Recent advances in H-phosphonate chemistry. Part 1. H-phosphonate esters: synthesis and basic reactions.

PubMed

Sobkowski, Michal; Kraszewski, Adam; Stawinski, Jacek

2015-01-01

This review covers recent progress in the preparation of H-phosphonate mono- and diesters, basic studies on mechanistic and stereochemical aspects of this class of phosphorus compounds, and their fundamental chemistry in terms of transformation of P-H bonds into P-heteroatom bonds. Selected recent applications of H-phosphonate derivatives in basic organic phosphorus chemistry and in the synthesis of biologically important phosphorus compounds are also discussed.

Modular magnetic tweezers for single-molecule characterizations of helicases.

PubMed

Kemmerich, Felix E; Kasaciunaite, Kristina; Seidel, Ralf

2016-10-01

Magnetic tweezers provide a versatile toolkit supporting the mechanistic investigation of helicases. In the present article, we show that custom magnetic tweezers setups are straightforward to construct and can easily be extended to provide adaptable platforms, capable of addressing a multitude of enquiries regarding the functions of these fascinating molecular machines. We first address the fundamental components of a basic magnetic tweezers scheme and review some previous results to demonstrate the versatility of this instrument. We then elaborate on several extensions to the basic magnetic tweezers scheme, and demonstrate their applications with data from ongoing research. As our methodological overview illustrates, magnetic tweezers are an extremely useful tool for the characterization of helicases and a custom built instrument can be specifically tailored to suit the experimenter's needs. Copyright © 2016 Elsevier Inc. All rights reserved.

In Silico Augmentation of the Drug Development Pipeline: Examples from the study of Acute Inflammation.

PubMed

An, Gary; Bartels, John; Vodovotz, Yoram

2011-03-01

The clinical translation of promising basic biomedical findings, whether derived from reductionist studies in academic laboratories or as the product of extensive high-throughput and -content screens in the biotechnology and pharmaceutical industries, has reached a period of stagnation in which ever higher research and development costs are yielding ever fewer new drugs. Systems biology and computational modeling have been touted as potential avenues by which to break through this logjam. However, few mechanistic computational approaches are utilized in a manner that is fully cognizant of the inherent clinical realities in which the drugs developed through this ostensibly rational process will be ultimately used. In this article, we present a Translational Systems Biology approach to inflammation. This approach is based on the use of mechanistic computational modeling centered on inherent clinical applicability, namely that a unified suite of models can be applied to generate in silico clinical trials, individualized computational models as tools for personalized medicine, and rational drug and device design based on disease mechanism.

Climate Change Conceptual Change: Scientific Information Can Transform Attitudes.

PubMed

Ranney, Michael Andrew; Clark, Dav

2016-01-01

Of this article's seven experiments, the first five demonstrate that virtually no Americans know the basic global warming mechanism. Fortunately, Experiments 2-5 found that 2-45 min of physical-chemical climate instruction durably increased such understandings. This mechanistic learning, or merely receiving seven highly germane statistical facts (Experiment 6), also increased climate-change acceptance-across the liberal-conservative spectrum. However, Experiment 7's misleading statistics decreased such acceptance (and dramatically, knowledge-confidence). These readily available attitudinal and conceptual changes through scientific information disconfirm what we term "stasis theory"--which some researchers and many laypeople varyingly maintain. Stasis theory subsumes the claim that informing people (particularly Americans) about climate science may be largely futile or even counterproductive--a view that appears historically naïve, suffers from range restrictions (e.g., near-zero mechanistic knowledge), and/or misinterprets some polarization and (noncausal) correlational data. Our studies evidenced no polarizations. Finally, we introduce HowGlobalWarmingWorks.org--a website designed to directly enhance public "climate-change cognition." Copyright © 2016 Cognitive Science Society, Inc.

Young children can be taught basic natural selection using a picture-storybook intervention.

PubMed

Kelemen, Deborah; Emmons, Natalie A; Seston Schillaci, Rebecca; Ganea, Patricia A

2014-04-01

Adaptation by natural selection is a core mechanism of evolution. It is also one of the most widely misunderstood scientific processes. Misconceptions are rooted in cognitive biases found in preschoolers, yet concerns about complexity mean that adaptation by natural selection is generally not comprehensively taught until adolescence. This is long after untutored theoretical misunderstandings are likely to have become entrenched. In a novel approach, we explored 5- to 8-year-olds' capacities to learn a basic but theoretically coherent mechanistic explanation of adaptation through a custom storybook intervention. Experiment 1 showed that children understood the population-based logic of natural selection and also generalized it. Furthermore, learning endured 3 months later. Experiment 2 replicated these results and showed that children understood and applied an even more nuanced mechanistic causal explanation. The findings demonstrate that, contrary to conventional educational wisdom, basic natural selection is teachable in early childhood. Theory-driven interventions using picture storybooks with rich explanatory structure are beneficial.

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

Early report: The use of Cytosorb™ haemabsorption column as an adjunct in managing severe sepsis: initial experiences, review and recommendations.

PubMed

Morris, Craig; Gray, Lewis; Giovannelli, Marco

2015-08-01

A novel synthetic haemabsorption column (Cytosorb™) has recently become commercially available. We describe its use in patients with overwhelming sepsis and consider the experience and evidence supporting its use. While Cytosorb haemabsorption is mechanistically distinct from other extracorporeal therapies in sepsis and appears effective in reducing inflammatory cytokines during sepsis, much of the basic science and clinical benefits remain unclear. Significant interactions including removal of antibiotics may be harmful and require further study. Suggestions for future research and how Cytosorb™ could be incorporated into practice are provided.

Early report: The use of Cytosorb™ haemabsorption column as an adjunct in managing severe sepsis: initial experiences, review and recommendations

PubMed Central

Gray, Lewis; Giovannelli, Marco

2015-01-01

A novel synthetic haemabsorption column (Cytosorb™) has recently become commercially available. We describe its use in patients with overwhelming sepsis and consider the experience and evidence supporting its use. While Cytosorb haemabsorption is mechanistically distinct from other extracorporeal therapies in sepsis and appears effective in reducing inflammatory cytokines during sepsis, much of the basic science and clinical benefits remain unclear. Significant interactions including removal of antibiotics may be harmful and require further study. Suggestions for future research and how Cytosorb™ could be incorporated into practice are provided. PMID:28979423

Translating birdsong: songbirds as a model for basic and applied medical research.

PubMed

Brainard, Michael S; Doupe, Allison J

2013-07-08

Songbirds, long of interest to basic neuroscience, have great potential as a model system for translational neuroscience. Songbirds learn their complex vocal behavior in a manner that exemplifies general processes of perceptual and motor skill learning and, more specifically, resembles human speech learning. Song is subserved by circuitry that is specialized for vocal learning and production but that has strong similarities to mammalian brain pathways. The combination of highly quantifiable behavior and discrete neural substrates facilitates understanding links between brain and behavior, both in normal states and in disease. Here we highlight (a) behavioral and mechanistic parallels between birdsong and aspects of speech and social communication, including insights into mirror neurons, the function of auditory feedback, and genes underlying social communication disorders, and (b) contributions of songbirds to understanding cortical-basal ganglia circuit function and dysfunction, including the possibility of harnessing adult neurogenesis for brain repair.

Translating Birdsong: Songbirds as a model for basic and applied medical research

PubMed Central

2014-01-01

Songbirds, long of interest to basic neuroscientists, have great potential as a model system for translational neuroscience. Songbirds learn their complex vocal behavior in a manner that exemplifies general processes of perceptual and motor skill learning, and more specifically resembles human speech learning. Song is subserved by circuitry that is specialized for vocal learning and production, but that has strong similarities to mammalian brain pathways. The combination of a highly quantifiable behavior and discrete neural substrates facilitates understanding links between brain and behavior, both normally and in disease. Here we highlight 1) behavioral and mechanistic parallels between birdsong and aspects of speech and social communication, including insights into mirror neurons, the function of auditory feedback, and genes underlying social communication disorders, and 2) contributions of songbirds to understanding cortical-basal ganglia circuit function and dysfunction, including the possibility of harnessing adult neurogenesis for brain repair. PMID:23750515

Substituent Effects in the Pyridinium Catalyzed Reduction of CO 2 to Methanol: Further Mechanistic Insights

DOE PAGES

Barton Cole, Emily E.; Baruch, Maor F.; L’Esperance, Robert P.; ...

2014-11-15

A series of substituted pyridiniums were examined for their catalytic ability to electrochemically reduce carbon dioxide to methanol. It is found that in general increased basicity of the nitrogen of the amine and higher LUMO energy of the pyridinium correlate with enhanced carbon dioxide reduction. The highest faradaic yield for methanol production at a platinum electrode was 39 ± 4 % for 4-aminopyridine compared to 22 ± 2 % for pyridine. However, 4-tertbutyl and 4-dimethylamino pyridine showed decreased catalytic behavior, contrary to the enhanced activity associated with the increased basicity and LUMO energy, and suggesting that steric effects also playmore » a significant role in the behavior of pyridinium electrocatalysts. As a result, mechanistic models for the the reaction of the pyridinium with carbon dioxide are considered.« less

Addressing unmet needs in understanding asthma mechanisms: From the European Asthma Research and Innovation Partnership (EARIP) Work Package (WP)2 collaborators.

PubMed

Edwards, Michael R; Saglani, Sejal; Schwarze, Jurgen; Skevaki, Chrysanthi; Smith, Jaclyn A; Ainsworth, Ben; Almond, Mark; Andreakos, Evangelos; Belvisi, Maria G; Chung, Kian Fan; Cookson, William; Cullinan, Paul; Hawrylowicz, Catherine; Lommatzsch, Marek; Jackson, David; Lutter, Rene; Marsland, Benjamin; Moffatt, Miriam; Thomas, Mike; Virchow, J Christian; Xanthou, Georgina; Edwards, Jessica; Walker, Samantha; Johnston, Sebastian L

2017-05-01

Asthma is a heterogeneous, complex disease with clinical phenotypes that incorporate persistent symptoms and acute exacerbations. It affects many millions of Europeans throughout their education and working lives and puts a heavy cost on European productivity. There is a wide spectrum of disease severity and control. Therapeutic advances have been slow despite greater understanding of basic mechanisms and the lack of satisfactory preventative and disease modifying management for asthma constitutes a significant unmet clinical need. Preventing, treating and ultimately curing asthma requires co-ordinated research and innovation across Europe. The European Asthma Research and Innovation Partnership (EARIP) is an FP7-funded programme which has taken a co-ordinated and integrated approach to analysing the future of asthma research and development. This report aims to identify the mechanistic areas in which investment is required to bring about significant improvements in asthma outcomes. Copyright ©ERS 2017.

The rebirth of neuroscience in psychosomatic medicine, Part I: historical context, methods, and relevant basic science.

PubMed

Lane, Richard D; Waldstein, Shari R; Chesney, Margaret A; Jennings, J Richard; Lovallo, William R; Kozel, Peter J; Rose, Robert M; Drossman, Douglas A; Schneiderman, Neil; Thayer, Julian F; Cameron, Oliver G

2009-02-01

Neuroscience was an integral part of psychosomatic medicine at its inception in the early 20th century. Since the mid-20th century, however, psychosomatic research has largely ignored the brain. The field of neuroscience has burgeoned in recent years largely because a variety of powerful new methods have become available. Many of these methods allow for the noninvasive study of the living human brain and thus are potentially available for integration into psychosomatic medicine research at this time. In this first paper we examine various methods available for human neuroscientific investigation and discuss their relative strengths and weaknesses. We next review some basic functional neuroanatomy involving structures that are increasingly being identified as relevant for psychosomatic processes. We then discuss, and provide examples of, how the brain influences end organs through "information transfer systems," including the autonomic, neuroendocrine, and immune systems. The evidence currently available suggests that neuroscience holds great promise for advancing the goal of understanding the mechanisms by which psychosocial variables influence physical disease outcomes. An increased focus on such mechanistic research in psychosomatic medicine is needed to further its acceptance into the field of medicine.

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

Weiss, Charles J.; Das, Partha Pratim; Higgins, Deanna LM

Nickel complexes were prepared with diphosphine ligands that contain pendant amines, and these complexes catalytically oxidize primary and secondary alcohols to their respective aldehydes and ketones. Kinetic and mechanistic studies of these prospective electrocatalysts were performed to understand what influences the catalytic activity. For the oxidation of diphenylmethanol, the catalytic rates were determined to be dependent on the concentration of both the catalyst and the alcohol. The catalytic rates were found to be independent of the concentration of base and oxidant. The incorporation of pendant amines to the phosphine ligand results in substantial increases in the rate of alcohol oxidationmore » with more electron-donating substituents on the pendant amine exhibiting the fastest rates. We thank Dr. John C. Linehan, Dr. Elliott B. Hulley, Dr. Jonathan M. Darmon, and Dr. Elizabeth L. Tyson for helpful discussions. Research by CJW, PD, DLM, and AMA was supported by the US Department of Energy, Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences & Biosciences. Research by MLH was supported as part of the Center for Molecular Electrocatalysis, an Energy Frontier Research Center funded by the U.S. Department of Energy, Office of Science, Basic Energy Sciences. Pacific Northwest National Laboratory (PNNL) is a multiprogram national laboratory operated for DOE by Battelle.« less

Mediationism and the obfuscation of memory

PubMed Central

Watkins, Michael J.

1996-01-01

Memory theorizing is going nowhere. The reason is that it is rooted in mediationism, the doctrine that memory is mediated by some sort of memory trace. Mediationism is the basic tenet of those who seek the substrate of memory; for students of memory per se it is merely a metaphor, and moreover an unfruitful one, for it cannot be penetrated by the methods of psychology. The rejection of mediationism would serve both to replace mechanistic theories with laws or other modes of explanation and to focus research on the actual experience of memory and on the context in which it occurs. The ensuing advantages are discussed and illustrated. PMID:22478247

Review of Antibiotic and Non-Antibiotic Properties of Beta-lactam Molecules.

PubMed

Ochoa-Aguilar, Abraham; Ventura-Martinez, Rosa; Sotomayor-Sobrino, Marco Antonio; Gómez, Claudia; Morales-Espinoza, María del Rosario

2016-01-01

Beta-lactam molecules are a family of drugs commonly used for their antibiotic properties; however, recent research has shown that several members of this group present a large number of other effects such as neuroprotective, antioxidant, analgesic or immunomodulatory capabilities. These properties have been used in both preclinical and clinical studies in different diseases such as hypoxic neuronal damage or acute and chronic pain. The present work briefly reviews the antibiotic effect of these molecules, and will then focus specially on the non-antibiotic effects of three beta-lactam subfamilies: penicillins, cephalosporins and beta lactamase inhibitors, each of which have different molecular structure and pharmacokinetics and therefore have several potential clinical applications. A thorough search of bibliographic databases for peer-reviewed research was performed including only classic experiments or high quality reviews for the antibiotic mechanisms of beta-lactam molecules and only experimental research papers where included when the non-antibiotic properties of these molecules were searched. Only published articles from indexed journals were included. Quality of retrieved papers was assessed using standard tools. The characteristics of screened papers were described and findings of included studies were contextualized to either a mechanistic or a clinical framework. Seventy-eight papers were included in the review; the majority (56) were relative to the non-antibiotic properties of beta-lactam molecules. The non-antibiotic effects reviewed were divided accordingly to the amount of information available for each one. Twelve papers outlined the epileptogenic effects induced by beta-lactam molecules administration; these included both clinical and basic research as well as probable mechanistic explanations. Eighteen papers described a potential neuroprotective effect, mostly in basic in vitro and in vivo experiments. Analgesic properties where identified in twelve papers and basic research was described alongside with both experimental and serendipic clinical findings. Seven papers described a down-regulation effect exerted by beta-lactam molecules administration in different addiction animal models. Finally other effects such as penile erection, dopamine release facilitation and anti-neoplasic effects where described from seven papers. The findings of this review show that beta-lactam molecules may induce several effects, which may be clinically relevant in a lot of different diseases. This paper is, to our knowledge, the first comprehensive review of the non-antibiotic effects shown by beta-lactam molecules and may help increase the interest in this field, which may result in a direct translation of this effects to a clinical context.

Extremity war injuries: collaborative efforts in research, host nation care, and disaster preparedness.

PubMed

Pollak, Andrew N; Ficke, Col James R

2010-01-01

The fourth annual Extremity War Injuries (EWI) Symposium addressed ongoing challenges and opportunities in the management of combat-related musculoskeletal injury. The symposium, which also examined host-nation care and disaster preparedness and response, defined opportunities for synergy between several organizations with similar missions and goals. Within the Department of Defense, the Orthopaedic Extremity Trauma Research Program (OETRP) has funded basic research related to a series of protocols first identified and validated at prior EWI symposia. A well-funded clinical research arm of OETRP has been developed to help translate and validate research advances from each of the protocols. The Armed Forces Institute for Regenerative Medicine, a consortium of academic research institutions, employs a tissue-engineering approach to EWI challenges, particularly with regard to tissue loss. Programs within the National Institute of Arthritis and Musculoskeletal and Skin Diseases and throughout the National Institutes of Health have also expanded tissue-engineering efforts by emphasizing robust mechanistic basic science programs. Much of the clinical care delivered by US military medical personnel and nongovernmental agencies has been to host-nation populations; coordinating delivery to maximize the number of injured who receive care requires understanding of the breadth and scope of resources available within the war zone. Similarly, providing the most comprehensive care to the greatest number of injured in the context of domestic mass casualty requires discussion and planning by all groups involved.

Reevaluating the conceptual framework for applied research on host-plant resistance.

PubMed

Stout, Michael J

2013-06-01

Applied research on host-plant resistance to arthropod pests has been guided over the past 60 years by a framework originally developed by Reginald Painter in his 1951 book, Insect Resistance in Crop Plants. Painter divided the "phenomena" of resistance into three "mechanisms," nonpreference (later renamed antixenosis), antibiosis, and tolerance. The weaknesses of this framework are discussed. In particular, this trichotomous framework does not encompass all known mechanisms of resistance, and the antixenosis and antibiosis categories are ambiguous and inseparable in practice. These features have perhaps led to a simplistic approach to understanding arthropod resistance in crop plants. A dichotomous scheme is proposed as a replacement, with a major division between resistance (plant traits that limit injury to the plant) and tolerance (plant traits that reduce amount of yield loss per unit injury), and the resistance category subdivided into constitutive/inducible and direct/indirect subcategories. The most important benefits of adopting this dichotomous scheme are to more closely align the basic and applied literatures on plant resistance and to encourage a more mechanistic approach to studying plant resistance in crop plants. A more mechanistic approach will be needed to develop novel approaches for integrating plant resistance into pest management programs. © 2012 Institute of Zoology, Chinese Academy of Sciences.

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…

In Silico Augmentation of the Drug Development Pipeline: Examples from the study of Acute Inflammation

PubMed Central

An, Gary; Bartels, John; Vodovotz, Yoram

2011-01-01

The clinical translation of promising basic biomedical findings, whether derived from reductionist studies in academic laboratories or as the product of extensive high-throughput and –content screens in the biotechnology and pharmaceutical industries, has reached a period of stagnation in which ever higher research and development costs are yielding ever fewer new drugs. Systems biology and computational modeling have been touted as potential avenues by which to break through this logjam. However, few mechanistic computational approaches are utilized in a manner that is fully cognizant of the inherent clinical realities in which the drugs developed through this ostensibly rational process will be ultimately used. In this article, we present a Translational Systems Biology approach to inflammation. This approach is based on the use of mechanistic computational modeling centered on inherent clinical applicability, namely that a unified suite of models can be applied to generate in silico clinical trials, individualized computational models as tools for personalized medicine, and rational drug and device design based on disease mechanism. PMID:21552346

History of Primary Immunodeficiency Diseases in Iran

PubMed Central

Aghamohammadi, Asghar; Moin, Mostafa; Rezaei, Nima

2010-01-01

Pediatric immunology came into sight in the second half of 20th century, when pediatricians and basic immunologists began to give attention to diagnosis and treatment of children with primary immunodeficiency diseases (PIDs). Understanding the genetic and mechanistic basis of PIDs provides unique insight into the functioning of the immune system. By progress in basic and clinical immunology, many infrastructural organizations and academic centers have been established in many countries worldwide to focus on training and research on the immune system and related disorders. Along with progress in basic and clinical immunology in the world, pediatric immunology had a good progress in Iran during the last 33-year period. Now, patients with PIDs can benefit from multidisciplinary comprehensive care, which is provided by clinical immunologists in collaboration with other specialists. Patients with history of recurrent and/or chronic infections suggestive of PIDs are evaluated by standard and research-based testing and receive appropriate treatment. The progress in PIDs can be described in three periods. Development of training program for clinical fellowship in allergy and immunology, multidisciplinary and international collaborative projects, primary immunodeficiency diseases textbooks, meetings on immunodeficiency disorders, improvement in diagnosis and treatment, and construction of Iranian primary immunodeficiency association, Students' research group for immunodeficiencies, Iranian primary immunodeficiency registry, and the immunological societies and centers were the main activities on PIDs during these years. In this article, we review the growth of modern pediatric immunology and PIDs status in Iran. PMID:23056678

BIOMARKERS OF EXPOSURE, EFFECT AND SUSCEPTIBILITY IN FISHES

EPA Science Inventory

Understanding basic mechanisms of toxicological processes is integral to assessment of risk, In aquatic toxicology, however, the mechanistic evaluation of environmental chemicals is a much younger area of investigation than in mammalian systems and only recently has received sig...

Dissolution-modulating mechanism of pH modifiers in solid dispersion containing weakly acidic or basic drugs with poor water solubility.

PubMed

Tran, Phuong Ha-Lien; Tran, Thao Truong-Dinh; Lee, Kyoung-Ho; Kim, Dong-Jin; Lee, Beom-Jin

2010-05-01

Although the solid dispersion method has been known to increase the dissolution rate of poorly water-soluble drugs by dispersing them in hydrophilic carriers, one obstacle of the solid dispersion method is its limited solubilization capacity, especially for pH-dependent soluble drugs. pH-modified solid dispersion, in which pH modifiers are incorporated, may be a useful method for increasing the dissolution rate of weakly acidic or basic drugs. Sufficient research, including the most recent reports, was undertaken in this review. How could the inclusion of the pH the pH modifiers in the solid dispersion system change drug structural behaviors, molecular interactions, microenvironmental pH, and/or release rate of pH modifiers, relating with the enhanced dissolution of weakly acidic or weakly basic drugs with poor water solubility? These questions have been investigated to determine the dissolution-modulating mechanism of pH modifiers in solid dispersion containing weakly acidic or basic drugs. It is believed that step-by-step mechanistic approaches could provide the ultimate solution for solubilizing several poorly water-soluble drugs with pH-dependent solubility from a solid dispersion system, as well as provide ideas for developing future dosage systems.

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 cell types. Despite this extensive lysosomal sequestration in the individual cells types, the maximal change in the overall predicted tissue Kpu was <3-fold for lysosome-rich tissues investigated here. Accounting for the variability in cellular physiological model input parameters, in particular lysosomal pH and fraction of the cellular volume occupied by the lysosomes, only partially explained discrepancies between observed and predicted Kpu data in the lung. Improved understanding of the system properties, e.g., cell/organelle composition is required to support further development of mechanistic equations for the prediction of drug tissue distribution. Application of this revised mechanistic model is recommended for prediction of Kpu in lysosome-rich tissue to facilitate the advancement of physiologically-based prediction of volume of distribution and drug exposure in the tissues. Copyright © 2017 Elsevier B.V. All rights reserved.

From molecules to behavior and the clinic: Integration in chronobiology.

PubMed

Bechtel, William

2013-12-01

Chronobiology, especially the study of circadian rhythms, provides a model scientific field in which philosophers can study how investigators from a variety of disciplines working at different levels of organization are each contributing to a multi-level account of the responsible mechanism. I focus on how the framework of mechanistic explanation integrates research designed to decompose the mechanism with efforts directed at recomposition that relies especially on computation models. I also examine how recently the integration has extended beyond basic research to the processes through which the disruption of circadian rhythms contributes to disease, including various forms of cancer. Understanding these linkages has been facilitated by discoveries about how circadian mechanisms interact with mechanisms involved in other physiological processes, including the cell cycle and the immune system. Copyright © 2012 Elsevier Ltd. All rights reserved.

Predicting ectotherm disease vector spread—benefits from multidisciplinary approaches and directions forward

NASA Astrophysics Data System (ADS)

Thomas, Stephanie Margarete; Beierkuhnlein, Carl

2013-05-01

The occurrence of ectotherm disease vectors outside of their previous distribution area and the emergence of vector-borne diseases can be increasingly observed at a global scale and are accompanied by a growing number of studies which investigate the vast range of determining factors and their causal links. Consequently, a broad span of scientific disciplines is involved in tackling these complex phenomena. First, we evaluate the citation behaviour of relevant scientific literature in order to clarify the question "do scientists consider results of other disciplines to extend their expertise?" We then highlight emerging tools and concepts useful for risk assessment. Correlative models (regression-based, machine-learning and profile techniques), mechanistic models (basic reproduction number R 0) and methods of spatial regression, interaction and interpolation are described. We discuss further steps towards multidisciplinary approaches regarding new tools and emerging concepts to combine existing approaches such as Bayesian geostatistical modelling, mechanistic models which avoid the need for parameter fitting, joined correlative and mechanistic models, multi-criteria decision analysis and geographic profiling. We take the quality of both occurrence data for vector, host and disease cases, and data of the predictor variables into consideration as both determine the accuracy of risk area identification. Finally, we underline the importance of multidisciplinary research approaches. Even if the establishment of communication networks between scientific disciplines and the share of specific methods is time consuming, it promises new insights for the surveillance and control of vector-borne diseases worldwide.

A white-box model of S-shaped and double S-shaped single-species population growth

PubMed Central

Kalmykov, Lev V.

2015-01-01

Complex systems may be mechanistically modelled by white-box modeling with using logical deterministic individual-based cellular automata. Mathematical models of complex systems are of three types: black-box (phenomenological), white-box (mechanistic, based on the first principles) and grey-box (mixtures of phenomenological and mechanistic models). Most basic ecological models are of black-box type, including Malthusian, Verhulst, Lotka–Volterra models. In black-box models, the individual-based (mechanistic) mechanisms of population dynamics remain hidden. Here we mechanistically model the S-shaped and double S-shaped population growth of vegetatively propagated rhizomatous lawn grasses. Using purely logical deterministic individual-based cellular automata we create a white-box model. From a general physical standpoint, the vegetative propagation of plants is an analogue of excitation propagation in excitable media. Using the Monte Carlo method, we investigate a role of different initial positioning of an individual in the habitat. We have investigated mechanisms of the single-species population growth limited by habitat size, intraspecific competition, regeneration time and fecundity of individuals in two types of boundary conditions and at two types of fecundity. Besides that, we have compared the S-shaped and J-shaped population growth. We consider this white-box modeling approach as a method of artificial intelligence which works as automatic hyper-logical inference from the first principles of the studied subject. This approach is perspective for direct mechanistic insights into nature of any complex systems. PMID:26038717

The Biology of Aging: Citizen Scientists and Their Pets as a Bridge Between Research on Model Organisms and Human Subjects.

PubMed

Kaeberlein, M

2016-03-01

A fundamental goal of research into the basic mechanisms of aging is to develop translational strategies that improve human health by delaying the onset and progression of age-related pathology. Several interventions have been discovered that increase life span in invertebrate organisms, some of which have similar effects in mice. These include dietary restriction and inhibition of the mechanistic target of rapamycin by treatment with rapamycin. Key challenges moving forward will be to assess the extent to which these and other interventions improve healthy longevity and increase life span in mice and to develop practical strategies for extending this work to the clinic. Companion animals may provide an optimal intermediate between laboratory models and humans. By improving healthy longevity in companion animals, important insights will be gained regarding human aging while improving the quality of life for people and their pets. © The Author(s) 2015.

Generation of human acute lymphoblastic leukemia xenografts for use in oncology drug discovery

PubMed Central

Holmfeldt, Linda

2015-01-01

The establishment of reproducible mouse models of acute lymphoblastic leukemia (ALL) is necessary to provide in vivo therapeutic models that recapitulate human ALL, and for amplification of limiting amounts of primary tumor material. A frequently used model is the primary xenograft model that utilizes immunocompromised mice and involves injection of primary patient tumor specimens into mice, and subsequent serial passaging of the tumors by retransplants of cells harvested from the mouse bone marrow and spleen. The tumors generated can then be used for genomic profiling, ex vivo compound testing, mechanistic studies and retransplantation. This unit describes detailed procedures for the establishment and maintenance of primary ALL xenograft panels for potential use in basic research or translational studies. PMID:25737157

Current directions in non-invasive low intensity electric brain stimulation for depressive disorder.

PubMed

Schutter, Dennis J L G; Sack, Alexander T

2014-01-01

Non-invasive stimulation of the human brain to improve depressive symptoms is increasingly finding its way in clinical settings as a viable form of somatic treatment. Following successful modulation of neural excitability with subsequent antidepressant effects, neural polarization by administrating weak direct currents to the scalp has gained renewed interest. A new wave of basic and clinical studies seems to underscore the potential therapeutic value of direct current stimulation in the treatment of depression. Issues concerning the lack of mechanistic insights into the workings of modifying brain function through neural polarization and how this process translates to its antidepressant properties calls for additional research. The range of its clinical applicability has yet to be established.

8(th) Symposium on Hemostasis: Translational and Basic Science Discoveries.

PubMed

Margaritis, Paris; Key, Nigel S

2016-05-01

It has been 14 years since the first symposium on hemostasis at UNC Chapel Hill that focused primarily on the tissue factor (TF) and Factor VIIa (FVIIa) biology, biochemistry and translational work for the treatment of bleeding. Concepts, mechanistic data and therapeutic agents have since emerged that permeate not only aspects of the TF and FVIIa functions, but also broader processes in hemostasis and thrombosis. These processes involve circulating proteins, receptors, cells and cellular components that interact within the coagulation system as well as with additional systems that are dysregulated in disorders seemingly unrelated to bleeding/thrombosis. The reviews in this symposium provide the research background to understand such interactions and integrations. Copyright © 2016 Elsevier Ltd. All rights reserved.

A Delineation of Epistemic Possibilities in Explanations of Cognitive Development.

ERIC Educational Resources Information Center

Price, Reese E.

Several epistemic formulations have been advanced to explain cognitive development. Many writers have divided the field of psychology into three basic underlying models: the mechanistic, organismic, and dialectic models. An examination of epistemic positions reveals five broadly defined positions on how behavior develops within a given organism.…

Spinal Cord Stimulation for Treating Chronic Pain: Reviewing Preclinical and Clinical Data on Paresthesia-Free High-Frequency Therapy.

PubMed

Chakravarthy, Krishnan; Richter, Hira; Christo, Paul J; Williams, Kayode; Guan, Yun

2018-01-01

Traditional spinal cord stimulation (SCS) requires that paresthesia overlaps chronic painful areas. However, the new paradigm high-frequency SCS (HF-SCS) does not rely on paresthesia. A review of preclinical and clinical studies regarding the use of paresthesia-free HF-SCS for various chronic pain states. We reviewed available literatures on HF-SCS, including Nevro's paresthesia-free ultra high-frequency 10 kHz therapy (HF10-SCS). Data sources included relevant literature identified through searches of PubMed, MEDLINE/OVID, and SCOPUS, and manual searches of the bibliographies of known primary and review articles. The primary goal is to describe the present developing conceptions of preclinical mechanisms of HF-SCS and to review clinical efficacy on paresthesia-free HF10-SCS for various chronic pain states. HF10-SCS offers a novel pain reduction tool without paresthesia for failed back surgery syndrome and chronic axial back pain. Preclinical findings indicate that potential mechanisms of action for paresthesia-free HF-SCS differ from those of traditional SCS. To fully understand and utilize paresthesia-free HF-SCS, mechanistic study and translational research will be very important, with increasing collaboration between basic science and clinical communities to design better trials and optimize the therapy based on mechanistic findings from effective preclinical models and approaches. Future research in these vital areas may include preclinical and clinical components conducted in parallel to optimize the potential of this technology. © 2017 International Neuromodulation Society.

Deducing Reaction Mechanism: A Guide for Students, Researchers, and Instructors

ERIC Educational Resources Information Center

Meek, Simon J.; Pitman, Catherine L.; Miller, Alexander J. M.

2016-01-01

An introductory guide to deducing the mechanism of chemical reactions is presented. Following a typical workflow for probing reaction mechanism, the guide introduces a wide range of kinetic and mechanistic tools. In addition to serving as a broad introduction to mechanistic analysis for students and researchers, the guide has also been used by…

Ion-Pairing Contribution to the Liposomal Transport of Topotecan as Revealed by Mechanistic Modeling.

PubMed

Fugit, Kyle D; Anderson, Bradley D

2017-04-01

Actively loaded liposomal formulations of anticancer agents have been widely explored due to their high drug encapsulation efficiencies and prolonged drug retention. Mathematical models to predict and optimize drug loading and release kinetics from these nanoparticle formulations would be useful in their development and may allow researchers to tune release profiles. Such models must account for the driving forces as influenced by the physicochemical properties of the drug and the microenvironment, and the liposomal barrier properties. This study employed mechanistic modeling to describe the active liposomal loading and release kinetics of the anticancer agent topotecan (TPT). The model incorporates ammonia transport resulting in generation of a pH gradient, TPT dimerization, TPT lactone ring-opening and -closing interconversion kinetics, chloride transport, and transport of TPT-chloride ion-pairs to describe the active loading and release kinetics of TPT in the presence of varying chloride concentrations. Model-based predictions of the kinetics of active loading at varying loading concentrations of TPT and release under dynamic dialysis conditions were in reasonable agreement with experiments. These findings identify key attributes to consider in optimizing and predicting loading and release of liposomal TPT that may also be applicable to liposomal formulations of other weakly basic pharmaceuticals. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Systems Toxicology: From Basic Research to Risk Assessment

PubMed Central

2014-01-01

Systems Toxicology is the integration of classical toxicology with quantitative analysis of large networks of molecular and functional changes occurring across multiple levels of biological organization. Society demands increasingly close scrutiny of the potential health risks associated with exposure to chemicals present in our everyday life, leading to an increasing need for more predictive and accurate risk-assessment approaches. Developing such approaches requires a detailed mechanistic understanding of the ways in which xenobiotic substances perturb biological systems and lead to adverse outcomes. Thus, Systems Toxicology approaches offer modern strategies for gaining such mechanistic knowledge by combining advanced analytical and computational tools. Furthermore, Systems Toxicology is a means for the identification and application of biomarkers for improved safety assessments. In Systems Toxicology, quantitative systems-wide molecular changes in the context of an exposure are measured, and a causal chain of molecular events linking exposures with adverse outcomes (i.e., functional and apical end points) is deciphered. Mathematical models are then built to describe these processes in a quantitative manner. The integrated data analysis leads to the identification of how biological networks are perturbed by the exposure and enables the development of predictive mathematical models of toxicological processes. This perspective integrates current knowledge regarding bioanalytical approaches, computational analysis, and the potential for improved risk assessment. PMID:24446777

Systems toxicology: from basic research to risk assessment.

PubMed

Sturla, Shana J; Boobis, Alan R; FitzGerald, Rex E; Hoeng, Julia; Kavlock, Robert J; Schirmer, Kristin; Whelan, Maurice; Wilks, Martin F; Peitsch, Manuel C

2014-03-17

Systems Toxicology is the integration of classical toxicology with quantitative analysis of large networks of molecular and functional changes occurring across multiple levels of biological organization. Society demands increasingly close scrutiny of the potential health risks associated with exposure to chemicals present in our everyday life, leading to an increasing need for more predictive and accurate risk-assessment approaches. Developing such approaches requires a detailed mechanistic understanding of the ways in which xenobiotic substances perturb biological systems and lead to adverse outcomes. Thus, Systems Toxicology approaches offer modern strategies for gaining such mechanistic knowledge by combining advanced analytical and computational tools. Furthermore, Systems Toxicology is a means for the identification and application of biomarkers for improved safety assessments. In Systems Toxicology, quantitative systems-wide molecular changes in the context of an exposure are measured, and a causal chain of molecular events linking exposures with adverse outcomes (i.e., functional and apical end points) is deciphered. Mathematical models are then built to describe these processes in a quantitative manner. The integrated data analysis leads to the identification of how biological networks are perturbed by the exposure and enables the development of predictive mathematical models of toxicological processes. This perspective integrates current knowledge regarding bioanalytical approaches, computational analysis, and the potential for improved risk assessment.

An Architecture for Controlling Multiple Robots

NASA Technical Reports Server (NTRS)

Aghazarian, Hrand; Pirjanian, Paolo; Schenker, Paul; Huntsberger, Terrance

2004-01-01

The Control Architecture for Multirobot Outpost (CAMPOUT) is a distributed-control architecture for coordinating the activities of multiple robots. In the CAMPOUT, multiple-agent activities and sensor-based controls are derived as group compositions and involve coordination of more basic controllers denoted, for present purposes, as behaviors. The CAMPOUT provides basic mechanistic concepts for representation and execution of distributed group activities. One considers a network of nodes that comprise behaviors (self-contained controllers) augmented with hyper-links, which are used to exchange information between the nodes to achieve coordinated activities. Group behavior is guided by a scripted plan, which encodes a conditional sequence of single-agent activities. Thus, higher-level functionality is composed by coordination of more basic behaviors under the downward task decomposition of a multi-agent planner

Of Metaphors and Paradigms: Rejecting the "Commonsense" View of Reading.

ERIC Educational Resources Information Center

Weaver, Constance

For many years, methods of teaching reading have been based upon a mechanistic paradigm that something can be understood by reducing it to its most basic parts. This scientific paradigm has led to several misconceptions about reading: (1) that comprehension can be reduced to separately identifiable parts, (2) that meaning is contained within the…

Iridium-catalysed ortho-H/D and -H/T exchange under basic conditions: C-H activation of unprotected tetrazoles.

PubMed

Kerr, William J; Lindsay, David M; Reid, Marc; Atzrodt, Jens; Derdau, Volker; Rojahn, Patrick; Weck, Remo

2016-05-10

The first examples of selective ortho-directed C-H activation with unprotected 2-aryltetrazoles are described. A new base-assisted protocol for iridium(i) hydrogen isotope exchange catalysis allows access to ortho-deuterated and tritiated tetrazoles, including the tetrazole-containing pharmaceutical, Valsartan. Preliminary mechanistic studies are also presented.

Challenges in Developing Models Describing Complex Soil Systems

NASA Astrophysics Data System (ADS)

Simunek, J.; Jacques, D.

2014-12-01

Quantitative mechanistic models that consider basic physical, mechanical, chemical, and biological processes have the potential to be powerful tools to integrate our understanding of complex soil systems, and the soil science community has often called for models that would include a large number of these diverse processes. However, once attempts have been made to develop such models, the response from the community has not always been overwhelming, especially after it discovered that these models are consequently highly complex, requiring not only a large number of parameters, not all of which can be easily (or at all) measured and/or identified, and which are often associated with large uncertainties, but also requiring from their users deep knowledge of all/most of these implemented physical, mechanical, chemical and biological processes. Real, or perceived, complexity of these models then discourages users from using them even for relatively simple applications, for which they would be perfectly adequate. Due to the nonlinear nature and chemical/biological complexity of the soil systems, it is also virtually impossible to verify these types of models analytically, raising doubts about their applicability. Code inter-comparisons, which is then likely the most suitable method to assess code capabilities and model performance, requires existence of multiple models of similar/overlapping capabilities, which may not always exist. It is thus a challenge not only to developed models describing complex soil systems, but also to persuade the soil science community in using them. As a result, complex quantitative mechanistic models are still an underutilized tool in soil science research. We will demonstrate some of the challenges discussed above on our own efforts in developing quantitative mechanistic models (such as HP1/2) for complex soil systems.

Combination of Lewis Basic Selenium Catalysis and Redox Selenium Chemistry: Synthesis of Trifluoromethylthiolated Tertiary Alcohols with Alkenes.

PubMed

Zhu, Zechen; Luo, Jie; Zhao, Xiaodan

2017-09-15

A new and efficient method for diaryl selenide catalyzed vicinal CF 3 S hydroxylation of 1,1-multisubstitued alkenes has been developed. Various trifluoromethylthiolated tertiary alcohols could be readily synthesized under mild conditions. This method is also effective for the intramolecular cyclization of alkenes tethered by carboxylic acid, hydroxy, sulfamide, or ester groups and is associated with the introduction of a CF 3 S group. Mechanistic studies have revealed that the pathway involves a redox cycle between Se(II) and Se(IV) and Lewis basic selenium catalysis.

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.

Chemopreventive properties of 3,3′-diindolylmethane in breast cancer: evidence from experimental and human studies

PubMed Central

Ho, Emily; Strom, Meghan B.

2016-01-01

Diet is a modifiable factor associated with the risk of several cancers, with convincing evidence showing a link between diet and breast cancer. The role of bioactive compounds of food origin, including those found in cruciferous vegetables, is an active area of research in cancer chemoprevention. This review focuses on 3,3′-diindolylmethane (DIM), the major bioactive indole in crucifers. Research of the cancer-preventive activity of DIM has yielded basic mechanistic, animal, and human trial data. Further, this body of evidence is largely supported by observational studies. Bioactive DIM has demonstrated chemopreventive activity in all stages of breast cancer carcinogenesis. This review describes current evidence related to the metabolism and mechanisms of DIM involved in the prevention of breast cancer. Importantly, this review also focuses on current evidence from human observational and intervention trials that have contributed to a greater understanding of exposure estimates that will inform recommendations for DIM intake. PMID:27261275

Homocysteine and disease: Causal associations or epiphenomenons?

PubMed

Hannibal, Luciana; Blom, Henk J

2017-02-01

Nutritional and genetic deficiencies of folate and vitamin B 12 lead to elevation of cellular homocysteine (Hcy), which translates in increased plasma Hcy. The sources and role of elevated plasma Hcy in pathology continues to be a subject of intense scientific debate. Whether a cause, mediator or marker, little is known about the molecular mechanisms and interactions of Hcy with cellular processes that lead to disease. The use of folic acid reduces the incidence of neural tube defects, but the effect of Hcy-lowering interventions with folic acid in cardiovascular disease and cognitive impairment remains controversial. The fact that levels of Hcy in plasma do not always reflect cellular status of this amino acid may account for the substantial gaps that exist between epidemiological, intervention and basic research studies. Understanding whether plasma Hcy is a mechanistic player or an epiphenomenon in pathogenesis requires further investigation, and this research is essential to improve the assessment and potential treatment of hyperhomocysteinemias. Copyright © 2016 Elsevier Ltd. All rights reserved.

The Basic Metabolic Profile in Heart Failure-Marker and Modifier.

PubMed

Elfar, Ahmed; Sambandam, Kamalanathan K

2017-08-01

The physiologic determinants of each of the components of the basic metabolic profile in patients with heart failure will be explored. Additionally, the review will discuss the prognostic value of alterations in the basic metabolic profile as well as their effects on management. Abnormalities in the basic metabolic profile have significant correlation with clinical outcomes and can modify treatment in heart failure. Hypochloremia has recently received increased attention for these reasons. Elevated creatinine, increased blood urea nitrogen, hyponatremia, and hypochloremia correlate with worse mortality and diuretic resistance in heart failure. Hypokalemia, even when mild, has proven to be a worse clinical indicator than modest elevations in serum potassium. Hypochloremia is mechanistically linked to hyponatremia and metabolic alkalosis, but recent compelling data suggests that it can provide more discriminating prognostic information. Knowledge of the physiologic basis for each of these alterations informs their management.

Translational cancer research: balancing prevention and treatment to combat cancer globally.

PubMed

Wild, Christopher P; Bucher, John R; de Jong, Bas W D; Dillner, Joakim; von Gertten, Christina; Groopman, John D; Herceg, Zdenko; Holmes, Elaine; Holmila, Reetta; Olsen, Jørgen H; Ringborg, Ulrik; Scalbert, Augustin; Shibata, Tatsuhiro; Smith, Martyn T; Ulrich, Cornelia; Vineis, Paolo; McLaughlin, John

2015-01-01

Cancer research is drawing on the human genome project to develop new molecular-targeted treatments. This is an exciting but insufficient response to the growing, global burden of cancer, particularly as the projected increase in new cases in the coming decades is increasingly falling on developing countries. The world is not able to treat its way out of the cancer problem. However, the mechanistic insights from basic science can be harnessed to better understand cancer causes and prevention, thus underpinning a complementary public health approach to cancer control. This manuscript focuses on how new knowledge about the molecular and cellular basis of cancer, and the associated high-throughput laboratory technologies for studying those pathways, can be applied to population-based epidemiological studies, particularly in the context of large prospective cohorts with associated biobanks to provide an evidence base for cancer prevention. This integrated approach should allow a more rapid and informed translation of the research into educational and policy interventions aimed at risk reduction across a population. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Final Technical Report of Research

DOE R&D Accomplishments Database

Taube, H.

1972-04-03

The studies conducted embrace the following subject areas: ion solvation, mechanistic studies on substitution reactions in metal complexes, oxidation of coordinated ligands, mechanistic studies on electron transfer reactions, preparation and characterization of new species in the aquo and ammino systems.

The structural basis for enhanced silver reflectance in Koi fish scale and skin.

PubMed

Gur, Dvir; Leshem, Ben; Oron, Dan; Weiner, Steve; Addadi, Lia

2014-12-10

Fish have evolved biogenic multilayer reflectors composed of stacks of intracellular anhydrous guanine crystals separated by cytoplasm, to produce the silvery luster of their skin and scales. Here we compare two different variants of the Japanese Koi fish; one of them with enhanced reflectivity. Our aim is to determine how biology modulates reflectivity, and from this to obtain a mechanistic understanding of the structure and properties governing the intensity of silver reflectance. We measured the reflectance of individual scales with a custom-made microscope, and then for each individual scale we characterized the structure of the guanine crystal/cytoplasm layers using high-resolution cryo-SEM. The measured reflectance and the structural-geometrical parameters were used to calculate the reflectance of each scale, and the results were compared to the experimental measurements. We show that enhanced reflectivity is obtained with the same basic guanine crystal/cytoplasm stacks, but the structural arrangement between the stack, inside the stacks, and relative to the scale surface is varied when reflectivity is enhanced. Finally, we propose a model that incorporates the basic building block parameters, the crystal orientation inside the tissue, and the resulting reflectance and explains the mechanistic basis for reflectance enhancement.

Clinical Use of Probiotics in Pediatric Allergy (cuppa): A World Allergy Organization Position Paper

PubMed Central

2012-01-01

Background Probiotic administration has been proposed for the prevention and treatment of specific allergic manifestations such as eczema, rhinitis, gastrointestinal allergy, food allergy, and asthma. However, published statements and scientific opinions disagree about the clinical usefulness. Objective A World Allergy Organization Special Committee on Food Allergy and Nutrition review of the evidence regarding the use of probiotics for the prevention and treatment of allergy. Methods A qualitative and narrative review of the literature on probiotic treatment of allergic disease was carried out to address the diversity and variable quality of relevant studies. This variability precluded systematization, and an expert panel group discussion method was used to evaluate the literature. In the absence of systematic reviews of treatment, meta-analyses of prevention studies were used to provide data in support of probiotic applications. Results Despite the plethora of literature, probiotic research is still in its infancy. There is a need for basic microbiology research on the resident human microbiota. Mechanistic studies from biology, immunology, and genetics are needed before we can claim to harness the potential of immune modulatory effects of microbiota. Meanwhile, clinicians must take a step back and try to link disease state with alterations of the microbiota through well-controlled long-term studies to identify clinical indications. Conclusions Probiotics do not have an established role in the prevention or treatment of allergy. No single probiotic supplement or class of supplements has been demonstrated to efficiently influence the course of any allergic manifestation or long-term disease or to be sufficient to do so. Further epidemiologic, immunologic, microbiologic, genetic, and clinical studies are necessary to determine whether probiotic supplements will be useful in preventing allergy. Until then, supplementation with probiotics remains empirical in allergy medicine. In the future, basic research should focus on homoeostatic studies, and clinical research should focus on preventive medicine applications, not only in allergy. Collaborations between allergo-immunologists and microbiologists in basic research and a multidisciplinary approach in clinical research are likely to be the most fruitful. PMID:23282383

The short-lived African turquoise killifish: an emerging experimental model for ageing

PubMed Central

Kim, Yumi; Nam, Hong Gil; Valenzano, Dario Riccardo

2016-01-01

ABSTRACT Human ageing is a fundamental biological process that leads to functional decay, increased risk for various diseases and, ultimately, death. Some of the basic biological mechanisms underlying human ageing are shared with other organisms; thus, animal models have been invaluable in providing key mechanistic and molecular insights into the common bases of biological ageing. In this Review, we briefly summarise the major applications of the most commonly used model organisms adopted in ageing research and highlight their relevance in understanding human ageing. We compare the strengths and limitations of different model organisms and discuss in detail an emerging ageing model, the short-lived African turquoise killifish. We review the recent progress made in using the turquoise killifish to study the biology of ageing and discuss potential future applications of this promising animal model. PMID:26839399

Nervous system regulation of the cancer genome

PubMed Central

Cole, Steven W.

2012-01-01

Genomics-based analyses have provided deep insight into the basic biology of cancer and are now clarifying the molecular pathways by which psychological and social factors can regulate tumor cell gene expression and genome evolution. This review summarizes basic and clinical research on neural and endocrine regulation of the cancer genome and its interactions with the surrounding tumor microenvironment, including the specific types of genes subject to neural and endocrine regulation, the signal transduction pathways that mediate such effects, and therapeutic approaches that might be deployed to mitigate their impact. Beta-adrenergic signaling from the sympathetic nervous system has been found to up-regulated a diverse array of genes that contribute to tumor progression and metastasis, whereas glucocorticoid-regulated genes can inhibit DNA repair and promote cancer cell survival and resistance to chemotherapy. Relationships between socio-environmental risk factors, neural and endocrine signaling to the tumor microenvironment, and transcriptional responses by cancer cells and surrounding stromal cells are providing new mechanistic insights into the social epidemiology of cancer, new therapeutic approaches for protecting the health of cancer patients, and new molecular biomarkers for assessing the impact of behavioral and pharmacologic interventions. PMID:23207104

The search of "canonical" explanations for the cerebral cortex.

