Electron Transport Chain-dependent and -independent Mechanisms of Mitochondrial H2O2 Emission during Long-chain Fatty Acid Oxidation*

PubMed Central

Seifert, Erin L.; Estey, Carmen; Xuan, Jian Y.; Harper, Mary-Ellen

2010-01-01

Oxidative stress in skeletal muscle is a hallmark of various pathophysiologic states that also feature increased reliance on long-chain fatty acid (LCFA) substrate, such as insulin resistance and exercise. However, little is known about the mechanistic basis of the LCFA-induced reactive oxygen species (ROS) burden in intact mitochondria, and elucidation of this mechanistic basis was the goal of this study. Specific aims were to determine the extent to which LCFA catabolism is associated with ROS production and to gain mechanistic insights into the associated ROS production. Because intermediates and by-products of LCFA catabolism may interfere with antioxidant mechanisms, we predicted that ROS formation during LCFA catabolism reflects a complex process involving multiple sites of ROS production as well as modified mitochondrial function. Thus, we utilized several complementary approaches to probe the underlying mechanism(s). Using skeletal muscle mitochondria, our findings indicate that even a low supply of LCFA is associated with ROS formation in excess of that generated by NADH-linked substrates. Moreover, ROS production was evident across the physiologic range of membrane potential and was relatively insensitive to membrane potential changes. Determinations of topology and membrane potential as well as use of inhibitors revealed complex III and the electron transfer flavoprotein (ETF) and ETF-oxidoreductase, as likely sites of ROS production. Finally, ROS production was sensitive to matrix levels of LCFA catabolic intermediates, indicating that mitochondrial export of LCFA catabolic intermediates can play a role in determining ROS levels. PMID:20032466

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

Cancer.gov

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

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

PubMed

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

2014-11-20

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

Integrating perspectives on vocal performance and consistency

PubMed Central

Sakata, Jon T.; Vehrencamp, Sandra L.

2012-01-01

SUMMARY Recent experiments in divergent fields of birdsong have revealed that vocal performance is important for reproductive success and under active control by distinct neural circuits. Vocal consistency, the degree to which the spectral properties (e.g. dominant or fundamental frequency) of song elements are produced consistently from rendition to rendition, has been highlighted as a biologically important aspect of vocal performance. Here, we synthesize functional, developmental and mechanistic (neurophysiological) perspectives to generate an integrated understanding of this facet of vocal performance. Behavioral studies in the field and laboratory have found that vocal consistency is affected by social context, season and development, and, moreover, positively correlated with reproductive success. Mechanistic investigations have revealed a contribution of forebrain and basal ganglia circuits and sex steroid hormones to the control of vocal consistency. Across behavioral, developmental and mechanistic studies, a convergent theme regarding the importance of vocal practice in juvenile and adult songbirds emerges, providing a basis for linking these levels of analysis. By understanding vocal consistency at these levels, we gain an appreciation for the various dimensions of song control and plasticity and argue that genes regulating the function of basal ganglia circuits and sex steroid hormones could be sculpted by sexual selection. PMID:22189763

An experimental test of host’s life history traits modulation in response to cuckoo parasitism risk

PubMed Central

Parejo, Deseada; Martínez, Juan Gabriel; Sánchez-Tójar, Alfredo; Precioso, Marta; Molina-Morales, Mercedes; Avilés, Jesús M.

2017-01-01

Hosts can counteract parasites through defences based on resistance and/or tolerance. The mechanistic basis of tolerance, which involve defensive mechanisms minimizing parasite damage after a successful parasitic attack, remains poorly explored in the study of cuckoo-host interactions. Here, we experimentally explore the possibility that the risk of great spotted cuckoo Clamator glandarius parasitism may induce tolerance defences in magpie Pica pica hosts through plasticity in life-history traits. We predict that magpies exposed to auditory cues indicating high parasitism risk will more likely exhibit resistance and/or modify their life-history traits to minimize parasitism costs (i.e. tolerance) compared to magpies under low parasitism risk. We found that manipulating the perceived parasitism risk did not affect host resistance (i.e. rejection of parasitic eggs) nor host life-history traits. Unexpectedly, host’s egg volume increased over the season in nests exposed to auditory cues of control non-harmful hoopoes Upupa epops. Our results do not provide support for inducible defences (either based on resistance or tolerance) in response to risk of parasitism in magpie hosts. Even so, we encourage studying plastic expression of breeding strategies in response to risk of cuckoo parasitism to achieve a better understanding of the mechanistic basis of tolerance defences. PMID:28658287

Overview of recent DNA vaccine development for fish

USGS Publications Warehouse

Kurath, G.; ,

2005-01-01

Since the first description of DNA vaccines for fish in 1996, numerous studies of genetic immunisation against the rhabdovirus pathogens infectious haematopoietic necrosis virus (IHNV) and viral haemorrhagic septicaemia virus (VHSV) have established their potential as both highly efficacious biologicals and useful basic research tools. Single small doses of rhabdovirus DNA constructs provide extremely strong protection against severe viral challenge under a variety of conditions. DNA vaccines for several other important fish viruses, bacteria, and parasites are under investigation, but they have not yet shown high efficacy. Therefore, current research is focussed on mechanistic studies to understand the basis of protection, and on improvement of the nucleic acid vaccine applications against a wider range of fish pathogens.

Developmental aspects of a life course approach to healthy ageing

PubMed Central

Cooper, C.; Aihie Sayer, A.; Eendebak, R. J.; Clough, G. F.; Beard, J. R.

2016-01-01

Abstract We examine the mechanistic basis and wider implications of adopting a developmental perspective on human ageing. Previous models of ageing have concentrated on its genetic basis, or the detrimental effects of accumulated damage, but also have raised issues about whether ageing can be viewed as adaptive itself, or is a consequence of other adaptive processes, for example if maintenance and repair processes in the period up to reproduction are traded off against later decline in function. A life course model places ageing in the context of the attainment of peak capacity for a body system, starting in early development when plasticity permits changes in structure and function induced by a range of environmental stimuli, followed by a period of decline, the rate of which depends on the peak attained as well as the later life conditions. Such path dependency in the rate of ageing may offer new insights into its modification. Focusing on musculoskeletal and cardiovascular function, we discuss this model and the possible underlying mechanisms, including endothelial function, oxidative stress, stem cells and nutritional factors such as vitamin D status. Epigenetic changes induced during developmental plasticity, and immune function may provide a common mechanistic process underlying a life course model of ageing. The life course trajectory differs in high and low resource settings. New insights into the developmental components of the life course model of ageing may lead to the design of biomarkers of later chronic disease risk and to new interventions to promote healthy ageing, with important implications for public health. PMID:26518329

Developmental aspects of a life course approach to healthy ageing.

PubMed

Hanson, M A; Cooper, C; Aihie Sayer, A; Eendebak, R J; Clough, G F; Beard, J R

2016-04-15

We examine the mechanistic basis and wider implications of adopting a developmental perspective on human ageing. Previous models of ageing have concentrated on its genetic basis, or the detrimental effects of accumulated damage, but also have raised issues about whether ageing can be viewed as adaptive itself, or is a consequence of other adaptive processes, for example if maintenance and repair processes in the period up to reproduction are traded off against later decline in function. A life course model places ageing in the context of the attainment of peak capacity for a body system, starting in early development when plasticity permits changes in structure and function induced by a range of environmental stimuli, followed by a period of decline, the rate of which depends on the peak attained as well as the later life conditions. Such path dependency in the rate of ageing may offer new insights into its modification. Focusing on musculoskeletal and cardiovascular function, we discuss this model and the possible underlying mechanisms, including endothelial function, oxidative stress, stem cells and nutritional factors such as vitamin D status. Epigenetic changes induced during developmental plasticity, and immune function may provide a common mechanistic process underlying a life course model of ageing. The life course trajectory differs in high and low resource settings. New insights into the developmental components of the life course model of ageing may lead to the design of biomarkers of later chronic disease risk and to new interventions to promote healthy ageing, with important implications for public health. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

A Murine Model for Human ECO Syndrome Reveals a Critical Role of Intestinal Cell Kinase in Skeletal Development.

PubMed

Ding, Mengmeng; Jin, Li; Xie, Lin; Park, So Hyun; Tong, Yixin; Wu, Di; Chhabra, A Bobby; Fu, Zheng; Li, Xudong

2018-03-01

An autosomal-recessive inactivating mutation R272Q in the human intestinal cell kinase (ICK) gene caused profound multiplex developmental defects in human endocrine-cerebro-osteodysplasia (ECO) syndrome. ECO patients exhibited a wide variety of skeletal abnormalities, yet the underlying mechanisms by which ICK regulates skeletal development remained largely unknown. The goal of this study was to understand the structural and mechanistic basis underlying skeletal anomalies caused by ICK dysfunction. Ick R272Q knock-in transgenic mouse model not only recapitulated major ECO skeletal defects such as short limbs and polydactyly but also revealed a deformed spine with defective intervertebral disk. Loss of ICK function markedly reduced mineralization in the spinal column, ribs, and long bones. Ick mutants showed a significant decrease in the proliferation zone of long bones and the number of type X collagen-expressing hypertrophic chondrocytes in the spinal column and the growth plate of long bones. These results implicate that ICK plays an important role in bone and cartilage development by promoting chondrocyte proliferation and maturation. Our findings provided new mechanistic insights into the skeletal phenotype of human ECO and ECO-like syndromes.

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

NASA Astrophysics Data System (ADS)

Miyakawa, Takuya; Tanokura, Masaru

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

Biochemical Basis of Sestrin Physiological Activities

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

Ho, Allison; Cho, Chun-Seok; Namkoong, Sim

Excessive accumulation of reactive oxygen species (ROS) and chronic activation of mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) are well-characterized promoters of aging and age-associated degenerative pathologies. Sestrins, a family of highly conserved stress-inducible proteins, are important negative regulators of both ROS and mTORC1 signaling pathways; however, the mechanistic basis of how Sestrins suppress these pathways remains elusive. In the past couple of years, breakthrough discoveries about Sestrin signaling and its molecular nature have markedly increased our biochemical understanding of Sestrin function. These discoveries have also uncovered new potential therapeutic strategies that may eventually enable us to attenuate agingmore » and age-associated diseases.« less

Autoimmunity in focus: from mechanisms to treatment.

PubMed

Kon, Yujiro

2012-05-01

The 5th Asian Congress on Autoimmunity took place in Suntec City, Singapore, on the 17-19 November 2011 under the presidency of Yehuda Shoenfeld (Chaim Sheba Medical Center, Ramat Gan, Israel). Senior investigators from a range of fields--including immunology, autoimmunity, rheumatology, neurology and hepatology--attended the conference. The scientific program placed an emphasis on the pathogenesis, genetic basis and mechanistic aspects of autoimmune diseases, as well as their clinical outcomes and treatment options. Particular focus was placed on systemic lupus erythematosus, rheumatoid arthritis, Type I diabetes, antiphospholipid syndrome and autoimmune hepatitis. Participants from over 50 countries attended the conference.

Food for Thought ... Mechanistic Validation

PubMed Central

Hartung, Thomas; Hoffmann, Sebastian; Stephens, Martin

2013-01-01

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

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

PubMed

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

2018-03-01

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

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.

Impact of excipient interactions on solid dosage form stability.

PubMed

Narang, Ajit S; Desai, Divyakant; Badawy, Sherif

2012-10-01

Drug-excipient interactions in solid dosage forms can affect drug product stability in physical aspects such as organoleptic changes and dissolution slowdown, or chemically by causing drug degradation. Recent research has allowed the distinction in chemical instability resulting from direct drug-excipient interactions and from drug interactions with excipient impurities. A review of chemical instability in solid dosage forms highlights common mechanistic themes applicable to multiple degradation pathways. These common themes include the role of water and microenvironmental pH. In addition, special aspects of solid-state reactions with excipients and/or excipient impurities add to the complexity in understanding and modeling reaction pathways. This paper discusses mechanistic basis of known drug-excipient interactions with case studies and provides an overview of common underlying themes. Recent developments in the understanding of degradation pathways further impact methodologies used in the pharmaceutical industry for prospective stability assessment. This paper discusses these emerging aspects in terms of limitations of drug-excipient compatibility studies, emerging paradigms in accelerated stability testing, and application of mathematical modeling for prediction of drug product stability.

Metabolomic profiling in Selaginella lepidophylla at various hydration states provides new insights into the mechanistic basis of desiccation tolerance

USDA-ARS?s Scientific Manuscript database

Selaginella lepidophylla is one of only a few species of spike mosses (Selaginellaceae) that have evolved desiccation tolerance (DT) or the ability to ‘resurrect’ from an air-dried state. In order to understand the metabolic basis of DT, S. lepidophylla was subjected to a five-stage, rehydration/de...

Stomatal control and hydraulic conductance, with special reference to tall trees.

PubMed

Franks, Peter J

2004-08-01

A better understanding of the mechanistic basis of stomatal control is necessary to understand why modes of stomatal response differ among individual trees, and to improve the theoretical foundation for predictive models and manipulative experiments. Current understanding of the mechanistic basis of stomatal control is reviewed here and discussed in relation to the plant hydraulic system. Analysis focused on: (1) the relative role of hydraulic conductance in the vicinity of the stomatal apparatus versus whole-plant hydraulic conductance; (2) the influence of guard cell inflation characteristics and the mechanical interaction between guard cells and epidermal cells; and (3) the system requirements for moderate versus dramatic reductions in stomatal conductance with increasing evaporation potential. Special consideration was given to the potential effect of changes in hydraulic properties as trees grow taller. Stomatal control of leaf gas exchange is coupled to the entire plant hydraulic system and the basis of this coupling is the interdependence of guard cell water potential and transpiration rate. This hydraulic feedback loop is always present, but its dynamic properties may be altered by growth or cavitation-induced changes in hydraulic conductance, and may vary with genetically related differences in hydraulic conductances. Mechanistic models should include this feedback loop. Plants vary in their ability to control transpiration rate sufficiently to maintain constant leaf water potential. Limited control may be achieved through the hydraulic feedback loop alone, but for tighter control, an additional element linking transpiration rate to guard cell osmotic pressure may be needed.

Mechanisms involved in epigenetic down-regulation of Gfap under maternal hypothyroidism.

PubMed

Kumar, Praveen; Godbole, Nachiket M; Chaturvedi, Chandra P; Singh, Ravi S; George, Nelson; Upadhyay, Aditya; Anjum, B; Godbole, Madan M; Sinha, Rohit A

2018-07-20

Thyroid hormones (TH) of maternal origin are crucial regulator of mammalian brain development during embryonic period. Although maternal TH deficiency during the critical periods of embryonic neo-cortical development often results in irreversible clinical outcomes, the fundamental basis of these abnormalities at a molecular level is still obscure. One of the key developmental process affected by maternal TH insufficiency is the delay in astrocyte maturation. Glial fibrillary acidic protein (Gfap) is a predominant cell marker of mature astrocyte and is regulated by TH status. Inspite, of being a TH responsive gene during neocortical development the mechanistic basis of Gfap transcriptional regulation by TH has remained elusive. In this study using rat model of maternal hypothyroidism, we provide evidence for an epigenetic silencing of Gfap under TH insufficiency and its recovery upon TH supplementation. Our results demonstrate increased DNA methylation coupled with decreased histone acetylation at the Gfap promoter leading to suppression of Gfap expression under maternal hypothyroidism. In concordance, we also observed a significant increase in histone deacetylase (HDAC) activity in neocortex of TH deficient embryos. Collectively, these results provide novel insight into the role of TH regulated epigenetic mechanisms, including DNA methylation, and histone modifications, which are critically important in mediating precise temporal neural gene regulation. Copyright © 2018 Elsevier Inc. All rights reserved.

Mechanistic insights into the one-pot synthesis of propargylamines from terminal alkynes and amines in chlorinated solvents catalyzed by gold compounds and nanoparticles.

PubMed

Aguilar, David; Contel, Maria; Urriolabeitia, Esteban P

2010-08-09

Propargylamines can be obtained from secondary amines and terminal alkynes in chlorinated solvents by a three- and two-component synthesis catalyzed by gold compounds and nanoparticles (Au-NP) under mild conditions. The use of dichloromethane allows for the activation of two C-Cl bonds and a clean transfer of the methylene fragment to the final product. The scope of the reaction as well as the influence of different gold(III) cycloaurated complexes and salts has been investigated. The involvement of gold nanoparticles generated in situ in the process is discussed and a plausible reaction mechanism is proposed on the basis of the data obtained.

Learning and cognition in insects.

PubMed

Giurfa, Martin

2015-01-01

Insects possess small brains but exhibit sophisticated behavioral performances. Recent works have reported the existence of unsuspected cognitive capabilities in various insect species, which go beyond the traditional studied framework of simple associative learning. In this study, I focus on capabilities such as attention, social learning, individual recognition, concept learning, and metacognition, and discuss their presence and mechanistic bases in insects. I analyze whether these behaviors can be explained on the basis of elemental associative learning or, on the contrary, require higher-order explanations. In doing this, I highlight experimental challenges and suggest future directions for investigating the neurobiology of higher-order learning in insects, with the goal of uncovering l architectures underlying cognitive processing. © 2015 John Wiley & Sons, Ltd.

A Closed-tube Loop-Mediated Isothermal Amplification Assay for the Visual Endpoint Detection of Brucella spp. and Mycobacterium avium subsp. paratuberculosis.

PubMed

Trangoni, Marcos D; Gioffré, Andrea K; Cravero, Silvio L

2017-01-01

LAMP (loop-mediated isothermal amplification) is an isothermal nucleic acid amplification technique that is characterized by its efficiency, rapidity, high yield of final product, robustness, sensitivity, and specificity, with the blueprint that it can be implemented in laboratories of low technological complexity. Despite the conceptual complexity underlying the mechanistic basis for the nucleic acid amplification, the technique is simple to use and the amplification and detection can be carried out in just one step. In this chapter, we present a protocol based on LAMP for the rapid identification of isolates of Brucella spp. and Mycobacterium avium subsp. paratuberculosis, two major bacterial pathogens in veterinary medicine.

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.

Ionizing Radiation: The issue of radiation quality

NASA Astrophysics Data System (ADS)

Prise, Kevin; Schettino, Giuseppe

Types of Ionising radiations are differentiated from each other by fundamental characteristics of their energy deposition patterns when they interact with biological materials. At the level of the DNA these non-random patterns drive differences in the yields and distributions of DNA damage patterns and specifically the production of clustered damage or complex lesions. The complex radiation fields found in space bring significant challenges for developing a mechanistic understanding of radiation effects from the perspective of radiation quality as these consist of a diverse range of particle and energy types unique to the space environment. Linear energy transfer, energy deposited per unit track length in units of keV per micron, has long been used as a comparator for different types of radiation but has limitations in that it is an average value. Difference in primary core ionizations relative to secondary delta ray ranges vary significantly with particle mass and energy leading to complex interrelationships with damage production at the cellular level. At the cellular level a greater mechanistic understanding is necessary, linking energy deposition patterns to DNA damage patterns and cellular response, to build appropriate biophysical models that are predictive for different radiation qualities and mixed field exposures. Defined studies using monoenergetic beams delivered under controlled conditions are building quantitative data sets of both initial and long term changes in cells as a basis for a great mechanistic understanding of radiation quality effects of relevance to not only space exposures but clinical application of ion-beams.

Structure alerts for carcinogenicity, and the Salmonella assay system: a novel insight through the chemical relational databases technology.

PubMed

Benigni, Romualdo; Bossa, Cecilia

2008-01-01

In the past decades, chemical carcinogenicity has been the object of mechanistic studies that have been translated into valuable experimental (e.g., the Salmonella assays system) and theoretical (e.g., compilations of structure alerts for chemical carcinogenicity) models. These findings remain the basis of the science and regulation of mutagens and carcinogens. Recent advances in the organization and treatment of large databases consisting of both biological and chemical information nowadays allows for a much easier and more refined view of data. This paper reviews recent analyses on the predictive performance of various lists of structure alerts, including a new compilation of alerts that combines previous work in an optimized form for computer implementation. The revised compilation is part of the Toxtree 1.50 software (freely available from the European Chemicals Bureau website). The use of structural alerts for the chemical biological profiling of a large database of Salmonella mutagenicity results is also reported. Together with being a repository of the science on the chemical biological interactions at the basis of chemical carcinogenicity, the SAs have a crucial role in practical applications for risk assessment, for: (a) description of sets of chemicals; (b) preliminary hazard characterization; (c) formation of categories for e.g., regulatory purposes; (d) generation of subsets of congeneric chemicals to be analyzed subsequently with QSAR methods; (e) priority setting. An important aspect of SAs as predictive toxicity tools is that they derive directly from mechanistic knowledge. The crucial role of mechanistic knowledge in the process of applying (Q)SAR considerations to risk assessment should be strongly emphasized. Mechanistic knowledge provides a ground for interaction and dialogue between model developers, toxicologists and regulators, and permits the integration of the (Q)SAR results into a wider regulatory framework, where different types of evidence and data concur or complement each other as a basis for making decisions and taking actions.

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

Yeast Terminator Function Can Be Modulated and Designed on the Basis of Predictions of Nucleosome Occupancy.

PubMed

Morse, Nicholas J; Gopal, Madan R; Wagner, James M; Alper, Hal S

2017-11-17

The design of improved synthetic parts is a major goal of synthetic biology. Mechanistically, nucleosome occupancy in the 3' terminator region of a gene has been found to correlate with transcriptional expression. Here, we seek to establish a predictive relationship between terminator function and predicted nucleosome positioning to design synthetic terminators in the yeast Saccharomyces cerevisiae. In doing so, terminators improved net protein output from these expression cassettes nearly 4-fold over their original sequence with observed increases in termination efficiency to 96%. The resulting terminators were indeed depleted of nucleosomes on the basis of mapping experiments. This approach was successfully applied to synthetic, de novo, and native terminators. The mode of action of these modifications was mainly through increased termination efficiency, rather than half-life increases, perhaps suggesting a role in improved mRNA maturation. Collectively, these results suggest that predicted nucleosome depletion can be used as a heuristic approach for improving terminator function, though the underlying mechanism remains to be shown.

Revisiting the mechanistic basis of the French Paradox: Red wine inhibits the activity of protein disulfide isomerase in vitro.

PubMed

Galinski, Christine N; Zwicker, Jeffrey I; Kennedy, Daniel R

2016-01-01

Although epidemiologic evidence points to cardioprotective activity of red wine, the mechanistic basis for antithrombotic activity has not been established. Quercetin and related flavonoids are present in high concentrations in red but not white wine. Quercetin-glycosides were recently shown to prevent thrombosis in animal models through the inhibition of extracellular protein disulfide isomerase (PDI). We evaluated whether red or white wine inhibited PDI activity in vitro. Quercetin levels in red and white wines were measured by HPLC analysis. Inhibition of PDI activity by red and white wines was assessed by an insulin reduction turbidity assay at various concentrations of wine. PDI inhibition was confirmed using a reduced peptide that contained a disulfide containing peptide as a substrate. The inhibition of PDI related thiol isomerases ERp5 and ERp57 was also assessed. We observed a dose-dependent decrease of PDI activity for a variety of red but not white wines. Red wine diluted to 3% final concentration resulted in over 80% inhibition of PDI activity by insulin reductase assay for all varieties tested. This inhibition was also observed in the peptide based assay. Red grape juice yielded similar results but ethanol alone did not affect PDI activity. Interestingly, red wine also inhibited the PDI related thiol isomerases ERp5 and ERp57, albeit to a lesser degree than PDI. PDI activity is inhibited by red wine and grape juice, identifying a potentially novel mechanism underlying the cardiovascular benefits attributed to wine consumption. Copyright © 2015 Elsevier Ltd. All rights reserved.

Revisiting the mechanistic basis of the French Paradox: red wine inhibits the activity of protein disulfide isomerase in vitro

PubMed Central

Galinski, Christine N.; Zwicker, Jeffrey I.; Kennedy, Daniel R.

2015-01-01

Introduction Although epidemiologic evidence points to cardioprotective activity of red wine, the mechanistic basis for antithrombotic activity has not been established. Quercetin and related flavonoids are present in high concentrations in red but not white wine. Quercetin-glycosides were recently shown to prevent thrombosis in animal models through the inhibition of extracellular protein disulfide isomerase (PDI). We evaluated whether red or white wine inhibited PDI activity in vitro. Methods Quercetin levels in red and white wines were measured by HPLC analysis. Inhibition of PDI activity by red and white wines was assessed by an insulin reduction turbidity assay at various concentrations of wine. PDI inhibition was confirmed using a reduced peptide that contained a disulfide containing peptide as a substrate. The inhibition of PDI related thiol isomerases ERp5 and ERp57 was also assessed. Results We observed a dose-dependent decrease of PDI activity for a variety of red but not white wines. Red wine diluted to 3% final concentration resulted in over 80% inhibition of PDI activity by insulin reductase assay for all varieties tested. This inhibition was also observed in the peptide based assay. Red grape juice yielded similar results but ethanol alone did not affect PDI activity. Interestingly, red wine also inhibited the PDI related thiol isomerases ERp5 and ERp57, albeit to a lesser degree than PDI. Conclusions PDI activity is inhibited by red wine and grape juice, identifying a potentially novel mechanism underlying the cardiovascular benefits attributed to wine consumption. PMID:26585763

Application of granular activated carbon/MnFe2O4 composite immobilized on C. glutamicum MTCC 2745 to remove As(III) and As(V): Kinetic, mechanistic and thermodynamic studies

NASA Astrophysics Data System (ADS)

Podder, M. S.; Majumder, C. B.

2016-01-01

The main objective of the present study was to investigate the efficiency of Corynebacterium glutamicum MTCC 2745 immobilized on granular activated carbon/MnFe2O4 (GAC/MnFe2O4) composite to treat high concentration of arsenic bearing wastewater. Non-linear regression analysis was done for determining the best-fit kinetic model on the basis of three correlation coefficients and three error functions and also for predicting the parameters involved in kinetic models. The results showed that Fractal-like mixed 1,2 order model for As(III) and Brouser-Weron-Sototlongo as well as Fractal-like pseudo second order models for As(V) were proficient to provide realistic description of biosorption/bioaccumulation kinetic. Applicability of mechanistic models in the current study exhibited that the rate governing step in biosorption/bioaccumulation of both As(III) and As(V) was film diffusion rather than intraparticle diffusion. The evaluated thermodynamic parameters ΔG0, ΔH0 and ΔS0 revealed that biosorption/bioaccumulation of both As(III) and As(V) was feasible, spontaneous and exothermic under studied conditions.

Fundamental Challenges in Mechanistic Enzymology: Progress toward Understanding the Rate Enhancements of Enzymes

PubMed Central

Herschlag, Daniel; Natarajan, Aditya

2013-01-01

Enzymes are remarkable catalysts that lie at the heart of biology, accelerating chemical reactions to an astounding extent with extraordinary specificity. Enormous progress in understanding the chemical basis of enzymatic transformations and the basic mechanisms underlying rate enhancements over the past decades is apparent. Nevertheless, it has been difficult to achieve a quantitative understanding of how the underlying mechanisms account for the energetics of catalysis, because of the complexity of enzyme systems and the absence of underlying energetic additivity. We review case studies from our own work that illustrate the power of precisely defined and clearly articulated questions when dealing with such complex and multi-faceted systems, and we also use this approach to evaluate our current ability to design enzymes. We close by highlighting a series of questions that help frame some of what remains to be understood, and we encourage the reader to define additional questions and directions that will deepen and broaden our understanding of enzymes and their catalysis. PMID:23488725

Fundamental challenges in mechanistic enzymology: progress toward understanding the rate enhancements of enzymes.

PubMed

Herschlag, Daniel; Natarajan, Aditya

2013-03-26

Enzymes are remarkable catalysts that lie at the heart of biology, accelerating chemical reactions to an astounding extent with extraordinary specificity. Enormous progress in understanding the chemical basis of enzymatic transformations and the basic mechanisms underlying rate enhancements over the past decades is apparent. Nevertheless, it has been difficult to achieve a quantitative understanding of how the underlying mechanisms account for the energetics of catalysis, because of the complexity of enzyme systems and the absence of underlying energetic additivity. We review case studies from our own work that illustrate the power of precisely defined and clearly articulated questions when dealing with such complex and multifaceted systems, and we also use this approach to evaluate our current ability to design enzymes. We close by highlighting a series of questions that help frame some of what remains to be understood, and we encourage the reader to define additional questions and directions that will deepen and broaden our understanding of enzymes and their catalysis.

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

NASA Astrophysics Data System (ADS)

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

2016-03-01

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

Ablation of an Ovarian Tumor Family Deubiquitinase Exposes the Underlying Regulation Governing the Plasticity of Cell Cycle Progression in Toxoplasma gondii.

PubMed

Dhara, Animesh; de Paula Baptista, Rodrigo; Kissinger, Jessica C; Snow, E Charles; Sinai, Anthony P

2017-11-21

The Toxoplasma genome encodes the capacity for distinct architectures underlying cell cycle progression in a life cycle stage-dependent manner. Replication in intermediate hosts occurs by endodyogeny, whereas a hybrid of schizogony and endopolygeny occurs in the gut of the definitive feline host. Here, we characterize the consequence of the loss of a cell cycle-regulated o varian tu mor (OTU family) deubiquitinase, OTUD3A of Toxoplasma gondii (TgOTUD3A; TGGT1_258780), in T. gondii tachyzoites. Rather than the mutation being detrimental, mutant parasites exhibited a fitness advantage, outcompeting the wild type. This phenotype was due to roughly one-third of TgOTUD3A-knockout (TgOTUD3A-KO) tachyzoites exhibiting deviations from endodyogeny by employing replication strategies that produced 3, 4, or 5 viable progeny within a gravid mother instead of the usual 2. We established the mechanistic basis underlying these altered replication strategies to be a dysregulation of centrosome duplication, causing a transient loss of stoichiometry between the inner and outer cores that resulted in a failure to terminate S phase at the attainment of 2N ploidy and/or the decoupling of mitosis and cytokinesis. The resulting dysregulation manifested as deviations in the normal transitions from S phase to mitosis (S/M) (endopolygeny-like) or M phase to cytokinesis (M/C) (schizogony-like). Notably, these imbalances are corrected prior to cytokinesis, resulting in the generation of normal progeny. Our findings suggest that decisions regarding the utilization of specific cell cycle architectures are controlled by a ubiquitin-mediated mechanism that is dependent on the absolute threshold levels of an as-yet-unknown target(s). Analysis of the TgOTUD3A-KO mutant provides new insights into mechanisms underlying the plasticity of apicomplexan cell cycle architecture. IMPORTANCE Replication by Toxoplasma gondii can occur by 3 distinct cell cycle architectures. Endodyogeny is used by asexual stages, while a hybrid of schizogony and endopolygeny is used by merozoites in the definitive feline host. Here, we establish that the disruption of an o varian- tu mor (OTU) family deubiquitinase, TgOTUD3A, in tachyzoites results in dysregulation of the mechanism controlling the selection of replication strategy in a subset of parasites. The mechanistic basis for these altered cell cycles lies in the unique biology of the bipartite centrosome that is associated with the transient loss of stoichiometry between the inner and outer centrosome cores in the TgOTUD3A-KO mutant. This highlights the importance of ubiquitin-mediated regulation in the transition from the nuclear to the budding phases of the cell cycle and provides new mechanistic insights into the regulation of the organization of the apicomplexan cell cycle. Copyright © 2017 Dhara et al.

Pooled Patient-Level Meta-analysis of Children and Adults Completing a Computer-Based Anxiety Intervention Targeting Attentional Bias

PubMed Central

Price, Rebecca B.; Wallace, Meredith; Kuckertz, Jennie M.; Amir, Nader; Graur, Simona; Cummings, Logan; Popa, Paul; Carlbring, Per; Bar-Haim, Yair

2016-01-01

Computer-based approaches, such as Attention Bias Modification (ABM), could help improve access to care for anxiety. Study-level meta-analyses of ABM have produced conflicting findings and leave critical questions unresolved regarding ABM’s mechanisms of action and clinical potential. We pooled patient-level datasets from randomized controlled trials of children and adults with high-anxiety. Attentional bias (AB) towards threat, the target mechanism of ABM, was tested as an outcome and a mechanistic mediator and moderator of anxiety reduction. Diagnostic remission and Liebowitz Social Anxiety Scale (LSAS) were clinical outcomes available in enough studies to enable pooling. Per-patient data were obtained on at least one outcome from 13/16 eligible studies [86% of eligible participants; n=778]. Significant main effects of ABM on diagnostic remission (ABM—22.6%, control—10.8%; OR=2.57; p=.006) and AB (β*(95%CI)=−.63(−.83, −.42); p<.00005) were observed. There was no main effect of ABM on LSAS. However, moderator analyses suggested ABM was effective for patients who were younger (≤37y), trained in the lab, and/or assessed by clinicians. Under the same conditions where ABM was effective, mechanistic links between AB and anxiety reduction were supported. Under these specific circumstances, ABM reduces anxiety and acts through its target mechanism, supporting ABM’s theoretical basis while simultaneously suggesting clinical indications and refinements to improve its currently limited clinical potential. PMID:27693664

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

DOT National Transportation Integrated Search

2009-10-01

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

Development of a Physiologically Based Pharmacokinetic Model for Sinogliatin, a First-in-Class Glucokinase Activator, by Integrating Allometric Scaling, In Vitro to In Vivo Exploration and Steady-State Concentration-Mean Residence Time Methods: Mechanistic Understanding of its Pharmacokinetics.

PubMed

Song, Ling; Zhang, Yi; Jiang, Ji; Ren, Shuang; Chen, Li; Liu, Dongyang; Chen, Xijing; Hu, Pei

2018-04-06

The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for sinogliatin (HMS-5552, dorzagliatin) by integrating allometric scaling (AS), in vitro to in vivo exploration (IVIVE), and steady-state concentration-mean residence time (C ss -MRT) methods and to provide mechanistic insight into its pharmacokinetic properties in humans. Human major pharmacokinetic parameters were analyzed using AS, IVIVE, and C ss -MRT methods with available preclinical in vitro and in vivo data to understand sinogliatin drug metabolism and pharmacokinetic (DMPK) characteristics and underlying mechanisms. On this basis, an initial mechanistic PBPK model of sinogliatin was developed. The initial PBPK model was verified using observed data from a single ascending dose (SAD) study and further optimized with various strategies. The final model was validated by simulating sinogliatin pharmacokinetics under a fed condition. The validated model was applied to support a clinical drug-drug interaction (DDI) study design and to evaluate the effects of intrinsic (hepatic cirrhosis, genetic) factors on drug exposure. The two-species scaling method using rat and dog data (TS- rat,dog ) was the best AS method in predicting human systemic clearance in the central compartment (CL). The IVIVE method confirmed that sinogliatin was predominantly metabolized by cytochrome P450 (CYP) 3A4. The C ss -MRT method suggested dog pharmacokinetic profiles were more similar to human pharmacokinetic profiles. The estimated CL using the AS and IVIVE approaches was within 1.5-fold of that observed. The C ss -MRT method in dogs also provided acceptable prediction of human pharmacokinetic characteristics. For the PBPK approach, the 90% confidence intervals (CIs) of the simulated maximum concentration (C max ), CL, and area under the plasma concentration-time curve (AUC) of sinogliatin were within those observed and the 90% CI of simulated time to C max (t max ) was closed to that observed for a dose range of 5-50 mg in the SAD study. The final PBPK model was validated by simulating sinogliatin pharmacokinetics with food. The 90% CIs of the simulated C max , CL, and AUC values for sinogliatin were within those observed and the 90% CI of the simulated t max was partially within that observed for the dose range of 25-200 mg in the multiple ascending dose (MAD) study. This PBPK model selected a final clinical DDI study design with itraconazole from four potential designs and also evaluated the effects of intrinsic (hepatic cirrhosis, genetic) factors on drug exposure. Sinogliatin pharmacokinetic properties were mechanistically understood by integrating all four methods and a mechanistic PBPK model was successfully developed and validated using clinical data. This PBPK model was applied to support the development of sinogliatin.

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

PubMed

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

2007-07-01

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

Mechanistic Basis of Calmodulin Mediated Estrogen Receptor Alpha Activation and Antiestrogen Resistance

DTIC Science & Technology

2008-06-01

Cross (UGA), going to dental school *Noelle Cheung (Carnegie Mellon University), graduate school or medical school *Leah Cho (Denver University...State University Dr. Vladimir Akoev, Kansas State University Prof. Carey K. Johnson, University of Kansas Previous Prof. Ann Hochschild

Computational Modeling of Cobalt-Based Water Oxidation: Current Status and Future Challenges

PubMed Central

Schilling, Mauro; Luber, Sandra

2018-01-01

A lot of effort is nowadays put into the development of novel water oxidation catalysts. In this context, mechanistic studies are crucial in order to elucidate the reaction mechanisms governing this complex process, new design paradigms and strategies how to improve the stability and efficiency of those catalysts. This review is focused on recent theoretical mechanistic studies in the field of homogeneous cobalt-based water oxidation catalysts. In the first part, computational methodologies and protocols are summarized and evaluated on the basis of their applicability toward real catalytic or smaller model systems, whereby special emphasis is laid on the choice of an appropriate model system. In the second part, an overview of mechanistic studies is presented, from which conceptual guidelines are drawn on how to approach novel studies of catalysts and how to further develop the field of computational modeling of water oxidation reactions. PMID:29721491

Computational Modeling of Cobalt-based Water Oxidation: Current Status and Future Challenges

NASA Astrophysics Data System (ADS)

Schilling, Mauro; Luber, Sandra

2018-04-01

A lot of effort is nowadays put into the development of novel water oxidation catalysts. In this context mechanistic studies are crucial in order to elucidate the reaction mechanisms governing this complex process, new design paradigms and strategies how to improve the stability and efficiency of those catalysis. This review is focused on recent theoretical mechanistic studies in the field of homogeneous cobalt-based water oxidation catalysts. In the first part, computational methodologies and protocols are summarized and evaluated on the basis of their applicability towards real catalytic or smaller model systems, whereby special emphasis is laid on the choice of an appropriate model system. In the second part, an overview of mechanistic studies is presented, from which conceptual guidelines are drawn on how to approach novel studies of catalysts and how to further develop the field of computational modeling of water oxidation reactions.

The role of the tumor-microenvironment in lung cancer-metastasis and its relationship to potential therapeutic targets.

PubMed

Wood, Steven L; Pernemalm, Maria; Crosbie, Philip A; Whetton, Anthony D

2014-05-01

Non-small cell lung cancer (NSCLC) accounts for >80% of lung cancer cases and currently has an overall five-year survival rate of only 15%. Patients presenting with advanced stage NSCLC die within 18-months of diagnosis. Metastatic spread accounts for >70% of these deaths. Thus elucidation of the mechanistic basis of NSCLC-metastasis has potential to impact on patient quality of life and survival. Research on NSCLC metastasis has recently expanded to include non-cancer cell components of tumors-the stromal cellular compartment and extra-cellular matrix components comprising the tumor-microenvironment. Metastasis (from initial primary tumor growth through angiogenesis, intravasation, survival in the bloodstream, extravasation and metastatic growth) is an inefficient process and few released cancer cells complete the entire process. Micro-environmental interactions assist each of these steps and discovery of the mechanisms by which tumor cells co-operate with the micro-environment are uncovering key molecules providing either biomarkers or potential drug targets. The major sites of NSCLC metastasis are brain, bone, adrenal gland and the liver. The mechanistic basis of this tissue-tropism is beginning to be elucidated offering the potential to target stromal components of these tissues thus targeting therapy to the tissues affected. This review covers the principal steps involved in tumor metastasis. The role of cell-cell interactions, ECM remodeling and autocrine/paracrine signaling interactions between tumor cells and the surrounding stroma is discussed. The mechanistic basis of lung cancer metastasis to specific organs is also described. The signaling mechanisms outlined have potential to act as future drug targets minimizing lung cancer metastatic spread and morbidity. Copyright © 2013 Elsevier Ltd. All rights reserved.

Factors Controlling Elevated Temperature Strength Degradation of Silicon Carbide Composites

NASA Technical Reports Server (NTRS)

2005-01-01

For 5 years, the cooperative agreement NCC3-763 has focused on the development and understanding of Sic-based composites. Most of the work was performed in the area of SiC fiber-reinforced composites for UEET and NGLT and in collaboration with Goodrich Corporation under a partially reimbursable Space Act Agreement. A smaller amount of work was performed on C fiber-reinforced SiC matrix composites for NGLT. Major accomplishments during this agreement included: Improvements to the interphase used in melt-infiltrated (MI) SiC/SiC composites which increases the life under stressed-oxidation at intermediate temperatures referred to as "outside-debonding". This concept is currently in the patent process and received a Space Act Award. Mechanistic-based models of intermediate temperature degradation for MI SiC/SiC Quantification and relatively robust relationships for matrix crack evolution under stress in SiC/SiC composites which serve as the basis for stress-strain and elevated temperature life models The furthering of acoustic emission as a useful tool in composite damage evolution and the extension of the technique to other composite systems Development of hybrid C-SiC fiber-reinforced SiC matrix composites Numerous presentations at conferences, industry partners, and government centers and publications in recognized proceedings and journals. Other recognition of the author's accomplishments by NASA with a TGIR award (2004), NASA's Medal for Public Service (2004), and The American Ceramic Society s Richard M. Fulrath Award (2005). The following will briefly describe the work of the past five years in the three areas of interest: SiC/SiC composite development, mechanistic understanding and modeling of SiC/SiC composites, and environmental durability of C/SiC composites. More detail can be found in the publications cited at the end of this report.

Differential gene expression is not required for facultative sex allocation: a transcriptome analysis of brain tissue in the parasitoid wasp Nasonia vitripennis

PubMed Central

Boulton, Rebecca A.; Green, Jade; Trivedi, Urmi; Pannebakker, Bart A.; Ritchie, Michael G.; Shuker, David M.

2018-01-01

Whole-transcriptome technologies have been widely used in behavioural genetics to identify genes associated with the performance of a behaviour and provide clues to its mechanistic basis. Here, we consider the genetic basis of sex allocation behaviour in the parasitoid wasp Nasonia vitripennis. Female Nasonia facultatively vary their offspring sex ratio in line with Hamilton's theory of local mate competition (LMC). A single female or ‘foundress’ laying eggs on a patch will lay just enough sons to fertilize her daughters. As the number of ‘foundresses’ laying eggs on a patch increases (and LMC declines), females produce increasingly male-biased sex ratios. Phenotypic studies have revealed the cues females use to estimate the level of LMC their sons will experience, but our understanding of the genetics underlying sex allocation is limited. Here, we exposed females to three foundress number conditions, i.e. three LMC conditions, and allowed them to oviposit. mRNA was extracted from only the heads of these females to target the brain tissue. The subsequent RNA-seq experiment confirmed that differential gene expression is not associated with the response to sex allocation cues and that we must instead turn to the underlying neuroscience to reveal the underpinnings of this impressive behavioural plasticity. PMID:29515880

Phylogenetic niche conservatism and the evolutionary basis of ecological speciation.

PubMed

Pyron, R Alexander; Costa, Gabriel C; Patten, Michael A; Burbrink, Frank T

2015-11-01

Phylogenetic niche conservatism (PNC) typically refers to the tendency of closely related species to be more similar to each other in terms of niche than they are to more distant relatives. This has been implicated as a potential driving force in speciation and other species-richness patterns, such as latitudinal gradients. However, PNC has not been very well defined in most previous studies. Is it a pattern or a process? What are the underlying endogenous (e.g. genetic) and exogenous (e.g. ecological) factors that cause niches to be conserved? What degree of similarity is necessary to qualify as PNC? Is it possible for the evolutionary processes causing niches to be conserved to also result in niche divergence in different habitats? Here, we revisit these questions, codifying a theoretical and operational definition of PNC as a mechanistic evolutionary process resulting from several factors. We frame this both from a macroevolutionary and population-genetic perspective. We discuss how different axes of physical (e.g. geographic) and environmental (e.g. climatic) heterogeneity interact with the fundamental process of PNC to produce different outcomes of ecological speciation. We also review tests for PNC, and suggest ways that these could be improved or better utilized in future studies. Ultimately, PNC as a process has a well-defined mechanistic basis in organisms, and future studies investigating ecological speciation would be well served to consider this, and frame hypothesis testing in terms of the processes and expected patterns described herein. The process of PNC may lead to patterns where niches are conserved (more similar than expected), constrained (divergent within a limited subset of available niches), or divergent (less similar than expected), based on degree of phylogenetic relatedness between species. © 2014 Cambridge Philosophical Society.

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...

Toxicologic Comparison between Libby Amphibole and Amosite Asbestos following Intratracheal Instillation in Rats

EPA Science Inventory

An abnormally high incidence of asbestosis and mesothelioma has been reported in residents of Libby, Montana, after exposure to amphibole-contaminated vermiculite. However, the mechanistic basis for the toxicity of the Libby amphibole (LA) remains unclear. In the present study,...

DEVELOPMENT OF DNA MICROARRAYS FOR ECOLOGICAL EXPOSURE ASSESSMENT

EPA Science Inventory

EPA/ORD is moving forward with a computational toxicology initiative in FY 04 which aims to integrate genomics and computational methods to provide a mechanistic basis for prediction of exposure and effects of chemical stressors in the environment.

The goal of the presen...

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

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

PubMed

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

2018-05-01

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

Structural basis of viral invasion: lessons from paramyxovirus F

PubMed Central

Lamb, Robert A.; Jardetzky, Theodore S.

2007-01-01

Summary The structures of glycoproteins that mediate enveloped virus entry into cells have revealed dramatic structural changes that accompany membrane fusion and provided mechanistic insights into this process. The group of class I viral fusion proteins includes the influenza hemagglutinin, paramyxovirus F, HIV env and other mechanistically related fusogens, but these proteins are unrelated in sequence and exhibit clearly distinct structural features. Recently determined crystal structures of the paramyxovirus F protein in two conformations, representing prefusion and postfusion states, reveal a novel protein architecture that undergoes large-scale, irreversible refolding during membrane fusion, extending our understanding of this diverse group of membrane fusion machines. PMID:17870467

Mechanistic Basis of Cocrystal Dissolution Advantage.

PubMed

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

2018-01-01

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

Asymmetric Synthesis of Rauhut-Currier type Products by a Regioselective Mukaiyama Reaction under Bifunctional Catalysis.

PubMed

Frias, María; Mas-Ballesté, Rubén; Arias, Saira; Alvarado, Cuauhtemoc; Alemán, José

2017-01-18

The reactivity and the regioselective functionalization of silyl-diene enol ethers under a bifunctional organocatalyst provokes a dramatic change in the regioselectivity, from the 1,5- to the 1,3-functionalization. This variation makes possible the 1,3-addition of silyl-dienol ethers to nitroalkenes, giving access to the synthesis of tri- and tetrasubstituted double bonds in Rauhut-Currier type products. The process takes place under smooth conditions, nonanionic conditions, and with a high enantiomeric excess. A rational mechanistic pathway is presented based on DFT and mechanistic experiments.

Structural and theoretical basis for ligand exchange on thiolate monolayer protected gold nanoclusters.

PubMed

Heinecke, Christine L; Ni, Thomas W; Malola, Sami; Mäkinen, Ville; Wong, O Andrea; Häkkinen, Hannu; Ackerson, Christopher J

2012-08-15

Ligand exchange reactions are widely used for imparting new functionality on or integrating nanoparticles into devices. Thiolate-for-thiolate ligand exchange in monolayer protected gold nanoclusters has been used for over a decade; however, a firm structural basis of this reaction has been lacking. Herein, we present the first single-crystal X-ray structure of a partially exchanged Au(102)(p-MBA)(40)(p-BBT)(4) (p-MBA = para-mercaptobenzoic acid, p-BBT = para-bromobenzene thiol) with p-BBT as the incoming ligand. The crystal structure shows that 2 of the 22 symmetry-unique p-MBA ligand sites are partially exchanged to p-BBT under the initial fast kinetics in a 5 min timescale exchange reaction. Each of these ligand-binding sites is bonded to a different solvent-exposed Au atom, suggesting an associative mechanism for the initial ligand exchange. Density functional theory calculations modeling both thiol and thiolate incoming ligands postulate a mechanistic pathway for thiol-based ligand exchange. The discrete modification of a small set of ligand binding sites suggests Au(102)(p-MBA)(44) as a powerful platform for surface chemical engineering.

EWS-FLI1 increases transcription to cause R-loops and block BRCA1 repair in Ewing sarcoma.

PubMed

Gorthi, Aparna; Romero, July Carolina; Loranc, Eva; Cao, Lin; Lawrence, Liesl A; Goodale, Elicia; Iniguez, Amanda Balboni; Bernard, Xavier; Masamsetti, V Pragathi; Roston, Sydney; Lawlor, Elizabeth R; Toretsky, Jeffrey A; Stegmaier, Kimberly; Lessnick, Stephen L; Chen, Yidong; Bishop, Alexander J R

2018-03-15

Ewing sarcoma is an aggressive paediatric cancer of the bone and soft tissue. It results from a chromosomal translocation, predominantly t(11;22)(q24:q12), that fuses the N-terminal transactivation domain of the constitutively expressed EWSR1 protein with the C-terminal DNA binding domain of the rarely expressed FLI1 protein. Ewing sarcoma is highly sensitive to genotoxic agents such as etoposide, but the underlying molecular basis of this sensitivity is unclear. Here we show that Ewing sarcoma cells display alterations in regulation of damage-induced transcription, accumulation of R-loops and increased replication stress. In addition, homologous recombination is impaired in Ewing sarcoma owing to an enriched interaction between BRCA1 and the elongating transcription machinery. Finally, we uncover a role for EWSR1 in the transcriptional response to damage, suppressing R-loops and promoting homologous recombination. Our findings improve the current understanding of EWSR1 function, elucidate the mechanistic basis of the sensitivity of Ewing sarcoma to chemotherapy (including PARP1 inhibitors) and highlight a class of BRCA-deficient-like tumours.

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...

Future Needs and Recommendations in the Development of ...

EPA Pesticide Factsheets

A species sensitivity distribution (SSD) is a probability model of the variation of species sensitivities to a stressor, in particular chemical exposure. The SSD approach has been used as a decision support tool in environmental protection and management since the 1980s, and the ecotoxicological, statistical and regulatory basis and applications continue to evolve. This article summarizes the findings of a 2014 workshop held by ECETOC (the European Center for Toxicology and Ecotoxicology of Chemicals) and the UK Environment Agency in Amsterdam, the Netherlands on the ecological relevance, statistical basis, and regulatory applications of SSDs. An array of research recommendations categorized under the topical areas of Use of SSDs, Ecological Considerations, Guideline Considerations, Method Development and Validation, Toxicity Data, Mechanistic Understanding and Uncertainty were identified and prioritized. A rationale for the most critical research needs identified in the workshop is provided. The workshop reviewed the technical basis and historical development and application of SSDs, described approaches to estimating generic and scenario specific SSD-based thresholds, evaluated utility and application of SSDs as diagnostic tools, and presented new statistical approaches to formulate SSDs. Collectively, these address many of the research needs to expand and improve their application. The highest priority work, from a pragmatic regulatory point of view, is t

Essential role for uncoupling protein-3 in mitochondrial adaptation to fasting but not in fatty acid oxidation or fatty acid anion export.

PubMed

Seifert, Erin L; Bézaire, Véronic; Estey, Carmen; Harper, Mary-Ellen

2008-09-12

Uncoupling protein-3 (UCP3) is a mitochondrial inner membrane protein expressed most abundantly in skeletal muscle and to a lesser extent in heart and brown adipose tissue. Evidence supports a role for UCP3 in fatty acid oxidation (FAO); however, the underlying mechanism has not been explored. In 2001 we proposed a role for UCP3 in fatty acid export, leading to higher FAO rates (Himms-Hagen, J., and Harper, M. E. (2001) Exp. Biol. Med. (Maywood) 226, 78-84). Specifically, this widely held hypothesis states that during elevated FAO rates, UCP3 exports fatty acid anions, thereby maintaining mitochondrial co-enzyme A availability; reactivation of exported fatty acid anions would ultimately enable increased FAO. Here we tested mechanistic aspects of this hypothesis as well as its functional implications, namely increased FAO rates. Using complementary mechanistic approaches in mitochondria from wild-type and Ucp3(-/-) mice, we find that UCP3 is not required for FAO regardless of substrate type or supply rate covering a 20-fold range. Fatty acid anion export and reoxidation during elevated FAO, although present in skeletal muscle mitochondria, are independent of UCP3 abundance. Interestingly, UCP3 was found to be necessary for the fasting-induced enhancement of FAO rate and capacity, possibly via mitigated mitochondrial oxidative stress. Thus, although our observations indicate that UCP3 can impact FAO rates, the mechanistic basis is not via an integral function for UCP3 in the FAO machinery. Overall our data indicate a function for UCP3 in mitochondrial adaptation to perturbed cellular energy balance and integrate previous observations that have linked UCP3 to reduced oxidative stress and FAO.

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.

Quantitative AOP-based predictions for two aromatase inhibitors evaluating the influence of bioaccumulation on prediction accuracy

EPA Science Inventory

The adverse outcome pathway (AOP) framework can be used to support the use of mechanistic toxicology data as a basis for risk assessment. For certain risk contexts this includes defining, quantitative linkages between the molecular initiating event (MIE) and subsequent key events...

Weight of evidence evaluation of adverse outcome pathways converging at impaired vitellogenin synthesis leading to reproductive impairment

EPA Science Inventory

Adverse outcome pathways (AOPs) provide a framework that supports greater use of mechanistic data measured at lower levels of biological organization as a basis for regulatory decision-making. However, it is recognized that different types of regulatory applications and decisions...

THE GOOD, THE BAD AND THE UGLY - DETERMINATION OF BACTERIAL VIRULENCE USING ANIMAL MODELS AND MICROARRAY TECHNOLOGY

EPA Science Inventory

In its Computational Toxicology Program, EPA/ORD proposes to integrate genomics and computational methods to provide a mechanistic basis for the prediction of toxicity of chemicals and the pathogenicity of microorganisms. The goal of microbiological water testing is to be able to...

Do key dimensions of seed and seedling functional trait variation capture variation in recruitment probability?

USDA-ARS?s Scientific Manuscript database

1. Plant functional traits provide a mechanistic basis for understanding ecological variation among plant species and the implications of this variation for species distribution, community assembly and restoration. 2. The bulk of our functional trait understanding, however, is centered on traits rel...

Chloroquine activates the p53 pathway and induces apoptosis in human glioma cells

PubMed Central

Kim, Ella L.; Wüstenberg, Robin; Rübsam, Anne; Schmitz-Salue, Christoph; Warnecke, Gabriele; Bücker, Eva-Maria; Pettkus, Nadine; Speidel, Daniel; Rohde, Veit; Schulz-Schaeffer, Walter; Deppert, Wolfgang; Giese, Alf

2010-01-01

Glioblastoma is the most common malignant brain tumor in adults. The currently available treatments offer only a palliative survival advantage and the need for effective treatments remains an urgent priority. Activation of the p53 growth suppression/apoptotic pathway is one of the promising strategies in targeting glioma cells. We show that the quinoline derivative chloroquine activates the p53 pathway and suppresses growth of glioma cells in vitro and in vivo in an orthotopic (U87MG) human glioblastoma mouse model. Induction of apoptosis is one of the mechanisms underlying the effects of chloroquine on suppressing glioma cell growth and viability. siRNA-mediated downregulation of p53 in wild-type but not mutant p53 glioblastoma cells substantially impaired chloroquine-induced apoptosis. In addition to its p53-activating effects, chloroquine may also inhibit glioma cell growth via p53-independent mechanisms. Our results clarify the mechanistic basis underlying the antineoplastic effect of chloroquine and reveal its therapeutic potential as an adjunct to glioma chemotherapy. PMID:20308316

The Big Breakfast Study: Chrono-nutrition influence on energy expenditure and bodyweight.

PubMed

Ruddick-Collins, L C; Johnston, J D; Morgan, P J; Johnstone, A M

2018-06-01

A growing body of evidence highlights the importance of the biological clock as a modulator of energy balance and metabolism. Recent studies in humans have shown that ingested calories are apparently utilised more efficiently in the morning than in the evening and this is manifest through improved weight loss, even under iso-energetic calorie intake. The mechanisms behind this enhanced morning energy metabolism are not yet clear, although it may result from behavioural adaptations or circadian driven variations in physiology and energy metabolism. A major objective of the newly funded Big Breakfast Study therefore is to investigate the mechanistic basis of this amplified morning thermogenesis leading to enhanced weight loss, by exploring behavioural and physiological adaptations in energy expenditure alongside the underlying circadian biology. This report briefly discusses the current research linking meal timing, circadian rhythms and metabolism; highlights the research gaps; and provides an overview of the studies being undertaken as part of the Medical Research Council-funded Big Breakfast Study .

A strong genetic correlation underlying a behavioural syndrome disappears during development because of genotype–age interactions

PubMed Central

Class, Barbara; Brommer, Jon E.

2015-01-01

In animal populations, as in humans, behavioural differences between individuals that are consistent over time and across contexts are considered to reflect personality, and suites of correlated behaviours expressed by individuals are known as behavioural syndromes. Lifelong stability of behavioural syndromes is often assumed, either implicitly or explicitly. Here, we use a quantitative genetic approach to study the developmental stability of a behavioural syndrome in a wild population of blue tits. We find that a behavioural syndrome formed by a strong genetic correlation of two personality traits in nestlings disappears in adults, and we demonstrate that genotype–age interaction is the likely mechanism underlying this change during development. A behavioural syndrome may hence change during organismal development, even when personality traits seem to be strongly physiologically or functionally linked in one age group. We outline how such developmental plasticity has important ramifications for understanding the mechanistic basis as well as the evolutionary consequences of behavioural syndromes. PMID:26041348

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…

The use of mechanistic evidence in drug approval.

PubMed

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

2018-06-11

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

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...

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...

Validity and validation of expert (Q)SAR systems.

PubMed

Hulzebos, E; Sijm, D; Traas, T; Posthumus, R; Maslankiewicz, L

2005-08-01

At a recent workshop in Setubal (Portugal) principles were drafted to assess the suitability of (quantitative) structure-activity relationships ((Q)SARs) for assessing the hazards and risks of chemicals. In the present study we applied some of the Setubal principles to test the validity of three (Q)SAR expert systems and validate the results. These principles include a mechanistic basis, the availability of a training set and validation. ECOSAR, BIOWIN and DEREK for Windows have a mechanistic or empirical basis. ECOSAR has a training set for each QSAR. For half of the structural fragments the number of chemicals in the training set is >4. Based on structural fragments and log Kow, ECOSAR uses linear regression to predict ecotoxicity. Validating ECOSAR for three 'valid' classes results in predictivity of > or = 64%. BIOWIN uses (non-)linear regressions to predict the probability of biodegradability based on fragments and molecular weight. It has a large training set and predicts non-ready biodegradability well. DEREK for Windows predictions are supported by a mechanistic rationale and literature references. The structural alerts in this program have been developed with a training set of positive and negative toxicity data. However, to support the prediction only a limited number of chemicals in the training set is presented to the user. DEREK for Windows predicts effects by 'if-then' reasoning. The program predicts best for mutagenicity and carcinogenicity. Each structural fragment in ECOSAR and DEREK for Windows needs to be evaluated and validated separately.

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

DOE PAGES

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

2014-11-07

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

Evidence That Chromium Modulates Cellular Cholesterol Homeostasis and ABCA1 Functionality Impaired By Hyperinsulinemia

PubMed Central

Sealls, Whitney; Penque, Brent A.; Elmendorf, Jeffrey S.

