recognition. Substituting this glutamine for a serine swapped the substrate specificity from glucoside to N -acetylglucosaminide. In summary, we present a high-throughput screening approach for identifying β-glycoside phosphorylases, which was robust, simple to implement, and useful in identifying active clones within a metagenomics library. Implementation of this screen enabled discovery of a new glycoside phosphorylase class and has paved the way to devising simple ways in which enzyme specificity can be encoded and swapped, which has implications for biotechnological applications. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

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

Treesearch

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

2010-01-01

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

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.

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

DOT National Transportation Integrated Search

2011-03-01

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

Establishing Appropriate Inputs When Using the Mechanistic-Empirical Pavement Design Guide To Design Rigid Pavements in Pennsylvania

DOT National Transportation Integrated Search

2011-03-01

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

Implications of mechanistic modeling of drought effects on growth and competition in forest landscape models

Treesearch

Eric J. Gustafson; Arjan M. G. De Bruijn; Brian R. Miranda; Brian R. Sturtevant; J. Thompson

2016-01-01

The incidence of drought is expected to increase worldwide as a factor structuring forested landscapes. Ecophysiological mechanisms are being added to Forest Landscape Models (FLMs) to increase their robustness to the novel environmental conditions of the future (including drought), but their behavior has not been evaluated for mixed temperate forests. We evaluated...

New insight in expression, transport, and secretion of brain-derived neurotrophic factor: Implications in brain-related diseases

PubMed Central

Adachi, Naoki; Numakawa, Tadahiro; Richards, Misty; Nakajima, Shingo; Kunugi, Hiroshi

2014-01-01

Brain-derived neurotrophic factor (BDNF) attracts increasing attention from both research and clinical fields because of its important functions in the central nervous system. An adequate amount of BDNF is critical to develop and maintain normal neuronal circuits in the brain. Given that loss of BDNF function has been reported in the brains of patients with neurodegenerative or psychiatric diseases, understanding basic properties of BDNF and associated intracellular processes is imperative. In this review, we revisit the gene structure, transcription, translation, transport and secretion mechanisms of BDNF. We also introduce implications of BDNF in several brain-related diseases including Alzheimer’s disease, Huntington’s disease, depression and schizophrenia. PMID:25426265

A mechanistic model for the evolution of multicellularity

NASA Astrophysics Data System (ADS)

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

2018-02-01

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

The activation of plasminogen by Hageman factor (Factor XII) and Hageman factor fragments.

PubMed Central

Goldsmith, G H; Saito, H; Ratnoff, O S

1978-01-01

Activation of plasminogen through surface-mediated reactions is well recognized. In the presence of kaolin, purified Hageman factor (Factor XII) changed plasminogen to plasmin, as assayed upon a synthetic amide substrate and by fibrinolysis. Kinetic studies suggested an enzymatic action of Hageman factor upon its substrate, plasminogen. Hageman factor fragments, at a protein concentration equivalent to whole Hageman factor, activated plasminogen to a lesser extent. These protein preparations were not contaminated with other agents implicated in surface-mediated fibrinolysis. Diisopropyl fluorophosphate treatment of plasminogen did not inhibit its activation by Hageman factor. These studies indicate that Hageman factor has a hitherto unsuspected function, the direct activation of plasminogen. PMID:659637

soc-2 encodes a leucine-rich repeat protein implicated in fibroblast growth factor receptor signaling

PubMed Central

Selfors, Laura M.; Schutzman, Jennifer L.; Borland, Christina Z.; Stern, Michael J.

1998-01-01

Activation of fibroblast growth factor (FGF) receptors elicits diverse cellular responses including growth, mitogenesis, migration, and differentiation. The intracellular signaling pathways that mediate these important processes are not well understood. In Caenorhabditis elegans, suppressors of clr-1 identify genes, termed soc genes, that potentially mediate or activate signaling through the EGL-15 FGF receptor. We demonstrate that three soc genes, soc-1, soc-2, and sem-5, suppress the activity of an activated form of the EGL-15 FGF receptor, consistent with the soc genes functioning downstream of EGL-15. We show that soc-2 encodes a protein composed almost entirely of leucine-rich repeats, a domain implicated in protein–protein interactions. We identified a putative human homolog, SHOC-2, which is 54% identical to SOC-2. We find that shoc-2 maps to 10q25, shoc-2 mRNA is expressed in all tissues assayed, and SHOC-2 protein is cytoplasmically localized. Within the leucine-rich repeats of both SOC-2 and SHOC-2 are two YXNX motifs that are potential tyrosine-phosphorylated docking sites for the SEM-5/GRB2 Src homology 2 domain. However, phosphorylation of these residues is not required for SOC-2 function in vivo, and SHOC-2 is not observed to be tyrosine phosphorylated in response to FGF stimulation. We conclude that this genetic system has allowed for the identification of a conserved gene implicated in mediating FGF receptor signaling in C. elegans. PMID:9618511

Mechanistic understanding of MeHg-Se antagonism in soil-rice systems: the key role of antagonism in soil

PubMed Central

Wang, Yongjie; Dang, Fei; Evans, R. Douglas; Zhong, Huan; Zhao, Jiating; Zhou, Dongmei

2016-01-01

Methylmercury (MeHg) accumulation in rice has great implications for human health. Here, effects of selenium (Se) on MeHg availability to rice are explored by growing rice under soil or foliar fertilization with Se. Results indicate that soil amendment with Se could reduce MeHg levels in soil and grain (maximally 73%). In contrast, foliar fertilization with Se enhanced plant Se levels (3–12 folds) without affecting grain MeHg concentrations. This evidence, along with the distinct distribution of MeHg and Se within the plant, demonstrate for the first time that Se-induced reduction in soil MeHg levels (i.e., MeHg-Se antagonism in soil) rather than MeHg-Se interactions within the plant might be the key process triggering the decreased grain MeHg levels under Se amendment. The reduction in soil MeHg concentrations could be mainly attributed to the formation of Hg-Se complexes (detected by TEM-EDX and XANES) and thus reduced microbial MeHg production. Moreover, selenite and selenate were equally effective in reducing soil MeHg concentrations, possibly because of rapid changes in Se speciation. The dominant role of Se-induced reduction in soil MeHg levels, which has been largely underestimated previously, together with the possible mechanisms advance our mechanistic understanding about MeHg dynamics in soil-rice systems. PMID:26778218

A MECHANISTIC MODEL FOR MERCURY CAPTURE WITH IN-SITU GENERATED TITANIA PARTICLES: ROLE OF WATER VAPOR

EPA Science Inventory

A mechanistic model to predict the capture of gas phase mercury species using in-situ generated titania nanosize particles activated by UV irradiation is developed. The model is an extension of a recently reported model1 for photochemical reactions that accounts for the rates of...

Secondary dispersal driven by overland flow in drylands: Review and mechanistic model development.

PubMed

Thompson, Sally E; Assouline, Shmuel; Chen, Li; Trahktenbrot, Ana; Svoray, Tal; Katul, Gabriel G

2014-01-01

Seed dispersal alters gene flow, reproduction, migration and ultimately spatial organization of dryland ecosystems. Because many seeds in drylands lack adaptations for long-distance dispersal, seed transport by secondary processes such as tumbling in the wind or mobilization in overland flow plays a dominant role in determining where seeds ultimately germinate. Here, recent developments in modeling runoff generation in spatially complex dryland ecosystems are reviewed with the aim of proposing improvements to mechanistic modeling of seed dispersal processes. The objective is to develop a physically-based yet operational framework for determining seed dispersal due to surface runoff, a process that has gained recent experimental attention. A Buoyant OBject Coupled Eulerian - Lagrangian Closure model (BOB-CELC) is proposed to represent seed movement in shallow surface flows. The BOB-CELC is then employed to investigate the sensitivity of seed transport to landscape and storm properties and to the spatial configuration of vegetation patches interspersed within bare earth. The potential to simplify seed transport outcomes by considering the limiting behavior of multiple runoff events is briefly considered, as is the potential for developing highly mechanistic, spatially explicit models that link seed transport, vegetation structure and water movement across multiple generations of dryland plants.

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.

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.

Hyperirisinemia is independently associated with subclinical hypothyroidism: correlations with cardiometabolic biomarkers and risk factors.

PubMed

Stratigou, Theodora; Dalamaga, Maria; Antonakos, Georgios; Marinou, Ioanna; Vogiatzakis, Evaggelos; Christodoulatos, Gerasimos Socrates; Karampela, Irene; Papavassiliou, Athanasios G

2018-02-17

Irisin, a newly discovered adipo-myokine, is implicated in the modulation of the adipose phenotype, increasing energy expenditure and ameliorating systemic metabolism. Our aim was to investigate circulating irisin in subclinical hypothyroidism (SH) and study its associations with cardiometabolic risk factors. In a large case-control study, serum irisin, insulin resistance and lipid parameters, classic adipokines, inflammatory and hepatic biomarkers, and cardiovascular risk factors were determined in 120 consecutive patients with SH and 120 healthy controls matched on age, gender, and date of blood draw. Sixteen patients with SH received L-T4 treatment and, after 6 months, serum irisin and other biomarkers were assessed. SH cases exhibited significantly higher circulating irisin than controls (p < 0.001). In all participants, irisin was positively associated with TSH, anti-TG, HOMA-IR, C-peptide, lipid and inflammatory biomarkers, leptin, and cardiovascular risk factors, including Framigham score and apolipoprotein B/apolipoprotein A-I. Irisin was negatively correlated with adiponectin, HDL-C, and thyroid hormones. Serum irisin was independently associated with SH, above and beyond body mass index and cardiometabolic factors (p = 0.02). TSH was an independent predictor of circulating irisin (p = 0.003). L-T4 therapy did not reverse considerably the hyperirisinemic status in treated SH patients (p = 0.09). Irisin may represent an adipo-myokine counterbalancing a potential, gradual deterioration of lipid metabolism and insulin sensitivity in SH as well as reflecting a protective compensatory mechanism against oxidative muscle and thyroid cell stress. More mechanistic and prospective studies shedding light on the pathogenetic role of irisin in SH are needed to confirm and extend these data.

Non-specific effects of vaccines: plausible and potentially important, but implications uncertain.

PubMed

Pollard, Andrew J; Finn, Adam; Curtis, Nigel

2017-11-01

Non-specific effects (NSE) or heterologous effects of vaccines are proposed to explain observations in some studies that certain vaccines have an impact beyond the direct protection against infection with the specific pathogen for which the vaccines were designed. The importance and implications of such effects remain controversial. There are several known immunological mechanisms which could lead to NSE, since it is widely recognised that the generation of specific immunity is initiated by non-specific innate immune mechanisms that may also have wider effects on adaptive immune function. However, there are no published studies that demonstrate a mechanistic link between such immunological phenomena and clinically relevant NSE in humans. While it is highly plausible that some vaccines do have NSE, their magnitude and duration, and thus importance, remain uncertain. Although the WHO recently concluded that current evidence does not justify changes to immunisation policy, further studies of sufficient size and quality are needed to assess the importance of NSE for all-cause mortality. This could provide insights into vaccine immunobiology with important implications for infant health and survival. © 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.

Genetic and mechanistic diversity of piRNA 3' end formation

PubMed Central

Handler, Dominik; Mohn, Fabio; Ameres, Stefan L.; Brennecke, Julius

2016-01-01

Small regulatory RNAs guide Argonaute (Ago) proteins in a sequence-specific manner to their targets and thereby play important roles in eukaryotic gene silencing1. Of the three small RNA classes, microRNAs and siRNAs are processed from double-stranded precursors into defined 21- to 23-mers by Dicer, an endoribonuclease with intrinsic ruler function. piRNAs—the 22-30 nt long guides for PIWI-clade Ago proteins that silence transposons in animal gonads—are generated Dicer-independently from single-stranded precursors2,3. piRNA 5' ends are defined either by Zucchini, a mitochondria-anchored endonuclease4,5, or by piRNA-guided target cleavage6,7. Formation of piRNA 3' ends is poorly understood. Here, we find that two genetically and mechanistically distinct pathways generate piRNA 3' ends in Drosophila. The initiating nucleases are either Zucchini or the PIWI-clade proteins Aubergine (Aub)/Ago3. While Zucchini-mediated cleavages directly define mature piRNA 3' ends8,9, Aub/Ago3-mediated cleavages liberate pre-piRNAs that require extensive resection by the 3'-to-5' exoribonuclease Nibbler/Mut-710–13. The relative activity of these two pathways dictates the extent to which piRNAs are fueled into cytoplasmic or nuclear PIWI-clade proteins and thereby sets the balance between post-transcriptional and transcriptional silencing. Strikingly, loss of both Zucchini and Nibbler reveals a minimal, Argonaute-driven small RNA biogenesis pathway where piRNA 5' and 3' ends are directly produced by closely spaced Aub/Ago3-mediated cleavage events. Our data establish a coherent blueprint for piRNA biogenesis, and set the stage for the mechanistic dissection of the processes that govern piRNA 3' end formation. PMID:27851737

Problems in mechanistic theoretical models for cell transformation by ionizing radiation

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

Chatterjee, A.; Holley, W.R.

1991-10-01

A mechanistic model based on yields of double strand breaks has been developed to determine the dose response curves for cell transformation frequencies. At its present stage the model is applicable to immortal cell lines and to various qualities (X-rays, Neon and Iron) of ionizing radiation. Presently, we have considered four types of processes which can lead to activation phenomena: (1) point mutation events on a regulatory segment of selected oncogenes, (2) inactivation of suppressor genes, through point mutation, (3) deletion of a suppressor gene by a single track, and (4) deletion of a suppressor gene by two tracks.

Hydration Effects on Skin Microstructure as Probed by High-Resolution Cryo-Scanning Electron Microscopy and Mechanistic Implications to Enhanced Transcutaneous Delivery of Biomacromolecules

PubMed Central

Tan, Grace; Xu, Peng; Lawson, Louise B.; He, Jibao; Freytag, Lucia C.; Clements, John D.; John, Vijay T.

2010-01-01

Although hydration is long known to improve the permeability of skin, penetration of macromolecules such as proteins is limited and the understanding of enhanced transport is based on empirical observations. This study uses high-resolution cryo-scanning electron microscopy to visualize microstructural changes in the stratum corneum (SC) and enable a mechanistic interpretation of biomacromolecule penetration through highly hydrated porcine skin. Swollen corneocytes, separation of lipid bilayers in the SC intercellular space to form cisternae, and networks of spherical particulates are observed in porcine skin tissue hydrated for a period of 4–10 h. This is explained through compaction of skin lipids when hydrated, a reversal in the conformational transition from unilamellar liposomes in lamellar granules to lamellae between keratinocytes when the SC skin barrier is initially established. Confocal microscopy studies show distinct enhancement in penetration of fluorescein isothiocyanate-bovine serum albumin (FITC-BSA) through skin hydrated for 4–10 h, and limited penetration of FITC-BSA once skin is restored to its natively hydrated structure when exposed to the environment for 2–3 h. These results demonstrate the effectiveness of a 4–10 h hydration period to enhance transcutaneous penetration of large biomacromolecules without permanently damaging the skin. PMID:19582754

Evaluation of current Louisiana flexible pavement structures using PMS data and new mechanistic-empirical pavement design guide.

DOT National Transportation Integrated Search

2012-04-01

The new Mechanistic-Empirical Pavement Design Guide (MEPDG) developed under the National Cooperative Highway Research Program (NCHRP) Project 1-37A represents a major change as compared to the 1993 AASHTO Pavement Design Guide. The MEPDG provides a r...

ROLE OF ENVIRONMENTAL AND PERSONAL FACTORS IN THE INITIATION OF ASTHMA IN SCHOOL-AGED CHILDREN: MICA STUDY

EPA Science Inventory

A number of environmental and personal factors have already been associated with the development and exacerbation of childhood asthma, but many aspects of this association require further research. The Mechanistic Indicators of Childhood Asthma (MICA) is an epidemiologic study t...

Genetic Variants of Microtubule Actin Cross-linking Factor 1 (MACF1) Confer Risk for Parkinson's Disease.

PubMed

Wang, Xin; Li, Nuomin; Xiong, Nian; You, Qi; Li, Jie; Yu, Jinlong; Qing, Hong; Wang, Tao; Cordell, Heather J; Isacson, Ole; Vance, Jeffery M; Martin, Eden R; Zhao, Ying; Cohen, Bruce M; Buttner, Edgar A; Lin, Zhicheng

2017-05-01

The cytoskeleton not only provides structure, it is an active component of cell function, and in several neurodegenerative disorders, there is evidence of cytoskeletal collapse. Cytoskeletal proteins have been specifically implicated in the pathogenesis of Parkinson's disease (PD), where degeneration of dopaminergic (DA) neurons is the hallmark, but in which many factors may determine the resilience of DA neurons during aging and stress. Here we report that the human Microtubule Actin Cross-linking Factor 1 gene (MACF1), a downstream target of PD biochemical pathways, was significantly associated with PD in 713 nuclear families. A significant allelic association between PD and rs12118033, with P = 0.0098, was observed, and a P < 0.03 was observed in the association analysis by both a trend test and an allelic test. We further observed that it is the MACF1b isoform, not the MACF1a isoform, which is expressed in DA neurons from six human postmortem brains. In a Caenorhabditis elegans system, used to explore the effect of altered MACF1b on neurons, knockdown or knockout of the MACF1b orthologue vab-10 resulted in the selective loss of DA neurons, which validated MACF1's risk candidacy in PD. These findings strongly suggest that MACF1b may contribute to the genetic etiology and mechanistic causation of PD.

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.

A Mechanistic-Based Healing Model for Self-Healing Glass Seals Used in Solid Oxide Fuel Cells

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

Xu, Wei; Sun, Xin; Stephens, Elizabeth V.

The usage of self-healing glass as hermetic seals is a recent advancement in sealing technology development for the planar solid oxide fuel cells (SOFCs). Because of its capability of restoring the mechanical properties at elevated temperatures, the self-healing glass seal is expected to provide high reliability in maintaining the long-term structural integrity and functionality of SOFCs. In order to accommodate the design and to evaluate the effectiveness of such engineering seals under various thermo-mechanical operating conditions, computational modeling framework needs to be developed to accurately capture and predict the healing behavior of the glass material. In the present work, amore » mechanistic-based two-stage model was developed to study the stress and temperature-dependent crack healing of the self-healing glass materials. The model was first calibrated by experimental measurements combined with the kinetic Monte Carlo (kMC) simulation results and then implemented into the finite element analysis (FEA). The effects of various factors, i.e. stress, temperature, crack morphology, on the healing behavior of the glass were investigated and discussed.« less

Preparation for implementation of the mechanistic-empirical pavement design guide in Michigan : part 1 - HMA mixture characterization.

