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Sample records for model developmental regulatory

  1. A developmental systems perspective on epistasis: computational exploration of mutational interactions in model developmental regulatory networks.

    Directory of Open Access Journals (Sweden)

    Jayson Gutiérrez

    2009-09-01

    Full Text Available The way in which the information contained in genotypes is translated into complex phenotypic traits (i.e. embryonic expression patterns depends on its decoding by a multilayered hierarchy of biomolecular systems (regulatory networks. Each layer of this hierarchy displays its own regulatory schemes (i.e. operational rules such as +/- feedback and associated control parameters, resulting in characteristic variational constraints. This process can be conceptualized as a mapping issue, and in the context of highly-dimensional genotype-phenotype mappings (GPMs epistatic events have been shown to be ubiquitous, manifested in non-linear correspondences between changes in the genotype and their phenotypic effects. In this study I concentrate on epistatic phenomena pervading levels of biological organization above the genetic material, more specifically the realm of molecular networks. At this level, systems approaches to studying GPMs are specially suitable to shed light on the mechanistic basis of epistatic phenomena. To this aim, I constructed and analyzed ensembles of highly-modular (fully interconnected networks with distinctive topologies, each displaying dynamic behaviors that were categorized as either arbitrary or functional according to early patterning processes in the Drosophila embryo. Spatio-temporal expression trajectories in virtual syncytial embryos were simulated via reaction-diffusion models. My in silico mutational experiments show that: 1 the average fitness decay tendency to successively accumulated mutations in ensembles of functional networks indicates the prevalence of positive epistasis, whereas in ensembles of arbitrary networks negative epistasis is the dominant tendency; and 2 the evaluation of epistatic coefficients of diverse interaction orders indicates that, both positive and negative epistasis are more prevalent in functional networks than in arbitrary ones. Overall, I conclude that the phenotypic and fitness effects of

  2. Current status of developmental neurotoxicity: regulatory view

    DEFF Research Database (Denmark)

    Hass, Ulla

    2003-01-01

    in the testing strategy for new and existing substances, and biocides. Hopefully, this will lead to an improved database for risk assessment of potential developmental neurotoxicants. However, the regulatory authorities and toxicologists will also be faced with the challenge that decisions have to be made......The need for developmental neurotoxicity testing has been recognized for decades and guidelines are available, as the USEPA guideline and the OECD draft TG 426. Regulatory testing of industrial chemicals for developmental neurotoxicity is required to some extent, especially for pesticides in the US....... Until recently, however, developmental neurotoxicity testing of industrial chemicals has not been a clear regulatory requirement in EU, probably due to the lack of an accepted OECD TG. The revised EU Technical Guidance Document for Risk Assessment (EU-TGD) has now included the OECD draft TG 426...

  3. Efficient Reverse-Engineering of a Developmental Gene Regulatory Network

    Science.gov (United States)

    Cicin-Sain, Damjan; Ashyraliyev, Maksat; Jaeger, Johannes

    2012-01-01

    Understanding the complex regulatory networks underlying development and evolution of multi-cellular organisms is a major problem in biology. Computational models can be used as tools to extract the regulatory structure and dynamics of such networks from gene expression data. This approach is called reverse engineering. It has been successfully applied to many gene networks in various biological systems. However, to reconstitute the structure and non-linear dynamics of a developmental gene network in its spatial context remains a considerable challenge. Here, we address this challenge using a case study: the gap gene network involved in segment determination during early development of Drosophila melanogaster. A major problem for reverse-engineering pattern-forming networks is the significant amount of time and effort required to acquire and quantify spatial gene expression data. We have developed a simplified data processing pipeline that considerably increases the throughput of the method, but results in data of reduced accuracy compared to those previously used for gap gene network inference. We demonstrate that we can infer the correct network structure using our reduced data set, and investigate minimal data requirements for successful reverse engineering. Our results show that timing and position of expression domain boundaries are the crucial features for determining regulatory network structure from data, while it is less important to precisely measure expression levels. Based on this, we define minimal data requirements for gap gene network inference. Our results demonstrate the feasibility of reverse-engineering with much reduced experimental effort. This enables more widespread use of the method in different developmental contexts and organisms. Such systematic application of data-driven models to real-world networks has enormous potential. Only the quantitative investigation of a large number of developmental gene regulatory networks will allow us to

  4. Developmental Education Evaluation Model.

    Science.gov (United States)

    Perry-Miller, Mitzi; And Others

    A developmental education evaluation model designed to be used at a multi-unit urban community college is described. The purpose of the design was to determine the cost effectiveness/worth of programs in order to initiate self-improvement. A needs assessment was conducted by interviewing and taping the responses of students, faculty, staff, and…

  5. Robustness and accuracy in sea urchin developmental gene regulatory networks

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    Smadar eBen-Tabou De-Leon

    2016-02-01

    Full Text Available Developmental gene regulatory networks robustly control the timely activation of regulatory and differentiation genes. The structure of these networks underlies their capacity to buffer intrinsic and extrinsic noise and maintain embryonic morphology. Here I illustrate how the use of specific architectures by the sea urchin developmental regulatory networks enables the robust control of cell fate decisions. The Wnt-βcatenin signaling pathway patterns the primary embryonic axis while the BMP signaling pathway patterns the secondary embryonic axis in the sea urchin embryo and across bilateria. Interestingly, in the sea urchin in both cases, the signaling pathway that defines the axis controls directly the expression of a set of downstream regulatory genes. I propose that this direct activation of a set of regulatory genes enables a uniform regulatory response and a clear cut cell fate decision in the endoderm and in the dorsal ectoderm. The specification of the mesodermal pigment cell lineage is activated by Delta signaling that initiates a triple positive feedback loop that locks down the pigment specification state. I propose that the use of compound positive feedback circuitry provides the endodermal cells enough time to turn off mesodermal genes and ensures correct mesoderm vs. endoderm fate decision. Thus, I argue that understanding the control properties of repeatedly used regulatory architectures illuminates their role in embryogenesis and provides possible explanations to their resistance to evolutionary change.

  6. Developmental evolution in social insects: regulatory networks from genes to societies.

    Science.gov (United States)

    Linksvayer, Timothy A; Fewell, Jennifer H; Gadau, Jürgen; Laubichler, Manfred D

    2012-05-01

    The evolution and development of complex phenotypes in social insect colonies, such as queen-worker dimorphism or division of labor, can, in our opinion, only be fully understood within an expanded mechanistic framework of Developmental Evolution. Conversely, social insects offer a fertile research area in which fundamental questions of Developmental Evolution can be addressed empirically. We review the concept of gene regulatory networks (GRNs) that aims to fully describe the battery of interacting genomic modules that are differentially expressed during the development of individual organisms. We discuss how distinct types of network models have been used to study different levels of biological organization in social insects, from GRNs to social networks. We propose that these hierarchical networks spanning different organizational levels from genes to societies should be integrated and incorporated into full GRN models to elucidate the evolutionary and developmental mechanisms underlying social insect phenotypes. Finally, we discuss prospects and approaches to achieve such an integration. © 2012 WILEY PERIODICALS, INC.

  7. Beyond traditional developmental models

    DEFF Research Database (Denmark)

    Becker, Alexander; zu Knyphausen-Aufseß, Dodo; Brem, Alexander

    2015-01-01

    outcome. The implication for entrepreneurs is that, beyond discovering a potential venture idea, substantial development efforts are required to form a sustainable business model. For entrepreneurship research, our model is a first step towards an integrative discussion of new venture emergence aimed...

  8. International STakeholder NETwork (ISTNET): creating a developmental neurotoxicity (DNT) testing road map for regulatory purposes.

    Science.gov (United States)

    Bal-Price, Anna; Crofton, Kevin M; Leist, Marcel; Allen, Sandra; Arand, Michael; Buetler, Timo; Delrue, Nathalie; FitzGerald, Rex E; Hartung, Thomas; Heinonen, Tuula; Hogberg, Helena; Bennekou, Susanne Hougaard; Lichtensteiger, Walter; Oggier, Daniela; Paparella, Martin; Axelstad, Marta; Piersma, Aldert; Rached, Eva; Schilter, Benoît; Schmuck, Gabriele; Stoppini, Luc; Tongiorgi, Enrico; Tiramani, Manuela; Monnet-Tschudi, Florianne; Wilks, Martin F; Ylikomi, Timo; Fritsche, Ellen

    2015-02-01

    A major problem in developmental neurotoxicity (DNT) risk assessment is the lack of toxicological hazard information for most compounds. Therefore, new approaches are being considered to provide adequate experimental data that allow regulatory decisions. This process requires a matching of regulatory needs on the one hand and the opportunities provided by new test systems and methods on the other hand. Alignment of academically and industrially driven assay development with regulatory needs in the field of DNT is a core mission of the International STakeholder NETwork (ISTNET) in DNT testing. The first meeting of ISTNET was held in Zurich on 23-24 January 2014 in order to explore the concept of adverse outcome pathway (AOP) to practical DNT testing. AOPs were considered promising tools to promote test systems development according to regulatory needs. Moreover, the AOP concept was identified as an important guiding principle to assemble predictive integrated testing strategies (ITSs) for DNT. The recommendations on a road map towards AOP-based DNT testing is considered a stepwise approach, operating initially with incomplete AOPs for compound grouping, and focussing on key events of neurodevelopment. Next steps to be considered in follow-up activities are the use of case studies to further apply the AOP concept in regulatory DNT testing, making use of AOP intersections (common key events) for economic development of screening assays, and addressing the transition from qualitative descriptions to quantitative network modelling.

  9. Developmental Risk and Young Children's Regulatory Strategies: Predicting Behavior Problems at Age Five

    Science.gov (United States)

    Gerstein, Emily D.; Pedersen y Arbona, Anita; Crnic, Keith A.; Ryu, Ehri; Baker, Bruce L.; Blacher, Jan

    2011-01-01

    Children with early developmental delays are at heightened risk for behavior problems and comorbid psychopathology. This study examined the trajectories of regulatory capabilities and their potentially mediating role in the development of behavior problems for children with and without early developmental delays. A sample of 231 children comprised…

  10. Developmental gene regulatory networks in sea urchins and what we can learn from them [version 1; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Megan L. Martik

    2016-02-01

    Full Text Available Sea urchin embryos begin zygotic transcription shortly after the egg is fertilized.  Throughout the cleavage stages a series of transcription factors are activated and, along with signaling through a number of pathways, at least 15 different cell types are specified by the beginning of gastrulation.  Experimentally, perturbation of contributing transcription factors, signals and receptors and their molecular consequences enabled the assembly of an extensive gene regulatory network model.  That effort, pioneered and led by Eric Davidson and his laboratory, with many additional insights provided by other laboratories, provided the sea urchin community with a valuable resource.  Here we describe the approaches used to enable the assembly of an advanced gene regulatory network model describing molecular diversification during early development.  We then provide examples to show how a relatively advanced authenticated network can be used as a tool for discovery of how diverse developmental mechanisms are controlled and work.

  11. Regulatory RNA at the root of animals: dynamic expression of developmental lincRNAs in the calcisponge Sycon ciliatum.

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    Bråte, Jon; Adamski, Marcin; Neumann, Ralf S; Shalchian-Tabrizi, Kamran; Adamska, Maja

    2015-12-22

    Long non-coding RNAs (lncRNAs) play important regulatory roles during animal development, and it has been hypothesized that an RNA-based gene regulation was important for the evolution of developmental complexity in animals. However, most studies of lncRNA gene regulation have been performed using model animal species, and very little is known about this type of gene regulation in non-bilaterians. We have therefore analysed RNA-Seq data derived from a comprehensive set of embryogenesis stages in the calcareous sponge Sycon ciliatum and identified hundreds of developmentally expressed intergenic lncRNAs (lincRNAs) in this species. In situ hybridization of selected lincRNAs revealed dynamic spatial and temporal expression during embryonic development. More than 600 lincRNAs constitute integral parts of differentially expressed gene modules, which also contain known developmental regulatory genes, e.g. transcription factors and signalling molecules. This study provides insights into the non-coding gene repertoire of one of the earliest evolved animal lineages, and suggests that RNA-based gene regulation was probably present in the last common ancestor of animals. © 2015 The Authors.

  12. Spatiotemporal network motif reveals the biological traits of developmental gene regulatory networks in Drosophila melanogaster

    Directory of Open Access Journals (Sweden)

    Kim Man-Sun

    2012-05-01

    Full Text Available Abstract Background Network motifs provided a “conceptual tool” for understanding the functional principles of biological networks, but such motifs have primarily been used to consider static network structures. Static networks, however, cannot be used to reveal time- and region-specific traits of biological systems. To overcome this limitation, we proposed the concept of a “spatiotemporal network motif,” a spatiotemporal sequence of network motifs of sub-networks which are active only at specific time points and body parts. Results On the basis of this concept, we analyzed the developmental gene regulatory network of the Drosophila melanogaster embryo. We identified spatiotemporal network motifs and investigated their distribution pattern in time and space. As a result, we found how key developmental processes are temporally and spatially regulated by the gene network. In particular, we found that nested feedback loops appeared frequently throughout the entire developmental process. From mathematical simulations, we found that mutual inhibition in the nested feedback loops contributes to the formation of spatial expression patterns. Conclusions Taken together, the proposed concept and the simulations can be used to unravel the design principle of developmental gene regulatory networks.

  13. Research Models in Developmental Behavioral Toxicology.

    Science.gov (United States)

    Dietrich, Kim N.; Pearson, Douglas T.

    Developmental models currently used by child behavioral toxicologists and teratologists are inadequate to address current issues in these fields. Both child behavioral teratology and toxicology scientifically study the impact of exposure to toxic agents on behavior development: teratology focuses on prenatal exposure and postnatal behavior…

  14. Experimental models of developmental hypothyroidism.

    Science.gov (United States)

    Argumedo, G S; Sanz, C R; Olguín, H J

    2012-02-01

    Hypothyroidism is a systemic disease resulting from either thyroid gland's anatomical and functional absence or lack of hypophyseal stimulation, both of which can lead to deficiency in thyroid hormone (TH) production. TH is essential for human and animal development, growth, and function of multiple organs. Children with deficient TH can develop alterations in central nervous system (CNS), striated muscle, bone tissue, liver, bone marrow, and cardiorespiratory system. Among the clinical outlook are signs like breathing difficulty, cardiac insufficiency, dysphagia, and repeated bronchial aspiration, constipation, muscle weakness, cognitive alterations, cochlear dysfunction, reduced height, defects in temperature regulation, anaemia, jaundice, susceptibility to infection, and others. Experimental and clinical studies have shown that TH is very essential for normal brain development. Other research work based on mice pointed out that a reduced level of TH in pregnant mother leads to congenital hypothyroidism in animal models and it is associated with mental retardation, deep neurologic deficiency that impacts on cognitive, learning, and memory functions. The principal experimental model studies that have focused on hypothyroidism are reviewed in this study. This is important on considering the fact that almost all animal species require thyroid hormones for their metabolism. © Georg Thieme Verlag KG Stuttgart · New York.

  15. Neuroimaging of developmental psychopathologies: the importance of self-regulatory and neuroplastic processes in adolescence.

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    Spessot, Alexandra L; Plessen, Kerstin J; Peterson, Bradley S

    2004-06-01

    Normal brain maturational and developmental processes, together with plastic reorganization of the brain in response to experiential demands, contribute to the acquisition of improved capacities for self-regulation and impulse control during adolescence. The frontal lobe is a main focus for these developmental and plastic processes during the transition from adolescence into adulthood. Tourette syndrome (TS), defined as the chronic presence of motor and vocal tics, has been increasingly conceptualized as a disorder of impaired self-regulatory control. This disordered control is thought to give rise to semicompulsory urges to perform the movements that constitute simple tics, complex tics, or compulsions. Neuroimaging studies suggest that the expression of the genetic diathesis to TS is influenced by genetic and nongenetic factors affecting activity-dependent reorganization of neuroregulatory systems, thereby influencing the phenotype, illness severity, and adult outcome of tic disorders. Similar developmental processes during adolescence likely determine the phenotype and natural history of a broad range of other complex neuropsychiatric disorders of childhood onset, and they likely contribute to the acquisition of improved self-regulatory capacities that characterize normal adolescent development.

  16. Avian models in teratology and developmental toxicology.

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    Smith, Susan M; Flentke, George R; Garic, Ana

    2012-01-01

    The avian embryo is a long-standing model for developmental biology research. It also has proven utility for toxicology research both in ovo and in explant culture. Like mammals, avian embryos have an allantois and their developmental pathways are highly conserved with those of mammals, thus avian models have biomedical relevance. Fertile eggs are inexpensive and the embryo develops rapidly, allowing for high-throughput. The chick genome is sequenced and significant molecular resources are available for study, including the ability for genetic manipulation. The absence of a placenta permits the direct study of an agent's embryotoxic effects. Here, we present protocols for using avian embryos in toxicology research, including egg husbandry and hatch, toxicant delivery, and assessment of proliferation, apoptosis, and cardiac structure and function.

  17. Neuroimaging of developmental psychopathologies: the importance of self-regulatory and neuroplastic processes in adolescence

    DEFF Research Database (Denmark)

    Spessot, Alexandra L; Plessen, Kerstin J; Peterson, Bradley S

    2004-01-01

    for these developmental and plastic processes during the transition from adolescence into adulthood. Tourette syndrome (TS), defined as the chronic presence of motor and vocal tics, has been increasingly conceptualized as a disorder of impaired self-regulatory control. This disordered control is thought to give rise...... to semicompulsory urges to perform the movements that constitute simple tics, complex tics, or compulsions. Neuroimaging studies suggest that the expression of the genetic diathesis to TS is influenced by genetic and nongenetic factors affecting activity-dependent reorganization of neuroregulatory systems, thereby...... influencing the phenotype, illness severity, and adult outcome of tic disorders. Similar developmental processes during adolescence likely determine the phenotype and natural history of a broad range of other complex neuropsychiatric disorders of childhood onset, and they likely contribute to the acquisition...