2011-01-01

Objective Trivalent chromium (Cr3+) is an essential micronutrient. Findings since the 1950s suggest that Cr3+ might benefit cholesterol homeostasis. Here we present mechanistic evidence in support of this role of Cr3+. Method and Results High-density lipoprotein cholesterol generation in 3T3-L1 adipocytes, rendered ineffective by hyperinsulinemia, known to accompany disorders of lipid metabolism was corrected by Cr3+. Mechanistically, Cr3+ reversed hyperinsulinemia-induced cellular cholesterol accrual and associated defects in cholesterol transporter ABCA1 trafficking and apolipoprotein A1-mediated cholesterol efflux. Moreover, direct activation of AMP-activated protein kinase (AMPK), known to be activated by Cr3+, and/or inhibition of hexosamine biosynthesis pathway (HBP) activity, known to be elevated by hyperinsulinemia, mimics Cr3+ action. Conclusion These findings suggest a mechanism of Cr3+ action that fits with long-standing claims of its role in cholesterol homeostasis. Furthermore, these data implicate a mechanistic basis for the coexistence of dyslipidemia with hyperinsulinemia. PMID:21311039

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

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

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

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 (316SS) 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)more » 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. In this paper (part-I) the fatigue experiments under different test and environment conditions and related stress-strain results for 316 SS are discussed. In a second paper (part-II) the related evolutionary cyclic plasticity material modeling techniques and results are discussed.« less

Factors controlling Eucalyptus productivity: How water availability and stand structure alter production and carbon allocation

Treesearch

Michael G. Ryan; Jose Luiz Stape; Dan Binkley; Sebastiao Fonseca; Rodolfo A. Loos; Ernesto N. Takahashi; Claudio R. Silva; Sergio R. Silva; Rodrigo E. Hakamada; Jose Mario Ferreira; Augusto M. N. Lima; Jose Luiz Gava; Fernando P. Leite; Helder B. Andrade; Jacyr M. Alves; Gualter G. C. Silva

2010-01-01

Wood production varies substantially with resource availability, and the variation in wood production can result from several mechanisms: increased photosynthesis, and changes in partitioning of photosynthesis to wood production, belowground flux, foliage production or respiration. An understanding of the mechanistic basis for patterns in wood production...

Linking mechanistic toxicology to population models in forecasting recovery from chemical stress: A case study from Jackfish Bay, Ontario, Canada

EPA Science Inventory

A Beneficial Use Impairment (BUI) common at Great Lakes Areas of Concern (AOCs) is loss of fish and wildlife populations. Consequently, recovery of populations after stressor mitigation serves as a basis for evaluating remediation success. We describe a framework that can be a...

Integrated approach to explore the mechanisms of aromatase inhibition and recovery in fathead minnows (Pimephales promelas)

EPA Science Inventory

Aromatase, a member of the cytochrome P450 superfamily, is a key enzyme in estradiol synthesis that catalyzes the aromatization of androgens into estrogens in ovaries. Here, we used an integrated approach to assess the mechanistic basis of the direct effects of aromatase inhibiti...

USE OF OUTPUT FROM THE NEW ENGLAND SPARROW MODEL TO ESTIMATE CONCENTRATIONS OF TOTAL NITROGEN IN ESTUARIES

EPA Science Inventory

The USGS=s SPARROW Model is a statistical model with mechanistic features that has been used to calculate annual nutrient fluxes in nontidal streams nationally on the basis of nitrogen sources, landscape characteristics, and stream properties. This model has been useful for asses...

Key Characteristics of Carcinogens as a Basis for Organizing Data on Mechanisms of Carcinogenesis

PubMed Central

Smith, Martyn T.; Guyton, Kathryn Z.; Gibbons, Catherine F.; Fritz, Jason M.; Portier, Christopher J.; Rusyn, Ivan; DeMarini, David M.; Caldwell, Jane C.; Kavlock, Robert J.; Lambert, Paul F.; Hecht, Stephen S.; Bucher, John R.; Stewart, Bernard W.; Baan, Robert A.; Cogliano, Vincent J.; Straif, Kurt

2015-01-01

Background: A recent review by the International Agency for Research on Cancer (IARC) updated the assessments of the > 100 agents classified as Group 1, carcinogenic to humans (IARC Monographs Volume 100, parts A–F). This exercise was complicated by the absence of a broadly accepted, systematic method for evaluating mechanistic data to support conclusions regarding human hazard from exposure to carcinogens. Objectives and Methods: IARC therefore convened two workshops in which an international Working Group of experts identified 10 key characteristics, one or more of which are commonly exhibited by established human carcinogens. Discussion: These characteristics provide the basis for an objective approach to identifying and organizing results from pertinent mechanistic studies. The 10 characteristics are the abilities of an agent to 1) act as an electrophile either directly or after metabolic activation; 2) be genotoxic; 3) alter DNA repair or cause genomic instability; 4) induce epigenetic alterations; 5) induce oxidative stress; 6) induce chronic inflammation; 7) be immunosuppressive; 8) modulate receptor-mediated effects; 9) cause immortalization; and 10) alter cell proliferation, cell death, or nutrient supply. Conclusion: We describe the use of the 10 key characteristics to conduct a systematic literature search focused on relevant end points and construct a graphical representation of the identified mechanistic information. Next, we use benzene and polychlorinated biphenyls as examples to illustrate how this approach may work in practice. The approach described is similar in many respects to those currently being implemented by the U.S. EPA’s Integrated Risk Information System Program and the U.S. National Toxicology Program. Citation: Smith MT, Guyton KZ, Gibbons CF, Fritz JM, Portier CJ, Rusyn I, DeMarini DM, Caldwell JC, Kavlock RJ, Lambert P, Hecht SS, Bucher JR, Stewart BW, Baan R, Cogliano VJ, Straif K. 2016. Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis. Environ Health Perspect 124:713–721; http://dx.doi.org/10.1289/ehp.1509912 PMID:26600562

Key Characteristics of Carcinogens as a Basis for Organizing Data on Mechanisms of Carcinogenesis.

PubMed

Smith, Martyn T; Guyton, Kathryn Z; Gibbons, Catherine F; Fritz, Jason M; Portier, Christopher J; Rusyn, Ivan; DeMarini, David M; Caldwell, Jane C; Kavlock, Robert J; Lambert, Paul F; Hecht, Stephen S; Bucher, John R; Stewart, Bernard W; Baan, Robert A; Cogliano, Vincent J; Straif, Kurt

2016-06-01

A recent review by the International Agency for Research on Cancer (IARC) updated the assessments of the > 100 agents classified as Group 1, carcinogenic to humans (IARC Monographs Volume 100, parts A-F). This exercise was complicated by the absence of a broadly accepted, systematic method for evaluating mechanistic data to support conclusions regarding human hazard from exposure to carcinogens. IARC therefore convened two workshops in which an international Working Group of experts identified 10 key characteristics, one or more of which are commonly exhibited by established human carcinogens. These characteristics provide the basis for an objective approach to identifying and organizing results from pertinent mechanistic studies. The 10 characteristics are the abilities of an agent to 1) act as an electrophile either directly or after metabolic activation; 2) be genotoxic; 3) alter DNA repair or cause genomic instability; 4) induce epigenetic alterations; 5) induce oxidative stress; 6) induce chronic inflammation; 7) be immunosuppressive; 8) modulate receptor-mediated effects; 9) cause immortalization; and 10) alter cell proliferation, cell death, or nutrient supply. We describe the use of the 10 key characteristics to conduct a systematic literature search focused on relevant end points and construct a graphical representation of the identified mechanistic information. Next, we use benzene and polychlorinated biphenyls as examples to illustrate how this approach may work in practice. The approach described is similar in many respects to those currently being implemented by the U.S. EPA's Integrated Risk Information System Program and the U.S. National Toxicology Program. Smith MT, Guyton KZ, Gibbons CF, Fritz JM, Portier CJ, Rusyn I, DeMarini DM, Caldwell JC, Kavlock RJ, Lambert P, Hecht SS, Bucher JR, Stewart BW, Baan R, Cogliano VJ, Straif K. 2016. Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis. Environ Health Perspect 124:713-721; http://dx.doi.org/10.1289/ehp.1509912.

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.

Real versus Artificial Variation in the Thermal Sensitivity of Biological Traits.

PubMed

Pawar, Samraat; Dell, Anthony I; Savage, Van M; Knies, Jennifer L

2016-02-01

Whether the thermal sensitivity of an organism's traits follows the simple Boltzmann-Arrhenius model remains a contentious issue that centers around consideration of its operational temperature range and whether the sensitivity corresponds to one or a few underlying rate-limiting enzymes. Resolving this issue is crucial, because mechanistic models for temperature dependence of traits are required to predict the biological effects of climate change. Here, by combining theory with data on 1,085 thermal responses from a wide range of traits and organisms, we show that substantial variation in thermal sensitivity (activation energy) estimates can arise simply because of variation in the range of measured temperatures. Furthermore, when thermal responses deviate systematically from the Boltzmann-Arrhenius model, variation in measured temperature ranges across studies can bias estimated activation energy distributions toward higher mean, median, variance, and skewness. Remarkably, this bias alone can yield activation energies that encompass the range expected from biochemical reactions (from ~0.2 to 1.2 eV), making it difficult to establish whether a single activation energy appropriately captures thermal sensitivity. We provide guidelines and a simple equation for partially correcting for such artifacts. Our results have important implications for understanding the mechanistic basis of thermal responses of biological traits and for accurately modeling effects of variation in thermal sensitivity on responses of individuals, populations, and ecological communities to changing climatic temperatures.

Reversal in the relationship between species richness and turnover in a phytoplankton community.

PubMed

Matthews, Blake; Pomati, Francesco

2012-11-01

Negative relationships between species richness and the rate of compositional turnover are common, suggesting that diverse communities have greater stability than depauperate ones; however, the mechanistic basis for this pattern is still widely debated. Species richness and turnover can covary either because they are mechanistically linked or because they share common environmental drivers. Few empirical studies have combined long-term changes in community composition with multiple drivers of environmental change, and so little is known about how the underlying mechanisms of species coexistence interact with changes in the mean and variability of environmental conditions. Here, we use a 33 year long time series (1976-2008) of phytoplankton community composition from Lake Zurich, to examine how environmental variation influences the relationship between richness and annual turnover. We find that the relationship between richness and annual turnover reverses midway through the time series (1992-1993), leading to a hump-shaped relationship between species richness and annual turnover. Using structural equation modeling we show that annual turnover and diversity are independently associated with different drivers of environmental change. Furthermore, we find that the observed annual sequences of community assembly give rise to rates of species accumulation that are more heterogeneous through time than expected by chance, likely owing to a high proportion of species showing significant autocorrelation and to strong positive covariation in the occurrences of species.

The missing link in parasite manipulation of host behaviour.

PubMed

Herbison, Ryan; Lagrue, Clement; Poulin, Robert

2018-04-03

The observation that certain species of parasite my adaptively manipulate its host behaviour is a fascinating phenomenon. As a result, the recently established field of 'host manipulation' has seen rapid expansion over the past few decades with public and scientific interest steadily increasing. However, progress appears to falter when researchers ask how parasites manipulate behaviour, rather than why. A vast majority of the published literature investigating the mechanistic basis underlying behavioural manipulation fails to connect the establishment of the parasite with the reported physiological changes in its host. This has left researchers unable to empirically distinguish/identify adaptive physiological changes enforced by the parasites from pathological side effects of infection, resulting in scientists relying on narratives to explain results, rather than empirical evidence. By contrasting correlative mechanistic evidence for host manipulation against rare cases of causative evidence and drawing from the advanced understanding of physiological systems from other disciplines it is clear we are often skipping over a crucial step in host-manipulation: the production, potential storage, and release of molecules (manipulation factors) that must create the observed physiological changes in hosts if they are adaptive. Identifying these manipulation factors, via associating gene expression shifts in the parasite with behavioural changes in the host and following their effects will provide researchers with a bottom-up approach to unraveling the mechanisms of behavioural manipulation and by extension behaviour itself.

A Parameterized Model of Amylopectin Synthesis Provides Key Insights into the Synthesis of Granular Starch

PubMed Central

Wu, Alex Chi; Morell, Matthew K.; Gilbert, Robert G.

2013-01-01

A core set of genes involved in starch synthesis has been defined by genetic studies, but the complexity of starch biosynthesis has frustrated attempts to elucidate the precise functional roles of the enzymes encoded. The chain-length distribution (CLD) of amylopectin in cereal endosperm is modeled here on the basis that the CLD is produced by concerted actions of three enzyme types: starch synthases, branching and debranching enzymes, including their respective isoforms. The model, together with fitting to experiment, provides four key insights. (1) To generate crystalline starch, defined restrictions on particular ratios of enzymatic activities apply. (2) An independent confirmation of the conclusion, previously reached solely from genetic studies, of the absolute requirement for debranching enzyme in crystalline amylopectin synthesis. (3) The model provides a mechanistic basis for understanding how successive arrays of crystalline lamellae are formed, based on the identification of two independent types of long amylopectin chains, one type remaining in the amorphous lamella, while the other propagates into, and is integral to the formation of, an adjacent crystalline lamella. (4) The model provides a means by which a small number of key parameters defining the core enzymatic activities can be derived from the amylopectin CLD, providing the basis for focusing studies on the enzymatic requirements for generating starches of a particular structure. The modeling approach provides both a new tool to accelerate efforts to understand granular starch biosynthesis and a basis for focusing efforts to manipulate starch structure and functionality using a series of testable predictions based on a robust mechanistic framework. PMID:23762422

The Spiritual and Educational Dimensions of The New Science Movement.

ERIC Educational Resources Information Center

Walz-Michaels, Gerda

With the emergence in physics of relativity and quantum theories in the first decade of this century a paradigm shift took place from a predominantly mechanistic to a dynamic world view. This shift formed the basis of the New Science Movement, including the new physics, in the 1970s. The movement is international, interdisciplinary, dynamic, and…

Photosynthetic declines are induced by Phytophthora ramorum infection and exposure to elicitins

Treesearch

Daniel K. Manter; Rick G. Kelsey; Joseph J. Karchesy

2008-01-01

Infection of compatible plants by Phytophthora spp. often leads to a decline in stomatal conductance and photosynthesis, although the mechanistic basis for such declines is not completely understood. In many cases, declines in leaf gas exchange rates have been linked to losses in water supply capacity associated with root and/or xylem. However, the...

On the formation of dense understory layers in forests worldwide: consequences and implications for forest dynamics, biodiversity, and succession

Treesearch

Alejandro A. Royo; Walter P. Carson

2006-01-01

The mechanistic basis underpinning forest succession is the gap-phase paradigm in which overstory disturbance interacts with seedling and sapling shade tolerance to determine successional trajectories. The theory, and ensuing simulation models, typically assume that understory plants have little impact on the advance regeneration layer's composition. We challenge...

The Oxidation of Ascorbic Acid by Hexacyanoferrate(III) Ion in Acidic Aqueous Media.

ERIC Educational Resources Information Center

Martins, Luis J. A.; da Costa, J. Barbosa

1988-01-01

Describes a kinetic and mechanistic investigation of ascorbic acid by a substitution-inert complex in acidic medium suitable for the undergraduate level. Discusses obtaining the second order rate constant for the rate determining step at a given temperature and comparison with the value predicted on the basis of the Marcus cross-relation. (CW)

EVALUATION OF THE MODEL ANTI-ANDROGEN FLUTAMIDE FOR ASSESSING THE MECHANISTIC BASIS OF RESPONSES TO AN ANDROGEN IN THE FATHEAD MINNOW (JOURNAL ARTICLE)

EPA Science Inventory

In this study we characterized the effects of flutamide, a model mammalian androgen receptor (AR) antagonist, on endocrine function in the fathead minnow (Pimephales promelas), a small fish species which is widely used for testing endocrine-disrupting chemicals (EDCs). Binding a...

Fishing-induced life-history changes degrade and destabilize harvested ecosystems

NASA Astrophysics Data System (ADS)

Kuparinen, Anna; Boit, Alice; Valdovinos, Fernanda S.; Lassaux, Hélène; Martinez, Neo D.

2016-02-01

Fishing is widely known to magnify fluctuations in targeted populations. These fluctuations are correlated with population shifts towards young, small, and more quickly maturing individuals. However, the existence and nature of the mechanistic basis for these correlations and their potential ecosystem impacts remain highly uncertain. Here, we elucidate this basis and associated impacts by showing how fishing can increase fluctuations in fishes and their ecosystem, particularly when coupled with decreasing body sizes and advancing maturation characteristic of the life-history changes induced by fishing. More specifically, using an empirically parameterized network model of a well-studied lake ecosystem, we show how fishing may both increase fluctuations in fish abundances and also, when accompanied by decreasing body size of adults, further decrease fish abundance and increase temporal variability of fishes’ food resources and their ecosystem. In contrast, advanced maturation has relatively little effect except to increase variability in juvenile populations. Our findings illustrate how different mechanisms underlying life-history changes that may arise as evolutionary responses to intensive, size-selective fishing can rapidly and continuously destabilize and degrade ecosystems even after fishing has ceased. This research helps better predict how life-history changes may reduce fishes’ resilience to fishing and ecosystems’ resistance to environmental variations.

Fishing-induced life-history changes degrade and destabilize harvested ecosystems.

PubMed

Kuparinen, Anna; Boit, Alice; Valdovinos, Fernanda S; Lassaux, Hélène; Martinez, Neo D

2016-02-26

Fishing is widely known to magnify fluctuations in targeted populations. These fluctuations are correlated with population shifts towards young, small, and more quickly maturing individuals. However, the existence and nature of the mechanistic basis for these correlations and their potential ecosystem impacts remain highly uncertain. Here, we elucidate this basis and associated impacts by showing how fishing can increase fluctuations in fishes and their ecosystem, particularly when coupled with decreasing body sizes and advancing maturation characteristic of the life-history changes induced by fishing. More specifically, using an empirically parameterized network model of a well-studied lake ecosystem, we show how fishing may both increase fluctuations in fish abundances and also, when accompanied by decreasing body size of adults, further decrease fish abundance and increase temporal variability of fishes' food resources and their ecosystem. In contrast, advanced maturation has relatively little effect except to increase variability in juvenile populations. Our findings illustrate how different mechanisms underlying life-history changes that may arise as evolutionary responses to intensive, size-selective fishing can rapidly and continuously destabilize and degrade ecosystems even after fishing has ceased. This research helps better predict how life-history changes may reduce fishes' resilience to fishing and ecosystems' resistance to environmental variations.

The essential role of coumarin secretion for Fe acquisition from alkaline soil

PubMed Central

Clemens, Stephan; Weber, Michael

2016-01-01

ABSTRACT Plant productivity is limited by the scarcity of the essential micronutrient iron particularly in alkaline soils. The root secretion of phenolics has long been recognized as a component of the acidification-reduction strategy to acquire iron (strategy I). However, very little molecular insight into this process was available until recently several research groups independently discovered the important role of coumarins for the growth of Arabidopsis thaliana under Fe-limited conditions. Genome-wide analyses of iron deficiency responses, mutant screening and metabolomics experiments all converged on the finding that the synthesis and root exudation of scopoletin, esculetin and other coumarins is essential for iron uptake from substrates with low iron availability. Here we describe the evidence supporting this conclusion and discuss important questions that now have to be addressed in order to better understand the mechanistic basis of coumarin-dependent iron uptake and its significance within the plant kingdom. PMID:26618918

Unifying concept of serotonin transporter-associated currents.

PubMed

Schicker, Klaus; Uzelac, Zeljko; Gesmonde, Joan; Bulling, Simon; Stockner, Thomas; Freissmuth, Michael; Boehm, Stefan; Rudnick, Gary; Sitte, Harald H; Sandtner, Walter

2012-01-02

Serotonin (5-HT) uptake by the human serotonin transporter (hSERT) is driven by ion gradients. The stoichiometry of transported 5-HT and ions is predicted to result in electroneutral charge movement. However, hSERT mediates a current when challenged with 5-HT. This discrepancy can be accounted for by an uncoupled ion flux. Here, we investigated the mechanistic basis of the uncoupled currents and its relation to the conformational cycle of hSERT. Our observations support the conclusion that the conducting state underlying the uncoupled ion flux is in equilibrium with an inward facing state of the transporter with K+ bound. We identified conditions associated with accumulation of the transporter in inward facing conformations. Manipulations that increased the abundance of inward facing states resulted in enhanced steady-state currents. We present a comprehensive kinetic model of the transport cycle, which recapitulates salient features of the recorded currents. This study provides a framework for exploring transporter-associated currents.

Unifying Concept of Serotonin Transporter-associated Currents*

PubMed Central

Schicker, Klaus; Uzelac, Zeljko; Gesmonde, Joan; Bulling, Simon; Stockner, Thomas; Freissmuth, Michael; Boehm, Stefan; Rudnick, Gary; Sitte, Harald H.; Sandtner, Walter

2012-01-01

Serotonin (5-HT) uptake by the human serotonin transporter (hSERT) is driven by ion gradients. The stoichiometry of transported 5-HT and ions is predicted to result in electroneutral charge movement. However, hSERT mediates a current when challenged with 5-HT. This discrepancy can be accounted for by an uncoupled ion flux. Here, we investigated the mechanistic basis of the uncoupled currents and its relation to the conformational cycle of hSERT. Our observations support the conclusion that the conducting state underlying the uncoupled ion flux is in equilibrium with an inward facing state of the transporter with K+ bound. We identified conditions associated with accumulation of the transporter in inward facing conformations. Manipulations that increased the abundance of inward facing states resulted in enhanced steady-state currents. We present a comprehensive kinetic model of the transport cycle, which recapitulates salient features of the recorded currents. This study provides a framework for exploring transporter-associated currents. PMID:22072712

Approaches and advances in the genetic causes of autoimmune disease and their implications.

PubMed

Inshaw, Jamie R J; Cutler, Antony J; Burren, Oliver S; Stefana, M Irina; Todd, John A

2018-06-20

Genome-wide association studies are transformative in revealing the polygenetic basis of common diseases, with autoimmune diseases leading the charge. Although the field is just over 10 years old, advances in understanding the underlying mechanistic pathways of these conditions, which result from a dense multifactorial blend of genetic, developmental and environmental factors, have already been informative, including insights into therapeutic possibilities. Nevertheless, the challenge of identifying the actual causal genes and pathways and their biological effects on altering disease risk remains for many identified susceptibility regions. It is this fundamental knowledge that will underpin the revolution in patient stratification, the discovery of therapeutic targets and clinical trial design in the next 20 years. Here we outline recent advances in analytical and phenotyping approaches and the emergence of large cohorts with standardized gene-expression data and other phenotypic data that are fueling a bounty of discovery and improved understanding of human physiology.

Structural and mechanistic basis of proton-coupled metal ion transport in the SLC11/NRAMP family

PubMed Central

Ehrnstorfer, Ines A.; Manatschal, Cristina; Arnold, Fabian M.; Laederach, Juerg; Dutzler, Raimund

2017-01-01

Secondary active transporters of the SLC11/NRAMP family catalyse the uptake of iron and manganese into cells. These proteins are highly conserved across all kingdoms of life and thus likely share a common transport mechanism. Here we describe the structural and functional properties of the prokaryotic SLC11 transporter EcoDMT. Its crystal structure reveals a previously unknown outward-facing state of the protein family. In proteoliposomes EcoDMT mediates proton-coupled uptake of manganese at low micromolar concentrations. Mutants of residues in the transition-metal ion-binding site severely affect transport, whereas a mutation of a conserved histidine located near this site results in metal ion transport that appears uncoupled to proton transport. Combined with previous results, our study defines the conformational changes underlying transition-metal ion transport in the SLC11 family and it provides molecular insight to its coupling to protons. PMID:28059071

Structural analysis of enzymes used for bioindustry and bioremediation.

PubMed

Tanokura, Masaru; Miyakawa, Takuya; Guan, Lijun; Hou, Feng

2015-01-01

Microbial enzymes have been widely applied in the large-scale, bioindustrial manufacture of food products and pharmaceuticals due to their high substrate specificity and stereoselectivity, and their effectiveness under mild conditions with low environmental burden. At the same time, bioremedial techniques using microbial enzymes have been developed to solve the problem of industrial waste, particularly with respect to persistent chemicals and toxic substances. And finally, structural studies of these enzymes have revealed the mechanistic basis of enzymatic reactions, including the stereoselectivity and binding specificity of substrates and cofactors. The obtained structural insights are useful not only to deepen our understanding of enzymes with potential bioindustrial and/or bioremedial application, but also for the functional improvement of enzymes through rational protein engineering. This review shows the structural bases for various types of enzymatic reactions, including the substrate specificity accompanying cofactor-controlled and kinetic mechanisms.

Neural plasticity of development and learning.

PubMed

Galván, Adriana

2010-06-01

Development and learning are powerful agents of change across the lifespan that induce robust structural and functional plasticity in neural systems. An unresolved question in developmental cognitive neuroscience is whether development and learning share the same neural mechanisms associated with experience-related neural plasticity. In this article, I outline the conceptual and practical challenges of this question, review insights gleaned from adult studies, and describe recent strides toward examining this topic across development using neuroimaging methods. I suggest that development and learning are not two completely separate constructs and instead, that they exist on a continuum. While progressive and regressive changes are central to both, the behavioral consequences associated with these changes are closely tied to the existing neural architecture of maturity of the system. Eventually, a deeper, more mechanistic understanding of neural plasticity will shed light on behavioral changes across development and, more broadly, about the underlying neural basis of cognition. (c) 2010 Wiley-Liss, Inc.

Kibdelones: novel anticancer polyketides from a rare Australian actinomycete.

PubMed

Ratnayake, Ranjala; Lacey, Ernest; Tennant, Shaun; Gill, Jennifer H; Capon, Robert J

2007-01-01

The kibdelones are a novel family of bioactive heterocyclic polyketides produced by a rare soil actinomycete, Kibdelosporangium sp. (MST-108465). Complete relative stereostructures were assigned to kibdelones A-C (1-3), kibdelone B rhamnoside (5), 13-oxokibdelone A (7), and 25-methoxy-24-oxokibdelone C (8) on the basis of detailed spectroscopic analysis and chemical interconversion, as well as mechanistic and biosynthetic considerations. Under mild conditions, kibdelones B (2) and C (3) undergo a facile equilibration to kibdelones A-C (1-3), while kibdelone B rhamnoside (5) equilibrates to a mixture of kibdelone A-C rhamnosides (4-6). A plausible mechanism for this equilibration is proposed and involves air oxidation, quinone/hydroquinone redox transformations, and a choreographed sequence of keto/enol tautomerizations that aromatize ring C via a quinone methide intermediate. Kibdelones exhibit potent and selective cytotoxicity against a panel of human tumor cell lines and display significant antibacterial and nematocidal activity.

Future needs and recommendations in the development of species sensitivity distributions: Estimating toxicity thresholds for aquatic ecological communities and assessing impacts of chemical exposures.

PubMed

Belanger, Scott; Barron, Mace; Craig, Peter; Dyer, Scott; Galay-Burgos, Malyka; Hamer, Mick; Marshall, Stuart; Posthuma, Leo; Raimondo, Sandy; Whitehouse, Paul

2017-07-01

A species sensitivity distribution (SSD) is a probability model of the variation of species sensitivities to a stressor, in particular chemical exposure. The SSD approach has been used as a decision support tool in environmental protection and management since the 1980s, and the ecotoxicological, statistical, and regulatory basis and applications continue to evolve. This article summarizes the findings of a 2014 workshop held by the European Centre for Toxicology and Ecotoxicology of Chemicals and the UK Environment Agency in Amsterdam, The Netherlands, on the ecological relevance, statistical basis, and regulatory applications of SSDs. An array of research recommendations categorized under the topical areas of use of SSDs, ecological considerations, guideline considerations, method development and validation, toxicity data, mechanistic understanding, and uncertainty were identified and prioritized. A rationale for the most critical research needs identified in the workshop is provided. The workshop reviewed the technical basis and historical development and application of SSDs, described approaches to estimating generic and scenario-specific SSD-based thresholds, evaluated utility and application of SSDs as diagnostic tools, and presented new statistical approaches to formulate SSDs. Collectively, these address many of the research needs to expand and improve their application. The highest priority work, from a pragmatic regulatory point of view, is to develop a guidance of best practices that could act as a basis for global harmonization and discussions regarding the SSD methodology and tools. Integr Environ Assess Manag 2017;13:664-674. © 2016 SETAC. © 2016 SETAC.

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.

Mechanisms of Zika Virus Infection and Neuropathogenesis.

PubMed

Olagnier, David; Muscolini, Michela; Coyne, Carolyn B; Diamond, Michael S; Hiscott, John

2016-08-01

A spotlight has been focused on the mosquito-borne Zika virus (ZIKV) because of its epidemic outbreak in Brazil and Latin America, as well as the severe neurological manifestations of microcephaly and Guillain-Barré syndrome associated with infection. In this review, we discuss the recent literature on ZIKV-host interactions, including new mechanistic insight concerning the basis of ZIKV-induced neuropathogenesis.

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.

Polyphenols of virgin coconut oil prevent pro-oxidant mediated cell death.

PubMed

Illam, Soorya Parathodi; Narayanankutty, Arunaksharan; Raghavamenon, Achuthan C

2017-07-01

Virgin coconut oil (VCO), extracted from the fresh coconut kernel, is a food supplement enriched with medium chain saturated fatty acids and polyphenolic antioxidants. It is reported to have several health benefits including lipid lowering, antioxidant and anti-inflammatory activities. The pharmacological benefits of VCO have been attributed to its polyphenol content (VCOP), the mechanistic basis of which is less explored. Liquid chromatography/mass spectroscopy (LC/MS) analysis of VCOP documented the presence of gallic acid, ferulic acid (FA), quercetin, methyl catechin, dihydrokaempferol and myricetin glycoside. Pre-treatment of VCOP at different concentrations (25-100 μg/mL) significantly reduced the H 2 O 2 and 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) induced cell death in HCT-15 cells. Giving further insight to its mechanistic basis, oxidative stress induced alterations in glutathione (GSH) levels and activities of GR (Glutathione-Reductase), GPx (Glutathione-Peroxidase), GST (Glutathione-S-Transferase) and catalase (CAT) were restored to near-normal by VCOP, concomitantly reducing lipid peroxidation. The efficacy of VCOP was similar to that of Trolox and FA added in culture. The study thus suggests that VCOP protects cells from pro-oxidant insults by modulating cellular antioxidant status.

A new mechanistic growth model for simultaneous determination of lag phase duration and exponential growth rate and a new Belehdradek-type model for evaluating the effect of temperature on growth rate

USDA-ARS?s Scientific Manuscript database

A new mechanistic growth model was developed to describe microbial growth under isothermal conditions. The new mathematical model was derived from the basic observation of bacterial growth that may include lag, exponential, and stationary phases. With this model, the lag phase duration and exponen...

Mechanisms, determination and the metaphysics of neuroscience.

PubMed

Soom, Patrice

2012-09-01

In this paper, I evaluate recently defended mechanistic accounts of the unity of neuroscience from a metaphysical point of view. Considering the mechanistic framework in general (Sections 2 and 3), I argue that explanations of this kind are essentially reductive (Section 4). The reductive character of mechanistic explanations provides a sufficiency criterion, according to which the mechanism underlying a certain phenomenon is sufficient for the latter. Thus, the concept of supervenience can be used in order to describe the relation between mechanisms and phenomena (Section 5). Against this background, I show that the mechanistic framework is subject to the causal exclusion problem and faces the classical metaphysical options when it comes to the relations obtaining between different levels of mechanisms (Section 6). Finally, an attempt to improve the metaphysics of mechanisms is made (Section 7) and further difficulties are pointed out (Section 8). Copyright © 2012 Elsevier Ltd. All rights reserved.

The Structural Basis of IKs Ion-Channel Activation: Mechanistic Insights from Molecular Simulations.

PubMed

Ramasubramanian, Smiruthi; Rudy, Yoram

2018-06-05

Relating ion channel (iCh) structural dynamics to physiological function remains a challenge. Current experimental and computational techniques have limited ability to explore this relationship in atomistic detail over physiological timescales. A framework associating iCh structure to function is necessary for elucidating normal and disease mechanisms. We formulated a modeling schema that overcomes the limitations of current methods through applications of artificial intelligence machine learning. Using this approach, we studied molecular processes that underlie human IKs voltage-mediated gating. IKs malfunction underlies many debilitating and life-threatening diseases. Molecular components of IKs that underlie its electrophysiological function include KCNQ1 (a pore-forming tetramer) and KCNE1 (an auxiliary subunit). Simulations, using the IKs structure-function model, reproduced experimentally recorded saturation of gating-charge displacement at positive membrane voltages, two-step voltage sensor (VS) movement shown by fluorescence, iCh gating statistics, and current-voltage relationship. Mechanistic insights include the following: 1) pore energy profile determines iCh subconductance; 2) the entire protein structure, not limited to the pore, contributes to pore energy and channel subconductance; 3) interactions with KCNE1 result in two distinct VS movements, causing gating-charge saturation at positive membrane voltages and current activation delay; and 4) flexible coupling between VS and pore permits pore opening at lower VS positions, resulting in sequential gating. The new modeling approach is applicable to atomistic scale studies of other proteins on timescales of physiological function. Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.

An updated model for nitrate uptake modelling in plants. I. Functional component: cross-combination of flow–force interpretation of nitrate uptake isotherms, and environmental and in planta regulation of nitrate influx

PubMed Central

Le Deunff, Erwan; Malagoli, Philippe

2014-01-01

Background and Aims In spite of major breakthroughs in the last three decades in the identification of root nitrate uptake transporters in plants and the associated regulation of nitrate transport activities, a simplified and operational modelling approach for nitrate uptake is still lacking. This is due mainly to the difficulty in linking the various regulations of nitrate transport that act at different levels of time and on different spatial scales. Methods A cross-combination of a Flow–Force approach applied to nitrate influx isotherms and experimentally determined environmental and in planta regulation is used to model nitrate in oilseed rape, Brassica napus. In contrast to ‘Enzyme–Substrate’ interpretations, a Flow–Force modelling approach considers the root as a single catalytic structure and does not infer hypothetical cellular processes among nitrate transporter activities across cellular layers in the mature roots. In addition, this approach accounts for the driving force on ion transport based on the gradient of electrochemical potential, which is more appropriate from a thermodynamic viewpoint. Key Results and Conclusions Use of a Flow–Force formalism on nitrate influx isotherms leads to the development of a new conceptual mechanistic basis to model more accurately N uptake by a winter oilseed rape crop under field conditions during the whole growth cycle. This forms the functional component of a proposed new structure–function mechanistic model of N uptake. PMID:24638820

Mechanistic Basis of Calmodulin Mediated Estrogen Receptor Alpha Activation and Antiestrogen Resistance

DTIC Science & Technology

2009-06-01

attending College of Dental Medicine, The Medical University of South Carolina --Aisha Mahmood (UGA), undergraduate Honors Student, The University...Paul A. Kitos Award for Excellence in Undergraduate Research and Academics (2002, KU) Marie Cross, 2007-2008, beginning dental school, fall 2009...University Prof. Thomas C. Squier, Pacific Northwest Labs Prof. Carey K. Johnson, University of Kansas SEMINARS BY INVITATION November 14

A predictive processing theory of sensorimotor contingencies: Explaining the puzzle of perceptual presence and its absence in synesthesia.

PubMed

Seth, Anil K

2014-01-01

Normal perception involves experiencing objects within perceptual scenes as real, as existing in the world. This property of "perceptual presence" has motivated "sensorimotor theories" which understand perception to involve the mastery of sensorimotor contingencies. However, the mechanistic basis of sensorimotor contingencies and their mastery has remained unclear. Sensorimotor theory also struggles to explain instances of perception, such as synesthesia, that appear to lack perceptual presence and for which relevant sensorimotor contingencies are difficult to identify. On alternative "predictive processing" theories, perceptual content emerges from probabilistic inference on the external causes of sensory signals, however, this view has addressed neither the problem of perceptual presence nor synesthesia. Here, I describe a theory of predictive perception of sensorimotor contingencies which (1) accounts for perceptual presence in normal perception, as well as its absence in synesthesia, and (2) operationalizes the notion of sensorimotor contingencies and their mastery. The core idea is that generative models underlying perception incorporate explicitly counterfactual elements related to how sensory inputs would change on the basis of a broad repertoire of possible actions, even if those actions are not performed. These "counterfactually-rich" generative models encode sensorimotor contingencies related to repertoires of sensorimotor dependencies, with counterfactual richness determining the degree of perceptual presence associated with a stimulus. While the generative models underlying normal perception are typically counterfactually rich (reflecting a large repertoire of possible sensorimotor dependencies), those underlying synesthetic concurrents are hypothesized to be counterfactually poor. In addition to accounting for the phenomenology of synesthesia, the theory naturally accommodates phenomenological differences between a range of experiential states including dreaming, hallucination, and the like. It may also lead to a new view of the (in)determinacy of normal perception.

A predictive processing theory of sensorimotor contingencies: Explaining the puzzle of perceptual presence and its absence in synesthesia

PubMed Central

Seth, Anil K.

2014-01-01

Normal perception involves experiencing objects within perceptual scenes as real, as existing in the world. This property of “perceptual presence” has motivated “sensorimotor theories” which understand perception to involve the mastery of sensorimotor contingencies. However, the mechanistic basis of sensorimotor contingencies and their mastery has remained unclear. Sensorimotor theory also struggles to explain instances of perception, such as synesthesia, that appear to lack perceptual presence and for which relevant sensorimotor contingencies are difficult to identify. On alternative “predictive processing” theories, perceptual content emerges from probabilistic inference on the external causes of sensory signals, however, this view has addressed neither the problem of perceptual presence nor synesthesia. Here, I describe a theory of predictive perception of sensorimotor contingencies which (1) accounts for perceptual presence in normal perception, as well as its absence in synesthesia, and (2) operationalizes the notion of sensorimotor contingencies and their mastery. The core idea is that generative models underlying perception incorporate explicitly counterfactual elements related to how sensory inputs would change on the basis of a broad repertoire of possible actions, even if those actions are not performed. These “counterfactually-rich” generative models encode sensorimotor contingencies related to repertoires of sensorimotor dependencies, with counterfactual richness determining the degree of perceptual presence associated with a stimulus. While the generative models underlying normal perception are typically counterfactually rich (reflecting a large repertoire of possible sensorimotor dependencies), those underlying synesthetic concurrents are hypothesized to be counterfactually poor. In addition to accounting for the phenomenology of synesthesia, the theory naturally accommodates phenomenological differences between a range of experiential states including dreaming, hallucination, and the like. It may also lead to a new view of the (in)determinacy of normal perception. PMID:24446823

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

Kozluk, M.J.; Vijay, D.K.

Postulated catastrophic rupture of high-energy piping systems is the fundamental criterion used for the safety design basis of both light and heavy water nuclear generating stations. Historically, the criterion has been applied by assuming a nonmechanistic instantaneous double-ended guillotine rupture of the largest diameter pipes inside of containment. Nonmechanistic, meaning that the assumption of an instantaneous guillotine rupture has not been based on stresses in the pipe, failure mechanisms, toughness of the piping material, nor the dynamics of the ruptured pipe ends as they separate. This postulated instantaneous double-ended guillotine rupture of a pipe was a convenient simplifying assumption thatmore » resulted in a conservative accident scenario. This conservative accident scenario has now become entrenched as the design basis accident for: containment design, shutdown system design, emergency fuel cooling systems design, and to establish environmental qualification temperature and pressure conditions. The requirement to address dynamic effects associated with the postulated pipe rupture subsequently evolved. The dynamic effects include: potential missiles, pipe whipping, blowdown jets, and thermal-hydraulic transients. Recent advances in fracture mechanics research have demonstrated that certain pipes under specific conditions cannot crack in ways that result in an instantaneous guillotine rupture. Canadian utilities are now using mechanistic fracture mechanics and leak-before-break assessments on a case-by-case basis, in limited applications, to support licensing cases which seek exemption from the need to consider the various dynamic effects associated with postulated instantaneous catastrophic rupture of high-energy piping systems inside and outside of containment.« less

Gel Filtration Of Dilute Human Embryonic Hemoglobins Reveals Basis For Their Increased Oxygen Binding

PubMed Central

Manning, Lois R.; Popowicz, Anthony M.; Padovan, Julio C.; Chait, Brian T.; Manning, James M.

2016-01-01

This report establishes a correlation between two known properties of the human embryonic hemoglobins-- their weak subunit assemblies as demonstrated here by gel filtration at very dilute protein concentrations and their high oxygen affinities and reduced cooperativities reported previously by others but without a mechanistic basis. We demonstrate here that their high oxygen affinities are a consequence of their weak assemblies. Weak vs strong hemoglobin tetramers represent a regulatory mechanism to modulate oxygen binding capacity by altering the equilibrium between the various steps in the assembly process that can be described as an inverse allosteric effect. PMID:27965062

Gel filtration of dilute human embryonic hemoglobins reveals basis for their increased oxygen binding.

PubMed

Manning, Lois R; Popowicz, Anthony M; Padovan, Julio C; Chait, Brian T; Manning, James M

2017-02-15

This report establishes a correlation between two known properties of the human embryonic hemoglobins-- their weak subunit assemblies as demonstrated here by gel filtration at very dilute protein concentrations and their high oxygen affinities and reduced cooperativities reported previously by others but without a mechanistic basis. We demonstrate here that their high oxygen affinities are a consequence of their weak assemblies. Weak vs strong hemoglobin tetramers represent a regulatory mechanism to modulate oxygen binding capacity by altering the equilibrium between the various steps in the assembly process that can be described as an inverse allosteric effect. Copyright © 2016 Elsevier Inc. All rights reserved.

How Does Rumination Impact Cognition? A First Mechanistic Model.

PubMed

van Vugt, Marieke K; van der Velde, Maarten

2018-01-01

Rumination is a process of uncontrolled, narrowly focused negative thinking that is often self-referential, and that is a hallmark of depression. Despite its importance, little is known about its cognitive mechanisms. Rumination can be thought of as a specific, constrained form of mind-wandering. Here, we introduce a cognitive model of rumination that we developed on the basis of our existing model of mind-wandering. The rumination model implements the hypothesis that rumination is caused by maladaptive habits of thought. These habits of thought are modeled by adjusting the number of memory chunks and their associative structure, which changes the sequence of memories that are retrieved during mind-wandering, such that during rumination the same set of negative memories is retrieved repeatedly. The implementation of habits of thought was guided by empirical data from an experience sampling study in healthy and depressed participants. On the basis of this empirically derived memory structure, our model naturally predicts the declines in cognitive task performance that are typically observed in depressed patients. This study demonstrates how we can use cognitive models to better understand the cognitive mechanisms underlying rumination and depression. Copyright © 2018 The Authors. Topics in Cognitive Science published by Wiley Periodicals, Inc. on behalf of Cognitive Science Society.

Critical weight mediates sex-specific body size plasticity and sexual dimorphism in the yellow dung fly Scathophaga stercoraria (Diptera: Scathophagidae).

PubMed

Rohner, Patrick T; Blanckenhorn, Wolf U; Schäfer, Martin A

2017-05-01

Ultimate factors driving insect body size are rather well understood, while-apart from a few model species-the underlying physiological and developmental mechanisms received less attention. We investigate the physiological basis of adaptive size variation in the yellow dung fly Scathophaga stercoraria, which shows pronounced male-biased sexual size dimorphism and strong body size plasticity. We estimate variation of a major physiological threshold, the critical weight, which is the mass at which a larva initiates pupariation. Critical weight was associated with sexual size dimorphism and sex-specific plasticity, and is thus a likely target of selection on adult size. Detailed larval growth trajectories derived from individuals raised at two food and temperature treatments further reveal that sex-specific size plasticity is mediated by faster initial growth of males that later becomes reduced by higher male weight loss during the wandering stage. We further demonstrate that integral growth rates, which are typically calculated as simple ratios of egg-to-adult development time and adult weight, do not necessarily well reflect variation in instantaneous growth rates. We illustrate the importance of detailed assessments of ontogenetic growth trajectories for the understanding of adaptive size variation and discuss the mechanistic basis of size determination in shaping sex-specific phenotypic plasticity. © 2017 Wiley Periodicals, Inc.

Using Zebrafish to Test the Genetic Basis of Human Craniofacial Diseases.

PubMed

Machado, R Grecco; Eames, B Frank

2017-10-01

Genome-wide association studies (GWASs) opened an innovative and productive avenue to investigate the molecular basis of human craniofacial disease. However, GWASs identify candidate genes only; they do not prove that any particular one is the functional villain underlying disease or just an unlucky genomic bystander. Genetic manipulation of animal models is the best approach to reveal which genetic loci identified from human GWASs are functionally related to specific diseases. The purpose of this review is to discuss the potential of zebrafish to resolve which candidate genetic loci are mechanistic drivers of craniofacial diseases. Many anatomic, embryonic, and genetic features of craniofacial development are conserved among zebrafish and mammals, making zebrafish a good model of craniofacial diseases. Also, the ability to manipulate gene function in zebrafish was greatly expanded over the past 20 y, enabling systems such as Gateway Tol2 and CRISPR-Cas9 to test gain- and loss-of-function alleles identified from human GWASs in coding and noncoding regions of DNA. With the optimization of genetic editing methods, large numbers of candidate genes can be efficiently interrogated. Finding the functional villains that underlie diseases will permit new treatments and prevention strategies and will increase understanding of how gene pathways operate during normal development.

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

NASA Technical Reports Server (NTRS)

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

2010-01-01

The broad-scale reductions and shifts that may be expected under climate change in the availability and quality of stopover habitat for long-distance migrants is an area of increasing concern for conservation biologists. Researchers generally have taken two broad approaches to the modeling of migration behaviour to understand the impact of these changes on migratory bird populations. These include models based on causal processes and their response to environmental stimulation, "mechanistic models", or models that primarily are based on observed animal distribution patterns and the correlation of these patterns with environmental variables, i.e. "data driven" models. Investigators have applied the latter technique to forecast changes in migration patterns with changes in the environment, for example, as might be expected under climate change, by forecasting how the underlying environmental data layers upon which the relationships are built will change over time. The learned geostatstical correlations are then applied to the modified data layers.. However, this is problematic. Even if the projections of how the underlying data layers will change are correct, it is not evident that the statistical relationships will remain the same, i.e. that the animal organism may not adapt its' behaviour to the changing conditions. Mechanistic models that explicitly take into account the physical, biological, and behaviour responses of an organism as well as the underlying changes in the landscape offer an alternative to address these shortcomings. The availability of satellite remote sensing observations at multiple spatial and temporal scales, coupled with advances in climate modeling and information technologies enable the application of the mechanistic models to predict how continental bird migration patterns may change in response to environmental change. In earlier work, we simulated the impact of effects of wetland loss and inter-annual variability on the fitness of migratory shorebirds in the central fly ways of North America. We demonstrated the phenotypic plasticity of a migratory population of Pectoral sandpipers consisting of an ensemble of 10,000 individual birds in response to changes in stopover locations using an individual based migration model driven by remotely sensed land surface data, climate data and biological field data. With the advent of new computing capabilities enabled hy recent GPU-GP computing paradigms and commodity hardware, it now is possible to simulate both larger ensemble populations and to incorporate more realistic mechanistic factors into migration models. Here, we take our first steps use these tools to study the impact of long-term drought variability on shorebird survival.

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

PubMed

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

2015-01-01

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

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

PubMed Central

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

2015-01-01

Species can respond to climate change by tracking appropriate environmental conditions in space, resulting in a range shift. Species Distribution Models (SDMs) can help forecast such range shift responses. For few species, both correlative and mechanistic SDMs were built, but allis shad (Alosa alosa), an endangered anadromous fish species, is one of them. The main purpose of this study was to provide a framework for joint analyses of correlative and mechanistic SDMs projections in order to strengthen conservation measures for species of conservation concern. Guidelines for joint representation and subsequent interpretation of models outputs were defined and applied. The present joint analysis was based on the novel mechanistic model GR3D (Global Repositioning Dynamics of Diadromous fish Distribution) which was parameterized on allis shad and then used to predict its future distribution along the European Atlantic coast under different climate change scenarios (RCP 4.5 and RCP 8.5). We then used a correlative SDM for this species to forecast its distribution across the same geographic area and under the same climate change scenarios. First, projections from correlative and mechanistic models provided congruent trends in probability of habitat suitability and population dynamics. This agreement was preferentially interpreted as referring to the species vulnerability to climate change. Climate change could not be accordingly listed as a major threat for allis shad. The congruence in predicted range limits between SDMs projections was the next point of interest. The difference, when noticed, required to deepen our understanding of the niche modelled by each approach. In this respect, the relative position of the northern range limit between the two methods strongly suggested here that a key biological process related to intraspecific variability was potentially lacking in the mechanistic SDM. Based on our knowledge, we hypothesized that local adaptations to cold temperatures deserved more attention in terms of modelling, but further in conservation planning as well. PMID:26426280

Plasticity in the Oxidative Folding Pathway of the High Affinity Nerita Versicolor Carboxypeptidase Inhibitor (NvCI).

PubMed

Esperante, Sebastián A; Covaleda, Giovanni; Trejo, Sebastián A; Bronsoms, Sílvia; Aviles, Francesc X; Ventura, Salvador

2017-07-14

Nerita Versicolor carboxypeptidase inhibitor (NvCI) is the strongest inhibitor reported so far for the M14A subfamily of carboxypeptidases. It comprises 53 residues and a protein fold composed of a two-stranded antiparallel β sheet connected by three loops and stabilized by three disulfide bridges. Here we report the oxidative folding and reductive unfolding pathways of NvCI. Much debate has gone on whether protein conformational folding guides disulfide bond formation or instead they are disulfide bonds that favour the arrangement of local or global structural elements. We show here that for NvCI both possibilities apply. Under physiological conditions, this protein folds trough a funnelled pathway involving a network of kinetically connected native-like intermediates, all sharing the disulfide bond connecting the two β-strands. In contrast, under denaturing conditions, the folding of NvCI is under thermodynamic control and follows a "trial and error" mechanism, in which an initial quasi-stochastic population of intermediates rearrange their disulfide bonds to attain the stable native topology. Despite their striking mechanistic differences, the efficiency of both folding routes is similar. The present study illustrates thus a surprising plasticity in the folding of this extremely stable small disulfide-rich inhibitor and provides the basis for its redesign for biomedical applications.

Neural mechanisms for the cannabinoid modulation of cognition and affect in man: a critical review of neuroimaging studies.

PubMed

Bhattacharyya, Sagnik; Atakan, Zerrin; Martin-Santos, Rocio; Crippa, Jose A; McGuire, Philip K

2012-01-01

Pharmacological challenge in conjunction with neuroimaging techniques has been employed for over two decades now to understand the neural basis of the cognitive, emotional and symptomatic effects of the main ingredients of cannabis, the most widely used illicit drug in the world. This selective critical review focuses on the human neuroimaging studies investigating the effects of delta-9- tetrahydrocannabinol (THC) and cannabidiol (CBD), the two main cannabinoids of interest present in the extract of the cannabis plant. These studies suggest that consistent with the polymorphic and heterogeneous nature of the effects of cannabis, THC and CBD have distinct and often opposing effects on widely distributed neural networks that include medial temporal and prefrontal cortex and striatum, brain regions that are rich in cannabinoid receptors and implicated in the pathophysiology of psychosis. They help elucidate the neurocognitive mechanisms underlying the acute induction of psychotic symptoms by cannabis and provide mechanistic understanding underlying the potential role of CBD as an anxiolytic and antipsychotic. Although there are ethical and methodological caveats, pharmacological neuroimaging studies such as those reviewed here may not only help model different aspects of the psychopathology of mental disorders such as schizophrenia and offer insights into their underlying mechanisms, but may suggest potentially new therapeutic targets for drug discovery.

Mechanistic Basis for Biological Polymer Stability, Electron Transfer and Molecular Sensing in Extreme Environments

DTIC Science & Technology

2015-12-02

electrically driven CO2 fixation. Many different types of extremophiles are known that are robust and resistant to heat or DISTRIBUTION A: Distribution...Metabolic and photosynthetic consequences of blocking starch biosynthesis in the green alga Chlamydomonas reinhardtii sta6 mutant. Plant Journal 81...photosynthetic consequences of blocking starch biosynthesis in the green alga Chlamydomonas reinhardtii sta6 mutant. Plant Journal 81, 947-960

Mechanistic Basis of Sensitivity/Resistance Towards Anti-Cancer Drugs Targeting Topoisomerase II

DTIC Science & Technology

2005-04-01

alkylation of hstopo Ilac by both anticancer drugs such as menadione and chemopreventive compounds such as diallyl trisulfide (DAT), which has been...putatively identified menadione as having reacted with Cys427 by matrix-assisted laser desorption ionization (MALDI) MS. Preliminary results from LC-ESI-MS...suggest that menadione reacts with additional thiol residues, albeit through indirect evidence. The indirect evidence is similar to that mentioned

Mechanistic Basis of Sensitivity/Resistance Towards Anti-cancer Drugs Targeting Topoisomerase II

DTIC Science & Technology

2006-04-01

of hstopo IIα by both anticancer drugs such as menadione and chemopreventive compounds such as 9 diallyl trisulfide (DAT), which has been shown to...we putatively identified menadione as having reacted with Cys427 by matrix-assisted laser desorption ionization (MALDI) MS. Preliminary results...from LC- ESI-MS suggest that menadione reacts with additional thiol residues, albeit through indirect evidence. The indirect evidence is similar to

Dual Visible Light Photoredox and Gold-Catalyzed Arylative Ring Expansion

PubMed Central

2015-01-01

A combination of visible light photocatalysis and gold catalysis is applied to a ring expansion–oxidative arylation reaction. The reaction provides an entry into functionalized cyclic ketones from the coupling reaction of alkenyl and allenyl cycloalkanols with aryl diazonium salts. A mechanism involving generation of an electrophilic gold(III)–aryl intermediate is proposed on the basis of mechanistic studies, including time-resolved FT-IR spectroscopy. PMID:24730447

Reconstruction of palaeoatmospheric carbon dioxide using stomatal densities of various beech plants (Fagaceae): testing and application of a mechanistic model

NASA Astrophysics Data System (ADS)

Grein, M.; Roth-Nebelsick, A.; Konrad, W.

2006-12-01

A mechanistic model (Konrad &Roth-Nebelsick a, in prep.) was applied for the reconstruction of atmospheric carbon dioxide using stomatal densities and photosynthesis parameters of extant and fossil Fagaceae. The model is based on an approach which couples diffusion and the biochemical process of photosynthesis. Atmospheric CO2 is calculated on the basis of stomatal diffusion and photosynthesis parameters of the considered taxa. The considered species include the castanoid Castanea sativa, two quercoids Quercus petraea and Quercus rhenana and an intermediate species Eotrigonobalanus furcinervis. In the case of Quercus petraea literature data were used. Stomatal data of Eotrigonobalanus furcinervis, Quercus rhenana and Castanea sativa were determined by the authors. Data of the extant Castanea sativa were collected by applying a peeling method and by counting of stomatal densities on the digitalized images of the peels. Additionally, isotope data of leaf samples of Castanea sativa were determined to estimate the ratio of intercellular to ambient carbon dioxide. The CO2 values calculated by the model (on the basis of stomatal data and measured or estimated biochemical parameters) are in good agreement with literature data, with the exception of the Late Eocene. The results thus demonstrate that the applied approach is principally suitable for reconstructing palaeoatmospheric CO2.

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

PubMed

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

2008-11-01

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

Phytoplankton defence mechanisms: traits and trade-offs.

PubMed

Pančić, Marina; Kiørboe, Thomas

2018-05-01

In aquatic ecosystems, unicellular algae form the basis of the food webs. Theoretical and experimental studies have demonstrated that one of the mechanisms that maintain high diversity of phytoplankton is through predation and the consequent evolution of defence mechanisms. Proposed defence mechanisms in phytoplankton are diverse and include physiological (e.g. toxicity, bioluminescence), morphological (e.g. silica shell, colony formation), and behavioural (e.g. escape response) traits. However, the function of many of the proposed defence mechanisms remains elusive, and the costs and benefits (trade-offs) are often unquantified or undocumented. Here, we provide an overview of suggested phytoplankton defensive traits and review their experimental support. Wherever possible we quantify the trade-offs from experimental evidence and theoretical considerations. In many instances, experimental evidence suggests that defences are costless. However, we argue that (i) some costs materialize only under natural conditions, for example, sinking losses, or dependency on the availability of specific nutrients, and (ii) other costs become evident only under resource-deficient conditions where a rivalry for limiting resources between growth and defence occurs. Based on these findings, we suggest two strategies for quantifying the costs of defence mechanisms in phytoplankton: (i) for the evaluation of defence costs that are realized under natural conditions, a mechanistic understanding of the hypothesized component processes is required; and (ii) the magnitude of the costs (i.e. growth reduction) must be assessed under conditions of resource limitation. © 2018 Cambridge Philosophical Society.

Testing mechanistic models of growth in insects.

PubMed

Maino, James L; Kearney, Michael R

2015-11-22

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

Fragile X-associated tremor/ataxia syndrome (FXTAS): Pathology and mechanisms

PubMed Central

Hagerman, Paul

2013-01-01

Since its discovery in 2001, our understanding of fragile X-associated tremor/ataxia syndrome (FXTAS) has undergone a remarkable transformation. Initially characterized rather narrowly as an adult-onset movement disorder, the definition of FXTAS is broadening; moreover, the disorder is now recognized as only one facet of a much broader clinical pleiotropy among children and adults who carry premutation alleles of the FMR1 gene. Furthermore, the intranuclear inclusions of FXTAS, once thought to be a CNS-specific marker of the disorder, are now known to be widely distributed in multiple non-CNS tissues; this observation fundamentally changes our concept of the disease, and may provide the basis for understanding the diverse medical problems associated with the premutation. Recent work on the pathogenic mechanisms underlying FXTAS indicates that the origins of the late-onset neurodegenerative disorder actually lie in early development, raising the likelihood that all forms of clinical involvement among premutation carriers have a common underlying mechanistic basis. There has also been great progress in our understanding of the triggering event(s) in FXTAS pathogenesis, which is now thought to involve sequestration of one or more nuclear proteins involved with microRNA biogenesis. Moreover, there is mounting evidence that mitochondrial dysregulation contributes to the decreased cell function and loss of viability, evident in mice even during the neonatal period. Taken together, these recent findings offer hope for early interventions for FXTAS, well before the onset of overt disease, and for the treatment of other forms of clinical involvement among premutation carriers. PMID:23793382

The thermal degradation of 5 alpha (H)-cholestane during closed-system pyrolysis

NASA Astrophysics Data System (ADS)

Abbott, Geoffrey D.; Bennett, Barry; Stuart Fetch, G.

1995-06-01

Involatile hydrocarbons were identified following the heating of 5α(H)-cholestane in water with reaction vessel walls composed of 316 grade stainless steel and borosilicate glass. These analyses were compared with the hydrocarbon product compositions from closed-system pyrolysis experiments with no added water. Unsaturated hydrocarbons dominate their saturated counterparts following hydrous pyrolysis in both stainless steel-316 and borosilicate glass. In the absence of added water the converse is true in that saturated components dominate the hydrocarbon mixture. Backbone rearrangement in the steroid nucleus leading to spirosterene formation was only observed under aqueous conditions in both borosilicate glass and stainless steel-316 vessels. These comparisons demonstrate that water, as opposed to reaction vessel surface catalytic effects, plays a central role in mediating hydrocarbon degradation during closed-system hydrous pyrolysis. 5α(H)-cholestane degradation under aqueous conditions is a complex composite of dissociative and rearrangement processes. These include (I) carbon-carbon bond cleavage in the sidechains as well as the ring system, (2) dehydrogenation, and (3) backbone rearrangement. These laboratory experiments provide a product description of the involatile hydrocarbons which will be the basis for a mechanistic study of 5α(H)-cholestane degradation in hot water.

Molecular Basis of Cardiac Delayed Rectifier Potassium Channel Function and Pharmacology.

PubMed

Wu, Wei; Sanguinetti, Michael C

2016-06-01

Human cardiomyocytes express 3 distinct types of delayed rectifier potassium channels. Human ether-a-go-go-related gene (hERG) channels conduct the rapidly activating current IKr; KCNQ1/KCNE1 channels conduct the slowly activating current IKs; and Kv1.5 channels conduct an ultrarapid activating current IKur. Here the authors provide a general overview of the mechanistic and structural basis of ion selectivity, gating, and pharmacology of the 3 types of cardiac delayed rectifier potassium ion channels. Most blockers bind to S6 residues that line the central cavity of the channel, whereas activators interact with the channel at 4 symmetric binding sites outside the cavity. Copyright © 2016 Elsevier Inc. All rights reserved.