DOT National Transportation Integrated Search

2013-03-01

This is the final report of the Part 1 (HMA Mixture Characterization) of the Preparation for Implementation of the Mechanistic-Empirical Pavement Design Guide in Michigan project. The main objectives of the Part 1 were (i) to conduct a literatu...

Risk Factor Knowledge, Perceived Threat, and Protective Health Behaviors: Implications for Type 2 Diabetes Control in Rural Communities.

PubMed

Paige, Samantha R; Bonnar, Kelly K; Black, David R; Coster, Daniel C

2018-02-01

Purpose The purpose of this study was to explore how perceived threat of type 2 diabetes (T2D) is shaped by risk factor knowledge and promotes the engagement of protective health behaviors among rural adults. Methods Participants (N = 252) completed a cross-sectional mixed-mode survey. Chi-squared analyses were computed to examine differences in perceived threat by demographic factors and knowledge of T2D risk factors. Logistic regressions were conducted to examine the relationship between T2D perceived threat and engagement in physical activity and health screenings. Results Perceived threat and knowledge of T2D risk factors were high. Perceived susceptibility was significantly higher among women, whites, and respondents with high body mass index (BMI). Respondents reporting physical activity most/almost every day had low perceived susceptibility to T2D. Perceived severity was significantly higher among respondents with high BMI. Blood cholesterol and glucose screenings were associated with greater T2D perceived susceptibility and severity. Higher BMI was associated with receiving a blood glucose screening. Conclusion Health education specialists and researchers should further explore the implications of using audience segmented fear appeal messages to promote T2D control through protective health behaviors.

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

PubMed

Kayala, Matthew A; Baldi, Pierre

2012-10-22

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

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

USGS Publications Warehouse

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

2018-01-01

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

Mechanistic Role of Thioredoxin 2 in Heart Failure.

PubMed

Chen, Chaofei; Chen, Haixuan; Zhou, Huanjiao Jenny; Ji, Weidong; Min, Wang

2017-01-01

Thioredoxin 2 (Trx2) is a pivotal mitochondrial protein that regulates redox signaling. The mitochondrial Trx2 is expressed ubiquitously, but it is found at the highest levels in metabolically active tissues like the heart. Global gene knockout of Trx2 results in embryonic lethality, likely due to the increased cellular oxidative stress. Moreover, mice with cardiac-specific Trx2 deletion develop spontaneous dilated cardiomyopathy (DCM), correlating with increased apoptosis stress kinase-1 (ASK1) signaling and increased cardiomyocyte apoptosis. Cardiomyocyte apoptosis is a common mechanism in the pathogenesis of heart failure. Our results show that Trx2 is essential for maintaining cardiac function. In this chapter, we summarize the key mechanistic role of Trx2 in preserving cardiac function by suppressing mitochondrial reactive oxygen species (ROS) generation and by inhibiting ASK1-dependent apoptosis in heart failure. Trx2 and ASK1 represent promising targets to develop therapeutic strategies for the treatment of DCM and heart failure.

Fibroblast Growth Factors and Vascular Endothelial Growth Factor Promote Cardiac Reprogramming under Defined Conditions

PubMed Central

Yamakawa, Hiroyuki; Muraoka, Naoto; Miyamoto, Kazutaka; Sadahiro, Taketaro; Isomi, Mari; Haginiwa, Sho; Kojima, Hidenori; Umei, Tomohiko; Akiyama, Mizuha; Kuishi, Yuki; Kurokawa, Junko; Furukawa, Tetsushi; Fukuda, Keiichi; Ieda, Masaki

2015-01-01

Summary Fibroblasts can be directly reprogrammed into cardiomyocyte-like cells (iCMs) by overexpression of cardiac transcription factors, including Gata4, Mef2c, and Tbx5; however, this process is inefficient under serum-based culture conditions, in which conversion of partially reprogrammed cells into fully reprogrammed functional iCMs has been a major hurdle. Here, we report that a combination of fibroblast growth factor (FGF) 2, FGF10, and vascular endothelial growth factor (VEGF), termed FFV, promoted cardiac reprogramming under defined serum-free conditions, increasing spontaneously beating iCMs by 100-fold compared with those under conventional serum-based conditions. Mechanistically, FFV activated multiple cardiac transcriptional regulators and converted partially reprogrammed cells into functional iCMs through the p38 mitogen-activated protein kinase and phosphoinositol 3-kinase/AKT pathways. Moreover, FFV enabled cardiac reprogramming with only Mef2c and Tbx5 through the induction of cardiac reprogramming factors, including Gata4. Thus, defined culture conditions promoted the quality of cardiac reprogramming, and this finding provides new insight into the mechanism of cardiac reprogramming. PMID:26626177

Development of a Mechanistically Based, Basin-Scale Stream Temperature Model: Applications to Cumulative Effects Modeling

Treesearch

Douglas Allen; William Dietrich; Peter Baker; Frank Ligon; Bruce Orr

2007-01-01

We describe a mechanistically-based stream model, BasinTemp, which assumes that direct shortwave radiation moderated by riparian and topographic shading, controls stream temperatures during the hottest part of the year. The model was developed to support a temperature TMDL for the South Fork Eel basin in Northern California and couples a GIS and a 1-D energy balance...

A Meta-Analysis of Factors Influencing the Development of Trust in Automation: Implications for Understanding Autonomy in Future Systems.

PubMed

Schaefer, Kristin E; Chen, Jessie Y C; Szalma, James L; Hancock, P A

2016-05-01

We used meta-analysis to assess research concerning human trust in automation to understand the foundation upon which future autonomous systems can be built. Trust is increasingly important in the growing need for synergistic human-machine teaming. Thus, we expand on our previous meta-analytic foundation in the field of human-robot interaction to include all of automation interaction. We used meta-analysis to assess trust in automation. Thirty studies provided 164 pairwise effect sizes, and 16 studies provided 63 correlational effect sizes. The overall effect size of all factors on trust development was ḡ = +0.48, and the correlational effect was [Formula: see text]  = +0.34, each of which represented medium effects. Moderator effects were observed for the human-related (ḡ  = +0.49; [Formula: see text] = +0.16) and automation-related (ḡ = +0.53; [Formula: see text] = +0.41) factors. Moderator effects specific to environmental factors proved insufficient in number to calculate at this time. Findings provide a quantitative representation of factors influencing the development of trust in automation as well as identify additional areas of needed empirical research. This work has important implications to the enhancement of current and future human-automation interaction, especially in high-risk or extreme performance environments. © 2016, Human Factors and Ergonomics Society.

Mesenchymal stem cells derived from human exocrine pancreas express transcription factors implicated in beta-cell development.

PubMed

Baertschiger, Reto M; Bosco, Domenico; Morel, Philippe; Serre-Beinier, Veronique; Berney, Thierry; Buhler, Leo H; Gonelle-Gispert, Carmen

2008-07-01

Transplantation of in vitro generated islets or insulin-producing cells represents an attractive option to overcome organ shortage. The aim of this study was to isolate, expand, and characterize cells from human exocrine pancreas and analyze their potential to differentiate into beta cells. Fibroblast-like cells growing out of human exocrine tissue were characterized by flow cytometry and by their capacity to differentiate into mesenchymal cell lineages. During cell expansion and after differentiation toward beta cells, expression of transcription factors of endocrine pancreatic progenitors was analyzed by reverse transcription polymerase chain reaction. Cells emerged from 14/18 human pancreatic exocrine fractions and were expanded up to 40 population doublings. These cells displayed surface antigens similar to mesenchymal stem cells from bone marrow. A culture of these cells in adipogenic and chondrogenic differentiation media allowed differentiation into adipocyte- and chondrocyte-like cells. During expansion, cells expressed transcription factors implicated in islet development such as Isl1, Nkx2.2, Nkx6.1, nestin, Ngn3, Pdx1, and NeuroD. Activin A and hepatocyte growth factor induced an expression of insulin, glucagon, and glucokinase. Proliferating cells with characteristics of mesenchymal stem cells and endocrine progenitors were isolated from exocrine tissue. Under specific conditions, these cells expressed little insulin. Human pancreatic exocrine tissue might thus be a source of endocrine cell progenitors.

PCDD/F TEQ INDICATORS AND THEIR MECHANISTIC IMPLICATIONS

EPA Science Inventory

Stack gas samples from two incinerator facilities with different operating conditions were investigated to find polychlorinated dibenzo-p-dioxin/furan (PCDD/F) toxic equivalent quantity (TEQ) indicators from amongst the 210 PCDD/F isomers. Similarities in isomer patterns were als...

Vascular endothelial growth factor is upregulated by l-dopa in the parkinsonian brain: implications for the development of dyskinesia

PubMed Central

Francardo, Veronica; Lindgren, Hanna S.; Sillivan, Stephanie E.; O’Sullivan, Sean S.; Luksik, Andrew S.; Vassoler, Fair M.; Lees, Andrew J.; Konradi, Christine

2011-01-01

Angiogenesis and increased permeability of the blood–brain barrier have been reported to occur in animal models of Parkinson’s disease and l-dopa-induced dyskinesia, but the significance of these phenomena has remained unclear. Using a validated rat model of l-dopa-induced dyskinesia, this study demonstrates that chronic treatment with l-dopa dose dependently induces the expression of vascular endothelial growth factor in the basal ganglia nuclei. Vascular endothelial growth factor was abundantly expressed in astrocytes and astrocytic processes in the proximity of blood vessels. When co-administered with l-dopa, a small molecule inhibitor of vascular endothelial growth factor signalling significantly attenuated the development of dyskinesia and completely blocked the angiogenic response and associated increase in blood–brain barrier permeability induced by the treatment. The occurrence of angiogenesis and vascular endothelial growth factor upregulation was verified in post-mortem basal ganglia tissue from patients with Parkinson’s disease with a history of dyskinesia, who exhibited increased microvascular density, microvascular nestin expression and an upregulation of vascular endothelial growth factor messenger ribonucleic acid. These congruent findings in the rat model and human patients indicate that vascular endothelial growth factor is implicated in the pathophysiology of l-dopa-induced dyskinesia and emphasize an involvement of the microvascular compartment in the adverse effects of l-dopa pharmacotherapy in Parkinson’s disease. PMID:21771855

Determination of the in-place hot-mix asphalt layer modulus for rehabilitation projects using a mechanistic-empirical procedure.

DOT National Transportation Integrated Search

2006-01-01

This project evaluated the procedures proposed by the Mechanistic-Empirical Pavement Design Guide (MEPDG) to characterize existing hot-mix asphalt (HMA) layers for rehabilitation purposes. Thirty-three cores were extracted from nine sites in Virginia...

Heat shock factor 1 suppresses the HIV-induced inflammatory response by inhibiting nuclear factor-κB.

PubMed

Pan, Xiaoyan; Lin, Jian; Zeng, Xiaoyun; Li, Wenjuan; Wu, Wenjiao; Lu, Wan Zhen; Liu, Jing; Liu, Shuwen

2018-05-01

The persistent inflammation aggravated by a disordered immune response is considered to be the major cause of CD4 + T cell depletion in lymphoid tissue, which impels the progression of AIDS. Here, we report that heat shock factor 1 (HSF1) works as an innate repressor of HIV-induced inflammation. The activation of HSF1 was found to accompany inflammation during HIV infection. Further research uncovered that HSF1 activation inhibited HIV-induced inflammation. In addition, HSF1 overexpression suppressed the inflammatory response induced by HIV, while HSF1 deficiency exacerbated that inflammation. Mechanistically, HSF1 was found to compete with nuclear factor-κB (NF-κB) in the nucleus. Generally, our report highlights that HSF1 is an important host factor in regulating HIV-induced inflammation and may work as a potential target for curing AIDS. Copyright © 2018 Elsevier Inc. All rights reserved.

In vitro evidence of a tissue factor-independent mode of action of recombinant factor VIIa in hemophilia.

PubMed

Augustsson, Cecilia; Persson, Egon

2014-11-13

Successful competition of activated factor VII (FVIIa) with zymogen factor VII (FVII) for tissue factor (TF) and loading of the platelet surface with FVIIa are plausible driving forces behind the pharmacological effect of recombinant FVIIa (rFVIIa) in hemophilia patients. Thrombin generation measurements in platelet-rich hemophilia A plasma revealed competition for TF, which potentially could reduce the effective (r)FVIIa:TF complex concentration and thereby attenuate factor Xa production. However, (auto)activation of FVII apparently counteracted the negative effect of zymogen binding; a small impact was observed at endogenous concentrations of FVII and FVIIa but was virtually absent at pharmacological amounts of rFVIIa. Moreover, corrections of the propagation phase in hemophilia A required rFVIIa concentrations above the range where a physiological level of FVII was capable to downregulate thrombin generation. These data strongly suggest that rFVIIa acts independently of TF in hemophilia therapy and that FVII displacement by rFVIIa is a negligible mechanistic component. © 2014 by The American Society of Hematology.

Progress toward an explicit mechanistic model for the light-driven pump, bacteriorhodopsin

NASA Technical Reports Server (NTRS)

Lanyi, J. K.

1999-01-01

Recent crystallographic information about the structure of bacteriorhodopsin and some of its photointermediates, together with a large amount of spectroscopic and mutational data, suggest a mechanistic model for how this protein couples light energy to the translocation of protons across the membrane. Now nearing completion, this detailed molecular model will describe the nature of the steric and electrostatic conflicts at the photoisomerized retinal, as well as the means by which it induces proton transfers in the two half-channels leading to the two membrane surfaces, thereby causing unidirectional, uphill transport.

Beneficial nutritional properties of olive oil: implications for postprandial lipoproteins and factor VII.

PubMed

Williams, C M

2001-08-01

Previous research concerning protective cardiovascular properties of olive oil has focussed on the beneficial consequences on blood cholesterol levels of substituting dietary saturated fatty acids with oleic acid. Despite evidence implicating raised circulating triglycerides in the postprandial state in the pathogenesis of atherosclerosis and thrombosis, little research had been conducted to investigate effects of monounsaturated fatty acids on postprandial events. In a case control study of southern (n = 30) versus northern European (n = 30) men, significant differences in postprandial triglyceride and apolipoprotein (apo) B-48 response were observed, with evidence of attenuated and potentially beneficial responses in the Southern Europeans. In a randomised controlled study manufactured foods typical of the Northern European food culture, were used to deliver diets rich in either saturated or monounsaturated fatty acids (from olive oil). During the period of the olive oil enriched diet, LDL-cholesterol levels were 15% lower (p < 0.001) than during the saturated fat diet. Postprandial triglyceride response was shifted towards the profile seen in southern European men and the postprandial activation of factor VII, as well as the production of factor VII antigen, was reduced on the olive oil diet. The study demonstrated significant improvements in biomarkers for cardiovascular disease in subjects osed to high olive oil diets (Southern Europeans) or transferred to such diets in the short term (Northern European volunteers). The study produced novel findings with respect to potential mechanisms by which diets high in monounsaturated fatty acids (MUFA) can reduce population risk of cardiovascular disease.

Krüppel-like Factor 3 (KLF3/BKLF) Is Required for Widespread Repression of the Inflammatory Modulator Galectin-3 (Lgals3)*

PubMed Central

Knights, Alexander J.; Yik, Jinfen J.; Mat Jusoh, Hanapi; Norton, Laura J.; Funnell, Alister P. W.; Pearson, Richard C. M.; Bell-Anderson, Kim S.; Crossley, Merlin; Quinlan, Kate G. R.

2016-01-01

The Lgals3 gene encodes a multifunctional β-galactoside-binding protein, galectin-3. Galectin-3 has been implicated in a broad range of biological processes from chemotaxis and inflammation to fibrosis and apoptosis. The role of galectin-3 as a modulator of inflammation has been studied intensively, and recent evidence suggests that it may serve as a protective factor in obesity and other metabolic disorders. Despite considerable interest in galectin-3, little is known about its physiological regulation at the transcriptional level. Here, using knockout mice, chromatin immunoprecipitations, and cellular and molecular analyses, we show that the zinc finger transcription factor Krüppel-like factor 3 (KLF3) directly represses galectin-3 transcription. We find that galectin-3 is broadly up-regulated in KLF3-deficient mouse tissues, that KLF3 occupies regulatory regions of the Lgals3 gene, and that KLF3 directly binds its cognate elements (CACCC boxes) in the galectin-3 promoter and represses its activation in cellular assays. We also provide mechanistic insights into the regulation of Lgals3, demonstrating that C-terminal binding protein (CtBP) is required to drive optimal KLF3-mediated silencing. These findings help to enhance our understanding of how expression of the inflammatory modulator galectin-3 is controlled, opening up avenues for potential therapeutic interventions in the future. PMID:27226561

An example problem illustrating the application of the national lime association mixture design and testing protocol (MDTP) to ascertain engineering properties of lime-treated subgrades for mechanistic pavement design/analysis.

DOT National Transportation Integrated Search

2001-09-01

This document presents an example of mechanistic design and analysis using a mix design and : testing protocol. More specifically, it addresses the structural properties of lime-treated subgrade, : subbase, and base layers through mechanistic design ...

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…

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

PubMed Central

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

2014-01-01

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

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

PubMed

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

2014-02-11

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

Factors that affect general practice as a choice of medical speciality: implications for policy development.

PubMed

Vohra, Amit; Ladyshewsky, Richard; Trumble, Stephen

2017-11-28

Objective This article critically appraises the range of personal, professional and social factors that affect the choice of speciality across medical students, prevocational doctors, general practice registrars and general practitioners. Methods This qualitative study applied constructs from the fields of decision theory and career theory to better understand the complex nature of choosing a speciality. In all, 47 in-depth interviews were conducted with participants at different stages of their career cycle. The data was codified and analysed using NVivo to identify key factors that influenced speciality choice. Results The research identified 77 individual findings influencing general practice as a choice of medical speciality. These were distilled into a matrix to show that factors such as money, prestige and peer interaction did not have a compelling effect, whereas clinical and academic role models, flexibility, work-life balance, scope of practice, connection with patients, training environment and practical opportunities did. Conclusion The findings indicate that the decision in relation to the choice of medical speciality is a complex cognitive process that is undertaken within a personal, social and professional context particular to each individual. What is known about the topic? Current literature aims to quantify changes in attitudes towards choice of speciality or the effect of particular variables in isolation while ignoring the complexity of this decision process and how the numerous variables compare with each other. What does this paper add? The present study is the first intergenerational research on this topic in the Australian context and the paper dismisses the role of prestige and remuneration as key drivers of choice in picking general practice as a speciality, noting that money is merely a 'hygiene factor'. What are the implications for policy makers? A policy framework outlining 10 key principles is presented to assist policy makers seeking

Recent advances in mathematical modeling of developmental abnormalities using mechanistic information.