  18. Self-Regulatory Skill Among Children with and without Developmental Coordination Disorder: An Exploratory Study.

    Science.gov (United States)

    Sangster Jokić, Claire A; Whitebread, David

    2016-11-01

    Children with developmental coordination disorder (DCD) experience difficulty learning and performing everyday motor tasks due to poor motor coordination. Recent research applying a cognitive learning paradigm has argued that children with DCD have less effective cognitive and metacognitive skills with which to effectively acquire motor skills. However, there is currently limited research examining individual differences in children's use of self-regulatory and metacognitive skill during motor learning. This exploratory study aimed to compare the self-regulatory performance of children with and without DCD. Using a mixed methods approach, this study observed and compared the self-regulatory behavior of 15 children with and without DCD, aged between 7 and 9 years, during socially mediated motor practice. Observation was conducted using a quantitative coding scheme and qualitative analysis of video-recorded sessions. This paper will focus on the results of quantitative analysis, while data arising from the qualitative analysis will be used to support quantitative findings. In general, findings indicate that children with DCD exhibit less independent and more ineffective self-regulatory skill during motor learning than their typically developing peers. In addition, children with DCD rely more heavily on external support for effective regulation and are more likely to exhibit negative patterns of motivational regulation. These findings provide further support for the notion that children with DCD experience difficulty effectively self-regulating motor learning. Implications for practice and directions for future research are discussed.

  19. Neuroimaging of developmental psychopathologies: the importance of self-regulatory and neuroplastic processes in adolescence

    DEFF Research Database (Denmark)

    Spessot, Alexandra L; Plessen, Kerstin J; Peterson, Bradley S

    2004-01-01

    Normal brain maturational and developmental processes, together with plastic reorganization of the brain in response to experiential demands, contribute to the acquisition of improved capacities for self-regulation and impulse control during adolescence. The frontal lobe is a main focus for these......Normal brain maturational and developmental processes, together with plastic reorganization of the brain in response to experiential demands, contribute to the acquisition of improved capacities for self-regulation and impulse control during adolescence. The frontal lobe is a main focus...... for these developmental and plastic processes during the transition from adolescence into adulthood. Tourette syndrome (TS), defined as the chronic presence of motor and vocal tics, has been increasingly conceptualized as a disorder of impaired self-regulatory control. This disordered control is thought to give rise...... to semicompulsory urges to perform the movements that constitute simple tics, complex tics, or compulsions. Neuroimaging studies suggest that the expression of the genetic diathesis to TS is influenced by genetic and nongenetic factors affecting activity-dependent reorganization of neuroregulatory systems, thereby...

  20. Current approaches to gene regulatory network modelling

    Directory of Open Access Journals (Sweden)

    Brazma Alvis

    2007-09-01

    Full Text Available Abstract Many different approaches have been developed to model and simulate gene regulatory networks. We proposed the following categories for gene regulatory network models: network parts lists, network topology models, network control logic models, and dynamic models. Here we will describe some examples for each of these categories. We will study the topology of gene regulatory networks in yeast in more detail, comparing a direct network derived from transcription factor binding data and an indirect network derived from genome-wide expression data in mutants. Regarding the network dynamics we briefly describe discrete and continuous approaches to network modelling, then describe a hybrid model called Finite State Linear Model and demonstrate that some simple network dynamics can be simulated in this model.

  1. Development of multipurpose regulatory PSA model

    International Nuclear Information System (INIS)

    Lee, Chang Ju; Sung, Key Yong; Kim, Hho Jung; Yang, Joon Eon; Ha, Jae Joo

    2004-01-01

    Generally, risk information for nuclear facilities comes from the results of Probabilistic safety assessment (PSA). PSA is a systematic tool to ensure the safety of nuclear facilities, since it is based on thorough and consistent application of probability models. In particular, the PSA has been widely utilized for risk-informed regulation (RIR), including various licensee-initiated risk-informed applications (RIA). In any regulatory decision, the main goal is to make a sound safety decision based on technically defensible information. Also, due to the increased public requests for giving a safety guarantee, the regulator should provide the visible means of safety. The use of PSA by the regulator can give the answer on this problem. Therefore, in order to study the applicability of risk information for regulatory safety management, it is a demanding task to prepare a well-established regulatory PSA model and tool. In 2002, KINS and KAERI together made a research cooperation to form a working group to develop the regulatory PSA model - so-called MPAS model. The MPAS stands for multipurpose probabilistic analysis of safety. For instance, a role of the MPAS model is to give some risk insights in the preparation of various regulatory programs. Another role of this model is to provide an independent risk information to the regulator during regulatory decision-making, not depending on the licensee's information

  2. Evolution of branched regulatory genetic pathways: directional selection on pleiotropic loci accelerates developmental system drift.

    Science.gov (United States)

    Johnson, Norman A; Porter, Adam H

    2007-01-01

    Developmental systems are regulated by a web of interacting loci. One common and useful approach in studying the evolution of development is to focus on classes of interacting elements within these systems. Here, we use individual-based simulations to study the evolution of traits controlled by branched developmental pathways involving three loci, where one locus regulates two different traits. We examined the system under a variety of selective regimes. In the case where one branch was under stabilizing selection and the other under directional selection, we observed "developmental system drift": the trait under stabilizing selection showed little phenotypic change even though the loci underlying that trait showed considerable evolutionary divergence. This occurs because the pleiotropic locus responds to directional selection and compensatory mutants are then favored in the pathway under stabilizing selection. Though developmental system drift may be caused by other mechanisms, it seems likely that it is accelerated by the same underlying genetic mechanism as that producing the Dobzhansky-Muller incompatibilities that lead to speciation in both linear and branched pathways. We also discuss predictions of our model for developmental system drift and how different selective regimes affect probabilities of speciation in the branched pathway system.

  3. Assessment of learning, memory and attention in developmental neurotoxicity regulatory studies: Introduction.

    Science.gov (United States)

    Makris, Susan L; Vorhees, Charles V

    2015-01-01

    There are a variety of chemicals, including pharmaceuticals, that alter neurobehavior following developmental exposure and guidelines for the conduct of studies to detect such effects by statute in the United States and Europe. Guidelines for Developmental Neurotoxicity Testing (DNT) studies issued by the U.S. Environmental Protection Agency (EPA) under prevailing law and European Organization for Economic Cooperation and Development (OECD) recommendations to member countries provide that such studies include a series of neurobehavioral and neuropathological assessments. Among these are assessment of cognitive function, specifically learning and memory. After reviewing 69 DNT studies submitted to the EPA, tests of learning and memory were noted to have detected the lowest observed adverse effect level (LOAELs) less frequently than behavioral tests of locomotor activity and acoustic/auditory startle, but slightly more than for the developmental Functional Observational Battery (devFOB; which is less extensive than the full FOB), but the reasons for the lower LOAEL detection rate for learning and memory assessment could not be determined. A major concern identified in the review, however, was the adequacy of the methods employed in these studies rather than on the importance of learning and memory to the proper assessment of brain function. Accordingly, a symposium was conducted to consider how the guidelines for tests of learning and memory might be improved. Four laboratories with established histories investigating the effects of chemical exposures during development on learning, memory, and attention, were invited to review the topic and offer recommendations, both theoretical and practical, on approaches to improve the assessment of these vital CNS functions. Reviewers were asked to recommend methods that are grounded in functional importance to CNS integrity, well-validated, reliable, and amenable to the context of regulatory studies as well as to basic

  4. Computerised modelling for developmental biology : an exploration with case studies

    NARCIS (Netherlands)

    Bertens, Laura M.F.

    2012-01-01

    Many studies in developmental biology rely on the construction and analysis of models. This research presents a broad view of modelling approaches for developmental biology, with a focus on computational methods. An overview of modelling techniques is given, followed by several case studies. Using

  5. Mustn1: A Developmentally Regulated Pan-Musculoskeletal Cell Marker and Regulatory Gene

    Directory of Open Access Journals (Sweden)

    Michael Hadjiargyrou

    2018-01-01

    Full Text Available The Mustn1 gene encodes a small nuclear protein (~9.6 kDa that does not belong to any known family. Its genomic organization consists of three exons interspersed by two introns and it is highly homologous across vertebrate species. Promoter analyses revealed that its expression is regulated by the AP family of transcription factors, especially c-Fos, Fra-2 and JunD. Mustn1 is predominantly expressed in the major tissues of the musculoskeletal system: bone, cartilage, skeletal muscle and tendon. Its expression has been associated with normal embryonic development, postnatal growth, exercise, and regeneration of bone and skeletal muscle. Moreover, its expression has also been detected in various musculoskeletal pathologies, including arthritis, Duchenne muscular dystrophy, other skeletal muscle myopathies, clubfoot and diabetes associated muscle pathology. In vitro and in vivo functional perturbation revealed that Mustn1 is a key regulatory molecule in myogenic and chondrogenic lineages. This comprehensive review summarizes our current knowledge of Mustn1 and proposes that it is a new developmentally regulated pan-musculoskeletal marker as well as a key regulatory protein for cell differentiation and tissue growth.

  6. Computational challenges in modeling gene regulatory events.

    Science.gov (United States)

    Pataskar, Abhijeet; Tiwari, Vijay K

    2016-10-19

    Cellular transcriptional programs driven by genetic and epigenetic mechanisms could be better understood by integrating "omics" data and subsequently modeling the gene-regulatory events. Toward this end, computational biology should keep pace with evolving experimental procedures and data availability. This article gives an exemplified account of the current computational challenges in molecular biology.

  7. Modeling Dynamic Regulatory Processes in Stroke

    Science.gov (United States)

    McDermott, Jason E.; Jarman, Kenneth; Taylor, Ronald; Lancaster, Mary; Shankaran, Harish; Vartanian, Keri B.; Stevens, Susan L.; Stenzel-Poore, Mary P.; Sanfilippo, Antonio

    2012-01-01

    The ability to examine the behavior of biological systems in silico has the potential to greatly accelerate the pace of discovery in diseases, such as stroke, where in vivo analysis is time intensive and costly. In this paper we describe an approach for in silico examination of responses of the blood transcriptome to neuroprotective agents and subsequent stroke through the development of dynamic models of the regulatory processes observed in the experimental gene expression data. First, we identified functional gene clusters from these data. Next, we derived ordinary differential equations (ODEs) from the data relating these functional clusters to each other in terms of their regulatory influence on one another. Dynamic models were developed by coupling these ODEs into a model that simulates the expression of regulated functional clusters. By changing the magnitude of gene expression in the initial input state it was possible to assess the behavior of the networks through time under varying conditions since the dynamic model only requires an initial starting state, and does not require measurement of regulatory influences at each time point in order to make accurate predictions. We discuss the implications of our models on neuroprotection in stroke, explore the limitations of the approach, and report that an optimized dynamic model can provide accurate predictions of overall system behavior under several different neuroprotective paradigms. PMID:23071432

  8. Boolean Dynamic Modeling Approaches to Study Plant Gene Regulatory Networks: Integration, Validation, and Prediction.

    Science.gov (United States)

    Velderraín, José Dávila; Martínez-García, Juan Carlos; Álvarez-Buylla, Elena R

    2017-01-01

    Mathematical models based on dynamical systems theory are well-suited tools for the integration of available molecular experimental data into coherent frameworks in order to propose hypotheses about the cooperative regulatory mechanisms driving developmental processes. Computational analysis of the proposed models using well-established methods enables testing the hypotheses by contrasting predictions with observations. Within such framework, Boolean gene regulatory network dynamical models have been extensively used in modeling plant development. Boolean models are simple and intuitively appealing, ideal tools for collaborative efforts between theorists and experimentalists. In this chapter we present protocols used in our group for the study of diverse plant developmental processes. We focus on conceptual clarity and practical implementation, providing directions to the corresponding technical literature.

  9. Characteristics of a third generation regulatory models

    International Nuclear Information System (INIS)

    Kallos, G.; Pilinis, C.; Kassomenos, P.; Hatzakis, G.

    1992-01-01

    A new class of air pollution dispersion models has to be used for regulatory purposes in the future and they should have the following capabilities: Adequate spatial and temporal characterization of the PBL, wind and turbulence fields, enhancement and regionalization of existing air quality models to yield a model applicable on both urban and regional scales, adequate characterization of the chemical transformation of the gaseous pollutants in the atmosphere, adequate description of the dispersion and the physical changes of the toxic material released (i.e. evaporation and condensation), good description of the chemistry in aqueous phases, like fog and cloud chemistry, and accurate predictions of the removal processes of the gas and particulate matter (i.e. wet an dry deposition). Some of these model requirements are already satisfied in some research oriented models. In general, there is no unique model that satisfies all of the above, and even if it existed there is not the necessary database for such application and testing. The two major areas of development of regulatory modeling in the future, i.e. development of a complete meteorological and air quality model and development of the database capabilities for the routine application of the model, in the urban and rural areas of interest. With the computer power available in the near future, this kind of models will be able to be used even for emergency cases. (AB) (20 refs.)

  10. Challenges for modeling global gene regulatory networks during development: insights from Drosophila.

    Science.gov (United States)

    Wilczynski, Bartek; Furlong, Eileen E M

    2010-04-15

    Development is regulated by dynamic patterns of gene expression, which are orchestrated through the action of complex gene regulatory networks (GRNs). Substantial progress has been made in modeling transcriptional regulation in recent years, including qualitative "coarse-grain" models operating at the gene level to very "fine-grain" quantitative models operating at the biophysical "transcription factor-DNA level". Recent advances in genome-wide studies have revealed an enormous increase in the size and complexity or GRNs. Even relatively simple developmental processes can involve hundreds of regulatory molecules, with extensive interconnectivity and cooperative regulation. This leads to an explosion in the number of regulatory functions, effectively impeding Boolean-based qualitative modeling approaches. At the same time, the lack of information on the biophysical properties for the majority of transcription factors within a global network restricts quantitative approaches. In this review, we explore the current challenges in moving from modeling medium scale well-characterized networks to more poorly characterized global networks. We suggest to integrate coarse- and find-grain approaches to model gene regulatory networks in cis. We focus on two very well-studied examples from Drosophila, which likely represent typical developmental regulatory modules across metazoans. Copyright (c) 2009 Elsevier Inc. All rights reserved.

  11. Sparsity in Model Gene Regulatory Networks

    International Nuclear Information System (INIS)

    Zagorski, M.

    2011-01-01

    We propose a gene regulatory network model which incorporates the microscopic interactions between genes and transcription factors. In particular the gene's expression level is determined by deterministic synchronous dynamics with contribution from excitatory interactions. We study the structure of networks that have a particular '' function '' and are subject to the natural selection pressure. The question of network robustness against point mutations is addressed, and we conclude that only a small part of connections defined as '' essential '' for cell's existence is fragile. Additionally, the obtained networks are sparse with narrow in-degree and broad out-degree, properties well known from experimental study of biological regulatory networks. Furthermore, during sampling procedure we observe that significantly different genotypes can emerge under mutation-selection balance. All the preceding features hold for the model parameters which lay in the experimentally relevant range. (author)

  12. Applying a Developmental Framework to the Self-Regulatory Difficulties of Young Children with Prenatal Alcohol Exposure: A Review.

    Science.gov (United States)

    Reid, Natasha; Petrenko, Christie L M

    2018-06-01

    Prenatal alcohol exposure (PAE) can be associated with significant difficulties in self-regulatory abilities. As such, interventions have been developed that focus on improving varying aspects of self-regulation for this population. The application of a multilevel theoretical framework that describes the development of self-regulation during early childhood could further advance the field. First, this framework could assist in elucidating mechanisms in the trajectories of early adjustment problems in this population and, second, informing the development of more precise assessment and interventions for those affected by PAE. The aims of the current review were to provide an overview of the self-regulatory framework proposed by Calkins and colleagues (e.g., Calkins, 2007; Calkins and Fox, 2002); examine the self-regulatory difficulties that are commonly experienced during infancy (i.e., 0 to 2 years) and early childhood (i.e., 3 to 8 years) in children with PAE in the context of the developmental framework; and describe how the framework can inform the development of future assessment and intervention provision for young children with PAE. The application of a developmental framework, such as proposed by Calkins and colleagues, allows for a systematic and theoretically driven approach to assessment and intervention programs for young children with PAE. Copyright © 2018 by the Research Society on Alcoholism.

  13. Smoking education and prevention: a developmental model.

    Science.gov (United States)

    Oei, T P; Baldwin, A R

    1992-01-01

    A developmental approach to smoking education and prevention for children and adolescents is proposed. Literature is reviewed concerning the most appropriate agent, content, and presentation, of anti-smoking education for each of three age groups: children to age ten, pre/early adolescents eleven to fifteen, and adolescents fifteen to eighteen. For children to age ten, it is suggested that parents are the best agents of education, with teachers, peers, and the mass media, also playing some role. For pre/early adolescents, peers are suggested as the best agents of education, building onto the earlier and ongoing work of the agents mentioned above. For adolescents, the role of the media hero-figure is discussed. It is emphasized that sources of influence may function additively in affecting the child or adolescent's decisions about smoking, and that education in each stage must build on the stage before.

  14. Deciphering RNA Regulatory Elements Involved in the Developmental and Environmental Gene Regulation of Trypanosoma brucei.

    Science.gov (United States)

    Gazestani, Vahid H; Salavati, Reza

    2015-01-01

    Trypanosoma brucei is a vector-borne parasite with intricate life cycle that can cause serious diseases in humans and animals. This pathogen relies on fine regulation of gene expression to respond and adapt to variable environments, with implications in transmission and infectivity. However, the involved regulatory elements and their mechanisms of actions are largely unknown. Here, benefiting from a new graph-based approach for finding functional regulatory elements in RNA (GRAFFER), we have predicted 88 new RNA regulatory elements that are potentially involved in the gene regulatory network of T. brucei. We show that many of these newly predicted elements are responsive to both transcriptomic and proteomic changes during the life cycle of the parasite. Moreover, we found that 11 of predicted elements strikingly resemble previously identified regulatory elements for the parasite. Additionally, comparison with previously predicted motifs on T. brucei suggested the superior performance of our approach based on the current limited knowledge of regulatory elements in T. brucei.