Censored rainfall modelling for estimation of fine-scale extremes

NASA Astrophysics Data System (ADS)

Cross, David; Onof, Christian; Winter, Hugo; Bernardara, Pietro

2018-01-01

Reliable estimation of rainfall extremes is essential for drainage system design, flood mitigation, and risk quantification. However, traditional techniques lack physical realism and extrapolation can be highly uncertain. In this study, we improve the physical basis for short-duration extreme rainfall estimation by simulating the heavy portion of the rainfall record mechanistically using the Bartlett-Lewis rectangular pulse (BLRP) model. Mechanistic rainfall models have had a tendency to underestimate rainfall extremes at fine temporal scales. Despite this, the simple process representation of rectangular pulse models is appealing in the context of extreme rainfall estimation because it emulates the known phenomenology of rainfall generation. A censored approach to Bartlett-Lewis model calibration is proposed and performed for single-site rainfall from two gauges in the UK and Germany. Extreme rainfall estimation is performed for each gauge at the 5, 15, and 60 min resolutions, and considerations for censor selection discussed.

Preparation and Analysis of Oligonucleotides Containing the C4′-Oxidized Abasic Site and Related Mechanistic Probes

PubMed Central

Kim, Jaeseung; Kreller, Cortney R.; Greenberg, Marc M.

2005-01-01

The C4′-oxidized abasic site (C4-AP) is produced by a variety of DNA damaging agents. This alkali labile lesion can exist in up to four diastereomeric cyclic forms, in addition to the acyclic keto-aldehyde. Synthetic oligonucleotides containing the lesion were prepared from a stable photochemical precursor. Chemical integrity of the lesion containing oligonucleotides was probed using phosphodiesterase lability. Analysis of the 3′,5′-phosphate diester of the monomeric lesion released from single diastereomers of photolabile precursors by 1H NMR indicates that isomerization of the hemiacetal and/or hemiketal is rapid. The syntheses and characterization of oligonucleotides containing configurationally stable analogues of C4-AP, which serve as mechanistic probes for deciphering the structural basis of the biochemical and biological effects of the C4′-oxidized abasic lesion, are also described. PMID:16277338

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

Energetic etiologies of acute pancreatitis: A report of five cases

PubMed Central

Shmelev, Artem; Abdo, Alain; Sachdev, Sarina; Shah, Urvi; Kowdley, Gopal C; Cunningham, Steven C

2015-01-01

There are several common causes of acute pancreatitis, principally excessive alcohol intake and gallstones, and there are many rare causes. However, cases of pancreatitis still occur in the absence of any recognizable factors, and these cases of idiopathic pancreatitis suggest the presence of unrecognized etiologies. Five cases of acute pancreatitis in four patients came to attention due to a strong temporal association with exposure to nerve stimulators and energy drinks. Given that these cases of pancreatitis were otherwise unexplained, and given that these exposures were not clearly known to be associated with pancreatitis, we performed a search for precedent cases and for mechanistic bases. No clear precedent cases were found in PubMed and only scant, weak precedent cases were found in public-health databases. However, there was a coherent body of intriguing literature in support of a mechanistic basis for these exposures playing a role in the etiology of pancreatitis. PMID:26600983

Mechanistic Insight of Probiotics Derived Anticancer Pharmaceuticals: A Road Forward for Cancer Therapeutics.

PubMed

Kumar, Raman; Dhanda, Suman

2017-04-01

Probiotics are living organisms that confer health benefits when administered in adequate amounts. Probiotics are continuously being explored for their different health beneficiary activities. Anticancer activity is one of the most important benefits both from a preventive and therapeutic point of view. Though not many studies have been conducted to date in this area, a number suggest using laboratory animal models and different cell lines that there may be a mechanistic basis for the anticancer effects of probiotics and require more scientific justification and clinical trials. Most studies of probiotics are conducted for colon cancer associated with inflammatory bowel disease. Studies are also being extended to other types of cancer in different cell lines. This review summarizes studied probiotics considered for treatment of colon cancer and some other cancers (in cancer cell lines) and also proposed mechanism how probiotics are inhibiting cancer growth along with some challenges and future perspectives.

The DART dispersion analysis research tool: A mechanistic model for predicting fission-product-induced swelling of aluminum dispersion fuels. User`s guide for mainframe, workstation, and personal computer applications

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

Rest, J.

1995-08-01

This report describes the primary physical models that form the basis of the DART mechanistic computer model for calculating fission-product-induced swelling of aluminum dispersion fuels; the calculated results are compared with test data. In addition, DART calculates irradiation-induced changes in the thermal conductivity of the dispersion fuel, as well as fuel restructuring due to aluminum fuel reaction, amorphization, and recrystallization. Input instructions for execution on mainframe, workstation, and personal computers are provided, as is a description of DART output. The theory of fission gas behavior and its effect on fuel swelling is discussed. The behavior of these fission products inmore » both crystalline and amorphous fuel and in the presence of irradiation-induced recrystallization and crystalline-to-amorphous-phase change phenomena is presented, as are models for these irradiation-induced processes.« less

The Effects of Lactobacillus acidophilus on the Intestinal Smooth Muscle Contraction through PKC/MLCK/MLC Signaling Pathway in TBI Mouse Model

PubMed Central

Fang, Huan; Zhu, Lina; Gao, Ning; Zhu, Jingci

2015-01-01

Clinical studies have shown that probiotics influence gastrointestinal motility. However, the molecular mechanisms by which probiotic Lactobacillus modulates intestinal motility in traumatic brain injury (TBI) mouse model have not been explored. In the present study, we provided evidence showing that treatment of TBI mice with Lactobacillus acidophilus significantly improved the terminal ileum villus morphology, restored the impaired interstitial cells of Cajal (ICC) and the disrupted ICC networks after TBI, and prevented TBI-mediated inhibition of contractile activity in intestinal smooth muscle. Mechanistically, the decreased concentration of MLCK, phospho-MLC20 and phospho-MYPT1 and increased concentration of MLCP and PKC were observed after TBI, and these events mediated by TBI were efficiently prevented by Lactobacillus acidophilus application. These findings may provide a novel mechanistic basis for the application of Lactobacillus acidophilus in the treatment of TBI. PMID:26030918

The Effects of Lactobacillus acidophilus on the Intestinal Smooth Muscle Contraction through PKC/MLCK/MLC Signaling Pathway in TBI Mouse Model.

PubMed

Sun, Bo; Hu, Chen; Fang, Huan; Zhu, Lina; Gao, Ning; Zhu, Jingci

2015-01-01

Clinical studies have shown that probiotics influence gastrointestinal motility. However, the molecular mechanisms by which probiotic Lactobacillus modulates intestinal motility in traumatic brain injury (TBI) mouse model have not been explored. In the present study, we provided evidence showing that treatment of TBI mice with Lactobacillus acidophilus significantly improved the terminal ileum villus morphology, restored the impaired interstitial cells of Cajal (ICC) and the disrupted ICC networks after TBI, and prevented TBI-mediated inhibition of contractile activity in intestinal smooth muscle. Mechanistically, the decreased concentration of MLCK, phospho-MLC20 and phospho-MYPT1 and increased concentration of MLCP and PKC were observed after TBI, and these events mediated by TBI were efficiently prevented by Lactobacillus acidophilus application. These findings may provide a novel mechanistic basis for the application of Lactobacillus acidophilus in the treatment of TBI.

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

PubMed

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

2016-10-10

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

Cell transformation assays for prediction of carcinogenic potential: state of the science and future research needs

PubMed Central

Creton, Stuart; Aardema, Marilyn J.; Carmichael, Paul L.; Harvey, James S.; Martin, Francis L.; Newbold, Robert F.; O’Donovan, Michael R.; Pant, Kamala; Poth, Albrecht; Sakai, Ayako; Sasaki, Kiyoshi; Scott, Andrew D.; Schechtman, Leonard M.; Shen, Rhine R.; Tanaka, Noriho; Yasaei, Hemad

2012-01-01

Cell transformation assays (CTAs) have long been proposed as in vitro methods for the identification of potential chemical carcinogens. Despite showing good correlation with rodent bioassay data, concerns over the subjective nature of using morphological criteria for identifying transformed cells and a lack of understanding of the mechanistic basis of the assays has limited their acceptance for regulatory purposes. However, recent drivers to find alternative carcinogenicity assessment methodologies, such as the Seventh Amendment to the EU Cosmetics Directive, have fuelled renewed interest in CTAs. Research is currently ongoing to improve the objectivity of the assays, reveal the underlying molecular changes leading to transformation and explore the use of novel cell types. The UK NC3Rs held an international workshop in November 2010 to review the current state of the art in this field and provide directions for future research. This paper outlines the key points highlighted at this meeting. PMID:21852270

MEK-Dependent Negative Feedback Underlies BCR-ABL-Mediated Oncogene Addiction

PubMed Central

Asmussen, Jennifer; Lasater, Elisabeth A.; Tajon, Cheryl; Oses-Prieto, Juan; Jun, Young-wook; Taylor, Barry S.; Burlingame, Alma; Craik, Charles S.; Shah, Neil P.

2014-01-01

The clinical experience with BCR-ABL tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML) provides compelling evidence for oncogene addiction. Yet, the molecular basis of oncogene addiction remains elusive. Through unbiased quantitative phosphoproteomic analyses of CML cells transiently exposed to BCR-ABL TKI, we identified persistent downregulation of growth factor receptor (GF-R) signaling pathways. We then established and validated a tissue-relevant isogenic model of BCR-ABL-mediated addiction, and found evidence for myeloid GF-R signaling pathway rewiring that profoundly and persistently dampens physiologic pathway activation. We demonstrate that eventual restoration of ligand-mediated GF-R pathway activation is insufficient to fully rescue cells from a competing apoptotic fate. In contrast to previous work with BRAFV600E in melanoma cells, feedback inhibition following BCR-ABL TKI treatment is markedly prolonged, extending beyond the time required to initiate apoptosis. Mechanistically, BCR-ABL-mediated oncogene addiction is facilitated by persistent high levels of MEK-dependent negative feedback. PMID:24362263

Structural basis for subtype-specific inhibition of the P2X7 receptor

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

Karasawa, Akira; Kawate, Toshimitsu

The P2X7 receptor is a non-selective cation channel activated by extracellular adenosine triphosphate (ATP). Chronic activation of P2X7 underlies many health problems such as pathologic pain, yet we lack effective antagonists due to poorly understood mechanisms of inhibition. Here we present crystal structures of a mammalian P2X7 receptor complexed with five structurally-unrelated antagonists. Unexpectedly, these drugs all bind to an allosteric site distinct from the ATP-binding pocket in a groove formed between two neighboring subunits. This novel drug-binding pocket accommodates a diversity of small molecules mainly through hydrophobic interactions. Functional assays propose that these compounds allosterically prevent narrowing of themore » drug-binding pocket and the turret-like architecture during channel opening, which is consistent with a site of action distal to the ATP-binding pocket. These novel mechanistic insights will facilitate the development of P2X7-specific drugs for treating human diseases.« less

Two-Step Amyloid Aggregation: Sequential Lag Phase Intermediates

NASA Astrophysics Data System (ADS)

Castello, Fabio; Paredes, Jose M.; Ruedas-Rama, Maria J.; Martin, Miguel; Roldan, Mar; Casares, Salvador; Orte, Angel

2017-01-01

The self-assembly of proteins into fibrillar structures called amyloid fibrils underlies the onset and symptoms of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. However, the molecular basis and mechanism of amyloid aggregation are not completely understood. For many amyloidogenic proteins, certain oligomeric intermediates that form in the early aggregation phase appear to be the principal cause of cellular toxicity. Recent computational studies have suggested the importance of nonspecific interactions for the initiation of the oligomerization process prior to the structural conversion steps and template seeding, particularly at low protein concentrations. Here, using advanced single-molecule fluorescence spectroscopy and imaging of a model SH3 domain, we obtained direct evidence that nonspecific aggregates are required in a two-step nucleation mechanism of amyloid aggregation. We identified three different oligomeric types according to their sizes and compactness and performed a full mechanistic study that revealed a mandatory rate-limiting conformational conversion step. We also identified the most cytotoxic species, which may be possible targets for inhibiting and preventing amyloid aggregation.

Aggression is associated with greater subsequent alcohol consumption: A shared neural basis in the ventral striatum.

PubMed

Chester, David S; DeWall, C Nathan

2018-05-01

Alcohol use and abuse (e.g., binge drinking) are among the most reliable causes of aggressive behavior. Conversely, people with aggressive dispositions (e.g., intermittent explosive disorder) are at greater risk for subsequent substance abuse. Yet it remains unknown why aggression might promote subsequent alcohol use. Both aggressive acts and alcohol use are rewarding and linked to greater activity in neural reward circuitry. Through this shared instantiation of reward, aggression may then increase subsequent alcohol consumption. Supporting this mechanistic hypothesis, participants' aggressive behavior directed at someone who had recently rejected them, was associated with more subsequent beer consumption on an ad-lib drinking task. Using functional MRI, both aggressive behavior and beer consumption were associated with greater activity in the bilateral ventral striatum during acts of retaliatory aggression. These results imply that aggression is linked to subsequent alcohol abuse, and that a mechanism underlying this effect is likely to be the activation of the brain's reward circuitry during aggressive acts. © 2018 Wiley Periodicals, Inc.

Variability in spectrophotometric pyruvate analyses for predicting onion pungency and nutraceutical value.

PubMed

Beretta, Vanesa H; Bannoud, Florencia; Insani, Marina; Galmarini, Claudio R; Cavagnaro, Pablo F

2017-06-01

Onion pyruvate concentration is used as a predictor of flavor intensity and nutraceutical value. The protocol of Schwimmer and Weston (SW) (1961) is the most widespread methodology for estimating onion pyruvate. Anthon and Barret (AB) (2003) proposed modifications to this procedure. Here, we compared these spectrophotometry-based procedures for pyruvate analysis using a diverse collection of onion cultivars. The SW method always led to over-estimation of pyruvate levels in colored, but not in white onions, by up to 65%. Identification of light-absorbance interfering compounds was performed by spectrophotometry and HPLC analysis. Interference by quercetin and anthocyanins, jointly, accounted for more than 90% of the over-estimation of pyruvate. Pyruvate determinations according to AB significantly reduced absorbance interference from compounds other than pyruvate. This study provides evidence about the mechanistic basis underlying differences between the SW and AB methods for indirect assessment of onion flavor and nutraceutical value. Copyright © 2016 Elsevier Ltd. All rights reserved.

Translational Regulation in Nutrigenomics12

PubMed Central

Liu, Botao; Qian, Shu-Bing

2011-01-01

The emergence of genome-wide analysis to interrogate cellular DNA, RNA, and protein content has revolutionized the study of the control network that mediates cellular homeostasis. Nutrigenomics addresses the effect of nutrients on gene expression, which provides a basis for understanding the biological activity of dietary components. Translation of mRNAs represents the last step of genetic flow and primarily defines the proteome. Translational regulation is thus critical for gene expression, in particular, under nutrient excess or deficiency. Until recently, it was unclear how the global effects of translational control are influenced by nutrient signaling. An emerging concept of translational reprogramming addresses how to maintain the expression of specific proteins during pathophysiological conditions by translation of selective mRNAs. Here we describe recent advances in our understanding of translational control, nutrient signaling, and their dysregulation in aging and cancer. The mechanistic understanding of translational regulation in response to different nutrient conditions may help identify potential dietary and therapeutic targets to improve human health. PMID:22332093

Facilitated diffusion in chromatin lattices: mechanistic diversity and regulatory potential.

PubMed

Kampmann, Martin

2005-08-01

The interaction between a protein and a specific DNA site is the molecular basis for vital processes in all organisms. Location of the DNA target site by the protein commonly involves facilitated diffusion. Mechanisms of facilitated diffusion vary among proteins; they include one- and two-dimensional sliding along DNA, direct transfer between uncorrelated sites, as well as combinations of these mechanisms. Facilitated diffusion has almost exclusively been studied in vitro. This review discusses facilitated diffusion in the context of the living cell and proposes a theoretical model for facilitated diffusion in chromatin lattices. Chromatin structure differentially affects proteins in different modes of diffusion. The interplay of facilitated diffusion and chromatin structure can determine the rate of protein association with the target site, the frequency of association-dissociation events at the target site, and, under particular conditions, the occupancy of the target site. Facilitated diffusion is required in vivo for efficient DNA repair and bacteriophage restriction and has potential roles in fine-tuning gene regulatory networks and kinetically compartmentalizing the eukaryotic nucleus.

Multicellularity arose several times in the evolution of eukaryotes (response to DOI 10.1002/bies.201100187).

PubMed

Parfrey, Laura Wegener; Lahr, Daniel J G

2013-04-01

The cellular slime mold Dictyostelium has cell-cell connections similar in structure, function, and underlying molecular mechanisms to animal epithelial cells. These similarities form the basis for the proposal that multicellularity is ancestral to the clade containing animals, fungi, and Amoebozoa (including Dictyostelium): Amorphea (formerly "unikonts"). This hypothesis is intriguing and if true could precipitate a paradigm shift. However, phylogenetic analyses of two key genes reveal patterns inconsistent with a single origin of multicellularity. A single origin in Amorphea would also require loss of multicellularity in each of the many unicellular lineages within this clade. Further, there are numerous other origins of multicellularity within eukaryotes, including three within Amorphea, that are not characterized by these structural and mechanistic similarities. Instead, convergent evolution resulting from similar selective pressures for forming multicellular structures with motile and differentiated cells is the most likely explanation for the observed similarities between animal and dictyostelid cell-cell connections. Copyright © 2013 WILEY Periodicals, Inc.

Structural basis of GM-CSF and IL-2 sequestration by the viral decoy receptor GIF

PubMed Central

Felix, Jan; Kandiah, Eaazhisai; De Munck, Steven; Bloch, Yehudi; van Zundert, Gydo C.P.; Pauwels, Kris; Dansercoer, Ann; Novanska, Katka; Read, Randy J.; Bonvin, Alexandre M.J.J.; Vergauwen, Bjorn; Verstraete, Kenneth; Gutsche, Irina; Savvides, Savvas N.

2016-01-01

Subversion of the host immune system by viruses is often mediated by molecular decoys that sequester host proteins pivotal to mounting effective immune responses. The widespread mammalian pathogen parapox Orf virus deploys GIF, a member of the poxvirus immune evasion superfamily, to antagonize GM-CSF (granulocyte macrophage colony-stimulating factor) and IL-2 (interleukin-2), two pleiotropic cytokines of the mammalian immune system. However, structural and mechanistic insights into the unprecedented functional duality of GIF have remained elusive. Here we reveal that GIF employs a dimeric binding platform that sequesters two copies of its target cytokines with high affinity and slow dissociation kinetics to yield distinct complexes featuring mutually exclusive interaction footprints. We illustrate how GIF serves as a competitive decoy receptor by leveraging binding hotspots underlying the cognate receptor interactions of GM-CSF and IL-2, without sharing any structural similarity with the cytokine receptors. Our findings contribute to the tracing of novel molecular mimicry mechanisms employed by pathogenic viruses. PMID:27819269

An Integrated Approach to Change the Outcome Part II: Targeted Neuromuscular Training Techniques to Reduce Identified ACL Injury Risk Factors

PubMed Central

Myer, Gregory D.; Ford, Kevin R.; Brent, Jensen L.; Hewett, Timothy E.

2014-01-01

Prior reports indicate that female athletes who demonstrate high knee abduction moments (KAMs) during landing are more responsive to neuromuscular training designed to reduce KAM. Identification of female athletes who demonstrate high KAM, which accurately identifies those at risk for noncontact anterior cruciate ligament (ACL) injury, may be ideal for targeted neuromuscular training. Specific neuromuscular training targeted to the underlying biomechanical components that increase KAM may provide the most efficient and effective training strategy to reduce noncontact ACL injury risk. The purpose of the current commentary is to provide an integrative approach to identify and target mechanistic underpinnings to increased ACL injury in female athletes. Specific neuromuscular training techniques will be presented that address individual algorithm components related to high knee load landing patterns. If these integrated techniques are employed on a widespread basis, prevention strategies for noncontact ACL injury among young female athletes may prove both more effective and efficient. PMID:22580980

Cooperative activation of cardiac transcription through myocardin bridging of paired MEF2 sites

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

Anderson, Courtney M.; Hu, Jianxin; Thomas, Reuben

2017-03-28

Enhancers frequently contain multiple binding sites for the same transcription factor. These homotypic binding sites often exhibit synergy, whereby the transcriptional output from two or more binding sites is greater than the sum of the contributions of the individual binding sites alone. Although this phenomenon is frequently observed, the mechanistic basis for homotypic binding site synergy is poorly understood. Here in this paper, we identify a bona fide cardiac-specific Prkaa2 enhancer that is synergistically activated by homotypic MEF2 binding sites. We show that two MEF2 sites in the enhancer function cooperatively due to bridging of the MEF2C-bound sites by themore » SAP domain-containing co-activator protein myocardin, and we show that paired sites buffer the enhancer from integration site-dependent effects on transcription in vivo. Paired MEF2 sites are prevalent in cardiac enhancers, suggesting that this might be a common mechanism underlying synergy in the control of cardiac gene expression in vivo.« less

The attention schema theory: a mechanistic account of subjective awareness

PubMed Central

Graziano, Michael S. A.; Webb, Taylor W.

2015-01-01

We recently proposed the attention schema theory, a novel way to explain the brain basis of subjective awareness in a mechanistic and scientifically testable manner. The theory begins with attention, the process by which signals compete for the brain’s limited computing resources. This internal signal competition is partly under a bottom–up influence and partly under top–down control. We propose that the top–down control of attention is improved when the brain has access to a simplified model of attention itself. The brain therefore constructs a schematic model of the process of attention, the ‘attention schema,’ in much the same way that it constructs a schematic model of the body, the ‘body schema.’ The content of this internal model leads a brain to conclude that it has a subjective experience. One advantage of this theory is that it explains how awareness and attention can sometimes become dissociated; the brain’s internal models are never perfect, and sometimes a model becomes dissociated from the object being modeled. A second advantage of this theory is that it explains how we can be aware of both internal and external events. The brain can apply attention to many types of information including external sensory information and internal information about emotions and cognitive states. If awareness is a model of attention, then this model should pertain to the same domains of information to which attention pertains. A third advantage of this theory is that it provides testable predictions. If awareness is the internal model of attention, used to help control attention, then without awareness, attention should still be possible but should suffer deficits in control. In this article, we review the existing literature on the relationship between attention and awareness, and suggest that at least some of the predictions of the theory are borne out by the evidence. PMID:25954242

An ecophysiological perspective on likely giant panda habitat responses to climate change.

PubMed

Zhang, Yuke; Mathewson, Paul D; Zhang, Qiongyue; Porter, Warren P; Ran, Jianghong

2018-04-01

Threatened and endangered species are more vulnerable to climate change due to small population and specific geographical distribution. Therefore, identifying and incorporating the biological processes underlying a species' adaptation to its environment are important for determining whether they can persist in situ. Correlative models are widely used to predict species' distribution changes, but generally fail to capture the buffering capacity of organisms. Giant pandas (Ailuropoda melanoleuca) live in topographically complex mountains and are known to avoid heat stress. Although many studies have found that climate change will lead to severe habitat loss and threaten previous conservation efforts, the mechanisms underlying panda's responses to climate change have not been explored. Here, we present a case study in Daxiangling Mountains, one of the six Mountain Systems that giant panda distributes. We used a mechanistic model, Niche Mapper, to explore what are likely panda habitat response to climate change taking physiological, behavioral and ecological responses into account, through which we map panda's climatic suitable activity area (SAA) for the first time. We combined SAA with bamboo forest distribution to yield highly suitable habitat (HSH) and seasonal suitable habitat (SSH), and their temporal dynamics under climate change were predicted. In general, SAA in the hottest month (July) would reduce 11.7%-52.2% by 2070, which is more moderate than predicted bamboo habitat loss (45.6%-86.9%). Limited by the availability of bamboo and forest, panda's suitable habitat loss increases, and only 15.5%-68.8% of current HSH would remain in 2070. Our method of mechanistic modeling can help to distinguish whether habitat loss is caused by thermal environmental deterioration or food loss under climate change. Furthermore, mechanistic models can produce robust predictions by incorporating ecophysiological feedbacks and minimizing extrapolation into novel environments. We suggest that a mechanistic approach should be incorporated into distribution predictions and conservation planning. © 2017 John Wiley & Sons Ltd.

Hydrolytic degradation of N,N‧-ethylenedimaleimide: Crystal structures of key intermediates and proposed mechanisms

NASA Astrophysics Data System (ADS)

Tan, Xue-Jie; Cheng, Shuang-Shuang; Shi, Yan; Xing, Dian-Xiang; Liu, Yun; Li, Hui; Feng, Wen-Quan; Yang, Jian-Bo

2016-12-01

Maleimide groups are used extensively in bioconjugation reactions, but limited mechanistic studies are available regarding their hydrolysis reactions. In this paper, five single-crystal structures related with the reaction of four-step hydrolytic degradation of N,N‧-ethylenedimaleimide have been investigated. On the basis of experimental results, the reaction mechanisms without or with water catalysis are proposed, which could provide some enlightenment into the study of similar hydrolytic degradations.

Preventing Ototoxic Synergy of Prior Noise Trauma During Aminoglycoside Therapy

DTIC Science & Technology

2015-12-01

cochlear blood flow . Hearing Research 313, 38-46 (2014). 12. Koo, J.-W. et al. Endotoxemia-mediated inflammation potentiates cochlear uptake of...event in response to a need for higher cochlear blood flow . A 3.7% dilation was adequate for a 20% increase of blood flow 10. On the contrary...summation of the two insults. We have found that prior sound exposure enhances cochlear uptake of aminoglycosides, providing a mechanistic basis for the

Dynamic Palmitoylation and the Role of DHHC Proteins in T Cell Activation and Anergy

PubMed Central

Ladygina, Nadejda; Martin, Brent R.; Altman, Amnon

2017-01-01

Although protein S-palmitoylation was first characterized >30 years ago, and is implicated in the function, trafficking, and localization of many proteins, little is known about the regulation and physiological implications of this posttranslational modification. Palmitoylation of various signaling proteins required for TCR-induced T cell activation is also necessary for their proper function. LAT (linker for activation of T cells) is an essential scaffolding protein involved in T cell development and activation, and we found that its palmitoylation is selectively impaired in anergic T cells. The recent discovery of the DHHC family of palmitoyl acyl transferases (PATs) and the establishment of sensitive and quantitative proteomics-based methods for global analysis of the palmitoyl proteome led to significant progress in studying the biology and underlying mechanisms of cellular protein palmitoylation. We are using these approaches to explore the palmitoyl proteome in T lymphocytes and, specifically, the mechanistic basis for the impaired palmitoylation of LAT in anergic T cells. This chapter reviews the history of protein palmitoylation and its role in T cell activation, the DHHC family and new methodologies for global analysis of the palmitoyl proteome, and summarizes our recent work in this area. The new methodologies will accelerate the pace of research and provide a greatly improved mechanistic and molecular understanding of the complex process of protein palmitoylation and its regulation, and the substrate specificity of the novel DHHC family. Reversible protein palmitoylation will likely prove to be an important posttranslational mechanism that regulates cellular responses, similar to protein phosphorylation and ubiquitination. PMID:21569911

All Bariatric Surgeries Are Not Created Equal: Insights from Mechanistic Comparisons

PubMed Central

Stefater, Margaret A.; Wilson-Pérez, Hilary E.; Chambers, Adam P.; Sandoval, Darleen A.

2012-01-01

Despite considerable scientific progress on the biological systems that regulate energy balance, we have made precious little headway in providing new treatments to curb the obesity epidemic. Diet and exercise are the most popular treatment options for obesity, but rarely are they sufficient to produce long-term weight loss. Bariatric surgery, on the other hand, results in dramatic, sustained weight loss and for this reason has gained increasing popularity as a treatment modality for obesity. At least some surgical approaches also reduce obesity-related comorbidities including type 2 diabetes and hyperlipidemia. This success puts a premium on understanding how these surgeries exert their effects. This review focuses on the growing human and animal model literature addressing the underlying mechanisms. We compare three common procedures: Roux-en-Y Gastric Bypass (RYGB), vertical sleeve gastrectomy (VSG), and adjustable gastric banding (AGB). Although many would group together VSG and AGB as restrictive procedures of the stomach, VSG is more like RYGB than AGB in its effects on a host of endpoints including intake, food choice, glucose regulation, lipids and gut hormone secretion. Our strong belief is that to advance our understanding of these procedures, it is necessary to group bariatric procedures not on the basis of surgical similarity but rather on how they affect key physiological variables. This will allow for greater mechanistic insight into how bariatric surgery works, making it possible to help patients better choose the best possible procedure and to develop new therapeutic strategies that can help a larger portion of the obese population. PMID:22550271

NEMA, a functional-structural model of nitrogen economy within wheat culms after flowering. II. Evaluation and sensitivity analysis.

PubMed

Bertheloot, Jessica; Wu, Qiongli; Cournède, Paul-Henry; Andrieu, Bruno

2011-10-01

Simulating nitrogen economy in crop plants requires formalizing the interactions between soil nitrogen availability, root nitrogen acquisition, distribution between vegetative organs and remobilization towards grains. This study evaluates and analyses the functional-structural and mechanistic model of nitrogen economy, NEMA (Nitrogen Economy Model within plant Architecture), developed for winter wheat (Triticum aestivum) after flowering. NEMA was calibrated for field plants under three nitrogen fertilization treatments at flowering. Model behaviour was investigated and sensitivity to parameter values was analysed. Nitrogen content of all photosynthetic organs and in particular nitrogen vertical distribution along the stem and remobilization patterns in response to fertilization were simulated accurately by the model, from Rubisco turnover modulated by light intercepted by the organ and a mobile nitrogen pool. This pool proved to be a reliable indicator of plant nitrogen status, allowing efficient regulation of nitrogen acquisition by roots, remobilization from vegetative organs and accumulation in grains in response to nitrogen treatments. In our simulations, root capacity to import carbon, rather than carbon availability, limited nitrogen acquisition and ultimately nitrogen accumulation in grains, while Rubisco turnover intensity mostly affected dry matter accumulation in grains. NEMA enabled interpretation of several key patterns usually observed in field conditions and the identification of plausible processes limiting for grain yield, protein content and root nitrogen acquisition that could be targets for plant breeding; however, further understanding requires more mechanistic formalization of carbon metabolism. Its strong physiological basis and its realistic behaviour support its use to gain insights into nitrogen economy after flowering.

The Role of Epigenetics in the Latent Effects of Early Life Exposure to Obesogenic Endocrine Disrupting Chemicals

PubMed Central

Stel, Jente

2015-01-01

Recent research supports a role for exposure to endocrine-disrupting chemicals (EDCs) in the global obesity epidemic. Obesogenic EDCs have the potential to inappropriately stimulate adipogenesis and fat storage, influence metabolism and energy balance and increase susceptibility to obesity. Developmental exposure to obesogenic EDCs is proposed to interfere with epigenetic programming of gene regulation, partly by activation of nuclear receptors, thereby influencing the risk of obesity later in life. The goal of this minireview is to briefly describe the epigenetic mechanisms underlying developmental plasticity and to evaluate the evidence of a mechanistic link between altered epigenetic gene regulation by early life EDC exposure and latent onset of obesity. We summarize the results of recent in vitro, in vivo, and transgenerational studies, which clearly show that the obesogenic effects of EDCs such as tributyltin, brominated diphenyl ether 47, and polycyclic aromatic hydrocarbons are mediated by the activation and associated altered methylation of peroxisome proliferator-activated receptor-γ, the master regulator of adipogenesis, or its target genes. Importantly, studies are emerging that assess the effects of EDCs on the interplay between DNA methylation and histone modifications in altered chromatin structure. These types of studies coupled with genome-wide rather than gene-specific analyses are needed to improve mechanistic understanding of epigenetic changes by EDC exposure. Current advances in the field of epigenomics have led to the first potential epigenetic markers for obesity that can be detected at birth, providing an important basis to determine the effects of developmental exposure to obesogenic EDCs in humans. PMID:26241072

The Role of Epigenetics in the Latent Effects of Early Life Exposure to Obesogenic Endocrine Disrupting Chemicals.

PubMed

Stel, Jente; Legler, Juliette

2015-10-01

Recent research supports a role for exposure to endocrine-disrupting chemicals (EDCs) in the global obesity epidemic. Obesogenic EDCs have the potential to inappropriately stimulate adipogenesis and fat storage, influence metabolism and energy balance and increase susceptibility to obesity. Developmental exposure to obesogenic EDCs is proposed to interfere with epigenetic programming of gene regulation, partly by activation of nuclear receptors, thereby influencing the risk of obesity later in life. The goal of this minireview is to briefly describe the epigenetic mechanisms underlying developmental plasticity and to evaluate the evidence of a mechanistic link between altered epigenetic gene regulation by early life EDC exposure and latent onset of obesity. We summarize the results of recent in vitro, in vivo, and transgenerational studies, which clearly show that the obesogenic effects of EDCs such as tributyltin, brominated diphenyl ether 47, and polycyclic aromatic hydrocarbons are mediated by the activation and associated altered methylation of peroxisome proliferator-activated receptor-γ, the master regulator of adipogenesis, or its target genes. Importantly, studies are emerging that assess the effects of EDCs on the interplay between DNA methylation and histone modifications in altered chromatin structure. These types of studies coupled with genome-wide rather than gene-specific analyses are needed to improve mechanistic understanding of epigenetic changes by EDC exposure. Current advances in the field of epigenomics have led to the first potential epigenetic markers for obesity that can be detected at birth, providing an important basis to determine the effects of developmental exposure to obesogenic EDCs in humans.

Revealing the Biochemical and Genetic Basis of Color Variation in a Polymorphic Lizard.

PubMed

McLean, Claire A; Lutz, Adrian; Rankin, Katrina J; Stuart-Fox, Devi; Moussalli, Adnan

2017-08-01

Determining the mechanistic and genetic basis of animal coloration is essential to understand the costs and constraints on color production, and the evolution and maintenance of phenotypic variation. However, genes underlying structural color and widespread pigment classes apart from melanin remain largely uncharacterized, in part due to restricted taxonomic focus. We combined liquid chromatography-mass spectrometry and RNA-seq gene expression analyses to characterize the pigments and genes associated with skin color in the polymorphic lizard, Ctenophorus decresii. Throat coloration in male C. decresii may be a combination of orange, yellow, grey, or ultra-violet blue. We confirmed the presence of two biochemically different pigment classes, pteridines (self-synthesized) and carotenoids (acquired through the diet), in all skin colors. Orange skin had the highest levels of pteridine pigments while yellow skin tended to have higher levels of carotenoids, of which the vitamin A precursors β-carotene and β-cryptoxanthin have not been previously confirmed in reptiles. These results were confirmed by gene expression analyses, which detected 489 genes differentially expressed between the skin colors, including genes associated with pteridine production, provitamin A carotenoid metabolism, iridophore-specific synthesis, melanin synthesis, and steroid hormone pathways. For the majority of these 489 genes, however, our study reveals a new association with color production in vertebrates. These data represent a significant contribution to understanding the genetic basis of color variation in vertebrates and a rich resource for further studies. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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

PubMed Central

Cotterell, James; Sharpe, James

2013-01-01

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

Roughness Versus Charge Contributions to Representative Discrete Heterogeneity Underlying Mechanistic Prediction of Colloid Attachment, Detachment and Breakthrough-Elution Behavior Under Environmental Conditions.

NASA Astrophysics Data System (ADS)

Johnson, William; Farnsworth, Anna; Vanness, Kurt; Hilpert, Markus

2017-04-01

The key element of a mechanistic theory to predict colloid attachment in porous media under environmental conditions where colloid-collector repulsion exists (unfavorable conditions for attachment) is representation of the nano-scale surface heterogeneity (herein called discrete heterogeneity) that drives colloid attachment under unfavorable conditions. The observed modes of colloid attachment under unfavorable conditions emerge from simulations that incorporate discrete heterogeneity. Quantitative prediction of attachment (and detachment) requires capturing the sizes, spatial frequencies, and other properties of roughness asperities and charge heterodomains in discrete heterogeneity representations of different surfaces. The fact that a given discrete heterogeneity representation will interact differently with different-sized colloids as well as different ionic strengths for a given sized colloid allows backing out representative discrete heterogeneity via comparison of simulations to experiments performed across a range of colloid size, solution IS, and fluid velocity. This has been achieved on unfavorable smooth surfaces yielding quantitative prediction of attachment, and qualitative prediction of detachment in response to ionic strength or flow perturbations. Extending this treatment to rough surfaces, and representing the contributions of nanoscale roughness as well as charge heterogeneity is a focus of this talk. Another focus of this talk is the upscaling the pore scale simulations to produce contrasting breakthrough-elution behaviors at the continuum (column) scale that are observed, for example, for different-sized colloids, or same-sized colloids under different ionic strength conditions. The outcome of mechanistic pore scale simulations incorporating discrete heterogeneity and subsequent upscaling is that temporal processes such as blocking and ripening will emerge organically from these simulations, since these processes fundamentally stem from the limited sites available for attachment as represented in discrete heterogeneity.

Translational systems biology using an agent-based approach for dynamic knowledge representation: An evolutionary paradigm for biomedical research.

PubMed

An, Gary C

2010-01-01

The greatest challenge facing the biomedical research community is the effective translation of basic mechanistic knowledge into clinically effective therapeutics. This challenge is most evident in attempts to understand and modulate "systems" processes/disorders, such as sepsis, cancer, and wound healing. Formulating an investigatory strategy for these issues requires the recognition that these are dynamic processes. Representation of the dynamic behavior of biological systems can aid in the investigation of complex pathophysiological processes by augmenting existing discovery procedures by integrating disparate information sources and knowledge. This approach is termed Translational Systems Biology. Focusing on the development of computational models capturing the behavior of mechanistic hypotheses provides a tool that bridges gaps in the understanding of a disease process by visualizing "thought experiments" to fill those gaps. Agent-based modeling is a computational method particularly well suited to the translation of mechanistic knowledge into a computational framework. Utilizing agent-based models as a means of dynamic hypothesis representation will be a vital means of describing, communicating, and integrating community-wide knowledge. The transparent representation of hypotheses in this dynamic fashion can form the basis of "knowledge ecologies," where selection between competing hypotheses will apply an evolutionary paradigm to the development of community knowledge.

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

Testing the effect of paraquat exposure on genomic recombination rates in queens of the western honey bee, Apis mellifera.

PubMed

Langberg, Kurt; Phillips, Matthew; Rueppell, Olav

2018-04-01

The rate of genomic recombination displays evolutionary plasticity and can even vary in response to environmental factors. The western honey bee (Apis mellifera L.) has an extremely high genomic recombination rate but the mechanistic basis for this genome-wide upregulation is not understood. Based on the hypothesis that meiotic recombination and DNA damage repair share common mechanisms in honey bees as in other organisms, we predicted that oxidative stress leads to an increase in recombination rate in honey bees. To test this prediction, we subjected honey bee queens to oxidative stress by paraquat injection and measured the rates of genomic recombination in select genome intervals of offspring produced before and after injection. The evaluation of 26 genome intervals in a total of over 1750 offspring of 11 queens by microsatellite genotyping revealed several significant effects but no overall evidence for a mechanistic link between oxidative stress and increased recombination was found. The results weaken the notion that DNA repair enzymes have a regulatory function in the high rate of meiotic recombination of honey bees, but they do not provide evidence against functional overlap between meiotic recombination and DNA damage repair in honey bees and more mechanistic studies are needed.

In Silico, Experimental, Mechanistic Model for Extended-Release Felodipine Disposition Exhibiting Complex Absorption and a Highly Variable Food Interaction

PubMed Central

Kim, Sean H. J.; Jackson, Andre J.; Hunt, C. Anthony

2014-01-01

The objective of this study was to develop and explore new, in silico experimental methods for deciphering complex, highly variable absorption and food interaction pharmacokinetics observed for a modified-release drug product. Toward that aim, we constructed an executable software analog of study participants to whom product was administered orally. The analog is an object- and agent-oriented, discrete event system, which consists of grid spaces and event mechanisms that map abstractly to different physiological features and processes. Analog mechanisms were made sufficiently complicated to achieve prespecified similarity criteria. An equation-based gastrointestinal transit model with nonlinear mixed effects analysis provided a standard for comparison. Subject-specific parameterizations enabled each executed analog’s plasma profile to mimic features of the corresponding six individual pairs of subject plasma profiles. All achieved prespecified, quantitative similarity criteria, and outperformed the gastrointestinal transit model estimations. We observed important subject-specific interactions within the simulation and mechanistic differences between the two models. We hypothesize that mechanisms, events, and their causes occurring during simulations had counterparts within the food interaction study: they are working, evolvable, concrete theories of dynamic interactions occurring within individual subjects. The approach presented provides new, experimental strategies for unraveling the mechanistic basis of complex pharmacological interactions and observed variability. PMID:25268237

Structural and molecular basis for resistance to aminoglycoside antibiotics by the adenylyltransferase ANT(2″)-Ia.

PubMed

Cox, Georgina; Stogios, Peter J; Savchenko, Alexei; Wright, Gerard D

2015-01-06

The aminoglycosides are highly effective broad-spectrum antimicrobial agents. However, their efficacy is diminished due to enzyme-mediated covalent modification, which reduces affinity of the drug for the target ribosome. One of the most prevalent aminoglycoside resistance enzymes in Gram-negative pathogens is the adenylyltransferase ANT(2″)-Ia, which confers resistance to gentamicin, tobramycin, and kanamycin. Despite the importance of this enzyme in drug resistance, its structure and molecular mechanism have been elusive. This study describes the structural and mechanistic basis for adenylylation of aminoglycosides by the ANT(2″)-Ia enzyme. ANT(2″)-Ia confers resistance by magnesium-dependent transfer of a nucleoside monophosphate (AMP) to the 2″-hydroxyl of aminoglycoside substrates containing a 2-deoxystreptamine core. The catalyzed reaction follows a direct AMP transfer mechanism from ATP to the substrate antibiotic. Central to catalysis is the coordination of two Mg(2+) ions, positioning of the modifiable substrate ring, and the presence of a catalytic base (Asp86). Comparative structural analysis revealed that ANT(2″)-Ia has a two-domain structure with an N-terminal active-site architecture that is conserved among other antibiotic nucleotidyltransferases, including Lnu(A), LinB, ANT(4')-Ia, ANT(4″)-Ib, and ANT(6)-Ia. There is also similarity between the nucleotidyltransferase fold of ANT(2″)-Ia and DNA polymerase β. This similarity is consistent with evolution from a common ancestor, with the nucleotidyltransferase fold having adapted for activity against chemically distinct molecules. IMPORTANCE  : To successfully manage the threat associated with multidrug-resistant infectious diseases, innovative therapeutic strategies need to be developed. One such approach involves the enhancement or potentiation of existing antibiotics against resistant strains of bacteria. The reduction in clinical usefulness of the aminoglycosides is a particular problem among Gram-negative human pathogens, since there are very few therapeutic options for infections caused by these organisms. In order to successfully circumvent or inhibit the activity of aminoglycoside-modifying enzymes, and to thus rejuvenate the activity of the aminoglycoside antibiotics against Gram-negative pathogens, structural and mechanistic information is crucial. This study reveals the structure of a clinically prevalent aminoglycoside resistance enzyme [ANT(2″)-Ia] and depicts the molecular basis underlying modification of antibiotic substrates. Combined, these findings provide the groundwork for the development of broad-spectrum inhibitors against antibiotic nucleotidyltransferases. Copyright © 2015 Cox et al.

Structural and Molecular Basis for Resistance to Aminoglycoside Antibiotics by the Adenylyltransferase ANT(2″)-Ia

PubMed Central

Cox, Georgina; Stogios, Peter J.; Savchenko, Alexei

2015-01-01

ABSTRACT   The aminoglycosides are highly effective broad-spectrum antimicrobial agents. However, their efficacy is diminished due to enzyme-mediated covalent modification, which reduces affinity of the drug for the target ribosome. One of the most prevalent aminoglycoside resistance enzymes in Gram-negative pathogens is the adenylyltransferase ANT(2″)-Ia, which confers resistance to gentamicin, tobramycin, and kanamycin. Despite the importance of this enzyme in drug resistance, its structure and molecular mechanism have been elusive. This study describes the structural and mechanistic basis for adenylylation of aminoglycosides by the ANT(2″)-Ia enzyme. ANT(2″)-Ia confers resistance by magnesium-dependent transfer of a nucleoside monophosphate (AMP) to the 2″-hydroxyl of aminoglycoside substrates containing a 2-deoxystreptamine core. The catalyzed reaction follows a direct AMP transfer mechanism from ATP to the substrate antibiotic. Central to catalysis is the coordination of two Mg2+ ions, positioning of the modifiable substrate ring, and the presence of a catalytic base (Asp86). Comparative structural analysis revealed that ANT(2″)-Ia has a two-domain structure with an N-terminal active-site architecture that is conserved among other antibiotic nucleotidyltransferases, including Lnu(A), LinB, ANT(4′)-Ia, ANT(4″)-Ib, and ANT(6)-Ia. There is also similarity between the nucleotidyltransferase fold of ANT(2″)-Ia and DNA polymerase β. This similarity is consistent with evolution from a common ancestor, with the nucleotidyltransferase fold having adapted for activity against chemically distinct molecules. Importance   To successfully manage the threat associated with multidrug-resistant infectious diseases, innovative therapeutic strategies need to be developed. One such approach involves the enhancement or potentiation of existing antibiotics against resistant strains of bacteria. The reduction in clinical usefulness of the aminoglycosides is a particular problem among Gram-negative human pathogens, since there are very few therapeutic options for infections caused by these organisms. In order to successfully circumvent or inhibit the activity of aminoglycoside-modifying enzymes, and to thus rejuvenate the activity of the aminoglycoside antibiotics against Gram-negative pathogens, structural and mechanistic information is crucial. This study reveals the structure of a clinically prevalent aminoglycoside resistance enzyme [ANT(2″)-Ia] and depicts the molecular basis underlying modification of antibiotic substrates. Combined, these findings provide the groundwork for the development of broad-spectrum inhibitors against antibiotic nucleotidyltransferases. PMID:25564464

Should the patient be allowed to die? 1

PubMed Central

Nicholson, Richard

1975-01-01

In considering the patient's right to a certain quality of dying, this essay outlines how the legal and ethical justifications for passive euthanasia depend on the doctrine of acts and omissions. It is suggested that this doctrine is untenable and that alternative justifications are needed. The development of the modern mechanistic approach to death is traced, showing that a possible basis for an humane way of death lies in a reacceptance of a metaphysical concept of life. PMID:1100831

Spotting and designing promiscuous ligands for drug discovery.

PubMed

Schneider, P; Röthlisberger, M; Reker, D; Schneider, G

2016-01-21

The promiscuous binding behavior of bioactive compounds forms a mechanistic basis for understanding polypharmacological drug action. We present the development and prospective application of a computational tool for identifying potential promiscuous drug-like ligands. In combination with computational target prediction methods, the approach provides a working concept for rationally designing such molecular structures. We could confirm the multi-target binding of a de novo generated compound in a proof-of-concept study relying on the new method.

Warming reduces metabolic rate in marine snails: adaptation to fluctuating high temperatures challenges the metabolic theory of ecology.

PubMed

Marshall, David J; McQuaid, Christopher D

2011-01-22

The universal temperature-dependence model (UTD) of the metabolic theory of ecology (MTE) proposes that temperature controls mass-scaled, whole-animal resting metabolic rate according to the first principles of physics (Boltzmann kinetics). Controversy surrounds the model's implication of a mechanistic basis for metabolism that excludes the effects of adaptive regulation, and it is unclear how this would apply to organisms that live in fringe environments and typically show considerable metabolic adaptation. We explored thermal scaling of metabolism in a rocky-shore eulittoral-fringe snail (Echinolittorina malaccana) that experiences constrained energy gain and fluctuating high temperatures (between 25°C and approximately 50°C) during prolonged emersion (weeks). In contrast to the prediction of the UTD model, metabolic rate was often negatively related to temperature over a benign range (30-40°C), the relationship depending on (i) the temperature range, (ii) the degree of metabolic depression (related to the quiescent period), and (iii) whether snails were isolated within their shells. Apparent activation energies (E) varied between 0.05 and -0.43 eV, deviating excessively from the UTD's predicted range of between 0.6 and 0.7 eV. The lowering of metabolism when heated should improve energy conservation in a high-temperature environment and challenges both the theory's generality and its mechanistic basis.

The General Adaptation Syndrome: A Foundation for the Concept of Periodization.

PubMed

Cunanan, Aaron J; DeWeese, Brad H; Wagle, John P; Carroll, Kevin M; Sausaman, Robert; Hornsby, W Guy; Haff, G Gregory; Triplett, N Travis; Pierce, Kyle C; Stone, Michael H

2018-04-01

Recent reviews have attempted to refute the efficacy of applying Selye's general adaptation syndrome (GAS) as a conceptual framework for the training process. Furthermore, the criticisms involved are regularly used as the basis for arguments against the periodization of training. However, these perspectives fail to consider the entirety of Selye's work, the evolution of his model, and the broad applications he proposed. While it is reasonable to critically evaluate any paradigm, critics of the GAS have yet to dismantle the link between stress and adaptation. Disturbance to the state of an organism is the driving force for biological adaptation, which is the central thesis of the GAS model and the primary basis for its application to the athlete's training process. Despite its imprecisions, the GAS has proven to be an instructive framework for understanding the mechanistic process of providing a training stimulus to induce specific adaptations that result in functional enhancements. Pioneers of modern periodization have used the GAS as a framework for the management of stress and fatigue to direct adaptation during sports training. Updates to the periodization concept have retained its founding constructs while explicitly calling for scientifically based, evidence-driven practice suited to the individual. Thus, the purpose of this review is to provide greater clarity on how the GAS serves as an appropriate mechanistic model to conceptualize the periodization of training.

Learning from connectomics on the fly.

PubMed

Schlegel, Philipp; Costa, Marta; Jefferis, Gregory Sxe

2017-12-01

Parallels between invertebrates and vertebrates in nervous system development, organisation and circuits are powerful reasons to use insects to study the mechanistic basis of behaviour. The last few years have seen the generation in Drosophila melanogaster of very large light microscopy data sets, genetic driver lines and tools to report or manipulate neural activity. These resources in conjunction with computational tools are enabling large scale characterisation of neuronal types and their functional properties. These are complemented by 3D electron microscopy, providing synaptic resolution data. A whole brain connectome of the fly larva is approaching completion based on manual reconstruction of electron-microscopy data. An adult whole brain dataset is already publicly available and focussed reconstruction is under way, but its 40× greater volume would require ∼500-5000 person-years of manual labour. Nevertheless rapid technical improvements in imaging and especially automated segmentation will likely deliver a complete adult connectome in the next 5 years. To enhance our understanding of the circuit basis of behaviour, light and electron microscopy outputs must be integrated with functional and physiological information into comprehensive databases. We review presently available data, tools and opportunities in Drosophila. We then consider the limits and potential of future progress and how this may impact neuroscience in rich model systems provided by larger insects and vertebrates. Copyright © 2017 Elsevier Inc. All rights reserved.

Precision about the automatic emotional brain.

PubMed

Vuilleumier, Patrik

2015-01-01

The question of automaticity in emotion processing has been debated under different perspectives in recent years. Satisfying answers to this issue will require a better definition of automaticity in terms of relevant behavioral phenomena, ecological conditions of occurrence, and a more precise mechanistic account of the underlying neural circuits.

Divergence of water balance mechanisms and acclimation potential in body color morphs of Drosophila ananassae.

PubMed

Parkash, Ravi; Aggarwal, Dau Dayal; Lambhod, Chanderkala; Singh, Divya

2014-01-01

Drosophila ananassae is a desiccation sensitive species, but the physiological basis of its abundance in the drier subtropical areas is largely unknown. We tested the hypothesis whether body color morphs of D. ananassae differ in the mechanistic basis of water conservation as well as desiccation acclimation potential, consistent with their distribution under dry or wet habitats. We observed reduced rate of water loss consistent with the greater desiccation potential of dark morph as compared with light morph, despite lack of quantitative differences in cuticular lipid mass between them. Dark morph evidenced greater wet and dry mass (∼1.17-fold) as well as higher hemolymph content (∼1.70-fold) and (∼17%) dehydration tolerance to sustain longer survival under desiccation stress (LT50 17.5 hr) as compared with light morph (LT50 4.3 hr). We found significant differences in the storage of energy metabolites in the body color morphs of D. ananassae, that is, carbohydrate content was significantly higher (∼0.18 mg/mg dry mass) in the dark morph as compared to light morph, but greater (∼0.05 mg/mg dry mass) body lipid content was evident in the light morph. Under desiccation stress, dark and light morphs utilized mainly carbohydrates but also lipids to a lesser extent. However, the rate of utilization of energy metabolites did not vary between dark and light morphs. Further, the dark morph consumed higher energy content derived from carbohydrates under desiccation stress as compared with the light morph. Finally, we found contrasting patterns of acclimation to desiccation stress in the two body color morphs, that is, increase in desiccation survival (4.7 hr), as well as in dehydration tolerance (∼6%) due to acclimation of the dark morph but no such effects were observed in the light morph. Thus, divergence in water balance mechanisms as well as acclimation potential reflects evolved physiological adaptations of the dark morph under drier but of the light morph to wet climatic conditions. © 2013 Wiley Periodicals, Inc.

The mechanistic basis of internal conductance: a theoretical analysis of mesophyll cell photosynthesis and CO2 diffusion.

PubMed

Tholen, Danny; Zhu, Xin-Guang

2011-05-01

Photosynthesis is limited by the conductance of carbon dioxide (CO(2)) from intercellular spaces to the sites of carboxylation. Although the concept of internal conductance (g(i)) has been known for over 50 years, shortcomings in the theoretical description of this process may have resulted in a limited understanding of the underlying mechanisms. To tackle this issue, we developed a three-dimensional reaction-diffusion model of photosynthesis in a typical C(3) mesophyll cell that includes all major components of the CO(2) diffusion pathway and associated reactions. Using this novel systems model, we systematically and quantitatively examined the mechanisms underlying g(i). Our results identify the resistances of the cell wall and chloroplast envelope as the most significant limitations to photosynthesis. In addition, the concentration of carbonic anhydrase in the stroma may also be limiting for the photosynthetic rate. Our analysis demonstrated that higher levels of photorespiration increase the apparent resistance to CO(2) diffusion, an effect that has thus far been ignored when determining g(i). Finally, we show that outward bicarbonate leakage through the chloroplast envelope could contribute to the observed decrease in g(i) under elevated CO(2). Our analysis suggests that physiological and anatomical features associated with g(i) have been evolutionarily fine-tuned to benefit CO(2) diffusion and photosynthesis. The model presented here provides a novel theoretical framework to further analyze the mechanisms underlying diffusion processes in the mesophyll.

The Mechanistic Basis of Internal Conductance: A Theoretical Analysis of Mesophyll Cell Photosynthesis and CO2 Diffusion1[W][OA

PubMed Central

Tholen, Danny; Zhu, Xin-Guang

2011-01-01

Photosynthesis is limited by the conductance of carbon dioxide (CO2) from intercellular spaces to the sites of carboxylation. Although the concept of internal conductance (gi) has been known for over 50 years, shortcomings in the theoretical description of this process may have resulted in a limited understanding of the underlying mechanisms. To tackle this issue, we developed a three-dimensional reaction-diffusion model of photosynthesis in a typical C3 mesophyll cell that includes all major components of the CO2 diffusion pathway and associated reactions. Using this novel systems model, we systematically and quantitatively examined the mechanisms underlying gi. Our results identify the resistances of the cell wall and chloroplast envelope as the most significant limitations to photosynthesis. In addition, the concentration of carbonic anhydrase in the stroma may also be limiting for the photosynthetic rate. Our analysis demonstrated that higher levels of photorespiration increase the apparent resistance to CO2 diffusion, an effect that has thus far been ignored when determining gi. Finally, we show that outward bicarbonate leakage through the chloroplast envelope could contribute to the observed decrease in gi under elevated CO2. Our analysis suggests that physiological and anatomical features associated with gi have been evolutionarily fine-tuned to benefit CO2 diffusion and photosynthesis. The model presented here provides a novel theoretical framework to further analyze the mechanisms underlying diffusion processes in the mesophyll. PMID:21441385

The Challenge of Characterizing Operations in the Mechanisms Underlying Behavior

ERIC Educational Resources Information Center

Bechtel, William

2005-01-01

Neuroscience and cognitive science seek to explain behavioral regularities in terms of underlying mechanisms. An important element of a mechanistic explanation is a characterization of the operations of the parts of the mechanism. The challenge in characterizing such operations is illustrated by an example from the history of physiological…

Mechanistic Basis of Sensitivity/Resistance Towards Anti-Cancer Drugs Targeting Topoisomerase II

DTIC Science & Technology

2004-04-01

spectrometry footprinting. With the cysteine footprinting technique, we have shown that menadione may induce conformational changes in hstopo Ila that...footprinting approach, we have located a potential cysteine residue on hstopo Ila that may be modified by menadione . These preliminary results provide...the first direct evidence that menadione may act as an anticancer drug by binding to a specific position(s) on hstopo Ila causing it to adopt a conformation contrary to the wild-type form.

Photoredox Catalysis Unlocks Single-Electron Elementary Steps in Transition Metal Catalyzed Cross-Coupling

PubMed Central

2016-01-01

Since initial reports, cross-coupling technologies employing photoredox catalysts to access novel reactivity have developed with increasing pace. In this Outlook, prominent examples from the recent literature are organized on the basis of the elementary transformation enabled by photoredox catalysis and are discussed in the context of relevant historical precedent in stoichiometric organometallic chemistry. This treatment allows mechanistic similarities inherent to odd-electron transition metal reactivity to be generalized to a set of lessons for future reaction development. PMID:27280163

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

PubMed

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

2015-02-01

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

Methodical thermolysis of [Ba2Ti2(thd)4(OnPr)8(nPrOH)2] under autogenous pressure followed by combustion for the synthesis of dielectric tetragonal BaTiO3 nanopowder.

PubMed

Pol, Vilas G; Thiyagarajan, P; Moreno, Jose M Calderon; Popa, Monica; Kessler, Vadim G; Gohil, Suresh; Seisenbaeva, Gulaim A

2009-07-06

The tetragonal BaTiO(3) nanopowder is synthesized in a solvent-less, efficient process by the thermolysis of a single [Ba(2)Ti(2)(thd)(4)(OnPr)(8)(nPrOH)(2)] precursor in a closed reactor at 700 degrees C under autogenous pressure, followed by combustion. This paper compiles the synthesis of the [Ba(2)Ti(2)(thd)(4)(OnPr)(8)(nPrOH)(2)] precursor, its analysis by mass spectrometry, and implementation for the fabrication of dielectric tetragonal BaTiO(3) nanopowder by controlled efficient thermal decomposition. The as-prepared, intermediate, and final forms of the obtained nanomaterials are systematically analysed by XRD, Raman, and EDS measurements to gain structural and compositional information. Employing HR-SEM, TEM, and HR-TEM techniques, the morphological changes during the structural evolution of all the phases are pursued. The mechanistic elucidation for the fabrication of BaTiO(3) nanopowder is developed on the basis of TGA and DTA data obtained for the initial [Ba(2)Ti(2)(thd)(4)(OnPr)(8)(nPrOH)(2)] reactant as well as the as-prepared BaCO(3) with amorphous Ti phase.

Genomic Changes Associated with Reproductive and Migratory Ecotypes in Sockeye Salmon (Oncorhynchus nerka)

PubMed Central

Veale, Andrew J.

2017-01-01

Mechanisms underlying adaptive evolution can best be explored using paired populations displaying similar phenotypic divergence, illuminating the genomic changes associated with specific life history traits. Here, we used paired migratory [anadromous vs. resident (kokanee)] and reproductive [shore- vs. stream-spawning] ecotypes of sockeye salmon (Oncorhynchus nerka) sampled from seven lakes and two rivers spanning three catchments (Columbia, Fraser, and Skeena) in British Columbia, Canada to investigate the patterns and processes underlying their divergence. Restriction-site associated DNA sequencing was used to genotype this sampling at 7,347 single nucleotide polymorphisms, 334 of which were identified as outlier loci and candidates for divergent selection within at least one ecotype comparison. Sixty-eight of these outliers were present in two or more comparisons, with 33 detected across multiple catchments. Of particular note, one locus was detected as the most significant outlier between shore and stream-spawning ecotypes in multiple comparisons and across catchments (Columbia, Fraser, and Snake). We also detected several genomic islands of divergence, some shared among comparisons, potentially showing linked signals of differential selection. The single nucleotide polymorphisms and genomic regions identified in our study offer a range of mechanistic hypotheses associated with the genetic basis of O. nerka life history variation and provide novel tools for informing fisheries management. PMID:29045601

The Light Intermediate Chain 2 Subpopulation of Dynein Regulates Mitotic Spindle Orientation.