PubMed

Plebe, Alessio

2018-06-15

This paper addresses a fundamental line of research in neuroscience: the identification of a putative neural processing core of the cerebral cortex, often claimed to be "canonical". This "canonical" core would be shared by the entire cortex, and would explain why it is so powerful and diversified in tasks and functions, yet so uniform in architecture. The purpose of this paper is to analyze the search for canonical explanations over the past 40 years, discussing the theoretical frameworks informing this research. It will highlight a bias that, in my opinion, has limited the success of this research project, that of overlooking the dimension of cortical development. The earliest explanation of the cerebral cortex as canonical was attempted by David Marr, deriving putative cortical circuits from general mathematical laws, loosely following a deductive-nomological account. Although Marr's theory turned out to be incorrect, one of its merits was to have put the issue of cortical circuit development at the top of his agenda. This aspect has been largely neglected in much of the research on canonical models that has followed. Models proposed in the 1980s were conceived as mechanistic. They identified a small number of components that interacted as a basic circuit, with each component defined as a function. More recent models have been presented as idealized canonical computations, distinct from mechanistic explanations, due to the lack of identifiable cortical components. Currently, the entire enterprise of coming up with a single canonical explanation has been criticized as being misguided, and the premise of the uniformity of the cortex has been strongly challenged. This debate is analyzed here. The legacy of the canonical circuit concept is reflected in both positive and negative ways in recent large-scale brain projects, such as the Human Brain Project. One positive aspect is that these projects might achieve the aim of producing detailed simulations of cortical electrical activity, a negative one regards whether they will be able to find ways of simulating how circuits actually develop.

MECHANISTIC AND SOURCE UNDERSTANDING OF PCDD/F FORMATION

EPA Science Inventory

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

A 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...

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...

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...

Cell-Based Genotoxicity Testing

NASA Astrophysics Data System (ADS)

Reifferscheid, Georg; Buchinger, Sebastian

Genotoxicity test systems that are based on bacteria display an important role in the detection and assessment of DNA damaging chemicals. They belong to the basic line of test systems due to their easy realization, rapidness, broad applicability, high sensitivity and good reproducibility. Since the development of the Salmonella microsomal mutagenicity assay by Ames and coworkers in the early 1970s, significant development in bacterial genotoxicity assays was achieved and is still a subject matter of research. The basic principle of the mutagenicity assay is a reversion of a growth inhibited bacterial strain, e.g., due to auxotrophy, back to a fast growing phenotype (regain of prototrophy). Deeper knowledge of the ­mutation events allows a mechanistic understanding of the induced DNA-damage by the utilization of base specific tester strains. Collections of such specific tester strains were extended by genetic engineering. Beside the reversion assays, test systems utilizing the bacterial SOS-response were invented. These methods are based on the fusion of various SOS-responsive promoters with a broad variety of reporter genes facilitating numerous methods of signal detection. A very important aspect of genotoxicity testing is the bioactivation of ­xenobiotics to DNA-damaging compounds. Most widely used is the extracellular metabolic activation by making use of rodent liver homogenates. Again, genetic engineering allows the construction of highly sophisticated bacterial tester strains with significantly enhanced sensitivity due to overexpression of enzymes that are involved in the metabolism of xenobiotics. This provides mechanistic insights into the toxification and detoxification pathways of xenobiotics and helps explaining the chemical nature of hazardous substances in unknown mixtures. In summary, beginning with "natural" tester strains the rational design of bacteria led to highly specific and sensitive tools for a rapid, reliable and cost effective ­genotoxicity testing that is of outstanding importance in the risk assessment of compounds (REACH) and in ecotoxicology.

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-...

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...

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 ...

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...

World-View Entrapment: Moral-Ethical Implications for Gifted Education.

ERIC Educational Resources Information Center

Ambrose, Don

2000-01-01

This article explores the moral-ethical implications of the mechanistic world view and related issues such as technological determinism, social Darwinism, and androcentrism. It finds that educational approaches reinforced by the mechanistic world view include positivistic approaches to curriculum, instruction, and research. Recommendations for…

Is timing the key to good fruit phenolics?: year 2

USDA-ARS?s Scientific Manuscript database

Despite a century of research, we still lack a concrete, mechanistic understanding of solar radiation and temperature effects on anthocyanin accumulation and composition, crucial for red wine grapes. Our aim was to elucidate the mechanistic response to microclimate of anthocyanin metabolism in Vitis...

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...

Rational and mechanistic perspectives on reinforcement learning.

PubMed

Chater, Nick

2009-12-01

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

Fasting, circadian rhythms, and time restricted feeding in healthy lifespan

PubMed Central

Longo, Valter D.; Panda, Satchidananda

2016-01-01

Summary Feeding in most animals is confined to a defined period, leaving short periods of fasting that coincide with sleep. Fasting enables organisms to enter alternative metabolic phases, which rely less on glucose and more on ketone body-like carbon sources. Both intermittent and periodic fasting result in benefits ranging from prevention to the enhanced treatment of diseases. Similarly, time-restricted feeding (TRF), in which feeding time is restricted to certain hours of the day, allows the daily fasting period to last >12 h, thus imparting pleiotropic benefits in multiple organisms. Understanding the mechanistic link between nutrients and the fasting benefits is leading to the identification of fasting mimicking diets (FMDs) that achieve changes similar to those caused by fasting. Given the pleiotropic and sustained benefits of TRF and FMD, both basic science and translational research are warranted to develop fasting-associated interventions into effective and inexpensive treatments with the potential to improve healthspan. PMID:27304506

The short-lived African turquoise killifish: an emerging experimental model for ageing.

PubMed

Kim, Yumi; Nam, Hong Gil; Valenzano, Dario Riccardo

2016-02-01

Human ageing is a fundamental biological process that leads to functional decay, increased risk for various diseases and, ultimately, death. Some of the basic biological mechanisms underlying human ageing are shared with other organisms; thus, animal models have been invaluable in providing key mechanistic and molecular insights into the common bases of biological ageing. In this Review, we briefly summarise the major applications of the most commonly used model organisms adopted in ageing research and highlight their relevance in understanding human ageing. We compare the strengths and limitations of different model organisms and discuss in detail an emerging ageing model, the short-lived African turquoise killifish. We review the recent progress made in using the turquoise killifish to study the biology of ageing and discuss potential future applications of this promising animal model. © 2016. Published by The Company of Biologists Ltd.

Advancing understanding of affect labeling with dynamic causal modeling

PubMed Central

Torrisi, Salvatore J.; Lieberman, Matthew D.; Bookheimer, Susan Y.; Altshuler, Lori L.

2013-01-01

Mechanistic understandings of forms of incidental emotion regulation have implications for basic and translational research in the affective sciences. In this study we applied Dynamic Causal Modeling (DCM) for fMRI to a common paradigm of labeling facial affect to elucidate prefrontal to subcortical influences. Four brain regions were used to model affect labeling, including right ventrolateral prefrontal cortex (vlPFC), amygdala and Broca’s area. 64 models were compared, for each of 45 healthy subjects. Family level inference split the model space to a likely driving input and Bayesian Model Selection within the winning family of 32 models revealed a strong pattern of endogenous network connectivity. Modulatory effects of labeling were most prominently observed following Bayesian Model Averaging, with the dampening influence on amygdala originating from Broca’s area but much more strongly from right vlPFC. These results solidify and extend previous correlation and regression-based estimations of negative corticolimbic coupling. PMID:23774393

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…

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...

Is solar radiation a key to good red wine grape anthocyanin?

USDA-ARS?s Scientific Manuscript database

Despite a century of research, we still lack a concrete, mechanistic understanding of solar radiation and temperature effects on anthocyanin accumulation and composition, crucial for red wine grapes. Our aim was to elucidate the mechanistic response to microclimate of anthocyanin metabolism in Viti...

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...

Bath salts, mephedrone, and methylenedioxypyrovalerone as emerging illicit drugs that will need targeted therapeutic intervention

PubMed Central

Glennon, Richard A.

2015-01-01

The term “synthetic cathinones” is fairly new; but, although the abuse of synthetic cathinones is a recent problem, research on cathinone analogs dates back >100 years. One structural element cathinone analogs have in common is an α-aminophenone moiety. Introduction of amine and/or aryl substituents affords a large number of agents. Today, >40 synthetic cathinones have been identified on the clandestine market and many have multiple “street names”. Many cathinone analogs, although not referred to as such until the late 1970s, were initially prepared as intermediates in the synthesis of ephedrine analogs. The cathinones do not represent a pharmacologically or mechanistically homogeneous class of agents. Currently abused synthetic cathinones are derived from earlier agents and seem to produce their actions primarily via the dopamine, norepinephrine, and/or serotonin transporter; that is, they either release and/or inhibit the reuptake of one or more of these neurotransmitters. The actions of these agents can resemble those of central stimulants such as methamphetamine, cocaine, and/or empathogens such as 1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA; Ecstasy) and/or produce other effects. Side effects are primarily of a neurological and/or cardiovascular nature. The use of the “and/or” term is emphasized because synthetic cathinones represent a broad class of agents that produce a variety of actions; the agents cannot be viewed as being pharmacologically equivalent. Until valid structure-activity relationships are formulated for each behavioral/mechanistic action, individual synthetic cathinones remain to be evaluated on a case-by-case basis. Treatment of synthetic cathinone intoxication requires more “basic science” research. At this time, treatment is mostly palliative. PMID:24484988

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

USGS Publications Warehouse

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

2013-01-01

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

Investigation of acyl migration in mono- and dicaffeoylquinic acids under aqueous basic, aqueous acidic, and dry roasting conditions.

PubMed

Deshpande, Sagar; Jaiswal, Rakesh; Matei, Marius Febi; Kuhnert, Nikolai

2014-09-17

Acyl migration in chlorogenic acids describes the process of migration of cinnamoyl moieties from one quinic acid alcohol group to another, thus interconverting chlorogenic acid regioisomers. It therefore constitutes a special case of transesterification reaction. Acyl migration constitutes an important reaction pathway in both coffee roasting and brewing, altering the structure of chlorogenic acid initially present in the green coffee bean. In this contribution we describe detailed and comprehensive mechanistic studies comparing inter- and intramolecular acyl migration involving the seven most common chlorogenic acids in coffee. We employe aqueous acidic and basic conditions mimicking the brewing of coffee along with dry roasting conditions. We show that under aqueous basic conditions intramolecular acyl migration is fully reversible with basic hydrolysis competing with acyl migration. 3-Caffeoylquinic acid was shown to be most labile to basic hydrolysis. We additionally show that the acyl migration process is strongly pH dependent with increased transesterification taking place at basic pH. Under dry roasting conditions acyl migration competes with dehydration to form lactones. We argue that acyl migration precedes lactonization, with 3-caffeoylquinic acid lactone being the predominant product.

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...

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

DOT National Transportation Integrated Search

2015-05-01

Improvements in the Long-Term Pavement Performance (LTPP) Programs climate data are needed to support current and future research into climate effects on pavement materials, design, and performance. The calibration and enhancement of the Mechanist...

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...

Small differences in temperature interact with solar radiation to alter anthocyanin in grapes

USDA-ARS?s Scientific Manuscript database

Despite a century of research, we still lack a concrete, mechanistic understanding of solar radiation and temperature effects on anthocyanin accumulation and composition, crucial for red wine grapes. Our aim was to elucidate the mechanistic response to microclimate of anthocyanin metabolism in Viti...

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

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...

WholeCellSimDB: a hybrid relational/HDF database for whole-cell model predictions

PubMed Central

Karr, Jonathan R.; Phillips, Nolan C.; Covert, Markus W.

2014-01-01

Mechanistic ‘whole-cell’ models are needed to develop a complete understanding of cell physiology. However, extracting biological insights from whole-cell models requires running and analyzing large numbers of simulations. We developed WholeCellSimDB, a database for organizing whole-cell simulations. WholeCellSimDB was designed to enable researchers to search simulation metadata to identify simulations for further analysis, and quickly slice and aggregate simulation results data. In addition, WholeCellSimDB enables users to share simulations with the broader research community. The database uses a hybrid relational/hierarchical data format architecture to efficiently store and retrieve both simulation setup metadata and results data. WholeCellSimDB provides a graphical Web-based interface to search, browse, plot and export simulations; a JavaScript Object Notation (JSON) Web service to retrieve data for Web-based visualizations; a command-line interface to deposit simulations; and a Python API to retrieve data for advanced analysis. Overall, we believe WholeCellSimDB will help researchers use whole-cell models to advance basic biological science and bioengineering. Database URL: http://www.wholecellsimdb.org Source code repository URL: http://github.com/CovertLab/WholeCellSimDB PMID:25231498

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

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

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

The influence of the microbiota on the immune response to transplantation

PubMed Central

Bartman, Caroline; Chong, Anita S.; Alegre, Maria-Luisa

2015-01-01

Purpose of review In the past decade, appreciation of the important effects of commensal microbes on immunity has grown exponentially. The effect of the microbiota on transplantation has only recently begun to be explored; however, our understanding of the mechanistic details of host-microbe interactions is still lacking. Recent findings It has become clear that transplantation is associated with changes in the microbiota in many different settings although what clinical events and therapeutic interventions contribute to these changes remains to be parsed out. Research groups have begun to identify associations between specific communities of organisms and transplant outcomes but it remains to be established whether microbial changes precede or follow transplant rejection episodes. Finally, results from continuing exploration of basic mechanisms by which microbial communities affect innate and adaptive immunity in various animal models of disease continues to inform research on the microbiota’s effects on immune responses against transplanted organs. Summary Commensal microbes may alter immune responses to organ transplantation, but direct experiments are only beginning in the field to identify species and immune pathways responsible for these putative effects. PMID:25563985

Brassinosteroids

PubMed Central

Clouse, Steven D.

2011-01-01

Brassinosteroids (BRs) are endogenous plant hormones essential for the proper regulation of multiple physiological processes required for normal plant growth and development. Since their discovery more than 30 years ago, extensive research on the mechanisms of BR action using biochemistry, mutant studies, proteomics and genome-wide transcriptome analyses, has helped refine the BR biosynthetic pathway, identify the basic molecular components required to relay the BR signal from perception to gene regulation, and expand the known physiological responses influenced by BRs. These mechanistic advances have helped answer the intriguing question of how BRs can have such dramatic pleiotropic effects on a broad range of diverse developmental pathways and have further pointed to BR interactions with other plant hormones and environmental cues. This chapter briefly reviews historical aspects of BR research and then summarizes the current state of knowledge on BR biosynthesis, metabolism and signal transduction. Recent studies uncovering novel phosphorelays and gene regulatory networks through which BR influences both vegetative and reproductive development are examined and placed in the context of known BR physiological responses including cell elongation and division, vascular differentiation, flowering, pollen development and photomorphogenesis. PMID:22303275

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…

Mechanistic-Empirical Pavement Design Guide Flexible Pavement Performance Prediction Models Volume III Field Guide - Calibration and User's Guide for the Mechanistic-Empirical Pavement Design Guide

DOT National Transportation Integrated Search

2007-08-01

The objective of this research study was to develop performance characteristics or variables (e.g., ride quality, rutting, : fatigue cracking, transverse cracking) of flexible pavements in Montana, and to use these characteristics in the : implementa...

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…

Developing the next generation of forest ecosystem models

Treesearch

Christopher R. Schwalm; Alan R. Ek

2002-01-01

Forest ecology and management are model-rich areas for research. Models are often cast as either empirical or mechanistic. With evolving climate change, hybrid models gain new relevance because of their ability to integrate existing mechanistic knowledge with empiricism based on causal thinking. The utility of hybrid platforms results in the combination of...

The Pd-Catalyzed Conversion of Aryl Chlorides, Triflates, and Nonaflates to Nitroaromatics

PubMed Central

Fors, Brett P.; Buchwald, Stephen L.

2009-01-01

An efficient Pd-catalyst for the transformation of aryl chlorides, triflates and nonaflates to nitroaromatics has been developed. This reaction proceeds under weekly basic conditions and displays a broad scope and excellent functional group compatibility. Moreover, this method allows for the synthesis of aromatic nitro compounds that cannot be accessed efficiently via other nitration protocols. Mechanistic insight into the trasmetallation step of the catalytic process is also reported. PMID:19737014

Software for pest-management science: computer models and databases from the United States Department of Agriculture-Agricultural Research Service.

PubMed

Wauchope, R Don; Ahuja, Lajpat R; Arnold, Jeffrey G; Bingner, Ron; Lowrance, Richard; van Genuchten, Martinus T; Adams, Larry D

2003-01-01

We present an overview of USDA Agricultural Research Service (ARS) computer models and databases related to pest-management science, emphasizing current developments in environmental risk assessment and management simulation models. The ARS has a unique national interdisciplinary team of researchers in surface and sub-surface hydrology, soil and plant science, systems analysis and pesticide science, who have networked to develop empirical and mechanistic computer models describing the behavior of pests, pest responses to controls and the environmental impact of pest-control methods. Historically, much of this work has been in support of production agriculture and in support of the conservation programs of our 'action agency' sister, the Natural Resources Conservation Service (formerly the Soil Conservation Service). Because we are a public agency, our software/database products are generally offered without cost, unless they are developed in cooperation with a private-sector cooperator. Because ARS is a basic and applied research organization, with development of new science as our highest priority, these products tend to be offered on an 'as-is' basis with limited user support except for cooperating R&D relationship with other scientists. However, rapid changes in the technology for information analysis and communication continually challenge our way of doing business.

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

PubMed

Woodward, Bill

2016-04-11

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

Identifying gnostic predictors of the vaccine response.

PubMed

Haining, W Nicholas; Pulendran, Bali

2012-06-01

Molecular predictors of the response to vaccination could transform vaccine development. They would allow larger numbers of vaccine candidates to be rapidly screened, shortening the development time for new vaccines. Gene-expression based predictors of vaccine response have shown early promise. However, a limitation of gene-expression based predictors is that they often fail to reveal the mechanistic basis of their ability to classify response. Linking predictive signatures to the function of their component genes would advance basic understanding of vaccine immunity and also improve the robustness of vaccine prediction. New analytic tools now allow more biological meaning to be extracted from predictive signatures. Functional genomic approaches to perturb gene expression in mammalian cells permit the function of predictive genes to be surveyed in highly parallel experiments. The challenge for vaccinologists is therefore to use these tools to embed mechanistic insights into predictors of vaccine response. Copyright © 2012 Elsevier Ltd. All rights reserved.

Identifying gnostic predictors of the vaccine response

PubMed Central

Haining, W. Nicholas; Pulendran, Bali

2012-01-01

Molecular predictors of the response to vaccination could transform vaccine development. They would allow larger numbers of vaccine candidates to be rapidly screened, shortening the development time for new vaccines. Gene-expression based predictors of vaccine response have shown early promise. However, a limitation of gene-expression based predictors is that they often fail to reveal the mechanistic basis for their ability to classify response. Linking predictive signatures to the function of their component genes would advance basic understanding of vaccine immunity and also improve the robustness of outcome classification. New analytic tools now allow more biological meaning to be extracted from predictive signatures. Functional genomic approaches to perturb gene expression in mammalian cells permit the function of predictive genes to be surveyed in highly parallel experiments. The challenge for vaccinologists is therefore to use these tools to embed mechanistic insights into predictors of vaccine response. PMID:22633886

Animal research for type 2 diabetes mellitus, its limited translation for clinical benefit, and the way forward.

PubMed

Ali, Zeeshan; Chandrasekera, P Charukeshi; Pippin, John J

2018-03-01

Obesity and type 2 diabetes mellitus (T2DM) have reached pandemic proportions worldwide, and considerable research efforts have been dedicated to investigating disease pathology and therapeutic options. The two hallmark features of T2DM, insulin resistance and pancreatic dysfunction, have been studied extensively by using various animal models. Despite the knowledge acquired from such models, particularly mechanistic discoveries that sometimes mimic human T2DM mechanisms or pathways, many details of human T2DM pathogenesis remain unknown, therapeutic options remain limited, and a cure has eluded research. Emerging human data have raised concern regarding inter-species differences at many levels (e.g. in gene regulation, pancreatic cytoarchitecture, glucose transport, and insulin secretion regulation), and the subsequent impact of these differences on the clinical translation of animal research findings. Therefore, it is important to recognise and address the translational gap between basic animal-based research and the clinical advances needed to prevent and treat T2DM. The purpose of this report is to identify some limitations of T2DM animal research, and to propose how greater human relevance and applicability of hypothesis-driven basic T2DM research could be achieved through the use of human-based data acquisition at various biological levels. This report addresses how in vitro, in vivo and in silico technologies could be used to investigate particular aspects of human glucose regulation. We do not propose that T2DM animal research has been without value in the identification of mechanisms, pathways, or potential targets for therapies, nor do we claim that human-based methods can provide all the answers. We recognise that the ultimate goal of T2DM animal research is to identify ways to advance the prevention, recognition and treatment of T2DM in humans, but postulate that this is where the use of animal models falls short, despite decades of effort. The best way to achieve this goal is by prioritising human-centred research. 2018 FRAME.

Dimensional psychiatry: mental disorders as dysfunctions of basic learning mechanisms.

PubMed

Heinz, Andreas; Schlagenhauf, Florian; Beck, Anne; Wackerhagen, Carolin

2016-08-01

It has been questioned that the more than 300 mental disorders currently listed in international disease classification systems all have a distinct neurobiological correlate. Here, we support the idea that basic dimensions of mental dysfunctions, such as alterations in reinforcement learning, can be identified, which interact with individual vulnerability and psychosocial stress factors and, thus, contribute to syndromes of distress across traditional nosological boundaries. We further suggest that computational modeling of learning behavior can help to identify specific alterations in reinforcement-based decision-making and their associated neurobiological correlates. For example, attribution of salience to drug-related cues associated with dopamine dysfunction in addiction can increase habitual decision-making via promotion of Pavlovian-to-instrumental transfer as indicated by computational modeling of the effect of Pavlovian-conditioned stimuli (here affectively positive or alcohol-related cues) on instrumental approach and avoidance behavior. In schizophrenia, reward prediction errors can be modeled computationally and associated with functional brain activation, thus revealing reduced encoding of such learning signals in the ventral striatum and compensatory activation in the frontal cortex. With respect to negative mood states, it has been shown that both reduced functional activation of the ventral striatum elicited by reward-predicting stimuli and stress-associated activation of the hypothalamic-pituitary-adrenal axis in interaction with reduced serotonin transporter availability and increased amygdala activation by aversive cues contribute to clinical depression; altogether these observations support the notion that basic learning mechanisms, such as Pavlovian and instrumental conditioning and Pavlovian-to-instrumental transfer, represent a basic dimension of mental disorders that can be mechanistically characterized using computational modeling and associated with specific clinical syndromes across established nosological boundaries. Instead of pursuing a narrow focus on single disorders defined by clinical tradition, we suggest that neurobiological research should focus on such basic dimensions, which can be studied in and compared among several mental disorders.

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…

Metal-ligand cooperation in catalytic intramolecular hydroamination: a computational study of iridium-pyrazolato cooperative activation of aminoalkenes.

PubMed

Tobisch, Sven

2012-06-04

The present study comprehensively explores diverse mechanistic pathways for intramolecular hydroamination of prototype 2,2-dimethyl-4-penten-1-amine by Cp*Ir chloropyrazole (1; Cp*=pentamethylcyclopentadienyl) in the presence of KOtBu base with the aid of density functional theory (DFT) calculations. The most accessible mechanistic pathway for catalytic turnover commences from Cp*Ir pyrazolato (Pz) substrate adduct 2⋅S, representing the catalytically competent compound and proceeds via initial electrophilic activation of the olefin C=C bond by the metal centre. It entails 1) facile and reversible anti nucleophilic amine attack on the iridium-olefin linkage; 2) Ir-C bond protonolysis via stepwise transfer of the ammonium N-H proton at the zwitterionic [Cp*IrPz-alkyl] intermediate onto the metal that is linked to turnover-limiting, reductive, cycloamine elimination commencing from a high-energy, metastable [Cp*IrPz-hydrido-alkyl] species; and 3) subsequent facile cycloamine liberation to regenerate the active catalyst species. The amine-iridium bound 2 a⋅S likely corresponds to the catalyst resting state and the catalytic reaction is expected to proceed with a significant primary kinetic isotope. This study unveils the vital role of a supportive hydrogen-bonded network involving suitably aligned β-basic pyrazolato and cycloamido moieties together with an external amine molecule in facilitating metal protonation and reductive elimination. Cooperative hydrogen bonding thus appears pivotal for effective catalysis. The mechanistic scenario is consonant with catalyst performance data and furthermore accounts for the variation in performance for [Cp*IrPz] compounds featuring a β- or γ-basic pyrazolato unit. As far as the route that involves amine N-H bond activation is concerned, a thus far undocumented pathway for concerted amidoalkene → cycloamine conversion through olefin protonation by the pyrazole N-H concurrent with N-C ring closure is disclosed as a favourable scenario. Although not practicable in the present system, this pathway describes a novel mechanistic variant in late transition metal-ligand bifunctional hydroamination catalysis that can perhaps be viable for tailored catalyst designs. The insights revealed herein concerning the operative mechanism and the structure-reactivity relationships will likely govern the rational design of late transition metal-ligand bifunctional catalysts and facilitate further conceptual advances in the area. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

How mechanisms explain interfield cooperation: biological-chemical study of plant growth hormones in Utrecht and Pasadena, 1930-1938.

PubMed

Schürch, Caterina

2017-09-01

This article examines to what extent a particular case of cross-disciplinary research in the 1930s was structured by mechanistic reasoning. For this purpose, it identifies the interfield theories that allowed biologists and chemists to use each other's techniques and findings, and that provided the basis for the experiments performed to identify plant growth hormones and to learn more about their role in the mechanism of plant growth. In 1930, chemists and biologists in Utrecht and Pasadena began to cooperatively study plant growth. I will argue that these researchers decided to join forces because they believed to rely on each other's findings and methods to solve their research problems adequately. In the course of the cooperation, organic chemists arrived at isolating plant growth hormones by using a test method developed in plant physiology. This achievement, in turn, facilitated biologists' investigation of the mechanism of plant growth. Researchers eventually believed to have the means to study the relation between a substance's molecular structure and its physiological activity. The way they conceptualized the problem of identifying hormones and unraveling the mechanism of plant growth, as well as their actual research actions are compatible with the new mechanists' account of mechanism research. The study illustrates that focusing on researchers' mechanistic reasoning can contribute considerably to explaining the structure of cross-disciplinary research projects.

Basic Science Evidence for the Link Between Erectile Dysfunction and Cardiometabolic Dysfunction

PubMed Central

Musicki, Biljana; Bella, Anthony J.; Bivalacqua, Trinity J.; Davies, Kelvin P.; DiSanto, Michael E.; Gonzalez-Cadavid, Nestor F.; Hannan, Johanna L.; Kim, Noel N.; Podlasek, Carol A.; Wingard, Christopher J.; Burnett, Arthur L.

2016-01-01

Introduction Although clinical evidence supports an association between cardiovascular/metabolic diseases (CVMD) and erectile dysfunction (ED), scientific evidence for this link is incompletely elucidated. Aim This study aims to provide scientific evidence for the link between CVMD and ED. Methods In this White Paper, the Basic Science Committee of the Sexual Medicine Society of North America assessed the current literature on basic scientific support for a mechanistic link between ED and CVMD, and deficiencies in this regard with a critical assessment of current preclinical models of disease. Results A link exists between ED and CVMD on several grounds: the endothelium (endothelium-derived nitric oxide and oxidative stress imbalance); smooth muscle (SM) (SM abundance and altered molecular regulation of SM contractility); autonomic innervation (autonomic neuropathy and decreased neuronal-derived nitric oxide); hormones (impaired testosterone release and actions); and metabolics (hyperlipidemia, advanced glycation end product formation). Conclusion Basic science evidence supports the link between ED and CVMD. The Committee also highlighted gaps in knowledge and provided recommendations for guiding further scientific study defining this risk relationship. This endeavor serves to develop novel strategic directions for therapeutic interventions. PMID:26646025

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.

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

PubMed

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

2015-01-01

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

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

PubMed Central

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

2015-01-01

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

ADVANCED CUTTINGS TRANSPORT STUDY

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

Stefan Miska; Troy Reed; Ergun Kuru

2004-09-30

The Advanced Cuttings Transport Study (ACTS) was a 5-year JIP project undertaken at the University of Tulsa (TU). The project was sponsored by the U.S. Department of Energy (DOE) and JIP member companies. The objectives of the project were: (1) to develop and construct a new research facility that would allow three-phase (gas, liquid and cuttings) flow experiments under ambient and EPET (elevated pressure and temperature) conditions, and at different angle of inclinations and drill pipe rotation speeds; (2) to conduct experiments and develop a data base for the industry and academia; and (3) to develop mechanistic models for optimizationmore » of drilling hydraulics and cuttings transport. This project consisted of research studies, flow loop construction and instrumentation development. Following a one-year period for basic flow loop construction, a proposal was submitted by TU to the DOE for a five-year project that was organized in such a manner as to provide a logical progression of research experiments as well as additions to the basic flow loop. The flow loop additions and improvements included: (1) elevated temperature capability; (2) two-phase (gas and liquid, foam etc.) capability; (3) cuttings injection and removal system; (4) drill pipe rotation system; and (5) drilling section elevation system. In parallel with the flow loop construction, hydraulics and cuttings transport studies were preformed using drilling foams and aerated muds. In addition, hydraulics and rheology of synthetic drilling fluids were investigated. The studies were performed under ambient and EPET conditions. The effects of temperature and pressure on the hydraulics and cuttings transport were investigated. Mechanistic models were developed to predict frictional pressure loss and cuttings transport in horizontal and near-horizontal configurations. Model predictions were compared with the measured data. Predominantly, model predictions show satisfactory agreements with the measured data. As a part of this project, instrumentation was developed to monitor cuttings beds and characterize foams in the flow loop. An ultrasonic-based monitoring system was developed to measure cuttings bed thickness in the flow loop. Data acquisition software controls the system and processes the data. Two foam generating devices were designed and developed to produce foams with specified quality and texture. The devices are equipped with a bubble recognition system and an in-line viscometer to measure bubble size distribution and foam rheology, respectively. The 5-year project is completed. Future research activities will be under the umbrella of Tulsa University Drilling Research Projects. Currently the flow loop is being used for testing cuttings transport capacity of aqueous and polymer-based foams under elevated pressure and temperature conditions. Subsequently, the effect of viscous sweeps on cuttings transport under elevated pressure and temperature conditions will be investigated using the flow loop. Other projects will follow now that the ''steady state'' phase of the project has been achieved.« less

A Question of Control? Examining the Role of Control Conditions in Experimental Psychopathology using the Example of Cognitive Bias Modification Research.

PubMed

Blackwell, Simon E; Woud, Marcella L; MacLeod, Colin

2017-10-26

While control conditions are vitally important in research, selecting the optimal control condition can be challenging. Problems are likely to arise when the choice of control condition is not tightly guided by the specific question that a given study aims to address. Such problems have become increasingly apparent in experimental psychopathology research investigating the experimental modification of cognitive biases, particularly as the focus of this research has shifted from theoretical questions concerning mechanistic aspects of the association between cognitive bias and emotional vulnerability, to questions that instead concern the clinical efficacy of 'cognitive bias modification' (CBM) procedures. We discuss the kinds of control conditions that have typically been employed in CBM research, illustrating how difficulties can arise when changes in the types of research questions asked are not accompanied by changes in the control conditions employed. Crucially, claims made on the basis of comparing active and control conditions within CBM studies should be restricted to those conclusions allowed by the specific control condition employed. CBM studies aiming to establish clinical utility are likely to require quite different control conditions from CBM studies aiming to illuminate mechanisms. Further, conclusions concerning the clinical utility of CBM interventions cannot necessarily be drawn from studies in which the control condition has been chosen to answer questions concerning mechanisms. Appreciating the need to appropriately alter control conditions in the transition from basic mechanisms-focussed investigations to applied clinical research could greatly facilitate the translational process.

Research on roadway performance and distress at low temperature.

DOT National Transportation Integrated Search

2012-06-01

This research project investigated the performance and damage characteristics of Nebraska roadways at low-temperature : conditions. To meet the research objective, laboratory tests were incorporated with mechanistic numerical modeling. The : three mo...

WholeCellSimDB: a hybrid relational/HDF database for whole-cell model predictions.

PubMed

Karr, Jonathan R; Phillips, Nolan C; Covert, Markus W

2014-01-01

Mechanistic 'whole-cell' models are needed to develop a complete understanding of cell physiology. However, extracting biological insights from whole-cell models requires running and analyzing large numbers of simulations. We developed WholeCellSimDB, a database for organizing whole-cell simulations. WholeCellSimDB was designed to enable researchers to search simulation metadata to identify simulations for further analysis, and quickly slice and aggregate simulation results data. In addition, WholeCellSimDB enables users to share simulations with the broader research community. The database uses a hybrid relational/hierarchical data format architecture to efficiently store and retrieve both simulation setup metadata and results data. WholeCellSimDB provides a graphical Web-based interface to search, browse, plot and export simulations; a JavaScript Object Notation (JSON) Web service to retrieve data for Web-based visualizations; a command-line interface to deposit simulations; and a Python API to retrieve data for advanced analysis. Overall, we believe WholeCellSimDB will help researchers use whole-cell models to advance basic biological science and bioengineering. http://www.wholecellsimdb.org SOURCE CODE REPOSITORY: URL: http://github.com/CovertLab/WholeCellSimDB. © The Author(s) 2014. Published by Oxford University Press.

A cytokine axis regulates elastin formation and degradation

PubMed Central

Sproul, Erin P.; Argraves, W. Scott

2013-01-01

Underlying the dynamic regulation of tropoelastin expression and elastin formation in development and disease are transcriptional and post-transcriptional mechanisms that have been the focus of much research. Of particular importance is the cytokine–governed elastin regulatory axis in which the pro-elastogenic activities of transforming growth factor β-1 (TGFβ1) and insulin-like growth factor-I (IGF-I) are opposed by anti-elastogenic activities of basic fibroblast growth factor (bFGF/FGF-2), heparin-binding epidermal growth factor-like growth factor (HB-EGF), EGF, PDGF-BB, TGFα, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β and noncanonical TGFβ1 signaling. A key mechanistic feature of the regulatory axis is that cytokines influence elastin formation through effects on the cell cycle involving control of cyclin–cyclin dependent kinase complexes and activation of the Ras/MEK/ERK signaling pathway. In this article we provide an overview of the major cytokines/growth factors that modulate elastogenesis and describe the underlying molecular mechanisms for their action on elastin production. PMID:23160093

A mathematical model for foreign body reactions in 2D.

PubMed

Su, Jianzhong; Gonzales, Humberto Perez; Todorov, Michail; Kojouharov, Hristo; Tang, Liping

2011-02-01

The foreign body reactions are commonly referred to the network of immune and inflammatory reactions of human or animals to foreign objects placed in tissues. They are basic biological processes, and are also highly relevant to bioengineering applications in implants, as fibrotic tissue formations surrounding medical implants have been found to substantially reduce the effectiveness of devices. Despite of intensive research on determining the mechanisms governing such complex responses, few mechanistic mathematical models have been developed to study such foreign body reactions. This study focuses on a kinetics-based predictive tool in order to analyze outcomes of multiple interactive complex reactions of various cells/proteins and biochemical processes and to understand transient behavior during the entire period (up to several months). A computational model in two spatial dimensions is constructed to investigate the time dynamics as well as spatial variation of foreign body reaction kinetics. The simulation results have been consistent with experimental data and the model can facilitate quantitative insights for study of foreign body reaction process in general.

The pathophysiology of heart failure: a tale of two old paradigms revisited.

PubMed

Ashrafian, Houman; Williams, Lynne; Frenneaux, Michael P

2008-04-01

Although our current appreciation of the detrimental role of neurohumoral activation in heart failure (HF) has been intellectually appealing and has led to neurohumoral antagonism that has reduced morbidity and mortality from HF, the persisting disability and death rates remain unacceptably high. In the search for novel strategies to improve on these outcomes, we must reacquaint ourselves with basic cardiac physiology at levels ranging from the molecular to the systemic in order to identify new targets for the treatment of HF. This approach has already begun to yield results; in this review, two such aspects will be focused on: diastolic ventricular interaction and cardiac energetics. These two examples will be used to illuminate how fundamental research has elucidated age-old, although mechanistically elusive, principles (for example, the Frank-Starling law), explained why existing and emerging therapeutic approaches (for example, biventricular pacing in HF) have proved successful, and successfully identified novel therapy modes (for example, perhexiline as an energy augmentation agent).

Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome

PubMed Central

Hagerman, Randi; Hagerman, Paul

2014-01-01

Summary Fragile X syndrome, the leading heritable form of cognitive impairment, is caused by epigenetic silencing of the fragile X (FMR1) gene consequent to large expansions (>200 repeats) of a non-coding CGG-repeat element. Smaller, “premutation” expansions (55–200 repeats) can give rise to a family of neurodevelopmental (ADHD, autism spectrum disorder, seizure disorder) and neurodegenerative (FXTAS) clinical phenotypes through an entirely distinct molecular mechanism involving increased FMR1 mRNA production and toxicity. Basic cellular, animal, and human studies have helped to elucidate the underlying RNA toxicity mechanism, while clinical research is providing a more nuanced picture of the spectrum of clinical involvement. Whereas advances on both mechanistic and clinical fronts are driving new approaches to targeted treatment, two important issues/needs are emerging: to define the extent to which the mechanisms contributing to FXTAS also contribute to other neurodegenerative and medical disorders, and to redefine FXTAS in light of its differing presentations and associated features. PMID:23867198

T Cell Production of GM-CSF Protects the Host during Experimental Tuberculosis.

PubMed

Robinson, Richard T

2017-12-12

Although classically associated with myelopoiesis, granulocyte-macrophage colony-stimulating factor (GM-CSF) is increasingly recognized as being important for tuberculosis (TB) resistance. GM-CSF is expressed by nonhematopoietic and hematopoietic lineages following infection with Mycobacterium tuberculosis and is necessary to restrict M. tuberculosis growth in experimental models. Until the recent study by Rothchild et al. (mBio 8:e01514-17, 2017, https://doi.org/10.1128/mBio.01514-17), it was unknown whether GM-CSF-producing T cells contribute to TB resistance. Rothchild et al. identify which conventional and nonconventional T cell subsets produce GM-CSF during experimental TB, establish their protective nature using a variety of approaches, and provide a mechanistic basis for their ability to restrict M. tuberculosis growth. This commentary discusses the significance of these findings to basic and applied TB research. As translated to human disease, these findings suggest vaccine-mediated expansion of GM-CSF-producing T cells could be an effective prophylactic or therapeutic TB strategy. Copyright © 2017 Robinson.

Incorporation of basic side chains into cryptolepine scaffold: structure-antimalarial activity relationships and mechanistic studies.

PubMed

Lavrado, João; Cabal, Ghislain G; Prudêncio, Miguel; Mota, Maria M; Gut, Jiri; Rosenthal, Philip J; Díaz, Cecília; Guedes, Rita C; dos Santos, Daniel J V A; Bichenkova, Elena; Douglas, Kenneth T; Moreira, Rui; Paulo, Alexandra

2011-02-10

The synthesis of cryptolepine derivatives containing basic side-chains at the C-11 position and their evaluations for antiplasmodial and cytotoxicity properties are reported. Propyl, butyl, and cycloalkyl diamine side chains significantly increased activity against chloroquine-resistant Plasmodium falciparum strains while reducing cytotoxicity when compared with the parent compound. Localization studies inside parasite blood stages by fluorescence microscopy showed that these derivatives accumulate inside the nucleus, indicating that the incorporation of a basic side chain is not sufficient enough to promote selective accumulation in the acidic digestive vacuole of the parasite. Most of the compounds within this series showed the ability to bind to a double-stranded DNA duplex as well to monomeric hematin, suggesting that these are possible targets associated with the observed antimalarial activity. Overall, these novel cryptolepine analogues with substantially improved antiplasmodial activity and selectivity index provide a promising starting point for development of potent and highly selective agents against drug-resistant malaria parasites.

When relationships estimated in the past cannot be used to predict the future: using mechanistic models to predict landscape ecological dynamics in a changing world

Treesearch

Eric J. Gustafson

2013-01-01

Researchers and natural resource managers need predictions of how multiple global changes (e.g., climate change, rising levels of air pollutants, exotic invasions) will affect landscape composition and ecosystem function. Ecological predictive models used for this purpose are constructed using either a mechanistic (process-based) or a phenomenological (empirical)...

Synthesis of 2D Metal Chalcogenide Thin Films through the Process Involving Solution-Phase Deposition.

PubMed

Giri, Anupam; Park, Gyeongbae; Yang, Heeseung; Pal, Monalisa; Kwak, Junghyeok; Jeong, Unyong

2018-04-24

2D metal chalcogenide thin films have recently attracted considerable attention owing to their unique physicochemical properties and great potential in a variety of applications. Synthesis of large-area 2D metal chalcogenide thin films in controllable ways remains a key challenge in this research field. Recently, the solution-based synthesis of 2D metal chalcogenide thin films has emerged as an alternative approach to vacuum-based synthesis because it is relatively simple and easy to scale up for high-throughput production. In addition, solution-based thin films open new opportunities that cannot be achieved from vacuum-based thin films. Here, a comprehensive summary regarding the basic structures and properties of different types of 2D metal chalcogenides, the mechanistic details of the chemical reactions in the synthesis of the metal chalcogenide thin films, recent successes in the synthesis by different reaction approaches, and the applications and potential uses is provided. In the last perspective section, the technical challenges to be overcome and the future research directions in the solution-based synthesis of 2D metal chalcogenides are discussed. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

More than just noise: Inter-individual differences in fear acquisition, extinction and return of fear in humans - Biological, experiential, temperamental factors, and methodological pitfalls.

PubMed

Lonsdorf, Tina B; Merz, Christian J

2017-09-01

Why do only some individuals develop pathological anxiety following adverse events? Fear acquisition, extinction and return of fear paradigms serve as experimental learning models for the development, treatment and relapse of anxiety. Individual differences in experimental performance were however mostly regarded as 'noise' by researchers interested in basic associative learning principles. Our work for the first time presents a comprehensive literature overview and methodological discussion on inter-individual differences in fear acquisition, extinction and return of fear. We tell a story from noise that steadily develops into a meaningful tune and converges to a model of mechanisms contributing to individual risk/resilience with respect to fear and anxiety-related behavior. Furthermore, in light of the present 'replicability crisis' we identify methodological pitfalls and provide suggestions for study design and analyses tailored to individual difference research in fear conditioning. Ultimately, synergistic transdisciplinary and collaborative efforts hold promise to not only improve our mechanistic understanding but can also be expected to contribute to the development of specifically tailored ('individualized') intervention and targeted prevention programs in the future. Copyright © 2017 Elsevier Ltd. All rights reserved.

Different methods and metaphysics in early molecular genetics--a case of disparity of research?

PubMed

Deichmann, Ute

2008-01-01

The encounter between two fundamentally different approaches in seminal research in molecular biology--the problems, aims, methods and metaphysics--is delineated and analyzed. They are exemplified by the microbiologist Oswald T. Avery who, in line with the reductionist mechanistic metaphysics of Jacques Loeb, attempted to explain basic life phenomena through chemistry; and the theoretical physicist Max Delbrück who, influenced by Bohr's antimechanistic views, preferred to explain these phenomena without chemistry. Avery's and Delbrück's most important studies took place concurrently. Thus analysis of their contrasting approaches lends itself to examination of the Weltanschauungen view concerning the role of fundamental (metaphysical) assumptions in scientific change, that is, the view that empirical research cannot be neutral in regard to the worldviews of the researchers. This study shows that the initial ostensible disparity (non-integratibility) of the two approaches lasted for just a short time. Ironically it was a student of Delbrück's school, James Watson, who (with Crick) proposed a chemical model, the DNA double helix, as a solution to Delbrück's problem. The structure of DNA has not been seriously challenged over the past half century Moreover, Watson's and Crick's work did not call into question the validity of Delbrück's research, but opened it up to entirely new approaches. The case of Avery and Delbrück demonstrates that after initial obstacles were overcome the different fundamental attitudes and the resulting research practices were capable of integration.

Highlights of the mechanistic and therapeutic cachexia and sarcopenia research 2010 to 2012 and their relevance for cardiology.

PubMed

Anker, Markus S; von Haehling, Stephan; Springer, Jochen; Banach, Maciej; Anker, Stefan D

2013-01-10

Sarcopenia and cachexia are significant medical problems with a high disease related burden in cardiovascular illness. Muscle wasting and weight loss are very frequent particularly in chronic heart failure and they relate to poor prognosis. Although clinically largely underestimated, the fields of cachexia and sarcopenia are of great relevance to cardiologists. In cachexia and sarcopenia a significant number of research publications related to basic science questions of muscle wasting and lipolysis were published between 2010 and 2012. Recently, the two processes of muscle wasting and lipolysis were found to be closely linked. Treatment research in pre-clinical models involves studies on a number of different therapeutic entities, including ghrelin, selective androgen receptor modulators (SARMs), as well as drugs targeting myostatin or melanocortin-4. In the human setting, studies using enobosarm (a SARM) and anamorelin (ghrelin) are in phase III. The last 3 years has seen significant efforts to define the field using consensus statements. In the future, these definitions should also be considered for guidelines and treatment trials in cardiovascular medicine. The current review aims to summarize important information and development in the fields of muscle wasting, sarcopenia and cachexia focussing on findings in cardiovascular research, in order for cardiologists to have a better understanding of the progress in the still not well enough known field. Copyright © 2012. Published by Elsevier Ireland Ltd.

Use of high-throughput in vitro toxicity screening data in cancer hazard evaluations by IARC Monograph Working Groups

PubMed Central

Chiu, Weihsueh A.; Guyton, Kathryn Z.; Martin, Matthew T.; Reif, David M.; Rusyn, Ivan

2017-01-01

Evidence regarding carcinogenic mechanisms serves a critical role in International Agency for Research on Cancer (IARC) Monograph evaluations. Three recent IARC Working Groups pioneered inclusion of the US Environmental Protection Agency (EPA) ToxCast program high-throughput screening (HTS) data to supplement other mechanistic evidence. In Monograph V110, HTS profiles were compared between perfluorooctanoic acid (PFOA) and prototypical activators across multiple nuclear receptors. For Monograph V112 -113, HTS assays were mapped to 10 key characteristics of carcinogens identified by an IARC expert group, and systematically considered as an additional mechanistic data stream. Both individual assay results and ToxPi-based rankings informed mechanistic evaluations. Activation of multiple nuclear receptors in HTS assays showed that PFOA targets peroxisome proliferator activated and other receptors. ToxCast assays substantially covered 5 of 10 key characteristics, corroborating literature evidence of “induces oxidative stress” and “alters cell proliferation, cell death or nutrient supply” and filling gaps for “modulates receptor-mediated effects.” Thus, ToxCast HTS data were useful both in evaluating specific mechanistic hypotheses and in the overall evaluation of mechanistic evidence. However, additional HTS assays are needed to provide more comprehensive coverage of the 10 key characteristics of carcinogens that form the basis of current IARC mechanistic evaluations. PMID:28738424

Use of high-throughput in vitro toxicity screening data in cancer hazard evaluations by IARC Monograph Working Groups.

PubMed

Chiu, Weihsueh A; Guyton, Kathryn Z; Martin, Matthew T; Reif, David M; Rusyn, Ivan

2018-01-01

Evidence regarding carcinogenic mechanisms serves a critical role in International Agency for Research on Cancer (IARC) Monograph evaluations. Three recent IARC Working Groups pioneered inclusion of the US Environmental Protection Agency (EPA) ToxCast program high-throughput screening (HTS) data to supplement other mechanistic evidence. In Monograph V110, HTS profiles were compared between perfluorooctanoic acid (PFOA) and prototypical activators across multiple nuclear receptors. For Monograph V112-113, HTS assays were mapped to 10 key characteristics of carcinogens identified by an IARC expert group, and systematically considered as an additional mechanistic data stream. Both individual assay results and ToxPi-based rankings informed mechanistic evaluations. Activation of multiple nuclear receptors in HTS assays showed that PFOA targets not only peroxisome proliferator activated receptors, but also other receptors. ToxCast assays substantially covered 5 of 10 key characteristics, corroborating literature evidence of "induces oxidative stress" and "alters cell proliferation, cell death or nutrient supply" and filling gaps for "modulates receptor-mediated effects." Thus, ToxCast HTS data were useful both in evaluating specific mechanistic hypotheses and in contributing to the overall evaluation of mechanistic evidence. However, additional HTS assays are needed to provide more comprehensive coverage of the 10 key characteristics of carcinogens that form the basis of current IARC mechanistic evaluations.

Teleomechanism redux? Functional physiology and hybrid models of life in early modern natural philosophy.

PubMed

Wolfe, Charles T

2014-01-01

The distinction between 'mechanical' and 'teleological' has been familiar since Kant; between a fully mechanistic, quantitative science of Nature and a teleological, qualitative approach to living beings, namely 'organisms' understood as purposive or at least functional entities. The beauty of this distinction is that it apparently makes intuitive sense and maps onto historico-conceptual constellations in the life sciences, regarding the status of the body versus that of the machine. I argue that the mechanism-teleology distinction is imprecise and flawed using examples including the 'functional' features present even in Cartesian physiology, the Oxford Physiologists' work on circulation and respiration, the fact that the model of the 'body-machine' is not a mechanistic reduction of organismic properties to basic physical properties but is focused on the uniqueness of organic life; and the concept of 'animal economy' in vitalist medicine, which I present as a 'teleomechanistic' concept of organism (borrowing a term of Lenoir's which he applied to nineteenth-century embryology)--neither mechanical nor teleological.

The Queen's English: an alternative, biosocial hypothesis for the distinctive features of "gay speech".

PubMed

Rendall, Drew; Vasey, Paul L; McKenzie, Jared

2008-02-01

Popular stereotypes concerning the speech of homosexuals typically attribute speech patterns characteristic of the opposite-sex, i.e., broadly feminized speech in gay men and broadly masculinized speech in lesbian women. A small body of recent empirical research has begun to address the subject more systematically and to consider specific mechanistic hypotheses to account for the potentially distinctive features of homosexual speech. Results do not yet fully endorse the stereotypes but they do not entirely discount them either; nor do they cleanly favor any single mechanistic hypothesis. To contribute to this growing body of research, we report acoustic analyses of 2,875 vowel sounds from a balanced set of 125 speakers representing heterosexual and homosexual individuals of each sex from southern Alberta, Canada. Analyses focused on voice pitch and formant frequencies which together determine the principle perceptual features of vowels. There was no significant difference in mean voice pitch between heterosexual and homosexual men or between heterosexual and homosexual women, but there were significant differences in the formant frequencies of vowels produced by both homosexual groups compared to their heterosexual counterparts. Formant frequency differences were specific to only certain vowel sounds and some could be attributed to basic differences in body size between heterosexual and homosexual speakers. The remaining formant frequency differences were not obviously due to differences in vocal tract anatomy between heterosexual and homosexual speakers, nor did they reflect global feminization or masculinization of vowel production patterns in homosexual men and women, respectively. The vowel-specific differences observed could reflect social modeling processes in which only certain speech patterns of the opposite-sex, or of same-sex homosexuals, are selectively adopted. However, we introduce an alternative biosocial hypothesis, specifically that the distinctive, vowel-specific features of homosexual speakers relative to heterosexual speakers arise incidentally as a product of broader psychobehavioral differences between the two groups that are, in turn, continuous with and flow from the physiological processes that affect sexual orientation to begin with.