PubMed

Kavlock, R J

1997-01-01

During the last several years, significant changes in the risk assessment process for developmental toxicity of environmental contaminants have begun to emerge. The first of these changes is the development and beginning use of statistically based dose-response models [the benchmark dose (BMD) approach] that better utilize data derived from existing testing approaches. Accompanying this change is the greater emphasis placed on understanding and using mechanistic information to yield more accurate, reliable, and less uncertain risk assessments. The next stage in the evolution of risk assessment will be the use of biologically based dose-response (BBDR) models that begin to build into the statistically based models factors related to the underlying kinetic, biochemical, and/or physiologic processes perturbed by a toxicant. Such models are now emerging from several research laboratories. The introduction of quantitative models and the incorporation of biologic information into them has pointed to the need for even more sophisticated modifications for which we offer the term embryologically based dose-response (EBDR) models. Because these models would be based upon the understanding of normal morphogenesis, they represent a quantum leap in our thinking, but their complexity presents daunting challenges both to the developmental biologist and the developmental toxicologist. Implementation of these models will require extensive communication between developmental toxicologists, molecular embryologists, and biomathematicians. The remarkable progress in the understanding of mammalian embryonic development at the molecular level that has occurred over the last decade combined with advances in computing power and computational models should eventually enable these as yet hypothetical models to be brought into use.

Alternative models of DSM-5 PTSD: Examining diagnostic implications.

PubMed

Murphy, Siobhan; Hansen, Maj; Elklit, Ask; Yong Chen, Yoke; Raudzah Ghazali, Siti; Shevlin, Mark

2018-04-01

The factor structure of DSM-5 posttraumatic stress disorder (PTSD) has been extensively debated with evidence supporting the recently proposed seven-factor Hybrid model. However, despite myriad studies examining PTSD symptom structure few have assessed the diagnostic implications of these proposed models. This study aimed to generate PTSD prevalence estimates derived from the 7 alternative factor models and assess whether pre-established risk factors associated with PTSD (e.g., transportation accidents and sexual victimisation) produce consistent risk estimates. Seven alternative models were estimated within a confirmatory factor analytic framework using the PTSD Checklist for DSM-5 (PCL-5). Data were analysed from a Malaysian adolescent community sample (n = 481) of which 61.7% were female, with a mean age of 17.03 years. The results indicated that all models provided satisfactory model fit with statistical superiority for the Externalising Behaviours and seven-factor Hybrid models. The PTSD prevalence estimates varied substantially ranging from 21.8% for the DSM-5 model to 10.0% for the Hybrid model. Estimates of risk associated with PTSD were inconsistent across the alternative models, with substantial variation emerging for sexual victimisation. These findings have important implications for research and practice and highlight that more research attention is needed to examine the diagnostic implications emerging from the alternative models of PTSD. Copyright © 2017 Elsevier B.V. All rights reserved.

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 Basis of Cocrystal Dissolution Advantage.

PubMed

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

2018-01-01

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

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.

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

ERIC Educational Resources Information Center

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

2008-01-01

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

Dynamic mechanistic explanation: computational modeling of circadian rhythms as an exemplar for cognitive science.

PubMed

Bechtel, William; Abrahamsen, Adele

2010-09-01

We consider computational modeling in two fields: chronobiology and cognitive science. In circadian rhythm models, variables generally correspond to properties of parts and operations of the responsible mechanism. A computational model of this complex mechanism is grounded in empirical discoveries and contributes a more refined understanding of the dynamics of its behavior. In cognitive science, on the other hand, computational modelers typically advance de novo proposals for mechanisms to account for behavior. They offer indirect evidence that a proposed mechanism is adequate to produce particular behavioral data, but typically there is no direct empirical evidence for the hypothesized parts and operations. Models in these two fields differ in the extent of their empirical grounding, but they share the goal of achieving dynamic mechanistic explanation. That is, they augment a proposed mechanistic explanation with a computational model that enables exploration of the mechanism's dynamics. Using exemplars from circadian rhythm research, we extract six specific contributions provided by computational models. We then examine cognitive science models to determine how well they make the same types of contributions. We suggest that the modeling approach used in circadian research may prove useful in cognitive science as researchers develop procedures for experimentally decomposing cognitive mechanisms into parts and operations and begin to understand their nonlinear interactions.

Public health implications of environmental exposures.

PubMed Central

De Rosa, C T; Pohl, H R; Williams, M; Ademoyero, A A; Chou, C H; Jones, D E

1998-01-01

The Agency for Toxic Substances and Disease Registry (ATSDR) is a public health agency with responsibility for assessing the public health implications associated with uncontrolled releases of hazardous substances into the environment. The biological effects of low-level exposures are a primary concern in these assessments. One of the tools used by the agency for this purpose is the risk assessment paradigm originally outlined and described by the National Academy of Science in 1983. Because of its design and inherent concepts, risk assessment has been variously employed by a number of environmental and public health agencies and programs as a means to organize information, as a decision support tool, and as a working hypothesis for biologically based inference and extrapolation. Risk assessment has also been the subject of significant critical review. The ATSDR recognizes the utility of both the qualitative and quantitative conclusions provided by traditional risk assessment, but the agency uses such estimates only in the broader context of professional judgment, internal and external peer review, and extensive public review and comment. This multifaceted approach is consistent with the Council on Environmental Quality's description and use of risk analysis as an organizing construct based on sound biomedical and other scientific judgment in concert with risk assessment to define plausible exposure ranges of concern rather than a single numerical estimate that may convey an artificial sense of precision. In this approach biomedical opinion, host factors, mechanistic interpretation, molecular epidemiology, and actual exposure conditions are all critically important in evaluating the significance of environmental exposure to hazardous substances. As such, the ATSDR risk analysis approach is a multidimensional endeavor encompassing not only the components of risk assessment but also the principles of biomedical judgment, risk management, and risk communication

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

ERIC Educational Resources Information Center

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

2008-01-01

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

Face-Recognition Memory: Implications for Children's Eyewitness Testimony.

ERIC Educational Resources Information Center

Chance, June E.; Goldstein, Alvin G.

1984-01-01

Reviews studies of face-recognition memory and considers implications for assessing the dependability of children's performances as eyewitnesses. Considers personal factors (age, intellectual differences, and gender) and situational factors (familiarity of face, retention interval, and others). Also identifies developmental questions for future…

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

ERIC Educational Resources Information Center

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

2018-01-01

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

Explaining the Rapid Increase in Nigeria's Sex Ratio at Birth: Factors and Implications.

PubMed

Kaba, Amadu J

2015-06-01

This paper examines the rapid increase in Nigeria's sex ratio at birth from 1.03 boys born for every 1 girl born in each year from 1996-2008 to 1.06 in each year from 2009-2014, second only to Tunisia in Africa at 1.07. The average sex ratio at birth in the world in 2014 was 1.07. In most Black African nations or Black majority nations, it is 1.03 or less. Among the factors presented for this development are: historical fluctuations of sex ratio at birth; geography and ethnicity; male preference/chasing a son; Age of parents; high death rates of male infants and males in general; and wealth/socioeconomic status. Among the potential implications are: young and poor men in Nigeria may not be able to find brides and form families due to a potential shortage of females; emigration of young and poor Nigerian men to West (Africa) and elsewhere to seek brides and form families; immigration of marriage age women from West (Africa) and around the world to Nigeria to seek husbands; and low contraceptive use and high fertility rates in Nigeria.

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

Transforming Growth Factor ß Recruits Persistent MAPK Signaling to Regulate Long-Term Memory Consolidation in "Aplysia Californica"

ERIC Educational Resources Information Center

Shobe, Justin; Philips, Gary T.; Carew, Thomas J.

2016-01-01

In this study, we explore the mechanistic relationship between growth factor signaling and kinase activity that supports the protein synthesis-dependent phase of long-term memory (LTM) consolidation for sensitization of "Aplysia." Specifically, we examine LTM for tail shock-induced sensitization of the tail-elicited siphon withdrawal…

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.

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.

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

Predicting subsurface uranium transport: Mechanistic modeling constrained by experimental data

NASA Astrophysics Data System (ADS)

Ottman, Michael; Schenkeveld, Walter D. C.; Kraemer, Stephan

2017-04-01

Depleted uranium (DU) munitions and their widespread use throughout conflict zones around the world pose a persistent health threat to the inhabitants of those areas long after the conclusion of active combat. However, little emphasis has been put on developing a comprehensive, quantitative tool for use in remediation and hazard avoidance planning in a wide range of environments. In this context, we report experimental data on U interaction with soils and sediments. Here, we strive to improve existing risk assessment modeling paradigms by incorporating a variety of experimental data into a mechanistic U transport model for subsurface environments. 20 different soils and sediments from a variety of environments were chosen to represent a range of geochemical parameters that are relevant to U transport. The parameters included pH, organic matter content, CaCO3, Fe content and speciation, and clay content. pH ranged from 3 to 10, organic matter content from 6 to 120 g kg-1, CaCO3 from 0 to 700 g kg-1, amorphous Fe content from 0.3 to 6 g kg-1 and clay content from 4 to 580 g kg-1. Sorption experiments were then performed, and linear isotherms were constructed. Sorption experiment results show that among separate sets of sediments and soils, there is an inverse correlation between both soil pH and CaCO¬3 concentration relative to U sorptive affinity. The geological materials with the highest and lowest sorptive affinities for U differed in CaCO3 and organic matter concentrations, as well as clay content and pH. In a further step, we are testing if transport behavior in saturated porous media can be predicted based on adsorption isotherms and generic geochemical parameters, and comparing these modeling predictions with the results from column experiments. The comparison of these two data sets will examine if U transport can be effectively predicted from reactive transport modeling that incorporates the generic geochemical parameters. This work will serve to show

Insulin-like growth factor 1, glycation and bone fragility: implications for fracture resistance of bone.

PubMed

Sroga, Grażyna E; Wu, Ping-Cheng; Vashishth, Deepak

2015-01-01

Despite our extensive knowledge of insulin-like growth factor 1 (IGF1) action on the growing skeleton, its role in skeletal homeostasis during aging and age-related development of certain diseases is still unclear. Advanced glycation end products (AGEs) derived from glucose are implicated in osteoporosis and a number of diabetic complications. We hypothesized that because in humans and rodents IGF1 stimulates uptake of glucose (a glycation substrate) from the bloodstream in a dose-dependent manner, the decline of IGF1 could be associated with the accumulation of glycation products and the decreasing resistance of bone to fracture. To test the aforementioned hypotheses, we used human tibial posterior cortex bone samples to perform biochemical (measurement of IGF1, fluorescent AGEs and pentosidine (PEN) contents) and mechanical tests (crack initiation and propagation using compact tension specimens). Our results for the first time show a significant, age-independent association between the levels of IGF1 and AGEs. Furthermore, AGEs (fAGEs, PEN) predict propensity of bone to fracture (initiation and propagation) independently of age in human cortical bone. Based on these results we propose a model of IGF1-based regulation of bone fracture. Because IGF1 level increases postnatally up to the juvenile developmental phase and decreases thereafter with aging, we propose that IGF1 may play a protective role in young skeleton and its age-related decline leads to bone fragility and an increased fracture risk. Our results may also have important implications for current understanding of osteoporosis- and diabetes-related bone fragility as well as in the development of new diagnostic tools to screen for fragile bones.

Insulin-Like Growth Factor 1, Glycation and Bone Fragility: Implications for Fracture Resistance of Bone

PubMed Central

Sroga, Grażyna E.; Wu, Ping-Cheng; Vashishth, Deepak

2015-01-01

Despite our extensive knowledge of insulin-like growth factor 1 (IGF1) action on the growing skeleton, its role in skeletal homeostasis during aging and age-related development of certain diseases is still unclear. Advanced glycation end products (AGEs) derived from glucose are implicated in osteoporosis and a number of diabetic complications. We hypothesized that because in humans and rodents IGF1 stimulates uptake of glucose (a glycation substrate) from the bloodstream in a dose-dependent manner, the decline of IGF1 could be associated with the accumulation of glycation products and the decreasing resistance of bone to fracture. To test the aforementioned hypotheses, we used human tibial posterior cortex bone samples to perform biochemical (measurement of IGF1, fluorescent AGEs and pentosidine (PEN) contents) and mechanical tests (crack initiation and propagation using compact tension specimens). Our results for the first time show a significant, age-independent association between the levels of IGF1 and AGEs. Furthermore, AGEs (fAGEs, PEN) predict propensity of bone to fracture (initiation and propagation) independently of age in human cortical bone. Based on these results we propose a model of IGF1-based regulation of bone fracture. Because IGF1 level increases postnatally up to the juvenile developmental phase and decreases thereafter with aging, we propose that IGF1 may play a protective role in young skeleton and its age-related decline leads to bone fragility and an increased fracture risk. Our results may also have important implications for current understanding of osteoporosis- and diabetes-related bone fragility as well as in the development of new diagnostic tools to screen for fragile bones. PMID:25629402

White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer's Disease.

PubMed

Klosinski, Lauren P; Yao, Jia; Yin, Fei; Fonteh, Alfred N; Harrington, Michael G; Christensen, Trace A; Trushina, Eugenia; Brinton, Roberta Diaz

2015-12-01

White matter degeneration is a pathological hallmark of neurodegenerative diseases including Alzheimer's. Age remains the greatest risk factor for Alzheimer's and the prevalence of age-related late onset Alzheimer's is greatest in females. We investigated mechanisms underlying white matter degeneration in an animal model consistent with the sex at greatest Alzheimer's risk. Results of these analyses demonstrated decline in mitochondrial respiration, increased mitochondrial hydrogen peroxide production and cytosolic-phospholipase-A2 sphingomyelinase pathway activation during female brain aging. Electron microscopic and lipidomic analyses confirmed myelin degeneration. An increase in fatty acids and mitochondrial fatty acid metabolism machinery was coincident with a rise in brain ketone bodies and decline in plasma ketone bodies. This mechanistic pathway and its chronologically phased activation, links mitochondrial dysfunction early in aging with later age development of white matter degeneration. The catabolism of myelin lipids to generate ketone bodies can be viewed as a systems level adaptive response to address brain fuel and energy demand. Elucidation of the initiating factors and the mechanistic pathway leading to white matter catabolism in the aging female brain provides potential therapeutic targets to prevent and treat demyelinating diseases such as Alzheimer's and multiple sclerosis. Targeting stages of disease and associated mechanisms will be critical.

White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer's Disease

PubMed Central

Klosinski, Lauren P.; Yao, Jia; Yin, Fei; Fonteh, Alfred N.; Harrington, Michael G.; Christensen, Trace A.; Trushina, Eugenia; Brinton, Roberta Diaz

2015-01-01

White matter degeneration is a pathological hallmark of neurodegenerative diseases including Alzheimer's. Age remains the greatest risk factor for Alzheimer's and the prevalence of age-related late onset Alzheimer's is greatest in females. We investigated mechanisms underlying white matter degeneration in an animal model consistent with the sex at greatest Alzheimer's risk. Results of these analyses demonstrated decline in mitochondrial respiration, increased mitochondrial hydrogen peroxide production and cytosolic-phospholipase-A2 sphingomyelinase pathway activation during female brain aging. Electron microscopic and lipidomic analyses confirmed myelin degeneration. An increase in fatty acids and mitochondrial fatty acid metabolism machinery was coincident with a rise in brain ketone bodies and decline in plasma ketone bodies. This mechanistic pathway and its chronologically phased activation, links mitochondrial dysfunction early in aging with later age development of white matter degeneration. The catabolism of myelin lipids to generate ketone bodies can be viewed as a systems level adaptive response to address brain fuel and energy demand. Elucidation of the initiating factors and the mechanistic pathway leading to white matter catabolism in the aging female brain provides potential therapeutic targets to prevent and treat demyelinating diseases such as Alzheimer's and multiple sclerosis. Targeting stages of disease and associated mechanisms will be critical. PMID:26844268

Factors affecting the job stress and job satisfaction of Australian nurses: implications for recruitment and retention.

PubMed

Bartram, Timothy; Joiner, Therese A; Stanton, Pauline

2004-10-01

Against a background of nurse shortages in Australian hospitals, a significant challenge facing the healthcare sector is the recruitment and retention of nurses. The job stress and job satisfaction of nurses have been associated with recruitment and retention. The aim of this study is to consider two factors that may contribute to the job satisfaction and job stress of nurses: social support and empowerment. Using a sample of 157 registered nurses in a private hospital in Melbourne, Australia, we found that social support derived from the nurse's supervisor and work colleagues lowered job stress and at the same time increased job satisfaction. The presence of nurse empowerment, meaning, impact, competence and self-determination, also lowered job stress and increased job satisfaction. Finally, we discuss contributions of this study and implications for recruitment and retention of nurses in the health sector.

Security Implications of ISAF Exit from Afghanistan on South Asia

DTIC Science & Technology

2014-12-12

Afghanistan for their security interests. Cindy A. Hurst and Robert Mathers , discussed the implications of US withdrawal with reference to the presence...... Mathers , “Strategic Implications of the Afghan Mother Lode.” 42 CHAPTER 5 ANALYSIS OF EXTERNAL FACTORS Afghanistan’s future will be determined by

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.

Evaluation of LTPP Climatic Data for Use in Mechanistic-Empirical Pavement Design Guide (MEPDG) Calibration and Other Pavement Analysis

DOT National Transportation Integrated Search

2015-02-01

This TechBrief describes evaluating the use of the Modern-Era Retrospective Analysis for Research and Applications (MERRA) product as an alternative climatic data source for the Mechanistic-Empirical Pavement Design Guide (MEPDG) and other transporta...

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.

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.

Mechanistic Target of Rapamycin (mTOR) Inhibition Synergizes with Reduced Internal Ribosome Entry Site (IRES)-mediated Translation of Cyclin D1 and c-MYC mRNAs to Treat Glioblastoma.