PubMed

Mahale, Sagar; Kumar, Megha; Sharma, Amit; Babu, Aswini; Ranjan, Shashi; Sachidanandan, Chetana; Mylavarapu, Sivaram V S

2016-12-23

Cytoplasmic dynein 1 is a multi-protein intracellular motor essential for mediating several mitotic functions, including the establishment of proper spindle orientation. The functional relevance and mechanistic distinctions between two discrete dynein subpopulations distinguished only by Light Intermediate Chain (LIC) homologues, LIC1 and LIC2 is unknown during mitosis. Here, we identify LIC2-dynein as the major mediator of proper spindle orientation and uncover its underlying molecular mechanism. Cortically localized dynein, essential for maintaining correct spindle orientation, consists majorly of LIC2-dynein, which interacts with cortical 14-3-3 ε- ζ and Par3, conserved proteins required for orienting the spindle. LIC2-dynein is also responsible for the majority of dynein-mediated asymmetric poleward transport of NuMA, helping focus microtubule minus ends. In addition, LIC2-dynein dominates in equatorially aligning chromosomes at metaphase and in regulating mitotic spindle length. Key mitotic functions of LIC2 were remarkably conserved in and essential for early embryonic divisions and development in zebrafish. Thus LIC2-dynein exclusively engages with two major cortical pathways to govern spindle orientation. Overall, we identify a novel selectivity of molecular interactions between the two LICs in mitosis as the underlying basis for their uneven distribution of labour in ensuring proper spindle orientation.

Dwell fatigue in two Ti alloys: An integrated crystal plasticity and discrete dislocation study

NASA Astrophysics Data System (ADS)

Zheng, Zebang; Balint, Daniel S.; Dunne, Fionn P. E.

2016-11-01

It is a well known and important problem in the aircraft engine industry that alloy Ti-6242 shows a significant reduction in fatigue life, termed dwell debit, if a stress dwell is included in the fatigue cycle, whereas Ti-6246 does not; the mechanistic explanation for the differing dwell debit of these alloys has remained elusive for decades. In this work, crystal plasticity modelling has been utilised to extract the thermal activation energies for pinned dislocation escape for both Ti alloys based on independent experimental data. This then allows the markedly different cold creep responses of the two alloys to be captured accurately and demonstrates why the observed near-identical rate sensitivity under non-dwell loading is entirely consistent with the dwell behaviour. The activation energies determined are then utilised within a recently developed thermally-activated discrete dislocation plasticity model to predict the strain rate sensitivities of the two alloys associated with nano-indentation into basal and prism planes. It is shown that Ti-6242 experiences a strong crystallographic orientation-dependent rate sensitivity while Ti-6246 does not which is shown to agree with recently published independent measurements; the dependence of rate sensitivity on indentation slip plane is also well captured. The thermally-activated discrete dislocation plasticity model shows that the incorporation of a stress dwell in fatigue loading leads to remarkable stress redistribution from soft to hard grains in the classical cold dwell fatigue rogue grain combination in alloy Ti-6242, but that no such load shedding occurs in alloy Ti-6246. The key property controlling the behaviour is the time constant of the thermal activation process relative to that of the loading. This work provides the first mechanistic basis to explain why alloy Ti-6242 shows a dwell debit but Ti-6246 does not.

Monitoring the Orientational Changes of Alamethicin during Incorporation into Bilayer Lipid Membranes.

PubMed

Forbrig, Enrico; Staffa, Jana K; Salewski, Johannes; Mroginski, Maria Andrea; Hildebrandt, Peter; Kozuch, Jacek

2018-02-13

Antimicrobial peptides (AMPs) are the first line of defense after contact of an infectious invader, for example, bacterium or virus, with a host and an integral part of the innate immune system of humans. Their broad spectrum of biological functions ranges from cell membrane disruption over facilitation of chemotaxis to interaction with membrane-bound or intracellular receptors, thus providing novel strategies to overcome bacterial resistances. Especially, the clarification of the mechanisms and dynamics of AMP incorporation into bacterial membranes is of high interest, and different mechanistic models are still under discussion. In this work, we studied the incorporation of the peptaibol alamethicin (ALM) into tethered bilayer lipid membranes on electrodes in combination with surface-enhanced infrared absorption (SEIRA) spectroscopy. This approach allows monitoring the spontaneous and potential-induced ion channel formation of ALM in situ. The complex incorporation kinetics revealed a multistep mechanism that points to peptide-peptide interactions prior to penetrating the membrane and adopting the transmembrane configuration. On the basis of the anisotropy of the backbone amide I and II infrared absorptions determined by density functional theory calculations, we employed a mathematical model to evaluate ALM reorientations monitored by SEIRA spectroscopy. Accordingly, ALM was found to adopt inclination angles of ca. 69°-78° and 21° in its interfacially adsorbed and transmembrane incorporated states, respectively. These orientations can be stabilized efficiently by the dipolar interaction with lipid head groups or by the application of a potential gradient. The presented potential-controlled mechanistic study suggests an N-terminal integration of ALM into membranes as monomers or parallel oligomers to form ion channels composed of parallel-oriented helices, whereas antiparallel oligomers are barred from intrusion.

[Investigation of noise hazards and hearing status of workers in outdoor quarries].

PubMed

Zhang, Guoying; Tang, Zhifeng; Yao, Yongping; Wang, Haiying

2014-08-01

To investigate the noise hazards in open quarries and to provide a basis for further control of noise hazards. An investigation was performed during 2010 to 2011 among all open quarries in Deqing County of Zhejiang Province, China. The investigation included basic information of the quarries, the occupational health situation and noise intensity at the workplace, and the hearing loss of workers exposed to noise in quarry enterprises. The hearing test results were evaluated based on the Diagnostic criteria of occupational noise-induced hearing loss (GBZ 49-2007). A total of 25 enterprises with open quarries were investigated, of which only 30.4% (17/56) workplaces met the national standard. The median noise level was 92.5 dB (A). Fifty-four (10.6%) out of 508 workers in the 25 enterprises were diagnosed with binaural hearing loss in the initial physical examination, with 18.3% (93/508) under surveillance. The rate of normal hearing among crushing workers, mechanists, drilling workers, and blasting workers ranged between 27.6% and 41.4%, which was significantly lower than that among workers exposed to slight noise hazards (80.0%) or other workers (63.7%) (P < 0.05). With increasing working years, the binaural hearing loss of crushing workers became serious. Serious occupational noise hazards existed in most jobs in open quarries, with crushing workers, mechanists, drilling workers, and blasting workers most seriously jeopardized. Among crushing workers, those working in the first-line or unprotected second?line positions suffered more than the others. Further measures should be taken by the supervision department and the enterprises to control the noise hazards in open quarries.

Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase

NASA Astrophysics Data System (ADS)

Hutchinson, Jonathan P.; Rowland, Paul; Taylor, Mark R. D.; Christodoulou, Erica M.; Haslam, Carl; Hobbs, Clare I.; Holmes, Duncan S.; Homes, Paul; Liddle, John; Mole, Damian J.; Uings, Iain; Walker, Ann L.; Webster, Scott P.; Mowat, Christopher G.; Chung, Chun-Wa

2017-06-01

Kynurenine-3-monooxygenase (KMO) is a key FAD-dependent enzyme of tryptophan metabolism. In animal models, KMO inhibition has shown benefit in neurodegenerative diseases such as Huntington's and Alzheimer's. Most recently it has been identified as a target for acute pancreatitis multiple organ dysfunction syndrome (AP-MODS); a devastating inflammatory condition with a mortality rate in excess of 20%. Here we report and dissect the molecular mechanism of action of three classes of KMO inhibitors with differentiated binding modes and kinetics. Two novel inhibitor classes trap the catalytic flavin in a previously unobserved tilting conformation. This correlates with picomolar affinities, increased residence times and an absence of the peroxide production seen with previous substrate site inhibitors. These structural and mechanistic insights culminated in GSK065(C1) and GSK366(C2), molecules suitable for preclinical evaluation. Moreover, revising the repertoire of flavin dynamics in this enzyme class offers exciting new opportunities for inhibitor design.

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.

A redox-mediated Kemp eliminase

NASA Astrophysics Data System (ADS)

Li, Aitao; Wang, Binju; Ilie, Adriana; Dubey, Kshatresh D.; Bange, Gert; Korendovych, Ivan V.; Shaik, Sason; Reetz, Manfred T.

2017-03-01

The acid/base-catalysed Kemp elimination of 5-nitro-benzisoxazole forming 2-cyano-4-nitrophenol has long served as a design platform of enzymes with non-natural reactions, providing new mechanistic insights in protein science. Here we describe an alternative concept based on redox catalysis by P450-BM3, leading to the same Kemp product via a fundamentally different mechanism. QM/MM computations show that it involves coordination of the substrate's N-atom to haem-Fe(II) with electron transfer and concomitant N-O heterolysis liberating an intermediate having a nitrogen radical moiety Fe(III)-N. and a phenoxyl anion. Product formation occurs by bond rotation and H-transfer. Two rationally chosen point mutations cause a notable increase in activity. The results shed light on the prevailing mechanistic uncertainties in human P450-catalysed metabolism of the immunomodulatory drug leflunomide, which likewise undergoes redox-mediated Kemp elimination by P450-BM3. Other isoxazole-based pharmaceuticals are probably also metabolized by a redox mechanism. Our work provides a basis for designing future artificial enzymes.

Online UV-visible spectroscopy and multivariate curve resolution as powerful tool for model-free investigation of laccase-catalysed oxidation.

PubMed

Kandelbauer, A; Kessler, W; Kessler, R W

2008-03-01

The laccase-catalysed transformation of indigo carmine (IC) with and without a redox active mediator was studied using online UV-visible spectroscopy. Deconvolution of the mixture spectra obtained during the reaction was performed on a model-free basis using multivariate curve resolution (MCR). Thereby, the time courses of educts, products, and reaction intermediates involved in the transformation were reconstructed without prior mechanistic assumptions. Furthermore, the spectral signature of a reactive intermediate which could not have been detected by a classical hard-modelling approach was extracted from the chemometric analysis. The findings suggest that the combined use of UV-visible spectroscopy and MCR may lead to unexpectedly deep mechanistic evidence otherwise buried in the experimental data. Thus, although rather an unspecific method, UV-visible spectroscopy can prove useful in the monitoring of chemical reactions when combined with MCR. This offers a wide range of chemists a cheap and readily available, highly sensitive tool for chemical reaction online monitoring.

Envelope Protein Dynamics in Paramyxovirus Entry

PubMed Central

Plattet, Philippe; Plemper, Richard K.

2013-01-01

ABSTRACT Paramyxoviruses include major pathogens with significant global health and economic impact. This large family of enveloped RNA viruses infects cells by employing two surface glycoproteins that tightly cooperate to fuse their lipid envelopes with the target cell plasma membrane, an attachment and a fusion (F) protein. Membrane fusion is believed to depend on receptor-induced conformational changes within the attachment protein that lead to the activation and subsequent refolding of F. While structural and mechanistic studies have considerably advanced our insight into paramyxovirus cell adhesion and the structural basis of F refolding, how precisely the attachment protein links receptor engagement to F triggering remained poorly understood. Recent reports based on work with several paramyxovirus family members have transformed our understanding of the triggering mechanism of the membrane fusion machinery. Here, we review these recent findings, which (i) offer a broader mechanistic understanding of the paramyxovirus cell entry system, (ii) illuminate key similarities and differences between entry strategies of different paramyxovirus family members, and (iii) suggest new strategies for the development of novel therapeutics. PMID:23820396

Envelope protein dynamics in paramyxovirus entry.

PubMed

Plattet, Philippe; Plemper, Richard K

2013-07-02

Paramyxoviruses include major pathogens with significant global health and economic impact. This large family of enveloped RNA viruses infects cells by employing two surface glycoproteins that tightly cooperate to fuse their lipid envelopes with the target cell plasma membrane, an attachment and a fusion (F) protein. Membrane fusion is believed to depend on receptor-induced conformational changes within the attachment protein that lead to the activation and subsequent refolding of F. While structural and mechanistic studies have considerably advanced our insight into paramyxovirus cell adhesion and the structural basis of F refolding, how precisely the attachment protein links receptor engagement to F triggering remained poorly understood. Recent reports based on work with several paramyxovirus family members have transformed our understanding of the triggering mechanism of the membrane fusion machinery. Here, we review these recent findings, which (i) offer a broader mechanistic understanding of the paramyxovirus cell entry system, (ii) illuminate key similarities and differences between entry strategies of different paramyxovirus family members, and (iii) suggest new strategies for the development of novel therapeutics.

Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase.

PubMed

Hutchinson, Jonathan P; Rowland, Paul; Taylor, Mark R D; Christodoulou, Erica M; Haslam, Carl; Hobbs, Clare I; Holmes, Duncan S; Homes, Paul; Liddle, John; Mole, Damian J; Uings, Iain; Walker, Ann L; Webster, Scott P; Mowat, Christopher G; Chung, Chun-Wa

2017-06-12

Kynurenine-3-monooxygenase (KMO) is a key FAD-dependent enzyme of tryptophan metabolism. In animal models, KMO inhibition has shown benefit in neurodegenerative diseases such as Huntington's and Alzheimer's. Most recently it has been identified as a target for acute pancreatitis multiple organ dysfunction syndrome (AP-MODS); a devastating inflammatory condition with a mortality rate in excess of 20%. Here we report and dissect the molecular mechanism of action of three classes of KMO inhibitors with differentiated binding modes and kinetics. Two novel inhibitor classes trap the catalytic flavin in a previously unobserved tilting conformation. This correlates with picomolar affinities, increased residence times and an absence of the peroxide production seen with previous substrate site inhibitors. These structural and mechanistic insights culminated in GSK065(C1) and GSK366(C2), molecules suitable for preclinical evaluation. Moreover, revising the repertoire of flavin dynamics in this enzyme class offers exciting new opportunities for inhibitor design.

Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase

PubMed Central

Hutchinson, Jonathan P.; Rowland, Paul; Taylor, Mark R. D.; Christodoulou, Erica M.; Haslam, Carl; Hobbs, Clare I.; Holmes, Duncan S.; Homes, Paul; Liddle, John; Mole, Damian J.; Uings, Iain; Walker, Ann L.; Webster, Scott P.; Mowat, Christopher G.; Chung, Chun-wa

2017-01-01

Kynurenine-3-monooxygenase (KMO) is a key FAD-dependent enzyme of tryptophan metabolism. In animal models, KMO inhibition has shown benefit in neurodegenerative diseases such as Huntington's and Alzheimer's. Most recently it has been identified as a target for acute pancreatitis multiple organ dysfunction syndrome (AP-MODS); a devastating inflammatory condition with a mortality rate in excess of 20%. Here we report and dissect the molecular mechanism of action of three classes of KMO inhibitors with differentiated binding modes and kinetics. Two novel inhibitor classes trap the catalytic flavin in a previously unobserved tilting conformation. This correlates with picomolar affinities, increased residence times and an absence of the peroxide production seen with previous substrate site inhibitors. These structural and mechanistic insights culminated in GSK065(C1) and GSK366(C2), molecules suitable for preclinical evaluation. Moreover, revising the repertoire of flavin dynamics in this enzyme class offers exciting new opportunities for inhibitor design. PMID:28604669

Oxygen Reduction Reaction on Ag(111) in Alkaline Solution: A Combined Density Functional Theory and Kinetic Monte Carlo Study

DOE PAGES

Liu, Shizhong; White, Michael G.; Liu, Ping

2018-01-25

We reported a detailed mechanistic study of the oxygen reduction reaction (ORR) on the model Ag(111) surface in alkaline solution by using density functional theory (DFT) and Kinetic Monte Carlo (KMC) simulations, in which multiple pathways involving either 2 e - or 4 e - mechanisms were included. The theoretical modelling presented here is able to reproduce the experimentally measured polarization curves in both low and high potential regions. An electrochemical 4 e - network including both a chemisorbed water (*H 2O)-mediated 4 e - associative pathway and the conventional associative pathway was identified to dominate the ORR mechanism. Onmore » the basis of the mechanistic understanding derived from these calculations, the ways to promote the ORR on Ag(111) were provided, including facilitating *OH removal, **O 2 reduction by *H 2O, and suppressing **O 2 desorption. Finally, the origin of the different ORR behaviors of Ag(111) and Pt(111) was also discussed in detail.« less

An in vitro assay for entry into cilia reveals unique properties of the soluble diffusion barrier

PubMed Central

Breslow, David K.; Koslover, Elena F.; Seydel, Federica; Spakowitz, Andrew J.

2013-01-01

Specific proteins are concentrated within primary cilia, whereas others remain excluded. To understand the mechanistic basis of entry into cilia, we developed an in vitro assay using cells in which the plasma membrane was permeabilized, but the ciliary membrane was left intact. Using a diffusion-to-capture system and quantitative analysis, we find that proteins >9 nm in diameter (∼100 kD) are restricted from entering cilia, and we confirm these findings in vivo. Interference with the nuclear pore complex (NPC) or the actin cytoskeleton in permeabilized cells demonstrated that the ciliary diffusion barrier is mechanistically distinct from those of the NPC or the axon initial segment. Moreover, applying a mass transport model to this system revealed diffusion coefficients for soluble and membrane proteins within cilia that are compatible with rapid exploration of the ciliary space in the absence of active transport. Our results indicate that large proteins require active transport for entry into cilia but not necessarily for movement inside cilia. PMID:24100294

Mourning dove hunting regulation strategy based on annual harvest statistics and banding data

USGS Publications Warehouse

Otis, D.L.

2006-01-01

Although managers should strive to base game bird harvest management strategies on mechanistic population models, monitoring programs required to build and continuously update these models may not be in place. Alternatively, If estimates of total harvest and harvest rates are available, then population estimates derived from these harvest data can serve as the basis for making hunting regulation decisions based on population growth rates derived from these estimates. I present a statistically rigorous approach for regulation decision-making using a hypothesis-testing framework and an assumed framework of 3 hunting regulation alternatives. I illustrate and evaluate the technique with historical data on the mid-continent mallard (Anas platyrhynchos) population. I evaluate the statistical properties of the hypothesis-testing framework using the best available data on mourning doves (Zenaida macroura). I use these results to discuss practical implementation of the technique as an interim harvest strategy for mourning doves until reliable mechanistic population models and associated monitoring programs are developed.

Oxygen Reduction Reaction on Ag(111) in Alkaline Solution: A Combined Density Functional Theory and Kinetic Monte Carlo Study

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

Liu, Shizhong; White, Michael G.; Liu, Ping

We reported a detailed mechanistic study of the oxygen reduction reaction (ORR) on the model Ag(111) surface in alkaline solution by using density functional theory (DFT) and Kinetic Monte Carlo (KMC) simulations, in which multiple pathways involving either 2 e - or 4 e - mechanisms were included. The theoretical modelling presented here is able to reproduce the experimentally measured polarization curves in both low and high potential regions. An electrochemical 4 e - network including both a chemisorbed water (*H 2O)-mediated 4 e - associative pathway and the conventional associative pathway was identified to dominate the ORR mechanism. Onmore » the basis of the mechanistic understanding derived from these calculations, the ways to promote the ORR on Ag(111) were provided, including facilitating *OH removal, **O 2 reduction by *H 2O, and suppressing **O 2 desorption. Finally, the origin of the different ORR behaviors of Ag(111) and Pt(111) was also discussed in detail.« less

Cross-benzoin and Stetter-type reactions mediated by KOtBu-DMF via an electron-transfer process.

PubMed

Ragno, Daniele; Zaghi, Anna; Di Carmine, Graziano; Giovannini, Pier Paolo; Bortolini, Olga; Fogagnolo, Marco; Molinari, Alessandra; Venturini, Alessandro; Massi, Alessandro

2016-10-18

The condensation of aromatic α-diketones (benzils) with aromatic aldehydes (benzoin-type reaction) and chalcones (Stetter-type reaction) in DMF in the presence of catalytic (25 mol%) KOtBu is reported. Both types of umpolung processes proceed with good efficiency and complete chemoselectivity. On the basis of spectroscopic evidence (MS analysis) of plausible intermediates and literature reports, the occurrence of different ionic pathways have been evaluated to elucidate the mechanism of a model cross-benzoin-like reaction along with a radical route initiated by an electron-transfer process to benzil from the carbamoyl anion derived from DMF. This mechanistic investigation has culminated in a different proposal, supported by calculations and a trapping experiment, based on double electron-transfer to benzil with formation of the corresponding enediolate anion as the key reactive intermediate. A mechanistic comparison between the activation modes of benzils in KOtBu-DMF and KOtBu-DMSO systems is also described.

The Revolution Continues: Newly Discovered Systems Expand the CRISPR-Cas Toolkit.

PubMed

Murugan, Karthik; Babu, Kesavan; Sundaresan, Ramya; Rajan, Rakhi; Sashital, Dipali G

2017-10-05

CRISPR-Cas systems defend prokaryotes against bacteriophages and mobile genetic elements and serve as the basis for revolutionary tools for genetic engineering. Class 2 CRISPR-Cas systems use single Cas endonucleases paired with guide RNAs to cleave complementary nucleic acid targets, enabling programmable sequence-specific targeting with minimal machinery. Recent discoveries of previously unidentified CRISPR-Cas systems have uncovered a deep reservoir of potential biotechnological tools beyond the well-characterized Type II Cas9 systems. Here we review the current mechanistic understanding of newly discovered single-protein Cas endonucleases. Comparison of these Cas effectors reveals substantial mechanistic diversity, underscoring the phylogenetic divergence of related CRISPR-Cas systems. This diversity has enabled further expansion of CRISPR-Cas biotechnological toolkits, with wide-ranging applications from genome editing to diagnostic tools based on various Cas endonuclease activities. These advances highlight the exciting prospects for future tools based on the continually expanding set of CRISPR-Cas systems. Copyright © 2017 Elsevier Inc. All rights reserved.

Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors.

PubMed

Wagner, Andrew J; Malinowska-Kolodziej, Izabela; Morgan, Jeffrey A; Qin, Wei; Fletcher, Christopher D M; Vena, Natalie; Ligon, Azra H; Antonescu, Cristina R; Ramaiya, Nikhil H; Demetri, George D; Kwiatkowski, David J; Maki, Robert G

2010-02-10

PURPOSE Perivascular epithelioid cell tumors (PEComas) represent a family of mesenchymal neoplasms, mechanistically linked through activation of the mTOR signaling pathway. There is no known effective therapy for PEComa, and the molecular pathophysiology of aberrant mTOR signaling provided us with a scientific rationale to target this pathway therapeutically. On this mechanistic basis, we treated three consecutive patients with metastatic PEComa with an oral mTOR inhibitor, sirolimus. PATIENTS AND METHODS Patients with advanced PEComa were treated with sirolimus and consented to retrospective collection of data from their medical records and analysis of archival tumor specimens. Tumor response was determined by computed tomography scans obtained at the clinical discretion of the treating physicians. Tumors were assessed for immunohistochemical evidence of mTORC1 activation and genetic evidence of alterations in TSC1 and TSC2. Results Radiographic responses to sirolimus were observed in all patients. PEComas demonstrated loss of TSC2 protein expression and evidence of baseline mTORC1 activation. Homozygous loss of TSC1 was identified in one PEComa. CONCLUSION Inhibition of mTORC1, pathologically activated by loss of the TSC1/TSC2 tumor suppressor complex, is a rational mechanistic target for therapy in PEComas. The clinical activity of sirolimus in PEComa additionally strengthens the pathobiologic similarities linking PEComas to other neoplasms related to the tuberous sclerosis complex.

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.

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

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

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

2011-04-15

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

Instrumentation for mechanistic design implementation.

DOT National Transportation Integrated Search

2010-02-01

The Oregon Department of Transportation (ODOT) Pavement Services Unit is in the process of implementing a new pavement design : procedure being developed under the sponsorship of the American Association of State Highway and Transportation Officials....

A model of strength

USGS Publications Warehouse

Johnson, Douglas H.; Cook, R.D.

2013-01-01

In her AAAS News & Notes piece "Can the Southwest manage its thirst?" (26 July, p. 362), K. Wren quotes Ajay Kalra, who advocates a particular method for predicting Colorado River streamflow "because it eschews complex physical climate models for a statistical data-driven modeling approach." A preference for data-driven models may be appropriate in this individual situation, but it is not so generally, Data-driven models often come with a warning against extrapolating beyond the range of the data used to develop the models. When the future is like the past, data-driven models can work well for prediction, but it is easy to over-model local or transient phenomena, often leading to predictive inaccuracy (1). Mechanistic models are built on established knowledge of the process that connects the response variables with the predictors, using information obtained outside of an extant data set. One may shy away from a mechanistic approach when the underlying process is judged to be too complicated, but good predictive models can be constructed with statistical components that account for ingredients missing in the mechanistic analysis. Models with sound mechanistic components are more generally applicable and robust than data-driven models.

Understanding and Exploitation of Neighboring Heteroatom Effect for the Mild N-Arylation of Heterocycles with Diaryliodonium Salts under Aqueous Conditions: A Theoretical and Experimental Mechanistic Study.

PubMed

Bihari, Tamás; Babinszki, Bence; Gonda, Zsombor; Kovács, Szabolcs; Novák, Zoltán; Stirling, András

2016-07-01

The mechanism of arylation of N-heterocycles with unsymmetric diaryliodonium salts is elucidated. The fast and efficient N-arylation reaction is interpreted in terms of the bifunctionality of the substrate: The consecutive actions of properly oriented Lewis base and Brønsted acid centers in sufficient proximity result in the fast and efficient N-arylation. The mechanistic picture points to a promising synthetic strategy where suitably positioned nucleophilic and acidic centers enable functionalization, and it is tested experimentally.

Chromosome territory relocation paradigm during DNA damage response: Some insights from molecular biology to physics.

PubMed

Fatakia, Sarosh N; Kulashreshtha, Mugdha; Mehta, Ishita S; Rao, Basuthkar J

2017-09-03

Among the many facets of DNA damage response (DDR), relocation of chromosome territories (CTs) is most intriguing. We have previously reported that cisplatin induced DDR in human dermal fibroblasts led to relocation of CTs 12, 15 from the nuclear periphery to its interior while CTs 19, 17 repositioned from the interior to its periphery. Studies of CT relocation remain nascent as we begin unraveling the role of key players in DDR to demonstrate its mechanistic basis. Consolidating our recent reports, we argue that γH2AX-signaling leads to enhanced recruitment of nuclear myosin 1 (NM1) to chromatin, which via its motor function, results in CT repositioning. Next, we invoke a novel systems-level theory that subsumed CTs as pairs, not solo entities, to present the physical basis for plasticity in interphase CT arrangement. Subsequently, we posited that our systems-level theory describes a unified physical basis for non-random positioning of CTs in interphase nuclei across disparate eukaryotes.

Mechanistic basis of infertility of mouse intersubspecific hybrids

PubMed Central

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

2013-01-01

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

Mechanistic basis of infertility of mouse intersubspecific hybrids.

PubMed

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

2013-02-05

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

Building functional groups of marine benthic macroinvertebrates on the basis of general community assembly mechanisms

NASA Astrophysics Data System (ADS)

Alexandridis, Nikolaos; Bacher, Cédric; Desroy, Nicolas; Jean, Fred

2017-03-01

The accurate reproduction of the spatial and temporal dynamics of marine benthic biodiversity requires the development of mechanistic models, based on the processes that shape macroinvertebrate communities. The modelled entities should, accordingly, be able to adequately represent the many functional roles that are performed by benthic organisms. With this goal in mind, we applied the emergent group hypothesis (EGH), which assumes functional equivalence within and functional divergence between groups of species. The first step of the grouping involved the selection of 14 biological traits that describe the role of benthic macroinvertebrates in 7 important community assembly mechanisms. A matrix of trait values for the 240 species that occurred in the Rance estuary (Brittany, France) in 1995 formed the basis for a hierarchical classification that generated 20 functional groups, each with its own trait values. The functional groups were first evaluated based on their ability to represent observed patterns of biodiversity. The two main assumptions of the EGH were then tested, by assessing the preservation of niche attributes among the groups and the neutrality of functional differences within them. The generally positive results give us confidence in the ability of the grouping to recreate functional diversity in the Rance estuary. A first look at the emergent groups provides insights into the potential role of community assembly mechanisms in shaping biodiversity patterns. Our next steps include the derivation of general rules of interaction and their incorporation, along with the functional groups, into mechanistic models of benthic biodiversity.

Structural basis of omalizumab therapy and omalizumab-mediated IgE exchange

DOE PAGES

Pennington, Luke F.; Tarchevskaya, Svetlana; Brigger, Daniel; ...

2016-05-19

Omalizumab is a widely used therapeutic anti-IgE antibody. Here we report the crystal structure of the omalizumab–Fab in complex with an IgE-Fc fragment. This structure reveals the mechanism of omalizumab-mediated inhibition of IgE interactions with both high- and low-affinity IgE receptors, and explains why omalizumab selectively binds free IgE. The structure of the complex also provides mechanistic insight into a class of disruptive IgE inhibitors that accelerate the dissociation of the high-affinity IgE receptor from IgE. We use this structural data to generate a mutant IgE-Fc fragment that is resistant to omalizumab binding. Treatment with this omalizumab-resistant IgE-Fc fragment, inmore » combination with omalizumab, promotes the exchange of cell-bound full-length IgE with omalizumab-resistant IgE-Fc fragments on human basophils. Furthermore, this combination treatment also blocks basophil activation more efficiently than either agent alone, providing a novel approach to probe regulatory mechanisms underlying IgE hypersensitivity with implications for therapeutic interventions.« less

DNA Damage, DNA Repair, Aging, and Neurodegeneration

PubMed Central

Maynard, Scott; Fang, Evandro Fei; Scheibye-Knudsen, Morten; Croteau, Deborah L.; Bohr, Vilhelm A.

2015-01-01

Aging in mammals is accompanied by a progressive atrophy of tissues and organs, and stochastic damage accumulation to the macromolecules DNA, RNA, proteins, and lipids. The sequence of the human genome represents our genetic blueprint, and accumulating evidence suggests that loss of genomic maintenance may causally contribute to aging. Distinct evidence for a role of imperfect DNA repair in aging is that several premature aging syndromes have underlying genetic DNA repair defects. Accumulation of DNA damage may be particularly prevalent in the central nervous system owing to the low DNA repair capacity in postmitotic brain tissue. It is generally believed that the cumulative effects of the deleterious changes that occur in aging, mostly after the reproductive phase, contribute to species-specific rates of aging. In addition to nuclear DNA damage contributions to aging, there is also abundant evidence for a causative link between mitochondrial DNA damage and the major phenotypes associated with aging. Understanding the mechanistic basis for the association of DNA damage and DNA repair with aging and age-related diseases, such as neurodegeneration, would give insight into contravening age-related diseases and promoting a healthy life span. PMID:26385091

FadA5 a thiolase from Mycobacterium tuberculosis - a unique steroid-binding pocket reveals the potential for drug development against tuberculosis

PubMed Central

Schaefer, Christin M.; Lu, Rui; Nesbitt, Natasha M.; Schiebel, Johannes; Sampson, Nicole S.; Kisker, Caroline

2014-01-01

Summary With the exception of HIV, tuberculosis (TB) is the leading cause of mortality among infectious diseases. The urgent need to develop new anti-tubercular drugs is apparent due to the increasing number of drug resistant Mycobacterium tuberculosis (Mtb) strains. Proteins involved in cholesterol import and metabolism have recently been discovered as potent targets against TB. FadA5, a thiolase from Mtb, is catalyzing the last step of the β-oxidation reaction of the cholesterol side-chain degradation under release of critical metabolites and was shown to be of importance during the chronic stage of TB infections. To gain structural and mechanistic insight on FadA5 we characterized the enzyme in different stages of the cleavage reaction and with a steroid bound to the binding pocket. Structural comparisons to human thiolases revealed that it should be possible to target FadA5 specifically and the steroid-bound structure provides a solid basis for the development of inhibitors against FadA5. PMID:25482540

Correlation of chemical evaporation rate with vapor pressure.

PubMed

Mackay, Donald; van Wesenbeeck, Ian

2014-09-02

A new one-parameter correlation is developed for the evaporation rate (ER) of chemicals as a function of molar mass (M) and vapor pressure (P) that is simpler than existing correlations. It applies only to liquid surfaces that are unaffected by the underlying solid substrate as occurs in the standard ASTM evaporation rate test and to quiescent liquid pools. The relationship has a sounder theoretical basis than previous correlations because ER is correctly correlated with PM rather than P alone. The inclusion of M increases the slope of previous log ER versus log P regressions to a value close to 1.0 and yields a simpler one-parameter correlation, namely, ER (μg m(-1) h(-1)) = 1464P (Pa) × M (g mol(-1)). Applications are discussed for the screening level assessment and ranking of chemicals for evaporation rate, such as pesticides, fumigants, and hydrocarbon carrier fluids used in pesticide formulations, liquid consumer products used indoors, and accidental spills of liquids. The mechanistic significance of the single parameter as a mass-transfer coefficient or velocity is discussed.

Tissue- and cell-type–specific manifestations of heteroplasmic mtDNA 3243A>G mutation in human induced pluripotent stem cell-derived disease model

PubMed Central

Hämäläinen, Riikka H.; Manninen, Tuula; Koivumäki, Hanna; Kislin, Mikhail; Otonkoski, Timo; Suomalainen, Anu

2013-01-01

Mitochondrial DNA (mtDNA) mutations manifest with vast clinical heterogeneity. The molecular basis of this variability is mostly unknown because the lack of model systems has hampered mechanistic studies. We generated induced pluripotent stem cells from patients carrying the most common human disease mutation in mtDNA, m.3243A>G, underlying mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. During reprogramming, heteroplasmic mtDNA showed bimodal segregation toward homoplasmy, with concomitant changes in mtDNA organization, mimicking mtDNA bottleneck during epiblast specification. Induced pluripotent stem cell–derived neurons and various tissues derived from teratomas manifested cell-type specific respiratory chain (RC) deficiency patterns. Similar to MELAS patient tissues, complex I defect predominated. Upon neuronal differentiation, complex I specifically was sequestered in perinuclear PTEN-induced putative kinase 1 (PINK1) and Parkin-positive autophagosomes, suggesting active degradation through mitophagy. Other RC enzymes showed normal mitochondrial network distribution. Our data show that cellular context actively modifies RC deficiency manifestation in MELAS and that autophagy is a significant component of neuronal MELAS pathogenesis. PMID:24003133

Structural and functional determinants of conserved lipid interaction domains of inward rectifying Kir6.2 channels.

PubMed

Cukras, Catherine A; Jeliazkova, Iana; Nichols, Colin G

2002-06-01

All members of the inward rectifiier K(+) (Kir) channel family are activated by phosphoinositides and other amphiphilic lipids. To further elucidate the mechanistic basis, we examined the membrane association of Kir6.2 fragments of K(ATP) channels, and the effects of site-directed mutations of these fragments and full-length Kir6.2 on membrane association and K(ATP) channel activity, respectively. GFP-tagged Kir6.2 COOH terminus and GFP-tagged pleckstrin homology domain from phospholipase C delta1 both associate with isolated membranes, and association of each is specifically reduced by muscarinic m1 receptor-mediated phospholipid depletion. Kir COOH termini are predicted to contain multiple beta-strands and a conserved alpha-helix (residues approximately 306-311 in Kir6.2). Systematic mutagenesis of D307-F315 reveals a critical role of E308, I309, W311 and F315, consistent with residues lying on one side of a alpha-helix. Together with systematic mutation of conserved charges, the results define critical determinants of a conserved domain that underlies phospholipid interaction in Kir channels.

Photodegradation of imidacloprid insecticide by Ag-deposited titanate nanotubes: a study of intermediates and their reaction pathways.

PubMed

Grover, Inderpreet Singh; Singh, Satnam; Pal, Bonamali

2014-12-31

The present work demonstrates the influence of Ag-loading (0.2-1.0 wt %) onto sodium titanate nanotubes (TNT) for complete photomineralization of the neurotoxic imidacloprid (IMI) insecticide under UV light illumination. It has been observed that degradation of IMI follows pseudo-first-order kinetics, where 0.5 wt % Ag-loaded TNT exhibited highest apparent rate constant (2.2 × 10(-2) min(-1)) and corresponding least half-life (t1/2) of 31 min for IMI relative to bare P25-TiO2 (3.4 × 10(-3) min(-1), t1/2 = 230 min). The mineralization of IMI intermediates to CO2 during its photooxidation has been described by time course GC-MS and GC analysis and has been correlated with the kinetic analysis. The investigation for the role and quantitative estimation of the fate of heteroatoms (N, O, and Cl) present in IMI revealed an increase in the amount of nitrate, nitrite, and chloride ions with time during its photooxidation. On the basis of these results a mechanistic pathway for photomineralization of IMI is proposed.

Environmental drivers defining linkages among life-history traits: mechanistic insights from a semiterrestrial amphipod subjected to macroscale gradients.

PubMed

Gómez, Julio; Barboza, Francisco R; Defeo, Omar

2013-10-01

Determining the existence of interconnected responses among life-history traits and identifying underlying environmental drivers are recognized as key goals for understanding the basis of phenotypic variability. We studied potentially interconnected responses among senescence, fecundity, embryos size, weight of brooding females, size at maturity and sex ratio in a semiterrestrial amphipod affected by macroscale gradients in beach morphodynamics and salinity. To this end, multiple modelling processes based on generalized additive mixed models were used to deal with the spatio-temporal structure of the data obtained at 10 beaches during 22 months. Salinity was the only nexus among life-history traits, suggesting that this physiological stressor influences the energy balance of organisms. Different salinity scenarios determined shifts in the weight of brooding females and size at maturity, having consequences in the number and size of embryos which in turn affected sex determination and sex ratio at the population level. Our work highlights the importance of analysing field data to find the variables and potential mechanisms that define concerted responses among traits, therefore defining life-history strategies.

The cell as the mechanistic basis for evolution.

PubMed

Torday, J S

2015-01-01

The First Principles for Physiology originated in and emanate from the unicellular state of life. Viewing physiology as a continuum from unicellular to multicellular organisms provides fundamental insight to ontogeny and phylogeny as a functionally integral whole. Such mechanisms are most evident under conditions of physiologic stress; all of the molecular pathways that evolved in service to the vertebrate water-land transition aided and abetted the evolution of the vertebrate lung, for example. Reduction of evolution to cell biology has an important scientific feature—it is predictive. One implication of this perspective on evolution is the likelihood that it is the unicellular state that is actually the object of selection. By looking at the process of evolution from its unicellular origins, the causal relationships between genotype and phenotype are revealed, as are many other aspects of physiology and medicine that have remained anecdotal and counter-intuitive. Evolutionary development can best be considered as a cyclical, epigenetic, reiterative environmental assessment process, originating from the unicellular state, both forward and backward, to sustain and perpetuate unicellular homeostasis. © 2015 Wiley Periodicals, Inc.

Specialists without spirit: crisis in the nursing profession.

PubMed Central

Hewa, S; Hetherington, R W

1990-01-01

This paper examines the crisis in the nursing profession in Western industrial societies in the light of Max Weber's theory of rationalisation. The domination of instrumental rational action in modern industrial societies in evident in the field of modern medicine. The burgeoning mechanistic approach to the human body and health makes modern health care services increasingly devoid of human values. Although the nursing profession has been influenced by various changes that took place in health care during the last few decades (for example greater reliance on technology), the underlying values of the nursing profession still emphasise a broad definition of the well-being of patients. Hence, in recent years the irrational consequences of growing technological medicine in North America has resulted in a serious crisis in the nursing profession. To resolve this crisis the authors propose a reorganisation of modern health care services on the basis of a new paradigm which is compatible with both the health care needs of the people and the main emphasis in education and training of the nursing profession. PMID:2287012

Asymmetrical Macromolecular Complex Formation of Lysophosphatidic Acid Receptor 2 (LPA2) Mediates Gradient Sensing in Fibroblasts*

PubMed Central

Ren, Aixia; Moon, Changsuk; Zhang, Weiqiang; Sinha, Chandrima; Yarlagadda, Sunitha; Arora, Kavisha; Wang, Xusheng; Yue, Junming; Parthasarathi, Kaushik; Heil-Chapdelaine, Rick; Tigyi, Gabor; Naren, Anjaparavanda P.

2014-01-01

Chemotactic migration of fibroblasts toward growth factors relies on their capacity to sense minute extracellular gradients and respond to spatially confined receptor-mediated signals. Currently, mechanisms underlying the gradient sensing of fibroblasts remain poorly understood. Using single-particle tracking methodology, we determined that a lysophosphatidic acid (LPA) gradient induces a spatiotemporally restricted decrease in the mobility of LPA receptor 2 (LPA2) on chemotactic fibroblasts. The onset of decreased LPA2 mobility correlates to the spatial recruitment and coupling to LPA2-interacting proteins that anchor the complex to the cytoskeleton. These localized PDZ motif-mediated macromolecular complexes of LPA2 trigger a Ca2+ puff gradient that governs gradient sensing and directional migration in response to LPA. Disruption of the PDZ motif-mediated assembly of the macromolecular complex of LPA2 disorganizes the gradient of Ca2+ puffs, disrupts gradient sensing, and reduces the directional migration of fibroblasts toward LPA. Our findings illustrate that the asymmetric macromolecular complex formation of chemoattractant receptors mediates gradient sensing and provides a new mechanistic basis for models to describe gradient sensing of fibroblasts. PMID:25542932

Synthesis and applications of [1-(15)N]-labeled 4,6-dimethyl-4H-[1,2,5]oxadiazolo[3,4-d]pyrimidine-5,7-dione 1-oxide as a useful tool for mechanistic investigations.

PubMed

Sako, M; Yaekura, I; Oda, S; Hirota, K

2000-10-06

[1-(15)N]-Labeled 4,6-dimethyl-4H-[1,2,5]oxadiazolo[3,4-d]pyrimidine-5,7-dione 1-oxide (1-(15)N1) was easily prepared by nitration of commercially available 6-amino-1,3-dimethyl-1H-pyrimidine-2,4-dione using 15N-enriched nitric acid followed by an intramolecular oxidative cyclization with iodosylbenzene diacetate under mild conditions. On the basis of the experimental results using 1-(15)N1, the formation of 8-phenyltheophylline (3), the 1,3-dimethylalloxazines (4: n = 0, 1), and 1,3,7,9-tetramethyl-1H,9H-pyrimido[5,4-g]pteridine-2,4,6,8-tetraone++ + (5) in the thermal reaction of the N-oxide 1 with benzylamine, aniline, or piperidine, and the generation of NO or NO-related species in the reaction with N-acetylcysteamine were reasonably explained by considering the initial attack of the employed nucleophiles on the 3a-position of 1.

Progesterone regulation of stem and progenitor cells in normal and malignant breast

PubMed Central

Axlund, Sunshine Daddario; Sartorius, Carol A.

2011-01-01

Progesterone plays an important, if not controversial, role in mammary epithelial cell proliferation and differentiation. Evidence supports that progesterone promotes rodent mammary carcinogenesis under some conditions, progesterone receptors (PR) are necessary for murine mammary gland tumorigenesis, and exogenous progestin use in post-menopausal women increases breast cancer risk. Thus, the progesterone/PR signaling axis can promote mammary tumorigenesis, albeit in a context dependent manner. A mechanistic basis for the tumor promoting actions of progesterone has thus far remained unknown. Recent studies, however, have identified a novel role for progesterone in controlling the number and function of stem and progenitor cell populations in the normal human and mouse mammary glands, and in human breast cancers. These discoveries promise to reshape our perception of progesterone function in the mammary gland, and have spawned new hypotheses for how progestins may increase the risk of breast cancer. Here we review studies on progesterone regulation of mammary stem cells in normal and malignant tissue, and their implications for breast cancer risk, tumorigenesis, and tumor behavior. PMID:21945473

Structural insights into the molecular mechanisms of myasthenia gravis and their therapeutic implications

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

Noridomi, Kaori; Watanabe, Go; Hansen, Melissa N.

The nicotinic acetylcholine receptor (nAChR) is a major target of autoantibodies in myasthenia gravis (MG), an autoimmune disease that causes neuromuscular transmission dysfunction. Despite decades of research, the molecular mechanisms underlying MG have not been fully elucidated. Here, we present the crystal structure of the nAChR α1 subunit bound by the Fab fragment of mAb35, a reference monoclonal antibody that causes experimental MG and competes with ~65% of antibodies from MG patients. Our structures reveal for the first time the detailed molecular interactions between MG antibodies and a core region on nAChR α1. These structures suggest a major nAChR-binding mechanismmore » shared by a large number of MG antibodies and the possibility to treat MG by blocking this binding mechanism. Structure-based modeling also provides insights into antibody-mediated nAChR cross-linking known to cause receptor degradation. Our studies establish a structural basis for further mechanistic studies and therapeutic development of MG.« less

Tissue-selective restriction of RNA editing of CaV1.3 by splicing factor SRSF9.

PubMed

Huang, Hua; Kapeli, Katannya; Jin, Wenhao; Wong, Yuk Peng; Arumugam, Thiruma Valavan; Koh, Joanne Huifen; Srimasorn, Sumitra; Mallilankaraman, Karthik; Chua, John Jia En; Yeo, Gene W; Soong, Tuck Wah

2018-05-04

Adenosine DeAminases acting on RNA (ADAR) catalyzes adenosine-to-inosine (A-to-I) conversion within RNA duplex structures. While A-to-I editing is often dynamically regulated in a spatial-temporal manner, the mechanisms underlying its tissue-selective restriction remain elusive. We have previously reported that transcripts of voltage-gated calcium channel CaV1.3 are subject to brain-selective A-to-I RNA editing by ADAR2. Here, we show that editing of CaV1.3 mRNA is dependent on a 40 bp RNA duplex formed between exon 41 and an evolutionarily conserved editing site complementary sequence (ECS) located within the preceding intron. Heterologous expression of a mouse minigene that contained the ECS, intermediate intronic sequence and exon 41 with ADAR2 yielded robust editing. Interestingly, editing of CaV1.3 was potently inhibited by serine/arginine-rich splicing factor 9 (SRSF9). Mechanistically, the inhibitory effect of SRSF9 required direct RNA interaction. Selective down-regulation of SRSF9 in neurons provides a basis for the neuron-specific editing of CaV1.3 transcripts.

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.

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

NASA Astrophysics Data System (ADS)

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

2016-04-01

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

Thermosensitivity of growth is determined by chaperone-mediated proteome reallocation

PubMed Central

Chen, Ke; Gao, Ye; Mih, Nathan; O’Brien, Edward J.; Yang, Laurence; Palsson, Bernhard O.

2017-01-01

Maintenance of a properly folded proteome is critical for bacterial survival at notably different growth temperatures. Understanding the molecular basis of thermoadaptation has progressed in two main directions, the sequence and structural basis of protein thermostability and the mechanistic principles of protein quality control assisted by chaperones. Yet we do not fully understand how structural integrity of the entire proteome is maintained under stress and how it affects cellular fitness. To address this challenge, we reconstruct a genome-scale protein-folding network for Escherichia coli and formulate a computational model, FoldME, that provides statistical descriptions of multiscale cellular response consistent with many datasets. FoldME simulations show (i) that the chaperones act as a system when they respond to unfolding stress rather than achieving efficient folding of any single component of the proteome, (ii) how the proteome is globally balanced between chaperones for folding and the complex machinery synthesizing the proteins in response to perturbation, (iii) how this balancing determines growth rate dependence on temperature and is achieved through nonspecific regulation, and (iv) how thermal instability of the individual protein affects the overall functional state of the proteome. Overall, these results expand our view of cellular regulation, from targeted specific control mechanisms to global regulation through a web of nonspecific competing interactions that modulate the optimal reallocation of cellular resources. The methodology developed in this study enables genome-scale integration of environment-dependent protein properties and a proteome-wide study of cellular stress responses. PMID:29073085

Diet discrimination factors are inversely related to δ15 N and δ13C values of food for fish under controlled conditions.

PubMed

Dennis, Caroline A; Macneil, M Aaron; Rosati, Jennifer Y; Pitcher, Trevor E; Fisk, Aaron T

2010-12-30

A recent literature review reported negative relationships between diet discrimination factors (DDFs = X(fish) - X(food) ; X = δ(15) N or δ(13) C) and the values of δ(15) N and δ(13) C in the food of wild organisms but there has been no laboratory-based confirmation of these relationships to date. Laboratory reared guppies (Poecilia reticulata) fed a series of diets with a range of δ(13) C (-22.9 to -6.6‰) and δ(15) N (6.5 to 1586‰) values were used to magnify diet-tissue dynamics in order to calculate DDFs once the fish had achieved equilibrium with each of the diets. Values of DDFs range widely for δ(15) N (7.1 to -849‰) and δ(13) C (1.1 to -7.0‰) and showed a strong negative correlation with the stable isotope value in the food for δ(15) N (slope = -0.59 ± 0.02, r(2)  = 0.95) and δ(13) C (slope = -0.56 ± 0.02, r(2)  = 0.94). Based on these relationships, the magnitude of DDF change over environmentally relevant values of δ(15) N or δ(13) C would be significant and could confound the interpretation of stable isotopes in the environment. Using highly enriched experimental diets, our study adds to a growing number of studies that undermine the consistent trophic enrichment paradigm with results that demonstrate the currently poor mechanistic understanding of how DDFs arise. The results of our study highlight that the magnitude of the stable isotope values in prey must be considered when choosing DDF values. Future laboratory studies should therefore be directed at uncovering the mechanistic basis of DDFs and, like others before, we recommend the determination of diet-dependent DDFs under laboratory conditions before modeling dietary proportions or calculating trophic positions. Copyright © 2010 John Wiley & Sons, Ltd.

Data-driven development of AOP knowledge

EPA Science Inventory

The Adverse Outcome Pathway framework represents a systematic way to organize mechanistic information underlying toxicology, and it is specifically designed to connect early stage molecular perturbations by chemicals and other stressors with adverse outcomes in humans and wildlif...

Solvent-free synthesis

EPA Science Inventory

This chapter gives a brief introduction about solvent-free reactions whose importance can be gauged by the increasing number of publications every year during the last decade. The mechanistic aspects of the reactions under solvent-free conditions have been highlighted. Our observ...

Cu-catalyzed esterification reaction via aerobic oxygenation and C-C bond cleavage: an approach to α-ketoesters.

PubMed

Zhang, Chun; Feng, Peng; Jiao, Ning

2013-10-09

The Cu-catalyzed novel aerobic oxidative esterification reaction of 1,3-diones for the synthesis of α-ketoesters has been developed. This method combines C-C σ-bond cleavage, dioxygen activation and oxidative C-H bond functionalization, as well as provides a practical, neutral, and mild synthetic approach to α-ketoesters which are important units in many biologically active compounds and useful precursors in a variety of functional group transformations. A plausible radical process is proposed on the basis of mechanistic studies.

Mechanistic Basis Of Calmodulin Mediated Estrogen Receptor Alpha Activation and Antiestrogen Resistance

DTIC Science & Technology

2010-06-01

for solubility (Figure 5). We call this protein Trx -ERA241-320. We also produced a similar protein construct, but with only residues 241-273 of...ERa, as a “control” (Figure 5). We call this protein Trx -ERA241-273. Because CaM binds tightly to the N-terminal extended ligand binding domain of...ERa (residues 286- 552, see above), we hypothesized that Trx - ERA241-320 would bind tightly to CaM, but that Trx -ERA241-273 would not. The genetic

Neurological Disease in Lupus: Toward a Personalized Medicine Approach.

PubMed

McGlasson, Sarah; Wiseman, Stewart; Wardlaw, Joanna; Dhaun, Neeraj; Hunt, David P J

2018-01-01

The brain and nervous system are important targets for immune-mediated damage in systemic lupus erythematosus (SLE), resulting in a complex spectrum of neurological syndromes. Defining nervous system disease in lupus poses significant challenges. Among the difficulties to be addressed are a diversity of clinical manifestations and a lack of understanding of their mechanistic basis. However, despite these challenges, progress has been made in the identification of pathways which contribute to neurological disease in SLE. Understanding the molecular pathogenesis of neurological disease in lupus will inform both classification and approaches to clinical trials.

From the seat of heat and intelligence to regular heart activity as automatic movement: progress in cardiology up to 1900 from a Dutch perspective.

PubMed

van Tellingen, C

2009-04-01

The development in cardiovascular anatomy and physiology is described from a Dutch perspective. The newly formed Republic in the 17th century, with its pragmatism and business-like character, became an ideal breeding ground for Descartes' new philosophy. His separation of body and soul provided a mechanistic model of body structure and formed a firm basis for anatomical and physiological research to become catalysts for a tempestuous growth and progress in medicine. (Neth Heart J 2009;17:130-5.).

Transcription as a Threat to Genome Integrity.

PubMed

Gaillard, Hélène; Aguilera, Andrés

2016-06-02

Genomes undergo different types of sporadic alterations, including DNA damage, point mutations, and genome rearrangements, that constitute the basis for evolution. However, these changes may occur at high levels as a result of cell pathology and trigger genome instability, a hallmark of cancer and a number of genetic diseases. In the last two decades, evidence has accumulated that transcription constitutes an important natural source of DNA metabolic errors that can compromise the integrity of the genome. Transcription can create the conditions for high levels of mutations and recombination by its ability to open the DNA structure and remodel chromatin, making it more accessible to DNA insulting agents, and by its ability to become a barrier to DNA replication. Here we review the molecular basis of such events from a mechanistic perspective with particular emphasis on the role of transcription as a genome instability determinant.

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.

Mechanistic modeling of reactive soil nitrogen emissions across agricultural management practices

NASA Astrophysics Data System (ADS)

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

2017-12-01

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

Mechanistic Analysis of the C-H Amination Reaction of Menthol by CuBr2 and Selectfluor.

PubMed

Sathyamoorthi, Shyam; Lai, Yin-Hung; Bain, Ryan M; Zare, Richard N

2018-05-18

The mechanism of the Ritter-type C-H amination reaction of menthol with acetonitrile using CuBr 2 , Selectfluor, and Zn(OTf) 2 , first disclosed by Baran and coworkers in 2012, was studied using a combination of online electrospray ionization mass spectrometry, continuous UV/vis spectrometric monitoring, and density functional theory calculations. In addition to corroborating Baran's original mechanistic proposal, these studies uncovered a second pathway to product formation, which likely only occurs in microdroplets. DFT calculations show that neither pathway has a barrier that is greater than 6.8 kcal/mol, suggesting that both mechanisms are potentially operative under ambient conditions.

Reductive half-reaction of aldehyde oxidoreductase toward acetaldehyde: Ab initio and free energy quantum mechanical/molecular mechanical calculations.

PubMed

Dieterich, Johannes M; Werner, Hans-Joachim; Mata, Ricardo A; Metz, Sebastian; Thiel, Walter

2010-01-21

Energy and free energy barriers for acetaldehyde conversion in aldehyde oxidoreductase are determined for three reaction pathways using quantum mechanical/molecular mechanical (QM/MM) calculations on the solvated enzyme. Ab initio single-point QM/MM energies are obtained at the stationary points optimized at the DFT(B3LYP)/MM level. These ab initio calculations employ local correlation treatments [LMP2 and LCCSD(T0)] in combination with augmented triple- and quadruple-zeta basis sets, and the final coupled cluster results include MP2-based corrections for basis set incompleteness and for the domain approximation. Free energy perturbation (FEP) theory is used to generate free energy profiles at the DFT(B3LYP)/MM level for the most important reaction steps by sampling along the corresponding reaction paths using molecular dynamics. The ab initio and FEP QM/MM results are combined to derive improved estimates of the free energy barriers, which differ from the corresponding DFT(B3LYP)/MM energy barriers by about 3 kcal mol(-1). The present results confirm the qualitative mechanistic conclusions from a previous DFT(B3LYP)/MM study. Most favorable is a three-step Lewis base catalyzed mechanism with an initial proton transfer from the cofactor to the Glu869 residue, a subsequent nucleophilic attack that yields a tetrahedral intermediate (IM2), and a final rate-limiting hydride transfer. The competing metal center activated pathway has the same final step but needs to overcome a higher barrier in the initial step on the route to IM2. The concerted mechanism has the highest free energy barrier and can be ruled out. While confirming the qualitative mechanistic scenario proposed previously on the basis of DFT(B3LYP)/MM energy profiles, the present ab initio and FEP QM/MM calculations provide corrections to the barriers that are important when aiming at high accuracy.

Structural Basis of Response Regulator Dephosphorylation by Rap Phosphatases

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

V Parashar; N Mirouze; D Dubnau

2011-12-31

Bacterial Rap family proteins have been most extensively studied in Bacillus subtilis, where they regulate activities including sporulation, genetic competence, antibiotic expression, and the movement of the ICEBs1 transposon. One subset of Rap proteins consists of phosphatases that control B. subtilis and B. anthracis sporulation by dephosphorylating the response regulator Spo0F. The mechanistic basis of Rap phosphatase activity was unknown. Here we present the RapH-Spo0F X-ray crystal structure, which shows that Rap proteins consist of a 3-helix bundle and a tetratricopeptide repeat domain. Extensive biochemical and genetic functional studies reveal the importance of the observed RapH-Spo0F interactions, including the catalyticmore » role of a glutamine in the RapH 3-helix bundle that inserts into the Spo0F active site. We show that in addition to dephosphorylating Spo0F, RapH can antagonize sporulation by sterically blocking phosphoryl transfer to and from Spo0F. Our structure-function analysis of the RapH-Spo0F interaction identified Rap protein residues critical for Spo0F phosphatase activity. This information enabled us to assign Spo0F phosphatase activity to a Rap protein based on sequence alone, which was not previously possible. Finally, as the ultimate test of our newfound understanding of the structural requirements for Rap phosphatase function, a non-phosphatase Rap protein that inhibits the binding of the response regulator ComA to DNA was rationally engineered to dephosphorylate Spo0F. In addition to revealing the mechanistic basis of response regulator dephosphorylation by Rap proteins, our studies support the previously proposed T-loop-Y allostery model of receiver domain regulation that restricts the aromatic 'switch' residue to an internal position when the {beta}4-{alpha}4 loop adopts an active-site proximal conformation.« less

Study the Cyclic Plasticity Behavior of 508 LAS under Constant, Variable and Grid-Load-Following Loading Cycles for Fatigue Evaluation of PWR Components

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

Mohanty, Subhasish; Barua, Bipul; Soppet, William K.

This report provides an update of an earlier assessment of environmentally assisted fatigue for components in light water reactors. This report is a deliverable in September 2016 under the work package for environmentally assisted fatigue under DOE’s Light Water Reactor Sustainability program. In an April 2016 report, we presented a detailed thermal-mechanical stress analysis model for simulating the stress-strain state of a reactor pressure vessel and its nozzles under grid-load-following conditions. In this report, we provide stress-controlled fatigue test data for 508 LAS base metal alloy under different loading amplitudes (constant, variable, and random grid-load-following) and environmental conditions (in airmore » or pressurized water reactor coolant water at 300°C). Also presented is a cyclic plasticity-based analytical model that can simultaneously capture the amplitude and time dependency of the component behavior under fatigue loading. Results related to both amplitude-dependent and amplitude-independent parameters are presented. The validation results for the analytical/mechanistic model are discussed. This report provides guidance for estimating time-dependent, amplitude-independent parameters related to material behavior under different service conditions. The developed mechanistic models and the reported material parameters can be used to conduct more accurate fatigue and ratcheting evaluation of reactor components.« less

Fluid mechanics of Windkessel effect.

PubMed

Mei, C C; Zhang, J; Jing, H X

2018-01-08

We describe a mechanistic model of Windkessel phenomenon based on the linear dynamics of fluid-structure interactions. The phenomenon has its origin in an old-fashioned fire-fighting equipment where an air chamber serves to transform the intermittent influx from a pump to a more steady stream out of the hose. A similar mechanism exists in the cardiovascular system where blood injected intermittantly from the heart becomes rather smooth after passing through an elastic aorta. In existing haeodynamics literature, this mechanism is explained on the basis of electric circuit analogy with empirical impedances. We present a mechanistic theory based on the principles of fluid/structure interactions. Using a simple one-dimensional model, wave motion in the elastic aorta is coupled to the viscous flow in the rigid peripheral artery. Explicit formulas are derived that exhibit the role of material properties such as the blood density, viscosity, wall elasticity, and radii and lengths of the vessels. The current two-element model in haemodynamics is shown to be the limit of short aorta and low injection frequency and the impedance coefficients are derived theoretically. Numerical results for different aorta lengths and radii are discussed to demonstrate their effects on the time variations of blood pressure, wall shear stress, and discharge. Graphical Abstract A mechanistic analysis of Windkessel Effect is described which confirms theoretically the well-known feature that intermittent influx becomes continuous outflow. The theory depends only on the density and viscosity of the blood, the elasticity and dimensions of the vessel. Empirical impedence parameters are avoided.