  15. Regulatory Models and the Environment: Practice, Pitfalls, and Prospects

    Energy Technology Data Exchange (ETDEWEB)

    Holmes, K. John; Graham, Judith A.; McKone, Thomas; Whipple, Chris

    2008-06-01

    Computational models support environmental regulatory activities by providing the regulator an ability to evaluate available knowledge, assess alternative regulations, and provide a framework to assess compliance. But all models face inherent uncertainties, because human and natural systems are always more complex and heterogeneous than can be captured in a model. Here we provide a summary discussion of the activities, findings, and recommendations of the National Research Council's Committee on Regulatory Environmental Models, a committee funded by the US Environmental Protection Agency to provide guidance on the use of computational models in the regulatory process. Modeling is a difficult enterprise even outside of the potentially adversarial regulatory environment. The demands grow when the regulatory requirements for accountability, transparency, public accessibility, and technical rigor are added to the challenges. Moreover, models cannot be validated (declared true) but instead should be evaluated with regard to their suitability as tools to address a specific question. The committee concluded that these characteristics make evaluation of a regulatory model more complex than simply comparing measurement data with model results. Evaluation also must balance the need for a model to be accurate with the need for a model to be reproducible, transparent, and useful for the regulatory decision at hand. Meeting these needs requires model evaluation to be applied over the"life cycle" of a regulatory model with an approach that includes different forms of peer review, uncertainty analysis, and extrapolation methods than for non-regulatory models.

  16. Mainstreaming solar : Stretching the regulatory regime through business model innovation

    NARCIS (Netherlands)

    Huijben, J.C.C.M.; Verbong, G.P.J.; Podoynitsyna, K.S.

    This paper explores how the regulatory regime for Solar PV, defined as a combination of niche shielding and mainstream regulations, affects niche business models, using the Dutch and Flemish regulatory regimes as examples. The regulatory regime does not influence all components of the business

  17. Why Are There Developmental Stages in Language Learning? A Developmental Robotics Model of Language Development.

    Science.gov (United States)

    Morse, Anthony F; Cangelosi, Angelo

    2017-02-01

    Most theories of learning would predict a gradual acquisition and refinement of skills as learning progresses, and while some highlight exponential growth, this fails to explain why natural cognitive development typically progresses in stages. Models that do span multiple developmental stages typically have parameters to "switch" between stages. We argue that by taking an embodied view, the interaction between learning mechanisms, the resulting behavior of the agent, and the opportunities for learning that the environment provides can account for the stage-wise development of cognitive abilities. We summarize work relevant to this hypothesis and suggest two simple mechanisms that account for some developmental transitions: neural readiness focuses on changes in the neural substrate resulting from ongoing learning, and perceptual readiness focuses on the perceptual requirements for learning new tasks. Previous work has demonstrated these mechanisms in replications of a wide variety of infant language experiments, spanning multiple developmental stages. Here we piece this work together as a single model of ongoing learning with no parameter changes at all. The model, an instance of the Epigenetic Robotics Architecture (Morse et al 2010) embodied on the iCub humanoid robot, exhibits ongoing multi-stage development while learning pre-linguistic and then basic language skills. Copyright © 2016 Cognitive Science Society, Inc.

  18. Regulatory T cell effects in antitumor laser immunotherapy: a mathematical model and analysis

    Science.gov (United States)

    Dawkins, Bryan A.; Laverty, Sean M.

    2016-03-01

    Regulatory T cells (Tregs) have tremendous influence on treatment outcomes in patients receiving immunotherapy for cancerous tumors. We present a mathematical model incorporating the primary cellular and molecular components of antitumor laser immunotherapy. We explicitly model developmental classes of dendritic cells (DCs), cytotoxic T cells (CTLs), primary and metastatic tumor cells, and tumor antigen. Regulatory T cells have been shown to kill antigen presenting cells, to influence dendritic cell maturation and migration, to kill activated killer CTLs in the tumor microenvironment, and to influence CTL proliferation. Since Tregs affect explicitly modeled cells, but we do not explicitly model dynamics of Treg themselves, we use model parameters to analyze effects of Treg immunosuppressive activity. We will outline a systematic method for assigning clinical outcomes to model simulations and use this condition to associate simulated patient treatment outcome with Treg activity.

  19. The Complexity of Developmental Predictions from Dual Process Models

    Science.gov (United States)

    Stanovich, Keith E.; West, Richard F.; Toplak, Maggie E.

    2011-01-01

    Drawing developmental predictions from dual-process theories is more complex than is commonly realized. Overly simplified predictions drawn from such models may lead to premature rejection of the dual process approach as one of many tools for understanding cognitive development. Misleading predictions can be avoided by paying attention to several…

  20. A Developmental Model for Educational Planning: Democratic Rationalities and Dispositions

    Science.gov (United States)

    Hess, Michael; Johnson, Jerry; Reynolds, Sharon

    2014-01-01

    The Developmental Democratic Planning (DDP) model frames educational planning as a process that extends beyond the immediate focus of a particular planning effort to acknowledge and cultivate the potential of all members of the organization to fulfill their roles as active participants in the democratic life of the organization. The DDP model…

  1. A Developmental Model of Research Mentoring

    Science.gov (United States)

    Revelo, Renata A.; Loui, Michael C.

    2016-01-01

    We studied mentoring relationships between undergraduate and graduate students in a summer undergraduate research program, over three years. Using a grounded theory approach, we created a model of research mentoring that describes how the roles of the mentor and the student can change. Whereas previous models of research mentoring ignored student…

  2. Simple mathematical models of gene regulatory dynamics

    CERN Document Server

    Mackey, Michael C; Tyran-Kamińska, Marta; Zeron, Eduardo S

    2016-01-01

    This is a short and self-contained introduction to the field of mathematical modeling of gene-networks in bacteria. As an entry point to the field, we focus on the analysis of simple gene-network dynamics. The notes commence with an introduction to the deterministic modeling of gene-networks, with extensive reference to applicable results coming from dynamical systems theory. The second part of the notes treats extensively several approaches to the study of gene-network dynamics in the presence of noise—either arising from low numbers of molecules involved, or due to noise external to the regulatory process. The third and final part of the notes gives a detailed treatment of three well studied and concrete examples of gene-network dynamics by considering the lactose operon, the tryptophan operon, and the lysis-lysogeny switch. The notes contain an index for easy location of particular topics as well as an extensive bibliography of the current literature. The target audience of these notes are mainly graduat...

  3. Computer modeling in developmental biology: growing today, essential tomorrow.

    Science.gov (United States)

    Sharpe, James

    2017-12-01

    D'Arcy Thompson was a true pioneer, applying mathematical concepts and analyses to the question of morphogenesis over 100 years ago. The centenary of his famous book, On Growth and Form , is therefore a great occasion on which to review the types of computer modeling now being pursued to understand the development of organs and organisms. Here, I present some of the latest modeling projects in the field, covering a wide range of developmental biology concepts, from molecular patterning to tissue morphogenesis. Rather than classifying them according to scientific question, or scale of problem, I focus instead on the different ways that modeling contributes to the scientific process and discuss the likely future of modeling in developmental biology. © 2017. Published by The Company of Biologists Ltd.

  4. 1974 annual report to Congress. Part one: operating and developmental functions. Part two: regulatory functions

    International Nuclear Information System (INIS)

    1974-01-01

    This report is of a nontechnical nature, with numerous photographs. The first part contains chapters on the reorganization of the AEC to ERDA and NRC, the history of the AEC: 1946--1975, energy research and development, breeder reactors, public health and safety, fusion research, environmental research, biomedical research, physical research, nuclear materials, national security, and management of radioactive waste. The part on regulatory functions contains chapters on nuclear regulation in 1974, 1974 nuclear power licensing, fuels and materials licensing, nuclear materials and plant protection, regulatory operations, nuclear standards development, public participation in regulation, and state and international liaison. Appendixes give membership of various boards and committees, changes in rules and regulations, a list of AEC regulatory guides, and a table of nuclear electric generating units in operation, under construction, or planned. (U.S.)

  5. Evidence for Deep Regulatory Similarities in Early Developmental Programs across Highly Diverged Insects

    Science.gov (United States)

    Zhang, Yinan; Samee, Md. Abul Hassan; Halfon, Marc S.; Sinha, Saurabh

    2014-01-01

    Many genes familiar from Drosophila development, such as the so-called gap, pair-rule, and segment polarity genes, play important roles in the development of other insects and in many cases appear to be deployed in a similar fashion, despite the fact that Drosophila-like “long germband” development is highly derived and confined to a subset of insect families. Whether or not these similarities extend to the regulatory level is unknown. Identification of regulatory regions beyond the well-studied Drosophila has been challenging as even within the Diptera (flies, including mosquitoes) regulatory sequences have diverged past the point of recognition by standard alignment methods. Here, we demonstrate that methods we previously developed for computational cis-regulatory module (CRM) discovery in Drosophila can be used effectively in highly diverged (250–350 Myr) insect species including Anopheles gambiae, Tribolium castaneum, Apis mellifera, and Nasonia vitripennis. In Drosophila, we have successfully used small sets of known CRMs as “training data” to guide the search for other CRMs with related function. We show here that although species-specific CRM training data do not exist, training sets from Drosophila can facilitate CRM discovery in diverged insects. We validate in vivo over a dozen new CRMs, roughly doubling the number of known CRMs in the four non-Drosophila species. Given the growing wealth of Drosophila CRM annotation, these results suggest that extensive regulatory sequence annotation will be possible in newly sequenced insects without recourse to costly and labor-intensive genome-scale experiments. We develop a new method, Regulus, which computes a probabilistic score of similarity based on binding site composition (despite the absence of nucleotide-level sequence alignment), and demonstrate similarity between functionally related CRMs from orthologous loci. Our work represents an important step toward being able to trace the evolutionary

  6. Utility of Small Animal Models of Developmental Programming.

    Science.gov (United States)

    Reynolds, Clare M; Vickers, Mark H

    2018-01-01

    Any effective strategy to tackle the global obesity and rising noncommunicable disease epidemic requires an in-depth understanding of the mechanisms that underlie these conditions that manifest as a consequence of complex gene-environment interactions. In this context, it is now well established that alterations in the early life environment, including suboptimal nutrition, can result in an increased risk for a range of metabolic, cardiovascular, and behavioral disorders in later life, a process preferentially termed developmental programming. To date, most of the mechanistic knowledge around the processes underpinning development programming has been derived from preclinical research performed mostly, but not exclusively, in laboratory mouse and rat strains. This review will cover the utility of small animal models in developmental programming, the limitations of such models, and potential future directions that are required to fully maximize information derived from preclinical models in order to effectively translate to clinical use.

  7. Human pluripotent stem cells: an emerging model in developmental biology.

    Science.gov (United States)

    Zhu, Zengrong; Huangfu, Danwei

    2013-02-01

    Developmental biology has long benefited from studies of classic model organisms. Recently, human pluripotent stem cells (hPSCs), including human embryonic stem cells and human induced pluripotent stem cells, have emerged as a new model system that offers unique advantages for developmental studies. Here, we discuss how studies of hPSCs can complement classic approaches using model organisms, and how hPSCs can be used to recapitulate aspects of human embryonic development 'in a dish'. We also summarize some of the recently developed genetic tools that greatly facilitate the interrogation of gene function during hPSC differentiation. With the development of high-throughput screening technologies, hPSCs have the potential to revolutionize gene discovery in mammalian development.

  8. [Modeling developmental aspects of sensorimotor control of speech production].

    Science.gov (United States)

    Kröger, B J; Birkholz, P; Neuschaefer-Rube, C

    2007-05-01

    Detailed knowledge of the neurophysiology of speech acquisition is important for understanding the developmental aspects of speech perception and production and for understanding developmental disorders of speech perception and production. A computer implemented neural model of sensorimotor control of speech production was developed. The model is capable of demonstrating the neural functions of different cortical areas during speech production in detail. (i) Two sensory and two motor maps or neural representations and the appertaining neural mappings or projections establish the sensorimotor feedback control system. These maps and mappings are already formed and trained during the prelinguistic phase of speech acquisition. (ii) The feedforward sensorimotor control system comprises the lexical map (representations of sounds, syllables, and words of the first language) and the mappings from lexical to sensory and to motor maps. The training of the appertaining mappings form the linguistic phase of speech acquisition. (iii) Three prelinguistic learning phases--i. e. silent mouthing, quasi stationary vocalic articulation, and realisation of articulatory protogestures--can be defined on the basis of our simulation studies using the computational neural model. These learning phases can be associated with temporal phases of prelinguistic speech acquisition obtained from natural data. The neural model illuminates the detailed function of specific cortical areas during speech production. In particular it can be shown that developmental disorders of speech production may result from a delayed or incorrect process within one of the prelinguistic learning phases defined by the neural model.

  9. Evidence for deep regulatory similarities in early developmental programs across highly diverged insects.

    Science.gov (United States)

    Kazemian, Majid; Suryamohan, Kushal; Chen, Jia-Yu; Zhang, Yinan; Samee, Md Abul Hassan; Halfon, Marc S; Sinha, Saurabh

    2014-09-01

    Many genes familiar from Drosophila development, such as the so-called gap, pair-rule, and segment polarity genes, play important roles in the development of other insects and in many cases appear to be deployed in a similar fashion, despite the fact that Drosophila-like "long germband" development is highly derived and confined to a subset of insect families. Whether or not these similarities extend to the regulatory level is unknown. Identification of regulatory regions beyond the well-studied Drosophila has been challenging as even within the Diptera (flies, including mosquitoes) regulatory sequences have diverged past the point of recognition by standard alignment methods. Here, we demonstrate that methods we previously developed for computational cis-regulatory module (CRM) discovery in Drosophila can be used effectively in highly diverged (250-350 Myr) insect species including Anopheles gambiae, Tribolium castaneum, Apis mellifera, and Nasonia vitripennis. In Drosophila, we have successfully used small sets of known CRMs as "training data" to guide the search for other CRMs with related function. We show here that although species-specific CRM training data do not exist, training sets from Drosophila can facilitate CRM discovery in diverged insects. We validate in vivo over a dozen new CRMs, roughly doubling the number of known CRMs in the four non-Drosophila species. Given the growing wealth of Drosophila CRM annotation, these results suggest that extensive regulatory sequence annotation will be possible in newly sequenced insects without recourse to costly and labor-intensive genome-scale experiments. We develop a new method, Regulus, which computes a probabilistic score of similarity based on binding site composition (despite the absence of nucleotide-level sequence alignment), and demonstrate similarity between functionally related CRMs from orthologous loci. Our work represents an important step toward being able to trace the evolutionary history of gene

  10. A developmental social neuroscience model for understanding loneliness in adolescence.

    Science.gov (United States)

    Wong, Nichol M L; Yeung, Patcy P S; Lee, Tatia M C

    2018-02-01

    Loneliness is prevalent in adolescents. Although it can be a normative experience, children and adolescents who experience loneliness are often at risk for anxiety, depression, and suicide. Research efforts have been made to identify the neurobiological basis of such distressful feelings in our social brain. In adolescents, the social brain is still undergoing significant development, which may contribute to their increased and differential sensitivity to the social environment. Many behavioral studies have shown the significance of attachment security and social skills in adolescents' interactions with the social world. In this review, we propose a developmental social neuroscience model that extends from the social neuroscience model of loneliness. In particular, we argue that the social brain and social skills are both important for the development of adolescents' perceived loneliness and that adolescents' familial attachment sets the baseline for neurobiological development. By reviewing the related behavioral and neuroimaging literature, we propose a developmental social neuroscience model to explain the heightened perception of loneliness in adolescents using social skills and attachment style as neurobiological moderators. We encourage future researchers to investigate adolescents' perceived social connectedness from the developmental neuroscience perspective.

  11. Developmental model of static allometry in holometabolous insects.

    Science.gov (United States)

    Shingleton, Alexander W; Mirth, Christen K; Bates, Peter W

    2008-08-22

    The regulation of static allometry is a fundamental developmental process, yet little is understood of the mechanisms that ensure organs scale correctly across a range of body sizes. Recent studies have revealed the physiological and genetic mechanisms that control nutritional variation in the final body and organ size in holometabolous insects. The implications these mechanisms have for the regulation of static allometry is, however, unknown. Here, we formulate a mathematical description of the nutritional control of body and organ size in Drosophila melanogaster and use it to explore how the developmental regulators of size influence static allometry. The model suggests that the slope of nutritional static allometries, the 'allometric coefficient', is controlled by the relative sensitivity of an organ's growth rate to changes in nutrition, and the relative duration of development when nutrition affects an organ's final size. The model also predicts that, in order to maintain correct scaling, sensitivity to changes in nutrition varies among organs, and within organs through time. We present experimental data that support these predictions. By revealing how specific physiological and genetic regulators of size influence allometry, the model serves to identify developmental processes upon which evolution may act to alter scaling relationships.

  12. A developmental approach to learning causal models for cyber security

    Science.gov (United States)

    Mugan, Jonathan

    2013-05-01

    To keep pace with our adversaries, we must expand the scope of machine learning and reasoning to address the breadth of possible attacks. One approach is to employ an algorithm to learn a set of causal models that describes the entire cyber network and each host end node. Such a learning algorithm would run continuously on the system and monitor activity in real time. With a set of causal models, the algorithm could anticipate novel attacks, take actions to thwart them, and predict the second-order effects flood of information, and the algorithm would have to determine which streams of that flood were relevant in which situations. This paper will present the results of efforts toward the application of a developmental learning algorithm to the problem of cyber security. The algorithm is modeled on the principles of human developmental learning and is designed to allow an agent to learn about the computer system in which it resides through active exploration. Children are flexible learners who acquire knowledge by actively exploring their environment and making predictions about what they will find,1, 2 and our algorithm is inspired by the work of the developmental psychologist Jean Piaget.3 Piaget described how children construct knowledge in stages and learn new concepts on top of those they already know. Developmental learning allows our algorithm to focus on subsets of the environment that are most helpful for learning given its current knowledge. In experiments, the algorithm was able to learn the conditions for file exfiltration and use that knowledge to protect sensitive files.