Upscaling of reaction rates in reactive transport using pore-scale reactive transport model

NASA Astrophysics Data System (ADS)

Yoon, H.; Dewers, T. A.; Arnold, B. W.; Major, J. R.; Eichhubl, P.; Srinivasan, S.

2013-12-01

Dissolved CO2 during geological CO2 storage may react with minerals in fractured rocks, confined aquifers, or faults, resulting in mineral precipitation and dissolution. The overall rate of reaction can be affected by coupled processes among hydrodynamics, transport, and reactions at the (sub) pore-scale. In this research pore-scale modeling of coupled fluid flow, reactive transport, and heterogeneous reaction at the mineral surface is applied to account for permeability alterations caused by precipitation-induced pore-blocking. This work is motivated by the observed CO2 seeps from a natural analog to geologic CO2 sequestration at Crystal Geyser, Utah. A key observation is the lateral migration of CO2 seep sites at a scale of ~ 100 meters over time. A pore-scale model provides fundamental mechanistic explanations of how calcite precipitation alters flow paths by pore plugging under different geochemical compositions and pore configurations. In addition, response function of reaction rates will be constructed from pore-scale simulations which account for a range of reaction regimes characterized by the Damkohler and Peclet numbers. Newly developed response functions will be used in a continuum scale model that may account for large-scale phenomena mimicking lateral migration of surface CO2 seeps. Comparison of field observations and simulations results will provide mechanistic explanations of the lateral migration and enhance our understanding of subsurface processes associated with the CO2 injection. This work is supported as part of the Center for Frontiers of Subsurface Energy Security, an Energy Frontier Research Center funded by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Award Number DE-SC0001114. Sandia National Laboratories is a multi-program laboratory managed and operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Corporation, for the U.S. Department of Energy's National Nuclear Security Administration under contract DE-AC04-94AL85000.

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

Future directions in research on sexual minority adolescent mental, behavioral, and sexual health

PubMed Central

Mustanski, Brian

2015-01-01

This article describes current knowledge on sexual, mental, and behavioral health of sexual minority (SM) youth and identifies gaps that would benefit from future research. A translational sciences framework is used to conceptualize the article, discussing findings and gaps along the spectrum from basic research on prevalence and mechanisms, to intervention development and testing, to implementation. Relative to adults, there has been much less research on adolescents and very few studies that had longitudinal follow-up beyond one year. Due to historical changes in the social acceptance of the SM community, new cohorts are needed to represent contemporary life experiences and associated health consequences. Important theoretical developments have occurred in conceptualizing mechanisms that drive SM health disparities and mechanistic research is underway, including studies that identify individual and structural risk/protective factors. Research opportunities exist in the utilization of sibling-comparison designs, inclusion of parents, and studying romantic relationships. Methodological innovation is needed in sampling SM populations. There has been less intervention research and approaches should consider natural resiliencies, life-course frameworks, prevention science, multiple levels of influence, and the importance of implementation. Regulatory obstacles are created when ethics boards elect to require parental permission and ethics research is needed. There has been inconsistent inclusion of SM populations in the definition of “health disparity population,” which impacts funding and training opportunities. There are incredible opportunities for scholars to make substantial and foundational contributions to help address the health of SM youth, and new funding opportunities to do so. PMID:25575125

The discovery and development of analgesics: new mechanisms, new modalities

PubMed Central

Burgess, Gillian; Williams, Dic

2010-01-01

Despite intensive research into pain mechanisms and significant investment in research and development, the majority of analgesics available to prescribers and patients are based on mechanistic classes of compounds that have been known for many years. With considerable ingenuity and innovation, researchers continue to make the best of the mechanistic approaches available, with novel formulations, routes of administration, and combination products. Here we review some of the mechanisms and modalities of analgesics that have recently entered into clinical development, which, coupled with advances in the understanding of the pathophysiology of chronic pain, will hopefully bring the promise of new therapeutics that have the potential to provide improved pain relief for those many patients whose needs remain poorly met. PMID:21041957

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

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 Insights into the Structure-Dependent Selectivity of Catalytic Furfural Conversion on Platinum Catalysts

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

Cai, Qiuxia; Wang, Jianguo; Wang, Yang-Gang

The effects of structure and size on the selectivity of catalytic furfural conversion over supported Pt catalysts in the presence of hydrogen have been studied using first principles density functional theory (DFT) calculations and microkinetic modeling. Four Pt model systems, i.e., periodic Pt(111), Pt(211) surfaces, as well as small nanoclusters (Pt13 and Pt55) are chosen to represent the terrace, step, and corner sites of Pt nanoparticles. Our DFT results show that the reaction routes for furfural hydrogenation and decarbonylation are strongly dependent on the type of reactive sites, which lead to the different selectivity. On the basis of the size-dependentmore » site distribution rule, we correlate the site distributions as a function of the Pt particle size. Our microkinetic results indicate the critical particle size that controls the furfural selectivity is about 1.0 nm, which is in good agreement with the reported experimental value under reaction conditions. This work was supported by National Basic Research Program of China (973 Program) (2013CB733501) and the National Natural Science Foundation of China (NSFC-21306169, 21176221, 21136001, 21101137 and 91334103). This work was also partially supported by the US Department of Energy (DOE), the Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences & Biosciences. Pacific Northwest National Laboratory (PNNL) is a multiprogram national laboratory operated for DOE by Battelle. Computing time was granted by the grand challenge of computational catalysis of the William R. Wiley Environmental Molecular Sciences Laboratory (EMSL). EMSL is a national scientific user facility located at Pacific Northwest National Laboratory (PNNL) and sponsored by DOE’s Office of Biological and Environmental Research.« less

On the chemistry of ethanol on basic oxides: revising mechanisms and intermediates in the Lebedev and Guerbet reactions.

PubMed

Chieregato, Alessandro; Velasquez Ochoa, Juliana; Bandinelli, Claudia; Fornasari, Giuseppe; Cavani, Fabrizio; Mella, Massimo

2015-01-01

A common way to convert ethanol into chemicals is by upgrading it over oxide catalysts with basic features; this method makes it possible to obtain important chemicals such as 1-butanol (Guerbet reaction) and 1,3-butadiene (Lebedev reaction). Despite their long history in chemistry, the details of the close inter-relationship of these reactions have yet to be discussed properly. Our present study focuses on reactivity tests, in situ diffuse reflectance infrared Fourier transform spectroscopy, MS analysis, and theoretical modeling. We used MgO as a reference catalyst with pure basic features to explore ethanol conversion from its very early stages. Based on the obtained results, we formulate a new mechanistic theory able to explain not only our results but also most of the scientific literature on Lebedev and Guerbet chemistry. This provides a rational description of the intermediates shared by the two reaction pathways as well as an innovative perspective on the catalyst requirements to direct the reaction pathway toward 1-butanol or butadiene. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Improved spring load restriction guidelines using mechanistic analysis

DOT National Transportation Integrated Search

2000-07-01

This project used research to develop more effective criteria for placement and removal of spring load restrictions (SLR). Researchers investigated a method that uses a thawing index equation based on air temperatures to predict thawing events. Resul...

Ground-Based Gas-Liquid Flow Research in Microgravity Conditions: State of Knowledge

NASA Technical Reports Server (NTRS)

McQuillen, J.; Colin, C.; Fabre, J.

1999-01-01

During the last decade, ground-based microgravity facilities have been utilized in order to obtain predictions for spacecraft system designers and further the fundamental understanding of two-phase flow. Although flow regime, pressure drop and heat transfer coefficient data has been obtained for straight tubes and a limited number of fittings, measurements of the void fraction, film thickness, wall shear stress, local velocity and void information are also required in order to develop general mechanistic models that can be utilized to ascertain the effects of fluid properties, tube geometry and acceleration levels. A review of this research is presented and includes both empirical data and mechanistic models of the flow behavior.

Oleogustus: The Unique Taste of Fat.

PubMed

Running, Cordelia A; Craig, Bruce A; Mattes, Richard D

2015-09-01

Considerable mechanistic data indicate there may be a sixth basic taste: fat. However, evidence demonstrating that the sensation of nonesterified fatty acids (NEFA, the proposed stimuli for "fat taste") differs qualitatively from other tastes is lacking. Using perceptual mapping, we demonstrate that medium and long-chain NEFA have a taste sensation that is distinct from other basic tastes (sweet, sour, salty, and bitter). Although some overlap was observed between these NEFA and umami taste, this overlap is likely due to unfamiliarity with umami sensations rather than true similarity. Shorter chain fatty acids stimulate a sensation similar to sour, but as chain length increases this sensation changes. Fat taste oral signaling, and the different signals caused by different alkyl chain lengths, may hold implications for food product development, clinical practice, and public health policy. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Basic, specific, mechanistic? Conceptualizing musical emotions in the brain.

PubMed

Omigie, Diana

2016-06-01

The number of studies investigating music processing in the human brain continues to increase, with a large proportion of them focussing on the correlates of so-called musical emotions. The current Review highlights the recent development whereby such studies are no longer concerned only with basic emotions such as happiness and sadness but also with so-called music-specific or "aesthetic" ones such as nostalgia and wonder. It also highlights how mechanisms such as expectancy and empathy, which are seen as inducing musical emotions, are enjoying ever-increasing investigation and substantiation with physiological and neuroimaging methods. It is proposed that a combination of these approaches, namely, investigation of the precise mechanisms through which so-called music-specific or aesthetic emotions may arise, will provide the most important advances for our understanding of the unique nature of musical experience. © 2015 Wiley Periodicals, Inc.

Chemical Foundations of Hydrogen Sulfide Biology

PubMed Central

Li, Qian; Lancaster, Jack R.

2013-01-01

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

Research News: Debate on Learning Theory Is Shifting.

ERIC Educational Resources Information Center

Fox, Jeffrey L.

1983-01-01

Discusses current learning theories, indicating that though many psychologists and ethologists now agree on using a mechanistic approach, some linguists doubt its adequacy. Implications of research on the mollusk "Aplasia" to understand the learning process are included. (JN)

Commentary.

ERIC Educational Resources Information Center

Scarr, Sandra

1995-01-01

Argues that Gottlieb rejects population sampling and statistical analyses of distributions as he proposes that his experimental brand of mechanistic science is the only legitimate approach to developmental research. Maintains that Gottlieb exaggerates developmental uncertainty, based on his own research with extreme environmental manipulations.…

Urine: Waste product or biologically active tissue?

PubMed

2018-03-01

Historically, urine has been viewed primarily as a waste product with little biological role in the overall health of an individual. Increasingly, data suggest that urine plays a role in human health beyond waste excretion. For example, urine might act as an irritant and contribute to symptoms through interaction with-and potential compromise of-the urothelium. To explore the concept that urine may be a vehicle for agents with potential or occult bioactivity and to discuss existing evidence and novel research questions that may yield insight into such a role, the National Institute of Diabetes and Digestive and Kidney Disease invited experts in the fields of comparative evolutionary physiology, basic science, nephrology, urology, pediatrics, metabolomics, and proteomics (among others) to a Urinology Think Tank meeting on February 9, 2015. This report reflects ideas that evolved from this meeting and current literature, including the concept of urine quality, the biological, chemical, and physical characteristics of urine, including the microbiota, cells, exosomes, pH, metabolites, proteins, and specific gravity (among others). Additionally, the manuscript presents speculative, and hopefully testable, ideas about the functional roles of urine constituents in health and disease. Moving forward, there are several questions that need further understanding and pursuit. There were suggestions to consider actively using various animal models and their biological specimens to elaborate on basic mechanistic information regarding human bladder dysfunction. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

Proceedings of the 3rd Annual Albert Institute for Bladder Cancer Research Symposium.

PubMed

Flaig, Thomas W; Kamat, Ashish M; Hansel, Donna; Ingersoll, Molly A; Barton Grossman, H; Mendelsohn, Cathy; DeGraff, David; Liao, Joseph C; Taylor, John A

2017-07-27

The Third Annual Albert Institute Bladder Symposium was held on September 8-10th, 2016, in Denver Colorado. Participants discussed several critical topics in the field of bladder cancer: 1) Best practices for tissue analysis and use to optimize correlative studies, 2) Modeling bladder cancer to facilitate understanding and innovation, 3) Targeted therapies for bladder cancer, 4) Tumor phylogeny in bladder cancer, 5) New Innovations in bladder cancer diagnostics. Our understanding of and approach to treating urothelial carcinoma is undergoing rapid advancement. Preclinical models of bladder cancer have been leveraged to increase our basic and mechanistic understanding of the disease. With the approval of immune checkpoint inhibitors for the treatment of advanced urothelial carcinoma, the treatment approach for these patients has quickly changed. In this light, molecularly-defined subtypes of bladder cancer and appropriate pre-clinical models are now essential to the further advancement and appropriate application of these therapeutic improvements. The optimal collection and processing of clinical urothelial carcinoma tissues samples will also be critical in the development of predictive biomarkers for therapeutic selection. Technological advances in other areas including optimal imaging technologies and micro/nanotechnologies are being applied to bladder cancer, especially in the localized setting, and hold the potential for translational impact in the treatment of bladder cancer patients. Taken together, advances in several basic science and clinical areas are now converging in bladder cancer. These developments hold the promise of shaping and improving the clinical care of those with the disease.

Current Challenges in Neurotoxicity Risk Assessment ...

EPA Pesticide Factsheets

Neurotoxicity risk assessment must continue to evolve in parallel with advances in basic research. Along with this evolution is an expansion in the scope of neurotoxicity assessments of environmental health risks. Examples of this expansion include an increasing emphasis on complex animal models that better replicate human behavior and a wider array of molecular and mechanistic data relevant to interpreting the underlying cause(s) of toxicity. However, modern neurotoxicology studies are often more nuanced and complicated than traditional studies, and they often vary considerably in evaluation methods from one study to the next, impeding comparisons. This can pose particular difficulties for risk assessors, especially given the recent demand for chemical risk assessments to be more systematic and transparent. This presentation will introduce and provide some examples of specific challenges in neurotoxicity assessments of environmental chemicals. Some of these challenges are relatively new to the field, such as the incorporation of data on neuron-supportive glial cells into hazard characterization, while other challenges have persisted for several decades, but only recently are studies being designed to evaluate them, including analyses of latent neurotoxicity. The examples provided illustrate some future research areas of interest for scientists and risk assessors examining human neurotoxicity risk. This abstract will be presented to internal U.S. Food and Drug A

Cellular and Animal Studies: Insights into Pathophysiology and Therapy of PCOS.

PubMed

Indran, Inthrani Raja; Lee, Bao Hui; Yong, Eu-Leong

2016-11-01

Basic science studies have advanced our understanding of the role of key enzymes in the steroidogenesis pathway and those that affect the pathophysiology of PCOS. Studies with ovarian theca cells taken from women with PCOS have demonstrated increased androgen production due to increased CYP17A1 and HSD3B2 enzyme activities. Furthermore, overexpression of DENND1A variant 2 in normal theca cells resulted in a PCOS phenotype with increased androgen production. Notably, cellular steroidogenesis models have facilitated the understanding of the mechanistic effects of pharmacotherapies, including insulin sensitizers (e.g., pioglitazone and metformin) used for the treatment of insulin resistance in PCOS, on androgen production. In addition, animal models of PCOS have provided a critical platform to study the effects of therapeutic agents in a manner closer to the physiological state. Indeed, recent breakthroughs have demonstrated that natural derivatives such as the dietary medium-chain fatty acid decanoic acid (DA) can restore estrous cyclicity and lower androgen levels in an animal model of PCOS, thus laying the platform for novel therapeutic developments in PCOS. This chapter reviews the current understanding on the pathways modulating androgen biosynthesis, and the cellular and animal models that form the basis for preclinical research in PCOS, and sets the stage for clinical research. Copyright © 2016. Published by Elsevier Ltd.

Current understanding of interactions between nanoparticles and the immune system

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

Dobrovolskaia, Marina A., E-mail: marina@mail.nih.

2016-05-15

The delivery of drugs, antigens, and imaging agents benefits from using nanotechnology-based carriers. The successful translation of nanoformulations to the clinic involves thorough assessment of their safety profiles, which, among other end-points, includes evaluation of immunotoxicity. The past decade of research focusing on nanoparticle interaction with the immune system has been fruitful in terms of understanding the basics of nanoparticle immunocompatibility, developing a bioanalytical infrastructure to screen for nanoparticle-mediated immune reactions, beginning to uncover the mechanisms of nanoparticle immunotoxicity, and utilizing current knowledge about the structure–activity relationship between nanoparticles' physicochemical properties and their effects on the immune system to guidemore » safe drug delivery. In the present review, we focus on the most prominent pieces of the nanoparticle–immune system puzzle and discuss the achievements, disappointments, and lessons learned over the past 15 years of research on the immunotoxicity of engineered nanomaterials. - Graphical abstract: API — active pharmaceutical ingredient; NP — nanoparticles; PCP — physicochemical properties, CARPA — complement activation-related pseudoallergy, ICH — International Conference on Harmonization. Display Omitted - Highlights: • Achievements, disappointments and lessons learned over past decade are reviewed. • Areas in focus include characterization, immunotoxicity and utility in drug delivery. • Future direction focusing on mechanistic immunotoxicity studies is proposed.« less

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.

Advanced glycation end-products: a biological consequence of lifestyle contributing to cancer disparity.

PubMed

Turner, David P

2015-05-15

Low income, poor diet, obesity, and a lack of exercise are interrelated lifestyle factors that can profoundly alter our biologic make up to increase cancer risk, growth, and development. We recently reported a potential mechanistic link between carbohydrate-derived metabolites and cancer, which may provide a biologic consequence of lifestyle that can directly affect tumor biology. Advanced glycation end-products (AGE) are reactive metabolites produced as a by-product of sugar metabolism. Failure to remove these highly reactive metabolites can lead to protein damage, aberrant cell signaling, increased stress responses, and decreased genetic fidelity. Critically, AGE accumulation is also directly affected by our lifestyle choices and shows a race-specific, tumor-dependent pattern of accumulation in cancer patients. This review will discuss the contribution of AGEs to the cancer phenotype, with a particular emphasis on their biologic links with the socioeconomic and environmental risk factors that drive cancer disparity. Given the potential benefits of lifestyle changes and the potential biologic role of AGEs in promoting cancer, opportunities exist for collaborations affecting basic, translational, epidemiologic, and cancer prevention initiatives. ©2015 American Association for Cancer Research.

TFEB at a glance.

PubMed

Napolitano, Gennaro; Ballabio, Andrea

2016-07-01

The transcription factor EB (TFEB) plays a pivotal role in the regulation of basic cellular processes, such as lysosomal biogenesis and autophagy. The subcellular localization and activity of TFEB are regulated by mechanistic target of rapamycin (mTOR)-mediated phosphorylation, which occurs at the lysosomal surface. Phosphorylated TFEB is retained in the cytoplasm, whereas dephosphorylated TFEB translocates to the nucleus to induce the transcription of target genes. Thus, a lysosome-to-nucleus signaling pathway regulates cellular energy metabolism through TFEB. Recently, in vivo studies have revealed that TFEB is also involved in physiological processes, such as lipid catabolism. TFEB has attracted a lot of attention owing to its ability to induce the intracellular clearance of pathogenic factors in a variety of murine models of disease, such as Parkinson's and Alzheimer's, suggesting that novel therapeutic strategies could be based on the modulation of TFEB activity. In this Cell Science at a Glance article and accompanying poster, we present an overview of the latest research on TFEB function and its implication in human diseases. © 2016. Published by The Company of Biologists Ltd.

Fundamental mechanisms of fatigue and fracture.

PubMed

Christ, Hans-Jürgen

2008-01-01

A brief overview is given in this article on the main design philosophies and the resulting description concepts used for components which undergo monotonic and cyclic loading. Emphasis is put on a mechanistic approach avoiding a plain reproduction of empirical laws. After a short consideration of fracture as a result of monotonic loading using fracture mechanics basics, the phenomena taking place as a consequence of cyclic plasticity are introduced. The development of fatigue damage is treated by introducing the physical processes which (i) are responsible for microstructural changes, (ii) lead to crack initiation and (iii) determine crack propagation. From the current research topics within the area of metal fatigue, two aspects are dealt with in more detail because of their relevance to biomechanics. The first one is the growth behaviour of microstructural short cracks, which controls cyclic life of smooth parts at low stress amplitudes. The second issue addresses the question of the existence of a true fatigue limit and is of particular interest for components which must sustain a very high number of loading cycles (very high cycle fatigue).

The Rat Grimace Scale: A partially automated method for quantifying pain in the laboratory rat via facial expressions

PubMed Central

2011-01-01

We recently demonstrated the utility of quantifying spontaneous pain in mice via the blinded coding of facial expressions. As the majority of preclinical pain research is in fact performed in the laboratory rat, we attempted to modify the scale for use in this species. We present herein the Rat Grimace Scale, and show its reliability, accuracy, and ability to quantify the time course of spontaneous pain in the intraplantar complete Freund's adjuvant, intraarticular kaolin-carrageenan, and laparotomy (post-operative pain) assays. The scale's ability to demonstrate the dose-dependent analgesic efficacy of morphine is also shown. In addition, we have developed software, Rodent Face Finder®, which successfully automates the most labor-intensive step in the process. Given the known mechanistic dissociations between spontaneous and evoked pain, and the primacy of the former as a clinical problem, we believe that widespread adoption of spontaneous pain measures such as the Rat Grimace Scale might lead to more successful translation of basic science findings into clinical application. PMID:21801409

Ischaemia–reperfusion injury in liver transplantation—from bench to bedside

PubMed Central

Zhai, Yuan; Petrowsky, Henrik; Hong, Johnny C.; Busuttil, Ronald W.; Kupiec-Weglinski, Jerzy W.

2013-01-01

Ischaemia–reperfusion injury (IRI) in the liver, a major complication of haemorrhagic shock, resection and transplantation, is a dynamic process that involves the two interrelated phases of local ischaemic insult and inflammation-mediated reperfusion injury. This Review highlights the latest mechanistic insights into innate–adaptive immune crosstalk and cell activation cascades that lead to inflammation-mediated injury in livers stressed by ischaemia–reperfusion, discusses progress in large animal experiments and examines efforts to minimize liver IRI in patients who have received a liver transplant. The interlinked signalling pathways in multiple hepatic cell types, the IRI kinetics and positive versus negative regulatory loops at the innate–adaptive immune interface are discussed. The current gaps in our knowledge and the pathophysiology aspects of IRI in which basic and translational research is still required are stressed. An improved appreciation of cellular immune events that trigger and sustain local inflammatory responses, which are ultimately responsible for organ injury, is fundamental to developing innovative strategies for treating patients who have received a liver transplant and developed ischaemia–reperfusion inflammation and organ dysfunction. PMID:23229329

Assessment, origin, and implementation of breath volatile cancer markers

PubMed Central

Haick, Hossam; Broza, Yoav Y.; Mochalski, Pawel; Ruzsanyi, Vera; Amann, Anton

2016-01-01

A new non-invasive and potentially inexpensive frontier in the diagnosis of cancer relies on the detection of volatile organic compounds (VOCs) in exhaled breath samples. Breath can be sampled and analyzed in real-time, leading to fascinating and cost-effective clinical diagnostic procedures. Nevertheless, breath analysis is a very young field of research and faces challenges, mainly because the biochemical mechanisms behind the cancer-related VOCs are largely unknown. In this review, we present a list of 115 validated cancer-related VOCs published in the literature during the past decade, and classify them with respect to their “fat-to-blood” and “blood-to-air” partition coefficients. These partition coefficients provide an estimation of the relative concentrations of VOCs in alveolar breath, in blood and in the fat compartments of the human body. Additionally, we try to clarify controversial issues concerning possible experimental malpractice in the field, and propose ways to translate the basic science results as well as the mechanistic understanding to tools (sensors) that could serve as point-of-care diagnostics of cancer. We end this review with a conclusion and a future perspective. PMID:24305596

Disentangling the Role of Domain-Specific Knowledge in Student Modeling

NASA Astrophysics Data System (ADS)

Ruppert, John; Duncan, Ravit Golan; Chinn, Clark A.

2017-08-01

This study explores the role of domain-specific knowledge in students' modeling practice and how this knowledge interacts with two domain-general modeling strategies: use of evidence and developing a causal mechanism. We analyzed models made by middle school students who had a year of intensive model-based instruction. These models were made to explain a familiar but unstudied biological phenomenon: late onset muscle pain. Students were provided with three pieces of evidence related to this phenomenon and asked to construct a model to account for this evidence. Findings indicate that domain-specific resources play a significant role in the extent to which the models accounted for provided evidence. On the other hand, familiarity with the situation appeared to contribute to the mechanistic character of models. Our results indicate that modeling strategies alone are insufficient for the development of a mechanistic model that accounts for provided evidence and that, while learners can develop a tentative model with a basic familiarity of the situation, scaffolding certain domain-specific knowledge is necessary to assist students with incorporating evidence in modeling tasks.

Finding the missing link between ictal bradyarrhythmia, ictal asystole, and sudden unexpected death in epilepsy.

PubMed

Leung, H; Kwan, P; Elger, C E

2006-08-01

Basic science studies of the human brain have supported the cortical representation of cardiovascular responses, including heart rate variability. Clinical observations of ictal bradyarrhythmia may be mechanistically explained by the influence of the central autonomic network, although the localization and lateralization issues need to be considered in the light of patterns of seizure spread, hand dominance, and presence of lesions. Ictal bradyarrhythmia also offers a mechanistic explanation of sudden unexpected death in epilepsy (SUDEP), though it may explain only some but not all cases of SUDEP. The missing links are (1) clinical evidence of common factors shared by patients with ictal bradyarrhythmia and patients who die from SUDEP, (2) evidence of arrhythmia as a risk factor for SUDEP from epidemiological studies, and, (3) determination of the importance of ictal bradyarrhythmia in SUDEP with respect to other proposed mechanisms including apnea and intrinsic cardiac abnormalities. There remains a need to review the seizure mechanisms in cases of SUDEP and to step up the amount of concurrent ECG/intracranial EEG analysis in both ictal bradyarrhythmia and SUDEP cases.

Dynamic Kinetic Resolution Enabled by Intramolecular Benzoin Reaction: Synthetic Applications and Mechanistic Insights.

PubMed

Zhang, Guoxiang; Yang, Shuang; Zhang, Xiaoyan; Lin, Qiqiao; Das, Deb K; Liu, Jian; Fang, Xinqiang

2016-06-29

The highly enantio-, diastereo-, and regioselective dynamic kinetic resolution of β-ketoesters and 1,3-diketones was achieved via a chiral N-heterocyclic carbene catalyzed intramolecular cross-benzoin reaction. A variety of tetralone derivatives bearing two contiguous stereocenters and multiple functionalities were liberated in moderate to excellent yields and with high levels of stereoselectivity (>95% ee and >20:1 dr in most cases). In addition, the excellent regioselectivity control for aryl/alkyl 1,3-diketones, and the superior electronic differentiation of 1,3-diarylketones were highlighted. Moreover, a set of new mechanistic rationale that differs with the currently widely accepted understanding of intramolecular benzoin reactions was established to demonstrate the superior preference of benzoin over aldol transformation: (1) A coexistence of competitive aldol and benzoin reactions was detected, but a retro-aldol-irreversible benzoin process performs a vital role in the generation of predominant benzoin products. (2) The most essential role of an N-electron-withdrawing substituent in triazolium catalysts was revealed to be accelerating the rate of the benzoin transformation, rather than suppressing the aldol process through reducing the inherent basicity of the catalyst.

The great diversity of HMX conformers: probing the potential energy surface using CCSD(T).

PubMed

Molt, Robert W; Watson, Thomas; Bazanté, Alexandre P; Bartlett, Rodney J

2013-04-25

The octahydro-1,3,5,7-tetranitro-1,3,5,7-tetraazocine (HMX) molecule is a very commonly studied system, in all 3 phases, because of its importance as an explosive; however, no one has ever attempted a systematic study of what all the major gas-phase conformers are. This is critical to a mechanistic study of the kinetics involved, as well as the viability of various crystalline polymorphs based on the gas-phase conformers. We have used existing knowledge of basic cyclooctane chemistry to survey all possible HMX conformers based on its fundamental ring structure. After studying what geometries are possible after second-order many-body perturbation theory (MBPT(2)) geometry optimization, we calculated the energetics using coupled cluster singles, doubles, and perturbative triples (CCSD(T))/cc-pVTZ. These highly accurate energies allow us to better calculate starting points for future mechanistic studies. Additionally, the plethora of structures are compared to existing experimental data of crystals. It is found that the crystal field effect is sometimes large and sometimes small for HMX.

Two (Very) Different Worlds: The Cultures of Policymaking and Qualitative Research

ERIC Educational Resources Information Center

Donmoyer, Robert

2012-01-01

This article brackets assumptions embedded in the framing of this special issue on "problematizing methodological simplicity in qualitative research" in a effort to understand why policymakers put pressure on all types of researchers, including those who use qualitative methods, to provide relatively simple, even somewhat mechanistic portrayals of…

Mechanistics and photo-energetics of macrocycles and photodynamic therapy: An overview of aspects to consider for research.

PubMed

Horne, Tamarisk K; Cronjé, Marianne J

2017-02-01

Research within the field of photodynamic therapy has escalated over the past 20 years. The required conjunctional use of photosensitizers, particularly of the macrocycle structure, has lead to a vast repertoire of derivatives that branch classes and subclasses thereof. Each exhibits a differential range of physiochemical properties that influence their potential applications within the larger phototherapy field for use in either diagnostics, photodynamic therapy, both or none. Herein, we provide an overview of these properties as they relate to photodynamic therapy and to a lesser extent diagnostics. By summarizing the mechanistics of photodynamic therapy coupled to the photo-energetics displayed by macrocycle photosensitizers, we aimed to highlight the critical aspects any researcher should be aware of and consider when selecting and performing research for therapeutic application purposes. These include photosensitizer, photophysical and structural properties, synthesis design and subsequent attributes, main applications within research, common shortcomings exhibited and the current methods practiced to overcome them. © 2017 John Wiley & Sons A/S.

32 CFR 272.3 - Definition of basic research.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 32 National Defense 2 2014-07-01 2014-07-01 false Definition of basic research. 272.3 Section 272...) MISCELLANEOUS ADMINISTRATION AND SUPPORT OF BASIC RESEARCH BY THE DEPARTMENT OF DEFENSE § 272.3 Definition of basic research. Basic research is systematic study directed toward greater knowledge or understanding of...

32 CFR 272.3 - Definition of basic research.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 32 National Defense 2 2012-07-01 2012-07-01 false Definition of basic research. 272.3 Section 272...) MISCELLANEOUS ADMINISTRATION AND SUPPORT OF BASIC RESEARCH BY THE DEPARTMENT OF DEFENSE § 272.3 Definition of basic research. Basic research is systematic study directed toward greater knowledge or understanding of...

Mechanistic approach to determine spring load restrictions in Maine.

DOT National Transportation Integrated Search

2008-03-01

This research will be using pavement deflections and frost gauges to determine if MaineDOT is placing : and removing weight restrictions at the proper time. In addition, this research will also investigate the use : of Freezing and Thawing Index form...

Material Testing and Initial Pavement Design Modeling: Minnesota Road Research Project

DOT National Transportation Integrated Search

1996-09-01

Between January 1990 and December 1994, a study verified and applied a Corps of Engineers-developed mechanistic design and evaluation method for pavements in seasonal frost areas as part of a Construction Productivity Advancement Research (CPAR) proj...

Heterolytic Activation of Hydrogen Promoted by Ruthenium Nanoparticles immobilized on Basic Supports and Hydrogenation of Aromatic Compounds

NASA Astrophysics Data System (ADS)

Fang, Minfeng

Despite the aggressive development and deployment of new renewable and nuclear technologies, petroleum-derived transportation fuels---gasoline, diesel and jet fuels---will continue to dominate the markets for decades. Environmental legislation imposes severe limits on the tolerable proportion of aromatics, sulfur and nitrogen contents in transportation fuels, which is difficult to achieve with current refining technologies. Catalytic hydrogenation plays an important role in the production of cleaner fuels, both as a direct means to reduce the aromatics and as a key step in the hydrodenitrogenation (HDN) and hydrodesulfurization (HDS) processes. However, conventional catalysts require drastic conditions and/or are easily poisoned by S or N aromatics. Therefore, there is still a need for new efficient catalysts for hydrogenation reactions relevant to the production of cleaner fossil fuels. Our catalyst design involves metallic nanoparticles intimately associated with a basic support, with the aim of creating a nanostructure capable of promoting the heterolytic activation of hydrogen and ionic hydrogenation mechanisms, as a strategy to avoid catalyst poisoning and enhance catalytic activity. We have designed and prepared a new nanostructured catalytic material composed of RuNPs immobilized on the basic polymer P4VPy. We have demonstrated that the Ru/P4VPy catalyst can promote heterolytic hydrogen activation and a unique surface ionic hydrogenation mechanism for the efficient hydrogenation of N-aromatics. This is the first time these ionic hydrogenation pathways have been demonstrated on solid surfaces. For the RuNPs surfaces without basic sites in close proximity, the conventional homolytic H2 splitting is otherwise involved. Using the mechanistic concepts from Ru/P4VPy, we have designed and prepared the Ru/MgO catalyst, with the aim to improve the catalytic efficiency for the hydrogenation of heteroatom aromatics operating by the ionic hydrogenation mechanism. The Ru/MgO catalyst significantly improves the catalytic efficiency for hydrogenation of a variety of N-/S-heteroaromatics and mono-/polycyclic aromatic hydrocarbons representative of components of petroleum-derived fuels. The catalyst is superior to the few other known supported noble metal catalysts for these reactions. Mechanistic studies also point to the ionic hydrogenation mechanism on the Ru/MgO surfaces. In addition, the Ru/MgO catalyst is highly recyclable and long-lived.

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.

Osteopathic research: elephants, enigmas, and evidence

PubMed Central

Licciardone, John C

2007-01-01

Background The growth and acceptance of osteopathic physicians as conventional medical practitioners in the United States has also raised questions about the distinctive aspects of osteopathic medicine. Although the use of osteopathic manipulative treatment (OMT) and a focus on primary care are most often cited as rationales for the uniqueness of osteopathic medicine, an osteopathic professional identity remains enigmatic. Discussion The fledgling basic osteopathic research efforts of the early and mid-twentieth century have not been sustained and expanded over time. Thus, there is presently a scarcity of basic mechanistic and translational research that can be considered to be uniquely osteopathic. To be sure, there have been advances in osteopathic clinical trials, particularly those involving OMT for low back pain. Meta-analysis of these low back pain trials has provided evidence that: (1) OMT affords greater pain reduction than active or placebo control treatments; (2) the effects of OMT are comparable regardless of whether treatment is provided by fully-licensed osteopathic physicians in the United States or by osteopaths in the United Kingdom; and (3) the effects of OMT increase over time. However, much more clinical research remains to be done. The planning and implementation of a large longitudinal study of the natural history and epidemiology of somatic dysfunction, including an OMT component, represents a much-needed step forward. Osteopathic medicine's use of OMT and its focus on primary care are not mutually exclusive aspects of its uniqueness. The intersection of these fundamental aspects of osteopathic medicine suggests that the profession may successfully adopt a generic strategy of "focused differentiation" to attain a competitive advantage in the health care arena. While there are both requisite demands and risks for the osteopathic profession in adopting such a strategy, these are reasonable in relation to the potential rewards to be attained. To help promote an osteopathic identity, "omtology" and its derivative terms are recommended in referring to the study of OMT. Conclusion The osteopathic profession should adopt a coherent strategy for developing and promoting its identity. Failure to do so will likely ensure that osteopathic medicine remains "stuck in the middle." PMID:17371583

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

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 mechanistic basis for cellular threshold responses. Environ Health Perspect 122:1261–1270; http://dx.doi.org/10.1289/ehp.1408244 PMID:25117432

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

Mechanistic-Empirical Pavement Design Guide Flexible Pavement Performance Prediction Models Volume I Executive Research Summary

DOT National Transportation Integrated Search

2007-08-01

The objective of this research study was to develop performance characteristics or variables (e.g., ride quality, rutting, : fatigue cracking, transverse cracking) of flexible pavements in Montana, and to use these characteristics in the : implementa...

Cognitive-Behavioral Therapy: Nature and Relation to Non-Cognitive Behavioral Therapy.

PubMed

Lorenzo-Luaces, Lorenzo; Keefe, John R; DeRubeis, Robert J

2016-11-01

Since the introduction of Beck's cognitive theory of emotional disorders, and their treatment with psychotherapy, cognitive-behavioral approaches have become the most extensively researched psychological treatment for a wide variety of disorders. Despite this, the relative contribution of cognitive to behavioral approaches to treatment are poorly understood and the mechanistic role of cognitive change in therapy is widely debated. We critically review this literature, focusing on the mechanistic role of cognitive change across cognitive and behavioral therapies for depressive and anxiety disorders. Copyright © 2016. Published by Elsevier Ltd.

32 CFR Appendix A to Part 272 - Principles for the Conduct and Support of Basic Research

Code of Federal Regulations, 2010 CFR

2010-07-01

... Research A Appendix A to Part 272 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) MISCELLANEOUS ADMINISTRATION AND SUPPORT OF BASIC RESEARCH BY THE... Research 1. Basic research is an investment. The DoD Components are to view and manage basic research...

The Russo-Williamson Theses in the social sciences: causal inference drawing on two types of evidence.

PubMed

Claveau, François

2012-12-01

This article examines two theses formulated by Russo and Williamson (2007) in their study of causal inference in the health sciences. The two theses are assessed against evidence from a specific case in the social sciences, i.e., research on the institutional determinants of the aggregate unemployment rate. The first Russo-Williamson Thesis is that a causal claim can only be established when it is jointly supported by difference-making and mechanistic evidence. This thesis is shown not to hold. While researchers in my case study draw extensively on both types of evidence, one causal claim out of the three analyzed is established even though it is exclusively supported by mechanistic evidence. The second Russo-Williamson Thesis is that standard accounts of causality fail to handle the dualist epistemology highlighted in the first Thesis. I argue that a counterfactual-manipulationist account of causality--which is endorsed by many philosophers as well as many social scientists--can perfectly make sense of the typical strategy in my case study to draw on both difference-making and mechanistic evidence; it is just an instance of the common strategy of increasing evidential variety. Copyright © 2012 Elsevier Ltd. All rights reserved.

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

Laskin, Julia

In this work, resonant ejection coupled with surface-induced dissociation (SID) in a Fourier transform ion cyclotron resonance mass spectrometer is used to examine fragmentation kinetics of two singly protonated hexapeptides, RYGGFL and KYGGFL, containing the basic arginine residue and less basic lysine residue at the N-terminus. The kinetics of individual reaction channels at different collision energies are probed by applying a short ejection pulse (1 ms) in resonance with the cyclotron frequency of a selected fragment ion and varying the delay time between ion-surface collision and resonant ejection while keeping total reaction delay time constant. Rice-Ramsperger-Kassel-Marcus (RRKM) modeling of themore » experimental data provides accurate threshold energies and activation entropies of individual reaction channels. Substitution of arginine with less basic lysine has a pronounced effect on the observed fragmentation kinetics of several pathways, including the b2 ion formation, but has little or no effect on formation of the b5+H2O fragment ion. The combination of resonant ejection SID, time- and collision energy-resolved SID, and RRKM modeling of both types of experimental data provides a detailed mechanistic understanding of the primary dissociation pathways of complex gaseous ions.« less

A movement ecology paradigm for unifying organismal movement research

PubMed Central

Nathan, Ran; Getz, Wayne M.; Revilla, Eloy; Holyoak, Marcel; Kadmon, Ronen; Saltz, David; Smouse, Peter E.

2008-01-01

Movement of individual organisms is fundamental to life, quilting our planet in a rich tapestry of phenomena with diverse implications for ecosystems and humans. Movement research is both plentiful and insightful, and recent methodological advances facilitate obtaining a detailed view of individual movement. Yet, we lack a general unifying paradigm, derived from first principles, which can place movement studies within a common context and advance the development of a mature scientific discipline. This introductory article to the Movement Ecology Special Feature proposes a paradigm that integrates conceptual, theoretical, methodological, and empirical frameworks for studying movement of all organisms, from microbes to trees to elephants. We introduce a conceptual framework depicting the interplay among four basic mechanistic components of organismal movement: the internal state (why move?), motion (how to move?), and navigation (when and where to move?) capacities of the individual and the external factors affecting movement. We demonstrate how the proposed framework aids the study of various taxa and movement types; promotes the formulation of hypotheses about movement; and complements existing biomechanical, cognitive, random, and optimality paradigms of movement. The proposed framework integrates eclectic research on movement into a structured paradigm and aims at providing a basis for hypothesis generation and a vehicle facilitating the understanding of the causes, mechanisms, and spatiotemporal patterns of movement and their role in various ecological and evolutionary processes. ”Now we must consider in general the common reason for moving with any movement whatever.“ (Aristotle, De Motu Animalium, 4th century B.C.) PMID:19060196

The current status of research on the structure of evaluative space

PubMed Central

Norris, Catherine J.; Gollan, Jackie; Berntson, Gary G.; Cacioppo, John T.

2009-01-01

The structure of evaluative space shapes emotional life. Although behavior may be constrained to a single bipolar dimension, for example as defined by the opposing movements of approach and withdrawal, the mechanisms underlying the affect system must be capable of an astonishing range of emotional experience and expression. The model of evaluative space (ESM; J. T. Cacioppo, W. L. Gardner, & G. G. Berntson, 1997, 1999) proposes that behavioral predispositions are the ultimate output of the affect system, which is defined by operating characteristics that differ both for positivity and negativity, as well as across levels of the nervous system. In this article, we outline the current status of theory and research on the structure of evaluative space. First, we summarize the basic tenets of the model, as well as recent research supporting these ideas and counterarguments that have been raised by other theorists. To address these counterarguments, we discuss the postulates of affective oscillation and calibration, two mechanistic features of the affect system proposed to underlie the durability and adaptability of affect. We summarize empirical support for the functional consequences of the principles of affective oscillation and calibration, with a focus on how oscillation and the “stickiness” of affect can lead to the emergence of ambivalence, whereas affective calibration and the flexibility of the affect system produce asymmetries in affective processing (e.g., the negativity bias). Finally, we consider the clinical implications of disorder in the structure of evaluative space for the comprehension and treatment of depression and anxiety. PMID:20346389

Imparting Catalyst-Control upon Classical Palladium-Catalyzed Alkenyl C–H Bond Functionalization Reactions

PubMed Central

Sigman, Matthew S.; Werner, Erik W.

2011-01-01

Conspectus The functional group transformations carried out by the palladium-catalyzed Wacker and Heck reactions are radically different, but they are both alkenyl C-H bond functionalization reactions that have found extensive use in organic synthesis. The synthetic community depends heavily on these important reactions, but selectivity issues arising from control by the substrate, rather than control by the catalyst, have prevented the realization of their full potential. Because of important similarities in the respective selectivity-determining nucleopalladation and β-hydride elimination steps of these processes, we posit that the mechanistic insight garnered through the development of one of these catalytic reactions may be applied to the other. In this Account, we detail our efforts to develop catalyst-controlled variants of both the Wacker oxidation and the Heck reaction to address synthetic limitations and provide mechanistic insight into the underlying organometallic processes of these reactions. In contrast to previous reports, we discovered that electrophilic palladium catalysts with non-coordinating counterions allowed for the use of a Lewis basic ligand to efficiently promote TBHP-mediated Wacker oxidation reactions of styrenes. This discovery led to the mechanistically guided development of a Wacker reaction catalyzed by a palladium complex with a bidentate ligand. This ligation may prohibit coordination of allylic heteroatoms, thereby allowing for the application of the Wacker oxidation to substrates that were poorly behaved under classical conditions. Likewise, we unexpectedly discovered that electrophilic Pd-σ-alkyl intermediates are capable of distinguishing between electronically inequivalent C–H bonds during β-hydride elimination. As a result, we have developed E-styrenyl selective oxidative Heck reactions of previously unsuccessful electronically non-biased alkene substrates using arylboronic acid derivatives. The mechanistic insight gained from the development of this chemistry allowed for the rational design of a similarly E-styrenyl selective classical Heck reaction using aryldiazonium salts and a broad range of alkene substrates. The key mechanistic findings from the development of these reactions provide new insight into how to predictably impart catalyst control in organometallic processes that would otherwise afford complex product mixtures. Given our new understanding, we are optimistic that reactions that introduce increased complexity relative to simple classical processes may now be developed based on our ability to predict the selectivity-determining nucleopalladation and β-hydride elimination steps through catalyst design. PMID:22111756

Is the use of sentient animals in basic research justifiable?

PubMed Central

2010-01-01

Animals can be used in many ways in science and scientific research. Given that society values sentient animals and that basic research is not goal oriented, the question is raised: "Is the use of sentient animals in basic research justifiable?" We explore this in the context of funding issues, outcomes from basic research, and the position of society as a whole on using sentient animals in research that is not goal oriented. We conclude that the use of sentient animals in basic research cannot be justified in light of society's priorities. PMID:20825676

Is the use of sentient animals in basic research justifiable?

PubMed

Greek, Ray; Greek, Jean

2010-09-08

Animals can be used in many ways in science and scientific research. Given that society values sentient animals and that basic research is not goal oriented, the question is raised: "Is the use of sentient animals in basic research justifiable?" We explore this in the context of funding issues, outcomes from basic research, and the position of society as a whole on using sentient animals in research that is not goal oriented. We conclude that the use of sentient animals in basic research cannot be justified in light of society's priorities.

An agent-based modeling framework linking inflammation and cancer using evolutionary principles: description of a generative hierarchy for the hallmarks of cancer and developing a bridge between mechanism and epidemiological data.

PubMed

An, Gary; Kulkarni, Swati

2015-02-01

Inflammation plays a critical role in the development and progression of cancer, evident in multiple patient populations manifesting increased, non-resolving inflammation, such as inflammatory bowel disease, viral hepatitis and obesity. Given the complexity of both the inflammatory response and the process of oncogenesis, we utilize principles from the field of Translational Systems Biology to bridge the gap between basic mechanistic knowledge and clinical/epidemiologic data by integrating inflammation and oncogenesis within an agent-based model, the Inflammation and Cancer Agent-based Model (ICABM). The ICABM utilizes two previously published and clinically/epidemiologically validated mechanistic models to demonstrate the role of an increased inflammatory milieu on oncogenesis. Development of the ICABM required the creation of a generative hierarchy of the basic hallmarks of cancer to provide a foundation to ground the plethora of molecular and pathway components currently being studied. The ordering schema emphasizes the essential role of a fitness/selection frame shift to sub-organismal evolution as a basic property of cancer, where the generation of genetic instability as a negative effect for multicellular eukaryotic organisms represents the restoration of genetic plasticity used as an adaptive strategy by colonies of prokaryotic unicellular organisms. Simulations with the ICABM demonstrate that inflammation provides a functional environmental context that drives the shift to sub-organismal evolution, where increasingly inflammatory environments led to increasingly damaged genomes in microtumors (tumors below clinical detection size) and cancers. The flexibility of this platform readily facilitates tailoring the ICABM to specific cancers, their associated mechanisms and available epidemiological data. One clinical example of an epidemiological finding that could be investigated with this platform is the increased incidence of triple negative breast cancers in the premenopausal African-American population, which has been identified as having up-regulated of markers of inflammation. The fundamental nature of the ICABM suggests its usefulness as a base platform upon which additional molecular detail could be added as needed. Copyright © 2014 Elsevier Inc. All rights reserved.

Some critical issues and concerns related to research advances on toxicology of chemical mixtures.

PubMed Central

Yang, R S

1998-01-01

This paper addresses some of the issues and concerns on research advances on the toxicology of chemical mixtures. Emphases will be selectively given to the following questions and answers: Can mechanistic studies be conducted on chemical mixtures? The fact that any studies, including mechanistic studies, of single chemicals are really the study of the parent chemical plus its metabolites underscores the relevance of mechanistic studies on chemical mixtures. Can predictions be made on the health effects of chemical mixtures? Some successes are already evident in the literature on simpler chemical mixtures. For more complex mixtures, it is possible and we propose an approach here. What can we learn from other disciplines (the importance of interdisciplinary collaboration)? Two aspects, the knowledge and methodologies available in clinical pharmacology and the latest advances in structure-oriented lumping in chemical engineering, are discussed in detail. Unrepeatable results: The possibility of magnification of biologic variability because of low-level exposures to chemical mixtures is suggested with special reference to some known examples, including the controversial study on synergistic interactions of endocrine disruptors. Is the driving force for scientific investigations on chemical mixtures the legislative and regulatory atmosphere? Two laws with chemical mixtures specifically in the language are quoted and discussed. Their implications regarding research funding and activities are described. What are the pitfalls of applying for research funding on investigating chemical mixtures? The dilemma at least one investigator faces in pursuing research funding is elaborated. The questions and issues listed above are not all inclusive, but they represent some of the aspects that need to be brought into the open in the scientific community for discussion and/or debate. Thus, the primary objective of this paper is to provide some momentum for the beginning of a fruitful and stimulating discussion. PMID:9703493

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.

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.

Stress and reproductive failure: past notions, present insights and future directions

PubMed Central

Sheps, Sam; Clara Arck, Petra

2008-01-01

Problem Maternal stress perception is frequently alleged as a cause of infertility, miscarriages, late pregnancy complications or impaired fetal development. The purpose of the present review is to critically assess the biological and epidemiological evidence that considers the plausibility of a stress link to human reproductive failure. Methods All epidemiological studies published between 1980 and 2007 that tested the link between stress exposure and impaired reproductive success in humans were identified. Study outcomes were evaluated on the basis of how associations were predicted, tested and integrated with theories of etiology arising from recent scientific developments in the basic sciences. Further, published evidence arising from basic science research has been assessed in order to provide a mechanistic concept and biological evidence for the link between stress perception and reproductive success. Results Biological evidence points to an immune–endocrine disequilibrium in response to stress and describes a hierarchy of biological mediators involved in a stress trigger to reproductive failure. Epidemiological evidence presents positive correlations between various pregnancy failure outcomes with pre-conception negative life events and elevated daily urinary cortisol. Strikingly, a relatively new conceptual approach integrating the two strands of evidence suggests the programming of stress susceptibility in mother and fetus via a so-called pregnancy stress syndrome. Conclusions An increasing specificity of knowledge is available about the types and impact of biological and social pathways involved in maternal stress responses. The present evidence is sufficient to warrant a reconsideration of conventional views on the etiology of reproductive failure. Physicians and patients will benefit from the adaptation of this integrated evidence to daily clinical practice. PMID:18274890

Pain, Nicotine, and Smoking: Research Findings and Mechanistic Considerations

ERIC Educational Resources Information Center

Ditre, Joseph W.; Brandon, Thomas H.; Zale, Emily L.; Meagher, Mary M.