PubMed

Holmes, Brent; Lee, Jihye; Landon, Kenna A; Benavides-Serrato, Angelica; Bashir, Tariq; Jung, Michael E; Lichtenstein, Alan; Gera, Joseph

2016-07-01

Our previous work has demonstrated an intrinsic mRNA-specific protein synthesis salvage pathway operative in glioblastoma (GBM) tumor cells that is resistant to mechanistic target of rapamycin (mTOR) inhibitors. The activation of this internal ribosome entry site (IRES)-dependent mRNA translation initiation pathway results in continued translation of critical transcripts involved in cell cycle progression in the face of global eIF-4E-mediated translation inhibition. Recently we identified compound 11 (C11), a small molecule capable of inhibiting c-MYC IRES translation as a consequence of blocking the interaction of a requisite c-MYC IRES trans-acting factor, heterogeneous nuclear ribonucleoprotein A1, with its IRES. Here we demonstrate that C11 also blocks cyclin D1 IRES-dependent initiation and demonstrates synergistic anti-GBM properties when combined with the mechanistic target of rapamycin kinase inhibitor PP242. The structure-activity relationship of C11 was investigated and resulted in the identification of IRES-J007, which displayed improved IRES-dependent initiation blockade and synergistic anti-GBM effects with PP242. Mechanistic studies with C11 and IRES-J007 revealed binding of the inhibitors within the UP1 fragment of heterogeneous nuclear ribonucleoprotein A1, and docking analysis suggested a small pocket within close proximity to RRM2 as the potential binding site. We further demonstrate that co-therapy with IRES-J007 and PP242 significantly reduces tumor growth of GBM xenografts in mice and that combined inhibitor treatments markedly reduce the mRNA translational state of cyclin D1 and c-MYC transcripts in these tumors. These data support the combined use of IRES-J007 and PP242 to achieve synergistic antitumor responses in GBM. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Fibroblast Growth Factors and Vascular Endothelial Growth Factor Promote Cardiac Reprogramming under Defined Conditions.

PubMed

Yamakawa, Hiroyuki; Muraoka, Naoto; Miyamoto, Kazutaka; Sadahiro, Taketaro; Isomi, Mari; Haginiwa, Sho; Kojima, Hidenori; Umei, Tomohiko; Akiyama, Mizuha; Kuishi, Yuki; Kurokawa, Junko; Furukawa, Tetsushi; Fukuda, Keiichi; Ieda, Masaki

2015-12-08

Fibroblasts can be directly reprogrammed into cardiomyocyte-like cells (iCMs) by overexpression of cardiac transcription factors, including Gata4, Mef2c, and Tbx5; however, this process is inefficient under serum-based culture conditions, in which conversion of partially reprogrammed cells into fully reprogrammed functional iCMs has been a major hurdle. Here, we report that a combination of fibroblast growth factor (FGF) 2, FGF10, and vascular endothelial growth factor (VEGF), termed FFV, promoted cardiac reprogramming under defined serum-free conditions, increasing spontaneously beating iCMs by 100-fold compared with those under conventional serum-based conditions. Mechanistically, FFV activated multiple cardiac transcriptional regulators and converted partially reprogrammed cells into functional iCMs through the p38 mitogen-activated protein kinase and phosphoinositol 3-kinase/AKT pathways. Moreover, FFV enabled cardiac reprogramming with only Mef2c and Tbx5 through the induction of cardiac reprogramming factors, including Gata4. Thus, defined culture conditions promoted the quality of cardiac reprogramming, and this finding provides new insight into the mechanism of cardiac reprogramming. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

TNF and granulocyte macrophage-colony stimulating factor interdependence mediates inflammation via CCL17

PubMed Central

Cook, Andrew D.; Khiew, Hsu-Wei; Christensen, Anne D.; Fleetwood, Andrew J.; Lacey, Derek C.; Smith, Julia E.; Förster, Irmgard

2018-01-01

TNF and granulocyte macrophage-colony stimulating factor (GM-CSF) have proinflammatory activity and both contribute, for example, to rheumatoid arthritis pathogenesis. We previously identified a new GM-CSF→JMJD3 demethylase→interferon regulatory factor 4 (IRF4)→CCL17 pathway that is active in monocytes/macrophages in vitro and important for inflammatory pain, as well as for arthritic pain and disease. Here we provide evidence for a nexus between TNF and this pathway, and for TNF and GM-CSF interdependency. We report that the initiation of zymosan-induced inflammatory pain and zymosan-induced arthritic pain and disease are TNF dependent. Once arthritic pain and disease are established, blockade of GM-CSF or CCL17, but not of TNF, is still able to ameliorate them. TNF is required for GM-CSF–driven inflammatory pain and for initiation of GM-CSF–driven arthritic pain and disease, but not once they are established. TNF-driven inflammatory pain and TNF-driven arthritic pain and disease are dependent on GM-CSF and mechanistically require the same downstream pathway involving GM-CSF→CCL17 formation via JMJD3-regulated IRF4 production, indicating that GM-CSF and CCL17 can mediate some of the proinflammatory and algesic actions of TNF. Given we found that TNF appears important only early in arthritic pain and disease progression, targeting a downstream mediator, such as CCL17, which appears to act throughout the course of disease, could be effective at ameliorating chronic inflammatory conditions where TNF is implicated. PMID:29563337

Mechanistically Distinct Mouse Models for CRX-Associated Retinopathy

PubMed Central

Tran, Nicholas M.; Zhang, Alan; Zhang, Xiaodong; Huecker, Julie B.; Hennig, Anne K.; Chen, Shiming

2014-01-01

Cone-rod homeobox (CRX) protein is a “paired-like” homeodomain transcription factor that is essential for regulating rod and cone photoreceptor transcription. Mutations in human CRX are associated with the dominant retinopathies Retinitis Pigmentosa (RP), Cone-Rod Dystrophy (CoRD) and Leber Congenital Amaurosis (LCA), with variable severity. Heterozygous Crx Knock-Out (KO) mice (“+/−”) have normal vision as adults and fail to model the dominant human disease. To investigate how different mutant CRX proteins produce distinct disease pathologies, we generated two Crx Knock-IN (K-IN) mouse models: CrxE168d2 (“E168d2”) and CrxR90W (“R90W”). E168d2 mice carry a frameshift mutation in the CRX activation domain, Glu168del2, which is associated with severe dominant CoRD or LCA in humans. R90W mice carry a substitution mutation in the CRX homeodomain, Arg90Trp, which is associated with dominant mild late-onset CoRD and recessive LCA. As seen in human patients, heterozygous E168d2 (“E168d2/+”) but not R90W (“R90W/+”) mice show severely impaired retinal function, while mice homozygous for either mutation are blind and undergo rapid photoreceptor degeneration. E168d2/+ mice also display abnormal rod/cone morphology, greater impairment of CRX target gene expression than R90W/+ or +/− mice, and undergo progressive photoreceptor degeneration. Surprisingly, E168d2/+ mice express more mutant CRX protein than wild-type CRX. E168d2neo/+, a subline of E168d2 with reduced mutant allele expression, displays a much milder retinal phenotype, demonstrating the impact of Crx expression level on disease severity. Both CRX[E168d2] and CRX[R90W] proteins fail to activate transcription in vitro, but CRX[E168d2] interferes more strongly with the function of wild type (WT) CRX, supporting an antimorphic mechanism. E168d2 and R90W are mechanistically distinct mouse models for CRX-associated disease that will allow the elucidation of molecular mechanisms and testing of

Evaluation of current Louisiana flexible pavement structures using PMS data and new mechanistic-empirical pavement design guide : tech summary.

DOT National Transportation Integrated Search

2012-04-01

The new Mechanistic-Empirical Pavement Design Guide (MEPDG) developed under the National Cooperative Highway : Research Program (NCHRP) Project 1-37A represents a major change as compared to the 1993 AASHTO Pavement : Design Guide. MEPDG provides a r...

On the Science of Consciousness: Epistemological Reflections and Clinical Implications.

PubMed

Facco, Enrico; Lucangeli, Daniela; Tressoldi, Patrizio

Consciousness has been one of the most important and tantalizing issues ever since the origin of philosophy and medicine. The concept of consciousness and the so-called "hard problem" (i.e., the mind-brain relationship) are highly complex topics that have yet to be elucidated, involving the realms of both science and philosophy with profound epistemological implications. In the lively debate on the foundations of the science of consciousness there are several potential biases of an essentially philosophical nature, such as those related to the paradigm and axioms adopted, and the ostensible logical contradiction between monism and dualism. Their origin dates back largely to Descartes' thinking and the birth of the new sciences as a compromise with the Inquisition, but they have been handed down through the Enlightenment and Positivism. A proper investigation of consciousness and the world of subjectivity demands a careful reflection on the paradigm of scientific medicine to identify possible flaws and overcome the limits of the mechanistic-reductionist approach. Copyright © 2017 Elsevier Inc. All rights reserved.

Emerging Mechanistic Targets in Lung Injury Induced by Combustion-Generated Particles

PubMed Central

Fariss, Marc W.; Gilmour, M. Ian; Reilly, Christopher A.; Liedtke, Wolfgang; Ghio, Andrew J.

2013-01-01

The mechanism for biological effect following exposure to combustion-generated particles is incompletely defined. The identification of pathways regulating the acute toxicological effects of these particles provides specific targets for therapeutic manipulation in an attempt to impact disease following exposures. Transient receptor potential (TRP) cation channels were identified as “particle sensors” in that their activation was coupled with the initiation of protective responses limiting airway deposition and inflammatory responses, which promote degradation and clearance of the particles. TRPA1, V1, V4, and M8 have a capacity to mediate adverse effects after exposure to combustion-generated particulate matter (PM); relative contributions of each depend upon particle composition, dose, and deposition. Exposure of human bronchial epithelial cells to an organic extract of diesel exhaust particle was followed by TRPV4 mediating Ca++ influx, increased RAS expression, mitogen-activated protein kinase signaling, and matrix metalloproteinase-1 activation. These novel pathways of biological effect can be targeted by compounds that specifically inhibit critical signaling reactions. In addition to TRPs and calcium biochemistry, humic-like substances (HLS) and cell/tissue iron equilibrium were identified as potential mechanistic targets in lung injury after particle exposure. In respiratory epithelial cells, iron sequestration by HLS in wood smoke particle (WSP) was associated with oxidant generation, cell signaling, transcription factor activation, and release of inflammatory mediators. Similar to WSP, cytotoxic insoluble nanosized spherical particles composed of HLS were isolated from cigarette smoke condensate. Therapies that promote bioelimination of HLS and prevent the disruption of iron homeostasis could function to reduce the harmful effects of combustion-generated PM exposure. PMID:23322347

Mechanistic origin of low polarization in aprotic Na-O2 batteries.

PubMed

Ma, Shunchao; McKee, William C; Wang, Jiawei; Guo, Limin; Jansen, Martin; Xu, Ye; Peng, Zhangquan

2017-05-21

Research interest in aprotic sodium-air (Na-O 2 ) batteries is growing because of their considerably high theoretical specific energy and potentially better reversibility than lithium-air (Li-O 2 ) batteries. While Li 2 O 2 has been unequivocally identified as the major discharge product in Li-O 2 batteries containing relatively stable electrolytes, a multitude of discharge products, including NaO 2 , Na 2 O 2 and Na 2 O 2 ·2H 2 O, have been reported for Na-O 2 batteries and the corresponding cathodic electrochemistry remains incompletely understood. Herein, we provide molecular-level insights into the key mechanistic differences between Na-O 2 and Li-O 2 batteries based on gold electrodes in strictly dry, aprotic dimethyl sulfoxide electrolytes through a combination of in situ spectroelectrochemistry and density functional theory based modeling. While like Li-O 2 batteries, the formation of oxygen reduction products (i.e., O 2 - , NaO 2 and Na 2 O 2 ) in Na-O 2 batteries depends critically on the electrode potential, two factors lead to a better reversibility of Na-O 2 electrochemistry, and are therefore highly beneficial to a viable rechargeable metal-air battery design: (i) only O 2 - and NaO 2 , and no Na 2 O 2 , form down to as low as ∼1.5 V vs. Na/Na + during discharge; (ii) solid NaO 2 is quite soluble and its formation and oxidation can proceed through micro-reversible EC (a chemical reaction of the product after the electron transfer) and CE (a chemical reaction preceding the electron transfer) processes, respectively, with O 2 - as the key intermediate.

Factors affecting computer mouse use for young children: implications for AAC.

PubMed

Costigan, F Aileen; Light, Janice C; Newell, Karl M

2012-06-01

More than 12% of preschoolers receiving special education services have complex communication needs, including increasing numbers of children who do not have significant motor impairments (e.g., children with autism spectrum disorders, Down syndrome, etc.). In order to meet their diverse communication needs (e.g., face-to-face, written, Internet, telecommunication), these children may use mainstream technologies accessed via the mouse, yet little is known about factors that affect the mouse performance of young children. This study used a mixed factorial design to investigate the effects of age, target size, and angle of approach on accuracy and time required for accurate target selection with a mouse for 20 3-year-old and 20 4-year-old children. The 4-year-olds were generally more accurate and faster than the 3-year-olds. Target size and angle mediated differences in performance within age groups. The 3-year-olds were more accurate and faster in selecting the medium and large targets relative to the small target, were faster in selecting the large relative to the medium target, and were faster in selecting targets along the vertical relative to the diagonal angle. The 4-year-olds were faster in selecting the medium and large targets relative to the small target. Implications for improving access to AAC include the preliminary suggestion of age-related threshold target sizes that support sufficient accuracy, the possibility of efficiency benefits when target size is increased up to an age-related threshold, and identification of the potential utility of the vertical angle as a context for training navigational input device use.

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

Toward a Rational and Mechanistic Account of Mental Effort.

PubMed

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

2017-07-25

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

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.

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

Implications of prognostic factors and risk groups in the management of differentiated thyroid cancer.

PubMed

Shaha, Ashok R

2004-03-01

The outcome in differentiated thyroid cancer generally depends on the stage of the disease at the time of presentation; prognostic factors such as age, grade, size, extension, or distant metastasis; and risk groups (eg, low or high risk). The author has reviewed a large number of patients with differentiated thyroid cancer to analyze their hypothesis and to confirm that various risk groups have a major implication in relation to extent of the treatment and outcome. Differentiated thyroid cancers make up 90% of all thyroid tumors. The prognostic factors are well defined, such as age, size of the tumor, extrathyroidal extension, presence of distant metastasis, histological appearance, and grade of the tumor. The author has previously divided the risk groups into low-, intermediate-, and high-risk categories based on prognostic factors. The study describes the author's treatment approach related to the extent of thyroidectomy and adjuvant therapy based on various risk groups and the long-term survival. Retrospective. In a retrospective review of 1038 patients with differentiated thyroid carcinoma, various prognostic factors were studied by univariate and multivariate analysis. The significant prognostic factors were studied in detail and, based on these prognostic factors, the patients were divided into low-, intermediate- and high-risk groups. The survival curves were plotted by Kaplan-Meier method. The long-term survivals in low-, intermediate- and high-risk groups were 99%, 87%, and 57% respectively. Based on these risk groups, a decision tree was made regarding extent of thyroidectomy and adjuvant treatment. In the high-risk group and selected patients in the intermediate-risk group, aggressive surgery including removal of all gross disease and extrathyroidal extension with postoperative radioactive iodine ablation is recommended. In the low-risk group and selected patients in the intermediate-risk group, lobectomy appears to be satisfactory with excellent long

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…

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

Channel microband electrode arrays for mechanistic electrochemistry. Two-dimensional voltammetry:  transport-limited currents.

PubMed

Alden, J A; Feldman, M A; Hill, E; Prieto, F; Oyama, M; Coles, B A; Compton, R G; Dobson, P J; Leigh, P A

1998-05-01

A channel electrode array, with electrodes ranging in size from the millimeter to the submicrometer scale, is used for the amperometric interrogation of mechanistically complex electrode processes. In this way, the transport-limited current, measured as a function of both electrode size and electrolyte flow rate (convection), is shown to provide a highly sensitive probe of mechanism and kinetics. The application of "two-dimensional voltammetry" to diverse electrode processes, including E, ECE, ECEE, EC', and DISP2 reactions, is reported.

A Biologically Informed, Mechanistic Model of Desert Shrub Population Dynamics Bearing on Arid Landscape Evolution

NASA Astrophysics Data System (ADS)

Worman, Stacey; Furbish, David; Fathel, Siobhan

2014-05-01

In arid landscapes, desert shrubs individually and collectively modify how sediment is transported (e.g by wind, overland-flow, and rain-splash). Addressing how desert shrubs modify landscapes on geomorphic timescales therefore necessitates spanning multiple shrub lifetimes and accounting for how processes affecting shrub dynamics on these longer timescales (e.g. fire, grazing, drought, and climate change) may in turn impact sediment transport. To fulfill this need, we present a mechanistic model of the spatiotemporal dynamics of a desert-shrub population that uses a simple accounting framework and tracks individual shrubs as they enter, age, and exit the population (via recruitment, growth, and mortality). Our model is novel insomuch as it (1) features a strong biophysical foundation, (2) mimics well-documented aspects of how shrub populations respond to changes in precipitation, and (3) possesses the process granularity appropriate for use in geomorphic simulations. In a complimentary abstract (Fathel et al. 2014), we demonstrate the potential of this biological model by coupling it to a physical model of rain-splash sediment transport: We mechanistically reproduce the empirical observation that the erosion rate of a hillslope decreases as its vegetation coverage increases and we predict erosion rates under different climate-change scenarios.

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

Inhibition of GNNQQNY prion peptide aggregation by trehalose: a mechanistic view.