Clinical Activity of mTOR Inhibition With Sirolimus in Malignant Perivascular Epithelioid Cell Tumors: Targeting the Pathogenic Activation of mTORC1 in Tumors

PubMed Central

Wagner, Andrew J.; Malinowska-Kolodziej, Izabela; Morgan, Jeffrey A.; Qin, Wei; Fletcher, Christopher D.M.; Vena, Natalie; Ligon, Azra H.; Antonescu, Cristina R.; Ramaiya, Nikhil H.; Demetri, George D.; Kwiatkowski, David J.; Maki, Robert G.

2010-01-01

Purpose Perivascular epithelioid cell tumors (PEComas) represent a family of mesenchymal neoplasms, mechanistically linked through activation of the mTOR signaling pathway. There is no known effective therapy for PEComa, and the molecular pathophysiology of aberrant mTOR signaling provided us with a scientific rationale to target this pathway therapeutically. On this mechanistic basis, we treated three consecutive patients with metastatic PEComa with an oral mTOR inhibitor, sirolimus. Patients and Methods Patients with advanced PEComa were treated with sirolimus and consented to retrospective collection of data from their medical records and analysis of archival tumor specimens. Tumor response was determined by computed tomography scans obtained at the clinical discretion of the treating physicians. Tumors were assessed for immunohistochemical evidence of mTORC1 activation and genetic evidence of alterations in TSC1 and TSC2. Results Radiographic responses to sirolimus were observed in all patients. PEComas demonstrated loss of TSC2 protein expression and evidence of baseline mTORC1 activation. Homozygous loss of TSC1 was identified in one PEComa. Conclusion Inhibition of mTORC1, pathologically activated by loss of the TSC1/TSC2 tumor suppressor complex, is a rational mechanistic target for therapy in PEComas. The clinical activity of sirolimus in PEComa additionally strengthens the pathobiologic similarities linking PEComas to other neoplasms related to the tuberous sclerosis complex. PMID:20048174

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

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

PubMed Central

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

2017-01-01

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

Pattern formation in mass conserving reaction-diffusion systems

NASA Astrophysics Data System (ADS)

Brauns, Fridtjof; Halatek, Jacob; Frey, Erwin

We present a rigorous theoretical framework able to generalize and unify pattern formation for quantitative mass conserving reaction-diffusion models. Mass redistribution controls chemical equilibria locally. Separation of diffusive mass redistribution on the level of conserved species provides a general mathematical procedure to decompose complex reaction-diffusion systems into effectively independent functional units, and to reveal the general underlying bifurcation scenarios. We apply this framework to Min protein pattern formation and identify the mechanistic roles of both involved protein species. MinD generates polarity through phase separation, whereas MinE takes the role of a control variable regulating the existence of MinD phases. Hence, polarization and not oscillations is the generic core dynamics of Min proteins in vivo. This establishes an intrinsic mechanistic link between the Min system and a broad class of intracellular pattern forming systems based on bistability and phase separation (wave-pinning). Oscillations are facilitated by MinE redistribution and can be understood mechanistically as relaxation oscillations of the polarization direction.

Idaho AASHTOWare pavement ME design user's guide, version 1.1.

DOT National Transportation Integrated Search

2014-03-01

The AASHTOWare Pavement ME Design procedure is based on mechanistic-empirical (M-E) design concepts. This means that the design procedure calculates pavement responses such as stresses, strains, and deflections under axle loads and climatic condition...

General and mechanistic optimal relationships for tensile strength of doubly convex tablets under diametrical compression.

PubMed

Razavi, Sonia M; Gonzalez, Marcial; Cuitiño, Alberto M

2015-04-30

We propose a general framework for determining optimal relationships for tensile strength of doubly convex tablets under diametrical compression. This approach is based on the observation that tensile strength is directly proportional to the breaking force and inversely proportional to a non-linear function of geometric parameters and materials properties. This generalization reduces to the analytical expression commonly used for flat faced tablets, i.e., Hertz solution, and to the empirical relationship currently used in the pharmaceutical industry for convex-faced tablets, i.e., Pitt's equation. Under proper parametrization, optimal tensile strength relationship can be determined from experimental results by minimizing a figure of merit of choice. This optimization is performed under the first-order approximation that a flat faced tablet and a doubly curved tablet have the same tensile strength if they have the same relative density and are made of the same powder, under equivalent manufacturing conditions. Furthermore, we provide a set of recommendations and best practices for assessing the performance of optimal tensile strength relationships in general. Based on these guidelines, we identify two new models, namely the general and mechanistic models, which are effective and predictive alternatives to the tensile strength relationship currently used in the pharmaceutical industry. Copyright © 2015 Elsevier B.V. All rights reserved.

No Photon Wasted: An Efficient and Selective Singlet Oxygen Photosensitizing Protein.

PubMed

Westberg, Michael; Bregnhøj, Mikkel; Etzerodt, Michael; Ogilby, Peter R

2017-10-12

Optogenetics has been, and will continue to be, a boon to mechanistic studies of cellular processes. Genetically encodable proteins that sensitize the production of reactive oxygen species (ROS) are expected to play an increasingly important role, particularly in elucidating mechanisms of temporally and spatially dependent cell signaling. However, a substantial challenge in developing such photosensitizing proteins has been to funnel the optical excitation energy into the initial selective production of only one ROS. Singlet molecular oxygen, O 2 (a 1 Δ g ), is a ROS known to have a wide range of effects on cell function. Nevertheless, mechanistic details of singlet oxygen's behavior in a cell are lacking. On the basis of the rational optimization of a LOV-derived flavoprotein, we now report the development and photophysical characterization of a protein-encased photosensitizer that efficiently and selectively produces singlet oxygen at the expense of other ROS, especially ROS that derive from photoinduced electron transfer reactions. These results set the stage for a plethora of new experiments to elucidate ROS-mediated events in cells.

Pain as metaphor: metaphor and medicine

PubMed Central

Neilson, Shane

2016-01-01

Like many other disciplines, medicine often resorts to metaphor in order to explain complicated concepts that are imperfectly understood. But what happens when medicine's metaphors close off thinking, restricting interpretations and opinions to those of the negative kind? This paper considers the deleterious effects of destructive metaphors that cluster around pain. First, the metaphoric basis of all knowledge is introduced. Next, a particular subset of medical metaphors in the domain of neurology (doors/keys/wires) are shown to encourage mechanistic thinking. Because schematics are often used in medical textbooks to simplify the complex, this paper traces the visual metaphors implied in such schematics. Mechanistic-metaphorical thinking results in the accumulation of vast amounts of data through experimentation, but this paper asks what the real value of the information is since patients can generally only expect modest benefits – or none at all – for relief from chronic pain conditions. Elucidation of mechanism through careful experimentation creates an illusion of vast medical knowledge that, to a significant degree, is metaphor-based. This paper argues that for pain outcomes to change, our metaphors must change first. PMID:26253331

Selective autophagy mediated by autophagic adapter proteins

PubMed Central

Lamark, Trond

2011-01-01

Mounting evidence suggests that autophagy is a more selective process than originally anticipated. The discovery and characterization of autophagic adapters, like p62 and NBR1, has provided mechanistic insight into this process. p62 and NBR1 are both selectively degraded by autophagy and able to act as cargo receptors for degradation of ubiquitinated substrates. A direct interaction between these autophagic adapters and the autophagosomal marker protein LC3, mediated by a so-called LIR (LC3-interacting region) motif, their inherent ability to polymerize or aggregate as well as their ability to specifically recognize substrates are required for efficient selective autophagy. These three required features of autophagic cargo receptors are evolutionarily conserved and also employed in the yeast cytoplasm-to-vacuole targeting (Cvt) pathway and in the degradation of P granules in C. elegans. Here, we review the mechanistic basis of selective autophagy in mammalian cells discussing the degradation of misfolded proteins, p62 bodies, aggresomes, mitochondria and invading bacteria. The emerging picture of selective autophagy affecting the regulation of cell signaling with consequences for oxidative stress responses, tumorigenesis and innate immunity is also addressed. PMID:21189453

Quantitative system drift compensates for altered maternal inputs to the gap gene network of the scuttle fly Megaselia abdita

PubMed Central

Wotton, Karl R; Jiménez-Guri, Eva; Crombach, Anton; Janssens, Hilde; Alcaine-Colet, Anna; Lemke, Steffen; Schmidt-Ott, Urs; Jaeger, Johannes

2015-01-01

The segmentation gene network in insects can produce equivalent phenotypic outputs despite differences in upstream regulatory inputs between species. We investigate the mechanistic basis of this phenomenon through a systems-level analysis of the gap gene network in the scuttle fly Megaselia abdita (Phoridae). It combines quantification of gene expression at high spatio-temporal resolution with systematic knock-downs by RNA interference (RNAi). Initiation and dynamics of gap gene expression differ markedly between M. abdita and Drosophila melanogaster, while the output of the system converges to equivalent patterns at the end of the blastoderm stage. Although the qualitative structure of the gap gene network is conserved, there are differences in the strength of regulatory interactions between species. We term such network rewiring ‘quantitative system drift’. It provides a mechanistic explanation for the developmental hourglass model in the dipteran lineage. Quantitative system drift is likely to be a widespread mechanism for developmental evolution. DOI: http://dx.doi.org/10.7554/eLife.04785.001 PMID:25560971

EPHRIN-B1 Mosaicism Drives Cell Segregation in Craniofrontonasal Syndrome hiPSC-Derived Neuroepithelial Cells.

PubMed

Niethamer, Terren K; Larson, Andrew R; O'Neill, Audrey K; Bershteyn, Marina; Hsiao, Edward C; Klein, Ophir D; Pomerantz, Jason H; Bush, Jeffrey O

2017-03-14

Although human induced pluripotent stem cells (hiPSCs) hold great potential for the study of human diseases affecting disparate cell types, they have been underutilized in seeking mechanistic insights into the pathogenesis of congenital craniofacial disorders. Craniofrontonasal syndrome (CFNS) is a rare X-linked disorder caused by mutations in EFNB1 and characterized by craniofacial, skeletal, and neurological anomalies. Heterozygous females are more severely affected than hemizygous males, a phenomenon termed cellular interference that involves mosaicism for EPHRIN-B1 function. Although the mechanistic basis for cellular interference in CFNS has been hypothesized to involve Eph/ephrin-mediated cell segregation, no direct evidence for this has been demonstrated. Here, by generating hiPSCs from CFNS patients, we demonstrate that mosaicism for EPHRIN-B1 expression induced by random X inactivation in heterozygous females results in robust cell segregation in human neuroepithelial cells, thus supplying experimental evidence that Eph/ephrin-mediated cell segregation is relevant to pathogenesis in human CFNS patients. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Structural, mutagenic and in silico studies of xyloglucan fucosylation in Arabidopsis thaliana suggest a water-mediated mechanism

DOE PAGES

Urbanowicz, Breeanna R.; Bharadwaj, Vivek S.; Alahuhta, Markus; ...

2017-07-03

The mechanistic underpinnings of the complex process of plant polysaccharide biosynthesis are poorly understood, largely due to the resistance of glycosyltransferase (GT) enzymes to structural characterization. In Arabidopsis thaliana, a glycosyl transferase family 37 (GT37) fucosyltransferase-1 (AtFUT1) catalyzes the regiospecific transfer of terminal 1,2-fucosyl residues to xyloglucan side chains - a key step in the biosynthesis of fucosylated sidechains of galactoxyloglucan. We unravel the mechanistic basis for fucosylation by AtFUT1 with a multipronged approach involving protein expression, X-ray crystallography, mutagenesis experiments and molecular simulations. Mammalian cell culture expressions enable sufficient production of the enzyme for X-ray crystallography, which reveals themore » structural architecture of AtFUT1 in complex with bound donor and acceptor substrate analogs. Here, the lack of an appropriately positioned active site residue as a catalytic base leads us to propose an atypical water-mediated fucosylation mechanism facilitated by an H-bonded network, which is corroborated by mutagenesis experiments as well as detailed atomistic simulations.« less

Leptin Downregulates Aggrecan through the p38-ADAMST Pathway in Human Nucleus Pulposus Cells

PubMed Central

Liang, Jinqian; Wu, William Ka Kei; Yu, Jun; Shen, Jianxiong

2014-01-01

The mechanistic basis of obesity-associated intervertebral disc degeneration (IDD) is unclear. Aberrant expression of aggrecan and its degrading enzymes ADAMTS-4 and ADAMTS-5 is implicated in the development of IDD. Here, we investigated the effect of leptin, a hormone with increased circulating levels in obesity, on the expression of aggrecan and ADAMTSs in primary human nucleus pulposus (NP) cells. Real-time PCR and Western blots showed that leptin increased the mRNA and protein expression of ADAMTS-4 and ADAMTS-5 and reduced the level of aggrecan in NP cells, accompanied by a prominent induction of p38 phosphorylation. Treatment of NP cells with SB203580 (a p38 inhibitor) abolished the regulation of aggrecan and ADAMTSs by leptin. Knockdown of ADAMTS-4 and ADAMTS-5 by siRNAs also attenuated the degradation of aggrecan in leptin-stimulated NP cells. To conclude, we demonstrated that leptin induces p38 to upregulate ADAMTSs and thereby promoting aggrecan degradation in human NP cells. These results provide a novel mechanistic insight into the molecular pathogenesis of obesity-associated IDD. PMID:25299465

Leptin downregulates aggrecan through the p38-ADAMST pathway in human nucleus pulposus cells.

PubMed

Li, Zheng; Yu, Xin; Liang, Jinqian; Wu, William Ka Kei; Yu, Jun; Shen, Jianxiong

2014-01-01

The mechanistic basis of obesity-associated intervertebral disc degeneration (IDD) is unclear. Aberrant expression of aggrecan and its degrading enzymes ADAMTS-4 and ADAMTS-5 is implicated in the development of IDD. Here, we investigated the effect of leptin, a hormone with increased circulating levels in obesity, on the expression of aggrecan and ADAMTSs in primary human nucleus pulposus (NP) cells. Real-time PCR and Western blots showed that leptin increased the mRNA and protein expression of ADAMTS-4 and ADAMTS-5 and reduced the level of aggrecan in NP cells, accompanied by a prominent induction of p38 phosphorylation. Treatment of NP cells with SB203580 (a p38 inhibitor) abolished the regulation of aggrecan and ADAMTSs by leptin. Knockdown of ADAMTS-4 and ADAMTS-5 by siRNAs also attenuated the degradation of aggrecan in leptin-stimulated NP cells. To conclude, we demonstrated that leptin induces p38 to upregulate ADAMTSs and thereby promoting aggrecan degradation in human NP cells. These results provide a novel mechanistic insight into the molecular pathogenesis of obesity-associated IDD.

Matrix isolation as a tool for studying interstellar chemical reactions

NASA Technical Reports Server (NTRS)

Ball, David W.; Ortman, Bryan J.; Hauge, Robert H.; Margrave, John L.

1989-01-01

Since the identification of the OH radical as an interstellar species, over 50 molecular species were identified as interstellar denizens. While identification of new species appears straightforward, an explanation for their mechanisms of formation is not. Most astronomers concede that large bodies like interstellar dust grains are necessary for adsorption of molecules and their energies of reactions, but many of the mechanistic steps are unknown and speculative. It is proposed that data from matrix isolation experiments involving the reactions of refractory materials (especially C, Si, and Fe atoms and clusters) with small molecules (mainly H2, H2O, CO, CO2) are particularly applicable to explaining mechanistic details of likely interstellar chemical reactions. In many cases, matrix isolation techniques are the sole method of studying such reactions; also in many cases, complexations and bond rearrangements yield molecules never before observed. The study of these reactions thus provides a logical basis for the mechanisms of interstellar reactions. A list of reactions is presented that would simulate interstellar chemical reactions. These reactions were studied using FTIR-matrix isolation techniques.

Mechanistic solutions to the opening of the Gulf of Mexico

USGS Publications Warehouse

Schouten, Hans; Klitgord, Kim D.

1994-01-01

Two mechanistic models-which are unlike the traditional plate-tectonic landfill models used for most proposed Pangea reconstructions of the Yucatán block-relate the Mesozoic opening of the Gulf of Mexico directly to the movement of the North and South American plates: (1) a previous piggyback model in which Yucatán moves with South America out of the western gulf and (2) a new edge-driven model in which the motion of the Yucatán block is caused by forces applied to its margins by the movement of the North and South American plates. In the second model, Yucatán moves out of the northern Gulf of Mexico as a gear or roller bearing. On the basis of magnetic edge anomalies around the gulf, this edge-driven model predicts that from the Bathonian to Tithonian (~170 to ~50 Ma), Yucatán was rotated ~60° counterclockwise as a rigid block between North and South America with rift propagation and extension occurring simultaneously in the Gulf of Mexico and Yucatán Basin.

Structural, mutagenic and in silico studies of xyloglucan fucosylation in Arabidopsis thaliana suggest a water-mediated mechanism

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

Urbanowicz, Breeanna R.; Bharadwaj, Vivek S.; Alahuhta, Markus

The mechanistic underpinnings of the complex process of plant polysaccharide biosynthesis are poorly understood, largely due to the resistance of glycosyltransferase (GT) enzymes to structural characterization. In Arabidopsis thaliana, a glycosyl transferase family 37 (GT37) fucosyltransferase-1 (AtFUT1) catalyzes the regiospecific transfer of terminal 1,2-fucosyl residues to xyloglucan side chains - a key step in the biosynthesis of fucosylated sidechains of galactoxyloglucan. We unravel the mechanistic basis for fucosylation by AtFUT1 with a multipronged approach involving protein expression, X-ray crystallography, mutagenesis experiments and molecular simulations. Mammalian cell culture expressions enable sufficient production of the enzyme for X-ray crystallography, which reveals themore » structural architecture of AtFUT1 in complex with bound donor and acceptor substrate analogs. Here, the lack of an appropriately positioned active site residue as a catalytic base leads us to propose an atypical water-mediated fucosylation mechanism facilitated by an H-bonded network, which is corroborated by mutagenesis experiments as well as detailed atomistic simulations.« less

Occupational exposure to chrysotile asbestos and cancer risk: a review of the amphibole hypothesis.

PubMed Central

Stayner, L T; Dankovic, D A; Lemen, R A

1996-01-01

OBJECTIVES. This article examines the credibility and policy implications of the "amphibole hypothesis," which postulates that (1) the mesotheliomas observed among workers exposed to chrysotile asbestos may be explained by confounding exposures to amphiboles, and (2) chrysotile may have lower carcinogenic potency than amphiboles. METHODS. A critical review was conducted of the lung burden, epidemiologic, toxicologic, and mechanistic studies that provide the basis for the amphibole hypothesis. RESULTS. Mechanistic and lung burden studies do not provide convincing evidence for the amphibole hypothesis. Toxicologic and epidemiologic studies provide strong evidence that chrysotile is associated with an increased risk of lung cancer and mesothelioma. Chrysotile may be less potent than some amphiboles for inducing mesotheliomas, but there is little evidence to indicate lower lung cancer risk. CONCLUSIONS. Given the evidence of a significant lung cancer risk, the lack of conclusive evidence for the amphibole hypothesis, and the fact that workers are generally exposed to a mixture of fibers, we conclude that it is prudent to treat chrysotile with virtually the same level of concern as the amphibole forms of asbestos. PMID:8633733

Evolving Mechanistic Views and Emerging Therapeutic Strategies for Cystic Fibrosis–Related Diabetes

PubMed Central

2017-01-01

Diabetes is a common and important complication of cystic fibrosis, an autosomal recessive genetic disease due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Cystic fibrosis–related diabetes (CFRD) is associated with profound detrimental effects on the disease course and mortality and is expected to increase in prevalence as the survival of patients with cystic fibrosis continues to improve. Despite progress in the functional characterization of CFTR molecular defects, the mechanistic basis of CFRD is not well understood, in part because of the relative inaccessibility of the pancreatic tissue and the limited availability of representative animal models. This review presents a concise overview of the current understanding of CFRD pathogenesis and provides a cutting-edge update on novel findings from human and animal studies. Potential contributions from paracrine mechanisms and β-cell compensatory mechanisms are highlighted, as well as functional β-cell and α-cell defects, incretin defects, exocrine pancreatic insufficiency, and loss of islet cell mass. State-of-the-art and emerging treatment options are explored, including advances in insulin administration, CFTR modulators, cell replacement, gene replacement, and gene editing therapies. PMID:29264462

Learning to predict chemical reactions.

PubMed

Kayala, Matthew A; Azencott, Chloé-Agathe; Chen, Jonathan H; Baldi, Pierre

2011-09-26

Being able to predict the course of arbitrary chemical reactions is essential to the theory and applications of organic chemistry. Approaches to the reaction prediction problems can be organized around three poles corresponding to: (1) physical laws; (2) rule-based expert systems; and (3) inductive machine learning. Previous approaches at these poles, respectively, are not high throughput, are not generalizable or scalable, and lack sufficient data and structure to be implemented. We propose a new approach to reaction prediction utilizing elements from each pole. Using a physically inspired conceptualization, we describe single mechanistic reactions as interactions between coarse approximations of molecular orbitals (MOs) and use topological and physicochemical attributes as descriptors. Using an existing rule-based system (Reaction Explorer), we derive a restricted chemistry data set consisting of 1630 full multistep reactions with 2358 distinct starting materials and intermediates, associated with 2989 productive mechanistic steps and 6.14 million unproductive mechanistic steps. And from machine learning, we pose identifying productive mechanistic steps as a statistical ranking, information retrieval problem: given a set of reactants and a description of conditions, learn a ranking model over potential filled-to-unfilled MO interactions such that the top-ranked mechanistic steps yield the major products. The machine learning implementation follows a two-stage approach, in which we first train atom level reactivity filters to prune 94.00% of nonproductive reactions with a 0.01% error rate. Then, we train an ensemble of ranking models on pairs of interacting MOs to learn a relative productivity function over mechanistic steps in a given system. Without the use of explicit transformation patterns, the ensemble perfectly ranks the productive mechanism at the top 89.05% of the time, rising to 99.86% of the time when the top four are considered. Furthermore, the system is generalizable, making reasonable predictions over reactants and conditions which the rule-based expert does not handle. A web interface to the machine learning based mechanistic reaction predictor is accessible through our chemoinformatics portal ( http://cdb.ics.uci.edu) under the Toolkits section.

Learning to Predict Chemical Reactions

PubMed Central

Kayala, Matthew A.; Azencott, Chloé-Agathe; Chen, Jonathan H.

2011-01-01

Being able to predict the course of arbitrary chemical reactions is essential to the theory and applications of organic chemistry. Approaches to the reaction prediction problems can be organized around three poles corresponding to: (1) physical laws; (2) rule-based expert systems; and (3) inductive machine learning. Previous approaches at these poles respectively are not high-throughput, are not generalizable or scalable, or lack sufficient data and structure to be implemented. We propose a new approach to reaction prediction utilizing elements from each pole. Using a physically inspired conceptualization, we describe single mechanistic reactions as interactions between coarse approximations of molecular orbitals (MOs) and use topological and physicochemical attributes as descriptors. Using an existing rule-based system (Reaction Explorer), we derive a restricted chemistry dataset consisting of 1630 full multi-step reactions with 2358 distinct starting materials and intermediates, associated with 2989 productive mechanistic steps and 6.14 million unproductive mechanistic steps. And from machine learning, we pose identifying productive mechanistic steps as a statistical ranking, information retrieval, problem: given a set of reactants and a description of conditions, learn a ranking model over potential filled-to-unfilled MO interactions such that the top ranked mechanistic steps yield the major products. The machine learning implementation follows a two-stage approach, in which we first train atom level reactivity filters to prune 94.00% of non-productive reactions with a 0.01% error rate. Then, we train an ensemble of ranking models on pairs of interacting MOs to learn a relative productivity function over mechanistic steps in a given system. Without the use of explicit transformation patterns, the ensemble perfectly ranks the productive mechanism at the top 89.05% of the time, rising to 99.86% of the time when the top four are considered. Furthermore, the system is generalizable, making reasonable predictions over reactants and conditions which the rule-based expert does not handle. A web interface to the machine learning based mechanistic reaction predictor is accessible through our chemoinformatics portal (http://cdb.ics.uci.edu) under the Toolkits section. PMID:21819139

Mouse ACF7 and drosophila short stop modulate filopodia formation and microtubule organisation during neuronal growth.

PubMed

Sanchez-Soriano, Natalia; Travis, Mark; Dajas-Bailador, Federico; Gonçalves-Pimentel, Catarina; Whitmarsh, Alan J; Prokop, Andreas

2009-07-15

Spectraplakins are large actin-microtubule linker molecules implicated in various processes, including gastrulation, wound healing, skin blistering and neuronal degeneration. Expression data for the mammalian spectraplakin ACF7 and genetic analyses of the Drosophila spectraplakin Short stop (Shot) suggest an important role during neurogenesis. Using three parallel neuronal culture systems we demonstrate that, like Shot, ACF7 is essential for axon extension and describe, for the first time, their subcellular functions during axonal growth. Firstly, both ACF7 and Shot regulate the organisation of neuronal microtubules, a role dependent on both the F-actin- and microtubule-binding domains. This role in microtubule organisation is probably the key mechanism underlying the roles of Shot and ACF7 in growth cone advance. Secondly, we found a novel role for ACF7 and Shot in regulating the actin cytoskeleton through their ability to control the formation of filopodia. This function in F-actin regulation requires EF-hand motifs and interaction with the translational regulator Krasavietz/eIF5C, indicating that the underlying mechanisms are completely different from those used to control microtubules. Our data provide the basis for the first mechanistic explanation for the role of Shot and ACF7 in the developing nervous system and demonstrate their ability to coordinate the organisation of both actin and microtubule networks during axonal growth.

Genomic Changes Associated with Reproductive and Migratory Ecotypes in Sockeye Salmon (Oncorhynchus nerka).

PubMed

Veale, Andrew J; Russello, Michael A

2017-10-01

Mechanisms underlying adaptive evolution can best be explored using paired populations displaying similar phenotypic divergence, illuminating the genomic changes associated with specific life history traits. Here, we used paired migratory [anadromous vs. resident (kokanee)] and reproductive [shore- vs. stream-spawning] ecotypes of sockeye salmon (Oncorhynchus nerka) sampled from seven lakes and two rivers spanning three catchments (Columbia, Fraser, and Skeena) in British Columbia, Canada to investigate the patterns and processes underlying their divergence. Restriction-site associated DNA sequencing was used to genotype this sampling at 7,347 single nucleotide polymorphisms, 334 of which were identified as outlier loci and candidates for divergent selection within at least one ecotype comparison. Sixty-eight of these outliers were present in two or more comparisons, with 33 detected across multiple catchments. Of particular note, one locus was detected as the most significant outlier between shore and stream-spawning ecotypes in multiple comparisons and across catchments (Columbia, Fraser, and Snake). We also detected several genomic islands of divergence, some shared among comparisons, potentially showing linked signals of differential selection. The single nucleotide polymorphisms and genomic regions identified in our study offer a range of mechanistic hypotheses associated with the genetic basis of O. nerka life history variation and provide novel tools for informing fisheries management. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Experimental Models of Maternal Obesity and Neuroendocrine Programming of Metabolic Disorders in Offspring.

PubMed

Reynolds, Clare M; Segovia, Stephanie A; Vickers, Mark H

2017-01-01

Evidence from epidemiological, clinical, and experimental studies have clearly shown that disease risk in later life is increased following a poor early life environment, a process preferentially termed developmental programming. In particular, this work clearly highlights the importance of the nutritional environment during early development with alterations in maternal nutrition, including both under- and overnutrition, increasing the risk for a range of cardiometabolic and neurobehavioral disorders in adult offspring characterized by both adipokine resistance and obesity. Although the mechanistic basis for such developmental programming is not yet fully defined, a common feature derived from experimental animal models is that of alterations in the wiring of the neuroendocrine pathways that control energy balance and appetite regulation during early stages of developmental plasticity. The adipokine leptin has also received significant attention with clear experimental evidence that normal regulation of leptin levels during the early life period is critical for the normal development of tissues and related signaling pathways that are involved in metabolic and cardiovascular homeostasis. There is also increasing evidence that alterations in the epigenome and other underlying mechanisms including an altered gut-brain axis may contribute to lasting cardiometabolic dysfunction in offspring. Ongoing studies that further define the mechanisms between these associations will allow for identification of early risk markers and implementation of strategies around interventions that will have obvious beneficial implications in breaking a programmed transgenerational cycle of metabolic disorders.

Mouse ACF7 and Drosophila Short stop modulate filopodia formation and microtubule organisation during neuronal growth

PubMed Central

Sanchez-Soriano, Natalia; Travis, Mark; Dajas-Bailador, Federico; Gonçalves-Pimentel, Catarina; Whitmarsh, Alan J.; Prokop, Andreas

2009-01-01

Summary Spectraplakins are large actin-microtubule linker molecules implicated in various processes, including gastrulation, wound healing, skin blistering and neuronal degeneration. Expression data for the mammalian spectraplakin ACF7 and genetic analyses of the Drosophila spectraplakin Short stop (Shot) suggest an important role during neurogenesis. Using three parallel neuronal culture systems we demonstrate that, like Shot, ACF7 is essential for axon extension and describe, for the first time, their subcellular functions during axonal growth. Firstly, both ACF7 and Shot regulate the organisation of neuronal microtubules, a role dependent on both the F-actin- and microtubule-binding domains. This role in microtubule organisation is probably the key mechanism underlying the roles of Shot and ACF7 in growth cone advance. Secondly, we found a novel role for ACF7 and Shot in regulating the actin cytoskeleton through their ability to control the formation of filopodia. This function in F-actin regulation requires EF-hand motifs and interaction with the translational regulator Krasavietz/eIF5C, indicating that the underlying mechanisms are completely different from those used to control microtubules. Our data provide the basis for the first mechanistic explanation for the role of Shot and ACF7 in the developing nervous system and demonstrate their ability to coordinate the organisation of both actin and microtubule networks during axonal growth. PMID:19571116

Rice Fertilization-Independent Endosperm1 Regulates Seed Size under Heat Stress by Controlling Early Endosperm Development1[W

PubMed Central

Folsom, Jing J.; Begcy, Kevin; Hao, Xiaojuan; Wang, Dong; Walia, Harkamal

2014-01-01

Although heat stress reduces seed size in rice (Oryza sativa), little is known about the molecular mechanisms underlying the observed reduction in seed size and yield. To elucidate the mechanistic basis of heat sensitivity and reduced seed size, we imposed a moderate (34°C) and a high (42°C) heat stress treatment on developing rice seeds during the postfertilization stage. Both stress treatments reduced the final seed size. At a cellular level, the moderate heat stress resulted in precocious endosperm cellularization, whereas severe heat-stressed seeds failed to cellularize. Initiation of endosperm cellularization is a critical developmental transition required for normal seed development, and it is controlled by Polycomb Repressive Complex2 (PRC2) in Arabidopsis (Arabidopsis thaliana). We observed that a member of PRC2 called Fertilization-Independent Endosperm1 (OsFIE1) was sensitive to temperature changes, and its expression was negatively correlated with the duration of the syncytial stage during heat stress. Seeds from plants overexpressing OsFIE1 had reduced seed size and exhibited precocious cellularization. The DNA methylation status and a repressive histone modification of OsFIE1 were observed to be temperature sensitive. Our data suggested that the thermal sensitivity of seed enlargement could partly be caused by altered epigenetic regulation of endosperm development during the transition from the syncytial to the cellularized state. PMID:24590858

The importance of mechanisms for the evolution of cooperation

PubMed Central

van den Berg, Pieter; Weissing, Franz J.

2015-01-01

Studies aimed at explaining the evolution of phenotypic traits have often solely focused on fitness considerations, ignoring underlying mechanisms. In recent years, there has been an increasing call for integrating mechanistic perspectives in evolutionary considerations, but it is not clear whether and how mechanisms affect the course and outcome of evolution. To study this, we compare four mechanistic implementations of two well-studied models for the evolution of cooperation, the Iterated Prisoner's Dilemma (IPD) game and the Iterated Snowdrift (ISD) game. Behavioural strategies are either implemented by a 1 : 1 genotype–phenotype mapping or by a simple neural network. Moreover, we consider two different scenarios for the effect of mutations. The same set of strategies is feasible in all four implementations, but the probability that a given strategy arises owing to mutation is largely dependent on the behavioural and genetic architecture. Our individual-based simulations show that this has major implications for the evolutionary outcome. In the ISD, different evolutionarily stable strategies are predominant in the four implementations, while in the IPD each implementation creates a characteristic dynamical pattern. As a consequence, the evolved average level of cooperation is also strongly dependent on the underlying mechanism. We argue that our findings are of general relevance for the evolution of social behaviour, pleading for the integration of a mechanistic perspective in models of social evolution. PMID:26246554

Application of comparative vibrational spectroscopic and mechanistic studies in analysis of fisetin structure

NASA Astrophysics Data System (ADS)

Dimitrić Marković, Jasmina M.; Marković, Zoran S.; Milenković, Dejan; Jeremić, Svetlana

2011-12-01

This paper addresses experimental and theoretical research in fisetin (2-(3,4-dihydroxyphenyl)-3,7-dihydroxychromen-4-one) structure by means of experimental IR and Raman spectroscopies and mechanistic calculations. Density Functional Theory calculations, with M05-2X functional and the 6-311+G (2df, p) basis set implemented in the Gaussian 09 package, are performed with the aim to support molecular structure, vibrational bands' positions and their intensities. Potential energy distribution (PED) values and the description of the largest vibrational contributions to the normal modes are calculated. The most intense bands appear in the 1650-1500 cm -1 wavenumber region. This region involves a combination of the C dbnd O, C2 dbnd C3 and C-C stretching vibrational modes. Most of the bands in the 1500-1000 cm -1 range involve C-C stretching, O-C stretching and in-plane C-C-H, C-O-H, C-C-O and C-C-C bending vibrations of the rings. The region below 1000 cm -1 is characteristic to the combination of in plane C-C-C-H, H-C-C-H, C-C-C-C, C-C-O-C and out of plane O-C-C-C, C-C-O-C, C-C-C-C torsional modes. The Raman spectra of baicalein and quercetin were used for qualitative comparison with fisetin spectrum and verification of band assignments. The applied detailed vibrational spectral analysis and the assignments of the bands, proposed on the basis of fundamentals, reproduced the experimental results with high degree of accuracy.

Application of comparative vibrational spectroscopic and mechanistic studies in analysis of fisetin structure.

PubMed

Dimitrić Marković, Jasmina M; Marković, Zoran S; Milenković, Dejan; Jeremić, Svetlana

2011-12-01

This paper addresses experimental and theoretical research in fisetin (2-(3,4-dihydroxyphenyl)-3,7-dihydroxychromen-4-one) structure by means of experimental IR and Raman spectroscopies and mechanistic calculations. Density Functional Theory calculations, with M05-2X functional and the 6-311+G (2df, p) basis set implemented in the Gaussian 09 package, are performed with the aim to support molecular structure, vibrational bands' positions and their intensities. Potential energy distribution (PED) values and the description of the largest vibrational contributions to the normal modes are calculated. The most intense bands appear in the 1650-1500 cm(-1) wavenumber region. This region involves a combination of the CO, C2C3 and C-C stretching vibrational modes. Most of the bands in the 1500-1000 cm(-1) range involve C-C stretching, O-C stretching and in-plane C-C-H, C-O-H, C-C-O and C-C-C bending vibrations of the rings. The region below 1000 cm(-1) is characteristic to the combination of in plane C-C-C-H, H-C-C-H, C-C-C-C, C-C-O-C and out of plane O-C-C-C, C-C-O-C, C-C-C-C torsional modes. The Raman spectra of baicalein and quercetin were used for qualitative comparison with fisetin spectrum and verification of band assignments. The applied detailed vibrational spectral analysis and the assignments of the bands, proposed on the basis of fundamentals, reproduced the experimental results with high degree of accuracy. Copyright © 2011 Elsevier B.V. All rights reserved.

Can biosemiotics be a "science" if its purpose is to be a bridge between the natural, social and human sciences?

PubMed

Brier, Søren

2015-12-01

Central to the attempt to develop a biosemiotics has been the discussion of what it means to be scientific. In Marcello Barbieri's latest argument for leaving Peircean biosemiotics and creating an alternative code-biology the definition of what it means to be scientific plays a major role. For Barbieri "scientific knowledge is obtained by building machine-like models of what we observe in nature". Barbieri interestingly claims that - in combination with the empirical and experimental basis - mechanism is virtually equivalent to the scientific method. The consequences of this statement seem to be that the optimal type of knowledge science can produce about living system is to model them as machines. But the explicit goal of a Peircean semiotically based biosemiotics is (also) to model living systems as cognitive and communicative systems working on the basis of meaning and signification. These two concepts are not part of the mechanistic models of natural science today, not even of cognitive science. Barbieri tries to solve this problem by introducing a new concept of biological meaning that is separate from the Peircean biosemiotics and then add Peirce's semiotics on top. This article argues why this view is inconsistent on the grounds that Peirce's semiotic paradigm only gives meaning in its pragmaticist conception of a fallibilist view of science, which again is intrinsic connected to its non-mechanistic metaphysics of Tychism, Synechism and Agapism. The core of the biosemiotic enterprise is to establish another type of trans- and interdisciplinary wissenschaft than the received view of "science". Copyright © 2015. Published by Elsevier Ltd.

Mechanistic species distribution modeling reveals a niche shift during invasion.

PubMed

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

2017-06-01

Niche shifts of nonnative plants can occur when they colonize novel climatic conditions. However, the mechanistic basis for niche shifts during invasion is poorly understood and has rarely been captured within species distribution models. We quantified the consequence of between-population variation in phenology for invasion of common ragweed (Ambrosia artemisiifolia L.) across Europe. Ragweed is of serious concern because of its harmful effects as a crop weed and because of its impact on public health as a major aeroallergen. We developed a forward mechanistic species distribution model based on responses of ragweed development rates to temperature and photoperiod. The model was parameterized and validated from the literature and by reanalyzing data from a reciprocal common garden experiment in which native and invasive populations were grown within and beyond the current invaded range. It could therefore accommodate between-population variation in the physiological requirements for flowering, and predict the potentially invaded ranges of individual populations. Northern-origin populations that were established outside the generally accepted climate envelope of the species had lower thermal requirements for bud development, suggesting local adaptation of phenology had occurred during the invasion. The model predicts that this will extend the potentially invaded range northward and increase the average suitability across Europe by 90% in the current climate and 20% in the future climate. Therefore, trait variation observed at the population scale can trigger a climatic niche shift at the biogeographic scale. For ragweed, earlier flowering phenology in established northern populations could allow the species to spread beyond its current invasive range, substantially increasing its risk to agriculture and public health. Mechanistic species distribution models offer the possibility to represent niche shifts by varying the traits and niche responses of individual populations. Ignoring such effects could substantially underestimate the extent and impact of invasions. © 2017 by the Ecological Society of America.

Iron diminishes the in vitro biological effect of vanadium.

EPA Science Inventory

Mechanistic pathways underlying inflammatory injury following exposures to vanadium-containing compounds are not defined. We tested the postulate that the in vitro biological effect of vanadium results from its impact on iron homeostasis. Human bronchial epithelial (HBE) cells ex...

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

PubMed

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

2017-03-01

How climate constrains species' distributions through time and space is an important question in the context of conservation planning for climate change. Despite increasing awareness of the need to incorporate mechanism into species distribution models (SDMs), mechanistic modeling of endotherm distributions remains limited in this literature. Using the American pika (Ochotona princeps) as an example, we present a framework whereby mechanism can be incorporated into endotherm SDMs. Pika distribution has repeatedly been found to be constrained by warm temperatures, so we used Niche Mapper, a mechanistic heat-balance model, to convert macroclimate data to pika-specific surface activity time in summer across the western United States. We then explored the difference between using a macroclimate predictor (summer temperature) and using a mechanistic predictor (predicted surface activity time) in SDMs. Both approaches accurately predicted pika presences in current and past climate regimes. However, the activity models predicted 8-19% less habitat loss in response to annual temperature increases of ~3-5 °C predicted in the region by 2070, suggesting that pikas may be able to buffer some climate change effects through behavioral thermoregulation that can be captured by mechanistic modeling. Incorporating mechanism added value to the modeling by providing increased confidence in areas where different modeling approaches agreed and providing a range of outcomes in areas of disagreement. It also provided a more proximate variable relating animal distribution to climate, allowing investigations into how unique habitat characteristics and intraspecific phenotypic variation may allow pikas to exist in areas outside those predicted by generic SDMs. Only a small number of easily obtainable data are required to parameterize this mechanistic model for any endotherm, and its use can improve SDM predictions by explicitly modeling a widely applicable direct physiological effect: climate-imposed restrictions on activity. This more complete understanding is necessary to inform climate adaptation actions, management strategies, and conservation plans. © 2016 John Wiley & Sons Ltd.

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

USGS Publications Warehouse

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

2017-01-01

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

Data-Driven Mechanistic Modeling of Influence of Microstructure on High-Cycle Fatigue Life of Nickel Titanium

NASA Astrophysics Data System (ADS)

Kafka, Orion L.; Yu, Cheng; Shakoor, Modesar; Liu, Zeliang; Wagner, Gregory J.; Liu, Wing Kam

2018-04-01

A data-driven mechanistic modeling technique is applied to a system representative of a broken-up inclusion ("stringer") within drawn nickel-titanium wire or tube, e.g., as used for arterial stents. The approach uses a decomposition of the problem into a training stage and a prediction stage. It is applied to compute the fatigue crack incubation life of a microstructure of interest under high-cycle fatigue. A parametric study of a matrix-inclusion-void microstructure is conducted. The results indicate that, within the range studied, a larger void between halves of the inclusion increases fatigue life, while larger inclusion diameter reduces fatigue life.

Dissepiments, density bands and signatures of thermal stress in Porites skeletons

NASA Astrophysics Data System (ADS)

DeCarlo, Thomas M.; Cohen, Anne L.

2017-09-01

The skeletons of many reef-building corals are accreted with rhythmic structural patterns that serve as valuable sclerochronometers. Annual high- and low-density band couplets, visible in X-radiographs or computed tomography scans, are used to construct age models for paleoclimate reconstructions and to track variability in coral growth over time. In some corals, discrete, anomalously high-density bands, called "stress bands," preserve information about coral bleaching. However, the mechanisms underlying the formation of coral skeletal density banding remain unclear. Dissepiments—thin, horizontal sheets of calcium carbonate accreted by the coral to support the living polyp—play a key role in the upward growth of the colony. Here, we first conducted a vital staining experiment to test whether dissepiments were accreted with lunar periodicity in Porites coral skeleton, as previously hypothesized. Over 6, 15, and 21 months, dissepiments consistently formed in a 1:1 ratio to the number of full moons elapsed over each study period. We measured dissepiment spacing to reconstruct multiple years of monthly skeletal extension rates in two Porites colonies from Palmyra Atoll and in another from Palau that bleached in 1998 under anomalously high sea temperatures. Spacing between successive dissepiments exhibited strong seasonality in corals containing annual density bands, with narrow (wide) spacing associated with high (low) density, respectively. A high-density "stress band" accreted during the 1998 bleaching event was associated with anomalously low dissepiment spacing and missed dissepiments, implying that thermal stress disrupts skeletal extension. Further, uranium/calcium ratios increased within stress bands, indicating a reduction in the carbonate ion concentration of the coral's calcifying fluid under stress. Our study verifies the lunar periodicity of dissepiments, provides a mechanistic basis for the formation of annual density bands in Porites, and reveals the underlying cause of high-density stress bands.

Molecular crowders and cosolutes promote folding cooperativity of RNA under physiological ionic conditions

PubMed Central

Strulson, Christopher A.; Boyer, Joshua A.; Whitman, Elisabeth E.; Bevilacqua, Philip C.

2014-01-01

Folding mechanisms of functional RNAs under idealized in vitro conditions of dilute solution and high ionic strength have been well studied. Comparatively little is known, however, about mechanisms for folding of RNA in vivo where Mg2+ ion concentrations are low, K+ concentrations are modest, and concentrations of macromolecular crowders and low-molecular-weight cosolutes are high. Herein, we apply a combination of biophysical and structure mapping techniques to tRNA to elucidate thermodynamic and functional principles that govern RNA folding under in vivo–like conditions. We show by thermal denaturation and SHAPE studies that tRNA folding cooperativity increases in physiologically low concentrations of Mg2+ (0.5–2 mM) and K+ (140 mM) if the solution is supplemented with physiological amounts (∼20%) of a water-soluble neutral macromolecular crowding agent such as PEG or dextran. Low-molecular-weight cosolutes show varying effects on tRNA folding cooperativity, increasing or decreasing it based on the identity of the cosolute. For those additives that increase folding cooperativity, the gain is manifested in sharpened two-state-like folding transitions for full-length tRNA over its secondary structural elements. Temperature-dependent SHAPE experiments in the absence and presence of crowders and cosolutes reveal extent of cooperative folding of tRNA on a nucleotide basis and are consistent with the melting studies. Mechanistically, crowding agents appear to promote cooperativity by stabilizing tertiary structure, while those low molecular cosolutes that promote cooperativity stabilize tertiary structure and/or destabilize secondary structure. Cooperative folding of functional RNA under physiological-like conditions parallels the behavior of many proteins and has implications for cellular RNA folding kinetics and evolution. PMID:24442612

Integrated approach to nitric oxide in animals and plants (mechanism and bioactivity): cell signaling and radicals.

PubMed

Kovacic, Peter; Somanathan, Ratnasamy

2011-04-01

Nitric oxide was first the object of extensive investigation in animals. It has been designated as the most widespread signaling molecule. An overview is presented with emphasis on cell signaling, mechanism, and physiological activity. Hence, a basis is provided for comparison of NO in plants with a similar approach. Mechanistically, cell signaling, electron transfer, radicals, and antioxidants are involved. A role is played by NO derivatives, such as peroxynitrite, nitroxyl, nitrite, nitrate, and S-nitroso derivatives. Comparison is made with ethylene. The multifaceted, interdisciplinary approach provides novel insight.

Structure-Based Drug Design of Novel Potent and Selective Tetrahydropyrazolo[1,5- a ]pyrazines as ATR Inhibitors

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

Barsanti, Paul A.; Aversa, Robert J.; Jin, Xianming

A saturation strategy focused on improving the selectivity and physicochemical properties of ATR inhibitor HTS hit 1 led to a novel series of highly potent and selective tetrahydropyrazolo[1,5-a]pyrazines. Use of PI3Kα mutants as ATR crystal structure surrogates was instrumental in providing cocrystal structures to guide the medicinal chemistry designs. Detailed DMPK studies involving cyanide and GSH as trapping agents during microsomal incubations, in addition to deuterium-labeled compounds as mechanistic probes uncovered the molecular basis for the observed CYP3A4 TDI in the series.

An experimental comparison between the continuum and single jump descriptions of nonactin-mediated potassium transport through black lipid membranes.

PubMed Central

van Dijk, C; de Levie, R

1985-01-01

The continuum and single jump treatments of ion transport through black lipid membranes predict experimentally distinguishable results, even when the same mechanistic assumptions are made and the same potential-distance profile is used. On the basis of steady-state current-voltage curves for nonactin-mediated transport of potassium ions, we find that the continuum model describes the data accurately, whereas the single jump model fails to do so, for all cases investigated in which capacitance measurements indicate that the membrane thickness varies little with applied potential. PMID:3839420

Environmental microbiology as related to planetary quarantine. [synergetic effect of heat and radiation

NASA Technical Reports Server (NTRS)

Pflug, I. J.

1973-01-01

The mechanistic basis of the synergetic effect of combined heat and radiation on microbial destruction was analyzed and results show that radiation intensity, temperature, and relative humidity are the determining factors. Dry heat resistance evaluation for selected bacterial spore crops indicates that different strains of Bacillus stearothermophilus demonstrate marked differences in resistance. Preliminary work to determine the effects of storage time, suspending medium, storage temperature and spore crop cleaning procedures on dry heat survival characteristics of Bacillus subtilis var. Niger, and dry heat resistance of natural microflora in soil particles is also reported.

From the seat of heat and intelligence to regular heart activity as automatic movement: progress in cardiology up to 1900 from a Dutch perspective

PubMed Central

van Tellingen, C.

2009-01-01

The development in cardiovascular anatomy and physiology is described from a Dutch perspective. The newly formed Republic in the 17th century, with its pragmatism and business-like character, became an ideal breeding ground for Descartes' new philosophy. His separation of body and soul provided a mechanistic model of body structure and formed a firm basis for anatomical and physiological research to become catalysts for a tempestuous growth and progress in medicine. (Neth Heart J 2009;17:130-5.19421357) PMID:19421357

Neurological Disease in Lupus: Toward a Personalized Medicine Approach

PubMed Central

McGlasson, Sarah; Wiseman, Stewart; Wardlaw, Joanna; Dhaun, Neeraj; Hunt, David P. J.

2018-01-01

The brain and nervous system are important targets for immune-mediated damage in systemic lupus erythematosus (SLE), resulting in a complex spectrum of neurological syndromes. Defining nervous system disease in lupus poses significant challenges. Among the difficulties to be addressed are a diversity of clinical manifestations and a lack of understanding of their mechanistic basis. However, despite these challenges, progress has been made in the identification of pathways which contribute to neurological disease in SLE. Understanding the molecular pathogenesis of neurological disease in lupus will inform both classification and approaches to clinical trials. PMID:29928273

The future trajectory of adverse outcome pathways: a commentary.

PubMed

Sewell, Fiona; Gellatly, Nichola; Beaumont, Maria; Burden, Natalie; Currie, Richard; de Haan, Lolke; Hutchinson, Thomas H; Jacobs, Miriam; Mahony, Catherine; Malcomber, Ian; Mehta, Jyotigna; Whale, Graham; Kimber, Ian

2018-04-01

The advent of adverse outcome pathways (AOPs) has provided a new lexicon for description of mechanistic toxicology, and a renewed enthusiasm for exploring modes of action resulting in adverse health and environmental effects. In addition, AOPs have been used successfully as a framework for the design and development of non-animal approaches to toxicity testing. Although the value of AOPs is widely recognised, there remain challenges and opportunities associated with their use in practise. The purpose of this article is to consider specifically how the future trajectory of AOPs may provide a basis for addressing some of those challenges and opportunities.

Epigenetic and chromatin-based mechanisms in environmental stress adaptation and stress memory in plants.

PubMed

Lämke, Jörn; Bäurle, Isabel

2017-06-27

Plants frequently have to weather both biotic and abiotic stressors, and have evolved sophisticated adaptation and defense mechanisms. In recent years, chromatin modifications, nucleosome positioning, and DNA methylation have been recognized as important components in these adaptations. Given their potential epigenetic nature, such modifications may provide a mechanistic basis for a stress memory, enabling plants to respond more efficiently to recurring stress or even to prepare their offspring for potential future assaults. In this review, we discuss both the involvement of chromatin in stress responses and the current evidence on somatic, intergenerational, and transgenerational stress memory.

Understanding the effect of carbon status on stem diameter variations

PubMed Central

De Swaef, Tom; Driever, Steven M.; Van Meulebroek, Lieven; Vanhaecke, Lynn; Marcelis, Leo F. M.; Steppe, Kathy

2013-01-01

Background Carbon assimilation and leaf-to-fruit sugar transport are, along with plant water status, the driving mechanisms for fruit growth. An integrated comprehension of the plant water and carbon relationships is therefore essential to better understand water and dry matter accumulation. Variations in stem diameter result from an integrated response to plant water and carbon status and are as such a valuable source of information. Methods A mechanistic water flow and storage model was used to relate variations in stem diameter to phloem sugar loading and sugar concentration dynamics in tomato. The simulation results were compared with an independent model, simulating phloem sucrose loading at the leaf level based on photosynthesis and sugar metabolism kinetics and enabled a mechanistic interpretation of the ‘one common assimilate pool’ concept for tomato. Key Results Combining stem diameter variation measurements and mechanistic modelling allowed us to distinguish instantaneous dynamics in the plant water relations and gradual variations in plant carbon status. Additionally, the model combined with stem diameter measurements enabled prediction of dynamic variables which are difficult to measure in a continuous and non-destructive way, such as xylem water potential and phloem hydrostatic potential. Finally, dynamics in phloem sugar loading and sugar concentration were distilled from stem diameter variations. Conclusions Stem diameter variations, when used in mechanistic models, have great potential to continuously monitor and interpret plant water and carbon relations under natural growing conditions. PMID:23186836

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.

The impact of domestication and crop improvement on arbuscular mycorrhizal symbiosis in cereals: insights from genetics and genomics.

PubMed

Sawers, Ruairidh J H; Ramírez-Flores, M Rosario; Olalde-Portugal, Víctor; Paszkowski, Uta

2018-04-15

Contents Summary I. Introduction II. Recruitment of plant metabolites and hormones as signals in AM symbiosis III. Phytohormones are regulators of AM symbiosis and targets of plant breeding IV. Variations in host response to AM symbiosis V. Outlook Acknowledgements References SUMMARY: Cereals (rice, maize, wheat, sorghum and the millets) provide over 50% of the world's caloric intake, a value that rises to > 80% in developing countries. Since domestication, cereals have been under artificial selection, largely directed towards higher yield. Throughout this process, cereals have maintained their capacity to interact with arbuscular mycorrhizal (AM) fungi, beneficial symbionts that associate with the roots of most terrestrial plants. It has been hypothesized that the shift from the wild to cultivation, and above all the last c. 50 years of intensive breeding for high-input farming systems, has reduced the capacity of the major cereal crops to gain full benefit from AM interactions. Recent studies have shed further light on the molecular basis of establishment and functioning of AM symbiosis in cereals, providing insight into where the breeding process might have had an impact. Classic phytohormones, targets of artificial selection during the generation of Green Revolution semi-dwarf varieties, have emerged as important regulators of AM symbiosis. Although there is still much to be learnt about the mechanistic basis of variation in symbiotic outcome, these advances are providing an insight into the role of arbuscular mycorrhiza in agronomic systems. © 2018 The Authors. New Phytologist © 2018 New Phytologist Trust.

Coupled metal partitioning dynamics and toxicodynamics at biointerfaces: a theory beyond the biotic ligand model framework.

PubMed

Duval, Jérôme F L

2016-04-14

A mechanistic understanding of the processes governing metal toxicity to microorganisms (bacteria, algae) calls for an adequate formulation of metal partitioning at biointerfaces during cell exposure. This includes the account of metal transport dynamics from bulk solution to biomembrane and the kinetics of metal internalisation, both potentially controlling the intracellular and surface metal fractions that originate cell growth inhibition. A theoretical rationale is developed here for such coupled toxicodynamics and interfacial metal partitioning dynamics under non-complexing medium conditions with integration of the defining cell electrostatic properties. The formalism explicitly considers intertwined metal adsorption at the biointerface, intracellular metal excretion, cell growth and metal depletion from bulk solution. The theory is derived under relevant steady-state metal transport conditions on the basis of coupled Nernst-Planck equation and continuous logistic equation modified to include metal-induced cell growth inhibition and cell size changes. Computational examples are discussed to identify limitations of the classical Biotic Ligand Model (BLM) in evaluating metal toxicity over time. In particular, BLM is shown to severely underestimate metal toxicity depending on cell exposure time, metal internalisation kinetics, cell surface electrostatics and initial cell density. Analytical expressions are provided for the interfacial metal concentration profiles in the limit where cell-growth is completely inhibited. A rigorous relationship between time-dependent cell density and metal concentrations at the biosurface and in bulk solution is further provided, which unifies previous equations formulated by Best and Duval under constant cell density and cell size conditions. The theory is sufficiently flexible to adapt to toxicity scenarios with involved cell survival-death processes.

Mild MPP+ exposure impairs autophagic degradation through a novel lysosomal acidity-independent mechanism.

PubMed

Miyara, Masatsugu; Kotake, Yaichiro; Tokunaga, Wataru; Sanoh, Seigo; Ohta, Shigeru

2016-10-01

Parkinson's disease (PD) is the second most common neurodegenerative disorder, but its underlying cause remains unknown. Although recent studies using PD-related neurotoxin MPP + suggest autophagy involvement in the pathogenesis of PD, the effect of MPP + on autophagic processes under mild exposure, which mimics the slow progressive nature of PD, remains largely unclear. We examined the effect of mild MPP + exposure (10 and 200 μM for 48 h), which induces a more slowly developing cell death, on autophagic processes and the mechanistic differences with acute MPP + toxicity (2.5 and 5 mM for 24 h). In SH-SY5Y cells, mild MPP + exposure predominantly inhibited autophagosome degradation, whereas acute MPP + exposure inhibited both autophagosome degradation and basal autophagy. Mild MPP + exposure reduced lysosomal hydrolase cathepsin D activity without changing lysosomal acidity, whereas acute exposure decreased lysosomal density. Lysosome biogenesis enhancers trehalose and rapamycin partially alleviated mild MPP + exposure induced impaired autophagosome degradation and cell death, but did not prevent the pathogenic response to acute MPP + exposure, suggesting irreversible lysosomal damage. We demonstrated impaired autophagic degradation by MPP + exposure and mechanistic differences between mild and acute MPP + toxicities. Mild MPP + toxicity impaired autophagosome degradation through novel lysosomal acidity-independent mechanisms. Sustained mild lysosomal damage may contribute to PD. We examined the effects of MPP + on autophagic processes under mild exposure, which mimics the slow progressive nature of Parkinson's disease, in SH-SY5Y cells. This study demonstrated impaired autophagic degradation through a reduction in lysosomal cathepsin D activity without altering lysosomal acidity by mild MPP + exposure. Mechanistic differences between acute and mild MPP + toxicity were also observed. Sustained mild damage of lysosome may be an underlying cause of Parkinson's disease. Cover Image for this issue: doi: 10.1111/jnc.13338. © 2016 International Society for Neurochemistry.

Validation of a patch clamp screening protocol that simultaneously measures compound activity in multiple states of the voltage-gated sodium channel Nav1.2.

PubMed

Liu, Yi; Beck, Edward J; Flores, Christopher M

2011-12-01

Hyperactivity of voltage-gated sodium channels underlies, at least in part, a range of pathological states, including pain and epilepsy. Selective blockers of these channels may offer effective treatment of such disorders. Currently employed methods to screen for sodium channel blockers, however, are inadequate to rationally identify mechanistically diverse blockers, limiting the potential range of indications that may be treated by such agents. Here, we describe an improved patch clamp screening assay that increases the mechanistic diversity of sodium channel blockers being identified. Using QPatch HT, a medium-throughput, automated patch clamp system, we tested three common sodium channel blockers (phenytoin, lidocaine, and tetrodotoxin) with distinct mechanistic profiles at Nav1.2. The single-voltage protocol employed in this assay simultaneously measured the compound activity in multiple states, including the slow inactivated state, of the channel. A long compound incubation period (10 s) was introduced during channel inactivation to increase the probability of identifying "slow binders." As such, phenytoin, which preferentially binds with slow kinetics to the fast inactivated state, exhibited significantly higher potency than that obtained from a brief exposure (100 ms) used in typical assays. This assay also successfully detected the use-dependent block of tetrodotoxin, a well-documented property of this molecule yet unobserved in typical patch clamp protocols. These results indicate that the assay described here can increase the likelihood of identification and mechanistic diversity of sodium channel blockers from a primary screen. It can also be used to efficiently guide the in vitro optimization of leads that retain the desired mechanistic properties. © MARY ANN LIEBERT, INC.

Analysis and remediation of aphasia in the U.S.S.R: the contribution of A. R. Luria.