  13. The guinea pig as an animal model for developmental and reproductive toxicology studies.

    Science.gov (United States)

    Rocca, Meredith S; Wehner, Nancy G

    2009-04-01

    Regulatory guidelines for developmental and reproductive toxicology (DART) studies require selection of "relevant" animal models as determined by kinetic, pharmacological, and toxicological data. Traditionally, rats, mice, and rabbits are the preferred animal models for these studies. However, for test articles that are pharmacologically inactive in the traditional animal models, the guinea pig may be a viable option. This choice should not be made lightly, as guinea pigs have many disadvantages compared to the traditional species, including limited historical control data, variability in pregnancy rates, small and variable litter size, long gestation, relative maturity at birth, and difficulty in dosing and breeding. This report describes methods for using guinea pigs in DART studies and provides results of positive and negative controls. Standard study designs and animal husbandry methods were modified to allow mating on the postpartum estrus in fertility studies and were used for producing cohorts of pregnant females for developmental studies. A positive control study with the pregnancy-disrupting agent mifepristone resulted in the anticipated failure of embryo implantation and supported the use of the guinea pig model. Control data for reproductive endpoints collected from 5 studies are presented. In cases where the traditional animal models are not relevant, the guinea pig can be used successfully for DART studies. (c) 2009 Wiley-Liss, Inc.

  14. The relative age effect in sport: a developmental systems model.

    Science.gov (United States)

    Wattie, Nick; Schorer, Jörg; Baker, Joseph

    2015-01-01

    The policies that dictate the participation structure of many youth sport systems involve the use of a set selection date (e.g. 31 December), which invariably produces relative age differences between those within the selection year (e.g. 1 January to 31 December). Those born early in the selection year (e.g. January) are relatively older—by as much as 12 months minus 1 day—than those born later in the selection year (e.g. December). Research in the area of sport has identified a number of significant developmental effects associated with such relative age differences. However, a theoretical framework that describes the breadth and complexity of relative age effects (RAEs) in sport does not exist in the literature. This paper reviews and summarizes the existing literature on relative age in sport, and proposes a constraints-based developmental systems model for RAEs in sport.

  15. Sub-circuits of a gene regulatory network control a developmental epithelial-mesenchymal transition.

    Science.gov (United States)

    Saunders, Lindsay R; McClay, David R

    2014-04-01

    Epithelial-mesenchymal transition (EMT) is a fundamental cell state change that transforms epithelial to mesenchymal cells during embryonic development, adult tissue repair and cancer metastasis. EMT includes a complex series of intermediate cell state changes including remodeling of the basement membrane, apical constriction, epithelial de-adhesion, directed motility, loss of apical-basal polarity, and acquisition of mesenchymal adhesion and polarity. Transcriptional regulatory state changes must ultimately coordinate the timing and execution of these cell biological processes. A well-characterized gene regulatory network (GRN) in the sea urchin embryo was used to identify the transcription factors that control five distinct cell changes during EMT. Single transcription factors were perturbed and the consequences followed with in vivo time-lapse imaging or immunostaining assays. The data show that five different sub-circuits of the GRN control five distinct cell biological activities, each part of the complex EMT process. Thirteen transcription factors (TFs) expressed specifically in pre-EMT cells were required for EMT. Three TFs highest in the GRN specified and activated EMT (alx1, ets1, tbr) and the 10 TFs downstream of those (tel, erg, hex, tgif, snail, twist, foxn2/3, dri, foxb, foxo) were also required for EMT. No single TF functioned in all five sub-circuits, indicating that there is no EMT master regulator. Instead, the resulting sub-circuit topologies suggest EMT requires multiple simultaneous regulatory mechanisms: forward cascades, parallel inputs and positive-feedback lock downs. The interconnected and overlapping nature of the sub-circuits provides one explanation for the seamless orchestration by the embryo of cell state changes leading to successful EMT.

  16. International STakeholder NETwork (ISTNET): creating a developmental neurotoxicity (DNT) testing road map for regulatory purposes

    DEFF Research Database (Denmark)

    Bal-Price, Anna; Crofton, Kevin M.; Leist, Marcel

    2015-01-01

    . The first meeting of ISTNET was held in Zurich on 23-24 January 2014 in order to explore the concept of adverse outcome pathway (AOP) to practical DNT testing. AOPs were considered promising tools to promote test systems development according to regulatory needs. Moreover, the AOP concept was identified...... as an important guiding principle to assemble predictive integrated testing strategies (ITSs) for DNT. The recommendations on a road map towards AOP-based DNT testing is considered a stepwise approach, operating initially with incomplete AOPs for compound grouping, and focussing on key events of neurodevelopment...

  17. An explanatory evo-devo model for the developmental hourglass [v1; ref status: indexed, http://f1000r.es/3s6

    Directory of Open Access Journals (Sweden)

    Saamer Akhshabi

    2014-07-01

    Full Text Available The "developmental hourglass'' describes a pattern of increasing morphological divergence towards earlier and later embryonic development, separated by a period of significant conservation across distant species (the "phylotypic stage''. Recent studies have found evidence in support of the hourglass effect at the genomic level. For instance, the phylotypic stage expresses the oldest and most conserved transcriptomes. However, the regulatory mechanism that causes the hourglass pattern remains an open question. Here, we use an evolutionary model of regulatory gene interactions during development to identify the conditions under which the hourglass effect can emerge in a general setting. The model focuses on the hierarchical gene regulatory network that controls the developmental process, and on the evolution of a population under random perturbations in the structure of that network. The model predicts, under fairly general assumptions, the emergence of an hourglass pattern in the structure of a temporal representation of the underlying gene regulatory network. The evolutionary age of the corresponding genes also follows an hourglass pattern, with the oldest genes concentrated at the hourglass waist. The key behind the hourglass effect is that developmental regulators should have an increasingly specific function as development progresses. Analysis of developmental gene expression profiles from Drosophila melanogaster and Arabidopsis thaliana provide consistent results with our theoretical predictions.

  18. An explanatory evo-devo model for the developmental hourglass [v2; ref status: indexed, http://f1000r.es/4x3

    Directory of Open Access Journals (Sweden)

    Saamer Akhshabi

    2014-12-01

    Full Text Available The "developmental hourglass'' describes a pattern of increasing morphological divergence towards earlier and later embryonic development, separated by a period of significant conservation across distant species (the "phylotypic stage''. Recent studies have found evidence in support of the hourglass effect at the genomic level. For instance, the phylotypic stage expresses the oldest and most conserved transcriptomes. However, the regulatory mechanism that causes the hourglass pattern remains an open question. Here, we use an evolutionary model of regulatory gene interactions during development to identify the conditions under which the hourglass effect can emerge in a general setting. The model focuses on the hierarchical gene regulatory network that controls the developmental process, and on the evolution of a population under random perturbations in the structure of that network. The model predicts, under fairly general assumptions, the emergence of an hourglass pattern in the structure of a temporal representation of the underlying gene regulatory network. The evolutionary age of the corresponding genes also follows an hourglass pattern, with the oldest genes concentrated at the hourglass waist. The key behind the hourglass effect is that developmental regulators should have an increasingly specific function as development progresses. Analysis of developmental gene expression profiles from Drosophila melanogaster and Arabidopsis thaliana provide consistent results with our theoretical predictions.

  19. A Practitioners’ Perspective on Developmental Models, Metrics and Community

    Directory of Open Access Journals (Sweden)

    Chad Stewart

    2009-12-01

    Full Text Available This article builds on a paper by Stein and Heikkinen (2009, and suggestsways to expand and improve our measurement of the quality of the developmentalmodels, metrics and instruments and the results we get in collaborating with clients. Wesuggest that this dialogue needs to be about more than stage development measured by(even calibrated stage development-focused, linguistic-based, developmental psychologymetrics that produce lead indicators and are shown to be reliable and valid bypsychometric qualities alone. The article first provides a brief overview of ourbackground and biases, and an applied version of Ken Wilber’s Integral OperatingSystem that has provided increased development, client satisfaction, and contribution toour communities measured by verifiable, tangible results (as well as intangible resultssuch as increased ability to cope with complex surroundings, reduced stress and growthin developmental stages to better fit to the environment in which our clients wereengaged at that time. It then addresses four key points raised by Stein and Heikkinen(need for quality control, defining and deciding on appropriate metrics, building a systemto evaluate models and metrics, and clarifying and increasing the reliability and validityof the models and metrics we use by providing initial concrete steps to:• Adopt a systemic value-chain approach• Measure results in addition to language• Build on the evaluation system for instruments, models and metrics suggested byStein & Heikkinen• Clarify and improve the reliability and validity of the instruments, models andmetrics we useWe complete the article with an echoing call for the community of AppliedDevelopmental Theory suggested by Ross (2008 and Stein and Heikkinen, a briefdescription of that community (from our perspective, and a table that builds on Table 2proposed by Stein and Heikkinen.

  20. Consensus statement on the need for innovation, transition and implementation of developmental neurotoxicity (DNT) testing for regulatory purposes

    DEFF Research Database (Denmark)

    Fritsche, Ellen; Grandjean, Philippe; Crofton, Kevin M

    2018-01-01

    in the environment, with high uncertainty concerning their developmental neurotoxicity (DNT) potential. Closing this data gap with the current test guideline approach is not feasible, because the in vivo bioassays are far too resource-intensive concerning time, money and number of animals. A variety of in vitro...... methods are now available, that have the potential to close this data gap by permitting mode-of-action-based DNT testing employing human stem cells-derived neuronal/glial models. In vitro DNT data together with in silico approaches will in the future allow development of predictive models for DNT effects...

  1. Measuring and Modeling the U.S. Regulatory Ecosystem

    Science.gov (United States)

    Bommarito, Michael J., II; Katz, Daniel Martin

    2017-09-01

    Over the last 23 years, the U.S. Securities and Exchange Commission has required over 34,000 companies to file over 165,000 annual reports. These reports, the so-called "Form 10-Ks," contain a characterization of a company's financial performance and its risks, including the regulatory environment in which a company operates. In this paper, we analyze over 4.5 million references to U.S. Federal Acts and Agencies contained within these reports to measure the regulatory ecosystem, in which companies are organisms inhabiting a regulatory environment. While individuals across the political, economic, and academic world frequently refer to trends in this regulatory ecosystem, far less attention has been paid to supporting such claims with large-scale, longitudinal data. In this paper, in addition to positing a model of regulatory ecosystems, we document an increase in the regulatory energy per filing, i.e., a warming "temperature." We also find that the diversity of the regulatory ecosystem has been increasing over the past two decades. These findings support the claim that regulatory activity and complexity are increasing, and this framework contributes an important step towards improving academic and policy discussions around legal complexity and regulation.

  2. Developmental trajectories of adolescent popularity: a growth curve modelling analysis.

    Science.gov (United States)

    Cillessen, Antonius H N; Borch, Casey

    2006-12-01

    Growth curve modelling was used to examine developmental trajectories of sociometric and perceived popularity across eight years in adolescence, and the effects of gender, overt aggression, and relational aggression on these trajectories. Participants were 303 initially popular students (167 girls, 136 boys) for whom sociometric data were available in Grades 5-12. The popularity and aggression constructs were stable but non-overlapping developmental dimensions. Growth curve models were run with SAS MIXED in the framework of the multilevel model for change [Singer, J. D., & Willett, J. B. (2003). Applied longitudinal data analysis. Oxford, UK: Oxford University Press]. Sociometric popularity showed a linear change trajectory; perceived popularity showed nonlinear change. Overt aggression predicted low sociometric popularity but an increase in perceived popularity in the second half of the study. Relational aggression predicted a decrease in sociometric popularity, especially for girls, and continued high-perceived popularity for both genders. The effect of relational aggression on perceived popularity was the strongest around the transition from middle to high school. The importance of growth curve models for understanding adolescent social development was discussed, as well as specific issues and challenges of growth curve analyses with sociometric data.

  3. An overview of the gene regulatory network controlling trichome development in the model plant, Arabidopsis

    Directory of Open Access Journals (Sweden)

    Sitakanta ePattanaik

    2014-06-01

    Full Text Available Trichomes are specialized epidermal cells located on aerial parts of plants and are associated with a wide array of biological processes. Trichomes protect plants from adverse conditions including UV light and herbivore attack and are also an important source of a number of phytochemicals. The simple unicellular trichomes of Arabidopsis serve as an excellent model to study molecular mechanism of cell differentiation and pattern formation in plants. The emerging picture suggests that the developmental process is controlled by a transcriptional network involving three major groups of transcription factors: the R2R3 MYB, basic helix-loop-helix (bHLH and WD40 repeat (WDR protein. These regulatory proteins form a trimeric activator complex that positively regulates trichome development. The single repeat R3 MYBs act as negative regulators of trichome development. They compete with the R2R3 MYBs to bind the bHLH factor and form a repressor complex. In addition to activator-repressor mechanism, a depletion mechanism may operate in parallel during trichome development. In this mechanism, the bHLH factor traps the WDR protein which results in depletion of WDR protein in neighboring cells. Consequently, the cells with high levels of bHLH and WDR proteins are developed into trichomes. A group of C2H2 zinc finger TFs has also been implicated in trichome development. Phytohormones, including gibberellins and jasmonic acid, play significant roles in this developmental process. Recently, microRNAs have been shown to be involved in trichome development. Furthermore, it has been demonstrated that the activities of the key regulatory proteins involved in trichome development are controlled by the 26S/ubiquitin proteasome system (UPS, highlighting the complexity of the regulatory network controlling this developmental process. To complement several excellent recent relevant reviews, this review focuses on the transcriptional network and hormonal interplay

  4. Model uncertainty from a regulatory point of view

    International Nuclear Information System (INIS)

    Abramson, L.R.

    1994-01-01

    This paper discusses model uncertainty in the larger context of knowledge and random uncertainty. It explores some regulatory implications of model uncertainty and argues that, from a regulator's perspective, a conservative approach must be taken. As a consequence of this perspective, averaging over model results is ruled out

  5. A model for investigating developmental eye repair in Xenopus laevis.

    Science.gov (United States)

    Kha, Cindy X; Son, Philip H; Lauper, Julia; Tseng, Kelly Ai-Sun

    2018-04-01

    Vertebrate eye development is complex and requires early interactions between neuroectoderm and surface ectoderm during embryogenesis. In the African clawed frog, Xenopus laevis, individual eye tissues such as the retina and lens can undergo regeneration. However, it has been reported that removal of either the specified eye field at the neurula stage or the eye during tadpole stage does not induce replacement. Here we describe a model for investigating Xenopus developmental eye repair. We found that tailbud embryos can readily regrow eyes after surgical removal of over 83% of the specified eye and lens tissues. The regrown eye reached a comparable size to the contralateral control by 5 days and overall animal development was normal. It contained the expected complement of eye cell types (including the pigmented epithelium, retina and lens), and is connected to the brain. Our data also demonstrate that apoptosis, an early mechanism that regulates appendage regeneration, is also required for eye regrowth. Treatment with apoptosis inhibitors (M50054 or NS3694) blocked eye regrowth by inhibiting caspase activation. Together, our findings indicate that frog embryos can undergo successful eye repair after considerable tissue loss and reveals a required role for apoptosis in this process. Furthermore, this Xenopus model allows for rapid comparisons of productive eye repair and developmental pathways. It can also facilitate the molecular dissection of signaling mechanisms necessary for initiating repair. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

  6. The search for evolutionary developmental origins of aging in zebrafish: a novel intersection of developmental and senescence biology in the zebrafish model system.

    Science.gov (United States)

    Kishi, Shuji

    2011-09-01

    Senescence may be considered the antithesis of early development, but yet there may be factors and mechanisms in common between these two phenomena during the process of aging. We investigated whether any relationship exists between the regulatory mechanisms that function in early development and in senescence using the zebrafish (Danio rerio), a small freshwater fish and a useful model animal for genetic studies. We conducted experiments to isolate zebrafish mutants expressing an apparent senescence phenotype during embryogenesis (embryonic senescence). Some of the genes we thereby identified had already been associated with cellular senescence and chronological aging in other organisms, but many had not yet been linked to these processes. Complete loss-of-function of developmentally essential genes induce embryonic (or larval) lethality, whereas it seems like their partial loss-of-function (i.e., decrease-of-function by heterozygote or hypomorphic mutations) still remains sufficient to go through the early developmental process because of its adaptive plasticity or rather heterozygote advantage. However, in some cases, such partial loss-of-function of genes compromise normal homeostasis due to haploinsufficiency later in adult life having many environmental stress challenges. By contrast, any heterozygote-advantageous genes might gain a certain benefit(s) (much more fitness) by such partial loss-of-function later in life. Physiological senescence may evolutionarily arise from both genetic and epigenetic drifts as well as from losing adaptive developmental plasticity in face of stress signals from the external environment that interacts with functions of multiple genes rather than effects of only a single gene mutation or defect. Previously uncharacterized developmental genes may thus mediate the aging process and play a pivotal role in senescence. Moreover, unexpected senescence-related genes might also be involved in the early developmental process and

  7. Sequence-based model of gap gene regulatory network.

    Science.gov (United States)

    Kozlov, Konstantin; Gursky, Vitaly; Kulakovskiy, Ivan; Samsonova, Maria

    2014-01-01

    The detailed analysis of transcriptional regulation is crucially important for understanding biological processes. The gap gene network in Drosophila attracts large interest among researches studying mechanisms of transcriptional regulation. It implements the most upstream regulatory layer of the segmentation gene network. The knowledge of molecular mechanisms involved in gap gene regulation is far less complete than that of genetics of the system. Mathematical modeling goes beyond insights gained by genetics and molecular approaches. It allows us to reconstruct wild-type gene expression patterns in silico, infer underlying regulatory mechanism and prove its sufficiency. We developed a new model that provides a dynamical description of gap gene regulatory systems, using detailed DNA-based information, as well as spatial transcription factor concentration data at varying time points. We showed that this model correctly reproduces gap gene expression patterns in wild type embryos and is able to predict gap expression patterns in Kr mutants and four reporter constructs. We used four-fold cross validation test and fitting to random dataset to validate the model and proof its sufficiency in data description. The identifiability analysis showed that most model parameters are well identifiable. We reconstructed the gap gene network topology and studied the impact of individual transcription factor binding sites on the model output. We measured this impact by calculating the site regulatory weight as a normalized difference between the residual sum of squares error for the set of all annotated sites and for the set with the site of interest excluded. The reconstructed topology of the gap gene network is in agreement with previous modeling results and data from literature. We showed that 1) the regulatory weights of transcription factor binding sites show very weak correlation with their PWM score; 2) sites with low regulatory weight are important for the model output; 3