PubMed

Katyal, Nidhi; Deep, Shashank

2017-07-26

Deposition of amyloid fibrils is the seminal event in the pathogenesis of numerous neurodegenerative diseases. The formation of this amyloid assembly is the manifestation of a cascade of structural transitions including toxic oligomer formation in the early stages of aggregation. Thus a viable therapeutic strategy involves the use of small molecular ligands to interfere with this assembly. In this perspective, we have explored the kinetics of aggregate formation of the fibril forming GNNQQNY peptide fragment from the yeast prion protein SUP35 using multiple all atom MD simulations with explicit solvent and provided mechanistic insights into the way trehalose, an experimentally known aggregation inhibitor, modulates the aggregation pathway. The results suggest that the assimilation process is impeded by different barriers at smaller and larger oligomeric sizes: the initial one being easily surpassed at higher temperatures and peptide concentrations. The kinetic profile demonstrates that trehalose delays the aggregation process by increasing both these activation barriers, specifically the latter one. It increases the sampling of small-sized aggregates that lack the beta sheet conformation. Analysis reveals that the barrier in the growth of larger stable oligomers causes the formation of multiple stable small oligomers which then fuse together bimolecularly. The PCA of 26 properties was carried out to deconvolute the events within the temporary lag phases, which suggested dynamism in lags involving an increase in interchain contacts and burial of SASA. The predominant growth route is monomer addition, which changes to condensation on account of a large number of depolymerisation events in the presence of trehalose. The favourable interaction of trehalose specifically with the sidechain of the peptide promotes crowding of trehalose molecules in its vicinity - the combination of both these factors imparts the observed behaviour. Furthermore, increasing trehalose

Bridging the boundaries between scientists and clinicians-mechanistic hypotheses and patient stories in risk assessment of drugs.

PubMed

Rocca, Elena

2017-02-01

The cultural divide between scientists and clinicians has been described as undermining the advance of medical science, by hindering the production of practice-relevant research and of research-informed clinical decisions. Here, I consider the field of post-marketing risk assessment of drugs as an example of strict interdependence between basic biomedical research, clinical research, and clinical evaluation and show how it would benefit from a closer collaboration between scientists and clinicians. The risk assessment of drugs after their marketing relies on spontaneous adverse effect reports to drug agencies and on peer-reviewed case reports. I emphasize the importance of qualitative analysis of such reports for the improvement of mechanistic understanding of harmful effects of drugs. I argue that mechanistic explanations of drug effects are at least as important as determination of their frequency, in order to establish causation. An ideal risk assessment, then, verifies not only the frequency of undesired effects but also why and how the harm happens. For this purpose, the frequency or novelty of the unintended outcome, although contextually indicative, should not determine the epistemic value of a report. Details about the context that generated an unexpected outcome, instead, can offer the chance of improving causal understanding about how the intervention works. This is illustrated through examples from medical research. Mechanistic understanding is a domain of joint collaboration among (1) clinicians, in charge of detailed, qualitative reporting of patient stories about side effects, (2) qualitative clinical researchers, in charge of analyzing clinical contexts or harmful effects and formulating explanatory hypotheses, and (3) basic biomedical researchers, in charge of verifying such hypotheses. In addition, direct information flow can on one side focus clinicians' attention on knowledge gaps about drugs/effects where more research is needed, while on the

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

PubMed

Stolle, Achim; Ondruschka, Bernd; Findeisen, Matthias

2008-11-07

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

Cadmium in edible mushrooms from NW Spain: Bioconcentration factors and consumer health implications.

PubMed

Melgar, M Julia; Alonso, Julián; García, M Angeles

2016-02-01

Mushrooms do not constitute a significant portion of the human diet, but the consumption of wild and cultivated mushrooms has become increasingly in recent years. Some species accumulate high levels of toxic metals, both in unpolluted and polluted areas. In this study, we examined the accumulation capacity of cadmium in edible mushrooms in relation to certain factors and their possible toxicological implications. Cadmium concentrations were determined by an ICP-MS spectrometer in 238 samples of the fruiting bodies of 28 wild and cultivated growing edible mushrooms species and the underlying soil. The hymenophore (H) and the rest of the fruiting body (RFB) were analysed separately. The highest mean cadmium concentration (mg/kg dry weight) was found in Agaricus macrosporus (52.9 in H and 28.3 in RFB). All mushroom species accumulated cadmium in relation to the underlying soils. There were statistically significant differences between the hymenophore and the rest of the fruiting body (p < 0.001). Cadmium concentrations were compared to data in the literature and to levels set by legislation. It was concluded that consumption of our studied mushrooms is not a toxicological risk as far as cadmium content is concerned, although the species A. macrosporus should not be consumed. Copyright © 2015 Elsevier Ltd. All rights reserved.

The effect of zinc on amyloid β-protein assembly and toxicity: A mechanistic investigation

NASA Astrophysics Data System (ADS)

Solomonov, Inna; Sagi, Irit

2014-10-01

Neurotoxic assemblies of amyloid β-protein (Aβ) are widely believed to be the cause for Alzheimer's disease (AD). Therefore, understanding the factors and mechanisms that control, modulate, and inhibit formation of these assemblies is crucial for the development of therapeutic intervention of AD. This information also can contribute significantly to our understanding of the mechanisms of other amyloidosis diseases, such as Parkinson's disease, Huntington's disease, type 2 diabetes, amyotrophic lateral sclerosis (Lou Gehrig's disease) and prion diseases (e.g. Mad Cow disease). We have developed a multidisciplinary experimental strategy to study structural and dynamic mechanistic aspects that underlie the Aβ assembly process. Utilizing this strategy, we explored the molecular basis leading to the perturbation of the Aβ assembly process by divalent metal ions, mainly Zn2+ ions. Using Zn2+ as reaction physiological relevant probes, it was demonstrated that Zn2+ rapidly (milliseconds) induce self-assembly of Aβ aggregates and stabilize them in a manner that prevents formation of Aβ fibrils. Importantly, the early-formed intermediates are substantially more neurotoxic than fibrils. Our results suggest that relevant Aβ modulators should be targeted against the rapidly evolved intermediate states of Aβ assembly. The design of such modulators is challenging, as they have to compete with different natural mediators (such as Zn2+) of Aβ aggregation, which diverse Aβ assemblies in both specific and nonspecific manners.

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.

Ventricular arrhythmias and sudden cardiac arrest in Takotsubo cardiomyopathy: Incidence, predictive factors, and clinical implications.

PubMed

Jesel, Laurence; Berthon, Charlotte; Messas, Nathan; Lim, Han S; Girardey, Mélanie; Marzak, Halim; Marchandot, Benjamin; Trinh, Annie; Ohlmann, Patrick; Morel, Olivier

2018-04-06

Takotsubo cardiomyopathy (TTC) is a stress-related transient cardiomyopathy. Life-threatening arrhythmias (LTA) can occur and worsen prognosis. The purpose of this study was to assess the incidence and outcome of LTA in TTC, as well as its predictive factors and clinical implications. We studied 214 consecutive cases of TTC over 8 years. The study cohort was divided into 2 groups: those with LTA (LTA group) and those without (non-LTA group). LTA was defined as ventricular tachycardia, ventricular fibrillation, or cardiac arrest. LTA occurred in 10.7% of patients mainly in the first 24 hours of hospitalization: ventricular tachycardia (n = 2), ventricular fibrillation (n = 11), cardiac arrest (n = 10: 5 asystole, 3 complete heart block, and 2 sinoatrial block). LTA were associated with lower left ventricular ejection fraction (LVEF) and a high rate of conduction disturbances. In-hospital (39.1% vs 8.9%; P < .001) and 1-year mortality (47.8% vs 14.1%; P < .001) rates were significantly increased in the LTA group. LVEF and QRS duration >105 ms were independent predictors of LTA. In cases where a device was implanted, conduction disturbances persisted after the index event despite complete recovery of LVEF. There was no ventricular arrhythmia recurrence during follow-up. LTA occur early in patients presenting with TTC and is associated with significantly worse short- and long-term prognosis. Left ventricular impairment and QRS duration >105 ms are independent predictors of LTA. Ventricular arrhythmias occurred in the acute phase without further recurrence recorded in hospital survivors, whereas severe conduction disorders persisted during long-term follow-up. These findings may have implications on the choice of device therapy for this specific patient subgroup. Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

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

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.

Aggressive behaviour in adolescent psychiatric settings: what are risk factors, possible interventions and implications for nursing practice? A literature review.

PubMed

Hage, S; Van Meijel, B; Fluttert, F; Berden, G F M G

2009-09-01

This study was aimed to identify the risk factors of aggressive behaviour in adolescents (1318 years), and to describe available intervention strategies. The findings are evaluated on the basis of their implications for nursing practice. Aggressive behaviour in adolescent psychiatric settings is a neglected research area. The consequences of aggressive behaviour on nurses, other patients and the therapeutic environment can be profound. For the development and implementation of innovative intervention strategies aimed at preventing aggressive behaviour in adolescent psychiatric patients, knowledge of risk factors and evidence-based interventions for aggressive behaviour are of the utmost importance. A systematic search of PubMed, Cinahl, PsychINFO and Cochrane Systematic Reviews (19912007) was employed. The risk factors for aggressive behaviour comprise personal and environmental risk factors. Some risk factors can be influenced by nursing intervention strategies. Available intervention programmes range from interpersonal skills training to massage therapy, parent management training, functional family therapy and multi-systemic therapy. The most effective programmes combine interpersonal skills training with parent management training. No specific nursing intervention programmes were found for dealing with aggressive behaviour in adolescent patients. Nursing staff can assist in achieving a systematic improvement in the treatment outcomes of existing intervention programmes for the prevention of aggression. There is a need for specific nursing intervention programmes to deal with aggressive behaviour in adolescent psychiatric settings.

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

Implications of nonrandom seed abscission and global stilling for migration of wind-dispersed plant species.

PubMed

Thompson, Sally E; Katul, Gabriel G

2013-06-01

Migration of plant populations is a potential survival response to climate change that depends critically on seed dispersal. Biological and physical factors determine dispersal and migration of wind-dispersed species. Recent field and wind tunnel studies demonstrate biological adaptations that bias seed release toward conditions of higher wind velocity, promoting longer dispersal distances and faster migration. However, another suite of international studies also recently highlighted a global decrease in near-surface wind speeds, or 'global stilling'. This study assessed the implications of both factors on potential plant population migration rates, using a mechanistic modeling framework. Nonrandom abscission was investigated using models of three seed release mechanisms: (i) a simple drag model; (ii) a seed deflection model; and (iii) a 'wear and tear' model. The models generated a single functional relationship between the frequency of seed release and statistics of the near-surface wind environment, independent of the abscission mechanism. An Inertial-Particle, Coupled Eulerian-Lagrangian Closure model (IP-CELC) was used to investigate abscission effects on seed dispersal kernels and plant population migration rates under contemporary and potential future wind conditions (based on reported global stilling trends). The results confirm that nonrandom seed abscission increased dispersal distances, particularly for light seeds. The increases were mitigated by two physical feedbacks: (i) although nonrandom abscission increased the initial acceleration of seeds from rest, the sensitivity of the seed dispersal to this initial condition declined as the wind speed increased; and (ii) while nonrandom abscission increased the mean dispersal length, it reduced the kurtosis of seasonal dispersal kernels, and thus the chance of long-distance dispersal. Wind stilling greatly reduced the modeled migration rates under biased seed release conditions. Thus, species that require

Mechanistic models as a transferable framework for projecting effects of habitat change on production and delivery of ecosystem services

EPA Science Inventory

Drawing a link between habitat change and the production and delivery of ecosystem services is a priority in coastal estuarine ecosystems. Mechanistic modeling tools are highly functional for exploring this link because they allow for the synthesis of multiple ecological and beh...

GENE ARRAYS FOR ELUCIDATING MECHANISTIC DATA FROM MODELS OF MALE INFERTILITY AND CHEMICAL EXPOSURE IN MICE, RATS AND HUMANS

EPA Science Inventory

Gene arrays for elucidating mechanistic data from models of male infertility and chemical exposure in mice, rats and humans
John C. Rockett and David J. Dix
Gamete and Early Embryo Biology Branch, Reproductive Toxicology Division, National Health and Environmental Effects ...

Redefining the WISC-R: Implications for Professional Practice and Public Policy.

ERIC Educational Resources Information Center

Macmann, Gregg M.; Barnett, David W.

1992-01-01

The factor structure of the Wechsler Intelligence Scale for Children (Revised) was examined in the standardization sample using new methods of factor analysis. The substantial overlap across factors was most parsimoniously represented by a single general factor. Implications for public policy regarding the purposes and outcomes of special…

Mechanistic insights into the link between visfatin gene C-1535T polymorphism and coronary artery disease: an in vitro study.

PubMed

Wang, Yong-Sheng; Gao, Wei; Li, Hong-Fen; Wang, Ze-Mu; Zhu, Jun; Zhao, Huan; Yan, Jian-Jun; Jia, En-Zhi; Yang, Zhi-Jian; Wang, Lian-Sheng

2012-04-01

Visfatin, a pro-inflammatory cytokine predominantly released from leucocytes, is correlated with coronary artery disease (CAD). We have previously reported that the -1535C>T polymorphism (rs1330082), which located on the promoter region of visfatin, was associated with decreased risk of CAD. Here, we investigated the underlying mechanism by which this polymorphism affects the genetic susceptibility to CAD. The difference of the promoter activities between -1535T variant and -1535C allele was tested by luciferase reporter gene assay. The difference of transcription factor binding activities between T and C allele was evaluated by electrophoretic mobility shift assay. In reporter gene assay, we showed that the T variant had a significantly reduced transcriptional activity compared with the C allele. The T-variant significantly attenuated the promoter binding affinity to nuclear transcription factors and this effect became much obvious after treatment with TNF-α. Moreover, competition experiment revealed that the retarded complex formed by T-1535- or C-1535-probe binding to nuclear extracts was nearly completely inhibited by unlabeled activator protein-1 (AP-1) specific probe, indicating that AP-1 might be the target nuclear effector. Taken together, our data provided potential mechanistic link between the visfatin -1535C>T polymorphism and reduced CAD risk.

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.

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.

How long bones grow children: Mechanistic paths to variation in human height growth.

PubMed

Lampl, Michelle; Schoen, Meriah

2017-03-01

Eveleth and Tanner's descriptive documentation of worldwide variability in human growth provided evidence of the interaction between genetics and environment during development that has been foundational to the science of human growth. There remains a need, however, to describe the mechanistic foundations of variability in human height growth patterns. A review of research documenting cellular activities at the endochondral growth plate aims to show how the unique microenvironment and cell functions during the sequential phases of the chondrocyte lifecycle affect long bone elongation, a fundamental source of height growth. There are critical junctures within the chondrocytic differentiation cascade at which environmental influences are integrated and have the ability to influence progression to the hypertrophic chondrocyte phase, the primary driver of long bone elongation. Phenotypic differences in height growth patterns reflect variability in amplitude and frequency of discretely timed hypertrophic cellular expansion events, the cellular basis of saltation and stasis growth biology. Final height is a summary of the dynamic processes carried out by the growth plate cellular machinery. As these cell-level mechanisms unfold in an individual, time-specific manner, there are many critical points at which a genetic growth program can be enhanced or perturbed. Recognizing both the complexity and fluidity of this adaptive system questions the likelihood of a single, optimal growth pattern and instead identifies a larger bandwidth of saltatory frequencies for "normal" growth. Further inquiry into mechanistic sources of variability acting at critical organizational points of chondrogenesis can provide new opportunities for growth interventions. © 2017 Wiley Periodicals, Inc.

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

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

NASA Astrophysics Data System (ADS)

Zhang, Wenyan; Wirtz, Kai

2017-10-01

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

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.

The crystal structure of the C45S mutant of annelid Arenicola marina peroxiredoxin 6 supports its assignment to the mechanistically typical 2-Cys subfamily without any formation of toroid-shaped decamers

PubMed Central

Smeets, Aude; Loumaye, Eléonore; Clippe, André; Rees, Jean-François; Knoops, Bernard; Declercq, Jean-Paul

2008-01-01

The peroxiredoxins (PRDXs) define a superfamily of thiol-dependent peroxidases able to reduce hydrogen peroxide, alkyl hydroperoxides, and peroxynitrite. Besides their cytoprotective antioxidant function, PRDXs have been implicated in redox signaling and chaperone activity, the latter depending on the formation of decameric high-molecular-weight structures. PRDXs have been mechanistically divided into three major subfamilies, namely typical 2-Cys, atypical 2-Cys, and 1-Cys PRDXs, based on the number and position of cysteines involved in the catalysis. We report the structure of the C45S mutant of annelid worm Arenicola marina PRDX6 in three different crystal forms determined at 1.6, 2.0, and 2.4 Å resolution. Although A. marina PRDX6 was cloned during the search of annelid homologs of mammalian 1-Cys PRDX6s, the crystal structures support its assignment to the mechanistically typical 2-Cys PRDX subfamily. The protein is composed of two distinct domains: a C-terminal domain and an N-terminal domain exhibiting a thioredoxin fold. The subunits are associated in dimers compatible with the formation of intersubunit disulfide bonds between the peroxidatic and the resolving cysteine residues in the wild-type enzyme. The packing of two crystal forms is very similar, with pairs of dimers associated as tetramers. The toroid-shaped decamers formed by dimer association and observed in most typical 2-Cys PRDXs is not present. Thus, A. marina PRDX6 presents structural features of typical 2-Cys PRDXs without any formation of toroid-shaped decamers, suggesting that it should function more like a cytoprotective antioxidant enzyme or a modulator of peroxide-dependent cell signaling rather than a molecular chaperone. PMID:18359859

Implication of novel thiazolo-thiophene derivative (MCD-KV-10) for management of asthma.

PubMed

Patil, Dhiraj; Dash, Ranjeet Prasad; Thakur, Sandeep Kumar; Pandya, Amit N; Venkatesh, P; Vasu, Kamala K; Nivsarkar, Manish

2015-04-01

Asthma is multifaceted disease where many targets contribute towards its development and progression. Among these, adenosine receptor subtypes play a major role. MCD-KV-10, a novel thiazolo-thiophene was designed and evaluated pre-clinically for its implication in management of asthma. This compound showed good affinity and selectivity towards A(2A)/A3 adenosine receptor (AR) subtypes. Furthermore, MCD-KV-10 was evaluated for in vitro lipoxygenase inhibition activity; in vivo mast cell stabilization potential and in vivo anti-asthmatic activity was done in ovalbumin-induced airway inflammation model in guinea pigs. The compound showed good (>57%) inhibition of lipoxygenase enzyme and also effectively protected mast cell degranulation (>63%). The compound showed good anti-asthmatic activity as inferred from the in vivo studies. These results indicate that MCD-KV-10 has an inhibitory effect on airway inflammation. Though, we have identified a potential candidate for management of asthma, further mechanistic studies are needed.

Dronabinol and chronic pain: importance of mechanistic considerations.