PubMed

Hatfield, F M

1981-11-01

This paper surveys the contribution of A. R. Luria to aphasiology, emphasising the unique extent to which he integrated theory and therapeutic practice. The influence exerted by two prominent Russian figures, Pavlov and Vygotskii, is discussed. Luria's view of the primary defects underlying the main forms of aphasia is summarised; this is followed by a brief account of his application of certain notions of structural linguistics, including Jakobson's interpretations of the breakdown of language following brain damage. Examples are given of the wide range of simple tests included in Luria's neuropsychological investigations. The factual part of the article culminates in some examples of his methods of restoring higher cortical functions, in particular, verbal skills. The summary criticises certain aspects of Luria's analysis as being too mechanistic and simplistic, and cites criticisms of details from other workers, but considers many of his insights and the total coherence of his view of cortical functioning and cortical disturbance to be still of the utmost importance for clinicians undertaking aphasia therapy. The need for therapists everywhere to develop language rehabilitation with as systematic a basis as Luria's is stressed.

Nature's Electric Potential: A Systematic Review of the Role of Bioelectricity in Wound Healing and Regenerative Processes in Animals, Humans, and Plants.

PubMed

Tyler, Sheena E B

2017-01-01

Natural endogenous voltage gradients not only predict and correlate with growth and development but also drive wound healing and regeneration processes. This review summarizes the existing literature for the nature, sources, and transmission of information-bearing bioelectric signals involved in controlling wound healing and regeneration in animals, humans, and plants. It emerges that some bioelectric characteristics occur ubiquitously in a range of animal and plant species. However, the limits of similarities are probed to give a realistic assessment of future areas to be explored. Major gaps remain in our knowledge of the mechanistic basis for these processes, on which regenerative therapies ultimately depend. In relation to this, it is concluded that the mapping of voltage patterns and the processes generating them is a promising future research focus, to probe three aspects: the role of wound/regeneration currents in relation to morphology; the role of endogenous flux changes in driving wound healing and regeneration; and the mapping of patterns in organisms of extreme longevity, in contrast with the aberrant voltage patterns underlying impaired healing, to inform interventions aimed at restoring them.

Pervasive sharing of genetic effects in autoimmune disease.

PubMed

Cotsapas, Chris; Voight, Benjamin F; Rossin, Elizabeth; Lage, Kasper; Neale, Benjamin M; Wallace, Chris; Abecasis, Gonçalo R; Barrett, Jeffrey C; Behrens, Timothy; Cho, Judy; De Jager, Philip L; Elder, James T; Graham, Robert R; Gregersen, Peter; Klareskog, Lars; Siminovitch, Katherine A; van Heel, David A; Wijmenga, Cisca; Worthington, Jane; Todd, John A; Hafler, David A; Rich, Stephen S; Daly, Mark J

2011-08-01

Genome-wide association (GWA) studies have identified numerous, replicable, genetic associations between common single nucleotide polymorphisms (SNPs) and risk of common autoimmune and inflammatory (immune-mediated) diseases, some of which are shared between two diseases. Along with epidemiological and clinical evidence, this suggests that some genetic risk factors may be shared across diseases-as is the case with alleles in the Major Histocompatibility Locus. In this work we evaluate the extent of this sharing for 107 immune disease-risk SNPs in seven diseases: celiac disease, Crohn's disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes. We have developed a novel statistic for Cross Phenotype Meta-Analysis (CPMA) which detects association of a SNP to multiple, but not necessarily all, phenotypes. With it, we find evidence that 47/107 (44%) immune-mediated disease risk SNPs are associated to multiple-but not all-immune-mediated diseases (SNP-wise P(CPMA)<0.01). We also show that distinct groups of interacting proteins are encoded near SNPs which predispose to the same subsets of diseases; we propose these as the mechanistic basis of shared disease risk. We are thus able to leverage genetic data across diseases to construct biological hypotheses about the underlying mechanism of pathogenesis.

A Theoretical Basis for the Transition to Denitrification at Nanomolar Oxygen Concentrations

NASA Astrophysics Data System (ADS)

Zakem, E.; Follows, M. J.

2016-02-01

Current climate change is likely to expand the size and intensity of marine oxygen minimum zones. How will this affect denitrification rates? Current global biogeochemical models typically prescribe a critical oxygen concentration below which anaerobic activity occurs, rather than resolve the underlying microbial processes. Here, we explore the dynamics of an idealized, simulated anoxic zone in which multiple prokaryotic metabolisms are resolved mechanistically, defined by redox chemistry and biophysical constraints. We first ask, what controls the critical oxygen concentration governing the favorability of aerobic or anaerobic respiration? The predicted threshold oxygen concentration varies as a function of the environment as well as of cell physiology, and lies within the nanomolar range. The model thus provides a theoretical underpinning for the recent observations of nanomolar oxygen concentrations in oxygen minimum zones. In the context of an idealized, two-dimensional intensified upwelling simulation, we also predict denitrification at oxygen concentrations orders of magnitude higher due to physical mixing, reconciling observations of denitrification over a similar range and demonstrating a decoupling of denitrification from the local oxygen concentration. In a sensitivity study with the idealized ocean model, we comment upon the relationship between the volume of anoxic waters and total denitrification.

SHINING A LIGHT ON XERODERMA PIGMENTOSUM

PubMed Central

DiGiovanna, John J.; Kraemer, Kenneth H.

2012-01-01

Xeroderma pigmentosum (XP) is a rare, autosomal recessive disorder of DNA repair characterized by sun sensitivity and ultraviolet (UV) induced skin and mucous membrane cancers. Described in 1874 by Moriz Kaposi in Vienna, nearly 100 years later James Cleaver in San Francisco reported defective DNA repair in XP cells. This eventually provided the basis for a mechanistic link between sun exposure, DNA damage, somatic mutations and skin cancer. XP cells were found to have defects in 7 of the proteins of the nucleotide excision repair pathway and in DNA polymerase eta. XP cells are hypersensitive to killing by UV and XP cancers have characteristic “UV signature” mutations. Clinical studies at NIH found a nearly 10,000-fold increase in skin cancer in XP patients under age 20 years demonstrating the substantial importance of DNA repair in cancer prevention in the general population. About 25 % of XP patients have progressive neurological degeneration with progressive loss of neurons, probably from DNA damage induced by oxidative metabolism which kills non-dividing cells in the nervous system. Interestingly, patients with another disorder, trichothiodystrophy have defects in some of the same genes as XP but they have primary developmental abnormalities without an increase in skin cancer. PMID:22217736

What is orgasm? A model of sexual trance and climax via rhythmic entrainment

PubMed Central

Safron, Adam

2016-01-01

Orgasm is one of the most intense pleasures attainable to an organism, yet its underlying mechanisms remain poorly understood. On the basis of existing literatures, this article introduces a novel mechanistic model of sexual stimulation and orgasm. In doing so, it characterizes the neurophenomenology of sexual trance and climax, describes parallels in dynamics between orgasms and seizures, speculates on possible evolutionary origins of sex differences in orgasmic responding, and proposes avenues for future experimentation. Here, a model is introduced wherein sexual stimulation induces entrainment of coupling mechanical and neuronal oscillatory systems, thus creating synchronized functional networks within which multiple positive feedback processes intersect synergistically to contribute to sexual experience. These processes generate states of deepening sensory absorption and trance, potentially culminating in climax if critical thresholds are surpassed. The centrality of rhythmic stimulation (and its modulation by salience) for surpassing these thresholds suggests ways in which differential orgasmic responding between individuals—or with different partners—may serve as a mechanism for ensuring adaptive mate choice. Because the production of rhythmic stimulation combines honest indicators of fitness with cues relating to potential for investment, differential orgasmic response may serve to influence the probability of continued sexual encounters with specific mates. PMID:27799079

Nature's Electric Potential: A Systematic Review of the Role of Bioelectricity in Wound Healing and Regenerative Processes in Animals, Humans, and Plants

PubMed Central

Tyler, Sheena E. B.

2017-01-01

Natural endogenous voltage gradients not only predict and correlate with growth and development but also drive wound healing and regeneration processes. This review summarizes the existing literature for the nature, sources, and transmission of information-bearing bioelectric signals involved in controlling wound healing and regeneration in animals, humans, and plants. It emerges that some bioelectric characteristics occur ubiquitously in a range of animal and plant species. However, the limits of similarities are probed to give a realistic assessment of future areas to be explored. Major gaps remain in our knowledge of the mechanistic basis for these processes, on which regenerative therapies ultimately depend. In relation to this, it is concluded that the mapping of voltage patterns and the processes generating them is a promising future research focus, to probe three aspects: the role of wound/regeneration currents in relation to morphology; the role of endogenous flux changes in driving wound healing and regeneration; and the mapping of patterns in organisms of extreme longevity, in contrast with the aberrant voltage patterns underlying impaired healing, to inform interventions aimed at restoring them. PMID:28928669

Resistance to MEK inhibitors: should we co-target upstream?

PubMed

Poulikakos, Poulikos I; Solit, David B

2011-03-29

Aberrant activation of the ERK pathway is common in human tumors. This pathway consists of a three-tiered kinase module [comprising the kinases RAF, mitogen-activated protein kinase (MAPK) kinase (MEK), and extracellular signal-regulated kinase (ERK)] that functions as a negative feedback amplifier to confer robustness and stabilization of pathway output. Because this pathway is frequently dysregulated in human cancers, intense efforts are under way to develop selective inhibitors of the ERK pathway as anticancer drugs. Although promising results have been reported in early trials for inhibitors of RAF or MEK, resistance invariably occurs. Amplification of the upstream oncogenic driver of ERK signaling has been identified as a mechanism for MEK inhibitor resistance in cells with mutant BRAF or KRAS. Increased abundance of the oncogenic driver (either KRAS or BRAF in the appropriate cellular context) in response to prolonged drug treatment results in increased flux through the ERK pathway and restoration of ERK activity above the threshold required for cell growth. For patients with BRAF mutant tumors, the results suggest that the addition of a RAF inhibitor to a MEK inhibitor may delay or overcome drug resistance. The data thus provide a mechanistic basis for ongoing trials testing concurrent treatment with RAF and MEK inhibitors.

SOURCES AND RADIATIVE PROPERTIES OF ORGANOSULFATES IN THE ATMOSPHERE

EPA Science Inventory

It is expected that these studies will provide mechanistic insight to how SOA forms under acidic conditions and how it impacts direct and indirect radiative forcing. Understanding the chemical and physical properties of SOA will lead to future advancements in the predictive...

Test-retest reliability of jump execution variables using mechanography: A comparison of jump protocols

USDA-ARS?s Scientific Manuscript database

Mechanography during the vertical jump test allows for evaluation of force-time variables reflecting jump execution, which may enhance screening for functional deficits that reduce physical performance and determining mechanistic causes underlying performance changes. However, utility of jump mechan...

Modeling of the nearshore marine ecosystem with the AQUATOX model

EPA Science Inventory

Process-based models can be used to forecast the responses of coastal ecosystems to changes under future scenarios. However, most models applied to coastal systems do not include higher trophic levels, which are important providers of ecosystem services. AQUATOX is a mechanistic...

Fracture Mechanisms For SiC Fibers And SiC/SiC Composites Under Stress-Rupture Conditions at High Temperatures

NASA Technical Reports Server (NTRS)

DiCarlo, James A.; Yun, Hee Mann; Hurst, Janet B.; Viterna, L. (Technical Monitor)

2002-01-01

The successful application of SiC/SiC ceramic matrix composites as high-temperature structural materials depends strongly on maximizing the fracture or rupture life of the load-bearing fiber and matrix constituents. Using high-temperature data measured under stress-rupture test conditions, this study examines in a mechanistic manner the effects of various intrinsic and extrinsic factors on the creep and fracture behavior of a variety of SiC fiber types. It is shown that although some fiber types fracture during a large primary creep stage, the fiber creep rate just prior to fracture plays a key role in determining fiber rupture time (Monkman-Grant theory). If it is assumed that SiC matrices rupture in a similar manner as fibers with the same microstructures, one can develop simple mechanistic models to analyze and optimize the stress-rupture behavior of SiC/SiC composites for applied stresses that are initially below matrix cracking.

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

PubMed

Lampl, Michelle; Schoen, Meriah

2017-03-01

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

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.

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

PubMed Central

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

2016-01-01

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

Assessing causal mechanistic interactions: a peril ratio index of synergy based on multiplicativity.

PubMed

Lee, Wen-Chung

2013-01-01

The assessments of interactions in epidemiology have traditionally been based on risk-ratio, odds-ratio or rate-ratio multiplicativity. However, many epidemiologists fail to recognize that this is mainly for statistical conveniences and often will misinterpret a statistically significant interaction as a genuine mechanistic interaction. The author adopts an alternative metric system for risk, the 'peril'. A peril is an exponentiated cumulative rate, or simply, the inverse of a survival (risk complement) or one plus an odds. The author proposes a new index based on multiplicativity of peril ratios, the 'peril ratio index of synergy based on multiplicativity' (PRISM). Under the assumption of no redundancy, PRISM can be used to assess synergisms in sufficient cause sense, i.e., causal co-actions or causal mechanistic interactions. It has a less stringent threshold to detect a synergy as compared to a previous index of 'relative excess risk due to interaction'. Using the new PRISM criterion, many situations in which there is not evidence of interaction judged by the traditional indices are in fact corresponding to bona fide positive or negative synergisms.

Assessing Causal Mechanistic Interactions: A Peril Ratio Index of Synergy Based on Multiplicativity

PubMed Central

Lee, Wen-Chung

2013-01-01

The assessments of interactions in epidemiology have traditionally been based on risk-ratio, odds-ratio or rate-ratio multiplicativity. However, many epidemiologists fail to recognize that this is mainly for statistical conveniences and often will misinterpret a statistically significant interaction as a genuine mechanistic interaction. The author adopts an alternative metric system for risk, the ‘peril’. A peril is an exponentiated cumulative rate, or simply, the inverse of a survival (risk complement) or one plus an odds. The author proposes a new index based on multiplicativity of peril ratios, the ‘peril ratio index of synergy based on multiplicativity’ (PRISM). Under the assumption of no redundancy, PRISM can be used to assess synergisms in sufficient cause sense, i.e., causal co-actions or causal mechanistic interactions. It has a less stringent threshold to detect a synergy as compared to a previous index of ‘relative excess risk due to interaction’. Using the new PRISM criterion, many situations in which there is not evidence of interaction judged by the traditional indices are in fact corresponding to bona fide positive or negative synergisms. PMID:23826299

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

Spices: the savory and beneficial science of pungency.

PubMed

Nilius, Bernd; Appendino, Giovanni

2013-01-01

Spicy food does not only provide an important hedonic input in daily life, but has also been anedoctically associated to beneficial effects on our health. In this context, the discovery of chemesthetic trigeminal receptors and their spicy ligands has provided the mechanistic basis and the pharmacological means to investigate this enticing possibility. This review discusses in molecular terms the connection between the neurophysiology of pungent spices and the "systemic" effects associated to their trigeminality. It commences with a cultural and historical overview on the Western fascination for spices, and, after analysing in detail the mechanisms underlying the trigeminality of food, the main dietary players from the transient receptor potential (TRP) family of cation channels are introduced, also discussing the "alien" distribution of taste receptors outside the oro-pharingeal cavity. The modulation of TRPV1 and TRPA1 by spices is next described, discussing how spicy sensations can be turned into hedonic pungency, and analyzing the mechanistic bases for the health benefits that have been associated to the consumption of spices. These include, in addition to a beneficial modulation of gastro-intestinal and cardio-vascular function, slimming, the optimization of skeletal muscle performance, the reduction of chronic inflammation, and the prevention of metabolic syndrome and diabetes. We conclude by reviewing the role of electrophilic spice constituents on cancer prevention in the light of their action on pro-inflammatory and pro-cancerogenic nuclear factors like NFκB, and on their interaction with the electrophile sensor protein Keap1 and the ensuing Nrf2-mediated transcriptional activity. Spicy compounds have a complex polypharmacology, and just like any other bioactive agent, show a balance of beneficial and bad actions. However, at least for moderate consumption, the balance seems definitely in favour of the positive side, suggesting that a spicy diet, a caveman-era technology, could be seriously considered in addition to caloric control and exercise as a measurement to prevent and control many chronic diseases associate to malnutrition from a Western diet.

Trade-offs in thermal adaptation: the need for a molecular to ecological integration.

PubMed

Pörtner, Hans O; Bennett, Albert F; Bozinovic, Francisco; Clarke, Andrew; Lardies, Marco A; Lucassen, Magnus; Pelster, Bernd; Schiemer, Fritz; Stillman, Jonathon H

2006-01-01

Through functional analyses, integrative physiology is able to link molecular biology with ecology as well as evolutionary biology and is thereby expected to provide access to the evolution of molecular, cellular, and organismic functions; the genetic basis of adaptability; and the shaping of ecological patterns. This paper compiles several exemplary studies of thermal physiology and ecology, carried out at various levels of biological organization from single genes (proteins) to ecosystems. In each of those examples, trade-offs and constraints in thermal adaptation are addressed; these trade-offs and constraints may limit species' distribution and define their level of fitness. For a more comprehensive understanding, the paper sets out to elaborate the functional and conceptual connections among these independent studies and the various organizational levels addressed. This effort illustrates the need for an overarching concept of thermal adaptation that encompasses molecular, organellar, cellular, and whole-organism information as well as the mechanistic links between fitness, ecological success, and organismal physiology. For this data, the hypothesis of oxygen- and capacity-limited thermal tolerance in animals provides such a conceptual framework and allows interpreting the mechanisms of thermal limitation of animals as relevant at the ecological level. While, ideally, evolutionary studies over multiple generations, illustrated by an example study in bacteria, are necessary to test the validity of such complex concepts and underlying hypotheses, animal physiology frequently is constrained to functional studies within one generation. Comparisons of populations in a latitudinal cline, closely related species from different climates, and ontogenetic stages from riverine clines illustrate how evolutionary information can still be gained. An understanding of temperature-dependent shifts in energy turnover, associated with adjustments in aerobic scope and performance, will result. This understanding builds on a mechanistic analysis of the width and location of thermal windows on the temperature scale and also on study of the functional properties of relevant proteins and associated gene expression mechanisms.

Evidence Coupling Increased Hexosamine Biosynthesis Pathway Activity to Membrane Cholesterol Toxicity and Cortical Filamentous Actin Derangement Contributing to Cellular Insulin Resistance†

PubMed Central

Bhonagiri, Padma; Pattar, Guruprasad R.; Habegger, Kirk M.; McCarthy, Alicia M.; Tackett, Lixuan

2011-01-01

Hyperinsulinemia is known to promote the progression/worsening of insulin resistance. Evidence reveals a hidden cost of hyperinsulinemia on plasma membrane (PM) phosphatidylinositol 4,5-bisphosphate (PIP2)-regulated filamentous actin (F-actin) structure, components critical to the normal operation of the insulin-regulated glucose transport system. Here we delineated whether increased glucose flux through the hexosamine biosynthesis pathway (HBP) causes PIP2/F-actin dysregulation and subsequent insulin resistance. Increased glycosylation events were detected in 3T3-L1 adipocytes cultured under conditions closely resembling physiological hyperinsulinemia (5 nm insulin; 12 h) and in cells in which HBP activity was amplified by 2 mm glucosamine (GlcN). Both the physiological hyperinsulinemia and experimental GlcN challenge induced comparable losses of PIP2 and F-actin. In addition to protecting against the insulin-induced membrane/cytoskeletal abnormality and insulin-resistant state, exogenous PIP2 corrected the GlcN-induced insult on these parameters. Moreover, in accordance with HBP flux directly weakening PIP2/F-actin structure, pharmacological inhibition of the rate-limiting HBP enzyme [glutamine-fructose-6-phosphate amidotransferase (GFAT)] restored PIP2-regulated F-actin structure and insulin responsiveness. Conversely, overexpression of GFAT was associated with a loss of detectable PM PIP2 and insulin sensitivity. Even less invasive challenges with glucose, in the absence of insulin, also led to PIP2/F-actin dysregulation. Mechanistically we found that increased HBP activity increased PM cholesterol, the removal of which normalized PIP2/F-actin levels. Accordingly, these data suggest that glucose transporter-4 functionality, dependent on PIP2 and/or F-actin status, can be critically compromised by inappropriate HBP activity. Furthermore, these data are consistent with the PM cholesterol accrual/toxicity as a mechanistic basis of the HBP-induced defects in PIP2/F-actin structure and impaired glucose transporter-4 regulation. PMID:21712361

Canopy structural complexity as a continental predictor of primary production: Using NEON to transform understanding of forest structure-function

NASA Astrophysics Data System (ADS)

Atkins, J. W.; Fahey, R. T.; Gough, C. M.; Hardiman, B. S.

2016-12-01

Ecosystem structure-function relationships represent a long-standing research area for ecosystem science. Relationships between canopy structural complexity (CSC) and net primary productivity (NPP), have been characterized for a limited number of sites, yet whether these relationships are conserved across eco-climatic boundaries remains unknown. We hypothesize an underlying mechanistic basis for global NPP-CSC linkages to include improved resource-use efficiency as CSC increases, examined here by correlating CSC with measures of light-use efficiency and nitrogen-use efficiency. Here we present a broad, continental scale analysis of CSC-NPP linkages. We are using multiple NEON sites coupled with other sites across a diverse array of temperate forest types spanning six eco-climatic domains of the continental United States to examine CSC-NPP relationships. Portable canopy LiDAR (PCL) data were used to calculate a suite of CSC metrics at the plot-level within each site. Ongoing work compares CSC to co-located measurements of wood net primary production estimated from the incremental change in woody biomass calculated using tree allometries. Results to date show CSC is highly variable across forest sites and may provide additional explanatory power for predicting NPP that is independent of other commonly used forest structural attributes such as leaf area index. CSC metrics such as rugosity vary widely across sites—ranging from high values (30 - 35) in complex canopies such as the Great Smoky Mountains to low values in open, savanna systems like North-Central Florida (< 0.5 - 2). NPP, and light- and nitrogen-use calculations are underway and will be paired with site-level CSC, with the expectation that CSC, resource-use efficiency, and NPP are positively correlated. Advancing understanding of how and why CSC affects forest NPP across a broad spatial dimension could transform mechanistic understanding of ecosystem structure-carbon cycling relationships, and greatly improve carbon cycling models and remote sensing applications, while providing a crucial linkage between the two.

Cytogenomics of hexavalent chromium (Cr6+) exposed cells: A comprehensive review

PubMed Central

Nigam, Akanksha; Priya, Shivam; Bajpai, Preeti; Kumar, Sushil

2014-01-01

The altered cellular gene expression profile is being hypothesized as the possible molecular basis navigating the onset or progress of various morbidities. This hypothesis has been evaluated here in respect of Cr6+ induced toxicity. Several studies using gene microarray show selective and strategic dysregulations of cellular genes and pathways induced by Cr6+. Relevant literature has been reviewed to unravel these changes in different test systems after exposure to Cr6+ and also to elucidate association if any, of the altered cytogenomics with Cr6+ induced toxicity or carcinogenicity. The aim was to verify the hypothesis for critical role of altered cytogenomics in onset of Cr6+ induced biological / clinical effects by identifying genes modulated commonly by the toxicant irrespective of test system or test concentrations / doses, and by scrutinizing their importance in regulation of the flow of mechanistically linked events crucial for resultant morbidities. Their probability as biomarkers to monitor the toxicant induced biological changes is speculative. The modulated genes have been found to cluster under the pathways that manage onset of oxidative stress, DNA damage, apoptosis, cell-cycle regulation, cytoskeleton, morphological changes, energy metabolism, biosynthesis, oncogenes, bioenergetics, and immune system critical for toxicity. In these studies, the identity of genes has been found to differ remarkably; albeit the trend of pathways’ dysregulation has been found to remain similar. We conclude that the intensity of dysregulation of genes or pathways involved in mechanistic events forms a sub-threshold or threshold level depending upon the dose and type (including speciation) of the toxicant, duration of exposure, type of target cells, and niche microenvironment of cells, and the intensity of sub-threshold or threshold level of the altered cytogenomics paves way in toxicant exposed cells eventually either to opt for reversal to differentiation and growth, or to result in toxicity like dedifferentiation and apoptosis, respectively. PMID:24820829

Oxygen Activation and Radical Transformations in Heme Proteins and Metalloporphyrins

PubMed Central

2017-01-01

As a result of the adaptation of life to an aerobic environment, nature has evolved a panoply of metalloproteins for oxidative metabolism and protection against reactive oxygen species. Despite the diverse structures and functions of these proteins, they share common mechanistic grounds. An open-shell transition metal like iron or copper is employed to interact with O2 and its derived intermediates such as hydrogen peroxide to afford a variety of metal–oxygen intermediates. These reactive intermediates, including metal-superoxo, -(hydro)peroxo, and high-valent metal–oxo species, are the basis for the various biological functions of O2-utilizing metalloproteins. Collectively, these processes are called oxygen activation. Much of our understanding of the reactivity of these reactive intermediates has come from the study of heme-containing proteins and related metalloporphyrin compounds. These studies not only have deepened our understanding of various functions of heme proteins, such as O2 storage and transport, degradation of reactive oxygen species, redox signaling, and biological oxygenation, etc., but also have driven the development of bioinorganic chemistry and biomimetic catalysis. In this review, we survey the range of O2 activation processes mediated by heme proteins and model compounds with a focus on recent progress in the characterization and reactivity of important iron–oxygen intermediates. Representative reactions initiated by these reactive intermediates as well as some context from prior decades will also be presented. We will discuss the fundamental mechanistic features of these transformations and delineate the underlying structural and electronic factors that contribute to the spectrum of reactivities that has been observed in nature as well as those that have been invented using these paradigms. Given the recent developments in biocatalysis for non-natural chemistries and the renaissance of radical chemistry in organic synthesis, we envision that new enzymatic and synthetic transformations will emerge based on the radical processes mediated by metalloproteins and their synthetic analogs. PMID:29286645

Bone as an endocrine organ relevant to diabetes

USDA-ARS?s Scientific Manuscript database

There are well-established associations between diabetes and fracture risk and yet the mechanism underlying these associations are controversial. Guided by a series of mouse studies, a specific form of the bone protein, osteocalcin, was proposed to be the mechanistic link between these two chronic d...

Organic Reaction Mechanisms in the Sixth Form Part 2.

ERIC Educational Resources Information Center

Simpson, Peter

1989-01-01

Presents the mechanistic ideas underlying reactions between nucleophiles and carbonyl compounds as well as some popular misconceptions. Relates reactions of carboxylic acid derivatives to those of aldehydes and ketones. Discusses leaving group ability and the ability of carbonyl oxygen to accept a negative charge. (Author/MVL)

Regulation of Aspergillus nidulans CreA-Mediated Catabolite Repression by the F-Box Proteins Fbx23 and Fbx47.

PubMed

de Assis, Leandro José; Ulas, Mevlut; Ries, Laure Nicolas Annick; El Ramli, Nadia Ali Mohamed; Sarikaya-Bayram, Ozlem; Braus, Gerhard H; Bayram, Ozgur; Goldman, Gustavo Henrique

2018-06-19

The attachment of one or more ubiquitin molecules by SCF ( S kp- C ullin- F -box) complexes to protein substrates targets them for subsequent degradation by the 26S proteasome, allowing the control of numerous cellular processes. Glucose-mediated signaling and subsequent carbon catabolite repression (CCR) are processes relying on the functional regulation of target proteins, ultimately controlling the utilization of this carbon source. In the filamentous fungus Aspergillus nidulans , CCR is mediated by the transcription factor CreA, which modulates the expression of genes encoding biotechnologically relevant enzymes. Although CreA-mediated repression of target genes has been extensively studied, less is known about the regulatory pathways governing CCR and this work aimed at further unravelling these events. The Fbx23 F-box protein was identified as being involved in CCR and the Δ fbx23 mutant presented impaired xylanase production under repressing (glucose) and derepressing (xylan) conditions. Mass spectrometry showed that Fbx23 is part of an SCF ubiquitin ligase complex that is bridged via the GskA protein kinase to the CreA-SsnF-RcoA repressor complex, resulting in the degradation of the latter under derepressing conditions. Upon the addition of glucose, CreA dissociates from the ubiquitin ligase complex and is transported into the nucleus. Furthermore, casein kinase is important for CreA function during glucose signaling, although the exact role of phosphorylation in CCR remains to be determined. In summary, this study unraveled novel mechanistic details underlying CreA-mediated CCR and provided a solid basis for studying additional factors involved in carbon source utilization which could prove useful for biotechnological applications. IMPORTANCE The production of biofuels from plant biomass has gained interest in recent years as an environmentally friendly alternative to production from petroleum-based energy sources. Filamentous fungi, which naturally thrive on decaying plant matter, are of particular interest for this process due to their ability to secrete enzymes required for the deconstruction of lignocellulosic material. A major drawback in fungal hydrolytic enzyme production is the repression of the corresponding genes in the presence of glucose, a process known as carbon catabolite repression (CCR). This report provides previously unknown mechanistic insights into CCR through elucidating part of the protein-protein interaction regulatory system that governs the CreA transcriptional regulator in the reference organism Aspergillus nidulans in the presence of glucose and the biotechnologically relevant plant polysaccharide xylan. Copyright © 2018 de Assis et al.

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

PubMed Central

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

2013-01-01

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

Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium.

PubMed

Decker, Keith F; Heijman, Jordi; Silva, Jonathan R; Hund, Thomas J; Rudy, Yoram

2009-04-01

Computational models of cardiac myocytes are important tools for understanding ionic mechanisms of arrhythmia. This work presents a new model of the canine epicardial myocyte that reproduces a wide range of experimentally observed rate-dependent behaviors in cardiac cell and tissue, including action potential (AP) duration (APD) adaptation, restitution, and accommodation. Model behavior depends on updated formulations for the 4-aminopyridine-sensitive transient outward current (I(to1)), the slow component of the delayed rectifier K(+) current (I(Ks)), the L-type Ca(2+) channel current (I(Ca,L)), and the Na(+)-K(+) pump current (I(NaK)) fit to data from canine ventricular myocytes. We found that I(to1) plays a limited role in potentiating peak I(Ca,L) and sarcoplasmic reticulum Ca(2+) release for propagated APs but modulates the time course of APD restitution. I(Ks) plays an important role in APD shortening at short diastolic intervals, despite a limited role in AP repolarization at longer cycle lengths. In addition, we found that I(Ca,L) plays a critical role in APD accommodation and rate dependence of APD restitution. Ca(2+) entry via I(Ca,L) at fast rate drives increased Na(+)-Ca(2+) exchanger Ca(2+) extrusion and Na(+) entry, which in turn increases Na(+) extrusion via outward I(NaK). APD accommodation results from this increased outward I(NaK). Our simulation results provide valuable insight into the mechanistic basis of rate-dependent phenomena important for determining the heart's response to rapid and irregular pacing rates (e.g., arrhythmia). Accurate simulation of rate-dependent phenomena and increased understanding of their mechanistic basis will lead to more realistic multicellular simulations of arrhythmia and identification of molecular therapeutic targets.

Linking chlorophyll a fluorescence to photosynthesis for remote sensing applications: mechanisms and challenges.

PubMed

Porcar-Castell, Albert; Tyystjärvi, Esa; Atherton, Jon; van der Tol, Christiaan; Flexas, Jaume; Pfündel, Erhard E; Moreno, Jose; Frankenberg, Christian; Berry, Joseph A

2014-08-01

Chlorophyll a fluorescence (ChlF) has been used for decades to study the organization, functioning, and physiology of photosynthesis at the leaf and subcellular levels. ChlF is now measurable from remote sensing platforms. This provides a new optical means to track photosynthesis and gross primary productivity of terrestrial ecosystems. Importantly, the spatiotemporal and methodological context of the new applications is dramatically different compared with most of the available ChlF literature, which raises a number of important considerations. Although we have a good mechanistic understanding of the processes that control the ChlF signal over the short term, the seasonal link between ChlF and photosynthesis remains obscure. Additionally, while the current understanding of in vivo ChlF is based on pulse amplitude-modulated (PAM) measurements, remote sensing applications are based on the measurement of the passive solar-induced chlorophyll fluorescence (SIF), which entails important differences and new challenges that remain to be solved. In this review we introduce and revisit the physical, physiological, and methodological factors that control the leaf-level ChlF signal in the context of the new remote sensing applications. Specifically, we present the basis of photosynthetic acclimation and its optical signals, we introduce the physical and physiological basis of ChlF from the molecular to the leaf level and beyond, and we introduce and compare PAM and SIF methodology. Finally, we evaluate and identify the challenges that still remain to be answered in order to consolidate our mechanistic understanding of the remotely sensed SIF signal. © The Author 2014. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Harmonization of cancer and noncancer risk assessment: proceedings of a consensus-building workshop.

PubMed

Bogdanffy, M S; Daston, G; Faustman, E M; Kimmel, C A; Kimmel, G L; Seed, J; Vu, V

2001-05-01

Significant advancements have been made toward the use of all relevant scientific information in health risk assessments. This principle has been set forth in risk-assessment guidance documents of international agencies including those of the World Health Organization's International Programme on Chemical Safety, the U.S. Environmental Protection Agency, and Health Canada. Improving the scientific basis of risk assessment is a leading strategic goal of the Society of Toxicology. In recent years, there has been a plethora of mechanistic research on modes of chemical toxicity that establishes mechanistic links between noncancer responses to toxic agents and subsequent overt manifestations of toxicity such as cancer. The research suggests that differences in approaches to assessing risk of cancer and noncancer toxicity need to be resolved and a common broad paradigm for dose-response assessments developed for all toxicity endpoints. In November 1999, a workshop entitled "Harmonization of Cancer and Noncancer Risk Assessment" was held to discuss the most critical issues involved in developing a more consistent and unified approach to risk assessment for all endpoints. Invited participants from government, industry, and academia discussed focus questions in the areas of mode of action as the basis for harmonization, common levels of adverse effect across toxicities for use in dose-response assessments, and scaling and uncertainty factors. This report summarizes the results of those discussions. There was broad agreement, albeit not unanimous, that current science supports the development of a harmonized set of principles that guide risk assessments for all toxic endpoints. There was an acceptance among the participants that understanding the mode of action of a chemical is ultimately critical for nondefault risk assessments, that common modes of action for different toxicities can be defined, and that our approach to assessing toxicity should be biologically consistent.

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.

Alpine treeline of western North America: Linking organism-to-landscape dynamics

USGS Publications Warehouse

Malanson, George P.; Butler, David R.; Fagre, Daniel B.; Walsh, Stephen J; Tomback, Diana F.; Daniels, Lori D.; Resler, Lynn M.; Smith, William K.; Weiss, Daniel J.; Peterson, David L.; Bunn, Andrew G.; Hiemstra, Christopher A.; Liptzin, Daniel; Bourgeron, Patrick S.; Shen, Zehao; Millar, Constance I.

2007-01-01

Although the ecological dynamics of the alpine treeline ecotone are influenced by climate, it is an imperfect indicator of climate change. Mechanistic processes that shape the ecotone—seed rain, seed germination, seedling establishment and subsequent tree growth form, or, conversely tree dieback—depend on microsite patterns. Growth forms affect wind and snow, and so develop positive and negative feedback loops that create these microsites. As a result, complex landscape patterns are generated at multiple spatial scales. Although these mechanistic processes are fundamentally the same for all forest-tundra ecotones across western North America, factors such as prior climate, underlying geology and geomorphology, and genetic constraints of dominant tree species lead to geographic differences in the responses of particular ecotones to climate change.

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.

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

PubMed

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

2018-03-16

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

Warming will affect phytoplankton differently: evidence through a mechanistic approach

PubMed Central

Huertas, I. Emma; Rouco, Mónica; López-Rodas, Victoria; Costas, Eduardo

2011-01-01

Although the consequences of global warming in aquatic ecosystems are only beginning to be revealed, a key to forecasting the impact on aquatic communities is an understanding of individual species' vulnerability to increased temperature. Despite their microscopic size, phytoplankton support about half of the global primary production, drive essential biogeochemical cycles and represent the basis of the aquatic food web. At present, it is known that phytoplankton are important targets and, consequently, harbingers of climate change in aquatic systems. Therefore, investigating the capacity of phytoplankton to adapt to the predicted warming has become a relevant issue. However, considering the polyphyletic complexity of the phytoplankton community, different responses to increased temperature are expected. We experimentally tested the effects of warming on 12 species of phytoplankton isolated from a variety of environments by using a mechanistic approach able to assess evolutionary adaptation (the so-called ratchet technique). We found different degrees of tolerance to temperature rises and an interspecific capacity for genetic adaptation. The thermal resistance level reached by each species is discussed in relation to their respective original habitats. Our study additionally provides evidence on the most resistant phytoplankton groups in a future warming scenario. PMID:21508031

Sean Michaletz Directors Post Doc Fellow Report

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

Wilson, Cathy Jean

Predicting climate change effects on plant function is a central challenge of global change biology and a primary mission of DOE. Although increasing temperatures and drought have been associated with reduced growth and increased mortality of plants, accurate prediction of such responses is limited by a lack of process-based theory linking climate and whole-plant physiology. This inability to predict forest mortality can cause significant biases in climate forecasts. One way forward is metabolic scaling theory (MST), which proposes that physiologic rates – from cells to the globe – are governed by the rates of resource distribution through vascular networks andmore » the kinetics of resource utilization by metabolic reactions. MST has traditionally not considered rates of resource acquisition from organism-environment interactions, but it has an ideal mechanistic basis for doing so. As a first step towards integrating these processes, Sean has extended MST to characterize effects of temperature and precipitation on plant growth and ecosystem production. Sean’s post doc fellowship aimed to address a remaining shortcoming in that the new theory does not yet consider the physical processes of resource acquisition, and thus cannot mechanistically predict plant performance in a changing climate.« less

Excess algal symbionts increase the susceptibility of reef corals to bleaching

NASA Astrophysics Data System (ADS)

Cunning, Ross; Baker, Andrew C.

2013-03-01

Rising ocean temperatures associated with global climate change are causing mass coral bleaching and mortality worldwide. Understanding the genetic and environmental factors that mitigate coral bleaching susceptibility may aid local management efforts to help coral reefs survive climate change. Although bleaching susceptibility depends partly on the genetic identity of a coral's algal symbionts, the effect of symbiont density, and the factors controlling it, remain poorly understood. By applying a new metric of symbiont density to study the coral Pocillopora damicornis during seasonal warming and acute bleaching, we show that symbiont cell ratio density is a function of both symbiont type and environmental conditions, and that corals with high densities are more susceptible to bleaching. Higher vulnerability of corals with more symbionts establishes a quantitative mechanistic link between symbiont density and the molecular basis for coral bleaching, and indicates that high densities do not buffer corals from thermal stress, as has been previously suggested. These results indicate that environmental conditions that increase symbiont densities, such as nutrient pollution, will exacerbate climate-change-induced coral bleaching, providing a mechanistic explanation for why local management to reduce these stressors will help coral reefs survive future warming.

Warming will affect phytoplankton differently: evidence through a mechanistic approach.

PubMed

Huertas, I Emma; Rouco, Mónica; López-Rodas, Victoria; Costas, Eduardo

2011-12-07

Although the consequences of global warming in aquatic ecosystems are only beginning to be revealed, a key to forecasting the impact on aquatic communities is an understanding of individual species' vulnerability to increased temperature. Despite their microscopic size, phytoplankton support about half of the global primary production, drive essential biogeochemical cycles and represent the basis of the aquatic food web. At present, it is known that phytoplankton are important targets and, consequently, harbingers of climate change in aquatic systems. Therefore, investigating the capacity of phytoplankton to adapt to the predicted warming has become a relevant issue. However, considering the polyphyletic complexity of the phytoplankton community, different responses to increased temperature are expected. We experimentally tested the effects of warming on 12 species of phytoplankton isolated from a variety of environments by using a mechanistic approach able to assess evolutionary adaptation (the so-called ratchet technique). We found different degrees of tolerance to temperature rises and an interspecific capacity for genetic adaptation. The thermal resistance level reached by each species is discussed in relation to their respective original habitats. Our study additionally provides evidence on the most resistant phytoplankton groups in a future warming scenario.

Radiation-induced cataracts: the Health Protection Agency's response to the ICRP statement on tissue reactions and recommendation on the dose limit for the eye lens.

PubMed

Bouffler, Simon; Ainsbury, Elizabeth; Gilvin, Phil; Harrison, John

2012-12-01

This paper presents the response of the Health Protection Agency (HPA) to the 2011 statement from the International Commission on Radiological Protection (ICRP) on tissue reactions and recommendation of a reduced dose limit for the lens of the eye. The response takes the form of a brief review of the most recent epidemiological and mechanistic evidence. This is presented together with a discussion of dose limits in the context of the related risk and the current status of eye dosimetry, which is relevant for implementation of the limits. It is concluded that although further work is desirable to quantify better the risk at low doses and following protracted exposures, along with research into the mechanistic basis for radiation cataractogenesis to inform selection of risk projection models, the HPA endorses the conclusion reached by the ICRP in their 2011 statement that the equivalent dose limit for the lens of the eye should be reduced from 150 to 20 mSv per year, averaged over a five year period, with no year's dose exceeding 50 mSv.

Microvesicating effects of sulfur mustard on an in vitro human skin model.

PubMed

Hayden, Patrick J; Petrali, John P; Stolper, Gina; Hamilton, Tracey A; Jackson, George R; Wertz, Philip W; Ito, Susumu; Smith, William J; Klausner, Mitchell

2009-10-01

Bis-(beta-chloroethyl) sulfide (SM) is a potent skin vesicant previously used for chemical warfare. Progress in determination of the mechanistic basis of SM pathology, and development of prophylactic and/or therapeutic countermeasures to SM exposure has been hampered by lack of physiologically relevant models of human skin. The current work evaluated a newly developed tissue engineered full-thickness human skin model in a completely in vitro approach to investigation of SM-induced dermal pathology. The model was first characterized with regard to overall morphology, lipid composition, basement membrane (BM) composition and ultrastructural features that are important targets of SM pathologic activity. Well-developed BM ultrastructural features were observed at the dermal-epidermal junction (DEJ), thus demonstrating successful resolution of a primary deficiency of models previously evaluated for SM studies. Studies were then conducted to evaluate histopathological effects of SM on the model. Good replication of in vivo effects was observed, including apoptosis of basal keratinocytes (KC) and microblister formation at the DEJ. Tissue engineered skin models with well-developed basement membrane structures thus appear to be useful tools for in vitro mechanistic studies of SM vesicant activity and development of preventive/therapeutic approaches for SM pathology.

Cotransin induces accumulation of a cytotoxic clusterin variant that cotranslationally rerouted to the cytosol

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

Choi, Ilho; Kim, Jiyeon; Park, Joong-Yeol

2013-05-01

Although clusterin (CLU) was originally identified as a secreted glycoprotein that plays cytoprotective role, several intracellular CLU variants have been recently identified in the diverse pathological conditions. The mechanistic basis of these variants is now believed to be alternative splicing and retrotranslocation. Here, we uncovered, an unglycosylated and signal sequence-unprocessed, CLU variant in the cytosol. This variant proved to be a product that cotranslationally rerouted to the cytosol during translocation. Cytosolic CLU was prone to aggregation at peri-nuclear region of cells and induced cell death. Signal sequence is shown to be an important determinant for cytosolic CLU generation and aggregation.more » These results provide not only a new mechanistic insight into the cytosolic CLU generation but also an idea for therapeutic mislocalization of CLU as a strategy for cancer treatment. - Highlights: ► Intracellular CLU variants have been recently identified in the diverse pathological conditions. ► Translocation of clusterin is less efficient than that of Prl. ► We identified a new cytotoxic clusterin variant whose signal sequence was unprocessed. ► This variant proved to be a product that cotranslationally rerouted to cytosol.« less

Characterization of subgrade resilient modulus for Virginia soils and its correlation with the results of other soil tests.

DOT National Transportation Integrated Search

2008-01-01

In 2004, the Guide for the Mechanistic-Empirical Design of New & Rehabilitated Pavement Structures (MEPDG) was developed under NCHRP Project 1-37A to replace the currently used 1993 Guide for Design of Pavement Structures by the American Association ...

From the Beauty of Genomic Landscapes to the Strength of Transcriptional Mechanisms.

PubMed

Natoli, Gioacchino

2016-03-24

Genomic analyses are commonly used to infer trends and broad rules underlying transcriptional control. The innovative approach by Tong et al. to interrogate genomic datasets allows extracting mechanistic information on the specific regulation of individual genes. Copyright © 2016 Elsevier Inc. All rights reserved.

Lymphohematopoietic Cancers Induced by Chemicals and Other Agents: Overview and Implications for Risk Assessment (External Review Draft)

EPA Science Inventory

This draft report provides an overview of the types of mechanisms underlying the lymphohematopoietic cancers induced by chemical agents and radiation in humans, with a primary emphasis on leukemia and leukemia-inducing agents. It focuses on how mechanistic information on human l...

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.…

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...

Aggregating Data for Computational Toxicology Applications: The U.S. Environmental Protection Agency (EPA) Aggregated Computational Toxicology Resource (ACToR) System

EPA Science Inventory

Computational toxicology combines data from high-throughput test methods, chemical structure analyses and other biological domains (e.g., genes, proteins, cells, tissues) with the goals of predicting and understanding the underlying mechanistic causes of chemical toxicity and for...

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...

Lipid Catabolism Fuels Drosophila Gut Immunity.

PubMed

Masuzzo, Ambra; Royet, Julien

2018-03-14

Immune responses and metabolic regulation are tightly coupled in animals, but the underlying mechanistic connections are not fully understood. In this issue of Cell Host & Microbe, Lee et al. (2018) reveal how sustained ROS production in the gut depends on an upstream metabolic switch. Copyright © 2018 Elsevier Inc. All rights reserved.

The VUELCO project consortium: new interdisciplinary research for improved risk mitigation and management during volcanic unrest

NASA Astrophysics Data System (ADS)

Gottsmann, J.

2012-04-01

Volcanic unrest is a complex multi-hazard phenomenon of volcanism. The fact that unrest may, but not necessarily must lead to an imminent eruption contributes significant uncertainty to short-term hazard assessment of volcanic activity world-wide. Although it is reasonable to assume that all eruptions are associated with precursory activity of some sort, the knowledge of the causative links between subsurface processes, resulting unrest signals and imminent eruption is, today, inadequate to deal effectively with crises of volcanic unrest. This results predominantly from the uncertainties in identifying the causative processes of unrest and as a consequence in forecasting its short-term evolution. However, key for effective risk mitigation and management during unrest is the early and reliable identification of changes in the subsurface dynamics of a volcano and their assessment as precursors to an impending eruption. The VUELCO project consortium has come together for a multi-disciplinary attack on the origin, nature and significance of volcanic unrest from the scientific contributions generated by collaboration of ten partners in Europe and Latin America. Dissecting the science of monitoring data from unrest periods at six type volcanoes in Italy, Spain, the West Indies, Mexico and Ecuador the consortium will create global strategies for 1) enhanced monitoring capacity and value, 2) mechanistic data interpretation and 3) identification of reliable eruption precursors; all from the geophysical, geochemical and geodetic fingerprints of unrest episodes. Experiments will establish a mechanistic understanding of subsurface processes capable of inducing unrest and aid in identifying key volcano monitoring parameters indicative of the nature of unrest processes. Numerical models will help establish a link between the processes and volcano monitoring data to inform on the causes of unrest and its short-term evolution. Using uncertainty assessment and new short-term probabilistic hazard forecasting tools the scientific knowledge base will provide the crucial parameters for a comprehensive and best-practice approach to 1) risk mitigation, 2) communication, 3) decision-making and 4) crisis management during unrest periods. The VUELCO project consortium efforts will generate guidance in the definition and implementation of strategic options for effective risk mitigation, management and governance during unrest episodes. Such a mechanistic platform of understanding, impacting on the synergy of scientists, policy-makers, civil protection authorities, decision-makers, and the public, will place volcanic unrest management on a new basis, with European expertise at its peak. The project is financed by the European Commission under the 7th Framework Programme for Research and Technological Development, Area "Environment".

Light environment change induces differential expression of guppy opsins in a multi-generational evolution experiment.

PubMed

Kranz, Alexandrea M; Forgan, Leonard G; Cole, Gemma L; Endler, John A

2018-06-19

Light environments critically impact species that rely on vision to survive and reproduce. Animal visual systems must accommodate changes in light that occur from minutes to years, yet the mechanistic basis of their response to spectral (color) changes is largely unknown. Here we used a laboratory experiment where replicate guppy populations were kept under three different light environments for up to 8-12 generations to explore possible differences in the expression levels of nine guppy opsin genes. Previous evidence for opsin expression-light environment 'tuning' has been either correlative or focused exclusively on the relationship between the light environment and opsin expression over one or two generations. In our multi-generation experiment, the relative expression levels of nine different guppy opsin genes responded differently to light environment changes: some did not respond, while others differed due to phenotypic plasticity. Moreover, for the LWS-1 opsin we found that, while we observed a wide range of plastic responses under different light conditions, common plastic responses (where the population replicates all followed the same trajectory) occurred only after multigenerational exposure to different light environments. Taken together this suggests that opsin expression plasticity plays an important role in light environment 'tuning' in different light environments on different time scales, and, in turn, has important implications for both visual system function and evolution. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

A UV-B-specific signaling component orchestrates plant UV protection

PubMed Central

Brown, Bobby A.; Cloix, Catherine; Jiang, Guang Huai; Kaiserli, Eirini; Herzyk, Pawel; Kliebenstein, Daniel J.; Jenkins, Gareth I.

2005-01-01

UV-B radiation in sunlight has diverse effects on humans, animals, plants, and microorganisms. UV-B can cause damage to molecules and cells, and consequently organisms need to protect against and repair UV damage to survive in sunlight. In plants, low nondamaging levels of UV-B stimulate transcription of genes involved in UV-protective responses. However, remarkably little is known about the underlying mechanisms of UV-B perception and signal transduction. Here we report that Arabidopsis UV RESISTANCE LOCUS 8 (UVR8) is a UV-B-specific signaling component that orchestrates expression of a range of genes with vital UV-protective functions. Moreover, we show that UVR8 regulates expression of the transcription factor HY5 specifically when the plant is exposed to UV-B. We demonstrate that HY5 is a key effector of the UVR8 pathway, and that it is required for survival under UV-B radiation. UVR8 has sequence similarity to the eukaryotic guanine nucleotide exchange factor RCC1, but we found that it has little exchange activity. However, UVR8, like RCC1, is located principally in the nucleus and associates with chromatin via histones. Chromatin immunoprecipitation showed that UVR8 associates with chromatin in the HY5 promoter region, providing a mechanistic basis for its involvement in regulating transcription. We conclude that UVR8 defines a UV-B-specific signaling pathway in plants that orchestrates the protective gene expression responses to UV-B required for plant survival in sunlight. PMID:16330762

The linkage between nutrient supply, intracellular enzyme abundances and bacterial growth: New evidences from the central carbon metabolism of Corynebacterium glutamicum.

PubMed

Noack, Stephan; Voges, Raphael; Gätgens, Jochem; Wiechert, Wolfgang

2017-09-20

Corynebacterium glutamicum serves as important production host for small molecular compounds that are derived from precursor molecules of the central carbon metabolism. It is therefore a well-studied model organism of industrial biotechnology. However, a deeper understanding of the regulatory principles underlying the synthesis of central metabolic enzymes under different environmental conditions as well as its impact on cell growth is still missing. We studied enzyme abundances in C. glutamicum in response to growth on: (i) one limiting carbon source by sampling chemostat and fed-batch cultivations and (ii) changing carbon sources provided in excess by sampling batch cultivations. The targeted quantification of 20 central metabolic enzymes by isotope dilution mass spectrometry revealed that cells maintain stable enzyme concentrations when grown on d-glucose as single carbon and energy source and, most importantly, independent of its availability. By contrast, switching from d-glucose to d-fructose, d-mannose, d-arabitol, acetate, l-lactate or l-glutamate results in highly specific enzyme regulation patterns that can partly be explained by the activity of known transcriptional regulators. Based on these experimental results we propose a simple framework for modeling cell population growth as a nested function of nutrient supply and intracellular enzyme abundances. In summary, our study extends the basis for the formulation of predictive mechanistic models of bacterial growth, applicable in industrial bioprocess development. Copyright © 2017 Elsevier B.V. All rights reserved.

Kinetic spectrophotometric method for trace determination of thiocyanate based on its inhibitory effect

NASA Astrophysics Data System (ADS)

Naik, Radhey M.; Kumar, Basant; Asthana, Abhas

2010-03-01

A kinetic spectrophotometric method for the determination of thiocyanate, based on its inhibitory effect on silver(I) catalyzed substitution of cyanide ion, by phenylhydrazine in hexacyanoferrate(II) is described. Thiocyanate ions form strong complexes with silver(I) catalyst which is used as the basis for its determination at trace level. The progress of reaction was monitored, spectrophotometrically, at 488 nm ( λmax of [Fe(CN) 5PhNHNH 2] 3-, complex) under the optimum reaction conditions at: 2.5 × 10 -3 M [Fe(CN) 6] 4-, 1.0 × 10 -3 M [PhNHNH 2], 8.0 × 10 -7 M [Ag +], pH 2.8 ± 0.02, ionic strength ( μ) 0.02 M (KNO 3) and temperature 30 ± 0.1 °C. A linear relationship obtained between absorbance (measured at 488 nm at different times) and inhibitor concentration, under specified conditions, has been used for the determination of [thiocyanate] in the range of 0.8-8.0 × 10 -8 M with a detection limit of 2 × 10 -9 M. The standard deviation and percentage error have been calculated and reported with each datum. A most plausible mechanistic scheme has been proposed for the reaction. The values of equilibrium constants for complex formation between catalyst-inhibitor ( KCI), catalyst-substrate ( Ks) and Michaelis-Menten constant ( Km) have been computed from the kinetic data. The influence of possible interference by major cations and anions on the determination of thiocyanate and their limits has been investigated.

Dehydrophenylnitrenes: matrix isolation and photochemical rearrangements.

PubMed

Sander, Wolfram; Winkler, Michael; Cakir, Bayram; Grote, Dirk; Bettinger, Holger F

2007-02-02

The photochemistry of 3-iodo-2,4,5,6-tetrafluorophenyl azide 8 and 3,5-diiodo-2,4,6-trifluorophenyl azide 9 was studied by IR and EPR spectroscopy in cryogenic argon and neon matrices. Both compounds form the corresponding nitrenes as primary photoproducts in photostationary equilibria with their azirine and ketenimine isomers. In contrast to fluorinated phenylnitrenes, ring-opened products are obtained upon short-wavelength irradiation of the iodine-containing systems, indicative of C-I bond cleavage in the nitrenes or didehydroazepines under these conditions. Neither 3-dehydrophenylnitrene 6 nor 3,5-didehydrophenylnitrene 7 could be detected directly. The structures of the acyclic photoproducts were identified by extensive comparison with DFT calculated spectra. Mechanistic aspects of the rearrangements leading to the observed products and the electronic properties of the title intermediates are discussed on the basis of DFT as well as high-level ab initio calculations. The computations indicate strong through-bond coupling of the exocyclic orbital in the meta position with the singly occupied in-plane nitrene orbital in the monoradical nitrenes. In contrast to the ortho or para isomers, this interaction results in low-spin ground states for meta nitrene radicals and a weakening of the C1-C2 bond causing the kinetic instability of these species even under low-temperature conditions. 3,5-Didehydrophenylnitrenes, on the other hand, in which a strong C3-C5 interaction reduces coupling of the radical sites with the nitrene unit, might be accessible synthetic targets if the intermediate formation of labile monoradicals could be circumvented.

Allelic variations and differential expressions detected at quantitative trait loci for salt stress tolerance in wheat.

PubMed

Oyiga, Benedict C; Sharma, Ram C; Baum, Michael; Ogbonnaya, Francis C; Léon, Jens; Ballvora, Agim

2018-05-01

The increasing salinization of agricultural lands is a threat to global wheat production. Understanding of the mechanistic basis of salt tolerance (ST) is essential for developing breeding and selection strategies that would allow for increased wheat production under saline conditions to meet the increasing global demand. We used a set that consists of 150 internationally derived winter and facultative wheat cultivars genotyped with a 90K SNP chip and phenotyped for ST across three growth stages and for ionic (leaf K + and Na +  contents) traits to dissect the genetic architecture regulating ST in wheat. Genome-wide association mapping revealed 187 Single Nucleotide Polymorphism (SNPs) (R 2  = 3.00-30.67%), representing 37 quantitative trait loci (QTL), significantly associated with the ST traits. Of these, four QTL on 1BS, 2AL, 2BS and 3AL were associated with ST across the three growth stages and with the ionic traits. Novel QTL were also detected on 1BS and 1DL. Candidate genes linked to these polymorphisms were uncovered, and expression analyses were performed and validated on them under saline and non-saline conditions using transcriptomics and qRT-PCR data. Expressed sequence comparisons in contrasting ST wheat genotypes identified several non-synonymous/missense mutation sites that are contributory to the ST trait variations, indicating the biological relevance of these polymorphisms that can be exploited in breeding for ST in wheat. © 2017 The Authors. Plant, Cell & Environment published by JohnWiley & Sons Ltd.

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

PubMed

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

2018-01-01

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

Speciation genetics: current status and evolving approaches

PubMed Central

Wolf, Jochen B. W.; Lindell, Johan; Backström, Niclas

2010-01-01

The view of species as entities subjected to natural selection and amenable to change put forth by Charles Darwin and Alfred Wallace laid the conceptual foundation for understanding speciation. Initially marred by a rudimental understanding of hereditary principles, evolutionists gained appreciation of the mechanistic underpinnings of speciation following the merger of Mendelian genetic principles with Darwinian evolution. Only recently have we entered an era where deciphering the molecular basis of speciation is within reach. Much focus has been devoted to the genetic basis of intrinsic postzygotic isolation in model organisms and several hybrid incompatibility genes have been successfully identified. However, concomitant with the recent technological advancements in genome analysis and a newfound interest in the role of ecology in the differentiation process, speciation genetic research is becoming increasingly open to non-model organisms. This development will expand speciation research beyond the traditional boundaries and unveil the genetic basis of speciation from manifold perspectives and at various stages of the splitting process. This review aims at providing an extensive overview of speciation genetics. Starting from key historical developments and core concepts of speciation genetics, we focus much of our attention on evolving approaches and introduce promising methodological approaches for future research venues. PMID:20439277

Structure of a tetrameric galectin from Cinachyrella sp. (ball sponge)

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

Freymann, Douglas M., E-mail: freymann@northwestern.edu; Nakamura, Yuka; Focia, Pamela J.

2012-09-01

The structure of a tetrameric sponge galectin suggests a basis for glutamate receptor potentiation. The galectins are a family of proteins that bind with highest affinity to N-acetyllactosamine disaccharides, which are common constituents of asparagine-linked complex glycans. They play important and diverse physiological roles, particularly in the immune system, and are thought to be critical metastatic agents for many types of cancer cells, including gliomas. A recent bioactivity-based screen of marine sponge (Cinachyrella sp.) extract identified an ancestral member of the galectin family based on its unexpected ability to positively modulate mammalian ionotropic glutamate receptor function. To gain insight intomore » the mechanistic basis of this activity, the 2.1 Å resolution X-ray structure of one member of the family, galectin CchG-1, is reported. While the protomer exhibited structural similarity to mammalian prototype galectin, CchG-1 adopts a novel tetrameric arrangement in which a rigid toroidal-shaped ‘donut’ is stabilized in part by the packing of pairs of vicinal disulfide bonds. Twofold symmetry between binding-site pairs provides a basis for a model for interaction with ionotropic glutamate receptors.« less

Motor cognition-motor semantics: action perception theory of cognition and communication.

PubMed

Pulvermüller, Friedemann; Moseley, Rachel L; Egorova, Natalia; Shebani, Zubaida; Boulenger, Véronique

2014-03-01

A new perspective on cognition views cortical cell assemblies linking together knowledge about actions and perceptions not only as the vehicles of integrated action and perception processing but, furthermore, as a brain basis for a wide range of higher cortical functions, including attention, meaning and concepts, sequences, goals and intentions, and even communicative social interaction. This article explains mechanisms relevant to mechanistic action perception theory, points to concrete neuronal circuits in brains along with artificial neuronal network simulations, and summarizes recent brain imaging and other experimental data documenting the role of action perception circuits in cognition, language and communication. © 2013 Published by Elsevier Ltd.

Human colon cancer HT-29 cell death responses to doxorubicin and Morus Alba leaves flavonoid extract.