  8. A developmental etiological model for drug abuse in men.

    Science.gov (United States)

    Kendler, Kenneth S; Ohlsson, Henrik; Edwards, Alexis C; Sundquist, Jan; Sundquist, Kristina

    2017-10-01

    We attempt to develop a relatively comprehensive structural model of risk factors for drug abuse (DA) in Swedish men that illustrates developmental and mediational processes. We examined 20 risk factors for DA in 48,369 men undergoing conscription examinations in 1969-70 followed until 2011 when 2.34% (n=1134) of them had DA ascertained in medical, criminal and pharmacy registries. Risk factors were organized into four developmental tiers reflecting i) birth, ii) childhood/early adolescence, iii) late adolescence, and iv) young adulthood. Structural equational model fitting was performed using Mplus. The best fitting model explained 47.8% of the variance in DA. The most prominent predictors, in order, were: early adolescent externalizing behavior, early adult criminal behavior, early adolescent internalizing behavior, early adult unemployment, early adult alcohol use disorder, and late adolescent drug use. Two major inter-connecting pathways emerged reflecting i) genetic/familial risk and ii) family dysfunction and psychosocial adversity. Generated on a first and tested on a second random half of the sample, a model from these variables predicted DA with an ROC area under the curve of 83.6%. Fifty-nine percent of DA cases arose from subjects in the top decile of risk. DA in men is a highly multifactorial syndrome with risk arising from familial-genetic, psychosocial, behavioral and psychological factors acting and interacting over development. Among the multiple predisposing factors for DA, a range of psychosocial adversities, externalizing psychopathology and lack of social constraints in early adulthood are predominant. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Towards Developmental Models of Psychiatric Disorders in Zebrafish

    Directory of Open Access Journals (Sweden)

    William Howard James Norton

    2013-04-01

    Full Text Available Psychiatric disorders are a diverse set of diseases that affect all aspects of mental function including social interaction, thinking, feeling and mood. Although psychiatric disorders place a large economic burden on society, the drugs available to treat them are often palliative with variable efficacy and intolerable side-effects. The development of novel drugs has been hindered by a lack of knowledge about the etiology of these diseases. It is thus necessary to further investigate psychiatric disorders using a combination of human molecular genetics, gene-by-environment studies, in vitro pharmacological and biochemistry experiments, animal models and investigation of the non-biological basis of these diseases, such as environmental effects.Many psychiatric disorders, including autism spectrum disorder, attention-deficit/hyperactivity disorder, mental retardation and schizophrenia can be triggered by alterations to neural development. The zebrafish is a popular model for developmental biology that is increasingly used to study human disease. Recent work has extended this approach to examine psychiatric disorders as well. However, since psychiatric disorders affect complex mental functions that might be human specific, it is not possible to fully model them in fish. In this review, I will propose that the suitability of zebrafish for developmental studies, and the genetic tools available to manipulate them, provide a powerful model to study the roles of genes that are linked to psychiatric disorders during neural development. The relative speed and ease of conducting experiments in zebrafish can be used to address two areas of future research: the contribution of environmental factors to disease onset, and screening for novel therapeutic compounds.

  10. Review of SFR Design Safety using Preliminary Regulatory PSA Model

    International Nuclear Information System (INIS)

    Na, Hyun Ju; Lee, Yong Suk; Shin, Andong; Suh, Nam Duk

    2013-01-01

    The major objective of this research is to develop a risk model for regulatory verification of the SFR design, and thereby, make sure that the SFR design is adequate from a risk perspective. In this paper, the development result of preliminary regulatory PSA model of SFR is discussed. In this paper, development and quantification result of preliminary regulatory PSA model of SFR is discussed. It was confirmed that the importance PDRC and ADRC dampers is significant as stated in the result of KAERI PSA model. However, the importance can be changed significantly depending on assumption of CCCG and CCF factor of PDRC and ADRC dampers. SFR (sodium-cooled fast reactor) which is Gen-IV nuclear energy system, is designed to accord with the concept of stability, sustainability and proliferation resistance. KALIMER-600, which is under development in Korea, includes passive safety systems (e. g. passive reactor shutdown, passive residual heat removal, and etc.) as well as active safety systems. Risk analysis from a regulatory perspective is needed to support the regulatory body in its safety and licensing review for SFR (KALIMER-600). Safety issues should be identified in the early design phase in order to prevent the unexpected cost increase and delay of the SFR licensing schedule that may be caused otherwise

  11. C. elegans as a model in developmental neurotoxicology.

    Science.gov (United States)

    Ruszkiewicz, Joanna A; Pinkas, Adi; Miah, Mahfuzur R; Weitz, Rebecca L; Lawes, Michael J A; Akinyemi, Ayodele J; Ijomone, Omamuyovwi M; Aschner, Michael

    2018-03-14

    Due to many advantages Caenorhabditis elegans (C. elegans) has become a preferred model of choice in many fields, including neurodevelopmental toxicity studies. This review discusses the benefits of using C. elegans as an alternative to mammalian systems and gives examples of the uses of the nematode in evaluating the effects of major known neurodevelopmental toxins, including manganese, mercury, lead, fluoride, arsenic and organophosphorus pesticides. Reviewed data indicates numerous similarities with mammals in response to these toxins. Thus, C. elegans studies have the potential to predict possible effects of developmental neurotoxicants in higher animals, and may be used to identify new molecular pathways behind neurodevelopmental disruptions, as well as new toxicants. Copyright © 2018 Elsevier Inc. All rights reserved.

  12. Modeling stochasticity and robustness in gene regulatory networks.

    Science.gov (United States)

    Garg, Abhishek; Mohanram, Kartik; Di Cara, Alessandro; De Micheli, Giovanni; Xenarios, Ioannis

    2009-06-15

    Understanding gene regulation in biological processes and modeling the robustness of underlying regulatory networks is an important problem that is currently being addressed by computational systems biologists. Lately, there has been a renewed interest in Boolean modeling techniques for gene regulatory networks (GRNs). However, due to their deterministic nature, it is often difficult to identify whether these modeling approaches are robust to the addition of stochastic noise that is widespread in gene regulatory processes. Stochasticity in Boolean models of GRNs has been addressed relatively sparingly in the past, mainly by flipping the expression of genes between different expression levels with a predefined probability. This stochasticity in nodes (SIN) model leads to over representation of noise in GRNs and hence non-correspondence with biological observations. In this article, we introduce the stochasticity in functions (SIF) model for simulating stochasticity in Boolean models of GRNs. By providing biological motivation behind the use of the SIF model and applying it to the T-helper and T-cell activation networks, we show that the SIF model provides more biologically robust results than the existing SIN model of stochasticity in GRNs. Algorithms are made available under our Boolean modeling toolbox, GenYsis. The software binaries can be downloaded from http://si2.epfl.ch/ approximately garg/genysis.html.

  13. Models in environmental regulatory decision making

    National Research Council Canada - National Science Library

    Committee on Models in the Regulatory Decision Process, National Research Council

    2007-01-01

    .... Models help EPA explain environmental phenomena in settings where direct observations are limited or unavailable, and anticipate the effects of agency policies on the environment, human health and the economy...

  14. Models in environmental regulatory decision making

    National Research Council Canada - National Science Library

    Committee on Models in the Regulatory Decision Process; National Research Council; Division on Earth and Life Studies; National Research Council

    2007-01-01

    .... The centerpiece of the book's recommended vision is a life-cycle approach to model evaluation which includes peer review, corroboration of results, and other activities. This will enhance the agency's ability to respond to requirements from a 2001 law on information quality and improve policy development and implementation.

  15. An examination of the developmental propensity model of conduct problems.

    Science.gov (United States)

    Rhee, Soo Hyun; Friedman, Naomi P; Corley, Robin P; Hewitt, John K; Hink, Laura K; Johnson, Daniel P; Smith Watts, Ashley K; Young, Susan E; Robinson, JoAnn; Waldman, Irwin D; Zahn-Waxler, Carolyn

    2016-05-01

    The present study tested specific hypotheses advanced by the developmental propensity model of the etiology of conduct problems in the Colorado Longitudinal Twin Study, a prospective, longitudinal, genetically informative sample. High negative emotionality, low behavioral inhibition, low concern and high disregard for others, and low cognitive ability assessed during toddlerhood (age 14 to 36 months) were examined as predictors of conduct problems in later childhood and adolescence (age 4 to 17 years). Each hypothesized antisocial propensity dimension predicted conduct problems, but some predictions may be context specific or due to method covariance. The most robust predictors were observed disregard for others (i.e., responding to others' distress with active, negative responses such as anger and hostility), general cognitive ability, and language ability, which were associated with conduct problems reported by parents, teachers, and adolescents, and change in observed negative emotionality (i.e., frustration tolerance), which was associated with conduct problems reported by teachers and adolescents. Furthermore, associations between the most robust early predictors and later conduct problems were influenced by the shared environment rather than genes. We conclude that shared environmental influences that promote disregard for others and detract from cognitive and language development during toddlerhood also predispose individuals to conduct problems in later childhood and adolescence. The identification of those shared environmental influences common to early antisocial propensity and later conduct problems is an important future direction, and additional developmental behavior genetic studies examining the interaction between children's characteristics and socializing influences on conduct problems are needed. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  16. Task-based dermal exposure models for regulatory risk assessment

    NARCIS (Netherlands)

    Warren, N.D.; Marquart, H.; Christopher, Y.; Laitinen, J.; Hemmen, J.J. van

    2006-01-01

    The regulatory risk assessment of chemicals requires the estimation of occupational dermal exposure. Until recently, the models used were either based on limited data or were specific to a particular class of chemical or application. The EU project RISKOFDERM has gathered a considerable number of

  17. A Developmental Model Applied to Problems of Deafness.

    Science.gov (United States)

    Schlesinger, Hilde S.

    2000-01-01

    This "classic" article (1972) in the field of deaf studies includes some interpretive notes for current readers. The article examines the effect of deafness on basic developmental tasks at each of the eight developmental stages of Erik Erikson's theory of psychosocial development and explains the more successful passage through these…

  18. Development of the Level 1 PSA Model for PGSFR Regulatory

    International Nuclear Information System (INIS)

    Na, Hyun Ju; Lee, Yong Suk; Shin, Andong; Suh, Nam Duk

    2014-01-01

    SFR (sodium-cooled fast reactor) is Gen-IV nuclear energy system, which is designed for stability, sustainability and proliferation resistance. KALIMER-600 and PGSFR (Prototype Gen-IV SFR) are under development in Korea with enhanced passive safety concepts, e.g. passive reactor shutdown, passive residual heat removal, and etc. Risk analysis from a regulatory perspective is necessary for regulatory body to support the safety and licensing review of SFR. Safety issues should be identified in the early design phase in order to prevent the unexpected cost increase and the delay of PGSFR licensing schedule. In this respect, the preliminary PSA Model of KALIMER-600 had been developed for regulatory. In this study, the development of PSA Level 1 Model is presented. The important impact factors in the risk analysis for the PGSFR, such as Core Damage Frequency (CDF), have been identified and the related safety insights have been derived. The PSA level 1 model for PGSFR regulatory is developed and the risk analysis is conducted. Regarding CDF, LOISF frequency, uncertainty parameter for passive system CCF, loss of 125V DC control center bus and damper CCF are identified as the important factors. Sensitivity analyses show that the CDF would be differentiated (lowered) according to their values

  19. HPRT deficiency coordinately dysregulates canonical Wnt and presenilin-1 signaling: a neuro-developmental regulatory role for a housekeeping gene?

    Directory of Open Access Journals (Sweden)

    Tae Hyuk Kang

    2011-01-01

    Full Text Available We have used microarray-based methods of global gene expression together with quantitative PCR and Western blot analysis to identify dysregulation of genes and aberrant cellular processes in human fibroblasts and in SH-SY5Y neuroblastoma cells made HPRT-deficient by transduction with a retrovirus stably expressing an shRNA targeted against HPRT. Analysis of the microarray expression data by Gene ontology (GO and Gene Set Enrichment Analysis (GSEA as well as significant pathway analysis by GeneSpring GX10 and Panther Classification System reveal that HPRT deficiency is accompanied by aberrations in a variety of pathways known to regulate neurogenesis or to be implicated in neurodegenerative disease, including the canonical Wnt/β-catenin and the Alzheimer's disease/presenilin signaling pathways. Dysregulation of the Wnt/β-catenin pathway is confirmed by Western blot demonstration of cytosolic sequestration of β-catenin during in vitro differentiation of the SH-SY5Y cells toward the neuronal phenotype. We also demonstrate that two key transcription factor genes known to be regulated by Wnt signaling and to be vital for the generation and function of dopaminergic neurons; i.e., Lmx1a and Engrailed 1, are down-regulated in the HPRT knockdown SH-SY5Y cells. In addition to the Wnt signaling aberration, we found that expression of presenilin-1 shows severely aberrant expression in HPRT-deficient SH-SY5Y cells, reflected by marked deficiency of the 23 kDa C-terminal fragment of presenilin-1 in knockdown cells. Western blot analysis of primary fibroblast cultures from two LND patients also shows dysregulated presenilin-1 expression, including aberrant proteolytic processing of presenilin-1. These demonstrations of dysregulated Wnt signaling and presenilin-1 expression together with impaired expression of dopaminergic transcription factors reveal broad pleitropic neuro-regulatory defects played by HPRT expression and suggest new directions for

  20. Xylogenesis in zinnia (Zinnia elegans) cell cultures: unravelling the regulatory steps in a complex developmental programmed cell death event.

    Science.gov (United States)

    Iakimova, Elena T; Woltering, Ernst J

    2017-04-01

    Physiological and molecular studies support the view that xylogenesis can largely be determined as a specific form of vacuolar programmed cell death (PCD). The studies in xylogenic zinnia cell culture have led to many breakthroughs in xylogenesis research and provided a background for investigations in other experimental models in vitro and in planta . This review discusses the most essential earlier and recent findings on the regulation of xylem elements differentiation and PCD in zinnia and other xylogenic systems. Xylogenesis (the formation of water conducting vascular tissue) is a paradigm of plant developmental PCD. The xylem vessels are composed of fused tracheary elements (TEs)-dead, hollow cells with patterned lignified secondary cell walls. They result from the differentiation of the procambium and cambium cells and undergo cell death to become functional post-mortem. The TE differentiation proceeds through a well-coordinated sequence of events in which differentiation and the programmed cellular demise are intimately connected. For years a classical experimental model for studies on xylogenesis was the xylogenic zinnia (Zinnia elegans) cell culture derived from leaf mesophyll cells that, upon induction by cytokinin and auxin, transdifferentiate into TEs. This cell system has been proven very efficient for investigations on the regulatory components of xylem differentiation which has led to many discoveries on the mechanisms of xylogenesis. The knowledge gained from this system has potentiated studies in other xylogenic cultures in vitro and in planta. The present review summarises the previous and latest findings on the hormonal and biochemical signalling, metabolic pathways and molecular and gene determinants underlying the regulation of xylem vessels differentiation in zinnia cell culture. Highlighted are breakthroughs achieved through the use of xylogenic systems from other species and newly introduced tools and analytical approaches to study the

  1. The power of an ontology-driven developmental toxicity database for data mining and computational modeling

    Science.gov (United States)

    Modeling of developmental toxicology presents a significant challenge to computational toxicology due to endpoint complexity and lack of data coverage. These challenges largely account for the relatively few modeling successes using the structure–activity relationship (SAR) parad...

  2. Violent Victimization and Perpetration during Adolescence: Developmental Stage Dependent Ecological Models

    Science.gov (United States)

    Matjasko, Jennifer L.; Needham, Belinda L.; Grunden, Leslie N.; Farb, Amy Feldman

    2010-01-01

    Using a variant of the ecological-transactional model and developmental theories of delinquency on a nationally representative sample of adolescents, the current study explored the ecological predictors of violent victimization, perpetration, and both for three different developmental stages during adolescence. We examined the relative influence…

  3. A system-level model for the microbial regulatory genome.

    Science.gov (United States)

    Brooks, Aaron N; Reiss, David J; Allard, Antoine; Wu, Wei-Ju; Salvanha, Diego M; Plaisier, Christopher L; Chandrasekaran, Sriram; Pan, Min; Kaur, Amardeep; Baliga, Nitin S

    2014-07-15

    Microbes can tailor transcriptional responses to diverse environmental challenges despite having streamlined genomes and a limited number of regulators. Here, we present data-driven models that capture the dynamic interplay of the environment and genome-encoded regulatory programs of two types of prokaryotes: Escherichia coli (a bacterium) and Halobacterium salinarum (an archaeon). The models reveal how the genome-wide distributions of cis-acting gene regulatory elements and the conditional influences of transcription factors at each of those elements encode programs for eliciting a wide array of environment-specific responses. We demonstrate how these programs partition transcriptional regulation of genes within regulons and operons to re-organize gene-gene functional associations in each environment. The models capture fitness-relevant co-regulation by different transcriptional control mechanisms acting across the entire genome, to define a generalized, system-level organizing principle for prokaryotic gene regulatory networks that goes well beyond existing paradigms of gene regulation. An online resource (http://egrin2.systemsbiology.net) has been developed to facilitate multiscale exploration of conditional gene regulation in the two prokaryotes. © 2014 The Authors. Published under the terms of the CC BY 4.0 license.

  4. The impact of gene expression variation on the robustness and evolvability of a developmental gene regulatory network.

    Directory of Open Access Journals (Sweden)

    David A Garfield

    2013-10-01

    Full Text Available Regulatory interactions buffer development against genetic and environmental perturbations, but adaptation requires phenotypes to change. We investigated the relationship between robustness and evolvability within the gene regulatory network underlying development of the larval skeleton in the sea urchin Strongylocentrotus purpuratus. We find extensive variation in gene expression in this network throughout development in a natural population, some of which has a heritable genetic basis. Switch-like regulatory interactions predominate during early development, buffer expression variation, and may promote the accumulation of cryptic genetic variation affecting early stages. Regulatory interactions during later development are typically more sensitive (linear, allowing variation in expression to affect downstream target genes. Variation in skeletal morphology is associated primarily with expression variation of a few, primarily structural, genes at terminal positions within the network. These results indicate that the position and properties of gene interactions within a network can have important evolutionary consequences independent of their immediate regulatory role.