PubMed

de Vries, Marjan; van Rijckevorsel, Dagmar C M; Wilder-Smith, Oliver H G; van Goor, Harry

2014-08-01

Although medicinal cannabis has been used for many centuries, the therapeutic potential of delta-9-tetrahydrocannabinol (Δ9-THC; international non-proprietary name = dronabinol) in current pain management remains unclear. Several pharmaceutical products with defined natural or synthesized Δ9-THC content have been developed, resulting in increasing numbers of clinical trials investigating the analgesic efficacy of dronabinol in various pain conditions. Different underlying pain mechanisms, including sensitization of nociceptive sensory pathways and alterations in cognitive and autonomic processing, might explain the varying analgesic effects of dronabinol in chronic pain states. The pharmacokinetics, pharmacodynamics and mechanisms of action of products with a defined dronabinol content are summarized. Additionally, randomized clinical trials investigating the analgesic efficacy of pharmaceutical cannabis based products are reviewed for the treatment of chronic nonmalignant pain. We suggest a mechanism-based approach beyond measurement of subjective pain relief to evaluate the therapeutic potential of dronabinol in chronic pain management. Development of objective mechanistic diagnostic biomarkers reflecting altered sensory and cognitive processing in the brain is essential to evaluate dronabinol induced analgesia, and to permit identification of responders and/or non-responders to dronabinol treatment.

At the Intersection of Attention and Memory: The Mechanistic Role of the Posterior Parietal Lobe in Working Memory

ERIC Educational Resources Information Center

Berryhill, Marian E.; Chein, Jason; Olson, Ingrid R.

2011-01-01

Portions of the posterior parietal cortex (PPC) play a role in working memory (WM) yet the precise mechanistic function of this region remains poorly understood. The "pure storage" hypothesis proposes that this region functions as a short-lived modality-specific memory store. Alternatively, the "internal attention" hypothesis proposes that the PPC…

MECHANISTIC ROLES OF SOIL HUMUS AND MINERALS IN THE SORPTION OF NONIONIC ORGANIC COMPOUNDS FROM AQUEOUS AND ORGANIC SOLUTIONS

EPA Science Inventory

Mechanistic roles of soil humus and soil minerals and their contributions to soil sorption of nonionic organic compounds from aqueous and organic solutions are illustrated. Parathion and lindane are used as model solutes on two soils that differ greatly in their humic and mineral...

Brain-Derived Neurotrophic Factor Signaling Rewrites the Glucocorticoid Transcriptome via Glucocorticoid Receptor Phosphorylation

PubMed Central

Lambert, W. Marcus; Xu, Chong-Feng; Neubert, Thomas A.; Chao, Moses V.

2013-01-01

Abnormal glucocorticoid and neurotrophin signaling has been implicated in numerous psychiatric disorders. However, the impact of neurotrophic signaling on glucocorticoid receptor (GR)-dependent gene expression is not understood. We therefore examined the impact of brain-derived neurotrophic factor (BDNF) signaling on GR transcriptional regulatory function by gene expression profiling in primary rat cortical neurons stimulated with the selective GR agonist dexamethasone (Dex) and BDNF, alone or in combination. Simultaneous treatment with BDNF and Dex elicited a unique set of GR-responsive genes associated with neuronal growth and differentiation and also enhanced the induction of a large number of Dex-sensitive genes. BDNF via its receptor TrkB enhanced the transcriptional activity of a synthetic GR reporter, suggesting a direct effect of BDNF signaling on GR function. Indeed, BDNF treatment induces the phosphorylation of GR at serine 155 (S155) and serine 287 (S287). Expression of a nonphosphorylatable mutant (GR S155A/S287A) impaired the induction of a subset of BDNF- and Dex-regulated genes. Mechanistically, BDNF-induced GR phosphorylation increased GR occupancy and cofactor recruitment at the promoter of a BDNF-enhanced gene. GR phosphorylation in vivo is sensitive to changes in the levels of BDNF and TrkB as well as stress. Therefore, BDNF signaling specifies and amplifies the GR transcriptome through a coordinated GR phosphorylation-dependent detection mechanism. PMID:23878391

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.

Wear-dependent specific coefficients in a mechanistic model for turning of nickel-based superalloy with ceramic tools

NASA Astrophysics Data System (ADS)

López de Lacalle, Luis Norberto; Urbicain Pelayo, Gorka; Fernández-Valdivielso, Asier; Alvarez, Alvaro; González, Haizea

2017-09-01

Difficult to cut materials such as nickel and titanium alloys are used in the aeronautical industry, the former alloys due to its heat-resistant behavior and the latter for the low weight - high strength ratio. Ceramic tools made out alumina with reinforce SiC whiskers are a choice in turning for roughing and semifinishing workpiece stages. Wear rate is high in the machining of these alloys, and consequently cutting forces tends to increase along one operation. This paper establishes the cutting force relation between work-piece and tool in the turning of such difficult-to-cut alloys by means of a mechanistic cutting force model that considers the tool wear effect. The cutting force model demonstrates the force sensitivity to the cutting engagement parameters (ap, f) when using ceramic inserts and wear is considered. Wear is introduced through a cutting time factor, being useful in real conditions taking into account that wear quickly appears in alloys machining. A good accuracy in the cutting force model coefficients is the key issue for an accurate prediction of turning forces, which could be used as criteria for tool replacement or as input for chatter or other models.

Exogenous factors in panic disorder: clinical and research implications.

PubMed

Roy-Byrne, P P; Uhde, T W

1988-02-01

Because panic disorder has an underlying biologic and probably genetic basis, the role of factors outside the organism in initiating and sustaining panic is often overlooked. The authors review certain exogenous factors that seem capable of triggering attacks and/or increasing their frequency and intensity: self-administered pharmacologic agents (caffeine, alcohol, nicotine, over-the-counter cold preparations, cannabis, cocaine); habits (sleep deprivation, diet, exercise, relaxation, hyperventilation); and aspects of the environment (fluorescent lighting, life stressors). There may be a specificity to the action of some of these factors, because certain factors previously thought to trigger panic attacks (e.g., pain, hypoglycemia) have been proved not to have this effect. Although the clinical significance of many of the exogenous factors discussed still awaits empirical confirmation, attention to such factors during the initial evaluation of a patient with panic disorder may be helpful in formulating a successful treatment plan.

Implications of the Fukushima Nuclear Disaster: Man-Made Hazards, Vulnerability Factors, and Risk to Environmental Health.

PubMed

Eddy, Christopher; Sase, Eriko

2015-01-01

The objective of this article was to examine the environmental health implications of the 2011 Fukushima nuclear disaster from an all-hazards perspective. The authors performed a literature review that included Japanese and international nuclear guidance and policy, scientific papers, and reports on the Chernobyl and Three Mile Island disasters while also considering all-hazards preparedness rubrics in the U.S. The examination of the literature resulted in the following: a) the authors' "All-Hazards Planning Reference Model" that distinguishes three planning categories-Disaster Trigger Event, Man-Made Hazards, and Vulnerability Factors; b) the generalization of their model to other countries; and c) advocacy for environmental health end fate to be considered in planning phases to minimize risk to environmental health. This article discusses inconsistencies in disaster planning and nomenclature existing in the studied materials and international guidance and proposes new opportunity for developing predisaster risk assessment, risk communication, and prevention capacity building.

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 ...

Heregulin/ErbB3 Signaling Enhances CXCR4-Driven Rac1 Activation and Breast Cancer Cell Motility via Hypoxia-Inducible Factor 1α

PubMed Central

Lopez-Haber, Cynthia; Barrio-Real, Laura; Casado-Medrano, Victoria

2016-01-01

The growth factor heregulin (HRG), a ligand of ErbB3 and ErbB4 receptors, contributes to breast cancer development and the promotion of metastatic disease, and its expression in breast tumors has been associated with poor clinical outcome and resistance to therapy. In this study, we found that breast cancer cells exposed to sustained HRG treatment show markedly enhanced Rac1 activation and migratory activity in response to the CXCR4 ligand SDF-1/CXCL12, effects mediated by P-Rex1, a Rac-guanine nucleotide exchange factor (GEF) aberrantly expressed in breast cancer. Notably, HRG treatment upregulates surface expression levels of CXCR4, a G protein-coupled receptor (GPCR) implicated in breast cancer metastasis and an indicator of poor prognosis in breast cancer patients. A detailed mechanistic analysis revealed that CXCR4 upregulation and sensitization of the Rac response/motility by HRG are mediated by the transcription factor hypoxia-inducible factor 1α (HIF-1α) via ErbB3 and independently of ErbB4. HRG caused prominent induction in the nuclear expression of HIF-1α, which transcriptionally activates the CXCR4 gene via binding to a responsive element located in positions −1376 to −1372 in the CXCR4 promoter, as revealed by mutagenesis analysis and chromatin immunoprecipitation (ChIP). Our results uncovered a novel function for ErbB3 in enhancing breast cancer cell motility and sensitization of the P-Rex1/Rac1 pathway through HIF-1α-mediated transcriptional induction of CXCR4. PMID:27185877

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

USGS Publications Warehouse

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

2011-01-01

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

Cas9 versus Cas12a/Cpf1: Structure-function comparisons and implications for genome editing.

PubMed

Swarts, Daan C; Jinek, Martin

2018-05-22

Cas9 and Cas12a are multidomain CRISPR-associated nucleases that can be programmed with a guide RNA to bind and cleave complementary DNA targets. The guide RNA sequence can be varied, making these effector enzymes versatile tools for genome editing and gene regulation applications. While Cas9 is currently the best-characterized and most widely used nuclease for such purposes, Cas12a (previously named Cpf1) has recently emerged as an alternative for Cas9. Cas9 and Cas12a have distinct evolutionary origins and exhibit different structural architectures, resulting in distinct molecular mechanisms. Here we compare the structural and mechanistic features that distinguish Cas9 and Cas12a, and describe how these features modulate their activity. We discuss implications for genome editing, and how they may influence the choice of Cas9 or Cas12a for specific applications. Finally, we review recent studies in which Cas12a has been utilized as a genome editing tool. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications Regulatory RNAs/RNAi/Riboswitches > Biogenesis of Effector Small RNAs RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes. © 2018 Wiley Periodicals, Inc.

Ataxin-2: A versatile posttranscriptional regulator and its implication in neural function.

PubMed

Lee, Jongbo; Kim, Minjong; Itoh, Taichi Q; Lim, Chunghun

2018-06-05

Ataxin-2 (ATXN2) is a eukaryotic RNA-binding protein that is conserved from yeast to human. Genetic expansion of a poly-glutamine tract in human ATXN2 has been implicated in several neurodegenerative diseases, likely acting through gain-of-function effects. Emerging evidence, however, suggests that ATXN2 plays more direct roles in neural function via specific molecular and cellular pathways. ATXN2 and its associated protein complex control distinct steps in posttranscriptional gene expression, including poly-A tailing, RNA stabilization, microRNA-dependent gene silencing, and translational activation. Specific RNA substrates have been identified for the functions of ATXN2 in aspects of neural physiology, such as circadian rhythms and olfactory habituation. Genetic models of ATXN2 loss-of-function have further revealed its significance in stress-induced cytoplasmic granules, mechanistic target of rapamycin signaling, and cellular metabolism, all of which are crucial for neural homeostasis. Accordingly, we propose that molecular evolution has been selecting the ATXN2 protein complex as an important trans-acting module for the posttranscriptional control of diverse neural functions. This explains how ATXN2 intimately interacts with various neurodegenerative disease genes, and suggests that loss-of-function effects of ATXN2 could be therapeutic targets for ATXN2-related neurological disorders. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications. © 2018 Wiley Periodicals, Inc.

Tumorigenic and Antiproliferative Properties of the TALE-Transcription Factors MEIS2D and MEIS2A in Neuroblastoma.

PubMed

Groß, Anja; Schulz, Catrine; Kolb, Jasmine; Koster, Jan; Wehner, Sibylle; Czaplinski, Sebastian; Khilan, Abdulghani; Rohrer, Hermann; Harter, Patrick N; Klingebiel, Thomas; Langer, Julian D; Geerts, Dirk; Schulte, Dorothea

2018-04-15

Neuroblastoma is one of only a few human cancers that can spontaneously regress even after extensive dissemination, a poorly understood phenomenon that occurs in as many as 10% of patients. In this study, we identify the TALE-homeodomain transcription factor MEIS2 as a key contributor to this phenomenon. We identified MEIS2 as a MYCN-independent factor in neuroblastoma and showed that in this setting the alternatively spliced isoforms MEIS2A and MEIS2D exert antagonistic functions. Specifically, expression of MEIS2A was low in aggressive stage 4 neuroblastoma but high in spontaneously regressing stage 4S neuroblastoma. Moderate elevation of MEIS2A expression reduced proliferation of MYCN -amplified human neuroblastoma cells, induced neuronal differentiation and impaired the ability of these cells to form tumors in mice. In contrast, MEIS2A silencing or MEIS2D upregulation enhanced the aggressiveness of the tumor phenotype. Mechanistically, MEIS2A uncoupled a negative feedback loop that restricts accumulation of cellular retinoic acid, an effective agent in neuroblastoma treatment. Overall, our results illuminate the basis for spontaneous regression in neuroblastoma and identify an MEIS2A-specific signaling network as a potential therapeutic target in this common pediatric malignancy. Significance: This study illuminates the basis for spontaneous regressions that can occur in a common pediatric tumor, with implications for the development of new treatment strategies. Cancer Res; 78(8); 1935-47. ©2018 AACR . ©2018 American Association for Cancer Research.

"implicate Order" and the Good Life: Applying David Bohm's Ontology in Human World

NASA Astrophysics Data System (ADS)

Ravn, Ib.

In an attempt to formulate a coherent view of quantum reality, the theoretical physicist David Bohm has proposed a new concept of order to supplement the mechanistic Cartesian order of traditional physics. The "implicate" order is a subtler and deeper order that emphasizes "unbroken wholeness in flowing movement," in contrast to the coarser and more superficial, "explicate" Cartesian order of distinct phenomena. This dissertation attempts to develop a meaning for the idea of implicate order in the world of human experience. First is offered an account of some evolutionary episodes in terms of implicate and explicate order which draws on compatible work in cosmology, embryogenesis, visual perception, brain memory, decision making and phenomenology. Two important characteristics of the implicate order are then identified: in an implicate order, the whole is enfolded (or represented) in its parts; and all parts render different perspectives of the whole. Using arguments from decision making, the study of "flow" in human consciousness, and a model of skill acquisition, it is suggested that these characteristics manifest themselves in the human world as the "unity experience" and the "diversity experience," respectively. The former is the experience that a given part of one's life reveals a larger wholeness or unity; the subject-object distinction is transcended and one becomes absorbed in the flow of whatever activity is pursued. The latter is a deep appreciation of the diversity of ways in which people may seek the unity experience. These experiences are proposed as general values: social and psychological conditions ought to be such that these experiences are enhanced in all people. A two-by-two matrix of the two experiences demonstrates the danger of pursuing one to the exclusion of the other. The experience of unity without diversity turns into absolutism, the insistence that one's chosen activities or beliefs are the only right ones. The experience of diversity

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

NASA Technical Reports Server (NTRS)

Hoehler, Tori M.

2010-01-01

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

Pesticides exposure as etiological factors of Parkinson's disease and other neurodegenerative diseases--a mechanistic approach.

PubMed

Baltazar, Maria Teresa; Dinis-Oliveira, Ricardo Jorge; de Lourdes Bastos, Maria; Tsatsakis, Aristidis M; Duarte, José Alberto; Carvalho, Félix

2014-10-15

The etiology of most neurodegenerative disorders is multifactorial and consists of an interaction between environmental factors and genetic predisposition. The role of pesticide exposure in neurodegenerative disease has long been suspected, but the specific causative agents and the mechanisms underlying are not fully understood. For the main neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis there are evidences linking their etiology with long-term/low-dose exposure to pesticides such as paraquat, maneb, dieldrin, pyrethroids and organophosphates. Most of these pesticides share common features, namely the ability to induce oxidative stress, mitochondrial dysfunction, α-synuclein fibrillization and neuronal cell loss. This review aims to clarify the role of pesticides as environmental risk factors in genesis of idiopathic PD and other neurological syndromes. For this purpose, the most relevant epidemiological and experimental data is highlighted in order to discuss the molecular mechanisms involved in neurodegeneration. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

A Methodology for the Integration of a Mechanistic Source Term Analysis in a Probabilistic Framework for Advanced Reactors

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

Grabaskas, Dave; Brunett, Acacia J.; Bucknor, Matthew

GE Hitachi Nuclear Energy (GEH) and Argonne National Laboratory are currently engaged in a joint effort to modernize and develop probabilistic risk assessment (PRA) techniques for advanced non-light water reactors. At a high level, the primary outcome of this project will be the development of next-generation PRA methodologies that will enable risk-informed prioritization of safety- and reliability-focused research and development, while also identifying gaps that may be resolved through additional research. A subset of this effort is the development of PRA methodologies to conduct a mechanistic source term (MST) analysis for event sequences that could result in the release ofmore » radionuclides. The MST analysis seeks to realistically model and assess the transport, retention, and release of radionuclides from the reactor to the environment. The MST methods developed during this project seek to satisfy the requirements of the Mechanistic Source Term element of the ASME/ANS Non-LWR PRA standard. The MST methodology consists of separate analysis approaches for risk-significant and non-risk significant event sequences that may result in the release of radionuclides from the reactor. For risk-significant event sequences, the methodology focuses on a detailed assessment, using mechanistic models, of radionuclide release from the fuel, transport through and release from the primary system, transport in the containment, and finally release to the environment. The analysis approach for non-risk significant event sequences examines the possibility of large radionuclide releases due to events such as re-criticality or the complete loss of radionuclide barriers. This paper provides details on the MST methodology, including the interface between the MST analysis and other elements of the PRA, and provides a simplified example MST calculation for a sodium fast reactor.« less

Enzymatic Halogenation and Dehalogenation Reactions: Pervasive and Mechanistically Diverse.

PubMed

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

2017-04-26

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

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.