2011-01-01

Tobacco addiction and chronic pain represent 2 highly prevalent and comorbid conditions that engender substantial burdens upon individuals and systems. Interrelations between pain and smoking have been of clinical and empirical interest for decades, and research in this area has increased dramatically over the past 5 years. We conceptualize the…

Clinical Research Strategies for Fructose Metabolism12

PubMed Central

Laughlin, Maren R.; Bantle, John P.; Havel, Peter J.; Parks, Elizabeth; Klurfeld, David M.; Teff, Karen; Maruvada, Padma

2014-01-01

Fructose and simple sugars are a substantial part of the western diet, and their influence on human health remains controversial. Clinical studies in fructose nutrition have proven very difficult to conduct and interpret. NIH and USDA sponsored a workshop on 13–14 November 2012, “Research Strategies for Fructose Metabolism,” to identify important scientific questions and parameters to be considered while designing clinical studies. Research is needed to ascertain whether there is an obesogenic role for fructose-containing sugars via effects on eating behavior and energy balance and whether there is a dose threshold beyond which these sugars promote progression toward diabetes and liver and cardiovascular disease, especially in susceptible populations. Studies tend to fall into 2 categories, and design criteria for each are described. Mechanistic studies are meant to validate observations made in animals or to elucidate the pathways of fructose metabolism in humans. These highly controlled studies often compare the pure monosaccharides glucose and fructose. Other studies are focused on clinically significant disease outcomes or health behaviors attributable to amounts of fructose-containing sugars typically found in the American diet. These are designed to test hypotheses generated from short-term mechanistic or epidemiologic studies and provide data for health policy. Discussion brought out the opinion that, although many mechanistic questions concerning the metabolism of monosaccharide sugars in humans remain to be addressed experimentally in small highly controlled studies, health outcomes research meant to inform health policy should use large, long-term studies using combinations of sugars found in the typical American diet rather than pure fructose or glucose. PMID:24829471

Phosphodiester models for cleavage of nucleic acids

PubMed Central

2018-01-01

Nucleic acids that store and transfer biological information are polymeric diesters of phosphoric acid. Cleavage of the phosphodiester linkages by protein enzymes, nucleases, is one of the underlying biological processes. The remarkable catalytic efficiency of nucleases, together with the ability of ribonucleic acids to serve sometimes as nucleases, has made the cleavage of phosphodiesters a subject of intensive mechanistic studies. In addition to studies of nucleases by pH-rate dependency, X-ray crystallography, amino acid/nucleotide substitution and computational approaches, experimental and theoretical studies with small molecular model compounds still play a role. With small molecules, the importance of various elementary processes, such as proton transfer and metal ion binding, for stabilization of transition states may be elucidated and systematic variation of the basicity of the entering or departing nucleophile enables determination of the position of the transition state on the reaction coordinate. Such data is important on analyzing enzyme mechanisms based on synergistic participation of several catalytic entities. Many nucleases are metalloenzymes and small molecular models offer an excellent tool to construct models for their catalytic centers. The present review tends to be an up to date summary of what has been achieved by mechanistic studies with small molecular phosphodiesters. PMID:29719577

The role of photorespiration during the evolution of C4 photosynthesis in the genus Flaveria.

PubMed

Mallmann, Julia; Heckmann, David; Bräutigam, Andrea; Lercher, Martin J; Weber, Andreas P M; Westhoff, Peter; Gowik, Udo

2014-06-16

C4 photosynthesis represents a most remarkable case of convergent evolution of a complex trait, which includes the reprogramming of the expression patterns of thousands of genes. Anatomical, physiological, and phylogenetic and analyses as well as computational modeling indicate that the establishment of a photorespiratory carbon pump (termed C2 photosynthesis) is a prerequisite for the evolution of C4. However, a mechanistic model explaining the tight connection between the evolution of C4 and C2 photosynthesis is currently lacking. Here we address this question through comparative transcriptomic and biochemical analyses of closely related C3, C3-C4, and C4 species, combined with Flux Balance Analysis constrained through a mechanistic model of carbon fixation. We show that C2 photosynthesis creates a misbalance in nitrogen metabolism between bundle sheath and mesophyll cells. Rebalancing nitrogen metabolism requires anaplerotic reactions that resemble at least parts of a basic C4 cycle. Our findings thus show how C2 photosynthesis represents a pre-adaptation for the C4 system, where the evolution of the C2 system establishes important C4 components as a side effect.

The Role of Oxygen in Avascular Tumor Growth

PubMed Central

Grimes, David Robert; Kannan, Pavitra; McIntyre, Alan; Kavanagh, Anthony; Siddiky, Abul; Wigfield, Simon; Harris, Adrian; Partridge, Mike

2016-01-01

The oxygen status of a tumor has significant clinical implications for treatment prognosis, with well-oxygenated subvolumes responding markedly better to radiotherapy than poorly supplied regions. Oxygen is essential for tumor growth, yet estimation of local oxygen distribution can be difficult to ascertain in situ, due to chaotic patterns of vasculature. It is possible to avoid this confounding influence by using avascular tumor models, such as tumor spheroids, a much better approximation of realistic tumor dynamics than monolayers, where oxygen supply can be described by diffusion alone. Similar to in situ tumours, spheroids exhibit an approximately sigmoidal growth curve, often approximated and fitted by logistic and Gompertzian sigmoid functions. These describe the basic rate of growth well, but do not offer an explicitly mechanistic explanation. This work examines the oxygen dynamics of spheroids and demonstrates that this growth can be derived mechanistically with cellular doubling time and oxygen consumption rate (OCR) being key parameters. The model is fitted to growth curves for a range of cell lines and derived values of OCR are validated using clinical measurement. Finally, we illustrate how changes in OCR due to gemcitabine treatment can be directly inferred using this model. PMID:27088720

Ionic liquids as transesterification catalysts: applications for the synthesis of linear and cyclic organic carbonates

PubMed Central

Perosa, Alvise; Guidi, Sandro; Cattelan, Lisa

2016-01-01

Summary The use of ionic liquids (ILs) as organocatalysts is reviewed for transesterification reactions, specifically for the conversion of nontoxic compounds such as dialkyl carbonates to both linear mono-transesterification products or alkylene carbonates. An introductory survey compares pros and cons of classic catalysts based on both acidic and basic systems, to ionic liquids. Then, innovative green syntheses of task-specific ILs and their representative applications are introduced to detail the efficiency and highly selective outcome of ILs-catalyzed transesterification reactions. A mechanistic hypothesis is discussed by the concept of cooperative catalysis based on the dual (electrophilic/nucleophilic) activation of reactants. PMID:27829898

Experimental and modelling studies for the validation of the mechanistic basis of the Local Effect Model

NASA Astrophysics Data System (ADS)

Tommasino, F.

2016-03-01

This review will summarize results obtained in the recent years applying the Local Effect Model (LEM) approach to the study of basic radiobiological aspects, as for instance DNA damage induction and repair, and charged particle track structure. The promising results obtained using different experimental techniques and looking at different biological end points, support the relevance of the LEM approach for the description of radiation effects induced by both low- and high-LET radiation. Furthermore, they suggest that nowadays the appropriate combination of experimental and modelling tools can lead to advances in the understanding of several open issues in the field of radiation biology.

Structural and mechanistic insights into phospholipid transfer by Ups1-Mdm35 in mitochondria

NASA Astrophysics Data System (ADS)

Watanabe, Yasunori; Tamura, Yasushi; Kawano, Shin; Endo, Toshiya

2015-08-01

Eukaryotic cells are compartmentalized into membrane-bounded organelles whose functions rely on lipid trafficking to achieve membrane-specific compositions of lipids. Here we focused on the Ups1-Mdm35 system, which mediates phosphatidic acid (PA) transfer between the outer and inner mitochondrial membranes, and determined the X-ray structures of Mdm35 and Ups1-Mdm35 with and without PA. The Ups1-Mdm35 complex constitutes a single domain that has a deep pocket and flexible Ω-loop lid. Structure-based mutational analyses revealed that a basic residue at the pocket bottom and the Ω-loop lid are important for PA extraction from the membrane following Ups1 binding. Ups1 binding to the membrane is enhanced by the dissociation of Mdm35. We also show that basic residues around the pocket entrance are important for Ups1 binding to the membrane and PA extraction. These results provide a structural basis for understanding the mechanism of PA transfer between mitochondrial membranes.

Basic nursing care: The most provided, the least evidence based - A discussion paper.

PubMed

Zwakhalen, Sandra M G; Hamers, Jan P H; Metzelthin, Silke F; Ettema, Roelof; Heinen, Maud; de Man-Van Ginkel, Janneke M; Vermeulen, Hester; Huisman-de Waal, Getty; Schuurmans, Marieke J

2018-06-01

To describe and discuss the "Basic Care Revisited" (BCR) research programme, a collaborative initiative that contributes to evidence-based basic nursing care and raises awareness about the importance of basic nursing care activities. While basic nursing care serves nearly all people at some point in their lifetime, it is poorly informed by evidence. There is a need to prioritise and evaluate basic nursing care activities to improve patient outcomes and improve the quality of care. Discussion paper METHOD: The discussion presented in this paper is based on nursing literature and theory and supported by the authors' clinical and research experiences. We present the developmental process and content of a research programme called "Basic Care Revisited" (BCR) as a solution to move forward and improve basic nursing care. To prioritise basic nursing care, we propose a research programme entitled "Basic Care Revisited" that aims to create awareness and expand knowledge on evidence-based basic nursing care by addressing four basic nursing care themes (bathing and dressing, communication, mobility, and nutrition) in different settings. The paper discusses a pathway to create a sustainable and productive research collaborative on basic nursing care and addresses issues to build research capacity. Revaluation of these important nursing activities will not only positively influence patient outcomes, but also have an impact on staff outcomes and organisational outcomes. © 2018 John Wiley & Sons Ltd.

Performance evaluation of Louisiana superpave mixtures : tech summary.

DOT National Transportation Integrated Search

2008-12-01

The primary objective of this research was to evaluate the fundamental engineering : properties and mixture performance of Superpave hot mix asphalt (HMA) mixtures : in Louisiana through laboratory mechanistic tests, aggregate gradation analysis, and...

Minnesota low volume road design 1998

DOT National Transportation Integrated Search

1999-09-01

In this project, researchers examined the current practices that local agencies use and evaluated the thickness design procedures by comparing predicted lives for the current designs with those obtained from the mechanistic-empirical design procedure...

26 CFR 1.41-5A - Basic research for taxable years beginning before January 1, 1987.

Code of Federal Regulations, 2010 CFR

2010-04-01

... was for basic research performed in the United States). (2) Research in the social sciences or humanities. Basic research does not include research in the social sciences or humanities, within the meaning...

26 CFR 1.41-5A - Basic research for taxable years beginning before January 1, 1987.

Code of Federal Regulations, 2011 CFR

2011-04-01

... was for basic research performed in the United States). (2) Research in the social sciences or humanities. Basic research does not include research in the social sciences or humanities, within the meaning...

26 CFR 1.41-5A - Basic research for taxable years beginning before January 1, 1987.

Code of Federal Regulations, 2014 CFR

2014-04-01

... was for basic research performed in the United States). (2) Research in the social sciences or humanities. Basic research does not include research in the social sciences or humanities, within the meaning...

26 CFR 1.41-5A - Basic research for taxable years beginning before January 1, 1987.

Code of Federal Regulations, 2013 CFR

2013-04-01

... was for basic research performed in the United States). (2) Research in the social sciences or humanities. Basic research does not include research in the social sciences or humanities, within the meaning...

26 CFR 1.41-5A - Basic research for taxable years beginning before January 1, 1987.

Code of Federal Regulations, 2012 CFR

2012-04-01

... was for basic research performed in the United States). (2) Research in the social sciences or humanities. Basic research does not include research in the social sciences or humanities, within the meaning...

Non-specific activities of the major herbicide-resistance gene BAR.

PubMed

Christ, Bastien; Hochstrasser, Ramon; Guyer, Luzia; Francisco, Rita; Aubry, Sylvain; Hörtensteiner, Stefan; Weng, Jing-Ke

2017-12-01

Bialaphos resistance (BAR) and phosphinothricin acetyltransferase (PAT) genes, which convey resistance to the broad-spectrum herbicide phosphinothricin (also known as glufosinate) via N-acetylation, have been globally used in basic plant research and genetically engineered crops 1-4 . Although early in vitro enzyme assays showed that recombinant BAR and PAT exhibit substrate preference toward phosphinothricin over the 20 proteinogenic amino acids 1 , indirect effects of BAR-containing transgenes in planta, including modified amino acid levels, have been seen but without the identification of their direct causes 5,6 . Combining metabolomics, plant genetics and biochemical approaches, we show that transgenic BAR indeed converts two plant endogenous amino acids, aminoadipate and tryptophan, to their respective N-acetylated products in several plant species. We report the crystal structures of BAR, and further delineate structural basis for its substrate selectivity and catalytic mechanism. Through structure-guided protein engineering, we generated several BAR variants that display significantly reduced non-specific activities compared with its wild-type counterpart in vivo. The transgenic expression of enzymes can result in unintended off-target metabolism arising from enzyme promiscuity. Understanding such phenomena at the mechanistic level can facilitate the design of maximally insulated systems featuring heterologously expressed enzymes.

Recent advances in understanding trans-epithelial acid-base regulation and excretion mechanisms in cephalopods

PubMed Central

Hu, Marian Y; Hwang, Pung-Pung; Tseng, Yung-Che

2015-01-01

Cephalopods have evolved complex sensory systems and an active lifestyle to compete with fish for similar resources in the marine environment. Their highly active lifestyle and their extensive protein metabolism has led to substantial acid-base regulatory abilities enabling these organisms to cope with CO2 induced acid-base disturbances. In convergence to teleost, cephalopods possess an ontogeny-dependent shift in ion-regulatory epithelia with epidermal ionocytes being the major site of embryonic acid-base regulation and ammonia excretion, while gill epithelia take these functions in adults. Although the basic morphology and excretory function of gill epithelia in cephalopods were outlined almost half a century ago, modern immunohistological and molecular techniques are bringing new insights to the mechanistic basis of acid-base regulation and excretion of nitrogenous waste products (e.g. NH3/NH4+) across ion regulatory epithelia of cephalopods. Using cephalopods as an invertebrate model, recent findings reveal partly conserved mechanisms but also novel aspects of acid-base regulation and nitrogen excretion in these exclusively marine animals. Comparative studies using a range of marine invertebrates will create a novel and exciting research direction addressing the evolution of pH regulatory and excretory systems. PMID:26716070

Less travelled roads in clinical immunology and allergy: drug reactions and the environmental influence.

PubMed

Selmi, Carlo; Crotti, Chiara; Meroni, Pier Luigi

2013-08-01

Allergy and clinical immunology are examples of areas of knowledge in which working hypotheses are dominant over mechanistic understanding. As such, sometimes scientific efforts follow major streams and overlook some epidemiologically prevalent conditions that thus become underestimated by the research community. For this reason, we welcome the present issue of Clinical Reviews in Allergy and Immunology that is dedicated to uncommon themes in clinical immunology and allergy. First, comprehensive discussions are provided for allergy phenomena of large potential impact in clinical practice such as reactions to cephalosporins or aspirin-induced asthma and in everyday life such as allergies to food additives or legumes. Further, the issue addresses other uncommon themes such as urticaria and angioedema, cercarial dermatitis, or late-onset inflammation to soft tissue fillers. Last, there will be discussion on transversal issues such as olfactory defects in autoimmunity, interleukin 1 beta pathway, and the search for new serological markers in chronic inflammation. As a result, we are convinced that this issue will be of help to clinicians involved in internal medicine as well as to allergists and clinical immunologists. More importantly, we are convinced that these discussions will be of interest also to basic scientists for the numerous translational implications.

Computational Phenotyping in Psychiatry: A Worked Example

PubMed Central

2016-01-01

Abstract Computational psychiatry is a rapidly emerging field that uses model-based quantities to infer the behavioral and neuronal abnormalities that underlie psychopathology. If successful, this approach promises key insights into (pathological) brain function as well as a more mechanistic and quantitative approach to psychiatric nosology—structuring therapeutic interventions and predicting response and relapse. The basic procedure in computational psychiatry is to build a computational model that formalizes a behavioral or neuronal process. Measured behavioral (or neuronal) responses are then used to infer the model parameters of a single subject or a group of subjects. Here, we provide an illustrative overview over this process, starting from the modeling of choice behavior in a specific task, simulating data, and then inverting that model to estimate group effects. Finally, we illustrate cross-validation to assess whether between-subject variables (e.g., diagnosis) can be recovered successfully. Our worked example uses a simple two-step maze task and a model of choice behavior based on (active) inference and Markov decision processes. The procedural steps and routines we illustrate are not restricted to a specific field of research or particular computational model but can, in principle, be applied in many domains of computational psychiatry. PMID:27517087

Credibility, Replicability, and Reproducibility in Simulation for Biomedicine and Clinical Applications in Neuroscience

PubMed Central

Mulugeta, Lealem; Drach, Andrew; Erdemir, Ahmet; Hunt, C. A.; Horner, Marc; Ku, Joy P.; Myers Jr., Jerry G.; Vadigepalli, Rajanikanth; Lytton, William W.

2018-01-01

Modeling and simulation in computational neuroscience is currently a research enterprise to better understand neural systems. It is not yet directly applicable to the problems of patients with brain disease. To be used for clinical applications, there must not only be considerable progress in the field but also a concerted effort to use best practices in order to demonstrate model credibility to regulatory bodies, to clinics and hospitals, to doctors, and to patients. In doing this for neuroscience, we can learn lessons from long-standing practices in other areas of simulation (aircraft, computer chips), from software engineering, and from other biomedical disciplines. In this manuscript, we introduce some basic concepts that will be important in the development of credible clinical neuroscience models: reproducibility and replicability; verification and validation; model configuration; and procedures and processes for credible mechanistic multiscale modeling. We also discuss how garnering strong community involvement can promote model credibility. Finally, in addition to direct usage with patients, we note the potential for simulation usage in the area of Simulation-Based Medical Education, an area which to date has been primarily reliant on physical models (mannequins) and scenario-based simulations rather than on numerical simulations. PMID:29713272

Computational Phenotyping in Psychiatry: A Worked Example.

PubMed

Schwartenbeck, Philipp; Friston, Karl

2016-01-01

Computational psychiatry is a rapidly emerging field that uses model-based quantities to infer the behavioral and neuronal abnormalities that underlie psychopathology. If successful, this approach promises key insights into (pathological) brain function as well as a more mechanistic and quantitative approach to psychiatric nosology-structuring therapeutic interventions and predicting response and relapse. The basic procedure in computational psychiatry is to build a computational model that formalizes a behavioral or neuronal process. Measured behavioral (or neuronal) responses are then used to infer the model parameters of a single subject or a group of subjects. Here, we provide an illustrative overview over this process, starting from the modeling of choice behavior in a specific task, simulating data, and then inverting that model to estimate group effects. Finally, we illustrate cross-validation to assess whether between-subject variables (e.g., diagnosis) can be recovered successfully. Our worked example uses a simple two-step maze task and a model of choice behavior based on (active) inference and Markov decision processes. The procedural steps and routines we illustrate are not restricted to a specific field of research or particular computational model but can, in principle, be applied in many domains of computational psychiatry.

Credibility, Replicability, and Reproducibility in Simulation for Biomedicine and Clinical Applications in Neuroscience.

PubMed

Mulugeta, Lealem; Drach, Andrew; Erdemir, Ahmet; Hunt, C A; Horner, Marc; Ku, Joy P; Myers, Jerry G; Vadigepalli, Rajanikanth; Lytton, William W

2018-01-01

Modeling and simulation in computational neuroscience is currently a research enterprise to better understand neural systems. It is not yet directly applicable to the problems of patients with brain disease. To be used for clinical applications, there must not only be considerable progress in the field but also a concerted effort to use best practices in order to demonstrate model credibility to regulatory bodies, to clinics and hospitals, to doctors, and to patients. In doing this for neuroscience, we can learn lessons from long-standing practices in other areas of simulation (aircraft, computer chips), from software engineering, and from other biomedical disciplines. In this manuscript, we introduce some basic concepts that will be important in the development of credible clinical neuroscience models: reproducibility and replicability; verification and validation; model configuration; and procedures and processes for credible mechanistic multiscale modeling. We also discuss how garnering strong community involvement can promote model credibility. Finally, in addition to direct usage with patients, we note the potential for simulation usage in the area of Simulation-Based Medical Education, an area which to date has been primarily reliant on physical models (mannequins) and scenario-based simulations rather than on numerical simulations.

Use of ferrets for electrophysiologic monitoring of ion transport

PubMed Central

Kaza, Niroop; Raju, S. Vamsee; Cadillac, Joan M.; Trombley, John A.; Rasmussen, Lawrence; Tang, Liping; Dohm, Erik; Harrod, Kevin S.

2017-01-01

Limited success achieved in translating basic science discoveries into clinical applications for chronic airway diseases is attributed to differences in respiratory anatomy and physiology, poor approximation of pathologic processes, and lack of correlative clinical endpoints between humans and laboratory animal models. Here, we discuss advantages of using ferrets (Mustela putorus furo) as a model for improved understanding of human airway physiology and demonstrate assays for quantifying airway epithelial ion transport in vivo and ex vivo, and establish air-liquid interface cultures of ferret airway epithelial cells as a complementary in vitro model for mechanistic studies. We present data here that establishes the feasibility of measuring these human disease endpoints in ferrets. Briefly, potential difference across the nasal and the lower airway epithelium in ferrets could be consistently assessed, were highly reproducible, and responsive to experimental interventions. Additionally, ferret airway epithelial cells were amenable to primary cell culture methods for in vitro experiments as was the use of ferret tracheal explants as an ex vivo system for assessing ion transport. The feasibility of conducting multiple assessments of disease outcomes supports the adoption of ferrets as a highly relevant model for research in obstructive airway diseases. PMID:29077751

Use of ferrets for electrophysiologic monitoring of ion transport.

PubMed

Kaza, Niroop; Raju, S Vamsee; Cadillac, Joan M; Trombley, John A; Rasmussen, Lawrence; Tang, Liping; Dohm, Erik; Harrod, Kevin S; Rowe, Steven M

2017-01-01

Limited success achieved in translating basic science discoveries into clinical applications for chronic airway diseases is attributed to differences in respiratory anatomy and physiology, poor approximation of pathologic processes, and lack of correlative clinical endpoints between humans and laboratory animal models. Here, we discuss advantages of using ferrets (Mustela putorus furo) as a model for improved understanding of human airway physiology and demonstrate assays for quantifying airway epithelial ion transport in vivo and ex vivo, and establish air-liquid interface cultures of ferret airway epithelial cells as a complementary in vitro model for mechanistic studies. We present data here that establishes the feasibility of measuring these human disease endpoints in ferrets. Briefly, potential difference across the nasal and the lower airway epithelium in ferrets could be consistently assessed, were highly reproducible, and responsive to experimental interventions. Additionally, ferret airway epithelial cells were amenable to primary cell culture methods for in vitro experiments as was the use of ferret tracheal explants as an ex vivo system for assessing ion transport. The feasibility of conducting multiple assessments of disease outcomes supports the adoption of ferrets as a highly relevant model for research in obstructive airway diseases.

Basic Skills, Basic Writing, Basic Research.

ERIC Educational Resources Information Center

Trimmer, Joseph F.

1987-01-01

Overviews basic writing instruction and research by briefly discussing the history of remediation, results of a survey of basic writing programs in U.S. colleges and universities, and interviews with developmental textbook editors at major publishing houses. Finds that basic writing instruction continues to focus on sentence grammar. (MM)

34 CFR 350.5 - What definitions apply?

Code of Federal Regulations, 2010 CFR

2010-07-01

... classified on a continuum from basic to applied: (1) Basic research is research in which the investigator is... immediate application or utility. (2) Applied research is research in which the investigator is primarily... rehabilitation problem or need. Applied research builds on selected findings from basic research. (Authority: Sec...

Hyperphagia: current concepts and future directions proceedings of the 2nd international conference on hyperphagia.

PubMed

Heymsfield, Steven B; Avena, Nicole M; Baier, Leslie; Brantley, Phillip; Bray, George A; Burnett, Lisa C; Butler, Merlin G; Driscoll, Daniel J; Egli, Dieter; Elmquist, Joel; Forster, Janice L; Goldstone, Anthony P; Gourash, Linda M; Greenway, Frank L; Han, Joan C; Kane, James G; Leibel, Rudolph L; Loos, Ruth J F; Scheimann, Ann O; Roth, Christian L; Seeley, Randy J; Sheffield, Val; Tauber, Maïthé; Vaisse, Christian; Wang, Liheng; Waterland, Robert A; Wevrick, Rachel; Yanovski, Jack A; Zinn, Andrew R

2014-02-01

Hyperphagia is a central feature of inherited disorders (e.g., Prader-Willi Syndrome) in which obesity is a primary phenotypic component. Hyperphagia may also contribute to obesity as observed in the general population, thus raising the potential importance of common underlying mechanisms and treatments. Substantial gaps in understanding the molecular basis of inherited hyperphagia syndromes are present as are a lack of mechanistic of mechanistic targets that can serve as a basis for pharmacologic and behavioral treatments. International conference with 28 experts, including scientists and caregivers, providing presentations, panel discussions, and debates. The reviewed collective research and clinical experience provides a critical body of new and novel information on hyperphagia at levels ranging from molecular to population. Gaps in understanding and tools needed for additional research were identified. This report documents the full scope of important topics reviewed at a comprehensive international meeting devoted to the topic of hyperphagia and identifies key areas for future funding and research. Copyright © 2013 The Obesity Society.

Preventable Exposures Associated With Human Cancers

PubMed Central

Baan, Robert; Straif, Kurt; Grosse, Yann; Lauby-Secretan, Béatrice; El Ghissassi, Fatiha; Bouvard, Véronique; Benbrahim-Tallaa, Lamia; Guha, Neela; Freeman, Crystal; Galichet, Laurent; Wild, Christopher P.

2011-01-01

Information on the causes of cancer at specific sites is important to cancer control planners, cancer researchers, cancer patients, and the general public. The International Agency for Research on Cancer (IARC) Monograph series, which has classified human carcinogens for more than 40 years, recently completed a review to provide up-to-date information on the cancer sites associated with more than 100 carcinogenic agents. Based on IARC’s review, we listed the cancer sites associated with each agent and then rearranged this information to list the known and suspected causes of cancer at each site. We also summarized the rationale for classifications that were based on mechanistic data. This information, based on the forthcoming IARC Monographs Volume 100, offers insights into the current state-of-the-science of carcinogen identification. Use of mechanistic data to identify carcinogens is increasing, and epidemiological research is identifying additional carcinogens and cancer sites or confirming carcinogenic potential under conditions of lower exposure. Nevertheless, some common human cancers still have few (or no) identified causal agents. PMID:22158127

Hyperphagia: Current Concepts and Future Directions Proceedings of the 2nd International Conference on Hyperphagia

PubMed Central

Heymsfield, Steven B.; Avena, Nicole M.; Baier, Leslie; Brantley, Phillip; Bray, George A.; Burnett, Lisa C.; Butler, Merlin G.; Driscoll, Daniel J.; Egli, Dieter; Elmquist, Joel; Forster, Janice L.; Goldstone, Anthony P.; Gourash, Linda M.; Greenway, Frank L.; Han, Joan C.; Kane, James G.; Leibel, Rudolph L.; Loos, Ruth J.F.; Scheimann, Ann O.; Roth, Christian L.; Seeley, Randy J.; Sheffield, Val; Tauber, Maïthé; Vaisse, Christian; Wang, Liheng; Waterland, Robert A.; Wevrick, Rachel; Yanovski, Jack A.; Zinn, Andrew R.

2014-01-01

Objective Hyperphagia is a central feature of inherited disorders (e.g., Prader–Willi Syndrome) in which obesity is a primary phenotypic component. Hyperphagia may also contribute to obesity as observed in the general population, thus raising the potential importance of common underlying mechanisms and treatments. Substantial gaps in understanding the molecular basis of inherited hyperphagia syndromes are present as are a lack of mechanistic of mechanistic targets that can serve as a basis for pharmacologic and behavioral treatments. Design and Methods International conference with 28 experts, including scientists and caregivers, providing presentations, panel discussions, and debates. Results The reviewed collective research and clinical experience provides a critical body of new and novel information on hyperphagia at levels ranging from molecular to population. Gaps in understanding and tools needed for additional research were identified. Conclusions This report documents the full scope of important topics reviewed at a comprehensive international meeting devoted to the topic of hyperphagia and identifies key areas for future funding and research. PMID:24574081

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.

NREL Researchers Discover How a Bacterium, Clostridium thermocellum,

Science.gov Websites

containing the bacterium actually promotes the growth of C. thermocellum, yet its mechanistic details remained a puzzle. This enhanced growth implied the bacterium had the ability to use CO2 and prompted NREL researchers to investigate the phenomena enhancing the bacterium's growth. "It took us by surprise that

Disposal of Information Seeking and Retrieval Research: Replacement with a Radical Proposition

ERIC Educational Resources Information Center

Budd, John M.; Anstaett, Ashley

2013-01-01

Introduction: Research and theory on the topics of information seeking and retrieval have been plagued by some fundamental problems for several decades. Many of the difficulties spring from mechanistic and instrumental thinking and modelling. Method: Existing models of information retrieval and information seeking are examined for efficacy in a…

76 FR 6487 - National Center for Complementary and Alternative Medicine; Announcement of Workshop on...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-04

... Mechanistic and Translational Research on Omega-3 Fatty Acids and Their Metabolites ACTION: Notice. SUMMARY... Research on Omega-3 Fatty Acids and their Metabolites. The purpose of this workshop is to bring together... the underlying mechanisms of Omega-3 fatty acids and their metabolites. The goal is to identify...

Decorating with Arrows: Toward the Development of Representational Competence in Organic Chemistry

ERIC Educational Resources Information Center

Grove, Nathaniel P.; Cooper, Melanie M.; Rush, Kelli M.

2012-01-01

Much effort has been expended in developing improved methods for presenting mechanistic thinking and the curved-arrow notation to organic chemistry students; however, most of these techniques are not research-based. The little research that has been conducted has mainly focused on understanding the meaning that students associate with the…

"The Dilemma That Still Counts": Basic Writing at a Political Crossroads.

ERIC Educational Resources Information Center

Harrington, Susanmarie; Adler-Kassner, Linda

1998-01-01

Reviews definitions of basic writers and basic writing over the last 20 years. Argues that basic writers are not defined only in terms of institutional convenience. Offers future directions for basic writing research, suggesting that to learn more about basic writers, researchers must return to studies of error informed by basic writing's rich…

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

A physical description of fission product behavior fuels for advanced power reactors.

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

Kaganas, G.; Rest, J.; Nuclear Engineering Division

2007-10-18

The Global Nuclear Energy Partnership (GNEP) is considering a list of reactors and nuclear fuels as part of its chartered initiative. Because many of the candidate materials have not been explored experimentally under the conditions of interest, and in order to economize on program costs, analytical support in the form of combined first principle and mechanistic modeling is highly desirable. The present work is a compilation of mechanistic models developed in order to describe the fission product behavior of irradiated nuclear fuel. The mechanistic nature of the model development allows for the possibility of describing a range of nuclear fuelsmore » under varying operating conditions. Key sources include the FASTGRASS code with an application to UO{sub 2} power reactor fuel and the Dispersion Analysis Research Tool (DART ) with an application to uranium-silicide and uranium-molybdenum research reactor fuel. Described behavior mechanisms are divided into subdivisions treating fundamental materials processes under normal operation as well as the effect of transient heating conditions on these processes. Model topics discussed include intra- and intergranular gas-atom and bubble diffusion, bubble nucleation and growth, gas-atom re-solution, fuel swelling and ?scion gas release. In addition, the effect of an evolving microstructure on these processes (e.g., irradiation-induced recrystallization) is considered. The uranium-alloy fuel, U-xPu-Zr, is investigated and behavior mechanisms are proposed for swelling in the {alpha}-, intermediate- and {gamma}-uranium zones of this fuel. The work reviews the FASTGRASS kinetic/mechanistic description of volatile ?scion products and, separately, the basis for the DART calculation of bubble behavior in amorphous fuels. Development areas and applications for physical nuclear fuel models are identified.« less

Sustainable Mitigation of Stormwater Runoff Through Fully Permeable Pavement

DOT National Transportation Integrated Search

2018-03-01

This report presents the implementation of new design method developed using mechanistic-empirical design approach by University of California Pavement Research Center (UCPRC) through building two test sections at California State University Long Bea...

LEARNING AND ASSOCIATED PHENOMENA IN INVERTEBRATES.

DTIC Science & Technology

cnidarians; Cannibals, chemicals and contiguity; Behaviour of planaria in instrumental learning paradigms; Learning in planarians ; Learning in annelids...Research and theory on conditioning of annelids; Descartes, mechanistic biology and animal behaviour; Planarian learning; Learning and movement in

The structural basis of secondary active transport mechanisms.

PubMed

Forrest, Lucy R; Krämer, Reinhard; Ziegler, Christine

2011-02-01

Secondary active transporters couple the free energy of the electrochemical potential of one solute to the transmembrane movement of another. As a basic mechanistic explanation for their transport function the model of alternating access was put forward more than 40 years ago, and has been supported by numerous kinetic, biochemical and biophysical studies. According to this model, the transporter exposes its substrate binding site(s) to one side of the membrane or the other during transport catalysis, requiring a substantial conformational change of the carrier protein. In the light of recent structural data for a number of secondary transport proteins, we analyze the model of alternating access in more detail, and correlate it with specific structural and chemical properties of the transporters, such as their assignment to different functional states in the catalytic cycle of the respective transporter, the definition of substrate binding sites, the type of movement of the central part of the carrier harboring the substrate binding site, as well as the impact of symmetry on fold-specific conformational changes. Besides mediating the transmembrane movement of solutes, the mechanism of secondary carriers inherently involves a mechanistic coupling of substrate flux to the electrochemical potential of co-substrate ions or solutes. Mainly because of limitations in resolution of available transporter structures, this important aspect of secondary transport cannot yet be substantiated by structural data to the same extent as the conformational change aspect. We summarize the concepts of coupling in secondary transport and discuss them in the context of the available evidence for ion binding to specific sites and the impact of the ions on the conformational state of the carrier protein, which together lead to mechanistic models for coupling. Copyright © 2010 Elsevier B.V. All rights reserved.

Observational and Modeling Studies of Radiative, Chemical, and Dynamical Interactions in the Earth''s Atmosphere

NASA Technical Reports Server (NTRS)

Salby, Murry

1998-01-01

A 3-dimensional model was developed to support mechanistic studies. The model solves the global primitive equations in isentropic coordinates, which directly characterize diabatic processes forcing the Brewer-Dobson circulation of the middle atmosphere. It's numerical formulation is based on Hough harmonics, which partition horizontal motion into its rotational and divergent components. These computational features, along with others, enable 3D integrations to be performed practically on RISC computer architecture, on which they can be iterated to support mechanistic studies. The model conserves potential vorticity quite accurately under adiabatic conditions. Forced by observed tropospheric structure, in which integrations are anchored, the model generates a diabatic circulation that is consistent with satellite observations of tracer behavior and diabatic cooling rates. The model includes a basic but fairly complete treatment of gas-phase photochemistry that represents some 20 chemical species and 50 governing reactions with diurnally-varying shortwave absorption. The model thus provides a reliable framework to study transport and underlying diabatic processes, which can then be compared against chemical and dynamical structure observed and in GCM integrations. Integrations with the Langley GCM were performed to diagnose feedback between simulated convection and the tropical circulation. These were studied in relation to tropospheric properties controlling moisture convergence and environmental conditions supporting deep convection, for comparison against mechanistic integrations of wave CISK that successfully reproduce the Madden-Julian Oscillation (MJO) of the tropical circulation. These comparisons were aimed at identifying and ultimately improving aspects of the convective simulation, with the objective of recovering a successful simulation of the MJO in the Langley GCM, behavior that should be important to budgets of upper-tropospheric water vapor and chemical species.

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.

Current limitations and recommendations to improve testing for the environmental assessment of endocrine active substances

USGS Publications Warehouse

Coady, Katherine K.; Biever, Ronald C.; Denslow, Nancy D.; Gross, Melanie; Guiney, Patrick D.; Holbech, Henrik; Karouna-Renier, Natalie K.; Katsiadaki, Ioanna; Krueger, Hank; Levine, Steven L.; Maack, Gerd; Williams, Mike; Wolf, Jeffrey C.; Ankley, Gerald T.

2017-01-01

In the present study, existing regulatory frameworks and test systems for assessing potential endocrine active chemicals are described, and associated challenges are discussed, along with proposed approaches to address these challenges. Regulatory frameworks vary somewhat across geographies, but all basically evaluate whether a chemical possesses endocrine activity and whether this activity can result in adverse outcomes either to humans or to the environment. Current test systems include in silico, in vitro, and in vivo techniques focused on detecting potential endocrine activity, and in vivo tests that collect apical data to detect possible adverse effects. These test systems are currently designed to robustly assess endocrine activity and/or adverse effects in the estrogen, androgen, and thyroid hormone signaling pathways; however, there are some limitations of current test systems for evaluating endocrine hazard and risk. These limitations include a lack of certainty regarding: 1) adequately sensitive species and life stages; 2) mechanistic endpoints that are diagnostic for endocrine pathways of concern; and 3) the linkage between mechanistic responses and apical, adverse outcomes. Furthermore, some existing test methods are resource intensive with regard to time, cost, and use of animals. However, based on recent experiences, there are opportunities to improve approaches to and guidance for existing test methods and to reduce uncertainty. For example, in vitro high-throughput screening could be used to prioritize chemicals for testing and provide insights as to the most appropriate assays for characterizing hazard and risk. Other recommendations include adding endpoints for elucidating connections between mechanistic effects and adverse outcomes, identifying potentially sensitive taxa for which test methods currently do not exist, and addressing key endocrine pathways of possible concern in addition to those associated with estrogen, androgen, and thyroid signaling. 

Focus on Basics: Connecting Research & Practice. Volume 7, Issue D

ERIC Educational Resources Information Center

Garner, Barbara, Ed.

2005-01-01

"Focus on Basics" is the quarterly publication of the National Center for the Study of Adult Learning and Literacy. It presents best practices, current research on adult learning and literacy, and how research is used by adult basic education teachers, counselors, program administrators, and policymakers. "Focus on Basics" is…

Focus on Basics: Connecting Research & Practice. Volume 8, Issue B

ERIC Educational Resources Information Center

Garner, Barbara, Ed.

2006-01-01

"Focus on Basics" is the quarterly publication of the National Center for the Study of Adult Learning and Literacy. It presents best practices, current research on adult learning and literacy, and how research is used by adult basic education teachers, counselors, program administrators, and policymakers. "Focus on Basics" is…

Focus on Basics: Connecting Research & Practice. Volume 6, Issue A

ERIC Educational Resources Information Center

Garner, Barbara, Ed.

2002-01-01

"Focus on Basics" is the quarterly publication of the National Center for the Study of Adult Learning and Literacy. It presents best practices, current research on adult learning and literacy, and how research is used by adult basic education teachers, counselors, program administrators, and policymakers. "Focus on Basics" is…

Focus on Basics: Connecting Research & Practice. Volume 9, Issue B

ERIC Educational Resources Information Center

Garner, Barbara, Ed.

2008-01-01

"Focus on Basics" is a publication of the U.S. Division of World Education, Inc. It presents best practices, current research on adult learning and literacy, and how research is used by adult basic education teachers, counselors, program administrators, and policymakers. "Focus on Basics" is dedicated to connecting research…

Addressing the translational dilemma: dynamic knowledge representation of inflammation using agent-based modeling.

PubMed

An, Gary; Christley, Scott

2012-01-01

Given the panoply of system-level diseases that result from disordered inflammation, such as sepsis, atherosclerosis, cancer, and autoimmune disorders, understanding and characterizing the inflammatory response is a key target of biomedical research. Untangling the complex behavioral configurations associated with a process as ubiquitous as inflammation represents a prototype of the translational dilemma: the ability to translate mechanistic knowledge into effective therapeutics. A critical failure point in the current research environment is a throughput bottleneck at the level of evaluating hypotheses of mechanistic causality; these hypotheses represent the key step toward the application of knowledge for therapy development and design. Addressing the translational dilemma will require utilizing the ever-increasing power of computers and computational modeling to increase the efficiency of the scientific method in the identification and evaluation of hypotheses of mechanistic causality. More specifically, development needs to focus on facilitating the ability of non-computer trained biomedical researchers to utilize and instantiate their knowledge in dynamic computational models. This is termed "dynamic knowledge representation." Agent-based modeling is an object-oriented, discrete-event, rule-based simulation method that is well suited for biomedical dynamic knowledge representation. Agent-based modeling has been used in the study of inflammation at multiple scales. The ability of agent-based modeling to encompass multiple scales of biological process as well as spatial considerations, coupled with an intuitive modeling paradigm, suggest that this modeling framework is well suited for addressing the translational dilemma. This review describes agent-based modeling, gives examples of its applications in the study of inflammation, and introduces a proposed general expansion of the use of modeling and simulation to augment the generation and evaluation of knowledge by the biomedical research community at large.

Rational design of liposomal drug delivery systems, a review: Combined experimental and computational studies of lipid membranes, liposomes and their PEGylation.

PubMed

Bunker, Alex; Magarkar, Aniket; Viitala, Tapani

2016-10-01

Combined experimental and computational studies of lipid membranes and liposomes, with the aim to attain mechanistic understanding, result in a synergy that makes possible the rational design of liposomal drug delivery system (LDS) based therapies. The LDS is the leading form of nanoscale drug delivery platform, an avenue in drug research, known as "nanomedicine", that holds the promise to transcend the current paradigm of drug development that has led to diminishing returns. Unfortunately this field of research has, so far, been far more successful in generating publications than new drug therapies. This partly results from the trial and error based methodologies used. We discuss experimental techniques capable of obtaining mechanistic insight into LDS structure and behavior. Insight obtained purely experimentally is, however, limited; computational modeling using molecular dynamics simulation can provide insight not otherwise available. We review computational research, that makes use of the multiscale modeling paradigm, simulating the phospholipid membrane with all atom resolution and the entire liposome with coarse grained models. We discuss in greater detail the computational modeling of liposome PEGylation. Overall, we wish to convey the power that lies in the combined use of experimental and computational methodologies; we hope to provide a roadmap for the rational design of LDS based therapies. Computational modeling is able to provide mechanistic insight that explains the context of experimental results and can also take the lead and inspire new directions for experimental research into LDS development. This article is part of a Special Issue entitled: Biosimulations edited by Ilpo Vattulainen and Tomasz Róg. Copyright © 2016 Elsevier B.V. All rights reserved.

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

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

Japanese medical students' interest in basic sciences: a questionnaire survey of a medical school in Japan.

PubMed

Yamazaki, Yuka; Uka, Takanori; Shimizu, Haruhiko; Miyahira, Akira; Sakai, Tatsuo; Marui, Eiji

2013-02-01

The number of physicians engaged in basic sciences and teaching is sharply decreasing in Japan. To alleviate this shortage, central government has increased the quota of medical students entering the field. This study investigated medical students' interest in basic sciences in efforts to recruit talent. A questionnaire distributed to 501 medical students in years 2 to 6 of Juntendo University School of Medicine inquired about sex, grade, interest in basic sciences, interest in research, career path as a basic science physician, faculties' efforts to encourage students to conduct research, increases in the number of lectures, and practical training sessions on research. Associations between interest in basic sciences and other variables were examined using χ(2) tests. From among the 269 medical students (171 female) who returned the questionnaire (response rate 53.7%), 24.5% of respondents were interested in basic sciences and half of them considered basic sciences as their future career. Obstacles to this career were their original aim to become a clinician and concerns about salary. Medical students who were likely to be interested in basic sciences were fifth- and sixth-year students, were interested in research, considered basic sciences as their future career, considered faculties were making efforts to encourage medical students to conduct research, and wanted more research-related lectures. Improving physicians' salaries in basic sciences is important for securing talent. Moreover, offering continuous opportunities for medical students to experience research and encouraging advanced-year students during and after bedside learning to engage in basic sciences are important for recruiting talent.

Predicting colloid transport through saturated porous media: A critical review

NASA Astrophysics Data System (ADS)

Molnar, Ian L.; Johnson, William P.; Gerhard, Jason I.; Willson, Clinton S.; O'Carroll, Denis M.

2015-09-01

Understanding and predicting colloid transport and retention in water-saturated porous media is important for the protection of human and ecological health. Early applications of colloid transport research before the 1990s included the removal of pathogens in granular drinking water filters. Since then, interest has expanded significantly to include such areas as source zone protection of drinking water systems and injection of nanometals for contaminated site remediation. This review summarizes predictive tools for colloid transport from the pore to field scales. First, we review experimental breakthrough and retention of colloids under favorable and unfavorable colloid/collector interactions (i.e., no significant and significant colloid-surface repulsion, respectively). Second, we review the continuum-scale modeling strategies used to describe observed transport behavior. Third, we review the following two components of colloid filtration theory: (i) mechanistic force/torque balance models of pore-scale colloid trajectories and (ii) approximating correlation equations used to predict colloid retention. The successes and limitations of these approaches for favorable conditions are summarized, as are recent developments to predict colloid retention under the unfavorable conditions particularly relevant to environmental applications. Fourth, we summarize the influences of physical and chemical heterogeneities on colloid transport and avenues for their prediction. Fifth, we review the upscaling of mechanistic model results to rate constants for use in continuum models of colloid behavior at the column and field scales. Overall, this paper clarifies the foundation for existing knowledge of colloid transport and retention, features recent advances in the field, critically assesses where existing approaches are successful and the limits of their application, and highlights outstanding challenges and future research opportunities. These challenges and opportunities include improving mechanistic descriptions, and subsequent correlation equations, for nanoparticle (i.e., Brownian particle) transport through soil, developing mechanistic descriptions of colloid retention in so-called "unfavorable" conditions via methods such as the "discrete heterogeneity" approach, and employing imaging techniques such as X-ray tomography to develop realistic expressions for grain topology and mineral distribution that can aid the development of these mechanistic approaches.

Contexts, concepts and cognition: principles for the transfer of basic science knowledge.

PubMed

Kulasegaram, Kulamakan M; Chaudhary, Zarah; Woods, Nicole; Dore, Kelly; Neville, Alan; Norman, Geoffrey

2017-02-01

Transfer of basic science aids novices in the development of clinical reasoning. The literature suggests that although transfer is often difficult for novices, it can be optimised by two complementary strategies: (i) focusing learners on conceptual knowledge of basic science or (ii) exposing learners to multiple contexts in which the basic science concepts may apply. The relative efficacy of each strategy as well as the mechanisms that facilitate transfer are unknown. In two sequential experiments, we compared both strategies and explored mechanistic changes in how learners address new transfer problems. Experiment 1 was a 2 × 3 design in which participants were randomised to learn three physiology concepts with or without emphasis on the conceptual structure of basic science via illustrative analogies and by means of one, two or three contexts during practice (operationalised as organ systems). Transfer of these concepts to explain pathologies in familiar organ systems (near transfer) and unfamiliar organ systems (far transfer) was evaluated during immediate and delayed testing. Experiment 2 examined whether exposure to conceptual analogies and multiple contexts changed how learners classified new problems. Experiment 1 showed that increasing context variation significantly improved far transfer performance but there was no difference between two and three contexts during practice. Similarly, the increased conceptual analogies led to higher performance for far transfer. Both interventions had independent but additive effects on overall performance. Experiment 2 showed that such analogies and context variation caused learners to shift to using structural characteristics to classify new problems even when there was superficial similarity to previous examples. Understanding problems based on conceptual structural characteristics is necessary for successful transfer. Transfer of basic science can be optimised by using multiple strategies that collectively emphasise conceptual structure. This means teaching must focus on conserved basic science knowledge and de-emphasise superficial features. © 2017 John Wiley & Sons Ltd and The Association for the Study of Medical Education.

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.

Treatment of anemia in chronic kidney disease: known, unknown, and both.

PubMed

Foley, Robert N

2011-01-01

Erythropoiesis is a rapidly evolving research arena and several mechanistic insights show therapeutic promise. In contrast with the rapid advance of mechanistic science, optimal management of anemia in patients with chronic kidney disease remains a difficult and polarizing issue. Although several large hemoglobin target trials have been performed, optimal treatment targets remain elusive, because none of the large trials to date have unequivocally identified differences in primary outcome rates or death rates, and because other reported outcomes indicate the potential for harm (rates of stroke, early requirement for dialysis, and vascular access thrombosis) and benefit (reductions in transfusion requirements and fatigue).

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.

Focus on Basics: Connecting Research & Practice. Volume 8, Issue D

ERIC Educational Resources Information Center

Garner, Barbara, Ed.

2007-01-01

Learning disabilities is the theme of the latest issue of "Focus on Basics," the World Education publication that brings together research, policy, and practice in adult basic education. Starting with an update on research on neurobiology and dyslexia, this issue also examines how the adult basic education system supports students with…

Focus on Basics: Connecting Research & Practice. Volume 6, Issue B

ERIC Educational Resources Information Center

Garner, Barbara, Ed.

2003-01-01

"Focus on Basics" is the quarterly publication of the National Center for the Study of Adult Learning and Literacy. It presents best practices, current research on adult learning and literacy, and how research is used by adult basic education teachers, counselors, program administrators, and policymakers. "Focus on Basics" is dedicated to…

Focus on Basics: Connecting Research and Practice. Volume 6, Issue D

ERIC Educational Resources Information Center

National Center for the Study of Adult Learning and Literacy (NCSALL), Harvard University, 2004

2004-01-01

"Focus on Basics" is the quarterly publication of the National Center for the Study of Adult Learning and Literacy. It presents best practices, current research on adult learning and literacy, and how research is used by adult basic education teachers, counselors, program administrators, and policymakers. "Focus on Basics" is dedicated to…

Standardizing lightweight deflectometer modulus measurements for compaction quality assurance : research summary.

DOT National Transportation Integrated Search

2017-09-01

The mechanistic-empirical pavement design method requires the elastic resilient modulus as the key input for characterization of geomaterials. Current density-based QA procedures do not measure resilient modulus. Additionally, the density-based metho...