  5. Developmental Education: A Proposed Model For Guidance and Counseling

    Science.gov (United States)

    Gazda, George M.

    1978-01-01

    Coins a new term for counselors--"developmental education"--which the author defines as developing specific life-coping skills. The article also examines some ethical questions which are related to this intentional manipulation of the human condition. (Author/HMV)

  6. Preliminary Development of Regulatory PSA Models for SFR

    International Nuclear Information System (INIS)

    Choi, Yong Won; Shin, Andong; Bae, Moohoon; Suh, Namduk; Lee, Yong Suk

    2013-01-01

    Well developed PRA methodology exists for LWR (Light Water Reactor) and PHWR (Pressurized Heavy Water Reactor). Since KAERI is developing a prototype SFR targeting to apply for a license by 2017, KINS needs to have a PRA models to assess the safety of this prototype reactor. The purpose of this study is to develop the regulatory PSA models for the independent verification of the SFR safety. Since the design of the prototype SFR is not mature yet, we have tried to develop the preliminary models based on the design data of KAERI's previous SFR design. In this study, the preliminary initiating events of level 1 internal event for SFR were selected through reviews of existing PRA (LWR, PRISM, ASTRID and KALIMER-600) models. Then, the event tree for each selected initiating event was developed. The regulatory PRA models of SFR developed are preliminary in a sense, because the prototype SFR design is not mature and provided yet. Still it might be utilized for the forthcoming licensing review in assessing the risk of safety issues and the configuration control of the design

  7. Synchronous versus asynchronous modeling of gene regulatory networks.

    Science.gov (United States)

    Garg, Abhishek; Di Cara, Alessandro; Xenarios, Ioannis; Mendoza, Luis; De Micheli, Giovanni

    2008-09-01

    In silico modeling of gene regulatory networks has gained some momentum recently due to increased interest in analyzing the dynamics of biological systems. This has been further facilitated by the increasing availability of experimental data on gene-gene, protein-protein and gene-protein interactions. The two dynamical properties that are often experimentally testable are perturbations and stable steady states. Although a lot of work has been done on the identification of steady states, not much work has been reported on in silico modeling of cellular differentiation processes. In this manuscript, we provide algorithms based on reduced ordered binary decision diagrams (ROBDDs) for Boolean modeling of gene regulatory networks. Algorithms for synchronous and asynchronous transition models have been proposed and their corresponding computational properties have been analyzed. These algorithms allow users to compute cyclic attractors of large networks that are currently not feasible using existing software. Hereby we provide a framework to analyze the effect of multiple gene perturbation protocols, and their effect on cell differentiation processes. These algorithms were validated on the T-helper model showing the correct steady state identification and Th1-Th2 cellular differentiation process. The software binaries for Windows and Linux platforms can be downloaded from http://si2.epfl.ch/~garg/genysis.html.

  8. Uncovering Transcriptional Regulatory Networks by Sparse Bayesian Factor Model

    Directory of Open Access Journals (Sweden)

    Qi Yuan(Alan

    2010-01-01

    Full Text Available Abstract The problem of uncovering transcriptional regulation by transcription factors (TFs based on microarray data is considered. A novel Bayesian sparse correlated rectified factor model (BSCRFM is proposed that models the unknown TF protein level activity, the correlated regulations between TFs, and the sparse nature of TF-regulated genes. The model admits prior knowledge from existing database regarding TF-regulated target genes based on a sparse prior and through a developed Gibbs sampling algorithm, a context-specific transcriptional regulatory network specific to the experimental condition of the microarray data can be obtained. The proposed model and the Gibbs sampling algorithm were evaluated on the simulated systems, and results demonstrated the validity and effectiveness of the proposed approach. The proposed model was then applied to the breast cancer microarray data of patients with Estrogen Receptor positive ( status and Estrogen Receptor negative ( status, respectively.

  9. Specifying theories of developmental dyslexia: a diffusion model analysis of word recognition

    NARCIS (Netherlands)

    Zeguers, M.H.T.; Snellings, P.; Tijms, J.; Weeda, W.D.; Tamboer, P.; Bexkens, A.; Huizenga, H.M.

    2011-01-01

    The nature of word recognition difficulties in developmental dyslexia is still a topic of controversy. We investigated the contribution of phonological processing deficits and uncertainty to the word recognition difficulties of dyslexic children by mathematical diffusion modeling of visual and

  10. Identifying developmental vascular disruptor compounds using a predictive signature and alternative toxicity models

    Science.gov (United States)

    Identifying Developmental Vascular Disruptor Compounds Using a Predictive Signature and Alternative Toxicity Models Presenting Author: Tamara Tal Affiliation: U.S. EPA/ORD/ISTD, RTP, NC, USA Chemically induced vascular toxicity during embryonic development can result in a wide...

  11. Analysis of deterministic cyclic gene regulatory network models with delays

    CERN Document Server

    Ahsen, Mehmet Eren; Niculescu, Silviu-Iulian

    2015-01-01

    This brief examines a deterministic, ODE-based model for gene regulatory networks (GRN) that incorporates nonlinearities and time-delayed feedback. An introductory chapter provides some insights into molecular biology and GRNs. The mathematical tools necessary for studying the GRN model are then reviewed, in particular Hill functions and Schwarzian derivatives. One chapter is devoted to the analysis of GRNs under negative feedback with time delays and a special case of a homogenous GRN is considered. Asymptotic stability analysis of GRNs under positive feedback is then considered in a separate chapter, in which conditions leading to bi-stability are derived. Graduate and advanced undergraduate students and researchers in control engineering, applied mathematics, systems biology and synthetic biology will find this brief to be a clear and concise introduction to the modeling and analysis of GRNs.

  12. REM sleep complicates period adding bifurcations from monophasic to polyphasic sleep behavior in a sleep-wake regulatory network model for human sleep

    OpenAIRE

    Kalmbach, K.; Booth, V.; Behn, C. G. Diniz

    2017-01-01

    The structure of human sleep changes across development as it consolidates from the polyphasic sleep of infants to the single nighttime sleep period typical in adults. Across this same developmental period, time scales of the homeostatic sleep drive, the physiological drive to sleep that increases with time spent awake, also change and presumably govern the transition from polyphasic to monophasic sleep behavior. Using a physiologically-based, sleep-wake regulatory network model for human sle...

  13. Comparison of evolutionary algorithms in gene regulatory network model inference.

    LENUS (Irish Health Repository)

    2010-01-01

    ABSTRACT: BACKGROUND: The evolution of high throughput technologies that measure gene expression levels has created a data base for inferring GRNs (a process also known as reverse engineering of GRNs). However, the nature of these data has made this process very difficult. At the moment, several methods of discovering qualitative causal relationships between genes with high accuracy from microarray data exist, but large scale quantitative analysis on real biological datasets cannot be performed, to date, as existing approaches are not suitable for real microarray data which are noisy and insufficient. RESULTS: This paper performs an analysis of several existing evolutionary algorithms for quantitative gene regulatory network modelling. The aim is to present the techniques used and offer a comprehensive comparison of approaches, under a common framework. Algorithms are applied to both synthetic and real gene expression data from DNA microarrays, and ability to reproduce biological behaviour, scalability and robustness to noise are assessed and compared. CONCLUSIONS: Presented is a comparison framework for assessment of evolutionary algorithms, used to infer gene regulatory networks. Promising methods are identified and a platform for development of appropriate model formalisms is established.

  14. Predictive modelling of gene expression from transcriptional regulatory elements.

    Science.gov (United States)

    Budden, David M; Hurley, Daniel G; Crampin, Edmund J

    2015-07-01

    Predictive modelling of gene expression provides a powerful framework for exploring the regulatory logic underpinning transcriptional regulation. Recent studies have demonstrated the utility of such models in identifying dysregulation of gene and miRNA expression associated with abnormal patterns of transcription factor (TF) binding or nucleosomal histone modifications (HMs). Despite the growing popularity of such approaches, a comparative review of the various modelling algorithms and feature extraction methods is lacking. We define and compare three methods of quantifying pairwise gene-TF/HM interactions and discuss their suitability for integrating the heterogeneous chromatin immunoprecipitation (ChIP)-seq binding patterns exhibited by TFs and HMs. We then construct log-linear and ϵ-support vector regression models from various mouse embryonic stem cell (mESC) and human lymphoblastoid (GM12878) data sets, considering both ChIP-seq- and position weight matrix- (PWM)-derived in silico TF-binding. The two algorithms are evaluated both in terms of their modelling prediction accuracy and ability to identify the established regulatory roles of individual TFs and HMs. Our results demonstrate that TF-binding and HMs are highly predictive of gene expression as measured by mRNA transcript abundance, irrespective of algorithm or cell type selection and considering both ChIP-seq and PWM-derived TF-binding. As we encourage other researchers to explore and develop these results, our framework is implemented using open-source software and made available as a preconfigured bootable virtual environment. © The Author 2014. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  15. Algebraic model checking for Boolean gene regulatory networks.

    Science.gov (United States)

    Tran, Quoc-Nam

    2011-01-01

    We present a computational method in which modular and Groebner bases (GB) computation in Boolean rings are used for solving problems in Boolean gene regulatory networks (BN). In contrast to other known algebraic approaches, the degree of intermediate polynomials during the calculation of Groebner bases using our method will never grow resulting in a significant improvement in running time and memory space consumption. We also show how calculation in temporal logic for model checking can be done by means of our direct and efficient Groebner basis computation in Boolean rings. We present our experimental results in finding attractors and control strategies of Boolean networks to illustrate our theoretical arguments. The results are promising. Our algebraic approach is more efficient than the state-of-the-art model checker NuSMV on BNs. More importantly, our approach finds all solutions for the BN problems.

  16. Regulatory agencies and regulatory risk

    OpenAIRE

    Knieps, Günter; Weiß, Hans-Jörg

    2008-01-01

    The aim of this paper is to show that regulatory risk is due to the discretionary behaviour of regulatory agencies, caused by a too extensive regulatory mandate provided by the legislator. The normative point of reference and a behavioural model of regulatory agencies based on the positive theory of regulation are presented. Regulatory risk with regard to the future behaviour of regulatory agencies is modelled as the consequence of the ex ante uncertainty about the relative influence of inter...

  17. An evaluation model for the definition of regulatory requirements on spent fuel pool cooling systems

    International Nuclear Information System (INIS)

    Izquierdo, J.M.

    1979-01-01

    A calculation model is presented for establishing regulatory requirements in the SFPCS System. The major design factors, regulatory and design limits and key parameters are discussed. A regulatory position for internal use is proposed. Finally, associated problems and experience are presented. (author)

  18. A developmental, biopsychosocial model for the treatment of children with gender identity disorder.

    Science.gov (United States)

    Zucker, Kenneth J; Wood, Hayley; Singh, Devita; Bradley, Susan J

    2012-01-01

    This article provides a summary of the therapeutic model and approach used in the Gender Identity Service at the Centre for Addiction and Mental Health in Toronto. The authors describe their assessment protocol, describe their current multifactorial case formulation model, including a strong emphasis on developmental factors, and provide clinical examples of how the model is used in the treatment.

  19. Using Video Modeling to Teach Young Children with Autism Developmentally Appropriate Play and Connected Speech

    Science.gov (United States)

    Scheflen, Sarah Clifford; Freeman, Stephanny F. N.; Paparella, Tanya

    2012-01-01

    Four children with autism were taught play skills through the use of video modeling. Video instruction was used to model play and appropriate language through a developmental sequence of play levels integrated with language techniques. Results showed that children with autism could successfully use video modeling to learn how to play appropriately…

  20. Task-based dermal exposure models for regulatory risk assessment.

    Science.gov (United States)

    Warren, Nicholas D; Marquart, Hans; Christopher, Yvette; Laitinen, Juha; VAN Hemmen, Joop J

    2006-07-01

    The regulatory risk assessment of chemicals requires the estimation of occupational dermal exposure. Until recently, the models used were either based on limited data or were specific to a particular class of chemical or application. The EU project RISKOFDERM has gathered a considerable number of new measurements of dermal exposure together with detailed contextual information. This article describes the development of a set of generic task-based models capable of predicting potential dermal exposure to both solids and liquids in a wide range of situations. To facilitate modelling of the wide variety of dermal exposure situations six separate models were made for groupings of exposure scenarios called Dermal Exposure Operation units (DEO units). These task-based groupings cluster exposure scenarios with regard to the expected routes of dermal exposure and the expected influence of exposure determinants. Within these groupings linear mixed effect models were used to estimate the influence of various exposure determinants and to estimate components of variance. The models predict median potential dermal exposure rates for the hands and the rest of the body from the values of relevant exposure determinants. These rates are expressed as mg or microl product per minute. Using these median potential dermal exposure rates and an accompanying geometric standard deviation allows a range of exposure percentiles to be calculated.

  1. An ensemble model of QSAR tools for regulatory risk assessment.

    Science.gov (United States)

    Pradeep, Prachi; Povinelli, Richard J; White, Shannon; Merrill, Stephen J

    2016-01-01

    Quantitative structure activity relationships (QSARs) are theoretical models that relate a quantitative measure of chemical structure to a physical property or a biological effect. QSAR predictions can be used for chemical risk assessment for protection of human and environmental health, which makes them interesting to regulators, especially in the absence of experimental data. For compatibility with regulatory use, QSAR models should be transparent, reproducible and optimized to minimize the number of false negatives. In silico QSAR tools are gaining wide acceptance as a faster alternative to otherwise time-consuming clinical and animal testing methods. However, different QSAR tools often make conflicting predictions for a given chemical and may also vary in their predictive performance across different chemical datasets. In a regulatory context, conflicting predictions raise interpretation, validation and adequacy concerns. To address these concerns, ensemble learning techniques in the machine learning paradigm can be used to integrate predictions from multiple tools. By leveraging various underlying QSAR algorithms and training datasets, the resulting consensus prediction should yield better overall predictive ability. We present a novel ensemble QSAR model using Bayesian classification. The model allows for varying a cut-off parameter that allows for a selection in the desirable trade-off between model sensitivity and specificity. The predictive performance of the ensemble model is compared with four in silico tools (Toxtree, Lazar, OECD Toolbox, and Danish QSAR) to predict carcinogenicity for a dataset of air toxins (332 chemicals) and a subset of the gold carcinogenic potency database (480 chemicals). Leave-one-out cross validation results show that the ensemble model achieves the best trade-off between sensitivity and specificity (accuracy: 83.8 % and 80.4 %, and balanced accuracy: 80.6 % and 80.8 %) and highest inter-rater agreement [kappa ( κ ): 0

  2. Fixed Points in Discrete Models for Regulatory Genetic Networks

    Directory of Open Access Journals (Sweden)

    Orozco Edusmildo

    2007-01-01

    Full Text Available It is desirable to have efficient mathematical methods to extract information about regulatory iterations between genes from repeated measurements of gene transcript concentrations. One piece of information is of interest when the dynamics reaches a steady state. In this paper we develop tools that enable the detection of steady states that are modeled by fixed points in discrete finite dynamical systems. We discuss two algebraic models, a univariate model and a multivariate model. We show that these two models are equivalent and that one can be converted to the other by means of a discrete Fourier transform. We give a new, more general definition of a linear finite dynamical system and we give a necessary and sufficient condition for such a system to be a fixed point system, that is, all cycles are of length one. We show how this result for generalized linear systems can be used to determine when certain nonlinear systems (monomial dynamical systems over finite fields are fixed point systems. We also show how it is possible to determine in polynomial time when an ordinary linear system (defined over a finite field is a fixed point system. We conclude with a necessary condition for a univariate finite dynamical system to be a fixed point system.

  3. Developmental maturation of dynamic causal control signals in higher-order cognition: a neurocognitive network model.

    Directory of Open Access Journals (Sweden)

    Kaustubh Supekar

    2012-02-01

    Full Text Available Cognitive skills undergo protracted developmental changes resulting in proficiencies that are a hallmark of human cognition. One skill that develops over time is the ability to problem solve, which in turn relies on cognitive control and attention abilities. Here we use a novel multimodal neurocognitive network-based approach combining task-related fMRI, resting-state fMRI and diffusion tensor imaging (DTI to investigate the maturation of control processes underlying problem solving skills in 7-9 year-old children. Our analysis focused on two key neurocognitive networks implicated in a wide range of cognitive tasks including control: the insula-cingulate salience network, anchored in anterior insula (AI, ventrolateral prefrontal cortex and anterior cingulate cortex, and the fronto-parietal central executive network, anchored in dorsolateral prefrontal cortex and posterior parietal cortex (PPC. We found that, by age 9, the AI node of the salience network is a major causal hub initiating control signals during problem solving. Critically, despite stronger AI activation, the strength of causal regulatory influences from AI to the PPC node of the central executive network was significantly weaker and contributed to lower levels of behavioral performance in children compared to adults. These results were validated using two different analytic methods for estimating causal interactions in fMRI data. In parallel, DTI-based tractography revealed weaker AI-PPC structural connectivity in children. Our findings point to a crucial role of AI connectivity, and its causal cross-network influences, in the maturation of dynamic top-down control signals underlying cognitive development. Overall, our study demonstrates how a unified neurocognitive network model when combined with multimodal imaging enhances our ability to generalize beyond individual task-activated foci and provides a common framework for elucidating key features of brain and cognitive

  4. Commentary: role of temperament in developmental models of psychopathology.

    Science.gov (United States)

    Lahey, Benjamin B

    2004-03-01

    The articles in this special section provide exciting and useful perspectives on the role of temperament in the development of child and adolescent psychopathology. These articles are valuable both in summarizing what is known and in highlighting issues that must be addressed before further progress can be made. In the future, it will be essential to distinguish between the constructs of temperament and psychopathology in ways that are both scientifically valid and useful to the study of developmental psychopathology. In particular, because existing measures of temperament were not designed to study relations between temperament and psychopathology, new measures are needed that focus on relevant aspects of temperament and are not confounded by the inclusion of items that are close synonyms and antonyms of psychopathology. If circular and mentalistic thinking can be avoided, important advances can be expected from studies of temperament and psychopathology in the context of development.