PubMed

Fallah, S; Karimi, A; Panahi, G; Gerayesh Nejad, S; Fadaei, R; Seifi, M

2016-03-31

The mechanistic basis for the biological properties of Morus alba flavonoid extract (MFE) and chemotherapy drug of doxorubicin on human colon cancer HT-29 cell line death are unknown. The effect of doxorubicin and flavonoid extract on colon cancer HT-29 cell line death and identification of APC gene expression and PARP concentration of HT-29 cell line were investigated. The results showed that flavonoid extract and doxorubicin induce a dose dependent cell death in HT-29 cell line. MFE and doxorubicin exert a cytotoxic effect on human colon cancer HT-29 cell line by probably promoting or induction of apoptosis.

Structural Basis for Methylarginine-dependent Recognition of Aubergine by Tudor

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

Liu, H.; Wang, J; Huang, Y

2010-01-01

Piwi proteins are modified by symmetric dimethylation of arginine (sDMA), and the methylarginine-dependent interaction with Tudor domain proteins is critical for their functions in germline development. Cocrystal structures of an extended Tudor domain (eTud) of Drosophila Tudor with methylated peptides of Aubergine, a Piwi family protein, reveal that sDMA is recognized by an asparagine-gated aromatic cage. Furthermore, the unexpected Tudor-SN/p100 fold of eTud is important for sensing the position of sDMA. The structural information provides mechanistic insights into sDMA-dependent Piwi-Tudor interaction, and the recognition of sDMA by Tudor domains in general.

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

Juberg, D.R.; Loch-Caruso, R.

Elevated levels of DDT and other organochlorine pesticides have been associated with spontaneous abortion and preterm birth in several species, including humans. Despite the prevalence of organochlorine pesticides in the environment, a mechanistic basis for this association has not been explored. Furthermore, while DDT has been associated with inhibition of calcium ATPases, altered gap junctional communication and electrophysiological changes, all of which could affect the excitation-contraction process characteristic of smooth muscle, direct effects of DDT on uterine smooth muscle have not been reported. This study was initiated to assess the direct effects of o,p{prime}-DDT (an estrogenic isomer present in themore » technical grade preparation) on pregnant rat uterine tissue.« less

Mechanism of epithelial lithium transport. Evidence for basolateral Na:Na and Na:Li exchange

PubMed Central

1983-01-01

Measurement of transmural sodium fluxes across isolated, ouabain- inhibited turtle colon in the presence of a serosal-to-mucosal sodium gradient shows that in the absence of active transport the amiloride- sensitive cellular path contains at least two routes for the transmural movement of sodium and lithium, one a conductive path and the other a nonconductive, cation-exchange mechanism. The latter transport element can exchange lithium for sodium, and the countertransport of these two cations provides a mechanistic basis for the ability of tight epithelia to actively absorb lithium despite the low affinity of the basolateral Na/K-ATPase for this cation. PMID:6644269

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.

Inhibiting Microbial Toxins Using Plant-Derived Compounds and Plant Extracts

PubMed Central

Upadhyay, Abhinav; Mooyottu, Shankumar; Yin, Hsinbai; Surendran Nair, Meera; Bhattaram, Varunkumar; Venkitanarayanan, Kumar

2015-01-01

Many pathogenic bacteria and fungi produce potentially lethal toxins that cause cytotoxicity or impaired cellular function either at the site of colonization or other locations in the body through receptor-mediated interactions. Various factors, including biotic and abiotic environments, competing microbes, and chemical cues affect toxin expression in these pathogens. Recent work suggests that several natural compounds can modulate toxin production in pathogenic microbes. However, studies explaining the mechanistic basis for their effect are scanty. This review discusses the potential of various plant-derived compounds for reducing toxin production in foodborne and other microbes. In addition, studies highlighting their anti-toxigenic mechanism(s) are discussed. PMID:28930207

Whole-body iron transport and metabolism: Mechanistic, multi-scale model to improve treatment of anemia in chronic kidney disease

PubMed Central

Sarkar, Joydeep

2018-01-01

Iron plays vital roles in the human body including enzymatic processes, oxygen-transport via hemoglobin and immune response. Iron metabolism is characterized by ~95% recycling and minor replenishment through diet. Anemia of chronic kidney disease (CKD) is characterized by a lack of synthesis of erythropoietin leading to reduced red blood cell (RBC) formation and aberrant iron recycling. Treatment of CKD anemia aims to normalize RBC count and serum hemoglobin. Clinically, the various fluxes of iron transport and accumulation are not measured so that changes during disease (e.g., CKD) and treatment are unknown. Unwanted iron accumulation in patients is known to lead to adverse effects. Current whole-body models lack the mechanistic details of iron transport related to RBC maturation, transferrin (Tf and TfR) dynamics and assume passive iron efflux from macrophages. Hence, they are not predictive of whole-body iron dynamics and cannot be used to design individualized patient treatment. For prediction, we developed a mechanistic, multi-scale computational model of whole-body iron metabolism incorporating four compartments containing major pools of iron and RBC generation process. The model accounts for multiple forms of iron in vivo, mechanisms involved in iron uptake and release and their regulation. Furthermore, the model is interfaced with drug pharmacokinetics to allow simulation of treatment dynamics. We calibrated our model with experimental and clinical data from peer-reviewed literature to reliably simulate CKD anemia and the effects of current treatment involving combination of epoietin-alpha and iron dextran. This in silico whole-body model of iron metabolism predicts that a year of treatment can potentially lead to 90% downregulation of ferroportin (FPN) levels, 15-fold increase in iron stores with only a 20% increase in iron flux from the reticulo-endothelial system (RES). Model simulations quantified unmeasured iron fluxes, previously unknown effects of treatment on FPN-level and iron stores in the RES. This mechanistic whole-body model can be the basis for future studies that incorporate iron metabolism together with related clinical experiments. Such an approach could pave the way for development of effective personalized treatment of CKD anemia. PMID:29659573

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.

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

PubMed

Klinke, David J; Wang, Qing

2016-01-01

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

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

NASA Astrophysics Data System (ADS)

Worman, Stacey; Furbish, David; Fathel, Siobhan

2014-05-01

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

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

NASA Astrophysics Data System (ADS)

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

2016-07-01

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

Mechanisms of Myofascial Pain

PubMed Central

Jafri, M. Saleet

2014-01-01

Myofascial pain syndrome is an important health problem. It affects a majority of the general population, impairs mobility, causes pain, and reduces the overall sense of well-being. Underlying this syndrome is the existence of painful taut bands of muscle that contain discrete, hypersensitive foci called myofascial trigger points. In spite of the significant impact on public health, a clear mechanistic understanding of the disorder does not exist. This is likely due to the complex nature of the disorder which involves the integration of cellular signaling, excitation-contraction coupling, neuromuscular inputs, local circulation, and energy metabolism. The difficulties are further exacerbated by the lack of an animal model for myofascial pain to test mechanistic hypothesis. In this review, current theories for myofascial pain are presented and their relative strengths and weaknesses are discussed. Based on new findings linking mechanoactivation of reactive oxygen species signaling to destabilized calcium signaling, we put forth a novel mechanistic hypothesis for the initiation and maintenance of myofascial trigger points. It is hoped that this lays a new foundation for understanding myofascial pain syndrome and how current therapies work, and gives key insights that will lead to the improvement of therapies for its treatment. PMID:25574501

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

PubMed

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

2016-04-01

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

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...

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...

Genetic effects on gene expression across human tissues

PubMed Central

2017-01-01

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease. PMID:29022597

Structure and Functional Diversity of GCN5-Related N-Acetyltransferases (GNAT)

PubMed Central

Salah Ud-Din, Abu Iftiaf Md; Tikhomirova, Alexandra; Roujeinikova, Anna

2016-01-01

General control non-repressible 5 (GCN5)-related N-acetyltransferases (GNAT) catalyze the transfer of an acyl moiety from acyl coenzyme A (acyl-CoA) to a diverse group of substrates and are widely distributed in all domains of life. This review of the currently available data acquired on GNAT enzymes by a combination of structural, mutagenesis and kinetic methods summarizes the key similarities and differences between several distinctly different families within the GNAT superfamily, with an emphasis on the mechanistic insights obtained from the analysis of the complexes with substrates or inhibitors. It discusses the structural basis for the common acetyltransferase mechanism, outlines the factors important for the substrate recognition, and describes the mechanism of action of inhibitors of these enzymes. It is anticipated that understanding of the structural basis behind the reaction and substrate specificity of the enzymes from this superfamily can be exploited in the development of novel therapeutics to treat human diseases and combat emerging multidrug-resistant microbial infections. PMID:27367672

Structural and Functional Basis of the Fidelity of Nucleotide Selection by Flavivirus RNA-Dependent RNA Polymerases

PubMed Central

Canard, Bruno

2018-01-01

Viral RNA-dependent RNA polymerases (RdRps) play a central role not only in viral replication, but also in the genetic evolution of viral RNAs. After binding to an RNA template and selecting 5′-triphosphate ribonucleosides, viral RdRps synthesize an RNA copy according to Watson-Crick base-pairing rules. The copy process sometimes deviates from both the base-pairing rules specified by the template and the natural ribose selectivity and, thus, the process is error-prone due to the intrinsic (in)fidelity of viral RdRps. These enzymes share a number of conserved amino-acid sequence strings, called motifs A–G, which can be defined from a structural and functional point-of-view. A co-relation is gradually emerging between mutations in these motifs and viral genome evolution or observed mutation rates. Here, we review our current knowledge on these motifs and their role on the structural and mechanistic basis of the fidelity of nucleotide selection and RNA synthesis by Flavivirus RdRps. PMID:29385764

Structural Basis of TLR5-Flagellin Recognition and Signaling

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

Yoon, Sung-il; Kurnasov, Oleg; Natarajan, Venkatesh

2012-03-01

Toll-like receptor 5 (TLR5) binding to bacterial flagellin activates signaling through the transcription factor NF-{kappa}B and triggers an innate immune response to the invading pathogen. To elucidate the structural basis and mechanistic implications of TLR5-flagellin recognition, we determined the crystal structure of zebrafish TLR5 (as a variable lymphocyte receptor hybrid protein) in complex with the D1/D2/D3 fragment of Salmonella flagellin, FliC, at 2.47 angstrom resolution. TLR5 interacts primarily with the three helices of the FliC D1 domain using its lateral side. Two TLR5-FliC 1:1 heterodimers assemble into a 2:2 tail-to-tail signaling complex that is stabilized by quaternary contacts of themore » FliC D1 domain with the convex surface of the opposing TLR5. The proposed signaling mechanism is supported by structure-guided mutagenesis and deletion analyses on CBLB502, a therapeutic protein derived from FliC.« less

The Bad, the Good, and the Ugly about Oxidative Stress

PubMed Central

Jimenez-Del-Rio, Marlene; Velez-Pardo, Carlos

2012-01-01

Alzheimer's disease (AD), Parkinson's disease (PD), and cancer (e.g., leukemia) are the most devastating disorders affecting millions of people worldwide. Except for some kind of cancers, no effective and/or definitive therapeutic treatment aimed to reduce or to retard the clinic and pathologic symptoms induced by AD and PD is presently available. Therefore, it is urgently needed to understand the molecular basis of these disorders. Since oxidative stress (OS) is an important etiologic factor of the pathologic process of AD, PD, and cancer, understanding how intracellular signaling pathways respond to OS will have a significant implication in the therapy of these diseases. Here, we propose a model of minimal completeness of cell death signaling induced by OS as a mechanistic explanation of neuronal and cancer cell demise. This mechanism might provide the basis for therapeutic design strategies. Finally, we will attempt to associate PD, cancer, and OS. This paper critically analyzes the evidence that support the “oxidative stress model” in neurodegeneration and cancer. PMID:22619696

Does CTCF mediate between nuclear organization and gene expression?

PubMed

Ohlsson, Rolf; Lobanenkov, Victor; Klenova, Elena

2010-01-01

The multifunctional zinc-finger protein CCCTC-binding factor (CTCF) is a very strong candidate for the role of coordinating the expression level of coding sequences with their three-dimensional position in the nucleus, apparently responding to a "code" in the DNA itself. Dynamic interactions between chromatin fibers in the context of nuclear architecture have been implicated in various aspects of genome functions. However, the molecular basis of these interactions still remains elusive and is a subject of intense debate. Here we discuss the nature of CTCF-DNA interactions, the CTCF-binding specificity to its binding sites and the relationship between CTCF and chromatin, and we examine data linking CTCF with gene regulation in the three-dimensional nuclear space. We discuss why these features render CTCF a very strong candidate for the role and propose a unifying model, the "CTCF code," explaining the mechanistic basis of how the information encrypted in DNA may be interpreted by CTCF into diverse nuclear functions.

Magnetic particle-mediated magnetoreception

PubMed Central

Shaw, Jeremy; Boyd, Alastair; House, Michael; Woodward, Robert; Mathes, Falko; Cowin, Gary; Saunders, Martin; Baer, Boris

2015-01-01

Behavioural studies underpin the weight of experimental evidence for the existence of a magnetic sense in animals. In contrast, studies aimed at understanding the mechanistic basis of magnetoreception by determining the anatomical location, structure and function of sensory cells have been inconclusive. In this review, studies attempting to demonstrate the existence of a magnetoreceptor based on the principles of the magnetite hypothesis are examined. Specific attention is given to the range of techniques, and main animal model systems that have been used in the search for magnetite particulates. Anatomical location/cell rarity and composition are identified as two key obstacles that must be addressed in order to make progress in locating and characterizing a magnetite-based magnetoreceptor cell. Avenues for further study are suggested, including the need for novel experimental, correlative, multimodal and multidisciplinary approaches. The aim of this review is to inspire new efforts towards understanding the cellular basis of magnetoreception in animals, which will in turn inform a new era of behavioural research based on first principles. PMID:26333810

Tracking footprints of artificial selection in the dog genome.

PubMed

Akey, Joshua M; Ruhe, Alison L; Akey, Dayna T; Wong, Aaron K; Connelly, Caitlin F; Madeoy, Jennifer; Nicholas, Thomas J; Neff, Mark W

2010-01-19

The size, shape, and behavior of the modern domesticated dog has been sculpted by artificial selection for at least 14,000 years. The genetic substrates of selective breeding, however, remain largely unknown. Here, we describe a genome-wide scan for selection in 275 dogs from 10 phenotypically diverse breeds that were genotyped for over 21,000 autosomal SNPs. We identified 155 genomic regions that possess strong signatures of recent selection and contain candidate genes for phenotypes that vary most conspicuously among breeds, including size, coat color and texture, behavior, skeletal morphology, and physiology. In addition, we demonstrate a significant association between HAS2 and skin wrinkling in the Shar-Pei, and provide evidence that regulatory evolution has played a prominent role in the phenotypic diversification of modern dog breeds. Our results provide a first-generation map of selection in the dog, illustrate how such maps can rapidly inform the genetic basis of canine phenotypic variation, and provide a framework for delineating the mechanistic basis of how artificial selection promotes rapid and pronounced phenotypic evolution.

Genetic effects on gene expression across human tissues.

PubMed

Battle, Alexis; Brown, Christopher D; Engelhardt, Barbara E; Montgomery, Stephen B

2017-10-11

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease.

Three-dimensional visualization of gammaherpesvirus life cycle in host cells by electron tomography.

PubMed

Peng, Li; Ryazantsev, Sergey; Sun, Ren; Zhou, Z Hong

2010-01-13

Gammaherpesviruses are etiologically associated with human tumors. A three-dimensional (3D) examination of their life cycle in the host is lacking, significantly limiting our understanding of the structural and molecular basis of virus-host interactions. Here, we report the first 3D visualization of key stages of the murine gammaherpesvirus 68 life cycle in NIH 3T3 cells, including viral attachment, entry, assembly, and egress, by dual-axis electron tomography. In particular, we revealed the transient processes of incoming capsids injecting viral DNA through nuclear pore complexes and nascent DNA being packaged into progeny capsids in vivo as a spool coaxial with the putative portal vertex. We discovered that intranuclear invagination of both nuclear membranes is involved in nuclear egress of herpesvirus capsids. Taken together, our results provide the structural basis for a detailed mechanistic description of gammaherpesvirus life cycle and also demonstrate the advantage of electron tomography in dissecting complex cellular processes of viral infection.

The bad, the good, and the ugly about oxidative stress.

PubMed

Jimenez-Del-Rio, Marlene; Velez-Pardo, Carlos

2012-01-01

Alzheimer's disease (AD), Parkinson's disease (PD), and cancer (e.g., leukemia) are the most devastating disorders affecting millions of people worldwide. Except for some kind of cancers, no effective and/or definitive therapeutic treatment aimed to reduce or to retard the clinic and pathologic symptoms induced by AD and PD is presently available. Therefore, it is urgently needed to understand the molecular basis of these disorders. Since oxidative stress (OS) is an important etiologic factor of the pathologic process of AD, PD, and cancer, understanding how intracellular signaling pathways respond to OS will have a significant implication in the therapy of these diseases. Here, we propose a model of minimal completeness of cell death signaling induced by OS as a mechanistic explanation of neuronal and cancer cell demise. This mechanism might provide the basis for therapeutic design strategies. Finally, we will attempt to associate PD, cancer, and OS. This paper critically analyzes the evidence that support the "oxidative stress model" in neurodegeneration and cancer.

PCAN: phenotype consensus analysis to support disease-gene association.

PubMed

Godard, Patrice; Page, Matthew

2016-12-07

Bridging genotype and phenotype is a fundamental biomedical challenge that underlies more effective target discovery and patient-tailored therapy. Approaches that can flexibly and intuitively, integrate known gene-phenotype associations in the context of molecular signaling networks are vital to effectively prioritize and biologically interpret genes underlying disease traits of interest. We describe Phenotype Consensus Analysis (PCAN); a method to assess the consensus semantic similarity of phenotypes in a candidate gene's signaling neighborhood. We demonstrate that significant phenotype consensus (p < 0.05) is observable for ~67% of 4,549 OMIM disease-gene associations, using a combination of high quality String interactions + Metabase pathways and use Joubert Syndrome to demonstrate the ease with which a significant result can be interrogated to highlight discriminatory traits linked to mechanistically related genes. We advocate phenotype consensus as an intuitive and versatile method to aid disease-gene association, which naturally lends itself to the mechanistic deconvolution of diverse phenotypes. We provide PCAN to the community as an R package ( http://bioconductor.org/packages/PCAN/ ) to allow flexible configuration, extension and standalone use or integration to supplement existing gene prioritization workflows.

Iron availability influences 15N-isotope fractionation during nitrogen fixation by aerobic chemoheterotroph Azotobacter vinelandii

NASA Astrophysics Data System (ADS)

Zhang, X.; Kopf, S.; Lee, A. C.

2016-12-01

The N stable isotope composition (δ15N) of biomass provides a powerful tool for reconstructing present and past N cycling, but its interpretation hinges on a complete understanding of the isotopic signature of biological nitrogen fixation, which sets the δ15N of newly fixed N. All biological nitrogen fixation is catalyzed by the metalloenzyme nitrogenase in a complex reaction that reduces inert atmospheric N2 gas into bioavailable ammonium. Recent investigations into the metal cofactor variants of nitrogenase revealed that the canonical Mo-, and alternative V-, and Fe-only isoforms of nitrogenase impart different isotope fractionations during N2 fixation in vivo, challenging the traditional view that N2 fixation only imparts small, invariable isotope effects of 0-2‰. However, the mechanistic basis for the fractionation of N2 fixation remains largely unknown. To better understand mechanisms underlying fractionation, we varied Fe availability and measured in vivo fractionations for the aerobic chemoheterotroph Azotobacter vinelandii utilizing Mo- or V-nitrogenase under batch culture conditions. Under all iron conditions, N2 fixation based on Mo-nitrogenase yielded lower fractionations (heavier biomasss δ15N) compared to V-nitrogenase. For fractionations associated with a single metalloenzyme, higher Fe concentrations, which correlated with faster growth rates, yielded small but systematically larger fractionations ( 1 ‰ increase for Mo- and V- nitrogenases). To directly determine the effect of growth rate on fractionation, we grew Mo-nitrogenase expressing A. vinelandii in Fe-replete medium at different growth rates using chemostats and found that growth rate alone does not alter fractionation. The results indicate that Fe availability, in addition to the type of nitrogenase metalloenzyme, controls 15N fractionation during N2 fixation by A. vinelandii.

Characterization of Photochemical Processes for H2 Production by CdS Nanorod-[FeFe] Hydrogenase Complexes

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

Brown, K. A.; Wilker, M. B.; Boehm, M.

2012-03-28

We have developed complexes of CdS nanorods capped with 3-mercaptopropionic acid (MPA) and Clostridium acetobutylicum [FeFe]-hydrogenase I (CaI) that photocatalyze reduction of H{sup +} to H{sub 2} at a CaI turnover frequency of 380-900 s{sup -1} and photon conversion efficiencies of up to 20% under illumination at 405 nm. In this paper, we focus on the compositional and mechanistic aspects of CdS:CaI complexes that control the photochemical conversion of solar energy into H{sub 2}. Self-assembly of CdS with CaI was driven by electrostatics, demonstrated as the inhibition of ferredoxin-mediated H{sub 2} evolution by CaI. Production of H{sub 2} by CdS:CaImore » was observed only under illumination and only in the presence of a sacrificial donor. We explored the effects of the CdS:CaI molar ratio, sacrificial donor concentration, and light intensity on photocatalytic H{sub 2} production, which were interpreted on the basis of contributions to electron transfer, hole transfer, or rate of photon absorption, respectively. Each parameter was found to have pronounced effects on the CdS:CaI photocatalytic activity. Specifically, we found that under 405 nm light at an intensity equivalent to total AM 1.5 solar flux, H{sub 2} production was limited by the rate of photon absorption ({approx}1 ms{sup -1}) and not by the turnover of CaI. Complexes were capable of H{sub 2} production for up to 4 h with a total turnover number of 106 before photocatalytic activity was lost. This loss correlated with inactivation of CaI, resulting from the photo-oxidation of the CdS capping ligand MPA.« less

Regulatory domain phosphorylation to distinguish the mechanistic basis underlying acute CFTR modulators

PubMed Central

Pyle, Louise C.; Ehrhardt, Annette; Mitchell, Lisa High; Fan, LiJuan; Ren, Aixia; Naren, Anjaparavanda P.; Li, Yao; Clancy, J. P.; Bolger, Graeme B.; Sorscher, Eric J.

2011-01-01

Modulator compounds intended to overcome disease-causing mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) show significant promise in clinical testing for cystic fibrosis. However, the mechanism(s) of action underlying these compounds are not fully understood. Activation of CFTR ion transport requires PKA-regulated phosphorylation of the regulatory domain (R-D) and dimerization of the nucleotide binding domains. Using a newly developed assay, we evaluated nine compounds including both CFTR potentatiators and activators discovered via various high-throughput screening strategies to acutely augment CFTR activity. We found considerable differences in the effects on R-D phosphorylation. Some (including UCCF-152) stimulated robust phosphorylation, and others had little effect (e.g., VRT-532 and VX-770). We then compared CFTR activation by UCCF-152 and VRT-532 in Ussing chamber studies using two epithelial models, CFBE41o− and Fischer rat thyroid cells, expressing various CFTR forms. UCCF-152 activated wild-type-, G551D-, and rescued F508del-CFTR currents but did not potentiate cAMP-mediated CFTR activation. In contrast, VRT-532 moderately activated CFTR short-circuit current and strongly potentiated forskolin-mediated current. Combined with the result that UCCF-152, but not VRT-532 or VX-770, acts by increasing CFTR R-D phosphorylation, these findings indicate that potentiation of endogenous cAMP-mediated activation of mutant CFTR is not due to a pathway involving augmented R-D phosphorylation. This study presents an assay useful to distinguish preclinical compounds by a crucial mechanism underlying CFTR activation, delineates two types of compound able to acutely augment CFTR activity (e.g., activators and potentiators), and demonstrates that a number of different mechanisms can be successfully employed to activate mutant CFTR. PMID:21724857

Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15

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

Hsu, Jer-Yuan; Crawley, Suzanne; Chen, Michael

Under homeostatic conditions, animals use well-defined hypothalamic neural circuits to help maintain stable body weight, by integrating metabolic and hormonal signals from the periphery to balance food consumption and energy expenditure1,2. In stressed or disease conditions, however, animals use alternative neuronal pathways to adapt to the metabolic challenges of altered energy demand3. Recent studies have identified brain areas outside the hypothalamus that are activated under these ‘non-homeostatic’ conditions4,5,6, but the molecular nature of the peripheral signals and brain-localized receptors that activate these circuits remains elusive. Here we identify glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as a brainstem-restricted receptormore » for growth and differentiation factor 15 (GDF15). GDF15 regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stresses; we show that Gfral knockout mice are hyperphagic under stressed conditions and are resistant to chemotherapy-induced anorexia and body weight loss. GDF15 activates GFRAL-expressing neurons localized exclusively in the area postrema and nucleus tractus solitarius of the mouse brainstem. It then triggers the activation of neurons localized within the parabrachial nucleus and central amygdala, which constitute part of the ‘emergency circuit’ that shapes feeding responses to stressful conditions7. GDF15 levels increase in response to tissue stress and injury, and elevated levels are associated with body weight loss in numerous chronic human diseases8,9. By isolating GFRAL as the receptor for GDF15-induced anorexia and weight loss, we identify a mechanistic basis for the non-homeostatic regulation of neural circuitry by a peripheral signal associated with tissue damage and stress. These findings provide opportunities to develop therapeutic agents for the treatment of disorders with altered energy demand.« less

Volatilization modeling of two herbicides from soil in a wind tunnel experiment under varying humidity conditions.

PubMed

Schneider, Martina; Goss, Kai-Uwe

2012-11-20

Volatilization of pesticides from the bare soil surface is drastically reduced when the soil is under dry conditions (i.e., water content lower than the permanent wilting point). This effect is caused by the hydrated mineral surfaces that become available as additional sorption sites under dry conditions. However, established volatilization models do not explicitly consider the hydrated mineral surfaces as an independent sorption compartment and cannot correctly cover the moisture effect on volatilization. Here we integrated the existing mechanistic understanding of sorption of organic compounds to mineral surfaces and its dependence on the hydration status into a simple volatilization model. The resulting model was tested with reported experimental data for two herbicides from a wind tunnel experiment under various well-defined humidity conditions. The required equilibrium sorption coefficients of triallate and trifluralin to the mineral surfaces, K(min/air), at 60% relative humidity were fitted to experimental data and extrapolated to other humidity conditions. The model captures the general trend of the volatilization in different humidity scenarios. The results reveal that it is essential to have high quality input data for K(min/air), the available specific surface area (SSA), the penetration depth of the applied pesticide solution, and the humidity conditions in the soil. The model approach presented here in combination with an improved description of the humidity conditions under dry conditions can be integrated into existing volatilization models that already work well for humid conditions but still lack the mechanistically based description of the volatilization process under dry conditions.

The pachytene checkpoint and its relationship to evolutionary patterns of polyploidization and hybrid sterility.

PubMed

Li, X C; Barringer, B C; Barbash, D A

2009-01-01

Sterility is a commonly observed phenotype in interspecific hybrids. Sterility may result from chromosomal or genic incompatibilities, and much progress has been made toward understanding the genetic basis of hybrid sterility in various taxa. The underlying mechanisms causing hybrid sterility, however, are less well known. The pachytene checkpoint is a meiotic surveillance system that many organisms use to detect aberrant meiotic products, in order to prevent the production of defective gametes. We suggest that activation of the pachytene checkpoint may be an important mechanism contributing to two types of hybrid sterility. First, the pachytene checkpoint may form the mechanistic basis of some gene-based hybrid sterility phenotypes. Second, the pachytene checkpoint may be an important mechanism that mediates chromosomal-based hybrid sterility phenotypes involving gametes with non-haploid (either non-reduced or aneuploid) chromosome sets. Studies in several species suggest that the strength of the pachytene checkpoint is sexually dimorphic, observations that warrant future investigation into whether such variation may contribute to differences in patterns of sterility between male and female interspecific hybrids. In addition, plants seem to lack the pachytene checkpoint, which correlates with increased production of unreduced gametes and a higher incidence of polyploid species in plants versus animals. Although the pachytene checkpoint occurs in many animals and in fungi, at least some of the genes that execute the pachytene checkpoint are different among organisms. This finding suggests that the penetrance of the pachytene checkpoint, and even its presence or absence can evolve rapidly. The surprising degree of evolutionary flexibility in this meiotic surveillance system may contribute to the observed variation in patterns of hybrid sterility and in rates of polyploidization.

The Eye Drop Preservative Benzalkonium Chloride Potently Induces Mitochondrial Dysfunction and Preferentially Affects LHON Mutant Cells.

PubMed

Datta, Sandipan; Baudouin, Christophe; Brignole-Baudouin, Francoise; Denoyer, Alexandre; Cortopassi, Gino A

2017-04-01

Benzalkonium chloride (BAK) is the most commonly used eye drop preservative. Benzalkonium chloride has been associated with toxic effects such as "dry eye" and trabecular meshwork degeneration, but the underlying biochemical mechanism of ocular toxicity by BAK is unclear. In this study, we propose a mechanistic basis for BAK's adverse effects. Mitochondrial O2 consumption rates of human corneal epithelial primary cells (HCEP), osteosarcoma cybrid cells carrying healthy (control) or Leber hereditary optic neuropathy (LHON) mutant mtDNA [11778(G>A)], were measured before and after acute treatment with BAK. Mitochondrial adenosine triphosphate (ATP) synthesis and cell viability were also measured in the BAK-treated control: LHON mutant and human-derived trabecular meshwork cells (HTM3). Benzalkonium chloride inhibited mitochondrial ATP (IC50, 5.3 μM) and O2 consumption (IC50, 10.9 μM) in a concentration-dependent manner, by directly targeting mitochondrial complex I. At its pharmaceutical concentrations (107-667 μM), BAK inhibited mitochondrial function >90%. In addition, BAK elicited concentration-dependent cytotoxicity to cybrid cells (IC50, 22.8 μM) and induced apoptosis in HTM3 cells at similar concentrations. Furthermore, we show that BAK directly inhibits mitochondrial O2 consumption in HCEP cells (IC50, 3.8 μM) at 50-fold lower concentrations than used in eye drops, and that cells bearing mitochondrial blindness (LHON) mutations are further sensitized to BAK's mitotoxic effect. Benzalkonium chloride inhibits mitochondria of human corneal epithelial cells and cells bearing LHON mutations at pharmacologically relevant concentrations, and we suggest this is the basis of BAK's ocular toxicity. Prescribing BAK-containing eye drops should be avoided in patients with mitochondrial deficiency, including LHON patients, LHON carriers, and possibly primary open-angle glaucoma patients.

The Eye Drop Preservative Benzalkonium Chloride Potently Induces Mitochondrial Dysfunction and Preferentially Affects LHON Mutant Cells

PubMed Central

Datta, Sandipan; Baudouin, Christophe; Brignole-Baudouin, Francoise; Denoyer, Alexandre; Cortopassi, Gino A.

2017-01-01

Purpose Benzalkonium chloride (BAK) is the most commonly used eye drop preservative. Benzalkonium chloride has been associated with toxic effects such as “dry eye” and trabecular meshwork degeneration, but the underlying biochemical mechanism of ocular toxicity by BAK is unclear. In this study, we propose a mechanistic basis for BAK's adverse effects. Method Mitochondrial O2 consumption rates of human corneal epithelial primary cells (HCEP), osteosarcoma cybrid cells carrying healthy (control) or Leber hereditary optic neuropathy (LHON) mutant mtDNA [11778(G>A)], were measured before and after acute treatment with BAK. Mitochondrial adenosine triphosphate (ATP) synthesis and cell viability were also measured in the BAK-treated control: LHON mutant and human-derived trabecular meshwork cells (HTM3). Results Benzalkonium chloride inhibited mitochondrial ATP (IC50, 5.3 μM) and O2 consumption (IC50, 10.9 μM) in a concentration-dependent manner, by directly targeting mitochondrial complex I. At its pharmaceutical concentrations (107–667 μM), BAK inhibited mitochondrial function >90%. In addition, BAK elicited concentration-dependent cytotoxicity to cybrid cells (IC50, 22.8 μM) and induced apoptosis in HTM3 cells at similar concentrations. Furthermore, we show that BAK directly inhibits mitochondrial O2 consumption in HCEP cells (IC50, 3.8 μM) at 50-fold lower concentrations than used in eye drops, and that cells bearing mitochondrial blindness (LHON) mutations are further sensitized to BAK's mitotoxic effect. Conclusions Benzalkonium chloride inhibits mitochondria of human corneal epithelial cells and cells bearing LHON mutations at pharmacologically relevant concentrations, and we suggest this is the basis of BAK's ocular toxicity. Prescribing BAK-containing eye drops should be avoided in patients with mitochondrial deficiency, including LHON patients, LHON carriers, and possibly primary open-angle glaucoma patients. PMID:28444329

Role of the Support and Reaction Conditions on the Vapor-Phase Deoxygenation of m-Cresol over Pt/C and Pt/TiO 2 Catalysts

DOE PAGES

Griffin, Michael B.; Ferguson, Glen A.; Ruddy, Daniel A.; ...

2016-03-23

The catalytic deoxygenation of biomass fast pyrolysis vapors offers a promising route for the sustainable production of liquid transportation fuels. However, a clear understanding of the mechanistic details involved in this process has yet to be achieved, and questions remain regarding the role of the catalyst support and the influence of reaction conditions. In order to gain insight into these questions, the deoxygenation of m-cresol was investigated over Pt/C and Pt/TiO 2 catalysts using experimental and computational techniques. The performance of each catalyst was evaluated in a packed-bed reactor under two conditions (523 K, 2.0 MPa and 623 K, 0.5more » MPa), and the energetics of the ring hydrogenation, direct deoxygenation, and tautomerization mechanisms were calculated over hydrogen-covered Pt(111) and oxygen vacancies on the surface of TiO 2(101). Over Pt(111), ring hydrogenation to 3-methylcyclohexanone and 3-methylcyclohexanol was found to be the most energetically favorable pathway. Over TiO 2(101), tautomerization and direct deoxygenation to toluene were identified as additional energetically favorable routes. These calculations are consistent with the experimental data, in which Pt/TiO 2 was more active on a metal site basis and exhibited higher selectivity to toluene at 623 K relative to Pt/C. On the basis of these results, it is likely that the reactivity of Pt/TiO 2 and Pt/C is driven by the metallic phase at 523 K, while contributions from the TiO 2 support enhance deoxygenation at 623 K. These results highlight the synergistic effects between hydrogenation catalysts and reducible metal oxide supports and provide insight into the reaction pathways responsible for their enhanced deoxygenation performance.« less

The Composite Regulatory Basis of the Large X-Effect in Mouse Speciation.

PubMed

Larson, Erica L; Keeble, Sara; Vanderpool, Dan; Dean, Matthew D; Good, Jeffrey M

2017-02-01

The disruption of meiotic sex chromosome inactivation (MSCI) has been proposed to be a major developmental mechanism underlying the rapid evolution of hybrid male sterility. We tested this idea by analyzing cell-specific gene expression across spermatogenesis in two lineages of house mice and their sterile and fertile reciprocal hybrids. We found pervasive disruption of sex chromosome gene expression in sterile hybrids at every stage of spermatogenesis. Failure of MSCI was developmentally preceded by increased silencing of autosomal genes, supporting the hypothesis that divergence at the hybrid incompatibility gene, Prdm9, results in increased rates of autosomal asynapsis which in turn triggers widespread silencing of unsynapsed chromatin. We also detected opposite patterns of postmeiotic overexpression or hyper-repression of the sex chromosomes in reciprocal hybrids, supporting the hypothesis that genomic conflict has driven functional divergence that leads to deleterious X-Y dosage imbalances in hybrids. Our developmental timeline also exposed more subtle patterns of mitotic misregulation on the X chromosome, a previously undocumented stage of spermatogenic disruption in this cross. These results indicate that multiple hybrid incompatibilities have converged on a common regulatory phenotype, the disrupted expression of the sex chromosomes during spermatogenesis. Collectively, these data reveal a composite regulatory basis to hybrid male sterility in mice that helps resolve the mechanistic underpinnings of the well-documented large X-effect in mice speciation. We propose that the inherent sensitivity of spermatogenesis to X-linked regulatory disruption has the potential to be a major driver of reproductive isolation in species with chromosomal sex determination. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

How to make a tree ring: Coupling stem water flow and cambial activity in mature Alpine conifers

NASA Astrophysics Data System (ADS)

Peters, Richard L.; Frank, David C.; Treydte, Kerstin; Steppe, Kathy; Kahmen, Ansgar; Fonti, Patrick

2017-04-01

Inter-annual tree-ring measurements are used to understand tree-growth responses to climatic variability and reconstruct past climate conditions. In parallel, mechanistic models use experimentally defined plant-atmosphere interactions to explain past growth responses and predict future environmental impact on forest productivity. Yet, substantial inconsistencies within mechanistic model ensembles and mismatches with empirical data indicate that significant progress is still needed to understand the processes occurring at an intra-annual resolution that drive annual growth. However, challenges arise due to i) few datasets describing climatic responses of high-resolution physiological processes over longer time-scales, ii) uncertainties on the main mechanistic process limiting radial stem growth and iii) complex interactions between multiple environmental factors which obscure detection of the main stem growth driver, generating a gap between our understanding of intra- and inter-annual growth mechanisms. We attempt to bridge the gap between inter-annual tree-ring width and sub-daily radial stem-growth and provide a mechanistic perspective on how environmental conditions affect physiological processes that shape tree rings in conifers. We combine sub-hourly sap flow and point dendrometer measurements performed on mature Alpine conifers (Larix decidua) into an individual-based mechanistic tree-growth model to simulate sub-hourly cambial activity. The monitored trees are located along a high elevational transect in the Swiss Alps (Lötschental) to analyse the effect of increasing temperature. The model quantifies internal tree hydraulic pathways that regulate the turgidity within the cambial zone and induce cell enlargement for radial growth. The simulations are validated against intra-annual growth patterns derived from xylogenesis data and anatomical analyses. Our efforts advance the process-based understanding of how climate shapes the annual tree-ring structures and could potentially improve our ability to reconstruct the climate of the past and predict future growth under changing climate.

Evolution of supersaturation of amorphous pharmaceuticals: the effect of rate of supersaturation generation.

PubMed

Sun, Dajun D; Lee, Ping I

2013-11-04

The combination of a rapidly dissolving and supersaturating "spring" with a precipitation retarding "parachute" has often been pursued as an effective formulation strategy for amorphous solid dispersions (ASDs) to enhance the rate and extent of oral absorption. However, the interplay between these two rate processes in achieving and maintaining supersaturation remains inadequately understood, and the effect of rate of supersaturation buildup on the overall time evolution of supersaturation during the dissolution of amorphous solids has not been explored. The objective of this study is to investigate the effect of supersaturation generation rate on the resulting kinetic solubility profiles of amorphous pharmaceuticals and to delineate the evolution of supersaturation from a mechanistic viewpoint. Experimental concentration-time curves under varying rates of supersaturation generation and recrystallization for model drugs, indomethacin (IND), naproxen (NAP) and piroxicam (PIR), were generated from infusing dissolved drug (e.g., in ethanol) into the dissolution medium and compared with that predicted from a comprehensive mechanistic model based on the classical nucleation theory taking into account both the particle growth and ripening processes. In the absence of any dissolved polymer to inhibit drug precipitation, both our experimental and predicted results show that the maximum achievable supersaturation (i.e., kinetic solubility) of the amorphous solids increases, the time to reach maximum decreases, and the rate of concentration decline in the de-supersaturation phase increases, with increasing rate of supersaturation generation (i.e., dissolution rate). Our mechanistic model also predicts the existence of an optimal supersaturation rate which maximizes the area under the curve (AUC) of the kinetic solubility concentration-time profile, which agrees well with experimental data. In the presence of a dissolved polymer from ASD dissolution, these observed trends also hold true except the de-supersaturation phase is more extended due to the crystallization inhibition effect. Since the observed kinetic solubility of nonequilibrium amorphous solids depends on the rate of supersaturation generation, our results also highlight the underlying difficulty in determining a reproducible solubility advantage for amorphous solids.

Modeling behavioral thermoregulation in a climate change sentinel.

PubMed

Moyer-Horner, Lucas; Mathewson, Paul D; Jones, Gavin M; Kearney, Michael R; Porter, Warren P

2015-12-01

When possible, many species will shift in elevation or latitude in response to rising temperatures. However, before such shifts occur, individuals will first tolerate environmental change and then modify their behavior to maintain heat balance. Behavioral thermoregulation allows animals a range of climatic tolerances and makes predicting geographic responses under future warming scenarios challenging. Because behavioral modification may reduce an individual's fecundity by, for example, limiting foraging time and thus caloric intake, we must consider the range of behavioral options available for thermoregulation to accurately predict climate change impacts on individual species. To date, few studies have identified mechanistic links between an organism's daily activities and the need to thermoregulate. We used a biophysical model, Niche Mapper, to mechanistically model microclimate conditions and thermoregulatory behavior for a temperature-sensitive mammal, the American pika (Ochotona princeps). Niche Mapper accurately simulated microclimate conditions, as well as empirical metabolic chamber data for a range of fur properties, animal sizes, and environmental parameters. Niche Mapper predicted pikas would be behaviorally constrained because of the need to thermoregulate during the hottest times of the day. We also showed that pikas at low elevations could receive energetic benefits by being smaller in size and maintaining summer pelage during longer stretches of the active season under a future warming scenario. We observed pika behavior for 288 h in Glacier National Park, Montana, and thermally characterized their rocky, montane environment. We found that pikas were most active when temperatures were cooler, and at sites characterized by high elevations and north-facing slopes. Pikas became significantly less active across a suite of behaviors in the field when temperatures surpassed 20°C, which supported a metabolic threshold predicted by Niche Mapper. In general, mechanistic predictions and empirical observations were congruent. This research is unique in providing both an empirical and mechanistic description of the effects of temperature on a mammalian sentinel of climate change, the American pika. Our results suggest that previously underinvestigated characteristics, specifically fur properties and body size, may play critical roles in pika populations' response to climate change. We also demonstrate the potential importance of considering behavioral thermoregulation and microclimate variability when predicting animal responses to climate change.

Dynamic Kinetic Asymmetric Transformations of β-Stereogenic-α-Keto Esters via Direct Aldolization

PubMed Central

Corbett, Michael T.; Johnson, Jeffrey S.

2014-01-01

Dynamic kinetic asymmetric transformations (DyKAT) of racemic β-bromo-α-keto esters via direct aldolization of nitromethane and acetone provide access to fully substituted α-glycolic acid derivatives bearing a β-stereocenter. The aldol adducts are obtained in excellent yield with high relative and absolute stereocontrol under mild reaction conditions. Mechanistic studies determined that the reactions proceed through a facile catalyst-mediated racemization of the β-bromo-α-keto esters under a DyKAT Type I manifold. PMID:24222195

Visible-Light Modulation on Lattice Dielectric Responses of a Piezo-Phototronic Soft Material.

PubMed

Huang, E-Wen; Hsu, Yu-Hsiang; Chuang, Wei-Tsung; Ko, Wen-Ching; Chang, Chung-Kai; Lee, Chih-Kung; Chang, Wen-Chi; Liao, Tzu-Kang; Thong, Hao Cheng

2015-12-16

In situ synchrotron X-ray diffraction is used to investigate a three-way piezo-phototronic soft material. This new system is composed of a semi-crystalline poly(vinylidene fluoride-co-trifluoroethylene) piezoelectric polymer and titanium oxide nanoparticles. Under light illumination, photon-induced piezoelectric responses are nearly two times higher at both the lattice-structure and the macroscopic level than under conditions without light illumination. A mechanistic model is proposed. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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…

Shape matters: Lifecycle of cooperative patches promotes cooperation in bulky populations

PubMed Central

Misevic, Dusan; Frénoy, Antoine; Lindner, Ariel B; Taddei, François

2015-01-01

Natural cooperative systems take many forms, ranging from one-dimensional cyanobacteria arrays to fractal-like biofilms. We use in silico experimental systems to study a previously overlooked factor in the evolution of cooperation, physical shape of the population. We compare the emergence and maintenance of cooperation in populations of digital organisms that inhabit bulky (100 × 100 cells) or slender (4 × 2500) toroidal grids. Although more isolated subpopulations of secretors in a slender population could be expected to favor cooperation, we find the opposite: secretion evolves to higher levels in bulky populations. We identify the mechanistic explanation for the shape effect by analyzing the lifecycle and dynamics of cooperator patches, from their emergence and growth, to invasion by noncooperators and extinction. Because they are constrained by the population shape, the cooperator patches expand less in slender than in bulky populations, leading to fewer cooperators, less public good secretion, and generally lower cooperation. The patch dynamics and mechanisms of shape effect are robust across several digital cooperation systems and independent of the underlying basis for cooperation (public good secretion or a cooperation game). Our results urge for a greater consideration of population shape in the study of the evolution of cooperation across experimental and modeling systems. PMID:25639379

UV-laser photochemistry of isoxazole isolated in a low-temperature matrix.

PubMed

Nunes, Cláudio M; Reva, Igor; Pinho e Melo, Teresa M V D; Fausto, Rui

2012-10-05

The photochemistry of matrix-isolated isoxazole, induced by narrowband tunable UV-light, was investigated by infrared spectroscopy, with the aid of MP2/6-311++G(d,p) calculations. The isoxazole photoreaction starts to occur upon irradiation at λ = 240 nm, with the dominant pathway involving decomposition to ketene and hydrogen cyanide. However, upon irradiation at λ = 221 nm, in addition to this decomposition, isoxazole was also found to isomerize into several products: 2-formyl-2H-azirine, 3-formylketenimine, 3-hydroxypropenenitrile, imidoylketene, and 3-oxopropanenitrile. The structural and spectroscopic assignment of the different photoisomerization products was achieved by additional irradiation of the λ = 221 nm photolyzed matrix, using UV-light with λ ≥ 240 nm: (i) irradiation in the 330 ≤ λ ≤ 340 nm range induced direct transformation of 2-formyl-2H-azirine into 3-formylketenimine; (ii) irradiation with 310 ≤ λ ≤ 318 nm light induced the hitherto unobserved transformation of 3-formylketenimine into 3-hydroxypropenenitrile and imidoylketene; (iii) irradiation with λ = 280 nm light permits direct identification of 3-oxopropanenitrile; (iv) under λ = 240 nm irradiation, tautomerization of 3-hydroxypropenenitrile to 3-oxopropanenitrile is observed. On the basis of these findings, a detailed mechanistic proposal for isoxazole photochemistry is presented.

Neuronal control of locomotor handedness in Drosophila.

PubMed

Buchanan, Sean M; Kain, Jamey S; de Bivort, Benjamin L

2015-05-26

Genetically identical individuals display variability in their physiology, morphology, and behaviors, even when reared in essentially identical environments, but there is little mechanistic understanding of the basis of such variation. Here, we investigated whether Drosophila melanogaster displays individual-to-individual variation in locomotor behaviors. We developed a new high-throughout platform capable of measuring the exploratory behavior of hundreds of individual flies simultaneously. With this approach, we find that, during exploratory walking, individual flies exhibit significant bias in their left vs. right locomotor choices, with some flies being strongly left biased or right biased. This idiosyncrasy was present in all genotypes examined, including wild-derived populations and inbred isogenic laboratory strains. The biases of individual flies persist for their lifetime and are nonheritable: i.e., mating two left-biased individuals does not yield left-biased progeny. This locomotor handedness is uncorrelated with other asymmetries, such as the handedness of gut twisting, leg-length asymmetry, and wing-folding preference. Using transgenics and mutants, we find that the magnitude of locomotor handedness is under the control of columnar neurons within the central complex, a brain region implicated in motor planning and execution. When these neurons are silenced, exploratory laterality increases, with more extreme leftiness and rightiness. This observation intriguingly implies that the brain may be able to dynamically regulate behavioral individuality.

Reviewing and Reconsidering Invasion Assays in Head and Neck Cancer

PubMed Central

Inglehart, Ronald C.; Scanlon, Christina S.; D’Silva, Nisha J.

2014-01-01

Head and neck squamous cell carcinomas (HNSCC) are malignant tumors that arise from the surface epithelium of the oral cavity, oropharynx and larynx, primarily due to exposure to chemical carcinogens or the human papilloma virus. Due to their location, dental practitioners are well-positioned to detect the lesions. Deadlier than lymphoma or melanoma, HNSCC is incompletely understood. For these reasons, dental practitioners and researchers are focused on understanding HNSCC and the processes driving it. One of these critical processes is invasion, the degradation of the basement membrane by HNSCC cells with subsequent movement into the underlying connective tissue, blood vessels or nerves. Cancer cells metastasize to distant sites via the blood vessels, lymphatics and nerves. Metastasis is associated with poor survival. Since invasion is essential for development and metastasis of HNSCC, it is essential to understand the mechanism(s) driving this process. Elucidation of the mechanisms involved will facilitate the development of targeted treatment, thereby accelerating development of precision/ personalized medicine to treat HNSCC. Robust in vitro and in vivo assays are required to investigate the mechanistic basis of invasion. This review will focus on in vitro and in vivo assays used to study invasion in HNSCC, with special emphasis on some of the latest assays to study HNSCC. PMID:25448226

Mechanistic Study on Electronic Excitation Dissociation of the Cellobiose-Na+ Complex

NASA Astrophysics Data System (ADS)

Huang, Yiqun; Pu, Yi; Yu, Xiang; Costello, Catherine E.; Lin, Cheng

2016-02-01

The recent development of electron activated dissociation (ExD) techniques has opened the door for high-throughput, detailed glycan structural elucidation. Among them, ExD methods employing higher-energy electrons offer several advantages over low-energy electron capture dissociation (ECD), owing to their applicability towards chromophore-labeled glycans and singly charged ions, and ability to provide more extensive structural information. However, a lack of understanding of these processes has hindered rational optimization of the experimental conditions for more efficient fragmentation as well as the development of informatics tools for interpretation of the complex glycan ExD spectra. Here, cellobiose-Na+ was used as the model system to investigate the fragmentation behavior of metal-adducted glycans under irradiation of electrons with energy exceeding their ionization potential, and served as the basis on which a novel electronic excitation dissociation (EED) mechanism was proposed. It was found that ionization of the glycan produces a mixture of radical cations and ring-opened distonic ions. These distonic ions then capture a low-energy electron to produce diradicals with trivial singlet-triplet splitting, and subsequently undergo radical-induced dissociation to produce a variety of fragment ions, the abundances of which are influenced by the stability of the distonic ions from which they originate.

Radiation Hormesis: Historical Perspective and Implications for Low-Dose Cancer Risk Assessment

PubMed Central

Vaiserman, Alexander M.

2010-01-01

Current guidelines for limiting exposure of humans to ionizing radiation are based on the linear-no-threshold (LNT) hypothesis for radiation carcinogenesis under which cancer risk increases linearly as the radiation dose increases. With the LNT model even a very small dose could cause cancer and the model is used in establishing guidelines for limiting radiation exposure of humans. A slope change at low doses and dose rates is implemented using an empirical dose and dose rate effectiveness factor (DDREF). This imposes usually unacknowledged nonlinearity but not a threshold in the dose-response curve for cancer induction. In contrast, with the hormetic model, low doses of radiation reduce the cancer incidence while it is elevated after high doses. Based on a review of epidemiological and other data for exposure to low radiation doses and dose rates, it was found that the LNT model fails badly. Cancer risk after ordinarily encountered radiation exposure (medical X-rays, natural background radiation, etc.) is much lower than projections based on the LNT model and is often less than the risk for spontaneous cancer (a hormetic response). Understanding the mechanistic basis for hormetic responses will provide new insights about both risks and benefits from low-dose radiation exposure. PMID:20585444

Photochemical synthesis of simple organic free radicals on simulated planetary surfaces - An ESR study

NASA Technical Reports Server (NTRS)

Tseng, S.-S.; Chang, S.

1975-01-01

Electron spin resonance (ESR) spectroscopy provided evidence for formation of hydroxyl radicals during ultraviolet photolysis (254 nm) at -170 C of H2O adsorbed on silica gel or of silica gel alone. The carboxyl radical was observed when CO or CO2 or a mixture of CO and CO2 adsorbed on silica gel at -170 C was irradiated. The ESR signals of these radicals slowly disappeared when the irradiated samples were warmed to room temperature. However, reirradiation of CO or CO2, or the mixture CO and CO2 on silica gel at room temperature then produced a new species, the carbon dioxide anion radical, which slowly decayed and was identical with that produced by direct photolysis of formic acid adsorbed on silica gel. The primary photochemical process may involve formation of hydrogen and hydroxyl radicals. Subsequent reactions of these radicals with adsorbed CO or CO2 or both yield carboxyl radicals, CO2H, the precursors of formic acid. These results confirm the formation of formic acid under simulated Martian conditions and provide a mechanistic basis for gauging the potential importance of gas-solid photochemistry for chemical evolution on other extraterrestrial bodies, on the primitive earth, and on dust grains in the interstellar medium.

Chemical Transformations in Proto-Cytoplasmic Media. Phosphorus Coupling in the Silica Hydrogel Phase

PubMed Central

Gorrell, Ian B.; Henderson, Timothy W.; Albdeery, Kamal; Savage, Philip M.; Kee, Terence P.

2017-01-01

It has been proposed that prebiotic chemical studies on the emergence of primitive life would be most relevant when performed in a hydrogel, rather than an aqueous, environment. In this paper we describe the ambient temperature coupling of phosphorus oxyacids [Pi] mediated by Fe(II) under aerobic conditions within a silica hydrogel (SHG) environment. We have chosen to examine SHGs as they have considerable geological precedence as key phases in silicification en route to rock formation. Following a description of the preparation and characterization studies on our SHG formulations, coupling experiments between Pi species are described across multiple permutations of (i) Pi compound; (ii) gel formulation; (iii) metal salt additive; and (iv) pH-modifying agent. The results suggest that successful Pi coupling, indicated by observation of pyrophosphate [PPi(V)] via 31P-NMR spectroscopy, takes place when the following components are present: (i) a mixture of mixture of Pi(III) and Pi(V) or pure PPi(III– V); (ii) Fe(II); (iii) acetic or formic acid (not hydrochloric acid); (iv) aerobic conditions or the presence of H2O2 as an oxidant; and (v) the presence of a gel system. On the basis of these, and aqueous control reactions, we suggest mechanistic possibilities. PMID:29156594

Elevated placental adenosine signaling contributes to the pathogenesis of preeclampsia.

PubMed

Iriyama, Takayuki; Sun, Kaiqi; Parchim, Nicholas F; Li, Jessica; Zhao, Cheng; Song, Anren; Hart, Laura A; Blackwell, Sean C; Sibai, Baha M; Chan, Lee-Nien L; Chan, Teh-Sheng; Hicks, M John; Blackburn, Michael R; Kellems, Rodney E; Xia, Yang

2015-02-24

Preeclampsia is a prevalent hypertensive disorder of pregnancy and a leading cause of maternal and neonatal morbidity and mortality worldwide. This pathogenic condition is speculated to be caused by placental abnormalities that contribute to the maternal syndrome. However, the specific factors and signaling pathways that lead to impaired placentas and maternal disease development remain elusive. Using 2 independent animal models of preeclampsia (genetically engineered pregnant mice with elevated adenosine exclusively in placentas and a pathogenic autoantibody-induced preeclampsia mouse model), we demonstrated that chronically elevated placental adenosine was sufficient to induce hallmark features of preeclampsia, including hypertension, proteinuria, small fetuses, and impaired placental vasculature. Genetic and pharmacological approaches revealed that elevated placental adenosine coupled with excessive A₂B adenosine receptor (ADORA2B) signaling contributed to the development of these features of preeclampsia. Mechanistically, we provided both human and mouse evidence that elevated placental CD73 is a key enzyme causing increased placental adenosine, thereby contributing to preeclampsia. We determined that elevated placental adenosine signaling is a previously unrecognized pathogenic factor for preeclampsia. Moreover, our findings revealed the molecular basis underlying the elevation of placental adenosine and the detrimental role of excess placental adenosine in the pathophysiology of preeclampsia, and thereby, we highlight novel therapeutic targets. © 2014 American Heart Association, Inc.

Effects of Natural Osmolytes on the Protein Structure in Supercritical CO2: Molecular Level Evidence.

PubMed

Monhemi, Hassan; Housaindokht, Mohammad Reza; Nakhaei Pour, Ali

2015-08-20

Protein instability in supercritical CO2 limits the application of this green solvent in enzyme-catalyzed reactions. CO2 molecules act as a protein denaturant at high pressure under supercritical conditions. Here, for the first time, we show that natural osmolytes could stabilize protein conformation in supercritical CO2. Molecular dynamics simulation is used to monitor the effects of adding different natural osmolytes on the conformation and dynamics of chymotrypsin inhibitor 2 (CI2) in supercritical CO2. Simulations showed that CI2 is denatured at 200 bar in supercritical CO2, which is in agreement with experimental observations. Interestingly, the protein conformation remains native after addition of ∼1 M amino acid- and sugar-based osmolyte models. These molecules stabilize protein through the formation of supramolecular self-assemblies resulting from macromolecule-osmolyte hydrogen bonds. Nevertheless, trimethylamine N-oxide, which is known as a potent osmolyte for protein stabilization in aqueous solutions, amplifies protein denaturation in supercritical CO2. On the basis of our structural analysis, we introduce a new mechanism for the osmolyte effect in supercritical CO2, an "inclusion mechanism". To the best of our knowledge, this is the first study that introduces the application of natural osmolytes in a supercritical fluid and describes mechanistic insights into osmolyte action in nonaqueous media.

Linking Pesticide Exposure with Pediatric Leukemia: Potential Underlying Mechanisms

PubMed Central

Hernández, Antonio F.; Menéndez, Pablo

2016-01-01

Leukemia is the most common cancer in children, representing 30% of all childhood cancers. The disease arises from recurrent genetic insults that block differentiation of hematopoietic stem and/or progenitor cells (HSPCs) and drives uncontrolled proliferation and survival of the differentiation-blocked clone. Pediatric leukemia is phenotypically and genetically heterogeneous with an obscure etiology. The interaction between genetic factors and environmental agents represents a potential etiological driver. Although information is limited, the principal toxic mechanisms of potential leukemogenic agents (e.g., etoposide, benzene metabolites, bioflavonoids and some pesticides) include topoisomerase II inhibition and/or excessive generation of free radicals, which may induce DNA single- and double-strand breaks (DNA-DSBs) in early HSPCs. Chromosomal rearrangements (duplications, deletions and translocations) may occur if these lesions are not properly repaired. The initiating hit usually occurs in utero and commonly leads to the expression of oncogenic fusion proteins. Subsequent cooperating hits define the disease latency and occur after birth and may be of a genetic, epigenetic or immune nature (i.e., delayed infection-mediated immune deregulation). Here, we review the available experimental and epidemiological evidence linking pesticide exposure to infant and childhood leukemia and provide a mechanistic basis to support the association, focusing on early initiating molecular events. PMID:27043530

Peeling off the genetics of atopic dermatitis-like congenital disorders.

PubMed

Samuelov, Liat; Sprecher, Eli

2014-10-01

The epidermis forms during the course of a complex differentiation process known as cornification, which culminates with the formation of the epidermal barrier. The epidermal barrier serves as a vital line of defense against the environment and mainly consists of 3 elements: intracellular keratin filaments, intercellular lipids, and the cornified cell envelope. Adequate epidermal barrier function is also critically dependent on normal shedding of terminally differentiated keratinocytes, a process termed desquamation, which requires the dissolution of cell-cell junctions in the upper granular layers. Although much has been learned about epidermal differentiation through the deciphering of the molecular basis of various cornification disorders, less is currently known about the mechanisms regulating epidermal desquamation and disorders resulting from disruption of this process. Netherton syndrome, peeling skin syndrome type B, and skin dermatitis--multiple severe allergies--metabolic wasting syndrome are 3 autosomal recessive conditions resulting from aberrant regulation of epidermal desquamation. The deciphering of their pathogenesis has not only broadened our understanding of this process but has also shed new light on clinical and mechanistic links between allergic reactions and abnormal desquamation, substantiating the notion that allergic manifestations might, under some circumstances, be the sole consequence of a primary epidermal defect. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Treatment options for nonalcoholic steatohepatitis - a safety evaluation.