76 FR 14979 - National Institute of Neurological Disorders and Stroke; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-18

... a new mechanistic finding and the lessons learned in current drug development programs. A panel will... Research in the Neurosciences, National Institutes of Health, HHS) Dated: March 11, 2011. Jennifer S...

Embracing Community Ecology in Plant Microbiome Research.

PubMed

Dini-Andreote, Francisco; Raaijmakers, Jos M

2018-06-01

Community assembly is mediated by selection, dispersal, drift, and speciation. Environmental selection is mostly used to date to explain patterns in plant microbiome assembly, whereas the influence of the other processes remains largely elusive. Recent studies highlight that adopting community ecology concepts provides a mechanistic framework for plant microbiome research. Copyright © 2018 Elsevier Ltd. All rights reserved.

75 FR 21003 - National Toxicology Program (NTP); Office of Liaison, Policy and Review Meeting of the NTP Board...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-22

... appropriate animal and non-animal experimental models for mechanistic-based research, including genetically... is June 7, 2010, and for pre- registration to attend the meeting, including registering to present... Building at the NIEHS, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709. Public comments on all...

Understanding essential tremor: progress on the biological front.

PubMed

Louis, Elan D

2014-06-01

For many years, little was written about the underlying biology of ET, despite its high prevalence. Discussions of disease mechanisms were dominated by a focus on tremor physiology. The traditional model of ET, the olivary model, was proposed in the 1970s. The model suffers from several critical problems, and its relevance to ET has been questioned. Recent mechanistic research has focused on the cerebellum. Clinical and neuroimaging studies strongly implicate the importance of this brain region in ET. Recent mechanistic research has been grounded more in tissue-based changes (i.e., postmortem studies of the brain). These studies have collectively and systematically identified a sizable number of changes in the ET cerebellum, and have led to a new model of ET, referred to as the cerebellar degenerative model. Hence, there is a renewed interest in the science behind the biology of ET. How the new understanding of ET will translate into treatment changes is an open question.

A tribute to Ulrich Heber (1930-2016) for his contribution to photosynthesis research: understanding the interplay between photosynthetic primary reactions, metabolism and the environment.

PubMed

Dietz, Karl-Josef; Krause, G Heinrich; Siebke, Katharina; Krieger-Liszkay, Anja

2018-07-01

The dynamic and efficient coordination of primary photosynthetic reactions with leaf energization and metabolism under a wide range of environmental conditions is a fundamental property of plants involving processes at all functional levels. The present historical perspective covers 60 years of research aiming to understand the underlying mechanisms, linking major breakthroughs to current progress. It centers on the contributions of Ulrich Heber who had pioneered novel concepts, fundamental methods, and mechanistic understanding of photosynthesis. An important first step was the development of non-aqueous preparation of chloroplasts allowing the investigation of chloroplast metabolites ex vivo (meaning that the obtained results reflect the in vivo situation). Later on, intact chloroplasts, retaining their functional envelope membranes, were isolated in aqueous media to investigate compartmentation and exchange of metabolites between chloroplasts and external medium. These studies elucidated metabolic interaction between chloroplasts and cytoplasm during photosynthesis. Experiments with isolated intact chloroplasts clarified that oxygenation of ribulose-1.5-bisphosphate generates glycolate in photorespiration. The development of non-invasive optical methods enabled researchers identifying mechanisms that balance electron flow in the photosynthetic electron transport system avoiding its over-reduction. Recording chlorophyll a (Chl a) fluorescence allowed one to monitor, among other parameters, thermal energy dissipation by means of 'nonphotochemical quenching' of the excited state of Chl a. Furthermore, studies both in vivo and in vitro led to basic understanding of the biochemical mechanisms of freezing damage and frost tolerance of plant leaves, to SO 2 tolerance of tree leaves and dehydrating lichens and mosses.

Renal lesions associated with plasma cell dyscrasias: practical approach to diagnosis, new concepts, and challenges.

PubMed

Herrera, Guillermo A

2009-02-01

Patients with plasma cell dyscrasias (myeloma) may exhibit a variety of renal manifestations as a result of damage from circulating light- and heavy-chain immunoglobulin components produced by the neoplastic plasma cells. The renal alterations can occur in any of the renal compartments, and in a significant number of the cases more than one compartment is affected. Research in the laboratory has helped considerably in providing a solid conceptual understanding of how renal damage occurs. To detail advances that have been made in the diagnosis of these conditions and to provide an account of research accomplishments that have solidified diagnostic criteria. The new knowledge that has been acquired serves to provide a solid platform for the future design of new therapeutic interventions aimed at ameliorating or abolishing the progressive renal damage that typically takes place. Translational efforts have substantially contributed to elucidate mechanistically the molecular events responsible for the renal damage. The spectrum of renal manifestations associated with plasma cell dyscrasias has expanded significantly in the last 10 years. Diagnostic criteria have also been refined. This information has been summarized from work done at several institutions. A number of significant challenges remain in the diagnosis of these conditions, some of which will be discussed in this article. Dealing with these challenges will require additional translational efforts and close cooperation between basic researchers, clinicians, and pathologists in order to improve the diagnostic tools available to renal pathologists and to acquire a more complete understanding of clinical and pathologic manifestations associated with these conditions.

Driving research in infant and children's nutrition: a perspective on industry.

PubMed

Rai, Deshanie; Larson, Brian

2009-05-01

As part of the workshop entitled "Early Risk Determinants and Later Health Outcomes: Implications for Research Prioritization and the Food Supply" (8-9 July 2008, Washington, DC), which was cosponsored by the International Life Sciences Institute of North America and the International Life Sciences Institute Research Foundation, representatives of the food industry discussed the practical application of nutrition science. Nutrition plays a key role in guiding health outcomes throughout the life cycle. In particular, the prenatal, postnatal, and early childhood periods are extremely sensitive to the presence of appropriate nutrition. A growing body of evidence shows that early nutrition may program the unborn and the infant's key physiologic systems, including the endocrine, cardiovascular, and central nervous systems, to influence later life outcomes. While scientists in academia continue to explore the multifactorial nature of early risk determinants and later life outcomes at a mechanistic and basic science level, it is important to understand the potential of the infant and child food industries to address questions such as what factors have been noted to drive research in these sectors of the food industry. How can scientists in these industries work alongside the scientists in academia and in government to set priorities, make decisions around these health issues, and translate academic insights into innovative nutritional solutions for the benefit of public health? Given the commitment of the infant and child food industries to deliver scientifically supported early life nutrition, it is easy to understand why this industry would work in partnership with both the scientists in academia and the government to identify a means of addressing the fundamental questions of this workshop.

Properties of Life: Toward a Coherent Understanding of the Organism.

PubMed

Rosslenbroich, Bernd

2016-09-01

The question of specific properties of life compared to nonliving things accompanied biology throughout its history. At times this question generated major controversies with largely diverging opinions. Basically, mechanistic thinkers, who tried to understand organismic functions in terms of nonliving machines, were opposed by those who tried to describe specific properties or even special forces being active within living entities. As this question included the human body, these controversies always have been of special relevance to our self-image and also touched practical issues of medicine. During the second half of the twentieth century, it seemed to be resolved that organisms are explainable basically as physicochemical machines. Especially from the perspective of molecular biology, it seemed to be clear that organisms need to be explained solely by the chemical functions of their component parts, although some resistance to this view never ceased. This research program has been working quite successfully, so that science today knows a lot about the physiological and chemical processes within organisms. However, again new doubts arise questioning whether the mere continuation of this analytical approach will finally generate a fundamental understanding of living entities. At the beginning of the twenty-first century the quest for a new synthesis actually comes from analytical empiricists themselves. The hypothesis of the present paper is that empirical research has been developed far enough today, that it reveals by itself the materials and the prerequisites to understand more of the specific properties of life. Without recourse to mysterious forces, it is possible to generate answers to this age-old question, just using recent, empirically generated knowledge. This view does not contradict the results of reductionistic research, but rather grants them meaning within the context of organismic systems and also may increase their practical usefulness. Although several of these properties have been discussed before, different authors usually concentrated on a single one or some of them. The paper describes ten specific properties of living entities as they can be deduced from contemporary science. The aim is to demonstrate that the results of empirical research show both the necessity as well as the possibility of the development of a new conception of life to build a coherent understanding of organismic functions.

The Relationship between Basic and Applied Research in Universities

ERIC Educational Resources Information Center

Bentley, Peter James; Gulbrandsen, Magnus; Kyvik, Svein

2015-01-01

What is the central research activity in modern universities? This paper uses a comprehensive survey among individuals from 15 countries to map differences in orientation towards basic/fundamental research, applied/practical research and a combination of the two. Despite some claims in the literature that basic research is no longer a…

Cellular and Synaptic Properties of Local Inhibitory Circuits.

PubMed

Hull, Court

2017-05-01

Inhibitory interneurons play a key role in sculpting the information processed by neural circuits. Despite the wide range of physiologically and morphologically distinct types of interneurons that have been identified, common principles have emerged that have shed light on how synaptic inhibition operates, both mechanistically and functionally, across cell types and circuits. This introduction summarizes how electrophysiological approaches have been used to illuminate these key principles, including basic interneuron circuit motifs, the functional properties of inhibitory synapses, and the main roles for synaptic inhibition in regulating neural circuit function. It also highlights how some key electrophysiological methods and experiments have advanced our understanding of inhibitory synapse function. © 2017 Cold Spring Harbor Laboratory Press.

Quantitative model of price diffusion and market friction based on trading as a mechanistic random process.

PubMed

Daniels, Marcus G; Farmer, J Doyne; Gillemot, László; Iori, Giulia; Smith, Eric

2003-03-14

We model trading and price formation in a market under the assumption that order arrival and cancellations are Poisson random processes. This model makes testable predictions for the most basic properties of markets, such as the diffusion rate of prices (which is the standard measure of financial risk) and the spread and price impact functions (which are the main determinants of transaction cost). Guided by dimensional analysis, simulation, and mean-field theory, we find scaling relations in terms of order flow rates. We show that even under completely random order flow the need to store supply and demand to facilitate trading induces anomalous diffusion and temporal structure in prices.

Quantitative Model of Price Diffusion and Market Friction Based on Trading as a Mechanistic Random Process

NASA Astrophysics Data System (ADS)

Daniels, Marcus G.; Farmer, J. Doyne; Gillemot, László; Iori, Giulia; Smith, Eric

2003-03-01

We model trading and price formation in a market under the assumption that order arrival and cancellations are Poisson random processes. This model makes testable predictions for the most basic properties of markets, such as the diffusion rate of prices (which is the standard measure of financial risk) and the spread and price impact functions (which are the main determinants of transaction cost). Guided by dimensional analysis, simulation, and mean-field theory, we find scaling relations in terms of order flow rates. We show that even under completely random order flow the need to store supply and demand to facilitate trading induces anomalous diffusion and temporal structure in prices.

Seeking evidence of multidisciplinarity in environmental geochemistry and health: an analysis of arsenic in drinking water research.

PubMed

Aderibigbe, Abiodun D; Stewart, Alex G; Hursthouse, Andrew S

2018-02-01

A multidisciplinary approach to research affords the opportunity of objectivity, creation of new knowledge and potentially a more generally acceptable solution to problems that informed the research in the first place. It increasingly features in national programmes supporting basic and applied research, but for over 40 years, has been the arena for many research teams in environmental geochemistry and health. This study explores the nature of multidisciplinary research in the earth and health sciences using a sample selected from co-authored articles reporting research on arsenic (As) in drinking water from 1979 to 2013. A total of 889 relevant articles were sourced using the online version of the science citation index-expanded (SCI-expanded). The articles were classified according to author affiliation and later by author discipline/research interests using the Revised Field of Science and Technology Frascati manual DSTI/EAS/STP/NESTI (2006) 19/FINAL and a decision algorithm. Few articles were published on the topic until 2000. More articles were published across all affiliations in the last 10 years of the review period (2004-2013) than in the first 10 years (1979-1988). Only 84 (~9%) articles fell within the "earth and health" only and "earth, health and other" categories when classification was undertaken by author affiliation alone. This suggests that level of collaboration between earth and health scientists in arsenic in drinking water research may be very low. By refining the classification further using author discipline/research interests, only 28 of the 84 articles appear to be co-authored by earth and health scientists alongside professionals in other fields. More than half of these 28 articles involved descriptive non-experimental, observational study designs, limited in direct causal hypotheses and mechanistic investigation. If collaborative research is to lead to the increased multidisciplinary research, early interaction should be encouraged between students from different disciplines. In order to achieve multidisciplinarity in practise, it is imperative that scientific communities and research agencies do more to encourage interaction and integration between researchers from different disciplines. This must develop from educational institutions seeing opportunities to improve graduate skills in an increasingly diverse research landscape.

Can Basic Research on Children and Families Be Useful for the Policy Process?

ERIC Educational Resources Information Center

Moore, Kristin A.

Based on the assumption that basic science is the crucial building block for technological and biomedical progress, this paper examines the relevance for public policy of basic demographic and behavioral sciences research on children and families. The characteristics of basic research as they apply to policy making are explored. First, basic…

32 CFR 37.1240 - Basic research.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 32 National Defense 1 2013-07-01 2013-07-01 false Basic research. 37.1240 Section 37.1240 National... TECHNOLOGY INVESTMENT AGREEMENTS Definitions of Terms Used in This Part § 37.1240 Basic research. Efforts... practical application of that knowledge and understanding. It typically is funded within Research...

32 CFR 37.1240 - Basic research.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 1 2011-07-01 2011-07-01 false Basic research. 37.1240 Section 37.1240 National... TECHNOLOGY INVESTMENT AGREEMENTS Definitions of Terms Used in This Part § 37.1240 Basic research. Efforts... practical application of that knowledge and understanding. It typically is funded within Research...

32 CFR 37.1240 - Basic research.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 32 National Defense 1 2014-07-01 2014-07-01 false Basic research. 37.1240 Section 37.1240 National... TECHNOLOGY INVESTMENT AGREEMENTS Definitions of Terms Used in This Part § 37.1240 Basic research. Efforts... practical application of that knowledge and understanding. It typically is funded within Research...

32 CFR 37.1240 - Basic research.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 1 2010-07-01 2010-07-01 false Basic research. 37.1240 Section 37.1240 National... TECHNOLOGY INVESTMENT AGREEMENTS Definitions of Terms Used in This Part § 37.1240 Basic research. Efforts... practical application of that knowledge and understanding. It typically is funded within Research...

32 CFR 37.1240 - Basic research.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 32 National Defense 1 2012-07-01 2012-07-01 false Basic research. 37.1240 Section 37.1240 National... TECHNOLOGY INVESTMENT AGREEMENTS Definitions of Terms Used in This Part § 37.1240 Basic research. Efforts... practical application of that knowledge and understanding. It typically is funded within Research...

Implementation of the MEPDG for flexible pavements in Idaho.

DOT National Transportation Integrated Search

2012-05-01

This study was conducted to assist the Idaho Transportation Department (ITD) in the implementation of the Mechanistic-Empirical Pavement Design Guide (MEPDG) for flexible pavements. The main research work in this study focused on establishing a mater...

Summary of lessons learned from the MDOT MEPDG materials library study.

DOT National Transportation Integrated Search

2010-06-01

From 2004 to 2009, Burns Cooley Dennis, Inc. (BCD) participated in two important research studies designed to populate the materials library for implementation of the new Mechanistic-Empirical pavement design method (MEPDG) in Mississippi. The purpos...

Continued Viability of Universities as Centers for Basic Research.

ERIC Educational Resources Information Center

Carter, Lisle C., Jr.; And Others

The findings and 13 recommendations of a NSF Advisory Council task force that evaluated universities as centers of basic research are presented. Listed are the major strengths of universities as centers for basic research (including continuity and tradition, freedom of research, interactions among disciplines) and such threats to their viability…

Adverse outcome pathway (AOP) development and evaluation ...

EPA Pesticide Factsheets

The Adverse Outcome Pathway provides a construct for assembling mechanistic information at different levels of biological organization in a form designed to support regulatory decision making. In particular, it frames the link between molecular and cellular events that can be measured in high throughput toxicity testing and the organism or population-level events that are commonly relevant in defining risk. Recognizing the importance of this emerging framework, the Organisation for Economic Co-operation and Development (OECD) launched a program to support the development, documentation and consideration of AOPs by the international community in 2012 (http://www.oecd.org/chemicalsafety/testing/adverse-outcome-pathways-molecular-screening-and-toxicogenomics.htm). In 2014, a handbook (https://aopkb.org/common/AOP_Handbook.pdf) was developed to guide users in the documentation and evaluation of AOPs and their entry into an official knowledgebase. The handbook draws on longstanding experience in consideration of mechanistic data (e.g., mode of action analysis) to inform risk assessment. To further assist users, a training program was developed by members of the OECD Extended Advisory Group to teach users the basic principles of AOP development and the best practices as outlined in the OECD AOP handbook. Training sessions began in early 2015, and this course will provide training for interested SOT scientists. Following this course, all participants will be familiar w

The role of photorespiration during the evolution of C4 photosynthesis in the genus Flaveria

PubMed Central

Mallmann, Julia; Heckmann, David; Bräutigam, Andrea; Lercher, Martin J; Weber, Andreas PM; Westhoff, Peter; Gowik, Udo

2014-01-01

C4 photosynthesis represents a most remarkable case of convergent evolution of a complex trait, which includes the reprogramming of the expression patterns of thousands of genes. Anatomical, physiological, and phylogenetic and analyses as well as computational modeling indicate that the establishment of a photorespiratory carbon pump (termed C2 photosynthesis) is a prerequisite for the evolution of C4. However, a mechanistic model explaining the tight connection between the evolution of C4 and C2 photosynthesis is currently lacking. Here we address this question through comparative transcriptomic and biochemical analyses of closely related C3, C3–C4, and C4 species, combined with Flux Balance Analysis constrained through a mechanistic model of carbon fixation. We show that C2 photosynthesis creates a misbalance in nitrogen metabolism between bundle sheath and mesophyll cells. Rebalancing nitrogen metabolism requires anaplerotic reactions that resemble at least parts of a basic C4 cycle. Our findings thus show how C2 photosynthesis represents a pre-adaptation for the C4 system, where the evolution of the C2 system establishes important C4 components as a side effect. DOI: http://dx.doi.org/10.7554/eLife.02478.001 PMID:24935935

Pharmacokinetic Modeling to Simulate the Concentration-Time Profiles After Dermal Application of Rivastigmine Patch.

PubMed

Nozaki, Sachiko; Yamaguchi, Masayuki; Lefèvre, Gilbert

2016-07-01

Rivastigmine is an inhibitor of acetylcholinesterases and butyrylcholinesterases for symptomatic treatment of Alzheimer disease and is available as oral and transdermal patch formulations. A dermal absorption pharmacokinetic (PK) model was developed to simulate the plasma concentration-time profile of rivastigmine to answer questions relative to the efficacy and safety risks after misuse of the patch (e.g., longer application than 24 h, multiple patches applied at the same time, and so forth). The model comprised 2 compartments which was a combination of mechanistic dermal absorption model and a basic 1-compartment model. The initial values for the model were determined based on the physicochemical characteristics of rivastigmine and PK parameters after intravenous administration. The model was fitted to the clinical PK profiles after single application of rivastigmine patch to obtain model parameters. The final model was validated by confirming that the simulated concentration-time curves and PK parameters (Cmax and area under the drug plasma concentration-time curve) conformed to the observed values and then was used to simulate the PK profiles of rivastigmine. This work demonstrated that the mechanistic dermal PK model fitted the clinical data well and was able to simulate the PK profile after patch misuse. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Pragmatic perspective on aerobic scope: peaking, plummeting, pejus and apportioning.

PubMed

Farrell, A P

2016-01-01

A major challenge for fish biologists in the 21st century is to predict the biotic effects of global climate change. With marked changes in biogeographic distribution already in evidence for a variety of aquatic animals, mechanistic explanations for these shifts are being sought, ones that then can be used as a foundation for predictive models of future climatic scenarios. One mechanistic explanation for the thermal performance of fishes that has gained some traction is the oxygen and capacity-limited thermal tolerance (OCLTT) hypothesis, which suggests that an aquatic organism's capacity to supply oxygen to tissues becomes limited when body temperature reaches extremes. Central to this hypothesis is an optimum temperature for absolute aerobic scope (AAS, loosely defined as the capacity to deliver oxygen to tissues beyond a basic need). On either side of this peak for AAS are pejus temperatures that define when AAS falls off and thereby reduces an animal's absolute capacity for activity. This article provides a brief perspective on the potential uses and limitations of some of the key physiological indicators related to aerobic scope in fishes. The intent is that practitioners who attempt predictive ecological applications can better recognize limitations and make better use of the OCLTT hypothesis and its underlying physiology. © 2015 The Fisheries Society of the British Isles.

Inferring Diffusion Dynamics from FCS in Heterogeneous Nuclear Environments

PubMed Central

Tsekouras, Konstantinos; Siegel, Amanda P.; Day, Richard N.; Pressé, Steve

2015-01-01

Fluorescence correlation spectroscopy (FCS) is a noninvasive technique that probes the diffusion dynamics of proteins down to single-molecule sensitivity in living cells. Critical mechanistic insight is often drawn from FCS experiments by fitting the resulting time-intensity correlation function, G(t), to known diffusion models. When simple models fail, the complex diffusion dynamics of proteins within heterogeneous cellular environments can be fit to anomalous diffusion models with adjustable anomalous exponents. Here, we take a different approach. We use the maximum entropy method to show—first using synthetic data—that a model for proteins diffusing while stochastically binding/unbinding to various affinity sites in living cells gives rise to a G(t) that could otherwise be equally well fit using anomalous diffusion models. We explain the mechanistic insight derived from our method. In particular, using real FCS data, we describe how the effects of cell crowding and binding to affinity sites manifest themselves in the behavior of G(t). Our focus is on the diffusive behavior of an engineered protein in 1) the heterochromatin region of the cell’s nucleus as well as 2) in the cell’s cytoplasm and 3) in solution. The protein consists of the basic region-leucine zipper (BZip) domain of the CCAAT/enhancer-binding protein (C/EBP) fused to fluorescent proteins. PMID:26153697

Current limitations and recommendations to improve testing ...

EPA Pesticide Factsheets

In this paper existing regulatory frameworks and test systems for assessing potential endocrine-active chemicals are described, and associated challenges discussed, along with proposed approaches to address these challenges. Regulatory frameworks vary somewhat across organizations, but all basically evaluate whether a chemical possesses endocrine activity and whether this activity can result in adverse outcomes either to humans or the environment. Current test systems include in silico, in vitro and in vivo techniques focused on detecting potential endocrine activity, and in vivo tests that collect apical data to detect possible adverse effects. These test systems are currently designed to robustly assess endocrine activity and/or adverse effects in the estrogen, androgen, and thyroid hormonal pathways; however, there are some limitations of current test systems for evaluating endocrine hazard and risk. These limitations include a lack of certainty regarding: 1)adequately sensitive species and life-stages, 2) mechanistic endpoints that are diagnostic for endocrine pathways of concern, and 3) the linkage between mechanistic responses and apical, adverse outcomes. Furthermore, some existing test methods are resource intensive in regard to time, cost, and use of animals. However, based on recent experiences, there are opportunities to improve approaches to, and guidance for existing test methods, and to reduce uncertainty. For example, in vitro high throughput

Oxidative Dehydrogenation on Nanocarbon: Insights into the Reaction Mechanism and Kinetics via in Situ Experimental Methods.

PubMed

Qi, Wei; Yan, Pengqiang; Su, Dang Sheng

2018-03-20

Sustainable and environmentally benign catalytic processes are vital for the future to supply the world population with clean energy and industrial products. The replacement of conventional metal or metal oxide catalysts with earth abundant and renewable nonmetallic materials has attracted considerable research interests in the field of catalysis and material science. The stable and efficient catalytic performance of nanocarbon materials was discovered at the end of last century, and these materials are considered as potential alternatives for conventional metal-based catalysts. With its rapid development in the past 20 years, the research field of carbon catalysis has been experiencing a smooth transition from the discovery of novel nanocarbon materials or related new reaction systems to the atomistic-level mechanistic understanding on the catalytic process and the subsequent rational design of the practical catalytic reaction systems. In this Account, we summarize the recent progress in the kinetic and mechanistic studies on nanocarbon catalyzed alkane oxidative dehydrogenation (ODH) reactions. The paper attempts to extract general concepts and basic regularities for carbon catalytic process directing us on the way for rational design of novel efficient metal-free catalysts. The nature of the active sites for ODH reactions has been revealed through microcalorimetric analysis, ambient pressure X-ray photoelectron spectroscopy (XPS) measurement, and in situ chemical titration strategies. The detailed kinetic analysis and in situ catalyst structure characterization suggests that carbon catalyzed ODH reactions involve the redox cycles of the ketonic carbonyl-hydroxyl pairs, and the key physicochemical parameters (activation energy, reaction order, and rate/equilibrium constants, etc.) of the carbon catalytic systems are proposed and compared with conventional transition metal oxide catalysts. The proposal of the intrinsic catalytic activity (TOF) provides the possibility for the fair comparisons of different nanocarbon catalysts and the consequent structure-function relation regularity. Surface modification and heteroatom doping are proved as the most effective strategies to adjust the catalytic property (activity and product selectivity etc.) of the nanocarbon catalysts. Nanocarbon is actually a proper candidate platform helping us to understand the classical catalytic reaction mechanism better, since there is no lattice oxygen and all the catalytic process happens on nanocarbon surface. This Account also exhibits the importance of the in situ structural characterizations for heterogeneous nanocarbon catalysis. The research strategy and methods proposed for carbon catalysts may also shed light on other complicated catalytic systems or fields concerning the applications of nonmetallic materials, such as energy storage and environment protection etc.

[Platforms are needed for innovative basic research in ophthalmology].

PubMed

Wang, Yi-qiang

2012-07-01

Basic research poses the cornerstone of technical innovation in all lines including medical sciences. Currently, there are shortages of professional scientists as well as technical supporting teams and facilities in the field of basic research of ophthalmology and visual science in China. Evaluation system and personnel policies are not supportive for innovative but high-risk-of-failure research projects. Discussion of reasons and possible solutions are given here to address these problems, aiming at promoting buildup of platforms hosting novel and important basic research in eye science in this country.

Sustainable Transportation Basics | Transportation Research | NREL

Science.gov Websites

Transportation Basics Sustainable Transportation Basics Compare Vehicle Technologies 3-D introduction to sustainable transportation. NREL research supports development of electric, hybrid, hydrogen

Research frontiers for improving our understanding of drought‐induced tree and forest mortality

USGS Publications Warehouse

Hartmann, Henrik; Moura, Catarina; Anderegg, William R. L.; Ruehr, Nadine; Salmon, Yann; Allen, Craig D.; Arndt, Stefan K.; Breshears, David D.; Davi, Hendrik; Galbraith, David; Ruthrof, Katinka X.; Wunder, Jan; Adams, Henry D.; Bloemen, Jasper; Cailleret, Maxime; Cobb, Richard; Gessler, Arthur; Grams, Thorsten E. E.; Jansen, Steven; Kautz, Markus; Lloret, Francisco; O’Brien, Michael

2018-01-01

Accumulating evidence highlights increased mortality risks for trees during severe drought, particularly under warmer temperatures and increasing vapour pressure deficit (VPD). Resulting forest die‐off events have severe consequences for ecosystem services, biophysical and biogeochemical land–atmosphere processes. Despite advances in monitoring, modelling and experimental studies of the causes and consequences of tree death from individual tree to ecosystem and global scale, a general mechanistic understanding and realistic predictions of drought mortality under future climate conditions are still lacking. We update a global tree mortality map and present a roadmap to a more holistic understanding of forest mortality across scales. We highlight priority research frontiers that promote: (1) new avenues for research on key tree ecophysiological responses to drought; (2) scaling from the tree/plot level to the ecosystem and region; (3) improvements of mortality risk predictions based on both empirical and mechanistic insights; and (4) a global monitoring network of forest mortality. In light of recent and anticipated large forest die‐off events such a research agenda is timely and needed to achieve scientific understanding for realistic predictions of drought‐induced tree mortality. The implementation of a sustainable network will require support by stakeholders and political authorities at the international level.

Yoga for Heart Failure: A Review and Future Research

PubMed Central

Pullen, Paula R; Seffens, William S; Thompson, Walter R

2018-01-01

Background: Complementary and alternative medicine is a rapidly growing area of biomedical inquiry. Yoga has emerged in the forefront of holistic medical care due to its long history of linking physical, mental, and spiritual well-being. Research in yoga therapy (YT) has associated improved cardiovascular and quality of life (QoL) outcomes for the special needs of heart failure (HF) patients. Aim: The aim of this study is to review yoga intervention studies on HF patients, discuss proposed mechanisms, and examine yoga's effect on physiological systems that have potential benefits for HF patients. Second, to recommend future research directions to find the most effective delivery methods of yoga to medically stable HF patients. Methods: The authors conducted a systematic review of the medical literature for RCTs involving HF patients as participants in yoga interventions and for studies utilizing mechanistic theories of stretch and new technologies. We examined physical intensity, mechanistic theories, and the use of the latest technologies. Conclusions: Based on the review, there is a need to further explore yoga mechanisms and research options for the delivery of YT. Software apps as exergames developed for use at home and community activity centers may minimize health disparities and increase QoL for HF patients. PMID:29755216

Comparative aspects of rodent and nonrodent animal models for mechanistic and translational diabetes research.

PubMed

Renner, Simone; Dobenecker, Britta; Blutke, Andreas; Zöls, Susanne; Wanke, Rüdiger; Ritzmann, Mathias; Wolf, Eckhard

2016-07-01

The prevalence of diabetes mellitus, which currently affects 387 million people worldwide, is permanently rising in both adults and adolescents. Despite numerous treatment options, diabetes mellitus is a progressive disease with severe comorbidities, such as nephropathy, neuropathy, and retinopathy, as well as cardiovascular disease. Therefore, animal models predictive of the efficacy and safety of novel compounds in humans are of great value to address the unmet need for improved therapeutics. Although rodent models provide important mechanistic insights, their predictive value for therapeutic outcomes in humans is limited. In recent years, the pig has gained importance for biomedical research because of its close similarity to human anatomy, physiology, size, and, in contrast to non-human primates, better ethical acceptance. In this review, anatomic, biochemical, physiological, and morphologic aspects relevant to diabetes research will be compared between different animal species, that is, mouse, rat, rabbit, pig, and non-human primates. The value of the pig as a model organism for diabetes research will be highlighted, and (dis)advantages of the currently available approaches for the generation of pig models exhibiting characteristics of metabolic syndrome or type 2 diabetes mellitus will be discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

Yoga for Heart Failure: A Review and Future Research.

PubMed

Pullen, Paula R; Seffens, William S; Thompson, Walter R

2018-01-01

Complementary and alternative medicine is a rapidly growing area of biomedical inquiry. Yoga has emerged in the forefront of holistic medical care due to its long history of linking physical, mental, and spiritual well-being. Research in yoga therapy (YT) has associated improved cardiovascular and quality of life (QoL) outcomes for the special needs of heart failure (HF) patients. The aim of this study is to review yoga intervention studies on HF patients, discuss proposed mechanisms, and examine yoga's effect on physiological systems that have potential benefits for HF patients. Second, to recommend future research directions to find the most effective delivery methods of yoga to medically stable HF patients. The authors conducted a systematic review of the medical literature for RCTs involving HF patients as participants in yoga interventions and for studies utilizing mechanistic theories of stretch and new technologies. We examined physical intensity, mechanistic theories, and the use of the latest technologies. Based on the review, there is a need to further explore yoga mechanisms and research options for the delivery of YT. Software apps as exergames developed for use at home and community activity centers may minimize health disparities and increase QoL for HF patients.

Driving forces of biomedical science education and research in state-of-the arts academic medical centres: the United States as example.

PubMed

John, T A

2011-06-01

Basic science departments in academic medical centres are influenced by changes that are commonly directed at medical education and financial gain. Some of such changes may have been detrimental to or may have enhanced basic science education. They may have determined basic science research focus or basic science research methods. However, there is lack of research on the educational process in the basic sciences including training of PhD's while there is ample research on medical education pertaining to training of medical doctors. The author here identifies, from university websites and available literature, some forces that have driven teaching and research focus and methods in state-of-the-arts academic medical centres in recent times with a view of seeing through their possible influences on basic science education and research, using the United States of America as an example. The "forces" are: Changes in medical schools; Medical educational philosophies: problem based learning, evidence based medicine, cyberlearning and self-directed learning; Shifting impressions of the value of basic sciences in medical schools; Research trends in Basic Sciences: role of antivivisectionists, alternative experimentations, explosion of molecular and cell biology; Technological advancements; Commercialization of research; and Funding agencies. The author encourages African leaders in academia to pay attention to such forces as the leadership seeks to raise African Universities as centres of knowledge that have a major role in acquiring, preserving, imparting, and utilizing knowledge.

Basic science research in urology training.

PubMed

Eberli, D; Atala, A

2009-04-01

The role of basic science exposure during urology training is a timely topic that is relevant to urologic health and to the training of new physician scientists. Today, researchers are needed for the advancement of this specialty, and involvement in basic research will foster understanding of basic scientific concepts and the development of critical thinking skills, which will, in turn, improve clinical performance. If research education is not included in urology training, future urologists may not be as likely to contribute to scientific discoveries.Currently, only a minority of urologists in training are currently exposed to significant research experience. In addition, the number of physician-scientists in urology has been decreasing over the last two decades, as fewer physicians are willing to undertake a career in academics and perform basic research. However, to ensure that the field of urology is driving forward and bringing novel techniques to patients, it is clear that more research-trained urologists are needed. In this article we will analyse the current status of basic research in urology training and discuss the importance of and obstacles to successful addition of research into the medical training curricula. Further, we will highlight different opportunities for trainees to obtain significant research exposure in urology.

32 CFR Appendix A to Part 272 - Principles for the Conduct and Support of Basic Research

Code of Federal Regulations, 2011 CFR

2011-07-01

... those agencies' investments as appropriate. 5. Merit review is used to select basic research projects... Research A Appendix A to Part 272 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) MISCELLANEOUS ADMINISTRATION AND SUPPORT OF BASIC RESEARCH BY THE...

Research-Based Reading Instruction in an Adult Basic Education Program

ERIC Educational Resources Information Center

Perin, Dolores; Greenberg, Daphne

2007-01-01

There is a growing emphasis in adult basic education on research-based reading instruction. Using Kruidenier's (2002) framework of principles and trends, we describe research-based techniques found during a visit to an adult basic education program. We also describe how the program moved to research-based instruction, and the factors that seem…

High-Potential Electrocatalytic O2 Reduction with Nitroxyl / NOx Mediators: Implications for Fuel Cells and Aerobic Oxidation Catalysis

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

Gerken, James B.; Stahl, Shannon S.

2015-07-15

Efficient reduction of O2 to water is a central challenge in energy conversion and aerobic oxidation catalysis. In the present study, we investigate the electrochemical reduction of O2 with soluble organic nitroxyl and nitrogen oxide (NOx) mediators. When used alone, neither organic nitroxyls, such as TEMPO (2,2,6,6-tetramethyl-1-piperidinyl-N-oxyl), nor NOx species, such as sodium nitrite, are effective mediators of electrochemical O2 reduction. The combination of nitroxyl/NOx species, however, mediates sustained O2 reduction at electrochemical potentials of 0.19–0.33 V (vs. Fc/Fc+) in acetonitrile containing trifluoroacetic acid. Mechanistic analysis of the coupled redox reactions supports a process in which the nitrogen oxide catalystmore » drives aerobic oxidation of a nitroxyl mediator to an oxoammonium species, which then is reduced back to the nitroxyl at the cathode. The electrolysis potential is dictated by the oxoammonium/nitroxyl reduction potential. The high potentials observed with this ORR system benefit from the mechanism-based specificity for four-electron reduction of oxygen to water mediated by NOx species, together with kinetically efficient reduction of oxidized NOx species by TEMPO and other organic nitroxyls. This research was supported as part of the Center for Molecular Electrocatalysis, an Energy Frontier Research Center, funded by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences.« less

A complex systems science perspective for whole systems of complementary and alternative medicine research.

PubMed

Koithan, Mary; Bell, Iris R; Niemeyer, Kathryn; Pincus, David

2012-01-01

Whole systems complementary and alternative medicine (WS-CAM) approaches share a basic worldview that embraces interconnectedness; emergent, non-linear outcomes to treatment that include both local and global changes in the human condition; a contextual view of human beings that are inseparable from and responsive to their environments; and interventions that are complex, synergistic, and interdependent. These fundamental beliefs and principles run counter to the assumptions of reductionism and conventional biomedical research methods that presuppose unidimensional simple causes and thus dismantle and individually test various interventions that comprise only single aspects of the WSCAM system. This paper will demonstrate the superior fit and practical advantages of using complex adaptive systems (CAS) and related modeling approaches to develop the scientific basis for WS-CAM. Furthermore, the details of these CAS models will be used to provide working hypotheses to explain clinical phenomena such as (a) persistence of changes for weeks to months between treatments and/or after cessation of treatment, (b) nonlocal and whole systems changes resulting from therapy, (c) Hering's law, and (d) healing crises. Finally, complex systems science will be used to offer an alternative perspective on cause, beyond the simple reductionism of mainstream mechanistic ontology and more parsimonious than the historical vitalism of WS-CAM. Rather, complex systems science provides a scientifically rigorous, yet essentially holistic ontological perspective with which to conceptualize and empirically explore the development of disease and illness experiences, as well as experiences of healing and wellness. Copyright © 2012 S. Karger AG, Basel.

Manipulating glucocorticoids in wild animals: basic and applied perspectives

PubMed Central

Sopinka, Natalie M.; Patterson, Lucy D.; Redfern, Julia C.; Pleizier, Naomi K.; Belanger, Cassia B.; Midwood, Jon D.; Crossin, Glenn T.; Cooke, Steven J.

2015-01-01

One of the most comprehensively studied responses to stressors in vertebrates is the endogenous production and regulation of glucocorticoids (GCs). Extensive laboratory research using experimental elevation of GCs in model species is instrumental in learning about stressor-induced physiological and behavioural mechanisms; however, such studies fail to inform our understanding of ecological and evolutionary processes in the wild. We reviewed emerging research that has used GC manipulations in wild vertebrates to assess GC-mediated effects on survival, physiology, behaviour, reproduction and offspring quality. Within and across taxa, exogenous manipulation of GCs increased, decreased or had no effect on traits examined in the reviewed studies. The notable diversity in responses to GC manipulation could be associated with variation in experimental methods, inherent differences among species, morphs, sexes and age classes, and the ecological conditions in which responses were measured. In their current form, results from experimental studies may be applied to animal conservation on a case-by-case basis in contexts such as threshold-based management. We discuss ways to integrate mechanistic explanations for changes in animal abundance in altered environments with functional applications that inform conservation practitioners of which species and traits may be most responsive to environmental change or human disturbance. Experimental GC manipulation holds promise for determining mechanisms underlying fitness impairment and population declines. Future work in this area should examine multiple life-history traits, with consideration of individual variation and, most importantly, validation of GC manipulations within naturally occurring and physiologically relevant ranges. PMID:27293716

Interactions of dendrimers with biological drug targets: reality or mystery - a gap in drug delivery and development research.

PubMed

Ahmed, Shaimaa; Vepuri, Suresh B; Kalhapure, Rahul S; Govender, Thirumala

2016-07-21

Dendrimers have emerged as novel and efficient materials that can be used as therapeutic agents/drugs or as drug delivery carriers to enhance therapeutic outcomes. Molecular dendrimer interactions are central to their applications and realising their potential. The molecular interactions of dendrimers with drugs or other materials in drug delivery systems or drug conjugates have been extensively reported in the literature. However, despite the growing application of dendrimers as biologically active materials, research focusing on the mechanistic analysis of dendrimer interactions with therapeutic biological targets is currently lacking in the literature. This comprehensive review on dendrimers over the last 15 years therefore attempts to identify the reasons behind the apparent lack of dendrimer-receptor research and proposes approaches to address this issue. The structure, hierarchy and applications of dendrimers are briefly highlighted, followed by a review of their various applications, specifically as biologically active materials, with a focus on their interactions at the target site. It concludes with a technical guide to assist researchers on how to employ various molecular modelling and computational approaches for research on dendrimer interactions with biological targets at a molecular level. This review highlights the impact of a mechanistic analysis of dendrimer interactions on a molecular level, serves to guide and optimise their discovery as medicinal agents, and hopes to stimulate multidisciplinary research between scientific, experimental and molecular modelling research teams.

Characterization of Wisconsin mixture low temperature properties for the AASHTO mechanistic-empirical pavement design guide.

DOT National Transportation Integrated Search

2011-12-01

This research evaluated the low temperature creep compliance and tensile strength properties of Wisconsin mixtures. : Creep compliance and tensile strength data were collected for 16 Wisconsin mixtures representing commonly used : aggregate sources a...

The World Hypotheses: Implications for Intercultural Communication Research.

ERIC Educational Resources Information Center

Ting-Toomey, Stella

The "sense making" process structures humans' categorization, perceptual, and expressive processes. These "sense making" references are ultimately derived from four distinct "root metaphors": mechanism or mechanistic thinking (machine), formism or formistic thinking (similarity), organicism or organistic thinking (organic process), and…

Mechanistic-Empirical Pavement Design Guide Flexible Pavement Performance Prediction Models Volume II Reference Manual

DOT National Transportation Integrated Search

2007-08-01

The objective of this research study was to develop performance characteristics or variables (e.g., ride quality, rutting, : fatigue cracking, transverse cracking) of flexible pavements in Montana, and to use these characteristics in the : implementa...

Research notes : measuring the strain of the road.

DOT National Transportation Integrated Search

2005-09-01

This study will monitor the pavement structure to investigate if the assumptions used in a mechanistic-empirical design analysis are valid, or if adjustments are needed. The study will be assessing the reaction of the pavement structure to traffic lo...

Structural and mechanistic insights into phospholipid transfer by Ups1–Mdm35 in mitochondria

PubMed Central

Watanabe, Yasunori; Tamura, Yasushi; Kawano, Shin; Endo, Toshiya

2015-01-01

Eukaryotic cells are compartmentalized into membrane-bounded organelles whose functions rely on lipid trafficking to achieve membrane-specific compositions of lipids. Here we focused on the Ups1–Mdm35 system, which mediates phosphatidic acid (PA) transfer between the outer and inner mitochondrial membranes, and determined the X-ray structures of Mdm35 and Ups1–Mdm35 with and without PA. The Ups1–Mdm35 complex constitutes a single domain that has a deep pocket and flexible Ω-loop lid. Structure-based mutational analyses revealed that a basic residue at the pocket bottom and the Ω-loop lid are important for PA extraction from the membrane following Ups1 binding. Ups1 binding to the membrane is enhanced by the dissociation of Mdm35. We also show that basic residues around the pocket entrance are important for Ups1 binding to the membrane and PA extraction. These results provide a structural basis for understanding the mechanism of PA transfer between mitochondrial membranes. PMID:26235513

Overview of the Muscle Cytoskeleton

PubMed Central

Henderson, Christine A.; Gomez, Christopher G.; Novak, Stefanie M.; Mi-Mi, Lei; Gregorio, Carol C.

2018-01-01

Cardiac and skeletal striated muscles are intricately designed machines responsible for muscle contraction. Coordination of the basic contractile unit, the sarcomere, and the complex cytoskeletal networks are critical for contractile activity. The sarcomere is comprised of precisely organized individual filament systems that include thin (actin), thick (myosin), titin, and nebulin. Connecting the sarcomere to other organelles (e.g., mitochondria and nucleus) and serving as the scaffold to maintain cellular integrity are the intermediate filaments. The costamere, on the other hand, tethers the sarcomere to the cell membrane. Unique structures like the intercalated disc in cardiac muscle and the myotendinous junction in skeletal muscle help synchronize and transmit force. Intense investigation has been done on many of the proteins that make up these cytoskeletal assemblies. Yet the details of their function and how they interconnect have just started to be elucidated. A vast number of human myopathies are contributed to mutations in muscle proteins; thus understanding their basic function provides a mechanistic understanding of muscle disorders. In this review, we highlight the components of striated muscle with respect to their interactions, signaling pathways, functions, and connections to disease. PMID:28640448

Homogeneously Catalyzed Electroreduction of Carbon Dioxide-Methods, Mechanisms, and Catalysts.

PubMed

Francke, Robert; Schille, Benjamin; Roemelt, Michael

2018-05-09

The utilization of CO 2 via electrochemical reduction constitutes a promising approach toward production of value-added chemicals or fuels using intermittent renewable energy sources. For this purpose, molecular electrocatalysts are frequently studied and the recent progress both in tuning of the catalytic properties and in mechanistic understanding is truly remarkable. While in earlier years research efforts were focused on complexes with rare metal centers such as Re, Ru, and Pd, the focus has recently shifted toward earth-abundant transition metals such as Mn, Fe, Co, and Ni. By application of appropriate ligands, these metals have been rendered more than competitive for CO 2 reduction compared to the heavier homologues. In addition, the important roles of the second and outer coordination spheres in the catalytic processes have become apparent, and metal-ligand cooperativity has recently become a well-established tool for further tuning of the catalytic behavior. Surprising advances have also been made with very simple organocatalysts, although the mechanisms behind their reactivity are not yet entirely understood. Herein, the developments of the last three decades in electrocatalytic CO 2 reduction with homogeneous catalysts are reviewed. A discussion of the underlying mechanistic principles is included along with a treatment of the experimental and computational techniques for mechanistic studies and catalyst benchmarking. Important catalyst families are discussed in detail with regard to mechanistic aspects, and recent advances in the field are highlighted.

What is Basic Research? Insights from Historical Semantics.

PubMed

Schauz, Désirée

2014-01-01

For some years now, the concept of basic research has been under attack. Yet although the significance of the concept is in doubt, basic research continues to be used as an analytical category in science studies. But what exactly is basic research? What is the difference between basic and applied research? This article seeks to answer these questions by applying historical semantics. I argue that the concept of basic research did not arise out of the tradition of pure science. On the contrary, this new concept emerged in the late 19th and early 20th centuries, a time when scientists were being confronted with rising expectations regarding the societal utility of science. Scientists used the concept in order to try to bridge the gap between the promise of utility and the uncertainty of scientific endeavour. Only after 1945, when United States science policy shaped the notion of basic research, did the concept revert to the older ideals of pure science. This revival of the purity discourse was caused by the specific historical situation in the US at that time: the need to reform federal research policy after the Second World War, the new dimension of ethical dilemmas in science and technology during the atomic era, and the tense political climate during the Cold War.

The quest for a mechanistic understanding of biodiversity–ecosystem services relationships

PubMed Central

Duncan, Clare; Thompson, Julian R.; Pettorelli, Nathalie

2015-01-01

Ecosystem services (ES) approaches to biodiversity conservation are currently high on the ecological research and policy agendas. However, despite a wealth of studies into biodiversity's role in maintaining ES (B–ES relationships) across landscapes, we still lack generalities in the nature and strengths of these linkages. Reasons for this are manifold, but can largely be attributed to (i) a lack of adherence to definitions and thus a confusion between final ES and the ecosystem functions (EFs) underpinning them, (ii) a focus on uninformative biodiversity indices and singular hypotheses and (iii) top-down analyses across large spatial scales and overlooking of context-dependency. The biodiversity–ecosystem functioning (B–EF) field provides an alternate context for examining biodiversity's mechanistic role in shaping ES, focusing on species' characteristics that may drive EFs via multiple mechanisms across contexts. Despite acknowledgements of a need for B–ES research to look towards underlying B–EF linkages, the connections between these areas of research remains weak. With this review, we pull together recent B–EF findings to identify key areas for future developments in B–ES research. We highlight a means by which B–ES research may begin to identify how and when multiple underlying B–EF relationships may scale to final ES delivery and trade-offs. PMID:26468240

The quest for a mechanistic understanding of biodiversity-ecosystem services relationships.

PubMed

Duncan, Clare; Thompson, Julian R; Pettorelli, Nathalie

2015-10-22

Ecosystem services (ES) approaches to biodiversity conservation are currently high on the ecological research and policy agendas. However, despite a wealth of studies into biodiversity's role in maintaining ES (B-ES relationships) across landscapes, we still lack generalities in the nature and strengths of these linkages. Reasons for this are manifold, but can largely be attributed to (i) a lack of adherence to definitions and thus a confusion between final ES and the ecosystem functions (EFs) underpinning them, (ii) a focus on uninformative biodiversity indices and singular hypotheses and (iii) top-down analyses across large spatial scales and overlooking of context-dependency. The biodiversity-ecosystem functioning (B-EF) field provides an alternate context for examining biodiversity's mechanistic role in shaping ES, focusing on species' characteristics that may drive EFs via multiple mechanisms across contexts. Despite acknowledgements of a need for B-ES research to look towards underlying B-EF linkages, the connections between these areas of research remains weak. With this review, we pull together recent B-EF findings to identify key areas for future developments in B-ES research. We highlight a means by which B-ES research may begin to identify how and when multiple underlying B-EF relationships may scale to final ES delivery and trade-offs. © 2015 The Author(s).

Editorial Commentary: A Model for Shoulder Rotator Cuff Repair and for Basic Science Investigations.

PubMed

Brand, Jefferson C

2018-04-01

"Breaking the fourth wall" is a theater convention where the narrator or character speaks directly to the audience. As an Assistant Editor-in-Chief, as I comment on a recent basic science study investigating rotator cuff repair, I break the fourth wall and articulate areas of basic science research excellence that align with the vision that we hold for our journal. Inclusion of a powerful video strengthens the submission. We prefer to publish clinical videos in our companion journal, Arthroscopy Techniques, and encourage basic science video submissions to Arthroscopy. Basic science research requires step-by-tedious-step analogous to climbing a mountain. Establishment of a murine rotator cuff repair model was rigorous and research intensive, biomechanically, radiographically, histologically, and genetically documented, a huge step toward the bone-to-tendon healing research summit. This research results in a model for both rotator cuff repair and the pinnacle of quality, basic science research. Copyright © 2018 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

Basic science research and education: a priority for training and capacity building in developing countries.

PubMed

Deckelbaum, Richard J; Ntambi, James M; Wolgemuth, Debra J

2011-09-01

This article provides evidence that basic science research and education should be key priorities for global health training, capacity building, and practice. Currently, there are tremendous gaps between strong science education and research in developed countries (the North) as compared to developing countries (the South). In addition, science research and education appear as low priorities in many developing countries. The need to stress basic science research beyond the typical investment of infectious disease basic service and research laboratories in developing areas is significant in terms of the benefits, not only to education, but also for economic strengthening and development of human resources. There are some indications that appreciation of basic science research education and training is increasing, but this still needs to be applied more rigorously and strengthened systematically in developing countries. Copyright © 2011 Elsevier Inc. All rights reserved.