  5. A model surveillance program based on regulatory experience

    International Nuclear Information System (INIS)

    Conte, R.J.

    1980-01-01

    A model surveillance program is presented based on regulatory experience. The program consists of three phases: Program Delineation, Data Acquistion and Data Analysis. Each phase is described in terms of key quality assurance elements and some current philosophies is the United States Licensing Program. Other topics include the application of these ideas to test equipment used in the surveillance progam and audits of the established program. Program Delineation discusses the establishment of administrative controls for organization and the description of responsibilities using the 'Program Coordinator' concept, with assistance from Data Acquisition and Analysis Teams. Ideas regarding frequency of surveillance testing are also presented. The Data Acquisition Phase discusses various methods for acquiring data including operator observations, test procedures, operator logs, and computer output, for trending equipment performance. The Data Analysis Phase discusses the process for drawing conclusions regarding component/equipment service life, proper application, and generic problems through the use of trend analysis and failure rate data. (orig.)

  6. The Sherborne Developmental Movement (SDM) Teaching Model for Pre-Service Teachers

    Science.gov (United States)

    Hen, Meirav; Walter, Ofra

    2012-01-01

    Previously, the Sherborne Developmental Movement (SDM) has been found to contribute to the development of emotional competencies in higher education. This study presents and evaluates a teaching model based on SDM for the development of emotional competencies in teacher education. The study examined the contributions of this model to the increase…

  7. Differential Susceptibility to the Environment: Are Developmental Models Compatible with the Evidence from Twin Studies?

    Science.gov (United States)

    Del Giudice, Marco

    2016-01-01

    According to models of differential susceptibility, the same neurobiological and temperamental traits that determine increased sensitivity to stress and adversity also confer enhanced responsivity to the positive aspects of the environment. Differential susceptibility models have expanded to include complex developmental processes in which genetic…

  8. Developmental Cascade Model for Adolescent Substance Use from Infancy to Late Adolescence

    Science.gov (United States)

    Eiden, Rina D.; Lessard, Jared; Colder, Craig R.; Livingston, Jennifer; Casey, Meghan; Leonard, Kenneth E.

    2016-01-01

    A developmental cascade model for adolescent substance use beginning in infancy was examined in a sample of children with alcoholic and nonalcoholic parents. The model examined the role of parents' alcohol diagnoses, depression and antisocial behavior in a cascading process of risk via 3 major hypothesized pathways: first, via parental…

  9. Regulatory focus at work : the moderating role of regulatory focus in the job demands-resources model

    NARCIS (Netherlands)

    Brenninkmeijer, V.; Demerouti, E.; Blanc, Le P.M.; Emmerik, van I.J.H.

    2010-01-01

    Purpose – The purpose of this study is to examine the moderating role of regulatory focus in the job demands-resources model. Design/methodology/approach – A questionnaire survey was conducted among 146 teachers in secondary education. It was expected that detrimental effects of job demands (i.e.

  10. Ecological models for regulatory risk assessments of pesticides: Developing a strategy for the future.

    NARCIS (Netherlands)

    Thorbek, P.; Forbes, V.; Heimbach, F.; Hommen, U.; Thulke, H.H.; Brink, van den P.J.

    2010-01-01

    Ecological Models for Regulatory Risk Assessments of Pesticides: Developing a Strategy for the Future provides a coherent, science-based view on ecological modeling for regulatory risk assessments. It discusses the benefits of modeling in the context of registrations, identifies the obstacles that

  11. Establishing a regulatory value chain model: An innovative approach to strengthening medicines regulatory systems in resource-constrained settings.

    Science.gov (United States)

    Chahal, Harinder Singh; Kashfipour, Farrah; Susko, Matt; Feachem, Neelam Sekhri; Boyle, Colin

    2016-05-01

    Medicines Regulatory Authorities (MRAs) are an essential part of national health systems and are charged with protecting and promoting public health through regulation of medicines. However, MRAs in resource-constrained settings often struggle to provide effective oversight of market entry and use of health commodities. This paper proposes a regulatory value chain model (RVCM) that policymakers and regulators can use as a conceptual framework to guide investments aimed at strengthening regulatory systems. The RVCM incorporates nine core functions of MRAs into five modules: (i) clear guidelines and requirements; (ii) control of clinical trials; (iii) market authorization of medical products; (iv) pre-market quality control; and (v) post-market activities. Application of the RVCM allows national stakeholders to identify and prioritize investments according to where they can add the most value to the regulatory process. Depending on the economy, capacity, and needs of a country, some functions can be elevated to a regional or supranational level, while others can be maintained at the national level. In contrast to a "one size fits all" approach to regulation in which each country manages the full regulatory process at the national level, the RVCM encourages leveraging the expertise and capabilities of other MRAs where shared processes strengthen regulation. This value chain approach provides a framework for policymakers to maximize investment impact while striving to reach the goal of safe, affordable, and rapidly accessible medicines for all.

  12. Sex determination strategies in 2012: towards a common regulatory model?

    Science.gov (United States)

    2012-01-01

    Sex determination is a complicated process involving large-scale modifications in gene expression affecting virtually every tissue in the body. Although the evolutionary origin of sex remains controversial, there is little doubt that it has developed as a process of optimizing metabolic control, as well as developmental and reproductive functions within a given setting of limited resources and environmental pressure. Evidence from various model organisms supports the view that sex determination may occur as a result of direct environmental induction or genetic regulation. The first process has been well documented in reptiles and fish, while the second is the classic case for avian species and mammals. Both of the latter have developed a variety of sex-specific/sex-related genes, which ultimately form a complete chromosome pair (sex chromosomes/gonosomes). Interestingly, combinations of environmental and genetic mechanisms have been described among different classes of animals, thus rendering the possibility of a unidirectional continuous evolutionary process from the one type of mechanism to the other unlikely. On the other hand, common elements appear throughout the animal kingdom, with regard to a) conserved key genes and b) a central role of sex steroid control as a prerequisite for ultimately normal sex differentiation. Studies in invertebrates also indicate a role of epigenetic chromatin modification, particularly with regard to alternative splicing options. This review summarizes current evidence from research in this hot field and signifies the need for further study of both normal hormonal regulators of sexual phenotype and patterns of environmental disruption. PMID:22357269

  13. A developmental cascade perspective of paediatric obesity: a conceptual model and scoping review.

    Science.gov (United States)

    Smith, Justin D; Egan, Kaitlyn N; Montaño, Zorash; Dawson-McClure, Spring; Jake-Schoffman, Danielle E; Larson, Madeline; St George, Sara M

    2018-04-05

    Considering the immense challenge of preventing obesity, the time has come to reconceptualise the way we study the obesity development in childhood. The developmental cascade model offers a longitudinal framework to elucidate the way cumulative consequences and spreading effects of risk and protective factors, across and within biopsychosocial spheres and phases of development, can propel individuals towards obesity. In this article, we use a theory-driven model-building approach and a scoping review that included 310 published studies to propose a developmental cascade model of paediatric obesity. The proposed model provides a basis for testing hypothesised cascades with multiple intervening variables and complex longitudinal processes. Moreover, the model informs future research by resolving seemingly contradictory findings on pathways to obesity previously thought to be distinct (low self-esteem, consuming sugary foods, and poor sleep cause obesity) that are actually processes working together over time (low self-esteem causes consumption of sugary foods which disrupts sleep quality and contributes to obesity). The findings of such inquiries can aid in identifying the timing and specific targets of preventive interventions across and within developmental phases. The implications of such a cascade model of paediatric obesity for health psychology and developmental and prevention sciences are discussed.

  14. Developmental programming: the concept, large animal models, and the key role of uteroplacental vascular development.

    Science.gov (United States)

    Reynolds, L P; Borowicz, P P; Caton, J S; Vonnahme, K A; Luther, J S; Hammer, C J; Maddock Carlin, K R; Grazul-Bilska, A T; Redmer, D A

    2010-04-01

    Developmental programming refers to the programming of various bodily systems and processes by a stressor of the maternal system during pregnancy or during the neonatal period. Such stressors include nutritional stress, multiple pregnancy (i.e., increased numbers of fetuses in the gravid uterus), environmental stress (e.g., high environmental temperature, high altitude, prenatal steroid exposure), gynecological immaturity, and maternal or fetal genotype. Programming refers to impaired function of numerous bodily systems or processes, leading to poor growth, altered body composition, metabolic dysfunction, and poor productivity (e.g., poor growth, reproductive dysfunction) of the offspring throughout their lifespan and even across generations. A key component of developmental programming seems to be placental dysfunction, leading to altered fetal growth and development. We discuss various large animal models of developmental programming and how they have and will continue to contribute to our understanding of the mechanisms underlying altered placental function and developmental programming, and, further, how large animal models also will be critical to the identification and application of therapeutic strategies that will alleviate the negative consequences of developmental programming to improve offspring performance in livestock production and human medicine.

  15. Hydrocephalus and arthrogryposis in an immunocompetent mouse model of ZIKA teratogeny: A developmental study

    Science.gov (United States)

    Xavier-Neto, Jose; Carvalho, Murilo; Pascoalino, Bruno dos Santos; Cardoso, Alisson Campos; Costa, Ângela Maria Sousa; Pereira, Ana Helena Macedo; Santos, Luana Nunes; Saito, Ângela; Marques, Rafael Elias; Smetana, Juliana Helena Costa; Consonni, Silvio Roberto; Bandeira, Carla; Costa, Vivian Vasconcelos; Bajgelman, Marcio Chaim; de Oliveira, Paulo Sérgio Lopes; Cordeiro, Marli Tenorio; Gonzales Gil, Laura Helena Vega; Pauletti, Bianca Alves; Granato, Daniela Campos; Paes Leme, Adriana Franco; Freitas-Junior, Lucio; Holanda de Freitas, Carolina Borsoi Moraes; Teixeira, Mauro Martins; Bevilacqua, Estela; Franchini, Kleber

    2017-01-01

    The teratogenic mechanisms triggered by ZIKV are still obscure due to the lack of a suitable animal model. Here we present a mouse model of developmental disruption induced by ZIKV hematogenic infection. The model utilizes immunocompetent animals from wild-type FVB/NJ and C57BL/6J strains, providing a better analogy to the human condition than approaches involving immunodeficient, genetically modified animals, or direct ZIKV injection into the brain. When injected via the jugular vein into the blood of pregnant females harboring conceptuses from early gastrulation to organogenesis stages, akin to the human second and fifth week of pregnancy, ZIKV infects maternal tissues, placentas and embryos/fetuses. Early exposure to ZIKV at developmental day 5 (second week in humans) produced complex manifestations of anterior and posterior dysraphia and hydrocephalus, as well as severe malformations and delayed development in 10.5 days post-coitum (dpc) embryos. Exposure to the virus at 7.5–9.5 dpc induces intra-amniotic hemorrhage, widespread edema, and vascular rarefaction, often prominent in the cephalic region. At these stages, most affected embryos/fetuses displayed gross malformations and/or intrauterine growth restriction (IUGR), rather than isolated microcephaly. Disrupted conceptuses failed to achieve normal developmental landmarks and died in utero. Importantly, this is the only model so far to display dysraphia and hydrocephalus, the harbinger of microcephaly in humans, as well as arthrogryposis, a set of abnormal joint postures observed in the human setting. Late exposure to ZIKV at 12.5 dpc failed to produce noticeable malformations. We have thus characterized a developmental window of opportunity for ZIKV-induced teratogenesis encompassing early gastrulation, neurulation and early organogenesis stages. This should not, however, be interpreted as evidence for any safe developmental windows for ZIKV exposure. Late developmental abnormalities correlated with

  16. Hydrocephalus and arthrogryposis in an immunocompetent mouse model of ZIKA teratogeny: A developmental study.

    Directory of Open Access Journals (Sweden)

    Jose Xavier-Neto

    2017-02-01

    Full Text Available The teratogenic mechanisms triggered by ZIKV are still obscure due to the lack of a suitable animal model. Here we present a mouse model of developmental disruption induced by ZIKV hematogenic infection. The model utilizes immunocompetent animals from wild-type FVB/NJ and C57BL/6J strains, providing a better analogy to the human condition than approaches involving immunodeficient, genetically modified animals, or direct ZIKV injection into the brain. When injected via the jugular vein into the blood of pregnant females harboring conceptuses from early gastrulation to organogenesis stages, akin to the human second and fifth week of pregnancy, ZIKV infects maternal tissues, placentas and embryos/fetuses. Early exposure to ZIKV at developmental day 5 (second week in humans produced complex manifestations of anterior and posterior dysraphia and hydrocephalus, as well as severe malformations and delayed development in 10.5 days post-coitum (dpc embryos. Exposure to the virus at 7.5-9.5 dpc induces intra-amniotic hemorrhage, widespread edema, and vascular rarefaction, often prominent in the cephalic region. At these stages, most affected embryos/fetuses displayed gross malformations and/or intrauterine growth restriction (IUGR, rather than isolated microcephaly. Disrupted conceptuses failed to achieve normal developmental landmarks and died in utero. Importantly, this is the only model so far to display dysraphia and hydrocephalus, the harbinger of microcephaly in humans, as well as arthrogryposis, a set of abnormal joint postures observed in the human setting. Late exposure to ZIKV at 12.5 dpc failed to produce noticeable malformations. We have thus characterized a developmental window of opportunity for ZIKV-induced teratogenesis encompassing early gastrulation, neurulation and early organogenesis stages. This should not, however, be interpreted as evidence for any safe developmental windows for ZIKV exposure. Late developmental abnormalities

  17. Developmental Immunotoxicity

    Science.gov (United States)

    Animal models suggest that the immature immune system is more susceptible to xenobiotics than the fully mature system, and sequelae of developmental immunotoxicant exposure may be persistent well into adulthood. Immune maturation may be delayed by xenobiotic exposure and recover...

  18. A Connectionist Model of a Continuous Developmental Transition in the Balance Scale Task

    Science.gov (United States)

    Schapiro, Anna C.; McClelland, James L.

    2009-01-01

    A connectionist model of the balance scale task is presented which exhibits developmental transitions between "Rule I" and "Rule II" behavior [Siegler, R. S. (1976). Three aspects of cognitive development. "Cognitive Psychology," 8, 481-520.] as well as the "catastrophe flags" seen in data from Jansen and van der Maas [Jansen, B. R. J., & van der…

  19. The dynamics of general developmental mechanisms : From Piaget and Vygotsky to dynamic systems models

    NARCIS (Netherlands)

    van Geert, P

    Dynamic systems theory conceives of development as a self-organizational process. Both complexity and order emerge as a product of elementary principles of interaction between components involved in the developmental process. This article presents a dynamic systems model based on a general dual

  20. A dynamic systems model of basic developmental mechanisms : Piaget, Vygotsky, and beyond

    NARCIS (Netherlands)

    van Geert, P

    1998-01-01

    A dynamic systems model is proposed on the basis of a general developmental mechanism adopted from the theories of J. Piaget and L. S. Vygotsky, more particularly a mechanism based on the concepts assimilation versus accommodation and actual development versus zone of proximal development. In the

  1. Investigation of a Developmental Model of Risk for Depression and Suicidality Following Spousal Bereavement

    Science.gov (United States)

    Johnson, Jeffrey G.; Zhang, Baohui; Prigerson, Holly G.

    2008-01-01

    Data from a community-based multi-wave investigation were used to examine a developmental model of risk for depression and suicidality following the death of a spouse. Measures of perceived parental affection and control during childhood were administered to 218 widowed adults 11 months after the death of the spouse. Self-esteem, spousal…

  2. Modeling Zebrafish Developmental Toxicity using a Concurrent In vitro Assay Battery (SOT)

    Science.gov (United States)

    We describe the development of computational models that predict activity in a repeat-dose zebrafish embryo developmental toxicity assay using a combination of physico-chemical parameters and in vitro (human) assay measurements. The data set covered 986 chemicals including pestic...

  3. Maintaining Vocational Skills of Individuals with Autism and Developmental Disabilities through Video Modeling

    Science.gov (United States)

    Van Laarhoven, Toni; Winiarski, Lauren; Blood, Erika; Chan, Jeffrey M.

    2012-01-01

    A modified pre/posttest control group design was used to measure the effectiveness of video modeling on the maintenance of vocational tasks for six students with autism spectrum disorder and/or developmental disabilities. Each student was assigned two vocational tasks at their employment settings and their independence with each task was measured…

  4. Alternative Models to Deliver Developmental Math: Issues of Use and Student Access

    Science.gov (United States)

    Kosiewicz, Holly; Ngo, Federick; Fong, Kristen

    2016-01-01

    Objective: Changing how community colleges deliver developmental education has become a key policy lever to increase student achievement. Alternative development education models reduce the amount of time a student spends in remediation, provide students with supplemental instruction and support, and contextualize content to align with student…

  5. Watershed monitoring and modelling and USA regulatory compliance.

    Science.gov (United States)

    Turner, B G; Boner, M C

    2004-01-01

    The aim of the Columbus program was to implement a comprehensive watershed monitoring-network including water chemistry, aquatic biology and alternative sensors to establish water environment health and methods for determining future restoration progress and early warning for protection of drinking water supplies. The program was implemented to comply with USA regulatory requirements including Total Maximum Daily Load (TMDL) rules of the Clean Water Act (CWA) and Source Water Assessment and Protection (SWAP) rules under the Safe Drinking Water Act (SDWA). The USEPA Office of Research and Development and the Water Environment Research Foundation provided quality assurance oversight. The results obtained demonstrated that significant wet weather data is necessary to establish relationships between land use, water chemistry, aquatic biology and sensor data. These measurements and relationships formed the basis for calibrating the US EPA BASINS Model, prioritizing watershed health and determination of compliance with water quality standards. Conclusions specify priorities of cost-effective drainage system controls that attenuate stormwater flows and capture flushed pollutants. A network of permanent long-term real-time monitoring using combination of continuous sensor measurements, water column sampling and aquatic biology surveys and a regional organization is prescribed to protect drinking water supplies and measure progress towards water quality targets.