PubMed

Issa, Danny; Wattacheril, Julia; Sanyal, Arun J

2017-08-01

There is an urgent as yet unmet need to develop highly effective and safe therapeutics for nonalcoholic fatty liver disease (NAFLD). The remarkable progress in understanding NAFLD pathogenesis allowed the identification of injury pathways which may be recruited as therapy targets. Areas covered: This article reviews the safety and tolerability data of the NAFLD therapies and explains the mechanistic basis for each of the established and investigational drugs. Treatment targets include: weight loss, anti-metabolic agents such as lipid lowering and anti-diabetic drugs, inflammation, fibrosis and others such as targeting gut microbiota, immune modulation and apoptosis. Expert opinion: Current therapies continue to remain suboptimal. Weight loss is effective but hard to achieve. Traditional and endoscopic bariatric procedures are promising although more randomized trials are needed and the long-term safety remains to be established. Clinical trials have demonstrated the efficacy of several drugs for the treatment of NASH. Of these, there remains some uncertainty about the long-term safety of vitamin E. Pioglitazone is associated with osteopenia, fluid retention and weight gain. Obeticholic acid causes pruritus in a substantial proportion of subjects and elafibranor has been associated with transient rises in creatinine. Several exciting therapies are under development and results of clinical and post-marketing trials will help elucidate their safety.

Mutual enhancement of IL-2 and IL-7 on DNA vaccine immunogenicity mainly involves regulations on their receptor expression and receptor-expressing lymphocyte generation.

PubMed

Zhang, Yonghong; Liang, Shuang; Li, Xiujin; Wang, Liyue; Zhang, Jianlou; Xu, Jian; Huo, Shanshan; Cao, Xuebin; Zhong, Zhenyu; Zhong, Fei

2015-07-09

Our previous study showed that IL-2 and IL-7 could mutually enhance the immunogenicity of canine parvovirus VP2 DNA vaccine, although the underlying mechanism remained unknown. Here, we used the OVA gene as a DNA vaccine in a mouse model to test their enhancement on DNA vaccine immunogenicity and to explore the molecular mechanism. Results showed that both IL-2 and IL-7 genes significantly increased the immunogenicity of OVA DNA vaccine in mice. Co-administration of IL-2 and IL-7 genes with OVA DNA significantly increased OVA-specific antibody titers, T cell proliferation and IFN-γ production compared with IL-2 or IL-7 alone, confirming that IL-2 and IL-7 mutually enhanced DNA vaccine immunogenicity. Mechanistically, we have shown that IL-2 significantly stimulated generation of IL-7 receptor-expressing lymphocytes, and that IL-7 significantly induced IL-2 receptor expression. These results contribute to an explanation of the mechanism of the mutual effects of IL-2 and IL-7 on enhancing DNA vaccine immunogenicity and provided a basis for further investigation on their mutual effects on adjuvant activity and immune regulation. Copyright © 2015 Elsevier Ltd. All rights reserved.

H2S Regulates Hypobaric Hypoxia-Induced Early Glio-Vascular Dysfunction and Neuro-Pathophysiological Effects

PubMed Central

Kumar, Gaurav; Chhabra, Aastha; Mishra, Shalini; Kalam, Haroon; Kumar, Dhiraj; Meena, Ramniwas; Ahmad, Yasmin; Bhargava, Kalpana; Prasad, Dipti N.; Sharma, Manish

2016-01-01

Hypobaric Hypoxia (HH) is an established risk factor for various neuro-physiological perturbations including cognitive impairment. The origin and mechanistic basis of such responses however remain elusive. We here combined systems level analysis with classical neuro-physiological approaches, in a rat model system, to understand pathological responses of brain to HH. Unbiased ‘statistical co-expression networks’ generated utilizing temporal, differential transcriptome signatures of hippocampus—centrally involved in regulating cognition—implicated perturbation of Glio-Vascular homeostasis during early responses to HH, with concurrent modulation of vasomodulatory, hemostatic and proteolytic processes. Further, multiple lines of experimental evidence from ultra-structural, immuno-histological, substrate-zymography and barrier function studies unambiguously supported this proposition. Interestingly, we show a significant lowering of H2S levels in the brain, under chronic HH conditions. This phenomenon functionally impacted hypoxia-induced modulation of cerebral blood flow (hypoxic autoregulation) besides perturbing the strength of functional hyperemia responses. The augmentation of H2S levels, during HH conditions, remarkably preserved Glio-Vascular homeostasis and key neuro-physiological functions (cerebral blood flow, functional hyperemia and spatial memory) besides curtailing HH-induced neuronal apoptosis in hippocampus. Our data thus revealed causal role of H2S during HH-induced early Glio-Vascular dysfunction and consequent cognitive impairment. PMID:27211559

Probing solid catalysts under operating conditions: electrons or X-rays?

PubMed

Thomas, John Meurig; Hernandez-Garrido, Juan-Carlos

2009-01-01

Seeing is believing: In light of recent advances, the pros and cons of using electrons and X-rays for in situ studies of catalysts are analyzed: by using X-rays the structure of bound reactants at steady state are obtained from extended X-ray adsorption fine structure spectroscopy (EXAFS) data (see graph), thereby affording mechanistic insights.

Computational Chemistry in the Undergraduate Laboratory: A Mechanistic Study of the Wittig Reaction

ERIC Educational Resources Information Center

Albrecht, Birgit

2014-01-01

The Wittig reaction is one of the most useful reactions in organic chemistry. Despite its prominence early in the organic chemistry curriculum, the exact mechanism of this reaction is still under debate, and this controversy is often neglected in the classroom. Introducing a simple computational study of the Wittig reaction illustrates the…

Mechanistic linkage of hydrologic regime to summer growth of age-0 Atlantic salmon

Treesearch

K.H. Nislow; A.J. Sepulveda; C.L. Folt

2004-01-01

Significant reductions in juvenile stream salmonid growth have been observed in association with low summer flow, but underlying mechanisms are poorly understood and predictive power is limited. We conducted a stage-specific analysis of the relationship between summer flow and the growth of age-0 Atlantic salmon Salmo salar in two rearing sites in...

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.

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...

Interactions of landscape disturbances and climate change dictate ecological pattern and process: spatial modeling of wildfire, insect, and disease dynamics under future climates

Treesearch

Rachel A. Loehman; Robert E. Keane; Lisa M. Holsinger; Zhiwei Wu

2017-01-01

Context: Interactions among disturbances, climate, and vegetation influence landscape patterns and ecosystem processes. Climate changes, exotic invasions, beetle outbreaks, altered fire regimes, and human activities may interact to produce landscapes that appear and function beyond historical analogs. Objectives We used the mechanistic...

A Recollection of mTOR Signaling in Learning and Memory

ERIC Educational Resources Information Center

Graber, Tyson E.; McCamphill, Patrick K.; Sossin, Wayne S.

2013-01-01

Mechanistic target of rapamcyin (mTOR) is a central player in cell growth throughout the organism. However, mTOR takes on an additional, more specialized role in the developed neuron, where it regulates the protein synthesis-dependent, plastic changes underlying learning and memory. mTOR is sequestered in two multiprotein complexes (mTORC1 and…

Boreal soil carbon dynamics under a changing climate: a model inversion approach

Treesearch

Zhaosheng Fan; Jason C. Neff; Jennifer W. Harden; Kimberly P. Wickland

2008-01-01

Several fundamental but important factors controlling the feedback of boreal organic carbon (OC) to climate change were examined using a mechanistic model of soil OC dynamics, including the combined effects of temperature and moisture on the decomposition of OC and the factors controlling carbon quality and decomposition with depth. To estimate decomposition rates and...

Semi-mechanistic modelling of ammonia absorption in an acid spray wet scrubber based on mass balance

USDA-ARS?s Scientific Manuscript database

A model to describe reactive absorption of ammonia (NH3) in an acid spray scrubber was developed as a function of the combined overall mass transfer coefficient K. An experimental study of NH3 absorption using 1% dilute sulphuric acid was carried out under different operating conditions. An empiric...

Cavallin et al 2015

EPA Pesticide Factsheets

This study demonstrates the potential of whole-mount in situ hybridization (WISH), in conjunction with quantitative real-time polymerase chain reaction (QPCR) assays, to examine the mechanistic basis of the effects of toxicants on early-lifestage fathead minnows. Specifically, fathead minnow embryos were exposed to the environmentally-relevant estrogen receptor agonist, estrone, and the data show that: (1) the estrogen-responsive gene transcripts esr1, vtg, and cyp19b can be up-regulated in very early-lifestages of the fathead minnow, (2) WISH methods developed for zebrafish can also be applied successfully to fathead minnows, and (3) WISH has potential to be a useful tool for toxicological studies pertaining to early-lifestage development in the fathead minnow. This type of mechanistic information relative to spatial distribution of gene expression is important in determining potential biological pathways that may be impacted by targeted chemicals and the development of associated adverse outcome pathways.This dataset is associated with the following publication:Cavallin, J., A. Schroeder, K. Jensen , D. Villeneuve , B. Blackwell, K. Carlson, M. Kahl , C. LaLone , E. Randolph , and G. Ankley. Evaluation of whole-mount in situ hybridization as a tool for pathway-based toxicological research with early-life stage fathead minnows. AQUATIC TOXICOLOGY. Elsevier Science Ltd, New York, NY, USA, 169: 19-26, (2015).

Rational Design in Catalysis: A Mechanistic Study of β-Hydride Eliminations in Gold(I) and Gold(III) Complexes Based on Features of the Reaction Valley.

PubMed

Castiñeira Reis, Marta; López, Carlos Silva; Kraka, Elfi; Cremer, Dieter; Faza, Olalla Nieto

2016-09-06

β-Hydride eliminations for ethylgold(III) dichloride complexes are identified as reactions with an unusually long prechemical stage corresponding to the conformational preparation of the reaction complex and spanning six phases. The prechemical process is characterized by a geared rotation of the L-Au-L group (L = Cl) driving methyl group rotation and causing a repositioning of the ligands. This requires more than 28 kcal/mol of the total barrier of 34.0 kcal/mol, according to the unified reaction valley approach, which also determines that the energy requirements of the actual chemical process leading to the β-elimination product are only about 5.5 kcal/mol. A detailed mechanistic analysis was used as a basis for a rational design of substrates (via substituents on the ethyl group) and/or ligands, which can significantly reduce the reaction barrier. This strategy takes advantage of either a higher trans activity of the ligands or a tuned electronic demand of the ethyl group. The β-hydride elimination of gold(I) was found to suffer from strong Coulomb and exchange repulsion when a positively charged hydrogen atom enforces a coordination position in a d(10)-configured gold atom, thus triggering an unassisted σ-π Au(I)-C conversion.

FXR activation by obeticholic acid or nonsteroidal agonists induces a human-like lipoprotein cholesterol change in mice with humanized chimeric liver.

PubMed

Papazyan, Romeo; Liu, Xueqing; Liu, Jingwen; Dong, Bin; Plummer, Emily M; Lewis, Ronald D; Roth, Jonathan D; Young, Mark A

2018-06-01

Obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist that regulates bile acid and lipid metabolism. FXR activation induces distinct changes in circulating cholesterol among animal models and humans. The mechanistic basis of these effects has been elusive because of difficulties in studying lipoprotein homeostasis in mice, which predominantly package circulating cholesterol in HDLs. Here, we tested the effects of OCA in chimeric mice whose livers are mostly composed (≥80%) of human hepatocytes. Chimeric mice exhibited a human-like ratio of serum LDL cholesterol (LDL-C) to HDL cholesterol (HDL-C) at baseline. OCA treatment in chimeric mice increased circulating LDL-C and decreased circulating HDL-C levels, demonstrating that these mice closely model the cholesterol effects of FXR activation in humans. Mechanistically, OCA treatment increased hepatic cholesterol in chimeric mice but not in control mice. This increase correlated with decreased SREBP-2 activity and target gene expression, including a significant reduction in LDL receptor protein. Cotreatment with atorvastatin reduced total cholesterol, rescued LDL receptor protein levels, and normalized serum LDL-C. Treatment with two clinically relevant nonsteroidal FXR agonists elicited similar lipoprotein and hepatic changes in chimeric mice, suggesting that the increase in circulating LDL-C is a class effect of FXR activation.

Superresolution Imaging of Dynamic MreB Filaments in B. subtilis—A Multiple-Motor-Driven Transport?

PubMed Central

Olshausen, Philipp v.; Defeu Soufo, Hervé Joël; Wicker, Kai; Heintzmann, Rainer; Graumann, Peter L.; Rohrbach, Alexander

2013-01-01

The cytoskeletal protein MreB is an essential component of the bacterial cell-shape generation system. Using a superresolution variant of total internal reflection microscopy with structured illumination, as well as three-dimensional stacks of deconvolved epifluorescence microscopy, we found that inside living Bacillus subtilis cells, MreB forms filamentous structures of variable lengths, typically not longer than 1 μm. These filaments move along their orientation and mainly perpendicular to the long bacterial axis, revealing a maximal velocity at an intermediate length and a decreasing velocity with increasing filament length. Filaments move along straight trajectories but can reverse or alter their direction of propagation. Based on our measurements, we provide a mechanistic model that is consistent with all observations. In this model, MreB filaments mechanically couple several motors that putatively synthesize the cell wall, whereas the filaments’ traces mirror the trajectories of the motors. On the basis of our mechanistic model, we developed a mathematical model that can explain the nonlinear velocity length dependence. We deduce that the coupling of cell wall synthesis motors determines the MreB filament transport velocity, and the filament mechanically controls a concerted synthesis of parallel peptidoglycan strands to improve cell wall stability. PMID:24010660

Superresolution imaging of dynamic MreB filaments in B. subtilis--a multiple-motor-driven transport?

PubMed

Olshausen, Philipp V; Defeu Soufo, Hervé Joël; Wicker, Kai; Heintzmann, Rainer; Graumann, Peter L; Rohrbach, Alexander

2013-09-03

The cytoskeletal protein MreB is an essential component of the bacterial cell-shape generation system. Using a superresolution variant of total internal reflection microscopy with structured illumination, as well as three-dimensional stacks of deconvolved epifluorescence microscopy, we found that inside living Bacillus subtilis cells, MreB forms filamentous structures of variable lengths, typically not longer than 1 μm. These filaments move along their orientation and mainly perpendicular to the long bacterial axis, revealing a maximal velocity at an intermediate length and a decreasing velocity with increasing filament length. Filaments move along straight trajectories but can reverse or alter their direction of propagation. Based on our measurements, we provide a mechanistic model that is consistent with all observations. In this model, MreB filaments mechanically couple several motors that putatively synthesize the cell wall, whereas the filaments' traces mirror the trajectories of the motors. On the basis of our mechanistic model, we developed a mathematical model that can explain the nonlinear velocity length dependence. We deduce that the coupling of cell wall synthesis motors determines the MreB filament transport velocity, and the filament mechanically controls a concerted synthesis of parallel peptidoglycan strands to improve cell wall stability. Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.

The Molecular Ecophysiology of Programmed Cell Death in Marine Phytoplankton

NASA Astrophysics Data System (ADS)

Bidle, Kay D.

2015-01-01

Planktonic, prokaryotic, and eukaryotic photoautotrophs (phytoplankton) share a diverse and ancient evolutionary history, during which time they have played key roles in regulating marine food webs, biogeochemical cycles, and Earth's climate. Because phytoplankton represent the basis of marine ecosystems, the manner in which they die critically determines the flow and fate of photosynthetically fixed organic matter (and associated elements), ultimately constraining upper-ocean biogeochemistry. Programmed cell death (PCD) and associated pathway genes, which are triggered by a variety of nutrient stressors and are employed by parasitic viruses, play an integral role in determining the cell fate of diverse photoautotrophs in the modern ocean. Indeed, these multifaceted death pathways continue to shape the success and evolutionary trajectory of diverse phytoplankton lineages at sea. Research over the past two decades has employed physiological, biochemical, and genetic techniques to provide a novel, comprehensive, mechanistic understanding of the factors controlling this key process. Here, I discuss the current understanding of the genetics, activation, and regulation of PCD pathways in marine model systems; how PCD evolved in unicellular photoautotrophs; how it mechanistically interfaces with viral infection pathways; how stress signals are sensed and transduced into cellular responses; and how novel molecular and biochemical tools are revealing the impact of PCD genes on the fate of natural phytoplankton assemblages.

Proteomic and metallomic strategies for understanding the mode of action of anticancer metallodrugs.

PubMed

Gabbiani, Chiara; Magherini, Francesca; Modesti, Alessandra; Messori, Luigi

2010-05-01

Since the discovery of cisplatin and its introduction in the clinics, metal compounds have been intensely investigated in view of their possible application in cancer therapy. In this frame, a deeper understanding of their mode of action, still rather obscure, might turn crucial for the design and the obtainment of new and better anticancer agents. Due to the extreme complexity of the biological systems, it is now widely accepted that innovative and information-rich methods are absolutely needed to afford such a goal. Recently, both proteomic and metallomic strategies were successfully implemented for the elucidation of specific mechanistic features of anticancer metallodrugs within an innovative "Systems Biology" perspective. Particular attention was paid to the following issues: i) proteomic studies of the molecular basis of platinum resistance; ii) proteomic analysis of cellular responses to cytotoxic metallodrugs; iii) metallomic studies of the transformation and fate of metallodrugs in cellular systems. Notably, those pioneering studies, that are reviewed here, allowed a significant progress in the understanding of the molecular mechanisms of metal based drugs at the cellular level. A further extension of those studies and a closer integration of proteomic and metallomic strategies and technologies might realistically lead to rapid and significant advancements in the mechanistic knowledge of anticancer metallodrugs.

Structure-activity relationships and prediction of the phototoxicity and phototoxic potential of new drugs.

PubMed

Barratt, Martin D

2004-11-01

Relationships between the structure and properties of chemicals can be programmed into knowledge-based systems such as DEREK for Windows (DEREK is an acronym for "Deductive Estimation of Risk from Existing Knowledge"). The DEREK for Windows computer system contains a subset of over 60 rules describing chemical substructures (toxophores) responsible for skin sensitisation. As part of the European Phototox Project, the rule base was supplemented by a number of rules for the prospective identification of photoallergens, either by extension of the scope of existing rules or by the generation of new rules where a sound mechanistic rationale for the biological activity could be established. The scope of the rules for photoallergenicity was then further refined by assessment against a list of chemicals identified as photosensitisers by the Centro de Farmacovigilancia de la Comunidad Valenciana, Valencia, Spain. This paper contains an analysis of the mechanistic bases of activity for eight important groups of photoallergens and phototoxins, together with rules for the prospective identification of the photobiological activity of new or untested chemicals belonging to those classes. The mechanism of action of one additional chemical, nitrofurantoin, is well established; however, it was deemed inappropriate to write a rule on the basis of a single chemical structure.

Sulfate Assimilation Mediates Tellurite Reduction and Toxicity in Saccharomyces cerevisiae▿†

PubMed Central

Ottosson, Lars-Göran; Logg, Katarina; Ibstedt, Sebastian; Sunnerhagen, Per; Käll, Mikael; Blomberg, Anders; Warringer, Jonas

2010-01-01

Despite a century of research and increasing environmental and human health concerns, the mechanistic basis of the toxicity of derivatives of the metalloid tellurium, Te, in particular the oxyanion tellurite, Te(IV), remains unsolved. Here, we provide an unbiased view of the mechanisms of tellurium metabolism in the yeast Saccharomyces cerevisiae by measuring deviations in Te-related traits of a complete collection of gene knockout mutants. Reduction of Te(IV) and intracellular accumulation as metallic tellurium strongly correlated with loss of cellular fitness, suggesting that Te(IV) reduction and toxicity are causally linked. The sulfate assimilation pathway upstream of Met17, in particular, the sulfite reductase and its cofactor siroheme, was shown to be central to tellurite toxicity and its reduction to elemental tellurium. Gene knockout mutants with altered Te(IV) tolerance also showed a similar deviation in tolerance to both selenite and, interestingly, selenomethionine, suggesting that the toxicity of these agents stems from a common mechanism. We also show that Te(IV) reduction and toxicity in yeast is partially mediated via a mitochondrial respiratory mechanism that does not encompass the generation of substantial oxidative stress. The results reported here represent a robust base from which to attack the mechanistic details of Te(IV) toxicity and reduction in a eukaryotic organism. PMID:20675578

The genetic basis of a plant–insect coevolutionary key innovation

PubMed Central

Wheat, Christopher W.; Vogel, Heiko; Wittstock, Ute; Braby, Michael F.; Underwood, Dessie; Mitchell-Olds, Thomas

2007-01-01

Ehrlich and Raven formally introduced the concept of stepwise coevolution using butterfly and angiosperm interactions in an attempt to account for the impressive biological diversity of these groups. However, many biologists currently envision butterflies evolving 50 to 30 million years (Myr) after the major angiosperm radiation and thus reject coevolutionary origins of butterfly biodiversity. The unresolved central tenet of Ehrlich and Raven's theory is that evolution of plant chemical defenses is followed closely by biochemical adaptation in insect herbivores, and that newly evolved detoxification mechanisms result in adaptive radiation of herbivore lineages. Using one of their original butterfly-host plant systems, the Pieridae, we identify a pierid glucosinolate detoxification mechanism, nitrile-specifier protein (NSP), as a key innovation. Larval NSP activity matches the distribution of glucosinolate in their host plants. Moreover, by using five different temporal estimates, NSP seems to have evolved shortly after the evolution of the host plant group (Brassicales) (≈10 Myr). An adaptive radiation of these glucosinolate-feeding Pierinae followed, resulting in significantly elevated species numbers compared with related clades. Mechanistic understanding in its proper historical context documents more ancient and dynamic plant–insect interactions than previously envisioned. Moreover, these mechanistic insights provide the tools for detailed molecular studies of coevolution from both the plant and insect perspectives. PMID:18077380

Introductory Biology Students’ Conceptual Models and Explanations of the Origin of Variation

PubMed Central

Shaw, Neil; Momsen, Jennifer; Reinagel, Adam; Le, Paul; Taqieddin, Ranya; Long, Tammy

2014-01-01

Mutation is the key molecular mechanism generating phenotypic variation, which is the basis for evolution. In an introductory biology course, we used a model-based pedagogy that enabled students to integrate their understanding of genetics and evolution within multiple case studies. We used student-generated conceptual models to assess understanding of the origin of variation. By midterm, only a small percentage of students articulated complete and accurate representations of the origin of variation in their models. Targeted feedback was offered through activities requiring students to critically evaluate peers’ models. At semester's end, a substantial proportion of students significantly improved their representation of how variation arises (though one-third still did not include mutation in their models). Students’ written explanations of the origin of variation were mostly consistent with their models, although less effective than models in conveying mechanistic reasoning. This study contributes evidence that articulating the genetic origin of variation is particularly challenging for learners and may require multiple cycles of instruction, assessment, and feedback. To support meaningful learning of the origin of variation, we advocate instruction that explicitly integrates multiple scales of biological organization, assessment that promotes and reveals mechanistic and causal reasoning, and practice with explanatory models with formative feedback. PMID:25185235

Cancer stem cell drugs target K-ras signaling in a stemness context

PubMed Central

Najumudeen, A K; Jaiswal, A; Lectez, B; Oetken-Lindholm, C; Guzmán, C; Siljamäki, E; Posada, I M D; Lacey, E; Aittokallio, T; Abankwa, D

2016-01-01

Cancer stem cells (CSCs) are considered to be responsible for treatment relapse and have therefore become a major target in cancer research. Salinomycin is the most established CSC inhibitor. However, its primary mechanistic target is still unclear, impeding the discovery of compounds with similar anti-CSC activity. Here, we show that salinomycin very specifically interferes with the activity of K-ras4B, but not H-ras, by disrupting its nanoscale membrane organization. We found that caveolae negatively regulate the sensitivity to this drug. On the basis of this novel mechanistic insight, we defined a K-ras-associated and stem cell-derived gene expression signature that predicts the drug response of cancer cells to salinomycin. Consistent with therapy resistance of CSC, 8% of tumor samples in the TCGA-database displayed our signature and were associated with a significantly higher mortality. Using our K-ras-specific screening platform, we identified several new candidate CSC drugs. Two of these, ophiobolin A and conglobatin A, possessed a similar or higher potency than salinomycin. Finally, we established that the most potent compound, ophiobolin A, exerts its K-ras4B-specific activity through inactivation of calmodulin. Our data suggest that specific interference with the K-ras4B/calmodulin interaction selectively inhibits CSC. PMID:26973241

Work values among Lebanese workers.

PubMed

Sidani, Y M; Gardner, W L

2000-10-01

On the basis of a review of the existing literature, the authors tested 4 hypotheses to determine the applicability of work values in Arab societies to employees in Lebanese organizations. Only 1 hypothesis was supported: Organizational policies that ran counter to the worker's religious values had an adverse effect on job satisfaction. There was no support for the hypotheses (a) that workers' religiosity in inversely related to positive attitudes toward women's involvement at work, (b) that employee satisfaction is related to a mechanistic organizational design, or (c) that workers with an internal locus of control experience higher job satisfaction. The Lebanese workers, thus, did not appear to share some of the attributes claimed to exist in Arab societies.

Unravelling the structural and mechanistic basis of CRISPR-Cas systems.

PubMed

van der Oost, John; Westra, Edze R; Jackson, Ryan N; Wiedenheft, Blake

2014-07-01

Bacteria and archaea have evolved sophisticated adaptive immune systems, known as CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR-associated proteins) systems, which target and inactivate invading viruses and plasmids. Immunity is acquired by integrating short fragments of foreign DNA into CRISPR loci, and following transcription and processing of these loci, the CRISPR RNAs (crRNAs) guide the Cas proteins to complementary invading nucleic acid, which results in target interference. In this Review, we summarize the recent structural and biochemical insights that have been gained for the three major types of CRISPR-Cas systems, which together provide a detailed molecular understanding of the unique and conserved mechanisms of RNA-guided adaptive immunity in bacteria and archaea.

Mechanistic examination of pre-exfoliating confinement of surface-active polystyrene nanobeads within pristine clay.

PubMed

Khvan, Svetlana; Kim, Junkyung; Lee, Sang-Soo

2007-02-01

Hydrophobic polymer (PS) nanoparticles preformed through an emulsifier-free emulsion polymerization method were successfully incorporated into a gallery of pristine sodium montmorillonite via interfacial cation exchange. The polymer beads confined between clay nanosheets were capable of (1) preventing the silicate layers from restacking and (2) maintaining the exfoliated state of clay. The increase in the abundance of surface groups promoted adsorption of the nanobeads onto the silicate surface and eventually led to the establishment of strong polymer-clay interactions. These findings suggest that, on the basis of the obtained pre-exfoliated clay masterbatch, the presence of strong polymer-clay interactions could improve the mechanical performance of nanocomposites.

The epigenetic basis for centromere identity.

PubMed

Panchenko, Tanya; Black, Ben E

2009-01-01

The centromere serves as the control locus for chromosome segregation at mitosis and meiosis. In most eukaryotes, including mammals, the location of the centromere is epigenetically defined. The contribution of both genetic and epigenetic determinants to centromere function is the subject of current investigation in diverse eukaryotes. Here we highlight key findings from several organisms that have shaped the current view of centromeres, with special attention to experiments that have elucidated the epigenetic nature of their specification. Recent insights into the histone H3 variant, CENP-A, which assembles into centromeric nucleosomes that serve as the epigenetic mark to perpetuate centromere identity, have added important mechanistic understanding of how centromere identity is initially established and subsequently maintained in every cell cycle.

Precision Dentistry in Early Childhood: The Central Role of Genomics.

PubMed

Divaris, Kimon

2017-07-01

Pediatric oral health is determined by the interaction of environmental factors and genetic influences. This is the case for early childhood caries, the most common disease of childhood. The complexity of exogenous-environmental factors interacting with innate biological predispositions results in a continuum of normal variation, as well as oral health and disease outcomes. Optimal oral health and care or precision dentistry warrants comprehensive understanding of these influences and tools enabling intervention on modifiable factors. This article reviews the current knowledge of the genomic basis of pediatric oral health and highlights known and postulated mechanistic pathways of action relevant to early childhood caries. Copyright © 2017 Elsevier Inc. All rights reserved.

Salmonella Typhi sense host neuroendocrine stress hormones and release the toxin haemolysin E

PubMed Central

Karavolos, Michail H; Bulmer, David M; Spencer, Hannah; Rampioni, Giordano; Schmalen, Ira; Baker, Stephen; Pickard, Derek; Gray, Joe; Fookes, Maria; Winzer, Klaus; Ivens, Alasdair; Dougan, Gordon; Williams, Paul; Khan, C M Anjam

2011-01-01

Salmonella enterica serovar Typhi (S. typhi) causes typhoid fever. We show that exposure of S. typhi to neuroendocrine stress hormones results in haemolysis, which is associated with the release of haemolysin E in membrane vesicles. This effect is attributed to increased expression of the small RNA micA and RNA chaperone Hfq, with concomitant downregulation of outer membrane protein A. Deletion of micA or the two-component signal-transduction system, CpxAR, abolishes the phenotype. The hormone response is inhibited by the β-blocker propranolol. We provide mechanistic insights into the basis of neuroendocrine hormone-mediated haemolysis by S. typhi, increasing our understanding of inter-kingdom signalling. PMID:21331094

Neurologic syndrome associated with homozygous mutation at MAG sialic acid binding site.

PubMed

Roda, Ricardo H; FitzGibbon, Edmond J; Boucekkine, Houda; Schindler, Alice B; Blackstone, Craig

2016-08-01

The MAG gene encodes myelin-associated glycoprotein (MAG), an abundant protein involved in axon-glial interactions and myelination during nerve regeneration. Several members of a consanguineous family with a clinical syndrome reminiscent of Pelizaeus-Merzbacher disease and demyelinating leukodystrophy on brain MRI were recently found to harbor a homozygous missense p.Ser133Arg MAG mutation. Here, we report two brothers from a nonconsanguineous family afflicted with progressive cognitive impairment, neuropathy, ataxia, nystagmus, and gait disorder. Exome sequencing revealed the homozygous missense mutation p.Arg118His in MAG. This Arg118 residue in immunoglobulin domain 1 is critical for sialic acid binding, providing a compelling mechanistic basis for disease pathogenesis.

Radiotherapy for stage I seminoma of the testis: Organ equivalent dose to partially in-field structures and second cancer risk estimates on the basis of a mechanistic, bell-shaped, and plateau model

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

Mazonakis, Michalis, E-mail: mazonak@med.uoc.gr; Damilakis, John; Varveris, Charalambos

Purpose: The aim of the current study was to (a) calculate the organ equivalent dose (OED) and (b) estimate the associated second cancer risk to partially in-field critical structures from adjuvant radiotherapy for stage I seminoma of the testis on the basis of three different nonlinear risk models. Methods: Three-dimensional plans were created for twelve patients who underwent a treatment planning computed tomography of the abdomen. The plans for irradiation of seminoma consisted of para-aortic anteroposterior and posteroanterior fields giving 20 Gy to the target site with 6 MV photons. The OED of stomach, colon, liver, pancreas, and kidneys, thatmore » were partially included in the treatment volume, was calculated using differential dose–volume histograms. The mechanistic, bell-shaped, and plateau models were employed for these calculations provided that organ-specific parameters were available for the subsequent assessment of the excess absolute risk (EAR) for second cancer development. The estimated organ-specific lifetime risks were compared with the respective nominal intrinsic probabilities for cancer induction. Results: The mean OED, which was calculated from the patients’ treatment plans, varied from 0.54 to 6.61 Gy by the partially in-field organ of interest and the model used for dosimetric calculations. The difference between the OED of liver derived from the mechanistic model with those from the bell-shaped and plateau models was less than 1.8%. An even smaller deviation of 1.0% was observed for colon. For the rest organs of interest, the differences between the OED values obtained by the examined models varied from 8.6% to 50.0%. The EAR for stomach, colon, liver, pancreas, and kidney cancer induction at an age of 70 yr because of treatment of a typical 39-yr-old individual was up to 4.24, 11.39, 0.91, 3.04, and 0.14 per 10 000 persons-yr, respectively. Patient’s irradiation was found to elevate the lifetime intrinsic risks by 8.3%–63.0% depending upon the organ of interest and the model employed for risk analysis. Conclusions: Radiotherapy for stage I seminoma of the testis may result in an excess risk for the appearance of secondary malignancies in partially in-field organs. The organ- and model-dependent second cancer risk assessments of this study may be of value for patient counseling and follow-up.« less

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.

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

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

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

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

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

PubMed Central

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

2017-01-01

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

Final Scientific/Technical Report

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

Reeder, Richard; Phillips, Brian

A variety of calcifying organisms produce a transient or metastable amorphous calcium carbonate (ACC) precursor phase that is assembled and subsequently transformed into a crystalline biomineral, typically calcite or aragonite. The complex shapes, hierarchical structures, and unique physical properties of the biominerals that result from this calcification pathway have stimulated interest in adapting these concepts for the design and creation of bio-inspired functional materials in the laboratory. ACC also forms as a reactive precursor in diverse inorganic systems and is likely to play a much broader role in calcium carbonate formation. Knowledge of the structure, composition, and behavior of thismore » metastable phase is critical for establishing a structural and mechanistic framework for calcium carbonate formation and its role in biogeochemical processes, including carbon cycling. Minor additives, such as magnesium, phosphorus, and organic macromolecules, are known to play important roles in controlling ACC stability, transformation kinetics, and selection of final crystalline polymorph. Molecular water also occurs in many types of ACC and is thought to play a structural role in its stability and transformation behavior. One of the major challenges that remain unresolved is identification of the structural basis for the role of these minor additives and molecular water. The absence of long-range order in ACC, and other amorphous phases, has posed a challenge for study by techniques commonly used for crystalline solids. Preliminary studies in our group show that the combination of two techniques, synchrotron X-ray-based pair distribution function (PDF) analysis and nuclear magnetic resonance (NMR) spectroscopy can provide entirely new insight to structural properties of synthetic ACC over length scales that are most relevant for understanding its transformation properties. Building on preliminary experiments, we propose a systematic study of synthesis, structure, and transformation behavior in abiotic systems. The work will specifically address the influence of phosphate as a minor additive. PDF analysis will utilize total X-ray scattering data collected at synchrotron facilities optimized for this method and will provide direct characterization of the short- and intermediate-range structure of ACC synthesized under controlled conditions. Parallel computational work using reverse Monte Carlo methods will allow structural models to be constructed for a more complete analysis of PDF results. NMR spectroscopy, using a variety of single- and double-resonance techniques, will provide information on H and CO3 components, including dynamical properties, and their relationship to stabilizing additives. PDF and NMR results will be complemented by parallel studies using X-ray absorption and FT-IR spectroscopy to allow direct comparison to previous studies. These techniques will be used to follow the transformation of different ACC samples, with specific additives, to crystalline phases under controlled condition (e.g., relative humidity). This work will provide the structural and mechanistic basis for understanding ACC stability, its transformation behavior, and the factors that govern polymorph selection. This new insight will directly benefit researchers in diverse fields, as well as adding to the framework of knowledge for understanding and controlling calcium carbonate formation in natural and engineered systems.« less

Disproportionation of hydroxylamine by water-soluble iron(III) porphyrinate compounds.

PubMed

Bari, Sara E; Amorebieta, Valentín T; Gutiérrez, María M; Olabe, José A; Doctorovich, Fabio

2010-01-01

The reactions of hydroxylamine (HA) with several water-soluble iron(III) porphyrinate compounds, namely iron(III) meso-tetrakis-(N-ethylpyridinium-2yl)-porphyrinate ([Fe(III)(TEPyP)](5+)), iron(III) meso-tetrakis-(4-sulphonatophenyl)-porphyrinate ([Fe(III)(TPPS)](3-)), and microperoxidase 11 ([Fe(III)(MP11)]) were studied for different [Fe(III)(Porph)]/[HA] ratios, under anaerobic conditions at neutral pH. Efficient catalytic processes leading to the disproportionation of HA by these iron(III) porphyrinates were evidenced for the first time. As a common feature, only N(2) and N(2)O were found as gaseous, nitrogen-containing oxidation products, while NH(3) was the unique reduced species detected. Different N(2)/N(2)O ratios obtained with these three porphyrinates strongly suggest distinctive mechanistic scenarios: while [Fe(III)(TEPyP)](5+) and [Fe(III)(MP11)] formed unknown steady-state porphyrinic intermediates in the presence of HA, [Fe(III)(TPPS)](3-) led to the well characterized soluble intermediate, [Fe(II)(TPPS)NO](4-). Free-radical formation was only evidenced for [Fe(III)(TEPyP)](5+), as a consequence of a metal centered reduction. We discuss the catalytic pathways of HA disproportionation on the basis of the distribution of gaseous products, free radicals formation, the nature of porphyrinic intermediates, the Fe(II)/Fe(III) redox potential, the coordinating capabilities of each complex, and the kinetic analysis. The absence of NO(2)(-) revealed either that no HAO-like activity was operative under our reaction conditions, or that NO(2)(-), if formed, was consumed in the reaction milieu.

Activity syndromes and metabolism in giant deep-sea isopods

NASA Astrophysics Data System (ADS)

Wilson, Alexander D. M.; Szekeres, Petra; Violich, Mackellar; Gutowsky, Lee F. G.; Eliason, Erika J.; Cooke, Steven J.

2017-03-01

Despite growing interest, the behavioural ecology of deep-sea organisms is largely unknown. Much of this scarcity in knowledge can be attributed to deepwater animals being secretive or comparatively 'rare', as well as technical difficulties associated with accessing such remote habitats. Here we tested whether two species of giant marine isopod (Bathynomus giganteus, Booralana tricarinata) captured from 653 to 875 m in the Caribbean Sea near Eleuthera, The Bahamas, exhibited an activity behavioural syndrome across two environmental contexts (presence/absence of food stimulus) and further whether this syndrome carried over consistently between sexes. We also measured routine metabolic rate and oxygen consumption in response to a food stimulus in B. giganteus to assess whether these variables are related to individual differences in personality. We found that both species show an activity syndrome across environmental contexts, but the underlying mechanistic basis of this syndrome, particularly in B. giganteus, is unclear. Contrary to our initial predictions, neither B. giganteus nor B. tricarinata showed any differences between mean expression of behavioural traits between sexes. Both sexes of B. tricarinata showed strong evidence of an activity syndrome underlying movement and foraging ecology, whereas only male B. giganteus showed evidence of an activity syndrome. Generally, individuals that were more active and bolder, in a standard open arena test were also more active when a food stimulus was present. Interestingly, individual differences in metabolism were not related to individual differences in behaviour based on present data. Our study provides the first measurements of behavioural syndromes and metabolism in giant deep-sea isopods.

Contrasting modes and tempos of venom expression evolution in two snake species.

PubMed

Margres, Mark J; McGivern, James J; Seavy, Margaret; Wray, Kenneth P; Facente, Jack; Rokyta, Darin R

2015-01-01

Selection is predicted to drive diversification within species and lead to local adaptation, but understanding the mechanistic details underlying this process and thus the genetic basis of adaptive evolution requires the mapping of genotype to phenotype. Venom is complex and involves many genes, but the specialization of the venom gland toward toxin production allows specific transcripts to be correlated with specific toxic proteins, establishing a direct link from genotype to phenotype. To determine the extent of expression variation and identify the processes driving patterns of phenotypic diversity, we constructed genotype-phenotype maps and compared range-wide toxin-protein expression variation for two species of snake with nearly identical ranges: the eastern diamondback rattlesnake (Crotalus adamanteus) and the eastern coral snake (Micrurus fulvius). We detected significant expression variation in C. adamanteus, identified the specific loci associated with population differentiation, and found that loci expressed at all levels contributed to this divergence. Contrary to expectations, we found no expression variation in M. fulvius, suggesting that M. fulvius populations are not locally adapted. Our results not only linked expression variation at specific loci to divergence in a polygenic, complex trait but also have extensive conservation and biomedical implications. C. adamanteus is currently a candidate for federal listing under the Endangered Species Act, and the loss of any major population would result in the irrevocable loss of a unique venom phenotype. The lack of variation in M. fulvius has significant biomedical application because our data will assist in the development of effective antivenom for this species. Copyright © 2015 by the Genetics Society of America.

Simultaneous GCaMP6-based fiber photometry and fMRI in rats.

PubMed

Liang, Zhifeng; Ma, Yuncong; Watson, Glenn D R; Zhang, Nanyin

2017-09-01

Understanding the relationship between neural and vascular signals is essential for interpretation of functional MRI (fMRI) results with respect to underlying neuronal activity. Simultaneously measuring neural activity using electrophysiology with fMRI has been highly valuable in elucidating the neural basis of the blood oxygenation-level dependent (BOLD) signal. However, this approach is also technically challenging due to the electromagnetic interference that is observed in electrophysiological recordings during MRI scanning. Recording optical correlates of neural activity, such as calcium signals, avoids this issue, and has opened a new avenue to simultaneously acquire neural and BOLD signals. The present study is the first to demonstrate the feasibility of simultaneously and repeatedly acquiring calcium and BOLD signals in animals using a genetically encoded calcium indicator, GCaMP6. This approach was validated with a visual stimulation experiment, during which robust increases of both calcium and BOLD signals in the superior colliculus were observed. In addition, repeated measurement in the same animal demonstrated reproducible calcium and BOLD responses to the same stimuli. Taken together, simultaneous GCaMP6-based fiber photometry and fMRI recording presents a novel, artifact-free approach to simultaneously measuring neural and fMRI signals. Furthermore, given the cell-type specificity of GCaMP6, this approach has the potential to mechanistically dissect the contributions of individual neuron populations to BOLD signal, and ultimately reveal its underlying neural mechanisms. The current study established the method for simultaneous GCaMP6-based fiber photometry and fMRI in rats. Copyright © 2017 Elsevier B.V. All rights reserved.

Mechanistic Basis for High Stereoselectivity and Broad Substrate Scope in the (salen)Co(III)-Catalyzed Hydrolytic Kinetic Resolution

PubMed Central

Ford, David D.; Nielsen, Lars P. C.; Zuend, Stephan J.; Jacobsen, Eric N.

2013-01-01

In the (salen)Co(III)-catalyzed hydrolytic kinetic resolution (HKR) of terminal epoxides, the rate- and stereoselectivity-determining epoxide ring-opening step occurs by a cooperative bimetallic mechanism with one Co(III) complex acting as a Lewis acid and another serving to deliver the hydroxide nucleophile. In this paper, we analyze the basis for the extraordinarily high stereoselectivity and broad substrate scope observed in the HKR. We demonstrate that the stereochemistry of each of the two (salen)Co(III) complexes in the rate-determining transition structure is important for productive catalysis: a measurable rate of hydrolysis occurs only if the absolute stereochemistry of each of these (salen)Co(III) complexes is the same. Experimental and computational studies provide strong evidence that stereochemical communication in the HKR is mediated by the stepped conformation of the salen ligand, and not the shape of the chiral diamine backbone of the ligand. A detailed computational analysis reveals that the epoxide binds the Lewis acidic Co(III) complex in a well-defined geometry imposed by stereoelectronic, rather than steric effects. This insight serves as the basis of a complete stereochemical and transition structure model that sheds light on the reasons for the broad substrate generality of the HKR. PMID:24041239

Mechanistic basis for high stereoselectivity and broad substrate scope in the (salen)Co(III)-catalyzed hydrolytic kinetic resolution.

PubMed

Ford, David D; Nielsen, Lars P C; Zuend, Stephan J; Musgrave, Charles B; Jacobsen, Eric N

2013-10-16

In the (salen)Co(III)-catalyzed hydrolytic kinetic resolution (HKR) of terminal epoxides, the rate- and stereoselectivity-determining epoxide ring-opening step occurs by a cooperative bimetallic mechanism with one Co(III) complex acting as a Lewis acid and another serving to deliver the hydroxide nucleophile. In this paper, we analyze the basis for the extraordinarily high stereoselectivity and broad substrate scope observed in the HKR. We demonstrate that the stereochemistry of each of the two (salen)Co(III) complexes in the rate-determining transition structure is important for productive catalysis: a measurable rate of hydrolysis occurs only if the absolute stereochemistry of each of these (salen)Co(III) complexes is the same. Experimental and computational studies provide strong evidence that stereochemical communication in the HKR is mediated by the stepped conformation of the salen ligand, and not the shape of the chiral diamine backbone of the ligand. A detailed computational analysis reveals that the epoxide binds the Lewis acidic Co(III) complex in a well-defined geometry imposed by stereoelectronic rather than steric effects. This insight serves as the basis of a complete stereochemical and transition structure model that sheds light on the reasons for the broad substrate generality of the HKR.

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

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.

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

PubMed

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

2011-01-01

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

Condensins under the microscope.

PubMed

Maeshima, Kazuhiro; Hibino, Kayo; Hudson, Damien F

2018-04-30

Condensins are key players in mitotic chromosome condensation. Using an elegant combination of state-of-the-art imaging techniques, Walther et al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201801048) counted the number of Condensins, examined their behaviors on human mitotic chromosomes, and integrated the quantitative data to propose a new mechanistic model for chromosome condensation. © 2018 Maeshima et al.

Perspective: The potential role of essential amino acids and the mechanistic target of rapamycin complex 1 (mTORC1) pathway in the pathogenesis of child stunting

USDA-ARS?s Scientific Manuscript database

Stunting is the best summary measure of chronic malnutrition in children. Approximately one-quarter of children under age 5 worldwide are stunted. Lipid-based or micronutrient supplementation has little to no impact in reducing stunting, which suggests that other critical dietary nutrients are missi...

Investigation of Chirality Selection Mechanism of Single-Walled Carbon Nanotube

DTIC Science & Technology

2015-07-17

Final 3. DATES COVERED (From - To) 01-June-2014 to 31-May-2015 4. TITLE AND SUBTITLE Investigation of Chirality Selection Mechanism of...of two significant mechanistic aspects of carbon nanotube (CNT) array growth under chemical vapor deposition conditions: chirality selectivity and...affected by the morphological evolution of catalyst particles. 15. SUBJECT TERMS Carbon Nanotubes, Chirality , Processing, Catalysis

Intestinal irony: how probiotic bacteria outcompete bad bugs.

PubMed

Weiss, Guenter

2013-07-17

In this issue of Cell Host & Microbe, Deriu et al. present a mechanistic explanation underlying the benefits of certain probiotic bacteria. Intestinal bacteria compete for the essential nutrient iron, leading to replacement of pathogenic Salmonella by the probiotic Escherichia coli Nissle, which is better equipped with iron acquisition systems, and resolution of infectious colitis. Copyright © 2013 Elsevier Inc. All rights reserved.

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.

Quantitative prediction of repaglinide-rifampicin complex drug interactions using dynamic and static mechanistic models: delineating differential CYP3A4 induction and OATP1B1 inhibition potential of rifampicin.

PubMed

Varma, Manthena V S; Lin, Jian; Bi, Yi-An; Rotter, Charles J; Fahmi, Odette A; Lam, Justine L; El-Kattan, Ayman F; Goosen, Theunis C; Lai, Yurong

2013-05-01

Repaglinide is mainly metabolized by cytochrome P450 enzymes CYP2C8 and CYP3A4, and it is also a substrate to a hepatic uptake transporter, organic anion transporting polypeptide (OATP)1B1. The purpose of this study is to predict the dosing time-dependent pharmacokinetic interactions of repaglinide with rifampicin, using mechanistic models. In vitro hepatic transport of repaglinide, characterized using sandwich-cultured human hepatocytes, and intrinsic metabolic parameters were used to build a dynamic whole-body physiologically-based pharmacokinetic (PBPK) model. The PBPK model adequately described repaglinide plasma concentration-time profiles and successfully predicted area under the plasma concentration-time curve ratios of repaglinide (within ± 25% error), dosed (staggered 0-24 hours) after rifampicin treatment when primarily considering induction of CYP3A4 and reversible inhibition of OATP1B1 by rifampicin. Further, a static mechanistic "extended net-effect" model incorporating transport and metabolic disposition parameters of repaglinide and interaction potency of rifampicin was devised. Predictions based on the static model are similar to those observed in the clinic (average error ∼19%) and to those based on the PBPK model. Both the models suggested that the combined effect of increased gut extraction and decreased hepatic uptake caused minimal repaglinide systemic exposure change when repaglinide is dosed simultaneously or 1 hour after the rifampicin dose. On the other hand, isolated induction effect as a result of temporal separation of the two drugs translated to an approximate 5-fold reduction in repaglinide systemic exposure. In conclusion, both dynamic and static mechanistic models are instrumental in delineating the quantitative contribution of transport and metabolism in the dosing time-dependent repaglinide-rifampicin interactions.

A global scale mechanistic model of photosynthetic capacity (LUNA V1.0)

DOE PAGES

Ali, Ashehad A.; Xu, Chonggang; Rogers, Alistair; ...

2016-02-12

Although plant photosynthetic capacity as determined by the maximum carboxylation rate (i.e., V c,max25) and the maximum electron transport rate (i.e., J max25) at a reference temperature (generally 25 °C) is known to vary considerably in space and time in response to environmental conditions, it is typically parameterized in Earth system models (ESMs) with tabulated values associated with plant functional types. In this study, we have developed a mechanistic model of leaf utilization of nitrogen for assimilation (LUNA) to predict photosynthetic capacity at the global scale under different environmental conditions. We adopt an optimality hypothesis to nitrogen allocation among lightmore » capture, electron transport, carboxylation and respiration. The LUNA model is able to reasonably capture the measured spatial and temporal patterns of photosynthetic capacity as it explains ~55 % of the global variation in observed values of V c,max25 and ~65 % of the variation in the observed values of J max25. Model simulations with LUNA under current and future climate conditions demonstrate that modeled values of V c,max25 are most affected in high-latitude regions under future climates. In conclusion, ESMs that relate the values of V c,max25 or J max25 to plant functional types only are likely to substantially overestimate future global photosynthesis.« less

Mechanistic Basis for the Bypass of a Bulky DNA Adduct Catalyzed by a Y-Family DNA Polymerase

PubMed Central

Vyas, Rajan; Efthimiopoulos, Georgia; Tokarsky, E. John; Malik, Chanchal K.; Basu, Ashis K.; Suo, Zucai

2015-01-01

1-Nitropyrene (1-NP), an environmental pollutant, induces DNA damage in vivo and is considered to be carcinogenic. The DNA adducts formed by the 1-NP metabolites stall replicative DNA polymerases but are presumably bypassed by error-prone Y-family DNA polymerases at the expense of replication fidelity and efficiency in vivo. Our running start assays confirmed that a site-specifically placed 8-(deoxyguanosin-N2-yl)-1-aminopyrene (dG1,8), one of the DNA adducts derived from 1-NP, can be bypassed by Sulfolobus solfataricus DNA polymerase IV (Dpo4), although this representative Y-family enzyme was paused strongly by the lesion. Pre-steady-state kinetic assays were employed to determine the low nucleotide incorporation fidelity and establish a minimal kinetic mechanism for the dG1,8 bypass by Dpo4. To reveal a structural basis for dCTP incorporation opposite dG1,8, we solved the crystal structures of the complexes of Dpo4 and DNA containing a templating dG1,8 lesion in the absence or presence of dCTP. The Dpo4·DNA-dG1,8 binary structure shows that the aminopyrene moiety of the lesion stacks against the primer/template junction pair, while its dG moiety projected into the cleft between the Finger and Little Finger domains of Dpo4. In the Dpo4·DNA-dG1,8·dCTP ternary structure, the aminopyrene moiety of the dG1,8 lesion, is sandwiched between the nascent and junction base pairs, while its base is present in the major groove. Moreover, dCTP forms a Watson–Crick base pair with dG, two nucleotides upstream from the dG1,8 site, creating a complex for “-2” frameshift mutation. Mechanistically, these crystal structures provide additional insight into the aforementioned minimal kinetic mechanism. PMID:26327169

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

NASA Astrophysics Data System (ADS)

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

2013-12-01

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

Antibiotic Stimulation of a Bacillus subtilis Migratory Response

PubMed Central

Liu, Yongjin; Kyle, Steven

2018-01-01

ABSTRACT Competitive interactions between bacteria reveal physiological adaptations that benefit fitness. Bacillus subtilis is a Gram-positive species with several adaptive mechanisms for competition and environmental stress. Biofilm formation, sporulation, and motility are the outcomes of widespread changes in a population of B. subtilis. These changes emerge from complex, regulated pathways for adapting to external stresses, including competition from other species. To identify competition-specific functions, we cultured B. subtilis with multiple species of Streptomyces and observed altered patterns of growth for each organism. In particular, when plated on agar medium near Streptomyces venezuelae, B. subtilis initiates a robust and reproducible mobile response. To investigate the mechanistic basis for the interaction, we determined the type of motility used by B. subtilis and isolated inducing metabolites produced by S. venezuelae. Bacillus subtilis has three defined forms of motility: swimming, swarming, and sliding. Streptomyces venezuelae induced sliding motility specifically in our experiments. The inducing agents produced by S. venezuelae were identified as chloramphenicol and a brominated derivative at subinhibitory concentrations. Upon further characterization of the mobile response, our results demonstrated that subinhibitory concentrations of chloramphenicol, erythromycin, tetracycline, and spectinomycin all activate a sliding motility response by B. subtilis. Our data are consistent with sliding motility initiating under conditions of protein translation stress. This report underscores the importance of hormesis as an early warning system for potential bacterial competitors and antibiotic exposure. IMPORTANCE Antibiotic resistance is a major challenge for the effective treatment of infectious diseases. Identifying adaptive mechanisms that bacteria use to survive low levels of antibiotic stress is important for understanding pathways to antibiotic resistance. Furthermore, little is known about the effects of individual bacterial interactions on multispecies communities. This work demonstrates that subinhibitory amounts of some antibiotics produced by streptomycetes induce active motility in B. subtilis, which may alter species interaction dynamics among species-diverse bacterial communities in natural environments. The use of antibiotics at subinhibitory concentrations results in many changes in bacteria, including changes in biofilm formation, small-colony variants, formation of persisters, and motility. Identifying the mechanistic bases of these adaptations is crucial for understanding how bacterial communities are impacted by antibiotics. PMID:29507890

Comparison of Stream Temperature Modeling Approaches: The Case of a High Alpine Watershed in the Context of Climate Change

NASA Astrophysics Data System (ADS)

Gallice, A.

2015-12-01

Stream temperature controls important aspects of the riverine habitat, such as the rate of spawning or death of many fish species, or the concentration of numerous dissolved substances. In the current context of accelerating climate change, the future evolution of stream temperature is regarded as uncertain, particularly in the Alps. This uncertainty fostered the development of many prediction models, which are usually classified in two categories: mechanistic models and statistical models. Based on the numerical resolution of physical conservation laws, mechanistic models are generally considered to provide more reliable long-term estimates than regression models. However, despite their physical basis, these models are observed to differ quite significantly in some aspects of their implementation, notably (1) the routing of water in the river channel and (2) the estimation of the temperature of groundwater discharging into the stream. For each one of these two aspects, we considered several of the standard modeling approaches reported in the literature and implemented them in a new modular framework. The latter is based on the spatially-distributed snow model Alpine3D, which is essentially used in the framework to compute the amount of water infiltrating in the upper soil layer. Starting from there, different methods can be selected for the computation of the water and energy fluxes in the hillslopes and in the river network. We relied on this framework to compare the various methodologies for river channel routing and groundwater temperature modeling. We notably assessed the impact of each these approaches on the long-term stream temperature predictions of the model under a typical climate change scenario. The case study was conducted over a high Alpine catchment in Switzerland, whose hydrological and thermal regimes are expected to be markedly affected by climate change. The results show that the various modeling approaches lead to significant differences in the model predictions, and that these differences may be larger than the uncertainties in future air temperature. It is also shown that the temperature of groundwater discharging into the stream has a marked impact on the modeled stream temperature at the catchment outlet.

An anatomical and physiological basis for the cardiovascular autonomic nervous system consequences of sport-related brain injury.

PubMed

La Fountaine, Michael F

2017-11-29

Concussion is defined as a complex pathophysiological process affecting the brain that is induced by the application or transmission of traumatic biomechanical forces to the head. The result of the impact is the onset of transient symptoms that may be experienced for approximately 2weeks in most individuals. However, in some individuals, symptoms may not resolve and persist for a protracted period and a chronic injury ensues. Concussion symptoms are generally characterized by their emergence through changes in affect, cognition, or multi-sensory processes including the visual and vestibular systems. An emerging consequence of concussion is the presence of cardiovascular autonomic nervous system dysfunction that is most apparent through hemodynamic perturbations and provocations. Further interrogation of data that are derived from continuous digital electrocardiograms and/or beat-to-beat blood pressure monitoring often reveal an imbalance of parasympathetic or sympathetic nervous system activity during a provocation after an injury. The disturbance is often greatest early after injury and a resolution of the dysfunction occurs in parallel with other symptoms. The possibility exists that the disturbance may remain if the concussion does not resolve. Unfortunately, there is little evidence in humans to support the etiology for the emergence of this post-injury dysfunction. As such, evidence from experimental models of traumatic brain injury and casual observations from human studies of concussion implicate a transient abnormality of the anatomical structures and functions of the cardiovascular autonomic nervous system. The purpose of this review article is to provide a mechanistic narrative of multi-disciplinary evidence to support the anatomical and physiological basis of cardiovascular autonomic nervous system dysfunction after concussion. The review article will identify the anatomical structures of the autonomic nervous system and propose a theoretical framework to demonstrate the potential effects of concussive head trauma on corresponding outcome measurements. Evidence from experimental models will be used to describe abnormal cellular functions and provide a hypothetical mechanistic basis for the respective responses of the anatomical structures to concussive head trauma. When available, example observations from the human concussion literature will be presented to demonstrate the effects of concussive head trauma that may be related to anomalous activity in the respective anatomical structures of the autonomic nervous system. Copyright © 2017 Elsevier B.V. All rights reserved.

Recent Developments in Hydrogen Evolving Molecular Cobalt(II)-Polypyridyl Catalysts

PubMed Central

Queyriaux, N.; Jane, R. T.; Massin, J.; Artero, V.; Chavarot-Kerlidou, M.

2015-01-01

The search for efficient noble metal-free hydrogen-evolving catalysts is the subject of intense research activity. A new family of molecular cobalt(II)-polypyridyl catalysts has recently emerged. These catalysts prove more robust under reductive conditions than other cobalt-based systems and display high activities under fully aqueous conditions. This review discusses the design, characterization, and evaluation of these catalysts for electrocatalytic and light-driven hydrogen production. Mechanistic considerations are addressed and structure-catalytic activity relationships identified in order to guide the future design of more efficient catalytic systems. PMID:26688590

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

PubMed Central

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

2015-01-01

Being overweight or obese is associated with an elevated risk of tendon pathology. However, for sportspeople the epidemiological data linking weight or adiposity on one hand, and risk of tendon pathology on the other, are less consistent. Indeed, the mechanistic links between diet, adiposity and tendon pathology remain largely unexamined. Recent studies have begun to examine the effects of dietary interventions on outcomes such as tendon biomechanics or pain. Oxidised low-density lipoprotein has been shown to (A) accumulate in the tendon tissues of mice that eat a fatty diet and (B) induce a pathological phenotype in human tendon cells. This paper addresses the current debate: is excessive body mass index (causing increased load and strain on tendon tissue) per se the underlying mechanism? Or do local or systemic influences of fat on tendons predispose to tendon pathology? This narrative review argues that excessive blood lipids may be an important avenue for clinical investigations. PMID:25488953

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

PubMed

Kuorikoski, Jaakko; Marchionni, Caterina

2014-12-01

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

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.

Belowground Carbon Cycling Processes at the Molecular Scale: An EMSL Science Theme Advisory Panel Workshop

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

Hess, Nancy J.; Brown, Gordon E.; Plata, Charity

2014-02-21

As part of the Belowground Carbon Cycling Processes at the Molecular Scale workshop, an EMSL Science Theme Advisory Panel meeting held in February 2013, attendees discussed critical biogeochemical processes that regulate carbon cycling in soil. The meeting attendees determined that as a national scientific user facility, EMSL can provide the tools and expertise needed to elucidate the molecular foundation that underlies mechanistic descriptions of biogeochemical processes that control carbon allocation and fluxes at the terrestrial/atmospheric interface in landscape and regional climate models. Consequently, the workshop's goal was to identify the science gaps that hinder either development of mechanistic description ofmore » critical processes or their accurate representation in climate models. In part, this report offers recommendations for future EMSL activities in this research area. The workshop was co-chaired by Dr. Nancy Hess (EMSL) and Dr. Gordon Brown (Stanford University).« less