From the Research Bench to the Teaching Laboratory: Gold Nanoparticle Layering

ERIC Educational Resources Information Center

Oliver-Hoyo, Maria; Gerber, Ralph W.

2007-01-01

The study presents an experimental approach, which is expected to be very useful for a better understanding of the synthetic, mechanistic and measurable properties of gold nanoparticle layering techniques. The experiment is found to serve numerous educational objectives as well.

Development of flexible pavement database for local calibration of MEPDG : volume 1.

DOT National Transportation Integrated Search

2011-06-01

The new mechanistic-empirical pavement design guide (MEPDG), based on the National Cooperative Highway : Research Program (NCHRP) study 1-37A, replaces the widely used but more empirical 1993 AASHTO Guide : for Design of Pavement Structures. The MEPD...

Informatics approaches in the Biological Characterization of Adverse Outcome Pathways

EPA Science Inventory

Adverse Outcome Pathways (AOPs) are a conceptual framework to characterize toxicity pathways by a series of mechanistic steps from a molecular initiating event to population outcomes. This framework helps to direct risk assessment research, for example by aiding in computational ...

A vision for modernizing environmental risk assessment

EPA Science Inventory

In 2007, the US National Research Council (NRC) published a Vision and Strategy for [human health] Toxicity Testing in the 21st century. Central to the vision was increased reliance on high throughput in vitro testing and predictive approaches based on mechanistic understanding o...

REPRODUCTIVE AND DEVELOPMENTAL PHARMACOKINETIC AND MECHANISTIC RESEARCH

EPA Science Inventory

In 1993, an expert panel convened by the EPA and the International Life Sciences Institute (ILSI) decided that: 1) screening studies should be implemented to fill critical data gaps; 2) fertility assessments should be enhanced; and 3) biomarkers of effect should be developed. Mor...

Landscape approaches to stream fish mechanistic aspects of habitat selection and behavioral ecology. Introduction and commentary

Treesearch

Pedro A. Rincón; N.F. Hughes; Gary D. Grossman

2000-01-01

The Ecology of Stream Fish Symposium (Lobón-Cerviá & Mortensen 1999) was structured as a number sessions destined to showcase the latest developments and prospects for the future in areas of research that, in the opinion of the meeting's Steering Committee and organizers, held particular interest. Convinced of the benefits of research that integrates across...

Descriptive vs mechanistic scientific approach to study wound healing and its inhibition: Is there a value of translational research involving human subjects?

PubMed

Pastar, Irena; Wong, Lulu L; Egger, Andjela N; Tomic-Canic, Marjana

2018-05-01

The clinical field of wound healing is challenged by numerous hurdles. Not only are wound-healing disorders complex and multifactorial, but the corresponding patient population is diverse, often elderly and burdened by multiple comorbidities such as diabetes and cardiovascular disease. The care of such patients requires a dedicated, multidisciplinary team of physicians, surgeons, nurses and scientists. In spite of the critical clinical need, it has been over 15 years since a treatment received approval for efficacy by the FDA in the United States. Among the reasons contributing to this lack of effective new treatment modalities is poor understanding of mechanisms that inhibit healing in patients. Additionally, preclinical models do not fully reflect the disease complexity of the human condition, which brings us to a paradox: if we are to use a "mechanistic" approach that favours animal models, we can dissect specific mechanisms using advanced genetic, molecular and cellular technologies, with the caveat that it may not be directly applicable to patients. Traditionally, scientific review panels, for either grant funding or manuscript publication purposes, favour such "mechanistic" approaches whereby human tissue analyses, deemed "descriptive" science, are characterized as a "fishing expedition" and are considered "fatally flawed." However, more emerging evidence supports the notion that the use of human samples provides significant new knowledge regarding the molecular and cellular mechanisms that control wound healing and contribute to inhibition of the process in patients. Here, we discuss the advances, benefits and challenges of translational research in wound healing focusing on human subject research. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

In-air and pressurized water reactor environment fatigue experiments of 316 stainless steel to study the effect of environment on cyclic hardening

NASA Astrophysics Data System (ADS)

Mohanty, Subhasish; Soppet, William K.; Majumdar, Saurindranath; Natesan, Krishnamurti

2016-05-01

Argonne National Laboratory (ANL), under the sponsorship of Department of Energy's Light Water Reactor Sustainability (LWRS) program, is trying to develop a mechanistic approach for more accurate life estimation of LWR components. In this context, ANL has conducted many fatigue experiments under different test and environment conditions on type 316 stainless steel (316 SS) material which is widely used in the US reactors. Contrary to the conventional S ∼ N curve based empirical fatigue life estimation approach, the aim of the present DOE sponsored work is to develop an understanding of the material ageing issues more mechanistically (e.g. time dependent hardening and softening) under different test and environmental conditions. Better mechanistic understanding will help develop computer-based advanced modeling tools to better extrapolate stress-strain evolution of reactor components under multi-axial stress states and hence help predict their fatigue life more accurately. Mechanics-based modeling of fatigue such as by using finite element (FE) tools requires the time/cycle dependent material hardening properties. Presently such time-dependent material hardening properties are hardly available in fatigue modeling literature even under in-air conditions. Getting those material properties under PWR environment, are even harder. Through this work we made preliminary attempt to generate time/cycle dependent stress-strain data both under in-air and PWR water conditions for further study such as for possible development of material models and constitutive relations for FE model implementation. Although, there are open-ended possibility to further improve the discussed test methods and related material estimation techniques we anticipate that the data presented in this paper will help the metal fatigue research community particularly, the researchers who are dealing with mechanistic modeling of metal fatigue such as using FE tools. In this paper the fatigue experiments under different test and environment conditions and related stress-strain results for 316 SS are discussed.

Biochar: from laboratory mechanisms through the greenhouse to field trials

NASA Astrophysics Data System (ADS)

Masiello, C. A.; Gao, X.; Dugan, B.; Silberg, J. J.; Zygourakis, K.; Alvarez, P. J. J.

2014-12-01

The biochar community is excellent at pointing to individual cases where biochar amendment has changed soil properties, with some studies showing significant improvements in crop yields, reduction in nutrient export, and remediation of pollutants. However, many studies exist which do not show improvements, and in some cases, studies clearly show detrimental outcomes. The next, crucial step in biochar science and engineering research will be to develop a process-based understanding of how biochar acts to improve soil properties. In particular, we need a better mechanistic understanding of how biochar sorbs and desorbs contaminants, how it interacts with soil water, and how it interacts with the soil microbial community. These mechanistic studies need to encompass processes that range from the nanometer to the kilometer scale. At the nanometer scale, we need a predictive model of how biochar will sorb and desorb hydrocarbons, nutrients, and toxic metals. At the micrometer scale we need models that explain biochar's effects on soil water, especially the plant-available fraction of soil water. The micrometer scale is also where mechanistic information is neeed about microbial processes. At the macroscale we need physical models to describe the landscape mobility of biochar, because biochar that washes away from fields can no longer provide crop benefits. To be most informative, biochar research should occur along a lab-greenhouse-field trial trajectory. Laboratory experiments should aim determine what mechanisms may act to control biochar-soil processes, and then greenhouse experiments can be used to test the significance of lab-derived mechanisms in short, highly replicated, controlled experiments. Once evidence of effect is determined from greenhouse experiments, field trials are merited. Field trials are the gold standard needed prior to full deployment, but results from field trials cannot be extrapolated to other field sites without the mechanistic backup provided by greenhouse and lab trials.

[Basic research in traumatology and its contribution to routine operation].

PubMed

Hausner, T; Redl, H

2017-02-01

Basic research in traumatology supports the clinical outcome of patients in trauma care and tries to find science-based solutions for clinical problems. Furthermore, institutions for basic research in traumatology usually offer training in different skills, such as how to write a scientific paper, or practice in microsurgery or intubation. Two examples of clinically significant research topics are presented.

The effectiveness of undergraduate researchers and the effect of undergraduate research on the student

NASA Astrophysics Data System (ADS)

Wray, Dwight D.

Despite wisdom's long and rich history our understanding of what is implied by the term remains quite vague. One hundred males and eighty-three females, aged 24 to 83 years, were asked to complete the Social Belief Paradigm Inventory, which is a measure of beliefs about the social world (Kramer, Kahlbaugh, & Goldston, 1992), and rate the degree to which thirty wise statements, phrases, and quotations reflect their conceptions of wisdom. When the sample was categorized by gender, age, and educational levels, males were found to be slightly more mechanistic than females, and equally dialectical. Dialectical thinking was found to be associated more with educational level than with age. A large proportion of dialectical thinkers possessed at least a baccalaureate degree. Overall, most young, middle-aged, and older adults were dominant in the dialectical worldview. The results of a MANOVA, which tested the between-subjects effects of each of the independent variables, age, gender, and educational level on the dependent variable, worldview; and each of the four statement types, revealed a statistically non-significant effect of age, gender, or educational level on worldview. However, there were significant findings with respect to the relationship between age and relativistic thinking, and age and mechanistic thinking. Relativistic thinkers tended to be the youngest of the participants, while mechanistic thinkers tended to be the oldest. Also, a significant negative relationship was found between absolute thinking (formistic and mechanistic) and educational attainment. Wisdom items dealing with life experience, self-knowledge, the acceptance of the inevitability of change, and of the uncertainties of life, were rated highest. Postformal (dialectical) and absolute (formistic and mechanistic) thinkers differed slightly in their conceptions of wisdom. Dialectical thinkers preferred items implying uncertainty with respect to reality; such as doubting the knowledge one holds, generativity, and active engagement in the development of wisdom. Absolute thinkers preferred items that implied certainty, such as holding a body knowledge, knowing eternal truths, and permanent ideals. The study also revealed that the older one is, the more likely he/she will define wisdom in terms of the acceptance of life and its limitations. This finding may bring forth the notion that wisdom is not universal in nature, but rather contextually-based. (Abstract shortened by UMI.)

Naturally occurring alkaline amino acids function as efficient catalysts on Knoevenagel condensation at physiological pH: a mechanistic elucidation.

PubMed

Li, Weina; Fedosov, Sergey; Tan, Tianwei; Xu, Xuebing; Guo, Zheng

2014-05-01

To maintain biological functions, thousands of different reactions take place in human body at physiological pH (7.0) and mild conditions, which is associated with health and disease. Therefore, to examine the catalytic function of the intrinsically occurring molecules, such as amino acids at neutral pH, is of fundamental interests. Natural basic α-amino acid of L-lysine, L-arginine, and L-histidine neutralized to physiological pH as salts were investigated for their ability to catalyze Knoevenagel condensation of benzaldehyde and ethyl cyanoacetate. Compared with their free base forms, although neutralized alkaline amino acid salts reduced the catalytic activity markedly, they were still capable to perform an efficient catalysis at physiological pH as porcine pancreatic lipase (PPL), one of the best enzymes that catalyze Knoevenagel condensation. In agreement with the fact that the three basic amino acids were well neutralized, stronger basic amino acid Arg and Lys showed more obvious variation in NH bend peak from the FTIR spectroscopy study. Study of ethanol/water system and quantitative kinetic analysis suggested that the microenvironment in the vicinity of amino acid salts and protonability/deprotonability of the amine moiety may determine their catalytic activity and mechanism. The kinetic study of best approximation suggested that the random binding might be the most probable catalytic mechanism for the neutralized alkaline amino acid salt-catalyzed Knoevenagel condensation.

The development of fuel performance models at the European institute for transuranium elements

NASA Astrophysics Data System (ADS)

Lassmann, K.; Ronchi, C.; Small, G. J.

1989-07-01

The design and operational performance of fuel rods for nuclear power stations has been the subject of detailed experimental research for over thirty years. In the last two decades the continuous demands for greater economy in conjunction with more stringent safety criteria have led to an increasing reliance on computer simulations. Conditions within a fuel rod must be calculated both for normal operation and for proposed reactor faults. It has thus been necessary to build up a reliable, theoretical understanding of the intricate physical, mechanical and chemical processes occurring under a wide range of conditions to obtain a quantitative insight into the behaviour of the fuel. A prime requirement, which has also proved to be the most taxing, is to predict the conditions under which failure of the cladding might occur, particularly in fuel nearing the end of its useful life. In this paper the general requirements of a fuel performance code are discussed briefly and an account is given of the basic concepts of code construction. An overview is then given of recent progress at the European Institute for Transuranium Elements in the development of a fuel rod performance code for general application and of more detailed mechanistic models for fission product behaviour.

Diagnosis and treatment of chronic cough in China: an insight into the status quo

PubMed Central

2012-01-01

Chronic cough is a very common complaint in clinics throughout China. Clinical and basic science research on chronic cough started late, but in recent years the effort has yielded promising findings regarding the etiological diagnosis, treatment and pathogenesis. We found that inflammation in nonasthmatic eosinophilic bronchitis has some similarities to cough variant asthma but also a number of distinct differences. Recent evidence has also suggested a mechanistic link between airway neurogenic inflammation and and gastroesophageal reflux cough (GERC). Cough-related animal models have been developed, including models for esophageal reflux, nonasthmatic eosinophilic bronchitis and allergic rhinitis. Normal reference values for differential cell counts in induced sputum, cough sensitivity and esophageal 24-h pH monitoring in Chinese healthy subjects have been established. By using a modified algorithm for the etiological diagnosis of chronic cough, the causes of chronic cough have been investigated across a number of cities in China. The most common causes of chronic cough are cough variant asthma, eosinophilic bronchitis, upper airway cough symptoms, atopic cough and GERC, however, there are some regional variations. The Chinese National Guidelines on Diagnosis and Management of Chronic Cough were drafted in 2005, updated in 2009, and have been widely publicized and disseminated through many channels since their publication. PMID:22839528

The role of local interaction mechanics in fiber optic smart structures

NASA Astrophysics Data System (ADS)

Sirkis, J. S.; Dasgupta, A.

1993-04-01

The concept of using 'smart' composite materials/structures with built-in self-diagnostic capabilities for health monitoring involves embedding discrete and/or distributed sensory networks in the host composite material, along with a central and/or distributed artificial intelligence capability for signal processing, data collection, interpretation and diagnostic evaluations. This article concentrates on the sensory functions in 'smart' structure applications and concentrates in particular on optical fiber sensors. Specifically, we present an overview of recent research dealing with the basic mechanics of local interactions between the embedded optical fiber sensors and the surrounding host composite. The term 'local' is defined by length scales on the order of several optical fiber diameters. We examine some generic issues, such as the 'calibration' and 'obtrusivity' of the sensor, and the inherent damage caused by the sensor inclusions to the surrounding host and vice-versa under internal and/or external applied loads. Analytical, numerical and experimental results are presented regarding the influence of local strain concentrations caused by the sensory inclusions on sensor and host performance. The important issues examined are the local mechanistic effects of optical fiber coatings on the behavior of the sensor and the host, and mechanical survivability of optical fibers experiencing quasi-static and time-varying thermomechanical loading.

Phylogenetic profiles reveal structural/functional determinants of TRPC3 signal-sensing antennae

PubMed Central

Ko, Kyung Dae; Bhardwaj, Gaurav; Hong, Yoojin; Chang, Gue Su; Kiselyov, Kirill

2009-01-01

Biochemical assessment of channel structure/function is incredibly challenging. Developing computational tools that provide these data would enable translational research, accelerating mechanistic experimentation for the bench scientist studying ion channels. Starting with the premise that protein sequence encodes information about structure, function and evolution (SF&E), we developed a unified framework for inferring SF&E from sequence information using a knowledge-based approach. The Gestalt Domain Detection Algorithm-Basic Local Alignment Tool (GDDA-BLAST) provides phylogenetic profiles that can model, ab initio, SF&E relationships of biological sequences at the whole protein, single domain and single-amino acid level.1,2 In our recent paper,4 we have applied GDDA-BLAST analysis to study canonical TRP (TRPC) channels1 and empirically validated predicted lipid-binding and trafficking activities contained within the TRPC3 TRP_2 domain of unknown function. Overall, our in silico, in vitro, and in vivo experiments support a model in which TRPC3 has signal-sensing antennae which are adorned with lipid-binding, trafficking and calmodulin regulatory domains. In this Addendum, we correlate our functional domain analysis with the cryo-EM structure of TRPC3.3 In addition, we synthesize recent studies with our new findings to provide a refined model on the mechanism(s) of TRPC3 activation/deactivation. PMID:19704910

R and D Evaluation Workshop report, U.S. Department of Energy, Office of Energy Research, September 7--8, 1995

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

Jordan, G.

1995-10-30

The objective of the workshop was to promote discussions between experts and research managers on developing approaches for assessing the impact of DOE`s basic energy research upon the energy mission, applied research, technology transfer, the economy, and society. The purpose of this impact assessment is to demonstrate results and improve ER research programs in this era when basic research is expected to meet changing national economic and social goals. The questions addressed were: (1) By what criteria and metrics does Energy Research measure performance and evaluate its impact on the DOE mission and society while maintaining an environment that fostersmore » basic research? (2) What combination of evaluation methods best applies to assessing the performance and impact of OBES basic research? The focus will be upon the following methods: Case studies, User surveys, Citation analysis, TRACES approach, Return on DOE investment (ROI)/Econometrics, and Expert panels. (3) What combination of methods and specific rules of thumb can be applied to capture impacts along the spectrum from basic research to products and societal impacts?« less

Regulation of autophagy by amino acid availability in S. cerevisiae and mammalian cells.

PubMed

Abeliovich, Hagai

2015-10-01

Autophagy is a catabolic membrane-trafficking process that occurs in all eukaryotic organisms analyzed to date. The study of autophagy has exploded over the last decade or so, branching into numerous aspects of cellular and organismal physiology. From basic functions in starvation and quality control, autophagy has expanded into innate immunity, aging, neurological diseases, redox regulation, and ciliogenesis, to name a few roles. In the present review, I would like to narrow the discussion to the more classical roles of autophagy in supporting viability under nutrient limitation. My aim is to provide a semblance of a historical overview, together with a concise, and perhaps subjective, mechanistic and functional analysis of the central questions in the autophagy field.

Development and validation of deterioration models for concrete bridge decks - phase 2 : mechanics-based degradation models.

DOT National Transportation Integrated Search

2013-06-01

This report summarizes a research project aimed at developing degradation models for bridge decks in the state of Michigan based on durability mechanics. A probabilistic framework to implement local-level mechanistic-based models for predicting the c...

Adverse Outcome Pathways: A Conceptual Framework to Support Ecotoxicology Research and Risk Assessment

EPA Science Inventory

Ecological risk assessors face increasing demands to assess more chemicals, with greater speed and accuracy, and to do so using fewer resources and experimental animals. New approaches in biological and computational sciences are being developed to generate mechanistic informatio...

Adverse Outcome Pathways: A Conceptual Framework to Support Ecotoxicology Research and Risk Assessment

EPA Science Inventory

Ecological risk assessors face increasing demands to assess more chemicals, with greater speed and accuracy, and to do so using fewer resources and experimental animals. New approaches in biological and computational sciences may be able to generate mechanistic information that ...

Epigenetic Contributions to Cognitive Aging: Disentangling Mindspan and Lifespan

ERIC Educational Resources Information Center

Spiegel, Amy M.; Sewal, Angila S.; Rapp, Peter R.

2014-01-01

Epigenetic modifications of chromatin structure provide a mechanistic interface for gene-environment interactions that impact the individualization of health trajectories across the lifespan. A growing body of research indicates that dysfunctional epigenetic regulation contributes to poor cognitive outcomes among aged populations. Here we review…

MECHANISTIC STUDIES ON THE VITAMIN B12-CATALYZED DECHLORINATION OF CHLORINATED ALKENES. (U915562)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

A Systems Biology Approach to Toxicology Research with Small Fish Models

EPA Science Inventory

Increasing use of mechanistically-based molecular and biochemical endpoints and in vitro assays is being advocated as a more efficient and cost-effective approach for generating chemical hazard data. However, development of effective assays and application of the resulting data i...

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.

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

Detailed qualitative dynamic knowledge representation using a BioNetGen model of TLR-4 signaling and preconditioning.

PubMed

An, Gary C; Faeder, James R

2009-01-01

Intracellular signaling/synthetic pathways are being increasingly extensively characterized. However, while these pathways can be displayed in static diagrams, in reality they exist with a degree of dynamic complexity that is responsible for heterogeneous cellular behavior. Multiple parallel pathways exist and interact concurrently, limiting the ability to integrate the various identified mechanisms into a cohesive whole. Computational methods have been suggested as a means of concatenating this knowledge to aid in the understanding of overall system dynamics. Since the eventual goal of biomedical research is the identification and development of therapeutic modalities, computational representation must have sufficient detail to facilitate this 'engineering' process. Adding to the challenge, this type of representation must occur in a perpetual state of incomplete knowledge. We present a modeling approach to address this challenge that is both detailed and qualitative. This approach is termed 'dynamic knowledge representation,' and is intended to be an integrated component of the iterative cycle of scientific discovery. BioNetGen (BNG), a software platform for modeling intracellular signaling pathways, was used to model the toll-like receptor 4 (TLR-4) signal transduction cascade. The informational basis of the model was a series of reference papers on modulation of (TLR-4) signaling, and some specific primary research papers to aid in the characterization of specific mechanistic steps in the pathway. This model was detailed with respect to the components of the pathway represented, but qualitative with respect to the specific reaction coefficients utilized to execute the reactions. Responsiveness to simulated lipopolysaccharide (LPS) administration was measured by tumor necrosis factor (TNF) production. Simulation runs included evaluation of initial dose-dependent response to LPS administration at 10, 100, 1000 and 10,000, and a subsequent examination of preconditioning behavior with increasing LPS at 10, 100, 1000 and 10,000 and a secondary dose of LPS at 10,000 administered at approximately 27h of simulated time. Simulations of 'knockout' versions of the model allowed further examination of the interactions within the signaling cascade. The model demonstrated a dose-dependent TNF response curve to increasing stimulus by LPS. Preconditioning simulations demonstrated a similar dose-dependency of preconditioning doses leading to attenuation of response to subsequent LPS challenge - a 'tolerance' dynamic. These responses match dynamics reported in the literature. Furthermore, the simulated 'knockout' results suggested the existence and need for dual negative feedback control mechanisms, represented by the zinc ring-finger protein A20 and inhibitor kappa B proteins (IkappaB), in order for both effective attenuation of the initial stimulus signal and subsequent preconditioned 'tolerant' behavior. We present an example of detailed, qualitative dynamic knowledge representation using the TLR-4 signaling pathway, its control mechanisms and overall behavior with respect to preconditioning. The intent of this approach is to demonstrate a method of translating the extensive mechanistic knowledge being generated at the basic science level into an executable framework that can provide a means of 'conceptual model verification.' This allows for both the 'checking' of the dynamic consequences of a mechanistic hypothesis and the creation of a modular component of an overall model directed at the engineering goal of biomedical research. It is hoped that this paper will increase the use of knowledge representation and communication in this fashion, and facilitate the concatenation and integration of community-wide knowledge.

48 CFR 35.001 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-10-01

... CONTRACTING RESEARCH AND DEVELOPMENT CONTRACTING 35.001 Definitions. Applied research means the effort that (a) normally follows basic research, but may not be severable from the related basic research; (b) attempts to...

Placental growth factor and its potential role in diabetic retinopathy and other ocular neovascular diseases.

PubMed

Nguyen, Quan Dong; De Falco, Sandro; Behar-Cohen, Francine; Lam, Wai-Ching; Li, Xuri; Reichhart, Nadine; Ricci, Federico; Pluim, Jennifer; Li, William W

2018-02-01

The role of vascular endothelial growth factor (VEGF), including in retinal vascular diseases, has been well studied, and pharmacological blockade of VEGF is the gold standard of treatment for neovascular age-related macular degeneration, retinal vein occlusion and diabetic macular oedema. Placental growth factor (PGF, previously known as PlGF), a homologue of VEGF, is a multifunctional peptide associated with angiogenesis-dependent pathologies in the eye and non-ocular conditions. Animal studies using genetic modification and pharmacological treatment have demonstrated a mechanistic role for PGF in pathological angiogenesis. Inhibition decreases neovascularization and microvascular abnormalities across different models, including oxygen-induced retinopathy, laser-induced choroidal neovascularization and in diabetic mice exhibiting retinopathies. High levels of PGF have been found in the vitreous of patients with diabetic retinopathy. Despite these strong animal data, the exact role of PGF in pathological angiogenesis in retinal vascular diseases remains to be defined, and the benefits of PGF-specific inhibition in humans with retinal neovascular diseases and macular oedema remain controversial. Comparative effectiveness research studies in patients with diabetic retinal disease have shown that treatment that inhibits both VEGF and PGF may provide superior outcomes in certain patients compared with treatment that inhibits only VEGF. This review summarizes current knowledge of PGF, including its relationship to VEGF and its role in pathological angiogenesis in retinal diseases, and identifies some key unanswered questions about PGF that can serve as a pathway for future basic, translational and clinical research. © 2016 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation and European Association for Vision & Eye Research.

Assessment of Department of Defense Basic Research

DTIC Science & Technology

2005-01-01

Sciences, the National Academy of Engineering, the Institute of Medicine, and the National Research Council: • Download hundreds of free books in PDF...with our innovative research tools Thank you for downloading this free PDF. If you have comments, questions or just want more information... downloaded from: http://www.nap.edu/catalog/11177.html Assessment of Department of Defense Basic Research Committee on Department of Defense Basic

America's Basic Research: Prosperity Through Discovery. A Policy Statement by the Research and Policy Committee of the Committee for Economic Development

ERIC Educational Resources Information Center

Committee for Economic Development, 1998

1998-01-01

This policy statement looks at America's basic research enterprise and lays out the processes and systematic reforms needed to meet emerging risks to the outcomes from investments in basic research. The Committee for Economic Development (CED) undertook this project in the belief that significant progress with many of society's problems and new…

Policies to increase the social value of science and the scientist satisfaction. An exploratory survey among Harvard bioscientists.

PubMed Central

Ballabeni, Andrea; Boggio, Andrea; Hemenway, David

2014-01-01

Basic research in the biomedical field generates both knowledge that has a value per se regardless of its possible practical outcome and knowledge that has the potential to produce more practical benefits. Policies can increase the benefit potential to society of basic biomedical research by offering various kinds of incentives to basic researchers. In this paper we argue that soft incentives or “nudges” are particularly promising. However, to be well designed, these incentives must take into account the motivations, goals and views of the basic scientists. In the paper we present the results of an investigation that involved more than 300 scientists at Harvard Medical School and affiliated institutes. The results of this study suggest that some soft incentives could be valuable tools to increase the transformative value of fundamental investigations without affecting the spirit of the basic research and scientists’ work satisfaction. After discussing the findings, we discuss a few examples of nudges for basic researchers in the biomedical fields. PMID:24795807

Policies to increase the social value of science and the scientist satisfaction. An exploratory survey among Harvard bioscientists.

PubMed

Ballabeni, Andrea; Boggio, Andrea; Hemenway, David

2014-01-01

Basic research in the biomedical field generates both knowledge that has a value per se regardless of its possible practical outcome and knowledge that has the potential to produce more practical benefits. Policies can increase the benefit potential to society of basic biomedical research by offering various kinds of incentives to basic researchers. In this paper we argue that soft incentives or "nudges" are particularly promising. However, to be well designed, these incentives must take into account the motivations, goals and views of the basic scientists. In the paper we present the results of an investigation that involved more than 300 scientists at Harvard Medical School and affiliated institutes. The results of this study suggest that some soft incentives could be valuable tools to increase the transformative value of fundamental investigations without affecting the spirit of the basic research and scientists' work satisfaction. After discussing the findings, we discuss a few examples of nudges for basic researchers in the biomedical fields.

Human-itarian aid? Two forms of dehumanization and willingness to help after natural disasters.

PubMed

Andrighetto, Luca; Baldissarri, Cristina; Lattanzio, Sara; Loughnan, Steve; Volpato, Chiara

2014-09-01

The present research explores the distinct effects of animalistic and mechanistic dehumanization on willingness to help natural disaster victims. We examined Japanese and Haitians, two national groups recently struck by earthquakes. We showed that Italian participants differently dehumanized the two outgroups: Japanese were attributed low human nature (dehumanized as automata), whereas Haitians were attributed low human uniqueness (dehumanized as animal-like). Ninety participants were then randomly assigned to the Japanese or Haitian target group condition. Mediation analyses showed that animalistic dehumanization decreased willingness to help Haitians, whereas mechanistic dehumanization decreased willingness to help Japanese, even when controlling for attitudes. Importantly, reduced empathy explained the effects of both forms of dehumanization on intergroup helping. © 2014 The British Psychological Society.

Determining environmental causes of biological effects: the need for a mechanistic physiological dimension in conservation biology.

PubMed

Seebacher, Frank; Franklin, Craig E

2012-06-19

The emerging field of Conservation Physiology links environmental change and ecological success by the application of physiological theory, approaches and tools to elucidate and address conservation problems. Human activity has changed the natural environment to a point where the viability of many ecosystems is now under threat. There are already many descriptions of how changes in biological patterns are correlated with environmental changes. The next important step is to determine the causative relationship between environmental variability and biological systems. Physiology provides the mechanistic link between environmental change and ecological patterns. Physiological research, therefore, should be integrated into conservation to predict the biological consequences of human activity, and to identify those species or populations that are most vulnerable.

Information-seeking behavior of basic science researchers: implications for library services.

PubMed

Haines, Laura L; Light, Jeanene; O'Malley, Donna; Delwiche, Frances A

2010-01-01

This study examined the information-seeking behaviors of basic science researchers to inform the development of customized library services. A qualitative study using semi-structured interviews was conducted on a sample of basic science researchers employed at a university medical school. The basic science researchers used a variety of information resources ranging from popular Internet search engines to highly technical databases. They generally relied on basic keyword searching, using the simplest interface of a database or search engine. They were highly collegial, interacting primarily with coworkers in their laboratories and colleagues employed at other institutions. They made little use of traditional library services and instead performed many traditional library functions internally. Although the basic science researchers expressed a positive attitude toward the library, they did not view its resources or services as integral to their work. To maximize their use by researchers, library resources must be accessible via departmental websites. Use of library services may be increased by cultivating relationships with key departmental administrative personnel. Despite their self-sufficiency, subjects expressed a desire for centralized information about ongoing research on campus and shared resources, suggesting a role for the library in creating and managing an institutional repository.

Information-seeking behavior of basic science researchers: implications for library services

PubMed Central

Haines, Laura L.; Light, Jeanene; O'Malley, Donna; Delwiche, Frances A.

2010-01-01

Objectives: This study examined the information-seeking behaviors of basic science researchers to inform the development of customized library services. Methods: A qualitative study using semi-structured interviews was conducted on a sample of basic science researchers employed at a university medical school. Results: The basic science researchers used a variety of information resources ranging from popular Internet search engines to highly technical databases. They generally relied on basic keyword searching, using the simplest interface of a database or search engine. They were highly collegial, interacting primarily with coworkers in their laboratories and colleagues employed at other institutions. They made little use of traditional library services and instead performed many traditional library functions internally. Conclusions: Although the basic science researchers expressed a positive attitude toward the library, they did not view its resources or services as integral to their work. To maximize their use by researchers, library resources must be accessible via departmental websites. Use of library services may be increased by cultivating relationships with key departmental administrative personnel. Despite their self-sufficiency, subjects expressed a desire for centralized information about ongoing research on campus and shared resources, suggesting a role for the library in creating and managing an institutional repository. PMID:20098658

Protozoan Parasites of Bivalve Molluscs: Literature Follows Culture

PubMed Central

Fernández Robledo, José A.; Vasta, Gerardo R.; Record, Nicholas R.

2014-01-01

Bivalve molluscs are key components of the estuarine environments as contributors to the trophic chain, and as filter –feeders, for maintaining ecosystem integrity. Further, clams, oysters, and scallops are commercially exploited around the world both as traditional local shellfisheries, and as intensive or semi–intensive farming systems. During the past decades, populations of those species deemed of environmental or commercial interest have been subject to close monitoring given the realization that these can suffer significant decline, sometimes irreversible, due to overharvesting, environmental pollution, or disease. Protozoans of the genera Perkinsus, Haplosporidium, Marteilia, and Bonamia are currently recognized as major threats for natural and farmed bivalve populations. Since their identification, however, the variable publication rates of research studies addressing these parasitic diseases do not always appear to reflect their highly significant environmental and economic impact. Here we analyzed the peer– reviewed literature since the initial description of these parasites with the goal of identifying potential milestone discoveries or achievements that may have driven the intensity of the research in subsequent years, and significantly increased publication rates. Our analysis revealed that after initial description of the parasite as the etiological agent of a given disease, there is a time lag before a maximal number of yearly publications are reached. This has already taken place for most of them and has been followed by a decrease in publication rates over the last decade (20– to 30– year lifetime in the literature). Autocorrelation analyses, however, suggested that advances in parasite purification and culture methodologies positively drive publication rates, most likely because they usually lead to novel molecular tools and resources, promoting mechanistic studies. Understanding these trends should help researchers in prioritizing research efforts for these and other protozoan parasites, together with their development as model systems for further basic and translational research in parasitic diseases. PMID:24955977

Hydrogen and Fuel Cell Basics | Hydrogen and Fuel Cells | NREL

Science.gov Websites

Hydrogen and Fuel Cell Basics Hydrogen and Fuel Cell Basics NREL researchers are working to unlock the potential of hydrogen as a fuel and to advance fuel cell technologies for automobiles, equipment basics of NREL's hydrogen and fuel cell research and development. Fuel cell electric vehicles (FCEVs

Effects of temperature segregation on the volumetric and mechanistic properties of asphalt mixtures : research project capsule.

DOT National Transportation Integrated Search

2015-02-01

Material segregation in asphalt mixtures is a non-uniform distribution of coarse : and fine aggregates through its masses, i.e., concentration of coarse materials : in some area and fine materials in others. During construction, the coarse and : fine...

MECHANISTIC STEPS IN THE PRODUCTION OF PCDD AND PCDF DURING WASTE COMBUSTION

EPA Science Inventory

Research has shown that synthesis of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) during municipal waste combustion can proceed through a three step mechanism including 1) production of Cl₂ from a metal-catalyzed reaction of HCl a...

SUPERCRITICAL-PHASE ALKYLATION REACTION ON SOLID ACID CATALYSTS: MECHANISTIC STUDY AND CATALYST DEVELOPMENT. (R824729)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

Immunotoxicity testing: Implementation of mechanistic understanding, key pathways of toxicological concern and components of these pathways.

EPA Science Inventory

At present, several animal-based assays are used to assess immunotoxic effects such as immunosuppression and sensitization. Growing societal and ethical concerns, European legislation and current research demands by industry are driving animal-based toxicity testing towards new a...

Disrupting Improvised Explosive Device Terror Campaigns: Basic Research Opportunities

DTIC Science & Technology

2008-01-01

2008 2. REPORT TYPE 3. DATES COVERED 00-00-2008 to 00-00-2008 4. TITLE AND SUBTITLE Disrupting Improvised Explosive Device Terror Campaigns... Explosive Device Terror Campaigns: Basic Research Opportunities A WORKSHOP REPORT Committee on Defeating Improvised Explosive Devices...iv v COMMITTEE ON DEFEATING IMPROVISED EXPLOSIVE DEVICES: BASIC RESEARCH TO INTERRUPT THE IED DELIVERY CHAIN Chairperson

Can an Understanding of Basic Research Facilitate the Effectiveness of Practitioners? Reflections and Personal Perspectives

ERIC Educational Resources Information Center

Sidman, Murray

2011-01-01

I have written before about the importance of applied behavior analysis to basic researchers. That relationship is, however, reciprocal; it is also critical for practitioners to understand and even to participate in basic research. Although applied problems are rarely the same as those investigated in the laboratory, practitioners who understand…

Clinical studies of the Research Committee on Intractable Vasculitides, the Ministry of Health, Labour and Welfare of Japan.

PubMed

Makino, Hirofumi; Sada, Ken-Ei

2013-10-01

In Japan, the Research Committee on Intractable Vasculitides, supported by the Ministry of Health, Labour and Welfare, has been promoting basic and clinical research on vasculitis since 1972. The present Research Committee on Intractable Vasculitides comprises 4 subcommittees under the direction of a Principal Investigator: Basic and Pathological Research Subcommittee, Clinical Research Subcommittee of Small and Medium-sized Vessel Vasculitis, Clinical Research Subcommittee of Large-sized Vessel Vasculitis, and International Cooperation Research Subcommittee. Since 2008, 9 nationwide clinical studies for vasculitis have been conducted and 8 clinical and basic studies are in progress.

Reflections on scientific collaboration between basic researchers and clinicians.

PubMed

Muia, J; Casari, C

2016-10-01

Early career researchers face uncertainties with respect to their job prospects due to dwindling job markets, decreased availability of funding and undefined career paths. As basic researchers and clinicians tend to have different approaches to scientific problems, there are many advantages from successful collaborations between them. Here, we discuss how collaborations between basic and clinical scientists should be promoted early in their careers. To achieve this, researchers, both basic and clinical, must be proactive during their training and early stages of their careers. Mentors can further augment collaborative links in many ways. We suggest that universities and institutions might reassess their involvement in promoting collaborations between basic and clinical researchers. We hope that this paper will serve as a reminder of the importance of such collaborations, and provide the opportunity for all members of the scientific community to reflect on and ameliorate their own contributions. © 2016 International Society on Thrombosis and Haemostasis.

Environmentally induced epigenetic toxicity: potential public health concerns

PubMed Central

Marczylo, Emma L.; Jacobs, Miriam N.; Gant, Timothy W.

2016-01-01

Abstract Throughout our lives, epigenetic processes shape our development and enable us to adapt to a constantly changing environment. Identifying and understanding environmentally induced epigenetic change(s) that may lead to adverse outcomes is vital for protecting public health. This review, therefore, examines the present understanding of epigenetic mechanisms involved in the mammalian life cycle, evaluates the current evidence for environmentally induced epigenetic toxicity in human cohorts and rodent models and highlights the research considerations and implications of this emerging knowledge for public health and regulatory toxicology. Many hundreds of studies have investigated such toxicity, yet relatively few have demonstrated a mechanistic association among specific environmental exposures, epigenetic changes and adverse health outcomes in human epidemiological cohorts and/or rodent models. While this small body of evidence is largely composed of exploratory in vivo high-dose range studies, it does set a precedent for the existence of environmentally induced epigenetic toxicity. Consequently, there is worldwide recognition of this phenomenon, and discussion on how to both guide further scientific research towards a greater mechanistic understanding of environmentally induced epigenetic toxicity in humans, and translate relevant research outcomes into appropriate regulatory policies for effective public health protection. PMID:27278298

The cultural evolution of fertility decline

PubMed Central

Colleran, Heidi

2016-01-01

Cultural evolutionists have long been interested in the problem of why fertility declines as populations develop. By outlining plausible mechanistic links between individual decision-making, information flow in populations and competition between groups, models of cultural evolution offer a novel and powerful approach for integrating multiple levels of explanation of fertility transitions. However, only a modest number of models have been published. Their assumptions often differ from those in other evolutionary approaches to social behaviour, but their empirical predictions are often similar. Here I offer the first overview of cultural evolutionary research on demographic transition, critically compare it with approaches taken by other evolutionary researchers, identify gaps and overlaps, and highlight parallel debates in demography. I suggest that researchers divide their labour between three distinct phases of fertility decline—the origin, spread and maintenance of low fertility—each of which may be driven by different causal processes, at different scales, requiring different theoretical and empirical tools. A comparative, multi-level and mechanistic framework is essential for elucidating both the evolved aspects of our psychology that govern reproductive decision-making, and the social, ecological and cultural contingencies that precipitate and sustain fertility decline. PMID:27022079

Environmentally induced epigenetic toxicity: potential public health concerns.

PubMed

Marczylo, Emma L; Jacobs, Miriam N; Gant, Timothy W

2016-09-01

Throughout our lives, epigenetic processes shape our development and enable us to adapt to a constantly changing environment. Identifying and understanding environmentally induced epigenetic change(s) that may lead to adverse outcomes is vital for protecting public health. This review, therefore, examines the present understanding of epigenetic mechanisms involved in the mammalian life cycle, evaluates the current evidence for environmentally induced epigenetic toxicity in human cohorts and rodent models and highlights the research considerations and implications of this emerging knowledge for public health and regulatory toxicology. Many hundreds of studies have investigated such toxicity, yet relatively few have demonstrated a mechanistic association among specific environmental exposures, epigenetic changes and adverse health outcomes in human epidemiological cohorts and/or rodent models. While this small body of evidence is largely composed of exploratory in vivo high-dose range studies, it does set a precedent for the existence of environmentally induced epigenetic toxicity. Consequently, there is worldwide recognition of this phenomenon, and discussion on how to both guide further scientific research towards a greater mechanistic understanding of environmentally induced epigenetic toxicity in humans, and translate relevant research outcomes into appropriate regulatory policies for effective public health protection.

Engaging basic scientists in translational research: identifying opportunities, overcoming obstacles

PubMed Central

2012-01-01

This report is based on the Federation of American Societies for Experimental Biology’s symposium, “Engaging basic Scientists in Translational Research: Identifying Opportunities, Overcoming Obstacles,” held in Chevy Chase, MD, March 24–25, 2011. Meeting participants examined the benefits of engaging basic scientists in translational research, the challenges to their participation in translational research, and the roles that research institutions, funding organizations, professional societies, and scientific publishers can play to address these challenges. PMID:22500917

Inferring diffusion dynamics from FCS in heterogeneous nuclear environments.

PubMed

Tsekouras, Konstantinos; Siegel, Amanda P; Day, Richard N; Pressé, Steve

2015-07-07

Fluorescence correlation spectroscopy (FCS) is a noninvasive technique that probes the diffusion dynamics of proteins down to single-molecule sensitivity in living cells. Critical mechanistic insight is often drawn from FCS experiments by fitting the resulting time-intensity correlation function, G(t), to known diffusion models. When simple models fail, the complex diffusion dynamics of proteins within heterogeneous cellular environments can be fit to anomalous diffusion models with adjustable anomalous exponents. Here, we take a different approach. We use the maximum entropy method to show-first using synthetic data-that a model for proteins diffusing while stochastically binding/unbinding to various affinity sites in living cells gives rise to a G(t) that could otherwise be equally well fit using anomalous diffusion models. We explain the mechanistic insight derived from our method. In particular, using real FCS data, we describe how the effects of cell crowding and binding to affinity sites manifest themselves in the behavior of G(t). Our focus is on the diffusive behavior of an engineered protein in 1) the heterochromatin region of the cell's nucleus as well as 2) in the cell's cytoplasm and 3) in solution. The protein consists of the basic region-leucine zipper (BZip) domain of the CCAAT/enhancer-binding protein (C/EBP) fused to fluorescent proteins. Copyright © 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Increasing both the public health potential of basic research and the scientist satisfaction. An international survey of bio-scientists.

PubMed

Sorrentino, Carmen; Boggio, Andrea; Confalonieri, Stefano; Hemenway, David; Scita, Giorgio; Ballabeni, Andrea

2016-01-01

Basic scientific research generates knowledge that has intrinsic value which is independent of future applications. Basic research may also lead to practical benefits, such as a new drug or diagnostic method. Building on our previous study of basic biomedical and biological researchers at Harvard, we present findings from a new survey of similar scientists from three countries. The goal of this study was to design policies to enhance both the public health potential and the work satisfaction and test scientists' attitudes towards these factors. The present survey asked about the scientists' motivations, goals and perspectives along with their attitudes concerning  policies designed to increase both the practical (i.e. public health) benefits of basic research as well as their own personal satisfaction. Close to 900 basic investigators responded to the survey; results corroborate the main findings from the previous survey of Harvard scientists. In addition, we find that most bioscientists disfavor present policies that require a discussion of the public health potential of their proposals in grants but generally favor softer policies aimed at increasing the quality of work and the potential practical benefits of basic research. In particular, bioscientists are generally supportive of those policies entailing the organization of more meetings between scientists and the general public, the organization of more academic discussion about the role of scientists in the society, and the implementation of a "basic bibliography" for each new approved drug.

Increasing both the public health potential of basic research and the scientist satisfaction. An international survey of bio-scientists

PubMed Central

Sorrentino, Carmen; Boggio, Andrea; Confalonieri, Stefano; Hemenway, David; Scita, Giorgio; Ballabeni, Andrea

2016-01-01

Basic scientific research generates knowledge that has intrinsic value which is independent of future applications. Basic research may also lead to practical benefits, such as a new drug or diagnostic method. Building on our previous study of basic biomedical and biological researchers at Harvard, we present findings from a new survey of similar scientists from three countries. The goal of this study was to design policies to enhance both the public health potential and the work satisfaction and test scientists’ attitudes towards these factors. The present survey asked about the scientists’ motivations, goals and perspectives along with their attitudes concerning  policies designed to increase both the practical (i.e. public health) benefits of basic research as well as their own personal satisfaction. Close to 900 basic investigators responded to the survey; results corroborate the main findings from the previous survey of Harvard scientists. In addition, we find that most bioscientists disfavor present policies that require a discussion of the public health potential of their proposals in grants but generally favor softer policies aimed at increasing the quality of work and the potential practical benefits of basic research. In particular, bioscientists are generally supportive of those policies entailing the organization of more meetings between scientists and the general public, the organization of more academic discussion about the role of scientists in the society, and the implementation of a “basic bibliography” for each new approved drug. PMID:27347372

[Basic research in ophthalmology in Germany and its international context].

PubMed

Schlötzer-Schrehardt, U; Cursiefen, C

2017-09-01

Experimental basic research provides the foundations for the elucidation of pathophysiological mechanisms of diseases and the development of novel diagnostic and therapeutic strategies for ophthalmological diseases. The objective of this contribution is to provide an overview of the international interconnection of basic research in ophthalmology in Germany. The international context of ophthalmological research conducted in Germany is presented by means of personal experiences and data published by the German Ophthalmological Society (DOG), the German Research Foundation (DFG) and the European Union (EU). Due to the lack of organized databases this article lays no claim to completeness. Basic research in ophthalmology in Germany is mainly conducted in university eye departments and is mainly related to the etiology, pathophysiology and therapy development for various ophthalmic diseases. It is primarily funded by the DFG, the Federal Ministry of Education and Research (BMBF) and the EU plays an increasingly important role. Thus, ophthalmological research is integrated into numerous European research networks and beyond that into many international interconnections and relationships. In Germany, both clinical and basic research in ophthalmology is integrated into many international networks and is only functionally viable in an international context; however, given the increasing impact of ophthalmological research in Asian countries, future strategies require a continued focus on career development, research infrastructure, working environment and international cooperation.

The Brown Superfund Basic Research Program: A Multistakeholder Partnership Addresses Real-World Problems in Contaminated Communities

PubMed Central

Senier, Laura; Hudson, Benjamin; Fort, Sarah; Hoover, Elizabeth; Tillson, Rebecca; Brown, Phil

2008-01-01

The NIEHS funds several basic and applied research programs, many of which also require research translation or outreach. This paper reports on a project by the Brown University Superfund Basic Research Program (SBRP), in which outreach and research translation teams collaborated with state regulatory agency personnel and community activists on a legislative initiative to mitigate the financial impacts of living in a contaminated community. The Environmentally Compromised Home Ownership (ECHO) program makes home equity loans of up to $25,000 available to qualified applicants. This collaboration provides a case study in community engagement and demonstrates how research translation and outreach activities that are clearly differentiated yet well integrated can improve a suite of basic and applied research. Although engaging diverse constituencies can be difficult, community-engaged translation and outreach have the potential to make research findings more useful to communities, address some of the social impacts of contamination, and empower stakeholders to pursue their individual and collectively-held goals for remediation. The NIEHS has recently renewed its commitment to community-engaged research and advocacy, making this an optimal time to reflect on how basic research programs that engage stakeholders through research translation and outreach can add value to the overall research enterprise. PMID:18677987

Brown Superfund Basic research Program: a multistakeholder partnership addresses real-world problems in contaminated communities.

PubMed

Senier, Laura; Hudson, Benjamin; Fort, Sarah; Hoover, Elizabeth; Tillson, Rebecca; Brown, Phil

2008-07-01

The NIEHS funds several basic and applied research programs, many of which also require research translation or outreach. This paper reports on a project by the Brown University Superfund Basic Research Program (SBRP), in which outreach and research translation teams collaborated with state regulatory agency personnel and community activists on a legislative initiative to mitigate the financial impacts of living in a contaminated community. The Environmentally Compromised Home Ownership (ECHO) program makes home equity loans of up to $25,000 available to qualified applicants. This collaboration provides a case study in community engagement and demonstrates how research translation and outreach activities that are clearly differentiated yet well-integrated can improve a suite of basic and applied research. Although engaging diverse constituencies can be difficult community-engaged translation and outreach have the potential to make research findings more useful to communities, address some of the social impacts of contamination, and empower stakeholders to pursue their individual and collectively held goals for remediation. The NIEHS has recently renewed its commitment to community-engaged research and advocacy, making this an optimal time to reflect on how basic research programs that engage stakeholders through research translation and outreach can add value to the overall research enterprise.

Nutritional Interventions in Primary Mitochondrial Disorders: Developing an Evidence Base✰

PubMed Central

Camp, Kathryn M.; Krotoski, Danuta; Parisi, Melissa A.; Gwinn, Katrina A.; Cohen, Bruce H.; Cox, Christine S.; Enns, Gregory M.; Falk, Marni J.; Goldstein, Amy C.; Gopal-Srivastava, Rashmi; Gorman, Gráinne S.; Hersh, Stephen P.; Hirano, Michio; Hoffman, Freddie Ann; Karaa, Amel; MacLeod, Erin L.; McFarland, Robert; Mohan, Charles; Mulberg, Andrew E.; Odenkirchen, Joanne C.; Parikh, Sumit; Rutherford, Patricia J.; Suggs-Anderson, Shawne K.; Tang, W.H. Wilson; Vockley, Jerry; Wolfe, Lynne A.; Yannicelli, Steven; Yeske, Philip E.; Coates, Paul M.