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

Non-Western students' causal reasoning about biologically adaptive changes in humans, other animals and plants: instructional and curricular implications

NASA Astrophysics Data System (ADS)

Mbajiorgu, Ngozika; Anidu, Innocent

2017-06-01

Senior secondary school students (N = 360), 14- to 18-year-olds, from the Igbo culture of eastern Nigeria responded to a questionnaire requiring them to give causal explanations of biologically adaptive changes in humans, other animals and plants. A student subsample (n = 36) was, subsequently, selected for in-depth interviews. Significant differences were found between prompts within the prompt categories, suggesting item feature effects. However, the most coherent pattern was found within the plant category as patterns differed for the mechanistic proximate (MP) reasoning category only. Patterns also differed highly significantly between the prompt categories, with patterns for teleology, MP, mechanistic ultimate and don't know categories similar for plants and other animals but different for the human category. Both urban and rural students recognise commonalities in causality between the three prompt categories, in that their preferences for causal explanations were similar across four reasoning categories. The rural students, however, were more likely than their urban counterparts to give multiple causal explanations in the span of a single response and less likely to attribute causal agency to God. Two factors, religious belief and language, for all the students; and one factor, ecological closeness to nature, for rural students were suspected to have produced these patterns.

Smad ubiquitination regulatory factor-2 in the fibrotic kidney: regulation, target specificity, and functional implication.

PubMed

Tan, Ruoyun; He, Weichun; Lin, Xia; Kiss, Lawrence P; Liu, Youhua

2008-05-01

Smad ubiquitination regulatory factor-2 (Smurf2) is an E3 ubiqutin ligase that plays a pivotal role in regulating TGF-beta signaling via selectively targeting key components of the Smad pathway for degradation. In this study, we have investigated the regulation of Smurf2 expression, its target specificity, and the functional implication of its induction in the fibrotic kidney. Immunohistochemical staining revealed that Smurf2 was upregulated specifically in renal tubules of kidney biopsies from patients with various nephropathies. In vitro, Smurf2 mRNA and protein were induced in human proximal tubular epithelial cells (HKC-8) upon TGF-beta1 stimulation. Ectopic expression of Smurf2 was sufficient to reduce the steady-state levels of Smad2, but not Smad1, Smad3, Smad4, and Smad7, in HKC-8 cells. Interestingly, Smurf2 was also able to downregulate the Smad transcriptional corepressors Ski, SnoN, and TG-interacting factor. Inhibition of the proteasomal pathway prevented Smurf2-mediated downregulation of Smad2 and Smad corepressors. Functionally, overexpression of Smurf2 enhanced the transcription of the TGF-beta-responsive promoter and augmented TGF-beta1-mediated E-cadherin suppression, as well as fibronectin and type I collagen induction in HKC-8 cells. These results indicate that Smurf2 specifically targets both positive and negative Smad regulators for destruction in tubular epithelial cells, thereby providing a complex fine-tuning of TGF-beta signaling. It appears that dysregulation of Smurf2 could contribute to an aberrant TGF-beta/Smad signaling in the pathogenesis of kidney fibrosis.

Atypical antipsychotics and metabolic syndrome in patients with schizophrenia: risk factors, monitoring, and healthcare implications.

PubMed

Riordan, Henry J; Antonini, Paola; Murphy, Michael F

2011-09-01

Metabolic syndrome is a leading cause of morbidity and mortality in patients with schizophrenia, with a prevalence rate double that of nonpsychiatric populations. Given the amount of evidence suggesting a link between atypical antipsychotic medications and metabolic syndrome, several agencies have recommended regular clinical monitoring of weight, symptoms of hyperglycemia, and glucose in chronically medicated patients with schizophrenia. To summarize the current literature on atypical antipsychotic-induced metabolic syndrome in patients with schizophrenia, outline some of the molecular mechanisms behind this syndrome, identify demographic and disease-related risk factors, and describe cost-effective methods for surveillance. The differential prevalence of metabolic syndrome associated with various atypical antipsychotic medications has been evidenced across numerous studies, with higher effects seen for certain antipsychotic medications on weight gain, waist circumference, fasting triglyceride level, and glucose levels. Given the association of these symptoms, all atypical antipsychotic medications currently include a warning about the risk of hyperglycemia and diabetes, as well as suggestions for regular monitoring. Despite this, very little data are available to support adherence to these monitoring recommendations. Lack of awareness and resources, diffusion of responsibility, policy implementation, and organizational structure have all been implicated. The treatment of schizophrenia involves a balance in terms of risks and benefits. Failing to treat because of risk for complications from metabolic syndrome may place the patient at a higher risk for more serious health outcomes. Supporting programs aimed at increasing monitoring of simple laboratory and clinical measures associated with metabolic syndrome may decrease important risk factors, improve patients' quality of life, and reduce healthcare costs.

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.

Factors influencing movement of two migratory fishes within the tailrace of a large neotropical dam and their implications for hydropower impacts

USGS Publications Warehouse

Suzuki, F. M.; Dunham, Jason B.; Silva, L. G. M.; Alves, C. B. M.; Pompeu, P.S.

2017-01-01

Fish attempting to move upstream through hydroelectric dams can be trapped and killed in turbines. Understanding fish movement patterns can provide useful insights for how to manage dam operations to minimize fish kill in turbines. We evaluated the movements of two migratory fish (Curimba-Prochilodus argenteus and Mandi-Pimelodus maculatus) using acoustic telemetry in the tailrace of Três Marias Dam (São Francisco River, Brazil) from 31 October 2011 to 16 February 2012. The majority of tagged fish left the tailrace in less than one week; however, some individuals returned, performing several visits to the tailrace. Mandi remained longer in the tailrace than Curimba. The number of visits was influenced by diel period, turbine and spillway discharge. Although the diel period was the only important contributor to the visits performed by Curimba, the movements of Mandi were significantly influenced by three factors. We found that whereas Curimba was predominantly diurnal, Mandi showed nocturnal habits. Additionally, visits of Mandi were significantly greater during higher turbine and spillway discharge. We discuss the implications of these results for understanding fish movements in the Três Marias Dam tailrace and their potential implications for adapting hydroelectric operations to minimize fish kills.

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.

Regulation of fibroblast growth factor receptor signalling and trafficking by Src and Eps8.

PubMed

Auciello, Giulio; Cunningham, Debbie L; Tatar, Tulin; Heath, John K; Rappoport, Joshua Z

2013-01-15

Fibroblast growth factor receptors (FGFRs) mediate a wide spectrum of cellular responses that are crucial for development and wound healing. However, aberrant FGFR activity leads to cancer. Activated growth factor receptors undergo stimulated endocytosis, but can continue to signal along the endocytic pathway. Endocytic trafficking controls the duration and intensity of signalling, and growth factor receptor signalling can lead to modifications of trafficking pathways. We have developed live-cell imaging methods for studying FGFR dynamics to investigate mechanisms that coordinate the interplay between receptor trafficking and signal transduction. Activated FGFR enters the cell following recruitment to pre-formed clathrin-coated pits (CCPs). However, FGFR activation stimulates clathrin-mediated endocytosis; FGF treatment increases the number of CCPs, including those undergoing endocytosis, and this effect is mediated by Src and its phosphorylation target Eps8. Eps8 interacts with the clathrin-mediated endocytosis machinery and depletion of Eps8 inhibits FGFR trafficking and immediate Erk signalling. Once internalized, FGFR passes through peripheral early endosomes en route to recycling and degredative compartments, through an Src- and Eps8-dependent mechanism. Thus Eps8 functions as a key coordinator in the interplay between FGFR signalling and trafficking. This work provides the first detailed mechanistic analysis of growth factor receptor clustering at the cell surface through signal transduction and endocytic trafficking. As we have characterised the Src target Eps8 as a key regulator of FGFR signalling and trafficking, and identified the early endocytic system as the site of Eps8-mediated effects, this work provides novel mechanistic insight into the reciprocal regulation of growth factor receptor signalling and trafficking.

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

Opposing tissue-specific roles of angiotensin in the pathogenesis of obesity, and implications for obesity-related hypertension

PubMed Central

Littlejohn, Nicole K.

2015-01-01

Metabolic disease, specifically obesity, has now become the greatest challenge to improving cardiovascular health. The renin-angiotensin system (RAS) exists as both a circulating hormone system and as a local paracrine signaling mechanism within various tissues including the brain, kidney, and adipose, and this system is strongly implicated in cardiovascular health and disease. Growing evidence also implicates the RAS in the control of energy balance, supporting the concept that the RAS may be mechanistically involved in the pathogenesis of obesity and obesity hypertension. Here, we review the involvement of the RAS in the entire spectrum of whole organism energy balance mechanisms, including behaviors (food ingestion and spontaneous physical activity) and biological processes (digestive efficiency and both aerobic and nonaerobic resting metabolic rates). We hypothesize that opposing, tissue-specific effects of the RAS to modulate these various components of energy balance can explain the apparently paradoxical results reported by energy-balance studies that involve stimulating, versus disrupting, the RAS. We propose a model in which such opposing and tissue-specific effects of the RAS can explain the failure of simple, global RAS blockade to result in weight loss in humans, and hypothesize that obesity-mediated uncoupling of endogenous metabolic rate control mechanisms can explain the phenomenon of obesity-related hypertension. PMID:26491099

Mechanistic insight of bivalent compound 21MO as potential neuroprotectant for Alzheimer’s disease

PubMed Central

Saathoff, John M.; Liu, Kai; Chojnacki, Jeremy E.; He, Liu; Chen, Qun; Lesnefsky, Edward J.; Zhang, Shijun

2016-01-01

We have recently developed a bivalent strategy to provide novel compounds that potentially target multiple risk factors involved in the development of Alzheimer’s disease (AD). Our previous studies employing a bivalent compound with a shorter spacer (17MN) implicated that this compound can localize into mitochondria and endoplasmic reticulum (ER), thus interfering with the change of mitochondria membrane potential (ΔΨm) and Ca2+ levels in MC65 cells upon removal of tetracycline (TC). In this report, we examined the effects by a bivalent compound with a longer spacer (21MO) in MC65 cells. Our results demonstrated that 21MO suppressed the change of ΔΨm, possibly via interaction with the mitochondrial complex I in MC65 cells. Interestingly, 21MO did not show any effects on the Ca2+ level upon TC removal in MC65 cells. Our previous studies suggested that the mobilization of Ca2+ in MC65 cells, upon withdraw of TC, is originated from ER, so the results implicated that 21MO may preferentially interact with mitochondria in MC65 cells under the current experimental conditions. Collectively, the results suggest that bivalent compounds with varied spacer length and cell membrane anchor moiety may exhibit neuroprotective activities via different mechanisms of action. PMID:27023508

Animal models of aging research: implications for human aging and age-related diseases.

PubMed

Mitchell, Sarah J; Scheibye-Knudsen, Morten; Longo, Dan L; de Cabo, Rafael

2015-01-01

Aging is characterized by an increasing morbidity and functional decline that eventually results in the death of an organism. Aging is the largest risk factor for numerous human diseases, and understanding the aging process may thereby facilitate the development of new treatments for age-associated diseases. The use of humans in aging research is complicated by many factors, including ethical issues; environmental and social factors; and perhaps most importantly, their long natural life span. Although cellular models of human disease provide valuable mechanistic information, they are limited in that they may not replicate the in vivo biology. Almost all organisms age, and thus animal models can be useful for studying aging. Herein, we review some of the major models currently used in aging research and discuss their benefits and pitfalls, including interventions known to extend life span and health span. Finally, we conclude by discussing the future of animal models in aging research.

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

Acrylamide formation in food: a mechanistic perspective.

PubMed

Yaylayan, Varoujan A; Stadler, Richard H

2005-01-01

Earliest reports on the origin of acrylamide in food have confirmed asparagine as the main amino acid responsible for its formation. Available evidence suggests that sugars and other carbonyl compounds play a specific role in the decarboxylation process of asparagine, a necessary step in the generation of acrylamide. It has been proposed that Schiff base intermediate formed between asparagine and the sugar provides a low energy alternative to the decarboxylation from the intact Amadori product through generation and decomposition of oxazolidin-5-one intermediate, leading to the formation of a relatively stable azomethine ylide. Literature data indicate the propensity of such protonated ylides to undergo irreversible 1,2-prototropic shift and produce, in this case, decarboxylated Schiff bases which can easily rearrange into corresponding Amadori products. Decarboxylated Amadori products can either undergo the well known beta-elimination process initiated by the sugar moiety to produce 3-aminopropanamide and 1-deoxyglucosone or undergo 1,2-elimination initiated by the amino acid moiety to directly generate acrylamide. On the other hand, the Schiff intermediate can either hydrolyze and release 3-aminopropanamide or similarly undergo amino acid initiated 1,2-elimination to directly form acrylamide. Other thermolytic pathways to acrylamide--considered marginal at this stage--via the Strecker aldehyde, acrolein, and acrylic acid, are also addressed. Despite significant progress in the understanding of the mechanistic aspects of acrylamide formation, concrete evidence for the role of the different proposed intermediates in foods is still lacking.

Drug-drug interactions involving lysosomes: mechanisms and potential clinical implications.

PubMed

Logan, Randall; Funk, Ryan S; Axcell, Erick; Krise, Jeffrey P

2012-08-01

Many commercially available, weakly basic drugs have been shown to be lysosomotropic, meaning they are subject to extensive sequestration in lysosomes through an ion trapping-type mechanism. The extent of lysosomal trapping of a drug is an important therapeutic consideration because it can influence both activity and pharmacokinetic disposition. The administration of certain drugs can alter lysosomes such that their accumulation capacity for co-administered and/or secondarily administered drugs is altered. In this review the authors explore what is known regarding the mechanistic basis for drug-drug interactions involving lysosomes. Specifically, the authors address the influence of drugs on lysosomal pH, volume and lipid processing. Many drugs are known to extensively accumulate in lysosomes and significantly alter their structure and function; however, the therapeutic and toxicological implications of this remain controversial. The authors propose that drug-drug interactions involving lysosomes represent an important potential source of variability in drug activity and pharmacokinetics. Most evaluations of drug-drug interactions involving lysosomes have been performed in cultured cells and isolated tissues. More comprehensive in vivo evaluations are needed to fully explore the impact of this drug-drug interaction pathway on therapeutic outcomes.

Induction of specific neuron types by overexpression of single transcription factors.

PubMed

Teratani-Ota, Yusuke; Yamamizu, Kohei; Piao, Yulan; Sharova, Lioudmila; Amano, Misa; Yu, Hong; Schlessinger, David; Ko, Minoru S H; Sharov, Alexei A

2016-10-01

Specific neuronal types derived from embryonic stem cells (ESCs) can facilitate mechanistic studies and potentially aid in regenerative medicine. Existing induction methods, however, mostly rely on the effects of the combined action of multiple added growth factors, which generally tend to result in mixed populations of neurons. Here, we report that overexpression of specific transcription factors (TFs) in ESCs can rather guide the differentiation of ESCs towards specific neuron lineages. Analysis of data on gene expression changes 2 d after induction of each of 185 TFs implicated candidate TFs for further ESC differentiation studies. Induction of 23 TFs (out of 49 TFs tested) for 6 d facilitated neural differentiation of ESCs as inferred from increased proportion of cells with neural progenitor marker PSA-NCAM. We identified early activation of the Notch signaling pathway as a common feature of most potent inducers of neural differentiation. The majority of neuron-like cells generated by induction of Ascl1, Smad7, Nr2f1, Dlx2, Dlx4, Nr2f2, Barhl2, and Lhx1 were GABA-positive and expressed other markers of GABAergic neurons. In the same way, we identified Lmx1a and Nr4a2 as inducers for neurons bearing dopaminergic markers and Isl1, Fezf2, and St18 for cholinergic motor neurons. A time-course experiment with induction of Ascl1 showed early upregulation of most neural-specific messenger RNA (mRNA) and microRNAs (miRNAs). Sets of Ascl1-induced mRNAs and miRNAs were enriched in Ascl1 targets. In further studies, enrichment of cells obtained with the induction of Ascl1, Smad7, and Nr2f1 using microbeads resulted in essentially pure population of neuron-like cells with expression profiles similar to neural tissues and expressed markers of GABAergic neurons. In summary, this study indicates that induction of transcription factors is a promising approach to generate cultures that show the transcription profiles characteristic of specific neural cell types.

Combining plasma measurements and mechanistic modeling to explore the effect of POPs on type 2 diabetes mellitus in Norwegian women.

PubMed

Rylander, Charlotta; Sandanger, Torkjel Manning; Nøst, Therese Haugdahl; Breivik, Knut; Lund, Eiliv

2015-10-01

The number of studies on persistent organic pollutants (POPs) and type 2 diabetes mellitus (T2DM) is growing steadily. Although concentrations of many POPs in humans have decreased substantially, only some studies consider temporal and inter-individual changes in POP concentrations when assessing exposure. Here we combined plasma measurements with mechanistic modeling to generate complementary exposure measures to our single blood draw after disease diagnosis. Blood was collected between 2003-2006 from 106 subjects with T2DM and 106 age-matched controls, and POP concentrations were compared after adjustment for relevant risk factors and multiple testing. Area under the curve (AUC) of PCB-153 from birth until age 18, representing early-life exposure, and AUC from birth until time of diagnosis were generated as well as examples of life-time exposure trajectories using a mechanistic exposure model. The rank sum of polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs, OR=16.9 (95% CI: 3.05-93.6)) as well as β-hexachlorocyclohexane (β-HCH, OR=203.8 (95% CI: 11.5-3620)) and 1, 1-dichloro-2,2-bis(p-chlorophenyl) ethylene (p,p'-DDE, OR=11.3 (95% CI: 2.55-49.9)) were associated with T2DM. Neither of the AUCs reflecting early life exposure and total life-time exposure at the time of diagnosis were associated with the disease. The predicted life course trajectories display clear differences within and between individuals in the past and suggest that a single blood draw provide limited information on POP exposure earlier in life. The predicted AUCs for PCB-153 did not support the positive association between T2DM and measured blood concentration of certain POPs. This may suggest that the model is either too simplistic and/or that strength of the association may vary through life and with time to/past diagnosis. Copyright © 2015 Elsevier Inc. All rights reserved.

Oleanolic Acid Alters Multiple Cell Signaling Pathways: Implication in Cancer Prevention and Therapy.