2016-01-01

In December 2014, a workshop entitled “Nutritional Interventions in Primary Mitochondrial Disorders: Developing an Evidence Base” was convened at the NIH with the goals of exploring the use of nutritional interventions in primary mitochondrial disorders (PMD) and identifying knowledge gaps regarding their safety and efficacy; identifying research opportunities; and forging collaborations among researchers, clinicians, patient advocacy groups, and federal partners. Sponsors included the NIH, the Wellcome Trust, and the United Mitochondrial Diseases Foundation. Dietary supplements have historically been used in the management of PMD due to their potential benefits and perceived low risk, even though little evidence exists regarding their effectiveness. PMD are rare and clinically, phenotypically, and genetically heterogeneous. Thus patient recruitment for randomized controlled trials (RCTs) has proven to be challenging. Only a few RCTs examining dietary supplements, singly or in combination with other vitamins and cofactors, are reported in the literature. Regulatory issues pertaining to the use of dietary supplements as treatment modalities further complicate the research and patient access landscape. As a preface to exploring a research agenda, the workshop included presentations and discussions on what PMD are; how nutritional interventions are used in PMD; challenges and barriers to their use; new technologies and approaches to diagnosis and treatment; research opportunities and resources; and perspectives from patient advocacy, industry, and professional organizations. Seven key areas were identified during the workshop. These areas were: 1) defining the disease, 2) clinical trial design, 3) biomarker selection, 4) mechanistic approaches, 5) challenges in using dietary supplements, 6) standards of clinical care, and 7) collaboration issues. Short and long-term goals within each of these areas were identified. An example of an overarching goal is the enrollment of all individuals with PMD in a natural history study and a patient registry to enhance research capability. The workshop demonstrates an effective model for fostering and enhancing collaborations among NIH and basic research, clinical, patient, pharmaceutical industry, and regulatory stakeholders in the mitochondrial disease community to address research challenges on the use of dietary supplements in PMD. PMID:27665271

Characteristics of physicians engaged in basic science: a questionnaire survey of physicians in basic science departments of a medical school in Japan.

PubMed

Yamazaki, Yuka; Uka, Takanori; Shimizu, Haruhiko; Miyahira, Akira; Sakai, Tatsuo; Marui, Eiji

2012-09-01

The number of physicians engaged in basic science and teaching is sharply decreasing in Japan. To alleviate this shortage, central government has increased the quota of medical students entering the field. This study aimed to determine the characteristics of physicians who are engaged in basic science in efforts to recruit talent. A questionnaire was distributed to all 30 physicians in the basic science departments of Juntendo University School of Medicine. Question items inquired about sex, years since graduation, years between graduation and time entering basic science, clinical experience, recommending the career to medical students, expected obstacles to students entering basic science, efforts to inspire students in research, increased number of lectures and practical training sessions on research, and career choice satisfaction. Correlations between the variables were examined using χ(2) tests. Overall, 26 physicians, including 7 female physicians, returned the questionnaire (response rate 86.7%). Most physicians were satisfied with their career choice. Medical students were deemed not to choose basic science as their future career, because they aimed to become clinicians and because they were concerned about salary. Women physicians in basic science departments were younger than men. Women physicians also considered themselves to make more efforts in inspiring medical students to be interested in research. Moreover, physicians who became basic scientists earlier in their career wanted more research-related lectures in medical education. Improving physicians' salaries in basic science is important to securing talent. In addition, basic science may be a good career path for women physicians to follow.

Left Ventricular Gene Expression Profile of Healthy and Cardiovascular Compromised Rat Models Used in Air Pollution Studies

EPA Science Inventory

The link between pollutant exposure and cardiovascular disease (CVD) has prompted mechanistic research with animal models of CVD. We hypothesized that the cardiac gene expression patterns of healthy and genetically compromised, CVD-prone rat models, with or without metabolic impa...

Copper Nanoparticle Induced Cytotoxicity to Nitrifying Bacteria in Wastewater Treatment: A Mechanistic Copper Speciation Study by X-ray Absorption Spectroscopy

EPA Science Inventory

With the inclusion of engineered nanomaterials in industrial processes and consumer products, wastewater treatments plants (WWTPs) will serve as a major sink for these emerging contaminants. Previous research has demonstrated that nanomaterials are potentially toxic to microbial ...

A rule-based expert system for chemical prioritization using effects-based chemical categories

EPA Science Inventory

A rule-based expert system (ES) was developed to predict chemical binding to the estrogen receptor (ER) patterned on the research approaches championed by Gilman Veith to whom this article and journal issue are dedicated. The ERES was built to be mechanistically-transparent and m...

Guidelines for Implementing NCHRP 1-37A M-E Design Procedures in Ohio : Volume 4 -- MEPDG Models Validation & Recalibration

DOT National Transportation Integrated Search

2009-11-01

The development of the Mechanistic-Empirical Pavement Design Guide (MEPDG) under National Cooperative Highway Research Program (NCHRP) projects 1-37A and 1-40D has significantly improved the ability of pavement designers to model and simulate the eff...

MECHANISTIC ASPECT OF REVERSE ATOM TRANSFER RADICAL POLYMERIZATION OF N-BUTYL METHACRYLATE IN AQUEOUS DISPERSED SYSTEM. (R826735)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

76 FR 10913 - National Center for Complementary & Alternative Medicine; Notice of Closed Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-28

... Complementary & Alternative Medicine; Notice of Closed Meeting Pursuant to section 10(d) of the Federal Advisory... Alternative Medicine Special Emphasis Panel, Mechanistic Research on CAM Natural Products (R01). Date: March... Alternative Medicine, National Institutes of Health, HHS). Dated: February 18, 2011. Jennifer S. Spaeth...

Guidelines for Implementing NCHRP 1-37A M-E Design Procedures in Ohio : Volume 2 -- Literature Review

DOT National Transportation Integrated Search

2009-11-01

The development of the Mechanistic-Empirical Pavement Design Guide (MEPDG) under National Cooperative Highway Research Program (NCHRP) projects 1-37A and 1-40D has significantly improved the ability of pavement designers to model and simulate the eff...

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...

Indigeneity and Homeland: Land, History, Ceremony, and Language

ERIC Educational Resources Information Center

Lerma, Michael

2012-01-01

What is the relationship between Indigenous peoples and violent reactions to contemporary states? This research explores differing, culturally informed notions of attachment to land or place territory. Mechanistic ties and organic ties to land are linked to a key distinction between Indigenous peoples and non-Indigenous peoples. Utilizing the…

A MECHANISTIC MODEL FOR ESTIMATING VOC EMISSIONS FROM INDUSTRIAL PROCESS DRAINS. II: THE WATER SEAL. (R823335)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

Profile of Knowledge Management, Basic Sanitation and Attitudes towards Clean and Health Community in Kupang City

ERIC Educational Resources Information Center

Nikmah; Ardi, Muhammad; Yahya, Mohamad; Upa, Muhamad D. Pua; Dirawan, Gufran Darma

2017-01-01

The objective of research is to describe the knowledge and attitude of basic sanitation management community in Kupang City. This type of research is a survey research using quantitative approach. Data were collected by using the instrument in the form of test knowledge of basic sanitation management and attitude questionnaire. The data was then…

26 CFR 1.41-5 - Basic research for taxable years beginning after December 31, 1986. [Reserved

Code of Federal Regulations, 2010 CFR

2010-04-01

... 26 Internal Revenue 1 2010-04-01 2010-04-01 true Basic research for taxable years beginning after December 31, 1986. [Reserved] 1.41-5 Section 1.41-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY INCOME TAX INCOME TAXES Credits Against Tax § 1.41-5 Basic research for taxable years...

Research projects in the Surgeon-Scientist and Clinician-Investigator programs at the University of Toronto (1987-2016): a cohort study.

PubMed

Goldenberg, Neil M; Steinberg, Benjamin E; Rutka, James T; Chen, Robert; Cabral, Val; Rosenblum, Norman D; Kapus, Andras; Lee, Warren L

2016-01-01

Physicians have traditionally been at the forefront of medical research, bringing clinical questions to the laboratory and returning with ideas for treatment. However, we have anecdotally observed a decline in the popularity of basic science research among trainees. We hypothesized that fewer resident physicians have been pursuing basic science research training over time. We examined records from residents in the Surgeon-Scientist and Clinician-Investigator programs at the University of Toronto (1987-2016). Research by residents was categorized independently by 2 raters as basic science, clinical epidemiology or education-related based on the title of the project, the name of the supervisor and Pubmed searches. The study population was divided into quintiles of time, and the proportion pursuing basic science training in each quintile was calculated. Agreement between the raters was 100%; the categorization of the research topic remained unclear in 9 cases. The proportion of trainees pursuing basic science training dropped by 60% from 1987 to 2016 ( p = 0.005). Significantly fewer residents in the Surgeon-Scientist and Clinician-Investigator Programs at the University of Toronto are pursuing training in the basic sciences as compared with previous years.

Materials Discovery | Materials Science | NREL

Science.gov Websites

measurement methods and specialized analysis algorithms. Projects Basic Research The basic research projects applications using high-throughput combinatorial research methods. Email | 303-384-6467 Photo of John Perkins

A stochastic automata network for earthquake simulation and hazard estimation

NASA Astrophysics Data System (ADS)

Belubekian, Maya Ernest

1998-11-01

This research develops a model for simulation of earthquakes on seismic faults with available earthquake catalog data. The model allows estimation of the seismic hazard at a site of interest and assessment of the potential damage and loss in a region. There are two approaches for studying the earthquakes: mechanistic and stochastic. In the mechanistic approach, seismic processes, such as changes in stress or slip on faults, are studied in detail. In the stochastic approach, earthquake occurrences are simulated as realizations of a certain stochastic process. In this dissertation, a stochastic earthquake occurrence model is developed that uses the results from dislocation theory for the estimation of slip released in earthquakes. The slip accumulation and release laws and the event scheduling mechanism adopted in the model result in a memoryless Poisson process for the small and moderate events and in a time- and space-dependent process for large events. The minimum and maximum of the hazard are estimated by the model when the initial conditions along the faults correspond to a situation right after a largest event and after a long seismic gap, respectively. These estimates are compared with the ones obtained from a Poisson model. The Poisson model overestimates the hazard after the maximum event and underestimates it in the period of a long seismic quiescence. The earthquake occurrence model is formulated as a stochastic automata network. Each fault is divided into cells, or automata, that interact by means of information exchange. The model uses a statistical method called bootstrap for the evaluation of the confidence bounds on its results. The parameters of the model are adjusted to the target magnitude patterns obtained from the catalog. A case study is presented for the city of Palo Alto, where the hazard is controlled by the San Andreas, Hayward and Calaveras faults. The results of the model are used to evaluate the damage and loss distribution in Palo Alto. The sensitivity analysis of the model results to the variation in basic parameters shows that the maximum magnitude has the most significant impact on the hazard, especially for long forecast periods.

3D-FE Modeling of 316 SS under Strain-Controlled Fatigue Loading and CFD Simulation of PWR Surge Line

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

Mohanty, Subhasish; Barua, Bipul; Listwan, Joseph

In financial year 2017, we are focusing on developing a mechanistic fatigue model of surge line pipes for pressurized water reactors (PWRs). To that end, we plan to perform the following tasks: (1) conduct stress- and strain-controlled fatigue testing of surge-line base metal such as 316 stainless steel (SS) under constant, variable, and random fatigue loading, (2) develop cyclic plasticity material models of 316 SS, (3) develop one-dimensional (1D) analytical or closed-form model to validate the material models and to understand the mechanics associated with 316 SS cyclic hardening and/or softening, (4) develop three-dimensional (3D) finite element (FE) models withmore » implementation of evolutionary cyclic plasticity, and (5) develop computational fluid dynamics (CFD) model for thermal stratification, thermal-mechanical stress, and fatigue of example reactor components, such as a PWR surge line under plant heat-up, cool-down, and normal operation with/without grid-load-following. This semi-annual progress report presents the work completed on the above tasks for a 316 SS laboratory-scale specimen subjected to strain-controlled cyclic loading with constant, variable, and random amplitude. This is the first time that the accurate 3D-FE modeling of the specimen for its entire fatigue life, including the hardening and softening behavior, has been achieved. We anticipate that this work will pave the way for the development of a fully mechanistic-computer model that can be used for fatigue evaluation of safety-critical metallic components, which are traditionally evaluated by heavy reliance on time-consuming and costly test-based approaches. This basic research will not only help the nuclear reactor industry for fatigue evaluation of reactor components in a cost effective and less time-consuming way, but will also help other safety-related industries, such as aerospace, which is heavily dependent on test-based approaches, where a single full-scale fatigue test can cost millions of dollars and require years of effort to conduct. Toward our goal of demonstration of fully mechanistic fatigue evaluation of reactor components, we also started work on developing a component-level computer model of reactor components, such as 316 SS surge line pipe. This requires developing a thermal-mechanical stress analysis model of the reactor surge line, which, in turn, requires time-dependent temperature and stratification information along the boundary of the pipe. Toward that goal, CFD models of surge lines are being developed. In this report, we also present some preliminary results showing the temperature conditions along the surge line wall under reactor heat-up, cool-down, and steady-state power operation.« less

Exploring Attractiveness of the Basic Sciences for Female Physicians.

PubMed

Yamazaki, Yuka; Fukushima, Shinji; Kozono, Yuki; Uka, Takanori; Marui, Eiji

2018-01-01

In Japan, traditional gender roles of women, especially the role of motherhood, may cause early career resignations in female physicians and a shortage of female researchers. Besides this gender issue, a general physician shortage is affecting basic science fields. Our previous study suggested that female physicians could be good candidates for the basic sciences because such work offers good work-life balance. However, the attractiveness for female physicians of working in the basic sciences, including work-life balance, is not known. In a 2012 nationwide cross-sectional questionnaire survey, female physicians holding tenured positions in the basic sciences at Japan's medical schools were asked an open-ended question about positive aspects of basic sciences that clinical medicine lacks, and we analyzed 58 respondents' comments. Qualitative analysis using the Kawakita Jiro method revealed four positive aspects: research attractiveness, priority on research productivity, a healthy work-life balance, and exemption from clinical duties. The most consistent positive aspect was research attractiveness, which was heightened by medical knowledge and clinical experience. The other aspects were double-edged swords; for example, while the priority on research productivity resulted in less gender segregation, it sometimes created tough competition, and while exemption from clinical duties contributed to a healthy work-life balance, it sometimes lowered motivation as a physician and provided unstable income. Overall, if female physicians lack an intrinsic interest in research and seek good work-life balance, they may drop out of research fields. Respecting and cultivating students' research interest is critical to alleviating the physician shortage in the basic sciences.

Proteomics and metabolomics in ageing research: from biomarkers to systems biology.

PubMed

Hoffman, Jessica M; Lyu, Yang; Pletcher, Scott D; Promislow, Daniel E L

2017-07-15

Age is the single greatest risk factor for a wide range of diseases, and as the mean age of human populations grows steadily older, the impact of this risk factor grows as well. Laboratory studies on the basic biology of ageing have shed light on numerous genetic pathways that have strong effects on lifespan. However, we still do not know the degree to which the pathways that affect ageing in the lab also influence variation in rates of ageing and age-related disease in human populations. Similarly, despite considerable effort, we have yet to identify reliable and reproducible 'biomarkers', which are predictors of one's biological as opposed to chronological age. One challenge lies in the enormous mechanistic distance between genotype and downstream ageing phenotypes. Here, we consider the power of studying 'endophenotypes' in the context of ageing. Endophenotypes are the various molecular domains that exist at intermediate levels of organization between the genotype and phenotype. We focus our attention specifically on proteins and metabolites. Proteomic and metabolomic profiling has the potential to help identify the underlying causal mechanisms that link genotype to phenotype. We present a brief review of proteomics and metabolomics in ageing research with a focus on the potential of a systems biology and network-centric perspective in geroscience. While network analyses to study ageing utilizing proteomics and metabolomics are in their infancy, they may be the powerful model needed to discover underlying biological processes that influence natural variation in ageing, age-related disease, and longevity. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Using the Wii Fit as a tool for balance assessment and neurorehabilitation: the first half decade of "Wii-search".

PubMed

Goble, Daniel J; Cone, Brian L; Fling, Brett W

2014-02-08

The Nintendo Wii Fit was released just over five years ago as a means of improving basic fitness and overall well-being. Despite this broad mission, the Wii Fit has generated specific interest in the domain of neurorehabilitation as a biobehavioral measurement and training device for balance ability. Growing interest in Wii Fit technology is likely due to the ubiquitous nature of poor balance and catastrophic falls, which are commonly seen in older adults and various disability conditions. The present review provides the first comprehensive summary of Wii Fit balance research, giving specific insight into the system's use for the assessment and training of balance. Overall, at the time of the fifth anniversary, work in the field showed that custom applications using the Wii Balance Board as a proxy for a force platform have great promise as a low cost and portable way to assess balance. On the other hand, use of Wii Fit software-based balance metrics has been far less effective in determining balance status. As an intervention tool, positive balance outcomes have typically been obtained using Wii Fit balance games, advocating their use for neurorehabilitative training. Despite this, limited sample sizes and few randomized control designs indicate that research regarding use of the Wii Fit system for balance intervention remains subject to improvement. Future work aimed at conducting studies with larger scale randomized control designs and a greater mechanistic focus is recommended to further advance the efficacy of this impactful neurorehabilitation tool.

Proteomics and metabolomics in ageing research: from biomarkers to systems biology

PubMed Central

Hoffman, Jessica M.; Lyu, Yang; Pletcher, Scott D.; Promislow, Daniel E.L.

2017-01-01

Age is the single greatest risk factor for a wide range of diseases, and as the mean age of human populations grows steadily older, the impact of this risk factor grows as well. Laboratory studies on the basic biology of ageing have shed light on numerous genetic pathways that have strong effects on lifespan. However, we still do not know the degree to which the pathways that affect ageing in the lab also influence variation in rates of ageing and age-related disease in human populations. Similarly, despite considerable effort, we have yet to identify reliable and reproducible ‘biomarkers’, which are predictors of one’s biological as opposed to chronological age. One challenge lies in the enormous mechanistic distance between genotype and downstream ageing phenotypes. Here, we consider the power of studying ‘endophenotypes’ in the context of ageing. Endophenotypes are the various molecular domains that exist at intermediate levels of organization between the genotype and phenotype. We focus our attention specifically on proteins and metabolites. Proteomic and metabolomic profiling has the potential to help identify the underlying causal mechanisms that link genotype to phenotype. We present a brief review of proteomics and metabolomics in ageing research with a focus on the potential of a systems biology and network-centric perspective in geroscience. While network analyses to study ageing utilizing proteomics and metabolomics are in their infancy, they may be the powerful model needed to discover underlying biological processes that influence natural variation in ageing, age-related disease, and longevity. PMID:28698311

Using the Wii Fit as a tool for balance assessment and neurorehabilitation: the first half decade of “Wii-search”

PubMed Central

2014-01-01

The Nintendo Wii Fit was released just over five years ago as a means of improving basic fitness and overall well-being. Despite this broad mission, the Wii Fit has generated specific interest in the domain of neurorehabilitation as a biobehavioral measurement and training device for balance ability. Growing interest in Wii Fit technology is likely due to the ubiquitous nature of poor balance and catastrophic falls, which are commonly seen in older adults and various disability conditions. The present review provides the first comprehensive summary of Wii Fit balance research, giving specific insight into the system’s use for the assessment and training of balance. Overall, at the time of the fifth anniversary, work in the field showed that custom applications using the Wii Balance Board as a proxy for a force platform have great promise as a low cost and portable way to assess balance. On the other hand, use of Wii Fit software-based balance metrics has been far less effective in determining balance status. As an intervention tool, positive balance outcomes have typically been obtained using Wii Fit balance games, advocating their use for neurorehabilitative training. Despite this, limited sample sizes and few randomized control designs indicate that research regarding use of the Wii Fit system for balance intervention remains subject to improvement. Future work aimed at conducting studies with larger scale randomized control designs and a greater mechanistic focus is recommended to further advance the efficacy of this impactful neurorehabilitation tool. PMID:24507245

The filamentous fungus Sordaria macrospora as a genetic model to study fruiting body development.

PubMed

Teichert, Ines; Nowrousian, Minou; Pöggeler, Stefanie; Kück, Ulrich

2014-01-01

Filamentous fungi are excellent experimental systems due to their short life cycles as well as easy and safe manipulation in the laboratory. They form three-dimensional structures with numerous different cell types and have a long tradition as genetic model organisms used to unravel basic mechanisms underlying eukaryotic cell differentiation. The filamentous ascomycete Sordaria macrospora is a model system for sexual fruiting body (perithecia) formation. S. macrospora is homothallic, i.e., self-fertile, easily genetically tractable, and well suited for large-scale genomics, transcriptomics, and proteomics studies. Specific features of its life cycle and the availability of a developmental mutant library make it an excellent system for studying cellular differentiation at the molecular level. In this review, we focus on recent developments in identifying gene and protein regulatory networks governing perithecia formation. A number of tools have been developed to genetically analyze developmental mutants and dissect transcriptional profiles at different developmental stages. Protein interaction studies allowed us to identify a highly conserved eukaryotic multisubunit protein complex, the striatin-interacting phosphatase and kinase complex and its role in sexual development. We have further identified a number of proteins involved in chromatin remodeling and transcriptional regulation of fruiting body development. Furthermore, we review the involvement of metabolic processes from both primary and secondary metabolism, and the role of nutrient recycling by autophagy in perithecia formation. Our research has uncovered numerous players regulating multicellular development in S. macrospora. Future research will focus on mechanistically understanding how these players are orchestrated in this fungal model system. Copyright © 2014 Elsevier Inc. All rights reserved.

Defence mechanisms: the role of physiology in current and future environmental protection paradigms

PubMed Central

Glover, Chris N

2018-01-01

Abstract Ecological risk assessments principally rely on simplified metrics of organismal sensitivity that do not consider mechanism or biological traits. As such, they are unable to adequately extrapolate from standard laboratory tests to real-world settings, and largely fail to account for the diversity of organisms and environmental variables that occur in natural environments. However, an understanding of how stressors influence organism health can compensate for these limitations. Mechanistic knowledge can be used to account for species differences in basal biological function and variability in environmental factors, including spatial and temporal changes in the chemical, physical and biological milieu. Consequently, physiological understanding of biological function, and how this is altered by stressor exposure, can facilitate proactive, predictive risk assessment. In this perspective article, existing frameworks that utilize physiological knowledge (e.g. biotic ligand models, adverse outcomes pathways and mechanistic effect models), are outlined, and specific examples of how mechanistic understanding has been used to predict risk are highlighted. Future research approaches and data needs for extending the incorporation of physiological information into ecological risk assessments are discussed. Although the review focuses on chemical toxicants in aquatic systems, physical and biological stressors and terrestrial environments are also briefly considered. PMID:29564135

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

PubMed Central

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

2014-01-01

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

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 Modeling of the Effects of Acidosis on Thrombin Generation

DTIC Science & Technology

2015-08-01

Telemedicine and Advanced Technology Research Center; U.S. Army Medical Research and Materiel Command, Ft. Detrick, MD; and Departments of...are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Army or of the U.S. Department ...of Defense . This paper has been approved for public release with unlimited distribution. Reprints will not be available from the authors. Address

Titanium Dioxide Photocatalytic Polymerization of Acrylamide for Gel Electrophoresis (TIPPAGE) of Proteins and Structural Identification by Mass Spectrometry

NASA Astrophysics Data System (ADS)

Zhang, Wenyang; Yuan, Zhiwei; Huang, Lulu; Kang, Jie; Jiang, Ruowei; Zhong, Hongying

2016-02-01

Polyacrylamide gel electrophoresis (PAGE) coupled with mass spectrometry has been well established for separating, identifying and quantifying protein mixtures from cell lines, tissues or other biological samples. The copolymerization process of acrylamide and bis-acrylamide is the key to mastering this powerful technique. In general, this is a vinyl addition reaction initiated by free radical-generating reagents such as ammonium persulfate (APS) and tetramethylethylenediamine (TEMED) under basic pH and degassing experimental condition. We report herein a photocatalytic polymerization approach that is based on photo-generated hydroxyl radicals with nanoparticles of titanium dioxide. It was shown that the polymerization process is greatly accelerated in acidic condition when ultraviolet light shots on the gel solution containing TiO2 nanoparticles without degassing. This feature makes it very useful in preparing Triton X-100 acid urea (TAU) gel that has been developed for separating basic proteins such as histones and variants in acidic experimental condition. Additionally, the presence of titanium dioxide in the gel not only improves mechanistic property of gels but also changes the migration pattern of different proteins that have different affinities to titanium dioxide.

Titanium Dioxide Photocatalytic Polymerization of Acrylamide for Gel Electrophoresis (TIPPAGE) of Proteins and Structural Identification by Mass Spectrometry.

PubMed

Zhang, Wenyang; Yuan, Zhiwei; Huang, Lulu; Kang, Jie; Jiang, Ruowei; Zhong, Hongying

2016-02-11

Polyacrylamide gel electrophoresis (PAGE) coupled with mass spectrometry has been well established for separating, identifying and quantifying protein mixtures from cell lines, tissues or other biological samples. The copolymerization process of acrylamide and bis-acrylamide is the key to mastering this powerful technique. In general, this is a vinyl addition reaction initiated by free radical-generating reagents such as ammonium persulfate (APS) and tetramethylethylenediamine (TEMED) under basic pH and degassing experimental condition. We report herein a photocatalytic polymerization approach that is based on photo-generated hydroxyl radicals with nanoparticles of titanium dioxide. It was shown that the polymerization process is greatly accelerated in acidic condition when ultraviolet light shots on the gel solution containing TiO2 nanoparticles without degassing. This feature makes it very useful in preparing Triton X-100 acid urea (TAU) gel that has been developed for separating basic proteins such as histones and variants in acidic experimental condition. Additionally, the presence of titanium dioxide in the gel not only improves mechanistic property of gels but also changes the migration pattern of different proteins that have different affinities to titanium dioxide.

Titanium Dioxide Photocatalytic Polymerization of Acrylamide for Gel Electrophoresis (TIPPAGE) of Proteins and Structural Identification by Mass Spectrometry

PubMed Central

Zhang, Wenyang; Yuan, Zhiwei; Huang, Lulu; Kang, Jie; Jiang, Ruowei; Zhong, Hongying

2016-01-01

Polyacrylamide gel electrophoresis (PAGE) coupled with mass spectrometry has been well established for separating, identifying and quantifying protein mixtures from cell lines, tissues or other biological samples. The copolymerization process of acrylamide and bis-acrylamide is the key to mastering this powerful technique. In general, this is a vinyl addition reaction initiated by free radical-generating reagents such as ammonium persulfate (APS) and tetramethylethylenediamine (TEMED) under basic pH and degassing experimental condition. We report herein a photocatalytic polymerization approach that is based on photo-generated hydroxyl radicals with nanoparticles of titanium dioxide. It was shown that the polymerization process is greatly accelerated in acidic condition when ultraviolet light shots on the gel solution containing TiO2 nanoparticles without degassing. This feature makes it very useful in preparing Triton X-100 acid urea (TAU) gel that has been developed for separating basic proteins such as histones and variants in acidic experimental condition. Additionally, the presence of titanium dioxide in the gel not only improves mechanistic property of gels but also changes the migration pattern of different proteins that have different affinities to titanium dioxide. PMID:26865351

Basic Research on Remote Sensing of Fissile Materials utilizing Gamma-rays and Neutrons

DTIC Science & Technology

2017-02-01

6201 Fort Belvoir, VA 22060-6201 T E C H N IC A L R E P O R T DTRA-TR-15-56 Basic Research on Remote Sensing of Fissile Materials...factor to get the U.S. customary unit. C Final Report, November 2013 Grant No. HDTRA1-09-1-0059 Title: Basic Research on Remote Sensing of Fissile

Neurocircuitry of drug reward

PubMed Central

Ikemoto, Satoshi; Bonci, Antonello

2013-01-01

In recent years, neuroscientists have produced profound conceptual and mechanistic advances on the neurocircuitry of reward and substance use disorders. Here, we will provide a brief review of intracranial drug self-administration and optogenetic self-stimulation studies that identified brain regions and neurotransmitter systems involved in drug- and reward-related behaviors. Also discussed is a theoretical framework that helps to understand the functional properties of the circuitry involved in these behaviors. The circuitry appears to be homeostatically regulated and mediate anticipatory processes that regulate behavioral interaction with the environment in response to salient stimuli. That is, abused drugs or, at least, some may act on basic motivation and mood processes, regulating behavior-environment interaction. Optogenetics and related technologies have begun to uncover detailed circuit mechanisms linking key brain regions in which abused drugs act for rewarding effects. PMID:23664810

More insights into the pharmacological effects of artemisinin.

PubMed

Zyad, Abdelmajid; Tilaoui, Mounir; Jaafari, Abdeslam; Oukerrou, Moulay Ali; Mouse, Hassan Ait

2018-02-01

Artemisinin is one of the most widely prescribed drugs against malaria and has recently received increased attention because of its other potential biological effects. The aim of this review is to summarize recent discoveries of the pharmaceutical effects of artemisinin in basic science along with its mechanistic action, as well as the intriguing results of recent clinical studies, with a focus on its antitumor activity. Scientific evidence indicates that artemisinin exerts its biological activity by generating reactive oxygen species that damage the DNA, mitochondrial depolarization, and cell death. In the present article review, scientific evidence suggests that artemisinin is a potential therapeutic agent for various diseases. Thus, this review is expected to encourage interested scientists to conduct further preclinical and clinical studies to evaluate these biological activities. Copyright © 2017 John Wiley & Sons, Ltd.

Connecting drug delivery reality to smart materials design.

PubMed

Grainger, David W

2013-09-15

Inflated claims to both design and mechanistic novelty in drug delivery and imaging systems, including most nanotechnologies, are not supported by the generally poor translation of these systems to clinical efficacy. The "form begets function" design paradigm is seductive but perhaps over-simplistic in translation to pharmaceutical efficacy. Most innovations show few clinically important distinctions in their therapeutic benefits in relevant preclinical disease and delivery models, despite frequent claims to the contrary. Long-standing challenges in drug delivery issues must enlist more realistic, back-to-basics approaches to address fundamental materials properties in complex biological systems, preclinical test beds, and analytical methods to more reliably determine fundamental pharmaceutical figures of merit, including drug carrier purity and batch-batch variability, agent biodistribution, therapeutic index (safety), and efficacy. Copyright © 2013 Elsevier B.V. All rights reserved.

On the making of a system theory of life: Paul A Weiss and Ludwig von Bertalanffy's conceptual connection.

PubMed

Drack, Manfred; Apfalter, Wilfried; Pouvreau, David

2007-12-01

In this article, we review how two eminent Viennese system thinkers, Paul A Weiss and Ludwig von Bertalanffy, began to develop their own perspectives toward a system theory of life in the 1920s. Their work is especially rooted in experimental biology as performed at the Biologische Versuchsanstalt, as well as in philosophy, and they converge in basic concepts. We underline the conceptual connections of their thinking, among them the organism as an organized system, hierarchical organization, and primary activity. With their system thinking, both biologists shared a strong desire to overcome what they viewed as a "mechanistic" approach in biology. Their interpretations are relevant to the renaissance of system thinking in biology--"systems biology." Unless otherwise noted, all translations are our own.

Transient-state kinetic approach to mechanisms of enzymatic catalysis.

PubMed

Fisher, Harvey F

2005-03-01

Transient-state kinetics by its inherent nature can potentially provide more directly observed detailed resolution of discrete events in the mechanistic time courses of enzyme-catalyzed reactions than its more widely used steady-state counterpart. The use of the transient-state approach, however, has been severely limited by the lack of any theoretically sound and applicable basis of interpreting the virtual cornucopia of time and signal-dependent phenomena that it provides. This Account describes the basic kinetic behavior of the transient state, critically examines some currently used analytic methods, discusses the application of a new and more soundly based "resolved component transient-state time-course method" to the L-glutamate-dehydrogenase reaction, and establishes new approaches for the analysis of both single- and multiple-step substituted transient-state kinetic isotope effects.

Mechanism-based approaches to treating fragile X.

PubMed

Dölen, Gül; Carpenter, Randall L; Ocain, Timothy D; Bear, Mark F

2010-07-01

Fragile X is the leading inherited cause of mental retardation and autism. Recent advances in our mechanistic understanding of the disease have led to the identification of the metabotropic glutamate receptor (mGluR) as a therapeutic target for the disease. These studies have revealed that core defects in multiple animal models can be corrected by down regulation of mGluR5 signaling. Although it remains to be seen if mGluR5 antagonists or related approaches will succeed in humans with fragile X, the progress in fragile X stands as a strong testament to the power of applying knowledge of basic neurobiology to understand pathophysiology in a genetically validated model of human psychiatric disease. These breakthroughs and several of the resulting drug development efforts are reviewed. (c) 2010 Elsevier Inc. All rights reserved.

Computation as the mechanistic bridge between precision medicine and systems therapeutics.

PubMed

Hansen, J; Iyengar, R

2013-01-01

Over the past 50 years, like molecular cell biology, medicine and pharmacology have been driven by a reductionist approach. The focus on individual genes and cellular components as disease loci and drug targets has been a necessary step in understanding the basic mechanisms underlying tissue/organ physiology and drug action. Recent progress in genomics and proteomics, as well as advances in other technologies that enable large-scale data gathering and computational approaches, is providing new knowledge of both normal and disease states. Systems-biology approaches enable integration of knowledge from different types of data for precision medicine and systems therapeutics. In this review, we describe recent studies that contribute to these emerging fields and discuss how together these fields can lead to a mechanism-based therapy for individual patients.

Computation as the Mechanistic Bridge Between Precision Medicine and Systems Therapeutics

PubMed Central

Hansen, J; Iyengar, R

2014-01-01

Over the past 50 years, like molecular cell biology, medicine and pharmacology have been driven by a reductionist approach. The focus on individual genes and cellular components as disease loci and drug targets has been a necessary step in understanding the basic mechanisms underlying tissue/organ physiology and drug action. Recent progress in genomics and proteomics, as well as advances in other technologies that enable large-scale data gathering and computational approaches, is providing new knowledge of both normal and disease states. Systems-biology approaches enable integration of knowledge from different types of data for precision medicine and systems therapeutics. In this review, we describe recent studies that contribute to these emerging fields and discuss how together these fields can lead to a mechanism-based therapy for individual patients. PMID:23212109

Photo- and radiation chemical induced degradation of lignin model compounds.

PubMed

Lanzalunga; Bietti, M

2000-07-01

The basic mechanistic aspects of the photo- and radiation chemistry of lignin model compounds (LMCs) are discussed with respect to important processes related to lignin degradation. Several reactions occur after direct irradiation, photosensitized or radiation chemically induced oxidation of LMCs. Direct irradiation studies on LMCs have provided supportive evidence for the involvement of hydrogen abstraction reactions from phenols, beta-cleavage of substituted alpha-aryloxyacetophenones and cleavage of ketyl radicals (formed by photoreduction of aromatic ketones or hydrogen abstraction from arylglycerol beta-aryl ethers) in the photoyellowing of lignin rich pulps. Photosensitized and radiation chemically induced generation of reactive oxygen species and their reaction with LMCs are reviewed. The side-chain reactivity of LMC radical cations, generated by radiation chemical means, is also discussed in relation with the enzymatic degradation of lignin.

PI3K-AKT-mTOR-Signaling and beyond: the Complex Network in Gastroenteropancreatic Neuroendocrine Neoplasms

PubMed Central

Briest, Franziska; Grabowski, Patricia

2014-01-01

Gastroenteropancreatic neuroendocrine neoplasms are heterogeneous in their clinical behavior and require therapies specially tailored according to staging, grading, origin and expression of peptide receptors. Despite extensive scientific efforts, the therapy options are still not satisfactory. The main reasons are due to the lack of a broad mechanistic knowledge, an insufficient classification of specific diagnostic sub-groups, and predictive markers. GEP-NEN tumors evade early diagnosis because of slow asymptomatic growth behavior and are frequently not detected until metastasized. How signaling networks contribute to tumor progression and how these networks interact remains unclear in large parts. In this review we summarize the knowledge on the growth factor responsive non-angiogenetic pathways in sporadic GEP-NENs, highlight promising mechanistic research approaches, and describe important therapy targets. PMID:24578720

The ACEE program and basic composites research at Langley Research Center (1975 to 1986): Summary and bibliography

NASA Technical Reports Server (NTRS)

Dow, Marvin B.

1987-01-01

Composites research conducted at the Langley Research Center during the period from 1975 to 1986 is described, and an annotated bibliography of over 600 documents (with their abstracts) is presented. The research includes Langley basic technology and the composite primary structures element of the NASA Aircraft Energy Efficiency (ACEE) Program. The basic technology documents cited in the bibliography are grouped according to the research activity such as design and analysis, fatigue and fracture, and damage tolerance. The ACEE documents cover development of composite structures for transport aircraft.

Affective science perspectives on cancer control: Strategically crafting a mutually beneficial research agenda

PubMed Central

Ferrer, Rebecca A.; McDonald, Paige Green; Barrett, Lisa Feldman

2015-01-01

Cancer control research involves the conduct of basic and applied behavioral and social sciences to reduce cancer incidence, morbidity, and mortality, and improve quality of life. Given the importance of behavior in cancer control, fundamental research is necessary to identify psychological mechanisms underlying cancer risk, prevention, and management behaviors. Cancer prevention, diagnosis, and treatment are often emotionally-laden. As such, affective science research to elucidate questions related to basic phenomenological nature of emotion, stress, and mood is necessary to understand how cancer control can be hindered or facilitated by emotional experiences. To date, the intersection of basic affective science research and cancer control remains largely unexplored. The goal of this paper is to outline key questions in the cancer control research domain that provide an ecologically valid context for new affective science discoveries. We also provide examples of ways in which basic affective discoveries could inform future cancer prevention and control research. These examples are not meant to be exhaustive or prescriptive, but instead are offered to generate creative thought about the promise of a cancer research context for answering basic affective science questions. Together, these examples provide a compelling argument for fostering collaborations between affective and cancer control scientists. PMID:25987511

Water Resources Research October 1, 1979 - September 30, 1980: Summary statements of research activities by the Water Resources Division

USGS Publications Warehouse

,

1981-01-01

Research in the WRD had its beginnings in the late 1950's when the "core research" line item was added to the Congressional budget. Since this time the Federal program has grown from a "basic sciences" program to one that includes a broad spectrum of basic and applied scientific investigations. Water resources research in WRD includes the study of water in all its phases and uses the basic sciences of mathematics, chemistry, physics, biology, geology and engineering to gain a fundamental understanding of the processes that affect the movement of water and its chemical constituents through hydrologic systems. The basic knowledge and methodologies derived from water resources research are applicable not only to the solution of current problems associated with the Nation's water resources, but also to anticipated hydrologic issues.

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

Fundamentals of neurogastroenterology: basic science.

PubMed

Grundy, David; Al-Chaer, Elie D; Aziz, Qasim; Collins, Stephen M; Ke, Meiyun; Taché, Yvette; Wood, Jackie D

2006-04-01

The focus of neurogastroenterology in Rome II was the enteric nervous system (ENS). To avoid duplication with Rome II, only advances in ENS neurobiology after Rome II are reviewed together with stronger emphasis on interactions of the brain, spinal cord, and the gut in terms of relevance for abdominal pain and disordered gastrointestinal function. A committee with expertise in selective aspects of neurogastroenterology was invited to evaluate the literature and provide a consensus overview of the Fundamentals of Neurogastroenterology textbook as they relate to functional gastrointestinal disorders (FGIDs). This review is an abbreviated version of a fuller account that appears in the forthcoming book, Rome III. This report reviews current basic science understanding of visceral sensation and its modulation by inflammation and stress and advances in the neurophysiology of the ENS. Many of the concepts are derived from animal studies in which the physiologic mechanisms underlying visceral sensitivity and neural control of motility, secretion, and blood flow are examined. Impact of inflammation and stress in experimental models relative to FGIDs is reviewed as is human brain imaging, which provides a means for translating basic science to understanding FGID symptoms. Investigative evidence and emerging concepts implicate dysfunction in the nervous system as a significant factor underlying patient symptoms in FGIDs. Continued focus on neurogastroenterologic factors that underlie the development of symptoms will lead to mechanistic understanding that is expected to directly benefit the large contingent of patients and care-givers who deal with FGIDs.

Adsorption behavior of benzenesulfonic acid by novel weakly basic anion exchange resins.

PubMed

Sun, Yue; Zuo, Peng; Luo, Junfen; Singh, Rajendra Prasad

2017-04-01

Two novel weakly basic anion exchange resins (SZ-1 and SZ-2) were prepared via the reaction of macroporous chloromethylated polystyrene-divinylbenzene (Cl-PS-DVB) beads with dicyclohexylamine and piperidine, respectively. The physicochemical structures of the resulting resins were characterized using Fourier Transform Infrared Spectroscopy and pore size distribution analysis. The adsorption behavior of SZ-1 and SZ-2 for benzenesulfonic acid (BA) was evaluated, and the common commercial weakly basic anion exchanger D301 was also employed for comparison purpose. Adsorption isotherms and influence of solution pH, temperature and coexisting competitive inorganic salts (Na 2 SO 4 and NaCl) on adsorption behavior were investigated and the optimum desorption agent was obtained. Adsorption isotherms of BA were found to be well represented by the Langmuir model. Thermodynamic parameters involving ΔH, ΔG and ΔS were also calculated and the results indicate that adsorption is an exothermic and spontaneous process. Enhanced selectivity of BA sorption over sulfate on the two novel resins was observed by comparison with the commercial anion exchanger D301. The fact that the tested resins loaded with BA can be efficiently regenerated by NaCl solution indicates the reversible sorption process. From a mechanistic viewpoint, this observation clearly suggests that electrostatic interaction is the predominant adsorption mechanism. Furthermore, results of column tests show that SZ-1 possesses a better adsorption property than D301, which reinforces the feasibility of SZ-1 for potential industrial application. Copyright © 2016. Published by Elsevier B.V.

Senior Computational Scientist | Center for Cancer Research

Cancer.gov

The Basic Science Program (BSP) pursues independent, multidisciplinary research in basic and applied molecular biology, immunology, retrovirology, cancer biology, and human genetics. Research efforts and support are an integral part of the Center for Cancer Research (CCR) at the Frederick National Laboratory for Cancer Research (FNLCR). The Cancer & Inflammation Program (CIP),

Secretary | Center for Cancer Research

Cancer.gov

The Basic Science Program (BSP) pursues independent, multidisciplinary research programs in basic or applied molecular biology, immunology, retrovirology, cancer biology, or human genetics. Research efforts and support are an integral part of the Center for Cancer Research (CCR) at the Frederick national Laboratory for Cancer Research (FNLCR). The BSP Office provides

Views of Translational Research from a Somewhat Translational Scientist

PubMed Central

Talman, William T.

2013-01-01

This review arose from a talk entitled “Identifying Targets” and given by the author at EB2011 at the invitation of the American Federation for Medical Research (AFMR). The presentation was part of the AFMR workshop entitled “Keys for Translation: Science and Strategy” and focused on identifying clinically relevant targets as a result of observations made during basic scientific studies. The review emphasizes that targets do not have to be the aim that drives basic discovery, but communication between the basic scientist and clinical investigators may aid recognition of such targets and their translation to clinical applications. Using one line of investigator-initiated research from his own laboratory as an example, the author emphasizes that basic discovery must be hypothesis driven and allowed to follow its logical sequence. Finding treatments, while always an aim of biomedical research, may arise as a result of basic studies that were not originally aimed at a target of translational research. PMID:22781556

Basic Research in the Mission Agencies: Agency Perspectives on the Conduct and Support of Basic Research. Report of the National Science Board, 1978.

ERIC Educational Resources Information Center

National Science Foundation, Washington, DC. National Science Board.

A survey was conducted by the National Science Board of the basic research supported by executive branch agencies of the federal government. Most of the data came from information solicited by the Board from federal agencies involved in science. Fourteen mission agencies and two agencies not so classified and 20 subunits of these responded.…

Basic and Applied Research on Education and Social Inequality: Proceedings of the New York Education Policy Seminar (6th, Albany, New York, November 1988).

ERIC Educational Resources Information Center

Alexander, Karl L.; And Others

A seminar paper concerning the relationship between applied and basic research in the study of educational and social inequality, and two commentaries are presented. The paper--"In Defense of Ivory-Towerism: Confessions of an Unreconstructed Basic Researcher," by Karl L. Alexander, the seminar's main speaker, presents the point of view of a…

[The Basic-Symptom Concept and its Influence on Current International Research on the Prediction of Psychoses].

PubMed

Schultze-Lutter, F

2016-12-01

The early detection of psychoses has become increasingly relevant in research and clinic. Next to the ultra-high risk (UHR) approach that targets an immediate risk of developing frank psychosis, the basic symptom approach that targets the earliest possible detection of the developing disorder is being increasingly used worldwide. The present review gives an introduction to the development and basic assumptions of the basic symptom concept, summarizes the results of studies on the specificity of basic symptoms for psychoses in different age groups as well as on studies of their psychosis-predictive value, and gives an outlook on future results. Moreover, a brief introduction to first recent imaging studies is given that supports one of the main assumptions of the basic symptom concept, i. e., that basic symptoms are the most immediate phenomenological expression of the cerebral aberrations underlying the development of psychosis. From this, it is concluded that basic symptoms might be able to provide important information on future neurobiological research on the etiopathology of psychoses. © Georg Thieme Verlag KG Stuttgart · New York.

A snapshot of translational research funded by the National Institutes of Health (NIH): A case study using behavioral and social science research awards and Clinical and Translational Science Awards funded publications.

PubMed

Han, Xueying; Williams, Sharon R; Zuckerman, Brian L

2018-01-01

The translation of biomedical research from basic knowledge to application has been a priority at the National Institute of Health (NIH) for many years. Tracking the progress of scientific research and knowledge through the translational process is difficult due to variation in the definition of translational research as well as the identification of benchmarks for the spread and application of biomedical research; quantitatively tracking this process is even more difficult. Using a simple and reproducible method to assess whether publications are translational, we examined NIH R01 behavioral and social science research (BSSR) awards funded between 2008 and 2014 to determine whether there are differences in the percent of translational research publications produced by basic and applied research awards. We also assessed the percent of translational research publications produced by the Clinical and Translational Science Awards (CTSA) program to evaluate whether targeted translational research awards result in increased translational research. We found that 3.9% of publications produced by basic research awards were translational; that the percent of translational research publications produced by applied research awards is approximately double that of basic research awards (7.4%); and that targeted translational research awards from the CTSA program produced the highest percentage of translational research publications (13.4%). In addition, we assessed differences in time to first publication, time to first citation, and publication quality by award type (basic vs. applied), and whether an award (or publication) is translational.

A snapshot of translational research funded by the National Institutes of Health (NIH): A case study using behavioral and social science research awards and Clinical and Translational Science Awards funded publications

PubMed Central

Williams, Sharon R.; Zuckerman, Brian L.

2018-01-01

The translation of biomedical research from basic knowledge to application has been a priority at the National Institute of Health (NIH) for many years. Tracking the progress of scientific research and knowledge through the translational process is difficult due to variation in the definition of translational research as well as the identification of benchmarks for the spread and application of biomedical research; quantitatively tracking this process is even more difficult. Using a simple and reproducible method to assess whether publications are translational, we examined NIH R01 behavioral and social science research (BSSR) awards funded between 2008 and 2014 to determine whether there are differences in the percent of translational research publications produced by basic and applied research awards. We also assessed the percent of translational research publications produced by the Clinical and Translational Science Awards (CTSA) program to evaluate whether targeted translational research awards result in increased translational research. We found that 3.9% of publications produced by basic research awards were translational; that the percent of translational research publications produced by applied research awards is approximately double that of basic research awards (7.4%); and that targeted translational research awards from the CTSA program produced the highest percentage of translational research publications (13.4%). In addition, we assessed differences in time to first publication, time to first citation, and publication quality by award type (basic vs. applied), and whether an award (or publication) is translational. PMID:29742129

Computational mechanistic investigation of radiation damage of adenine induced by hydroxyl radicals

NASA Astrophysics Data System (ADS)

Tan, Rongri; Liu, Huixuan; Xun, Damao; Zong, Wenjun

2018-02-01

Not Available Project supported by the National Natural Science Foundation of China (Grant Nos. 11564015 and 61404062), the Research Fund for the Doctoral Program of China (Grant No. 3000990110), and the Fund for Distinguished Young Scholars of Jiangxi Science & Technology Normal University (Grant Nos. 2015QNBJRC002 and 2016QNBJRC006).

CARDIOMETABOLIC, AUTONOMIC, AND AIRWAY TOXICITY OF ACUTE EXPOSURES TO PM2.5 FROM MULTIPOLLUTANT ATMOSPHERES IN THE GREAT LAKES REGION

EPA Science Inventory

Our research has the potential to identify potentially harmful effects of exposures to specific PM_2.5 components, emission sources, and O₃ to cardiovascular function. It will also provide mechanistic evidence for the dysregulation of normal cardiovascular...

78 FR 42528 - National Center for Complementary & Alternative Medicine; Notice of Closed Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-16

... Complementary & Alternative Medicine; Notice of Closed Meeting Pursuant to section 10(d) of the Federal Advisory... Alternative Medicine Special Emphasis Panel RFA-AT-11-011: Mechanistic Research on CAM Natural Products (R01... Center for Complementary & Alternative Medicine, NIH, 6707 Democracy Blvd., Suite 401, Bethesda, MD 20892...

The Self-Managing School: A Matter of Being and of Becoming.

ERIC Educational Resources Information Center

Beavis, Allan K.

This paper explores possibilities within a paradigm that is an alternative to the reductionist, mechanistic paradigm of school-based management. The use of a "sporting team" concept (from a dynamic, holistic paradigm) rather than a "ship's crew" model (from a reductionist approach) is advocated. Using research on the governance…

A MECHANISTIC MODEL FOR ESTIMATING VOC EMISSIONS FROM INDUSTRIAL PROCESS DRAINS PART I: THE UNDERLYING CHANNEL. (R823335)

EPA Science Inventory

Recent research has indicated the potential for emissions of volatile organic compound
(VOCs) from industrial process drains, and a need for better understanding of the mass transfer
kinetics associated with such emissions. rn this study, a two-zone model was developed in a...

Big data, big knowledge: big data for personalized healthcare.

PubMed

Viceconti, Marco; Hunter, Peter; Hose, Rod

2015-07-01

The idea that the purely phenomenological knowledge that we can extract by analyzing large amounts of data can be useful in healthcare seems to contradict the desire of VPH researchers to build detailed mechanistic models for individual patients. But in practice no model is ever entirely phenomenological or entirely mechanistic. We propose in this position paper that big data analytics can be successfully combined with VPH technologies to produce robust and effective in silico medicine solutions. In order to do this, big data technologies must be further developed to cope with some specific requirements that emerge from this application. Such requirements are: working with sensitive data; analytics of complex and heterogeneous data spaces, including nontextual information; distributed data management under security and performance constraints; specialized analytics to integrate bioinformatics and systems biology information with clinical observations at tissue, organ and organisms scales; and specialized analytics to define the "physiological envelope" during the daily life of each patient. These domain-specific requirements suggest a need for targeted funding, in which big data technologies for in silico medicine becomes the research priority.

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

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.

Planning for bird conservation: a tale of two models

USGS Publications Warehouse

Johnson, Douglas H.; Winter, Maiken

2005-01-01

Planning for bird conservation has become increasingly reliant on remote sensing, geographical information systems, and, especially, models used to predict the occurrence of bird species as well as their density and demographics. We address the role of such tools by contrasting two models used in bird conservation. One, the Mallard ( Anas platyrhynchos) productivity model, is very detailed, mechanistic, and based on an enormous body of research. The Mallard model has been extensively used with success to guide management efforts for Mallards and certain other species of ducks. The other model, the concept of Bird Conservation Areas, is more simple, less mechanistic, and less well-grounded in research. This concept proposes that large patches of suitable habitat in a proper landscape will be adequate to maintain populations of birds. The Bird Conservation Area concept recently has been evaluated in the northern tallgrass prairie, where its fundamental assumptions have been found not to hold consistently. We argue that a more comprehensive understanding of the biology of individual species, and how they respond to habitat features, will be essential before we can use remotely sensed information and geographic information system products with confidence.

Basic Research and Progress against Cancer

Cancer.gov

An infographic about the importance of basic research for making progress against cancer. The graphic shows the research milestones that led to the development and approval of crizotinib (Xalkori®) to treat certain non-small cell lung cancers.

A roadmap for bridging basic and applied research in forensic entomology.

PubMed

Tomberlin, J K; Mohr, R; Benbow, M E; Tarone, A M; VanLaerhoven, S

2011-01-01

The National Research Council issued a report in 2009 that heavily criticized the forensic sciences. The report made several recommendations that if addressed would allow the forensic sciences to develop a stronger scientific foundation. We suggest a roadmap for decomposition ecology and forensic entomology hinging on a framework built on basic research concepts in ecology, evolution, and genetics. Unifying both basic and applied research fields under a common umbrella of terminology and structure would facilitate communication in the field and the production of scientific results. It would also help to identify novel research areas leading to a better understanding of principal underpinnings governing ecosystem structure, function, and evolution while increasing the accuracy of and ability to interpret entomological evidence collected from crime scenes. By following the proposed roadmap, a bridge can be built between basic and applied decomposition ecology research, culminating in science that could withstand the rigors of emerging legal and cultural expectations.

Human reliability in petrochemical industry: an action research.

PubMed

Silva, João Alexandre Pinheiro; Camarotto, João Alberto

2012-01-01

This paper aims to identify conflicts and gaps between the operators' strategies and actions and the organizational managerial approach for human reliability. In order to achieve these goals, the research approach adopted encompasses literature review, mixing action research methodology and Ergonomic Workplace Analysis in field research. The result suggests that the studied company has a classical and mechanistic point of view focusing on error identification and building barriers through procedures, checklists and other prescription alternatives to improve performance in reliability area. However, it was evident the fundamental role of the worker as an agent of maintenance and construction of system reliability during the action research cycle.

National Institutes of Health Update: Translating Basic Behavioral Science into New Pediatric Obesity Interventions.

PubMed

Czajkowski, Susan M

2016-06-01

Pediatric obesity increases the risk of later-life obesity and chronic diseases. Basic research to better understand factors associated with excessive weight gain in early life and studies translating research findings into preventive and therapeutic strategies are essential to our ability to better prevent and treat childhood obesity. This overview describes several National Institutes of Health efforts designed to stimulate basic and translational research in childhood obesity prevention and treatment. These examples demonstrate the value of research in early phase translational pediatric obesity research and highlight some promising directions for this important area of research. Published by Elsevier Inc.

Structural Perspective on Enzymatic Halogenation

PubMed Central

2008-01-01

Simple halogen substituents frequently afford key structural features that account for the potency and selectivity of natural products, including antibiotics and hormones. For example, when a single chlorine atom on the antibiotic vancomycin is replaced by hydrogen, the resulting antibacterial activity decreases by up to 70% (HarrisC. M.; KannanR.; KopeckaH.; HarrisT. M.J. Am. Chem. Soc.1985, 107, 6652−6658). This Account analyzes how structure underlies mechanism in halogenases, the molecular machines designed by nature to incorporate halogens into diverse substrates. Traditional synthetic methods of integrating halogens into complex molecules are often complicated by a lack of specificity and regioselectivity. Nature, however, has developed a variety of elegant mechanisms for halogenating specific substrates with both regio- and stereoselectivity. An improved understanding of the biological routes toward halogenation could lead to the development of novel synthetic methods for the creation of new compounds with enhanced functions. Already, researchers have co-opted a fluorinase from the microorganism Streptomyces cattleya to produce 18F-labeled molecules for use in positron emission tomography (PET) (DengH.; CobbS. L.; GeeA. D.; LockhartA.; MartarelloL.; McGlincheyR. P.; O’HaganD.; OnegaM.Chem. Commun.2006, 652−654). Therefore, the discovery and characterization of naturally occurring enzymatic halogenation mechanisms has become an active area of research. The catalogue of known halogenating enzymes has expanded from the familiar haloperoxidases to include oxygen-dependent enzymes and fluorinases. Recently, the discovery of a nucleophilic halogenase that catalyzes chlorinations has expanded the repertoire of biological halogenation chemistry (DongC.; HuangF.; DengH.; SchaffrathC.; SpencerJ. B.; O’HaganD.; NaismithJ. H.Nature2004, 427, 561−56514765200). Structural characterization has provided a basis toward a mechanistic understanding of the specificity and chemistry of these enzymes. In particular, the latest crystallographic snapshots of active site architecture and halide binding sites have provided key insights into enzyme catalysis. Herein is a summary of the five classes of halogenases, focusing on the three most recently discovered: flavin-dependent halogenases, non-heme iron-dependent halogenases, and nucleophilic halogenases. Further, the potential roles of halide-binding sites in determining halide selectivity are discussed, as well as whether or not binding-site composition is always a seminal factor for selectivity. Expanding our understanding of the basic chemical principles that dictate the activity of the halogenases will advance both biology and chemistry. A thorough mechanistic analysis will elucidate the biological principles that dictate specificity, and the application of those principles to new synthetic techniques will expand the utility of halogenations in small-molecule development. PMID:18774824

University Research: The Role of Federal Funding

ERIC Educational Resources Information Center

Association of American Universities, 2011

2011-01-01

University research is a vital building block of the nation's research and development (R&D) enterprise. While U.S. universities perform just 13 percent of total national R&D, they perform 31 percent of the nation's total research--basic and applied--and 56 percent of the nation's basic research. Because there is broad consensus that…

THE DEVELOPING CLIMATE FOR READING RESEARCH--PROGRAMS VS. PROJECTS.

ERIC Educational Resources Information Center

ADAMS, RICHARD B.; PENNEY, MONTE

PROGRAMMATIC RESEARCH IS DISCUSSED AS ONE OF THE BASIC NEEDS OF READING RESEARCH. OTHER NEEDS ARE--(1) FOR BASIC RESEARCH THAT FOCUSES ON THE READING PROCESS, (2) FOR LEADERSHIP THAT VALUES SCIENTIFIC OBJECTIVITY AND INTELLECTUAL HONESTY, AND (3) TO INFORM AND CONVINCE THE PUBLIC OF THE POSSIBLE CONTRIBUTIONS OF READING RESEARCH. PROGRAMMATIC…

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 ...

An Introduction to Research and the Computer: A Self-Instructional Package.

ERIC Educational Resources Information Center

Vasu, Ellen Storey; Palmer, Richard I.

This self-instructional package includes learning objectives, definitions, exercises, and feedback for learning some basic concepts and skills involved in using computers for analyzing data and understanding basic research terminology. Learning activities are divided into four sections: research and research hypotheses; variables, cases, and…

[Protoplasm, coagulation and colloids : Forgotten chapter in the research history of anesthesia between Zeitgeist and paradigm].

PubMed

Perouansky, M

2015-05-01

The historically most important mechanistic theories attributed the fundamental cause of anesthesia to interactions betweeen anesthetics and proteins as early as the 1870s. According to the underlying thought, the resulting changes in the consistency of cellular protoplasm were the cause of the anesthetized state of the whole organism.These protoplasm coagulation theories, as they were collectively referred to, brought the contemporary enthusiasm for protoplasm, the rapid advances in colloid chemistry and the unified theory of narcosis proclamed by Claude Bernard under a unified mechanistic theory that reflected the Zeitgeist of the epoch.This research effort, on the intersection of the developing disciplines of cellular biology and colloid chemistry, lasted for almost a century. It involved scientists of worldwide reputation and resulted in a number of elegant theories. Contrary to widespread opinion, proteins and not lipids were recognized and investigated first as the critical molecular target of anesthetics more than a century prior to their much publicized rediscovery in 1984.The protoplasm coagulation theories of anesthesia were pursued after the First World War across ideological trenches by scientists in Europe, the Soviet Union and the United States. They united research in anesthesia with research of fundamental cell biology.In contrast to the much less fruitful lipid theories, protoplasm coagulation theories are largely forgotten without leaving a trace in contemporary discussions of the history of anesthesia. For many tyears, however, they constituted an essential part of fundamental anesthetic research and must therefore be mentioned in any historical review.

The Basic Regularities of Education and Their Application in Higher Education Research and Practice: Brief Description of the Basic Regularities ("Guilu") of Education

ERIC Educational Resources Information Center

Maoyuan, Pan

2007-01-01

Research on the issues of higher education has been going on for a long time. However, higher education pedagogy as independent discipline has been present in China for only about ten years. The structure of a discipline cannot consist merely of a compilation of the issues under research but must also include its basic theories and a system of…

Teacher Effectiveness as Correlate of Students' Cognitive Achievement at Upper Basic Education in Basic Technology

ERIC Educational Resources Information Center

Owoh, Titus M.

2016-01-01

This study sought to find out the relationship between students perception of their teacher effectiveness and academic achievement in Basic Technology. Teacher's personality, teaching techniques/classroom management strategy and appearance, all integrate to make for teacher effectiveness. To carry out this research, two research questions and one…

From Research to Practice in Adult Basic Education. Final Project Report.

ERIC Educational Resources Information Center

Schroeder, Wayne L., Comp.; Divita, Charles, Jr., Comp.

The strategies whereby relevant findings and implications of empirical research could become known to and employed by adult basic education practitioners in solving their problems are demonstrated. Efforts were made to: (1) Identify significant problems in the practice of adult basic education; (2) Conduct a thorough search of the research…

Roadsigns from Research. BASICS: Bridging Vocational and Academic Skills.

ERIC Educational Resources Information Center

Sechler, Judith A.; Crowe, Michael R.

This document responds to the need for integration of basic skills into vocational education by providing a summary of research findings, implications, and practical suggestions for teachers. The six sections and four complementary posters are intended as tools for staff development of teachers engaged in teaching basic skills. Sections can also…

Basic research needed for stimulating the development of behavioral technologies

PubMed Central

Mace, F. Charles

1994-01-01

The costs of disconnection between the basic and applied sectors of behavior analysis are reviewed, and some solutions to these problems are proposed. Central to these solutions are collaborations between basic and applied behavioral scientists in programmatic research that addresses the behavioral basis and solution of human behavior problems. This kind of collaboration parallels the deliberate interactions between basic and applied researchers that have proven to be so profitable in other scientific fields, such as medicine. Basic research questions of particular relevance to the development of behavioral technologies are posed in the following areas: response allocation, resistance to change, countercontrol, formation and differentiation/discrimination of stimulus and response classes, analysis of low-rate behavior, and rule-governed behavior. Three interrelated strategies to build connections between the basic and applied analysis of behavior are identified: (a) the development of nonhuman animal models of human behavior problems using operations that parallel plausible human circumstances, (b) replication of the modeled relations with human subjects in the operant laboratory, and (c) tests of the generality of the model with actual human problems in natural settings. PMID:16812734

Extraterrestrial research in the Federal Republic of Germany

NASA Technical Reports Server (NTRS)

1986-01-01

This German program for basic extraterrestrial research is an essential, successful, and worldwide recognized part of the space program and has the same attributes for basic research in the Federal Republic of Germany. It covers all major scientific disciplines.

Affective science perspectives on cancer control: strategically crafting a mutually beneficial research agenda.

PubMed

Ferrer, Rebecca A; Green, Paige A; Barrett, Lisa Feldman

2015-05-01

Cancer control research involves the conduct of basic and applied behavioral and social sciences to reduce cancer incidence, morbidity, and mortality and improve quality of life. Given the importance of behavior in cancer control, fundamental research is necessary to identify psychological mechanisms underlying cancer risk, prevention, and management behaviors. Cancer prevention, diagnosis, and treatment are often emotionally laden. As such, affective science research to elucidate questions related to the basic phenomenological nature of emotion, stress, and mood is necessary to understand how cancer control can be hindered or facilitated by emotional experiences. To date, the intersection of basic affective science research and cancer control remains largely unexplored. The goal of this article is to outline key questions in the cancer control research domain that provide an ecologically valid context for new affective science discoveries. We also provide examples of ways in which basic affective discoveries could inform future cancer prevention and control research. These examples are not meant to be exhaustive or prescriptive but instead are offered to generate creative thought about the promise of a cancer research context for answering basic affective science questions. Together, these examples provide a compelling argument for fostering collaborations between affective and cancer control scientists. © The Author(s) 2015.

Professional fulfillment and parenting work-life balance in female physicians in Basic Sciences and medical research: a nationwide cross-sectional survey of all 80 medical schools in Japan.

PubMed

Yamazaki, Yuka; Uka, Takanori; Marui, Eiji

2017-09-15

In Japan, the field of Basic Sciences encompasses clinical, academic, and translational research, as well as the teaching of medical sciences, with both an MD and PhD typically required. In this study, it was hypothesized that the characteristics of a Basic Sciences career path could offer the professional advancement and personal fulfillment that many female medical doctors would find advantageous. Moreover, encouraging interest in Basic Sciences could help stem shortages that Japan is experiencing in medical fields, as noted in the three principal contributing factors: premature resignation of female clinicians, an imbalance of female physicians engaged in research, and a shortage of medical doctors in the Basic Sciences. This study examines the professional and personal fulfillment expressed by Japanese female medical doctors who hold positions in Basic Sciences. Topics include career advancement, interest in medical research, and greater flexibility for parenting. A cross-sectional questionnaire survey was distributed at all 80 medical schools in Japan, directed to 228 female medical doctors whose academic rank was assistant professor or higher in departments of Basic Sciences in 2012. Chi-square tests and the binary logistic regression model were used to investigate the impact of parenthood on career satisfaction, academic rank, salary, etc. The survey response rate of female physicians in Basic Sciences was 54.0%. Regardless of parental status, one in three respondents cited research interest as their rationale for entering Basic Sciences, well over twice other motivations. A majority had clinical experience, with clinical duties maintained part-time by about half of respondents and particularly parents. Only one third expressed afterthoughts about relinquishing full-time clinical practice, with physicians who were parents expressing stronger regrets. Parental status had little effect on academic rank and income within the Basic Sciences, CONCLUSION: Scientific curiosity and a desire to improve community health are hallmarks of those choosing a challenging career in medicine. Therefore, it is unsurprising that interest in research is the primary motivation for a female medical doctor to choose a career in Basic Sciences. Additionally, as with many young professionals with families, female doctors seek balance in professional and private lives. Although many expressed afterthoughts relinquishing a full-time clinical practice, mothers generally benefited from greater job flexibility, with little significant effect on career development and income as Basic Scientists.

Stem Cell Basics

MedlinePlus

... Tips Info Center Research Topics Federal Policy Glossary Stem Cell Information General Information Clinical Trials Funding Information Current ... Basics » Stem Cell Basics I. Back to top Stem Cell Basics I. Introduction: What are stem cells, and ...

8-CPT-cAMP/all-trans retinoic acid targets t(11;17) acute promyelocytic leukemia through enhanced cell differentiation and PLZF/RARα degradation

PubMed Central

Jiao, Bo; Ren, Zhi-Hong; Liu, Ping; Chen, Li-Juan; Shi, Jing-Yi; Dong, Ying; Ablain, Julien; Shi, Lin; Gao, Li; Hu, Jun-Pei; Ren, Rui-Bao; de Thé, Hugues; Chen, Zhu; Chen, Sai-Juan

2013-01-01

The refractoriness of acute promyelocytic leukemia (APL) with t(11;17)(q23;q21) to all-trans retinoic acid (ATRA)-based therapy concerns clinicians and intrigues basic researchers. By using a murine leukemic model carrying both promyelocytic leukemia zinc finger/retinoic acid receptor-α (PLZF/RARα) and RARα/PLZF fusion genes, we discovered that 8-chlorophenylthio adenosine-3′, 5′-cyclic monophosphate (8-CPT-cAMP) enhances cellular differentiation and improves gene trans-activation by ATRA in leukemic blasts. Mechanistically, in combination with ATRA, 8-CPT-cAMP activates PKA, causing phosphorylation of PLZF/RARα at Ser765 and resulting in increased dissociation of the silencing mediator for retinoic acid and thyroid hormone receptors/nuclear receptor corepressor from PLZF/RARα. This process results in changes of local chromatin and transcriptional reactivation of the retinoic acid pathway in leukemic cells. Meanwhile, 8-CPT-cAMP also potentiated ATRA-induced degradation of PLZF/RARα through its Ser765 phosphorylation. In vivo treatment of the t(11;17) APL mouse model demonstrated that 8-CPT-cAMP could significantly improve the therapeutic effect of ATRA by targeting a leukemia-initiating cell activity. This combined therapy, which induces enhanced differentiation and oncoprotein degradation, may benefit t(11;17) APL patients. PMID:23382200

Mechanical constraint from growing jaw facilitates mammalian dental diversity

PubMed Central

Renvoisé, Elodie; Kavanagh, Kathryn D.; Lazzari, Vincent; Häkkinen, Teemu J.; Rice, Ritva; Pantalacci, Sophie; Salazar-Ciudad, Isaac; Jernvall, Jukka

2017-01-01

Much of the basic information about individual organ development comes from studies using model species. Whereas conservation of gene regulatory networks across higher taxa supports generalizations made from a limited number of species, generality of mechanistic inferences remains to be tested in tissue culture systems. Here, using mammalian tooth explants cultured in isolation, we investigate self-regulation of patterning by comparing developing molars of the mouse, the model species of mammalian research, and the bank vole. A distinct patterning difference between the vole and the mouse molars is the alternate cusp offset present in the vole. Analyses of both species using 3D reconstructions of developing molars and jaws, computational modeling of cusp patterning, and tooth explants cultured with small braces show that correct cusp offset requires constraints on the lateral expansion of the developing tooth. Vole molars cultured without the braces lose their cusp offset, and mouse molars cultured with the braces develop a cusp offset. Our results suggest that cusp offset, which changes frequently in mammalian evolution, is more dependent on the 3D support of the developing jaw than other aspects of tooth shape. This jaw–tooth integration of a specific aspect of the tooth phenotype indicates that organs may outsource specific aspects of their morphology to be regulated by adjacent body parts or organs. Comparative studies of morphologically different species are needed to infer the principles of organogenesis. PMID:28808032

Xenopus as a Model Organism for Birth Defects – Congenital Heart Disease and Heterotaxy

PubMed Central

Duncan, Anna R.; Khokha, Mustafa K.

2016-01-01

Congenital heart disease is the leading cause of birth defects, affecting 9 out of 1000 newborns each year. A particularly severe form of congenital heart disease is heterotaxy, a disorder of left-right development. Despite aggressive surgical management, patients with heterotaxy have poor survival rates and severe morbidity due to their complex congenital heart disease. Recent genetic analysis of affected patients has found novel candidate genes for heterotaxy although their underlying mechanisms remain unknown. In this review, we discuss the importance and challenges of birth defects research including high locus heterogeneity and few second alleles that make defining disease causality difficult. A powerful strategy moving forward is to analyze these candidate genes in a high-throughput human disease model. Xenopus is ideal for these studies. We present multiple examples demonstrating the power of Xenopus in discovery new biology from the analysis of candidate heterotaxy genes such as GALNT11, NEK2 and BCOR. These genes have diverse roles in embryos and have led to a greater understanding of complex signaling pathways and basic developmental biology. It is our hope that the mechanistic analysis of these candidate genes in Xenopus enabled by next generation sequencing of patients will provide clinicians with a greater understanding of patient pathophysiology allowing more precise and personalized medicine, to help them more effectively in the future. PMID:26910255

Dietary phytochemicals and neuro-inflammaging: from mechanistic insights to translational challenges.

PubMed

Davinelli, Sergio; Maes, Michael; Corbi, Graziamaria; Zarrelli, Armando; Willcox, Donald Craig; Scapagnini, Giovanni

2016-01-01

An extensive literature describes the positive impact of dietary phytochemicals on overall health and longevity. Dietary phytochemicals include a large group of non-nutrients compounds from a wide range of plant-derived foods and chemical classes. Over the last decade, remarkable progress has been made to realize that oxidative and nitrosative stress (O&NS) and chronic, low-grade inflammation are major risk factors underlying brain aging. Accumulated data strongly suggest that phytochemicals from fruits, vegetables, herbs, and spices may exert relevant negative immunoregulatory, and/or anti-O&NS activities in the context of brain aging. Despite the translational gap between basic and clinical research, the current understanding of the molecular interactions between phytochemicals and immune-inflammatory and O&NS (IO&NS) pathways could help in designing effective nutritional strategies to delay brain aging and improve cognitive function. This review attempts to summarise recent evidence indicating that specific phytochemicals may act as positive modulators of IO&NS pathways by attenuating pro-inflammatory pathways associated with the age-related redox imbalance that occurs in brain aging. We will also discuss the need to initiate long-term nutrition intervention studies in healthy subjects. Hence, we will highlight crucial aspects that require further study to determine effective physiological concentrations and explore the real impact of dietary phytochemicals in preserving brain health before the onset of symptoms leading to cognitive decline and inflammatory neurodegeneration.

More ecological ERA: incorporating natural environmental factors and animal behavior.

PubMed

Bednarska, Agnieszka J; Jevtić, Dragan M; Laskowski, Ryszard

2013-07-01

We discuss the importance of selected natural abiotic and biotic factors in ecological risk assessment based on simplistic laboratory bioassays. Although it is impossible to include all possible natural factors in standard lower-tier ecotoxicological testing, neglecting them is not an option. Therefore, we try to identify the most important factors and advocate redesigning standard testing procedures to include theoretically most potent interactions. We also point out a few potentially important factors that have not been studied enough so far. The available data allowed us to identify temperature and O2 depletion as the most critical factors that should be included in ecotoxicity testing as soon as possible. Temporal limitations and fluctuations in food availability also appear important, but at this point more fundamental research in this area is necessary before making decisions on their inclusion in risk assessment procedures. We propose using specific experimental designs, such as Box-Behnken or Central Composite, which allow for simultaneous testing of 3 or more factors for their individual and interactive effects with greater precision and without increasing the effort and costs of tests dramatically. Factorial design can lead to more powerful tests and help to extend the validity of conclusions. Finally, ecological risk assessment procedures should include information on animal behavior, especially feeding patterns. This requires more basic studies, but already at this point adequate mechanistic effect models can be developed for some species. Copyright © 2013 SETAC.

Quasi-equilibrium analysis of the ion-pair mediated membrane transport of low-permeability drugs.

PubMed

Miller, Jonathan M; Dahan, Arik; Gupta, Deepak; Varghese, Sheeba; Amidon, Gordon L

2009-07-01

The aim of this research was to gain a mechanistic understanding of ion-pair mediated membrane transport of low-permeability drugs. Quasi-equilibrium mass transport analyses were developed to describe the ion-pair mediated octanol-buffer partitioning and hydrophobic membrane permeation of the model basic drug phenformin. Three lipophilic counterions were employed: p-toluenesulfonic acid, 2-naphthalenesulfonic acid, and 1-hydroxy-2-naphthoic acid (HNAP). Association constants and intrinsic octanol-buffer partition coefficients (Log P(AB)) of the ion-pairs were obtained by fitting a transport model to double reciprocal plots of apparent octanol-buffer distribution coefficients versus counterion concentration. All three counterions enhanced the lipophilicity of phenformin, with HNAP providing the greatest increase in Log P(AB), 3.7 units over phenformin alone. HNAP also enhanced the apparent membrane permeability of phenformin, 27-fold in the PAMPA model, and 4.9-fold across Caco-2 cell monolayers. As predicted from a quasi-equilibrium analysis of ion-pair mediated membrane transport, an order of magnitude increase in phenformin flux was observed per log increase in counterion concentration, such that log-log plots of phenformin flux versus HNAP concentration gave linear relationships. These results provide increased understanding of the underlying mechanisms of ion-pair mediated membrane transport, emphasizing the potential of this approach to enable oral delivery of low-permeability drugs.

Hypoxia: From Placental Development to Fetal Programming.

PubMed

Fajersztajn, Lais; Veras, Mariana Matera

2017-10-16

Hypoxia may influence normal and different pathological processes. Low oxygenation activates a variety of responses, many of them regulated by hypoxia-inducible factor 1 complex, which is mostly involved in cellular control of O 2 consumption and delivery, inhibition of growth and development, and promotion of anaerobic metabolism. Hypoxia plays a significant physiological role in fetal development; it is involved in different embryonic processes, for example, placentation, angiogenesis, and hematopoiesis. More recently, fetal hypoxia has been associated directly or indirectly with fetal programming of heart, brain, and kidney function and metabolism in adulthood. In this review, the role of hypoxia in fetal development, placentation, and fetal programming is summarized. Hypoxia is a basic mechanism involved in different pregnancy disorders and fetal health developmental complications. Although there are scientific data showing that hypoxia mediates changes in the growth trajectory of the fetus, modulates gene expression by epigenetic mechanisms, and determines the health status later in adulthood, more mechanistic studies are needed. Furthermore, if we consider that intrauterine hypoxia is not a rare event, and can be a consequence of unavoidable exposures to air pollution, nutritional deficiencies, obesity, and other very common conditions (drug addiction and stress), the health of future generations may be damaged and the incidence of some diseases will markedly increase as a consequence of disturbed fetal programming. Birth Defects Research 109:1377-1385, 2017.© 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Tea, cocoa, coffee, and affective disorders: vicious or virtuous cycle?

PubMed

García-Blanco, Tatiana; Dávalos, Alberto; Visioli, Francesco

2017-12-15

The prevalence of psychiatric disorders is increasing worldwide, which underscores the importance of increasing research in this field, in terms of better detection, prevention based on improvement of lifestyle and diet, and effectiveness of treatment. Increasing evidence suggest that diet and exercise can affect proper neuronal development and physiology and protect the brain from neurological illnesses or injuries. Of note, cocoa, tea, and coffee are being actively investigated because they are rich in (poly)phenolic compounds that can modulate mental health, namely brain plasticity, behavior, mood, depression, and cognition. We here systematically review human studies conducted on tea, cocoa, and coffee as related to affective disorders such as depression and anxiety. We carried out a systematic literature search in April 2016, using MEDLINE, on data from the last 10 years. After screening 955 articles, we selected 17 articles that met the criteria of being human studies and that used whole foods or their components. The results of our systematic review indicate that consumption of tea, cocoa, or coffee might have protective effects against depression. Even though this is encouraging, it should be underscored that the near totality of the current evidence comes from observational studies. Ad-hoc human trials and mechanistic, basic science studies are needed before we can provide sound advice to the public. Copyright © 2016 Elsevier B.V. All rights reserved.

NCI’s Role in Immunotherapy Research

Cancer.gov

Advances in cancer immunotherapy are the result of several decades of basic research, much of it supported by NCI, on how the immune system responds to cancer. Learn how NCI continues to support a wide range of research, from basic research to clinical trials, to advance the field of cancer immunotherapy.

University Research: Understanding Its Role

ERIC Educational Resources Information Center

Association of American Universities, 2011

2011-01-01

Since World War II, the federal government has maintained a partnership with the nation's research universities, based on the bipartisan consensus that (1) the nation needs to invest its resources in curiosity-driven, competitively awarded basic research, and (2) basic research is best conducted at the nation's universities. As a result of that…

Summary of NIH Medical-Surgical Emergency Research Roundtable held on April 30 to May 1, 2009.

PubMed

Kaji, Amy H; Lewis, Roger J; Beavers-May, Tony; Berg, Robert; Bulger, Eileen; Cairns, Charles; Callaway, Clifton; Camargo, Carlos A; Carcillo, Joseph; DeBiasi, Roberta; Diaz, Tania; Ducharme, Francine; Glickman, Seth; Heilpern, Katherine; Hickey, Robert; Hoek, Terry Vanden; Hollander, Judd; Janson, Susan; Jurkovich, Gregory; Kellermann, Arthur; Kingsmore, Stephen; Kline, Jeffrey; Kuppermann, Nathan; Lowe, Robert; McLario, David; Nathanson, Larry; Nichol, Graham; Peitzman, Andrew; Richardson, Lynne; Sanders, Arthur; Shah, Manish; Shapiro, Nathan; Silverman, Robert; Than, Martin; Wilber, Scott; Yealy, Donald M

2010-11-01

In 2003, the Institute of Medicine Committee on the Future of Emergency Care in the United States Health System convened and identified a crisis in emergency care in the United States, including a need to enhance the research base for emergency care. As a result, the National Institutes of Health (NIH) formed an NIH Task Force on Research in Emergency Medicine to enhance NIH support for emergency care research. Members of the NIH Task Force and academic leaders in emergency care participated in 3 roundtable discussions to prioritize current opportunities for enhancing and conducting emergency care research. The objectives of these discussions were to identify key research questions essential to advancing the scientific underpinnings of emergency care and to discuss the barriers and best means to advance research by exploring the role of research networks and collaboration between the NIH and the emergency care community. The Medical-Surgical Research Roundtable was convened on April 30 to May 1, 2009. Before the roundtable, the emergency care domains to be discussed were selected and experts in each of the fields were invited to participate in the roundtable. Domain experts were asked to identify research priorities and challenges and separate them into mechanistic, translational, and clinical categories. After the conference, the lists were circulated among the participants and revised to reach a consensus. Emergency care research is characterized by focus on the timing, sequence, and time sensitivity of disease processes and treatment effects. Rapidly identifying the phenotype and genotype of patients manifesting a specific disease process and the mechanistic reasons for heterogeneity in outcome are important challenges in emergency care research. Other research priorities include the need to elucidate the timing, sequence, and duration of causal molecular and cellular events involved in time-critical illnesses and injuries, and the development of treatments capable of halting or reversing them; the need for novel animal models; and the need to understand why there are regional differences in outcome for the same disease processes. Important barriers to emergency care research include a limited number of trained investigators and experienced mentors, limited research infrastructure and support, and regulatory hurdles. The science of emergency care may be advanced by facilitating the following: (1) training emergency care investigators with research training programs; (2) developing emergency care clinical research networks; (3) integrating emergency care research into Clinical and Translational Science Awards; (4) developing emergency care-specific initiatives within the existing structure of NIH institutes and centers; (5) involving emergency specialists in grant review and research advisory processes; (6) supporting learn-phase or small, clinical trials; and (7) performing research to address ethical and regulatory issues. Enhancing the research base supporting the care of medical and surgical emergencies will require progress in specific mechanistic, translational, and clinical domains; effective collaboration of academic investigators across traditional clinical and scientific boundaries; federal support of research in high-priority areas; and overcoming limitations in available infrastructure, research training, and access to patient populations. Copyright © 2010 American College of Emergency Physicians. Published by Mosby, Inc. All rights reserved.

Using mixed methods research in medical education: basic guidelines for researchers.

PubMed

Schifferdecker, Karen E; Reed, Virginia A

2009-07-01

Mixed methods research involves the collection, analysis and integration of both qualitative and quantitative data in a single study. The benefits of a mixed methods approach are particularly evident when studying new questions or complex initiatives and interactions, which is often the case in medical education research. Basic guidelines for when to use mixed methods research and how to design a mixed methods study in medical education research are not readily available. The purpose of this paper is to remedy that situation by providing an overview of mixed methods research, research design models relevant for medical education research, examples of each research design model in medical education research, and basic guidelines for medical education researchers interested in mixed methods research. Mixed methods may prove superior in increasing the integrity and applicability of findings when studying new or complex initiatives and interactions in medical education research. They deserve an increased presence and recognition in medical education research.

Life-science research within US academic medical centers.

PubMed

Zinner, Darren E; Campbell, Eric G

2009-09-02

Besides the generic "basic" vs "applied" labels, little information is known about the types of life-science research conducted within academic medical centers (AMCs). To determine the relative proportion, characteristics, funding, and productivity of AMC faculty by the type of research they conduct. Mailed survey conducted in 2007 of 3080 life-science faculty at the 50 universities with medical schools that received the most funding from the National Institutes of Health in 2004. Response rate was 74%. Research faculty affiliated with a medical school or teaching hospital, representing 77% of respondents (n = 1663). Type of research (basic, translational, clinical trials, health services research/clinical epidemiology, multimode, other), total funding, industry funding, publications, professional activities, patenting behavior, and industry relationships. Among AMC research faculty, 33.6% exclusively conducted basic science research as principal investigators compared with translational researchers (9.1%), clinical trial investigators (7.1%), and health services researchers/clinical epidemiologists (9.0%). While principal investigators garnered a mean of $410,755 in total annual research funding, 22.1% of all AMC research faculty were unsponsored, a proportion that ranged from 11.5% for basic science researchers to 46.8% for health services researchers (P < .001). The average AMC faculty member received $33,417 in industry-sponsored funding, with most of this money concentrated among clinical trial ($110,869) and multimode ($59,916) principal investigators. Translational (61.3%), clinical trial (67.3%), and multimode (70.9%) researchers were significantly more likely than basic science researchers (41.9%) to report a relationship with industry and that these relationships contributed to their most important scientific work (P < .05 for all comparisons). The research function of AMCs is active and diverse, incorporating a substantial proportion of faculty who are conducting research and publishing without sponsorship.

Applied vs Basic Research: On Maintaining Your Balance with a Foot in Each Camp.

ERIC Educational Resources Information Center

Martin, David W.

The paper discusses a number of issues concerning the practical usefulness of cognitive psychology research, and presents a case study of pilot training methods to illustrate a model of research processes that produces outcomes which contribute to both basic and applied research goals. Research studies are described as varying in the degree to…

Integrating basic research and long-term management: a case study using avian research at the Savannah River Site

Treesearch

John B. Dunning; John C. Kilgo

2000-01-01

In this introduction to Avian Research at the Savannah River Site: A Model for Integrating Basic Research and Long-term Management, editors Dunning and Kilgo discuss the interrelationship between research and management at the Savannah River Site. They emphasize the increasing need for collaboration between scientists and land managers....

10 CFR Appendix A to Part 605 - The Energy Research Program Office Descriptions

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 4 2013-01-01 2013-01-01 false The Energy Research Program Office Descriptions A Appendix... RESEARCH FINANCIAL ASSISTANCE PROGRAM Pt. 605, App. A Appendix A to Part 605—The Energy Research Program Office Descriptions 1. Basic Energy Sciences This program supports basic science research efforts in a...

10 CFR Appendix A to Part 605 - The Energy Research Program Office Descriptions

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 4 2014-01-01 2014-01-01 false The Energy Research Program Office Descriptions A Appendix... RESEARCH FINANCIAL ASSISTANCE PROGRAM Pt. 605, App. A Appendix A to Part 605—The Energy Research Program Office Descriptions 1. Basic Energy Sciences This program supports basic science research efforts in a...

10 CFR Appendix A to Part 605 - The Energy Research Program Office Descriptions

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 4 2012-01-01 2012-01-01 false The Energy Research Program Office Descriptions A Appendix... RESEARCH FINANCIAL ASSISTANCE PROGRAM Pt. 605, App. A Appendix A to Part 605—The Energy Research Program Office Descriptions 1. Basic Energy Sciences This program supports basic science research efforts in a...

10 CFR Appendix A to Part 605 - The Energy Research Program Office Descriptions

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 4 2011-01-01 2011-01-01 false The Energy Research Program Office Descriptions A Appendix... RESEARCH FINANCIAL ASSISTANCE PROGRAM Pt. 605, App. A Appendix A to Part 605—The Energy Research Program Office Descriptions 1. Basic Energy Sciences This program supports basic science research efforts in a...

Research on Basic Design Education: An International Survey

ERIC Educational Resources Information Center

Boucharenc, C. G.

2006-01-01

This paper reports on the results of a survey and qualitative analysis on the teaching of "Basic Design" in schools of design and architecture located in 22 countries. In the context of this research work, Basic Design means the teaching and learning of design fundamentals that may also be commonly referred to as the Principles of Two- and…

Fisher's geometrical model emerges as a property of complex integrated phenotypic networks.

PubMed

Martin, Guillaume

2014-05-01

Models relating phenotype space to fitness (phenotype-fitness landscapes) have seen important developments recently. They can roughly be divided into mechanistic models (e.g., metabolic networks) and more heuristic models like Fisher's geometrical model. Each has its own drawbacks, but both yield testable predictions on how the context (genomic background or environment) affects the distribution of mutation effects on fitness and thus adaptation. Both have received some empirical validation. This article aims at bridging the gap between these approaches. A derivation of the Fisher model "from first principles" is proposed, where the basic assumptions emerge from a more general model, inspired by mechanistic networks. I start from a general phenotypic network relating unspecified phenotypic traits and fitness. A limited set of qualitative assumptions is then imposed, mostly corresponding to known features of phenotypic networks: a large set of traits is pleiotropically affected by mutations and determines a much smaller set of traits under optimizing selection. Otherwise, the model remains fairly general regarding the phenotypic processes involved or the distribution of mutation effects affecting the network. A statistical treatment and a local approximation close to a fitness optimum yield a landscape that is effectively the isotropic Fisher model or its extension with a single dominant phenotypic direction. The fit of the resulting alternative distributions is illustrated in an empirical data set. These results bear implications on the validity of Fisher's model's assumptions and on which features of mutation fitness effects may vary (or not) across genomic or environmental contexts.

The State of Space Propulsion Research

NASA Technical Reports Server (NTRS)

Sackheim, R. L.; Cole, J. W.; Litchford, R. J.

2006-01-01

The current state of space propulsion research is assessed from both a historical perspective, spanning the decades since Apollo, and a forward-looking perspective, as defined by the enabling technologies required for a meaningful and sustainable human and robotic exploration program over the forthcoming decades. Previous research and technology investment approaches are examined and a course of action suggested for obtaining a more balanced portfolio of basic and applied research. The central recommendation is the establishment of a robust national Space Propulsion Research Initiative that would run parallel with systems development and include basic research activities. The basic framework and technical approach for this proposed initiative are defined and a potential implementation approach is recommended.

Basic Science Research and the Protection of Human Research Participants

NASA Astrophysics Data System (ADS)

Eiseman, Elisa

2001-03-01

Technological advances in basic biological research have been instrumental in recent biomedical discoveries, such as in the understanding and treatment of cancer, HIV/AIDS, and heart disease. However, many of these advances also raise several new ethical challenges. For example, genetic research may pose no physical risk beyond that of obtaining the initial blood sample, yet it can pose significant psychological and economic risks to research participants, such as stigmatization, discrimination in insurance and employment, invasion of privacy, or breach of confidentiality. These harms may occur even when investigators do not directly interact with the person whose DNA they are studying. Moreover, this type of basic research also raises broader questions, such as what is the definition of a human subject, and what kinds of expertise do Institutional Review Boards (IRBs) need to review the increasingly diverse types of research made possible by these advances in technology. The National Bioethics Advisory Commission (NBAC), a presidentially appointed federal advisory committee, has addressed these and other ethical, scientific and policy issues that arise in basic science research involving human participants. Two of its six reports, in particular, have proposed recommendations in this regard. "Research Involving Human Biological Materials: Ethical and Policy Guidance" addresses the basic research use of human tissues, cells and DNA and the protection of human participants in this type of research. In "Ethical and Policy Issues in the Oversight of Human Research" NBAC proposes a definition of research involving human participants that would apply to all scientific disciplines, including physical, biological, and social sciences, as well as the humanities and related professions, such as business and law. Both of these reports make it clear that the protection of research participants is key to conducting ethically sound research. By ensuring that all participants in research are protected and by educating everyone involved in research with human participants, including the public, investigators, IRB members, institutions, and federal agencies, NBAC’s goal is to develop guidelines by which important basic research can proceed while making sure that the rights and welfare of human research participants are not compromised.

Basic Research Needs for Countering Terrorism

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

Stevens, W.; Michalske, T.; Trewhella, J.

2002-03-01

To identify connections between technology needs for countering terrorism and underlying science issues and to recommend investment strategies to increase the impact of basic research on efforts to counter terrorism.

10 CFR 605.3 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-01-01

... definitions are provided for purposes of this part— Basic and applied research means basic and applied research and that part of development not related to the development of specific systems or products. The... ENERGY (CONTINUED) ASSISTANCE REGULATIONS THE OFFICE OF ENERGY RESEARCH FINANCIAL ASSISTANCE PROGRAM...

RAT PLACENTATION: AN EXPERIMENTAL MODEL FOR INVESTIGATING THE HEMOCHORIAL MATERNAL-FETAL INTERFACE

PubMed Central

Soares, Michael J.; Chakraborty, Damayanti; Rumi, M.A. Karim; Konno, Toshihiro; Renaud, Stephen J.

2011-01-01

The rat possesses hemochorial placentation with deep intrauterine trophoblast cell invasion and trophoblast-directed uterine spiral artery remodeling; features shared with human placentation. Recognition of these similarities spurred the establishment of in vitro and in vivo research methods using the rat as an animal model to address mechanistic questions regarding development of the hemochorial placenta. The purpose of this review is to provide the requisite background to help move the rat to the forefront in placentation research. PMID:22284666

How Will Big Data Improve Clinical and Basic Research in Radiation Therapy?

PubMed Central

Rosenstein, Barry S.; Capala, Jacek; Efstathiou, Jason A.; Hammerbacher, Jeff; Kerns, Sarah; Kong, Feng-Ming (Spring); Ostrer, Harry; Prior, Fred W.; Vikram, Bhadrasain; Wong, John; Xiao, Ying

2015-01-01

Historically, basic scientists and clinical researchers have transduced reality into data so that they might explain or predict the world. Because data are fundamental to their craft, these investigators have been on the front lines of the Big Data deluge in recent years. Radiotherapy data are complex and longitudinal data sets are frequently collected to track both tumor and normal tissue response to therapy. As basic, translational and clinical investigators explore with increasingly greater depth the complexity of underlying disease processes and treatment outcomes, larger sample populations are required for research studies and greater quantities of data are being generated. In addition, well-curated research and trial data are being pooled in public data repositories to support large-scale analyses. Thus, the tremendous quantity of information produced in both basic and clinical research in radiation therapy can now be considered as having entered the realm of Big Data. PMID:26797542

Comparison of different stomatal conductance algorithms for ozone flux modelling

Treesearch

P. Buker; L.D. Emberson; M. R. Ashmore; H. M. Cambridge; C. M. Jacobs; W. J. Massman; J. Muller; N. Nikolov; K. Novak; E. Oksanen; M. Schaub; D. de la Torre

2007-01-01

A multiplicative and a semi-mechanistic, BWB-type [Ball, J.T., Woodrow, I.E., Berry, J.A., 1987. A model predicting stomatal conductance and its contribution to the control of photosynthesis under different environmental conditions. In: Biggens, J. (Ed.), Progress in Photosynthesis Research, vol. IV. Martinus Nijhoff, Dordrecht, pp. 221-224.] algorithm for calculating...

Towards to an Explanation for Conceptual Change: A Mechanistic Alternative

ERIC Educational Resources Information Center

Rusanen, Anna-Mari

2014-01-01

Conceptual change is one of the most studied fields in science education and psychology of learning. However, there are still some foundational issues in conceptual change research on which no clear consensus has emerged. Firstly, there is no agreement on what changes in belief and concept systems constitute conceptual change and what changes do…

Global topics and novel approaches in the study of air pollution, climate change and forest ecosystems

Treesearch

P. Sicard; A. Augustaitis; S. Belyazid; C. Calfapietra; A. De Marco; Mark E. Fenn; Andrzej Bytnerowicz; Nancy Grulke; S. He; R. Matyssek; Y. Serengil; G. Wieser; E. Paoletti

2016-01-01

Research directions from the 27th conference for Specialists in Air Pollution and Climate Change Effects on Forest Ecosystems (2015) reflect knowledge advancements about (i) Mechanistic bases of tree responses to multiple climate and pollution stressors, in particular the interaction of ozone (O3) with nitrogen (N) deposition and drought; (ii)...

Paradigm Thinking: Passionate Hopefulness and More than 20 Cents of Effort

ERIC Educational Resources Information Center

Schultz, Robert A.

2012-01-01

In their introduction to the idea of a systems approach to understanding talent and giftedness, Ziegler and Phillipson broach the larger issue of the positivistic or mechanistic mindset to knowing and understanding that pervades much of what is called educational research. This worthy tactic brings to light the need to move away from the status…

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.

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

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

Changes in Black-legged Tick Population in New England with Future Climate Change

NASA Astrophysics Data System (ADS)

Krishnan, S.; Huber, M.

2015-12-01

Lyme disease is one of the most frequently reported vector-borne diseases in the United States. In the Northeastern United States, vector transmission is maintained in a horizontal transmission cycle between the vector, the black-legged ticks, and the vertebrate reservoir hosts, which include white-tailed deer, rodents and other medium to large sized mammals. Predicting how vector populations change with future climate change is critical to understanding disease spread in the future, and for developing suitable regional adaptation strategies. For the United States, these predictions have mostly been made using regressions based on field and lab studies, or using spatial suitability studies. However, the relation between tick populations at various life-cycle stages and climate variables are complex, necessitating a mechanistic approach. In this study, we present a framework for driving a mechanistic tick population model with high-resolution regional climate modeling projections. The goal is to estimate changes in black-legged tick populations in New England for the 21st century. The tick population model used is based on the mechanistic approach of Ogden et al., (2005) developed for Canada. Dynamically downscaled climate projections at a 3-kms resolution using the Weather and Research Forecasting Model (WRF) are used to drive the tick population model.

Action Research of Computer-Assisted-Remediation of Basic Research Concepts.

ERIC Educational Resources Information Center

Packard, Abbot L.; And Others

This study investigated the possibility of creating a computer-assisted remediation program to assist students having difficulties in basic college research and statistics courses. A team approach involving instructors and students drove the research into and creation of the computer program. The effect of student use was reviewed by looking at…

Cruising through Research: Library Skills for Young Adults.

ERIC Educational Resources Information Center

Volkman, John D.

This book presents an approach for school librarians to use to introduce basic research tools to students in grades 7-12. Twelve "Excursions" (i.e., library research projects) are described. Excursions 1 and 2 provide an introduction to reference books, and Excursions 3 and 4 explore note-taking and basic organization of research papers. The…

Department of Defense Basic Research Program.

DTIC Science & Technology

1980-08-01

Oamond Laboratories, ERADCOM. Foreword This report has been prepared by the Research Office, ffice of the Deputy Under Secretary of Defense for... Research and Engineering ( Research and Advanced Technology~jlt is the first report ever written for the express purpose of describing the Department of...Defense basic research program. The report is part of an overall effort to improve communications with the national research community by increasing the

The Impact of "Coat Protein-Mediated Virus Resistance" in Applied Plant Pathology and Basic Research.

PubMed

Lindbo, John A; Falk, Bryce W

2017-06-01

Worldwide, plant viruses cause serious reductions in marketable crop yield and in some cases even plant death. In most cases, the most effective way to control virus diseases is through genetically controlled resistance. However, developing virus-resistant (VR) crops through traditional breeding can take many years, and in some cases is not even possible. Because of this, the demonstration of the first VR transgenic plants in 1985 generated much attention. This seminal report served as an inflection point for research in both basic and applied plant pathology, the results of which have dramatically changed both basic research and in a few cases, commercial crop production. The typical review article on this topic has focused on only basic or only applied research results stemming from this seminal discovery. This can make it difficult for the reader to appreciate the full impact of research on transgenic virus resistance, and the contributions from fundamental research that led to translational applications of this technology. In this review, we take a global view of this topic highlighting the significant changes to both basic and applied plant pathology research and commercial food production that have accumulated in the last 30 plus years. We present these milestones in the historical context of some of the scientific, economic, and environmental drivers for developing specific VR crops. The intent of this review is to provide a single document that adequately records the significant accomplishments of researchers in both basic and applied plant pathology research on this topic and how they relate to each other. We hope this review therefore serves as both an instructional tool for students new to the topic, as well as a source of conversation and discussion for how the technology of engineered virus resistance could be applied in the future.

Molecular characterization of novel pyridoxal-5'-phosphate-dependent enzymes from the human microbiome.

PubMed

Fleischman, Nicholas M; Das, Debanu; Kumar, Abhinav; Xu, Qingping; Chiu, Hsiu-Ju; Jaroszewski, Lukasz; Knuth, Mark W; Klock, Heath E; Miller, Mitchell D; Elsliger, Marc-André; Godzik, Adam; Lesley, Scott A; Deacon, Ashley M; Wilson, Ian A; Toney, Michael D

2014-08-01

Pyridoxal-5'-phosphate or PLP, the active form of vitamin B6, is a highly versatile cofactor that participates in a large number of mechanistically diverse enzymatic reactions in basic metabolism. PLP-dependent enzymes account for ∼1.5% of most prokaryotic genomes and are estimated to be involved in ∼4% of all catalytic reactions, making this an important class of enzymes. Here, we structurally and functionally characterize three novel PLP-dependent enzymes from bacteria in the human microbiome: two are from Eubacterium rectale, a dominant, nonpathogenic, fecal, Gram-positive bacteria, and the third is from Porphyromonas gingivalis, which plays a major role in human periodontal disease. All adopt the Type I PLP-dependent enzyme fold and structure-guided biochemical analysis enabled functional assignments as tryptophan, aromatic, and probable phosphoserine aminotransferases. © 2014 The Protein Society.

Using explanatory crop models to develop simple tools for Advanced Life Support system studies

NASA Technical Reports Server (NTRS)

Cavazzoni, J.

2004-01-01

System-level analyses for Advanced Life Support require mathematical models for various processes, such as for biomass production and waste management, which would ideally be integrated into overall system models. Explanatory models (also referred to as mechanistic or process models) would provide the basis for a more robust system model, as these would be based on an understanding of specific processes. However, implementing such models at the system level may not always be practicable because of their complexity. For the area of biomass production, explanatory models were used to generate parameters and multivariable polynomial equations for basic models that are suitable for estimating the direction and magnitude of daily changes in canopy gas-exchange, harvest index, and production scheduling for both nominal and off-nominal growing conditions. c2004 COSPAR. Published by Elsevier Ltd. All rights reserved.