PubMed

Žiberna, Lovro; Šamec, Dunja; Mocan, Andrei; Nabavi, Seyed Fazel; Bishayee, Anupam; Farooqi, Ammad Ahmad; Sureda, Antoni; Nabavi, Seyed Mohammad

2017-03-16

Nowadays, much attention has been paid to diet and dietary supplements as a cost-effective therapeutic strategy for prevention and treatment of a myriad of chronic and degenerative diseases. Rapidly accumulating scientific evidence achieved through high-throughput technologies has greatly expanded the understanding about the multifaceted nature of cancer. Increasingly, it is being realized that deregulation of spatio-temporally controlled intracellular signaling cascades plays a contributory role in the onset and progression of cancer. Therefore, targeting regulators of oncogenic signaling cascades is essential to prevent and treat cancer. A plethora of preclinical and epidemiological evidences showed promising role of phytochemicals against several types of cancer. Oleanolic acid, a common pentacyclic triterpenoid, is mainly found in olive oil, as well as several plant species. It is a potent inhibitor of cellular inflammatory process and a well-known inducer of phase 2 xenobiotic biotransformation enzymes. Main molecular mechanisms underlying anticancer effects of oleanolic acid are mediated by caspases, 5' adenosine monophosphate-activated protein kinase, extracellular signal-regulated kinase 1/2, matrix metalloproteinases, pro-apoptotic Bax and bid, phosphatidylinositide 3-kinase/Akt1/mechanistic target of rapamycin, reactive oxygen species/apoptosis signal-regulating kinase 1/p38 mitogen-activated protein kinase, nuclear factor-κB, cluster of differentiation 1, CKD4, s6k, signal transducer and activator of transcription 3, as well as aforementioned signaling pathways . In this work, we critically review the scientific literature on the molecular targets of oleanolic acid implicated in the prevention and treatment of several types of cancer. We also discuss chemical aspects, natural sources, bioavailability, and safety of this bioactive phytochemical.

Brain-derived neurotrophic factor and its clinical implications

PubMed Central

Bathina, Siresha

2015-01-01

Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal survival and growth, serves as a neurotransmitter modulator, and participates in neuronal plasticity, which is essential for learning and memory. It is widely expressed in the CNS, gut and other tissues. BDNF binds to its high affinity receptor TrkB (tyrosine kinase B) and activates signal transduction cascades (IRS1/2, PI3K, Akt), crucial for CREB and CBP production, that encode proteins involved in β cell survival. BDNF and insulin-like growth factor-1 have similar downstream signaling mechanisms incorporating both p-CAMK and MAPK that increase the expression of pro-survival genes. Brain-derived neurotrophic factor regulates glucose and energy metabolism and prevents exhaustion of β cells. Decreased levels of BDNF are associated with neurodegenerative diseases with neuronal loss, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis and Huntington's disease. Thus, BDNF may be useful in the prevention and management of several diseases including diabetes mellitus. PMID:26788077

N-acetyltransferase single nucleotide polymorphisms: Emerging concepts serve as a paradigm for understanding complexities of personalized medicine

PubMed Central

Hein, David W.

2009-01-01

Arylamine N-acetyltransferase 1 (NAT1) and 2 (NAT2) exhibit single nucleotide polymorphisms (SNPs) in human populations that modify drug and carcinogen metabolism. This paper updates the identity, location, and functional effects of these SNPs and then follows with emerging concepts for understanding why pharmacogenetic findings may not be replicated consistently. Using this paradigm as an example, laboratory-based mechanistic analyses can reveal complexities such that genetic polymorphisms become biologically and medically relevant when confounding factors are more fully understood and considered. As medical care moves to a more personalized approach, the implications of these confounding factors will be important in understanding the complexities of personalized medicine. PMID:19379125

Novel host restriction factors implicated in HIV-1 replication.

PubMed

Ghimire, Dibya; Rai, Madhu; Gaur, Ritu

2018-04-01

Human immunodeficiency virus-1 (HIV-1) is known to interact with multiple host cellular proteins during its replication in the target cell. While many of these host cellular proteins facilitate viral replication, a number of them are reported to inhibit HIV-1 replication at various stages of its life cycle. These host cellular proteins, which are known as restriction factors, constitute an integral part of the host's first line of defence against the viral pathogen. Since the discovery of apolipoprotein B mRNA-editing enzyme 3G (APOBEC3G) as an HIV-1 restriction factor, several human proteins have been identified that exhibit anti-HIV-1 restriction. While each restriction factor employs a distinct mechanism of inhibition, the HIV-1 virus has equally evolved complex counter strategies to neutralize their inhibitory effect. APOBEC3G, tetherin, sterile alpha motif and histidine-aspartate domain 1 (SAMHD1), and trim-5α are some of the best known HIV-1 restriction factors that have been studied in great detail. Recently, six novel restriction factors were discovered that exhibit significant antiviral activity: endoplasmic reticulum α1,2-mannosidase I (ERManI), translocator protein (TSPO), guanylate-binding protein 5 (GBP5), serine incorporator (SERINC3/5) and zinc-finger antiviral protein (ZAP). The focus of this review is to discuss the antiviral mechanism of action of these six restriction factors and provide insights into the probable counter-evasion strategies employed by the HIV-1 virus. The recent discovery of new restriction factors substantiates the complex host-pathogen interactions occurring during HIV-1 pathogenesis and makes it imperative that further investigations are conducted to elucidate the molecular basis of HIV-1 replication.

The relation between space and math: developmental and educational implications.

PubMed

Mix, Kelly S; Cheng, Yi-Ling

2012-01-01

There is a well-known relation between spatial ability and mathematics dating back to the work of early twentieth century factor analysts. This connection is a ripe opportunity for educators, who might use spatial training to improve math learning. However, a closer look at the literature reveals gaps that impede direct application. The primary problem is that although this relation is well established in older children and adults, its emergence in early development and subsequent developmental interactions are not well documented. Moreover, there is a need for more mechanistic explanations that might be leveraged to improve math education. In this chapter, we attempt to address these issues by reviewing the existing literature to identify instances where answers are available and others where further research is needed.

Psoriasis as a cardiovascular risk factor: updates and algorithmic approach.

PubMed

Cozzani, Emanuele; Rosa, Gianmarco; Burlando, Martina; Parodi, Aurora

2018-04-19

Although psoriasis is predominantly a chronic inflammatory skin disorder, it has been known to be associated with cardiovascular disease. Patients with psoriasis, particularly with moderate to severe forms, present an increased rate of cardiovascular mortality, myocardial infarction and stroke. However the pathophysiology of the relationship between psoriasis and cardiovascular risk and comorbidities has not yet completely known. Chronic inflammation may be considered a solid link between psoriasis and related cardiovascular events. Several cytokines and inflammatory cells play a pivotal role in the development of psoriatic lesions, resulting in angiogenesis and endothelial dysfunction. Furthermore, the imbalance between oxidative stress and anti-oxidant mechanisms in psoriatic patients may contribute to explain the pathogenesis of increased reactive oxygen species and the formation of atherosclerotic plaque. Other mechanistic pathways which may be involved in this relationship include cardiovascular effects of medications, a common genetic background and a higher prevalence of cardiovascular risk factors, which are often under-diagnosed and under-treated in psoriatic patients. Indeed, the early detection of specific markers of cardiovascular impairment, such as N-terminal pro B-type natriuretic peptide, homocysteine and YKL-40, may enable psoriatic patients at higher cardiovascular risk to be identified as soon as possible. This review examines the increased cardiovascular risk profile and high prevalence of cardiovascular disease associated with psoriasis, focusing on pathogenic links between psoriasis and atherosclerosis, serological markers of cardiovascular involvement and the implications of anti-psoriatic therapies on cardiovascular risk and proposes a flow chart, that every dermatologist should follow to screen psoriatic patients.

Explicit Memory among Individuals with Mild and Moderate Intellectual Disability: Educational Implications

ERIC Educational Resources Information Center

Lifshitz, Hefziba; Shtein, Sarit; Weiss, Itzhak; Svisrsky, Naama

2011-01-01

We previously reported a meta-analysis of explicit memory studies in populations with intellectual disability (ID). The current study discusses the educational implications of this meta-analysis. The main factors at the core of these implications can be divided into two categories: those related to task characteristics (e.g., depth of processing,…

The perinatal implications of angiogenic factors.

PubMed

Smith, Gordon C S; Wear, Helen

2009-04-01

To summarize recent findings relating maternal circulating levels of proteins associated with angiogenesis and the outcome of pregnancy. In preeclampsia, levels of placental growth factor (PlGF) become abnormal prior to soluble fms-like tyrosine kinase 1 (sFlt-1). Longitudinal measurement of changes in protein level are better predictors of disease than measurement at a single time point in pregnancy and also appear to be more strongly associated with early-onset disease. The levels of angiogenic proteins provide additional predictive information over abnormal uteroplacental Doppler. The preeclampsia-like phenotype of rats overexpressing sFlt-1 can be ameliorated by administration of a protein which binds and inactivates sFlt-1. Animal models demonstrate that uteroplacental ischemia leads to elevated maternal serum levels of sFlt-1 and decreased PlGF. Similarly, studies of human trophoblast cells demonstrate that hypoxia stimulates release of sFlt-1. Autocrine vascular endothelial growth factor (VEGF) has a trophic effect on the endothelium, distinct from its control of angiogenesis. By blocking this effect, elevated sFlt-1 could lead to systemic endothelial cell dysfunction, one of the key features of preeclampsia. Low levels of PlGF are associated with intrauterine growth restriction. However, in the first trimester of pregnancy, high levels of sFlt-1 were associated with reduced rates of growth restriction, preterm birth and stillbirth. Regulators of the VEGF system may have a causal role in the sequence of events leading to preeclampsia and may be targets for novel therapies. However, better knowledge of the biology is required prior to clinical trials of interventions.

The implications of renewable energy research and development: Policy scenario analysis with experience and learning effects

NASA Astrophysics Data System (ADS)

Kobos, Peter Holmes

This dissertation analyzes the current and potential future costs of renewable energy technology from an institutional perspective. The central hypothesis is that reliable technology cost forecasting can be achieved through standard and modified experience curves implemented in a dynamic simulation model. Additionally, drawing upon region-specific institutional lessons highlights the role of market, social, and political institutions throughout an economy. Socio-political influences and government policy pathways drive resource allocation decisions that may be predominately influenced by factors other than those considered in a traditional market-driven, mechanistic approach. Learning in economic systems as a research topic is an attractive complement to the notion of institutional pathways. The economic implications of learning by doing, as first outlined by Arrow (1962), highlight decreasing production costs as individuals, or more generally the firm, become more familiar with a production process. The standard approach in the literature has been to employ a common experience curve where cumulative production is the only independent variable affecting costs. This dissertation develops a two factor experience curve, adding research, development and demonstration (RD&D) expenditures as a second variable. To illustrate the concept in the context of energy planning, two factor experience curves are developed for wind energy technology and solar photovoltaic (PV) modules under different assumptions on learning rates for cumulative capacity and the knowledge stock (a function of past RD&D efforts). Additionally, a one factor experience curve and cost trajectory scenarios are developed for concentrated solar power and geothermal energy technology, respectively. Cost forecasts are then developed for all four of these technologies in a dynamic simulation model. Combining the theoretical framework of learning by doing with the fields of organizational learning and

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

PubMed Central

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

2017-01-01

Dye-decolorizing peroxidases (DyPs) are a family of H2O2-dependent heme peroxidases, which have shown potential applications in lignin degradation and valorization. However, the DyP kinetic mechanism remains underexplored. Using structural biology and solvent isotope (sKIE) and viscosity effects, many mechanistic characteristics have been uncovered for the B-class ElDyP from Enterobacter lignolyticus. Its structure revealed that a water molecule acts as the sixth axial ligand with two channels at diameters of ~3.0 and 8.0 Å leading to the heme center. A conformational change of ERS* to ERS, which have identical spectral characteristics, was proposed as the final step in DyPs’ bisubstrate Ping-Pong mechanism. This step is also the rate-determining step in ABTS oxidation. The normal KIE of wild-type ElDyP with D2O2 at pH 3.5 suggested that cmpd 0 deprotonation by the distal aspartate is rate-limiting in the formation of cmpd I, which is more reactive under acidic pH than under neutral or alkaline pH. The viscosity effects and other biochemical methods implied that the reducing substrate binds with cmpd I instead of the free enzyme. The significant inverse sKIEs of kcat/KM and kERS* suggested that the aquo release in DyPs is mechanistically important and may explain the enzyme’s adoption of two-electron reduction for cmpd I. The distal aspartate is catalytically more important than the distal arginine and plays key roles in determining DyPs’ acidic pH optimum. The kinetic mechanism of D143H-ElDyP was also briefly studied. The results obtained will pave the way for future protein engineering to improve DyPs’ lignolytic activity. PMID:29308295

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

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

Shrestha, Ruben; Huang, Gaochao; Meekins, David A.

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

Domain retention in transcription factor fusion genes and its biological and clinical implications: a pan-cancer study

PubMed Central

Kim, Pora; Ballester, Leomar Y.; Zhao, Zhongming

2017-01-01

Genomic rearrangements involving transcription factors (TFs) can form fusion proteins resulting in either enhanced, weakened, or even loss of TF activity. Functional domain (FD) retention is a critical factor in the activity of transcription factor fusion genes (TFFGs). A systematic investigation of FD retention in TFFGs and their outcome (e.g. expression changes) in a pan-cancer study has not yet been completed. Here, we examined the FD retention status in 386 TFFGs across 13 major cancer types and identified 83 TFFGs involving 67 TFs that retained FDs. To measure the potential biological relevance of TFs in TFFGs, we introduced a Major Active Isofusion Index (MAII) and built a prioritized TFFG network using MAII scores and the observed frequency of fusion positive samples. Interestingly, the four TFFGs (PML-RARA, RUNX1-RUNX1T1, TMPRSS2-ERG, and SFPQ-TFE3) with the highest MAII scores showed 50 differentially expressed target genes (DETGs) in fusion-positive versus fusion-negative cancer samples. DETG analysis revealed that they were involved in tumorigenesis-related processes in each cancer type. PLAU, which encodes plasminogen activator urokinase and serves as a biomarker for tumor invasion, was found to be consistently activated in the samples with the highest MAII scores. Among the 50 DETGs, 21 were drug targetable genes. Fourteen of these 21 DETGs were expressed in acute myeloid leukemia (AML) samples. Accordingly, we constructed an AML-specific TFFG network, which included 38 DETGs in RUNX1-RUNX1T1 or PML-RARA positive samples. In summary, this study revealed several TFFGs and their potential target genes, and provided insights into the clinical implications of TFFGs. PMID:29299133

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

PubMed

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

2016-04-05

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

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

PubMed

Zelić, B; Bolf, N; Vasić-Racki, D

2006-06-01

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

Mechanistic 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

Application of chemical reaction mechanistic domains to an ecotoxicity QSAR model, the KAshinhou Tool for Ecotoxicity (KATE).

PubMed

Furuhama, A; Hasunuma, K; Aoki, Y; Yoshioka, Y; Shiraishi, H

2011-01-01

The validity of chemical reaction mechanistic domains defined by skin sensitisation in the Quantitative Structure-Activity Relationship (QSAR) ecotoxicity system, KAshinhou Tools for Ecotoxicity (KATE), March 2009 version, has been assessed and an external validation of the current KATE system carried out. In the case of the fish end-point, the group of chemicals with substructures reactive to skin sensitisation always exhibited higher root mean square errors (RMSEs) than chemicals without reactive substructures under identical C- or log P-judgements in KATE. However, in the case of the Daphnia end-point this was not so, and the group of chemicals with reactive substructures did not always have higher RMSEs: the Schiff base mechanism did not function as a high error detector. In addition to the RMSE findings, the presence of outliers suggested that the KATE classification rules needs to be reconsidered, particularly for the amine group. Examination of the dependency of the organism on the toxic action of chemicals in fish and Daphnia revealed that some of the reactive substructures could be applied to the improvement of the KATE system. It was concluded that the reaction mechanistic domains of toxic action for skin sensitisation could provide useful complementary information in predicting acute aquatic ecotoxicity, especially at the fish end-point.

Refined pipe theory for mechanistic modeling of wood development.

PubMed

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

2006-06-01

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

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.

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

NASA Astrophysics Data System (ADS)

Johnson, N.; Tivnan, B.

2012-05-01

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

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.

Computational Identification of Mechanistic Factors That Determine the Timing and Intensity of the Inflammatory Response

PubMed Central

Nagaraja, Sridevi; Reifman, Jaques; Mitrophanov, Alexander Y.

2015-01-01

Timely resolution of inflammation is critical for the restoration of homeostasis in injured or infected tissue. Chronic inflammation is often characterized by a persistent increase in the concentrations of inflammatory cells and molecular mediators, whose distinct amount and timing characteristics offer an opportunity to identify effective therapeutic regulatory targets. Here, we used our recently developed computational model of local inflammation to identify potential targets for molecular interventions and to investigate the effects of individual and combined inhibition of such targets. This was accomplished via the development and application of computational strategies involving the simulation and analysis of thousands of inflammatory scenarios. We found that modulation of macrophage influx and efflux is an effective potential strategy to regulate the amount of inflammatory cells and molecular mediators in both normal and chronic inflammatory scenarios. We identified three molecular mediators − tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), and the chemokine CXCL8 − as potential molecular targets whose individual or combined inhibition may robustly regulate both the amount and timing properties of the kinetic trajectories for neutrophils and macrophages in chronic inflammation. Modulation of macrophage flux, as well as of the abundance of TNF-α, TGF-β, and CXCL8, may improve the resolution of chronic inflammation. PMID:26633296

Clinical implications of recent breakthroughs in amyotrophic lateral sclerosis.

PubMed

Van Damme, Philip; Robberecht, Wim

2013-10-01

This review examines the clinical implications of recent breakthroughs in amyotrophic lateral sclerosis (ALS). ALS has been found to be a highly variable condition at the clinical, genetic and mechanistic level. The study of newly discovered genetic causes for ALS has demonstrated that in addition to the effect of toxic mutant proteins, abnormalities of RNA householding contribute to motor neuron degeneration. Furthermore, the classic distinction between gain of function and loss of function may be an oversimplification of the biological reality. The most important clinical breakthrough was the finding of intronic hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) as a common cause of ALS, frontotemporal lobar degeneration (FTLD) and ALS with concomitant FTLD. This provides unambiguous evidence that ALS and FTLD represent the ends of one spectrum of neurodegenerative diseases. The high prevalence of C9orf72 mutations in patients without family history further blurs the distinction between sporadic and familial forms of ALS and FTLD. It also opens opportunities for stratified clinical trials in ALS and for the development of targeted therapies. ALS is a heterogeneous disorder that overlaps with FTLD. C9orf72 mutations are the most common cause of ALS, and add to the evidence that disturbances in RNA householding contribute to ALS.