  6. Reproductive/developmental toxicity and immunotoxicity assessment in the nonhuman primate model

    International Nuclear Information System (INIS)

    Buse, Eberhard; Habermann, Gunnar; Osterburg, Ingrid; Korte, Rainhart; Weinbauer, Gerhard F.

    2003-01-01

    Nonhuman primates are being used increasingly as a non-rodent animal model during preclinical toxicology and safety assessment on the basis of proven similarity and comparability between nonhuman primates and humans. The validity of the nonhuman primate models applies to many aspects of toxicological testing and holds particularly true for the evaluation of reproductive toxicology and developmental toxicology. More recently, the advent of humanized antibodies and vaccines imposed further demand on nonhuman primate models since many immunotherapeutics do not interact with rodent receptors but frequently only cross-react with primate tissue. In this paper we discuss the suitability of primate models for reproductive, developmental and immunotoxicology testing, and present our initial data on the development of lymphatic organs and immune system in a nonhuman primate model

  7. Thinking outside the boxes: Using current reading models to assess and treat developmental surface dyslexia.

    Science.gov (United States)

    Law, Caroline; Cupples, Linda

    2017-03-01

    Improving the reading performance of children with developmental surface dyslexia has proved challenging, with limited generalisation of reading skills typically reported after intervention. The aim of this study was to provide tailored, theoretically motivated intervention to two children with developmental surface dyslexia. Our objectives were to improve their reading performance, and to evaluate the utility of current reading models in therapeutic practice. Detailed reading and cognitive profiles for two male children with developmental surface dyslexia were compared to the results obtained by age-matched control groups. The specific area of single-word reading difficulty for each child was identified within the dual route model (DRM) of reading, following which a theoretically motivated intervention programme was devised. Both children showed significant improvements in single-word reading ability after training, with generalisation effects observed for untrained words. However, the assessment and intervention results also differed for each child, reinforcing the view that the causes and consequences of developmental dyslexia, even within subtypes, are not homogeneous. Overall, the results of the interventions corresponded more closely with the DRM than other current reading models, in that real word reading improved in the absence of enhanced nonword reading for both children.

  8. Dampened hippocampal oscillations and enhanced spindle activity in an asymptomatic model of developmental cortical malformations

    Directory of Open Access Journals (Sweden)

    Elena eCid

    2014-04-01

    Full Text Available Developmental cortical malformations comprise a large spectrum of histopathological brain abnormalities and syndromes. Their genetic, developmental and clinical complexity suggests they should be better understood in terms of the complementary action of independently timed perturbations (i.e. the multiple-hit hypothesis. However, understanding the underlying biological processes remains puzzling. Here we induced developmental cortical malformations in offspring, after intraventricular injection of methylazoxymethanol (MAM in utero in mice. We combined extensive histological and electrophysiological studies to characterize the model. We found that MAM injections at E14 and E15 induced a range of cortical and hippocampal malformations resembling histological alterations of specific genetic mutations and transplacental mitotoxic agent injections. However, in contrast to most of these models, intraventricularly MAM-injected mice remained asymptomatic and showed no clear epilepsy-related phenotype as tested in long-term chronic recordings and with pharmacological manipulations. Instead, they exhibited a non-specific reduction of hippocampal-related brain oscillations (mostly in CA1; including theta, gamma and HFOs; and enhanced thalamocortical spindle activity during non-REM sleep. These data suggest that developmental cortical malformations do not necessarily correlate with epileptiform activity. We propose that the intraventricular in utero MAM approach exhibiting a range of rhythmopathies is a suitable model for multiple-hit studies of associated neurological disorders.

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

    Science.gov (United States)

    Kavlock, R J

    1997-01-01

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

  10. Tissue-specific expression of aryl hydrocarbon receptor and putative developmental regulatory modules in Baltic salmon yolk-sac fry

    Energy Technology Data Exchange (ETDEWEB)

    Vuori, Kristiina A. [Centre of Excellence in Evolutionary Genetics and Physiology, Department of Biology, University of Turku, FI-20014 Turku (Finland)], E-mail: kristiina.vuori@utu.fi; Nordlund, Eija [Department of Information Technology, University of Turku, and Turku Centre for Computer Science (TUCS), FI-20014 Turku (Finland); Kallio, Jenny [Centre of Excellence in Evolutionary Genetics and Physiology, Department of Biology, University of Turku, FI-20014 Turku (Finland); Salakoski, Tapio [Department of Information Technology, University of Turku, and Turku Centre for Computer Science (TUCS), FI-20014 Turku (Finland); Nikinmaa, Mikko [Centre of Excellence in Evolutionary Genetics and Physiology, Department of Biology, University of Turku, FI-20014 Turku (Finland)

    2008-04-08

    The aryl hydrocarbon receptor (AhR) is an ancient protein that is conserved in vertebrates and invertebrates, indicating its important function throughout evolution. AhR has been studied largely because of its role in toxicology-gene expression via AhR is induced by many aromatic hydrocarbons in mammals. Recently, however, it has become clear that AhR is involved in various aspects of development such as cell proliferation and differentiation, and cell motility and migration. The mechanisms by which AhR regulates these various functions remain poorly understood. Across-species comparative studies of AhR in invertebrates, non-mammalian vertebrates and mammals may help to reveal the multiple functions of AhR. Here, we have studied AhR during larval development of Baltic salmon (Salmon salar). Our results indicate that AhR protein is expressed in nervous system, liver and muscle tissues. We also present putative regulatory modules and module-matching genes, produced by chromatin immunoprecipitation (ChIP) cloning and in silico analysis, which may be associated with evolutionarily conserved functions of AhR during development. For example, the module NFKB-AHRR-CREB found from salmon ChIP sequences is present in human ULK3 (regulating formation of granule cell axons in mouse and axon outgrowth in Caernohabditis elegans) and SRGAP1 (GTPase-activating protein involved in the Slit/Robo pathway) promoters. We suggest that AhR may have an evolutionarily conserved role in neuronal development and nerve cell targeting, and in Wnt signaling pathway.

  11. Tissue-specific expression of aryl hydrocarbon receptor and putative developmental regulatory modules in Baltic salmon yolk-sac fry

    International Nuclear Information System (INIS)

    Vuori, Kristiina A.; Nordlund, Eija; Kallio, Jenny; Salakoski, Tapio; Nikinmaa, Mikko

    2008-01-01

    The aryl hydrocarbon receptor (AhR) is an ancient protein that is conserved in vertebrates and invertebrates, indicating its important function throughout evolution. AhR has been studied largely because of its role in toxicology-gene expression via AhR is induced by many aromatic hydrocarbons in mammals. Recently, however, it has become clear that AhR is involved in various aspects of development such as cell proliferation and differentiation, and cell motility and migration. The mechanisms by which AhR regulates these various functions remain poorly understood. Across-species comparative studies of AhR in invertebrates, non-mammalian vertebrates and mammals may help to reveal the multiple functions of AhR. Here, we have studied AhR during larval development of Baltic salmon (Salmon salar). Our results indicate that AhR protein is expressed in nervous system, liver and muscle tissues. We also present putative regulatory modules and module-matching genes, produced by chromatin immunoprecipitation (ChIP) cloning and in silico analysis, which may be associated with evolutionarily conserved functions of AhR during development. For example, the module NFKB-AHRR-CREB found from salmon ChIP sequences is present in human ULK3 (regulating formation of granule cell axons in mouse and axon outgrowth in Caernohabditis elegans) and SRGAP1 (GTPase-activating protein involved in the Slit/Robo pathway) promoters. We suggest that AhR may have an evolutionarily conserved role in neuronal development and nerve cell targeting, and in Wnt signaling pathway

  12. New models and molecular markers in evaluation of developmental toxicity

    International Nuclear Information System (INIS)

    Huuskonen, Hannele

    2005-01-01

    Mammalian and non-mammalian embryos and embryonic stem cells may be used as models in mechanistic studies and in testing embryotoxicity of compounds. In addition to conventional culture methods, genetic modifications and use of molecular markers offer significant advantages in mechanistic studies as well as in developing new test methods for embryotoxicity. Zebrafish model has been used for a long time and at present several applications are available. It is an easy vertebral non-mammalian model, whose genome is largely known and several genetic modifications are easily constructed to study gene expression or knocked down genes. Fluorescent marker proteins can be used also in zebrafish to indicate gene activation in transgenic models. Chemical genetics approach has been developed using zebrafish model. This is a new approach to screen small molecules that regulate signaling pathways. Embryonic stem cells have been used in mechanistic studies and mouse embryonic stem cell test has been validated to study embryotoxicity in vitro. This method has been improved using quantitative measurements of molecular endpoints by real-time RT-PCR or fluorescent activated cell sorting methods (FACS). Methods facilitating differentiation to several different cell types are available. We have studied preimplantation mouse embryos as a possible model for in vitro testing. In this method, superovulated and in vivo fertilized preimplantation embryos were collected at morula stage and cultured up to blastocysts. The mouse preimplantation culture test was improved by quantitative gene expression measurement using two-step real-time RT-PCR methods. New endpoints improve the tests of in vitro embryotoxicity because subjective assessments are replaced by objective measurements. In addition, automation is possible and less time is needed for analysis. Thus, high throughput screening will come possible to test large numbers of compounds

  13. DREISS: Using State-Space Models to Infer the Dynamics of Gene Expression Driven by External and Internal Regulatory Networks.

    Directory of Open Access Journals (Sweden)

    Daifeng Wang

    2016-10-01

    Full Text Available Gene expression is controlled by the combinatorial effects of regulatory factors from different biological subsystems such as general transcription factors (TFs, cellular growth factors and microRNAs. A subsystem's gene expression may be controlled by its internal regulatory factors, exclusively, or by external subsystems, or by both. It is thus useful to distinguish the degree to which a subsystem is regulated internally or externally-e.g., how non-conserved, species-specific TFs affect the expression of conserved, cross-species genes during evolution. We developed a computational method (DREISS, dreiss.gerteinlab.org for analyzing the Dynamics of gene expression driven by Regulatory networks, both External and Internal based on State Space models. Given a subsystem, the "state" and "control" in the model refer to its own (internal and another subsystem's (external gene expression levels. The state at a given time is determined by the state and control at a previous time. Because typical time-series data do not have enough samples to fully estimate the model's parameters, DREISS uses dimensionality reduction, and identifies canonical temporal expression trajectories (e.g., degradation, growth and oscillation representing the regulatory effects emanating from various subsystems. To demonstrate capabilities of DREISS, we study the regulatory effects of evolutionarily conserved vs. divergent TFs across distant species. In particular, we applied DREISS to the time-series gene expression datasets of C. elegans and D. melanogaster during their embryonic development. We analyzed the expression dynamics of the conserved, orthologous genes (orthologs, seeing the degree to which these can be accounted for by orthologous (internal versus species-specific (external TFs. We found that between two species, the orthologs have matched, internally driven expression patterns but very different externally driven ones. This is particularly true for genes with

  14. Leadership Identity Development: Challenges in Applying a Developmental Model

    Science.gov (United States)

    Komives, Susan R.; Longerbeam, Susan D.; Mainella, Felicia; Osteen, Laura; Owen, Julie E.; Wagner, Wendy

    2009-01-01

    The leadership identity development (LID) grounded theory (Komives, Owen, Longerbeam, Mainella, & Osteen, 2005) and related LID model (Komives, Longerbeam, Owen, Mainella, & Osteen, 2006) present a framework for understanding how individual college students develop the social identity of being collaborative, relational leaders…

  15. THE DEUTSCH MODEL--INSTITUTE FOR DEVELOPMENTAL STUDIES.

    Science.gov (United States)

    New York Univ., NY. Inst. for Developmental Studies.

    THE DEUTSCH INTERVENTION MODEL IS BASED ON THE THEORY THAT ENVIRONMENT PLAYS A MAJOR ROLE IN THE DEVELOPMENT OF COGNITIVE SKILLS AND OF FUNCTIONAL USE OF INTELLECTUAL CAPABILITIES. DISADVANTAGED CHILDREN HAVE INTELLECTUAL DEFICITS WHICH MAY BE OVERCOME BY USE OF MATCHED REMEDIAL MEASURES. LANGUAGE SKILLS AND MOTIVATION CAN BE IMPROVED BY TEACHING…

  16. A developmental approach to mentalizing communities: I. A model for social change.

    Science.gov (United States)

    Twemlow, Stuart W; Fonagy, Peter; Sacco, Frank C

    2005-01-01

    A developmental model is proposed applying attachment theory to complex social systems to promote social change. The idea of mentalizing communities is outlined with a proposal for three projects testing the model: ways to reduce bullying and create a peaceful climate in schools, projects to promote compassion in cities by a focus of end-of-life care, and a mentalization-based intervention into parenting style of borderline and substance abusing parents.

  17. Future time perspective, regulatory focus, and selection, optimization, and compensation: Testing a longitudinal model

    NARCIS (Netherlands)

    Baltes, B.B.; Wynne, K.; Sirabian, M.; Krenn, D.; Lange, A.H. de

    2014-01-01

    This study examines the behavioral processes through which future time perspective (FTP) and regulatory focus may influence coping behaviors in older workers. A three-wave longitudinal study was conducted to test a novel model, positing that FTP affects regulatory focus, which then influences the

  18. DREISS: Using State-Space Models to Infer the Dynamics of Gene Expression Driven by External and Internal Regulatory Networks

    Science.gov (United States)

    Gerstein, Mark

    2016-01-01

    Gene expression is controlled by the combinatorial effects of regulatory factors from different biological subsystems such as general transcription factors (TFs), cellular growth factors and microRNAs. A subsystem’s gene expression may be controlled by its internal regulatory factors, exclusively, or by external subsystems, or by both. It is thus useful to distinguish the degree to which a subsystem is regulated internally or externally–e.g., how non-conserved, species-specific TFs affect the expression of conserved, cross-species genes during evolution. We developed a computational method (DREISS, dreiss.gerteinlab.org) for analyzing the Dynamics of gene expression driven by Regulatory networks, both External and Internal based on State Space models. Given a subsystem, the “state” and “control” in the model refer to its own (internal) and another subsystem’s (external) gene expression levels. The state at a given time is determined by the state and control at a previous time. Because typical time-series data do not have enough samples to fully estimate the model’s parameters, DREISS uses dimensionality reduction, and identifies canonical temporal expression trajectories (e.g., degradation, growth and oscillation) representing the regulatory effects emanating from various subsystems. To demonstrate capabilities of DREISS, we study the regulatory effects of evolutionarily conserved vs. divergent TFs across distant species. In particular, we applied DREISS to the time-series gene expression datasets of C. elegans and D. melanogaster during their embryonic development. We analyzed the expression dynamics of the conserved, orthologous genes (orthologs), seeing the degree to which these can be accounted for by orthologous (internal) versus species-specific (external) TFs. We found that between two species, the orthologs have matched, internally driven expression patterns but very different externally driven ones. This is particularly true for genes with

  19. Mapping regulatory models for medicinal cannabis: a matrix of options.

    Science.gov (United States)

    Belackova, Vendula; Shanahan, Marian; Ritter, Alison

    2017-05-30

    Objective The aim of the present study was to develop a framework for assessing regulatory options for medicinal cannabis in Australia. Methods International regulatory regimes for medicinal cannabis were reviewed with a qualitative policy analysis approach and key policy features were synthesised, leading to a conceptual framework that facilitates decision making across multiple dimensions. Results Two central organising dimensions of medicinal cannabis regulation were identified: cannabis supply and patient authorisation (including patient access). A number of the different supply options can be matched with a number of different patient authorisation options, leading to a matrix of possible regulatory regimes. Conclusions The regulatory options, as used internationally, involve different forms of cannabis (synthetic and plant-based pharmaceutical preparations or herbal cannabis) and the varying extent to which patient authorisation policies and procedures are stringently or more loosely defined. The optimal combination of supply and patient authorisation options in any jurisdiction that chooses to make medicinal cannabis accessible will depend on policy goals. What is known about the topic? Internationally, regulation of medicinal cannabis has developed idiosyncratically, depending on formulations that were made available and local context. There has been no attempt to date in the scientific literature to systematically document the variety of regulatory possibilities for medicinal cannabis. What does this paper add? This paper presents a new conceptual schema for considering options for the regulation of medicinal cannabis, across both supply and patient authorisation aspects. What are the implications for practitioners? The design of regulatory systems in Australia, whether for pharmaceutical or herbal products, is a vital issue for policy makers right now as federal and state and territory governments grapple with the complexities of medicinal cannabis

  20. Developmental models for estimating ecological responses to environmental variability: structural, parametric, and experimental issues.

    Science.gov (United States)

    Moore, Julia L; Remais, Justin V

    2014-03-01

    Developmental models that account for the metabolic effect of temperature variability on poikilotherms, such as degree-day models, have been widely used to study organism emergence, range and development, particularly in agricultural and vector-borne disease contexts. Though simple and easy to use, structural and parametric issues can influence the outputs of such models, often substantially. Because the underlying assumptions and limitations of these models have rarely been considered, this paper reviews the structural, parametric, and experimental issues that arise when using degree-day models, including the implications of particular structural or parametric choices, as well as assumptions that underlie commonly used models. Linear and non-linear developmental functions are compared, as are common methods used to incorporate temperature thresholds and calculate daily degree-days. Substantial differences in predicted emergence time arose when using linear versus non-linear developmental functions to model the emergence time in a model organism. The optimal method for calculating degree-days depends upon where key temperature threshold parameters fall relative to the daily minimum and maximum temperatures, as well as the shape of the daily temperature curve. No method is shown to be universally superior, though one commonly used method, the daily average method, consistently provides accurate results. The sensitivity of model projections to these methodological issues highlights the need to make structural and parametric selections based on a careful consideration of the specific biological response of the organism under study, and the specific temperature conditions of the geographic regions of interest. When degree-day model limitations are considered and model assumptions met, the models can be a powerful tool for studying temperature-dependent development.

  1. A Developmental-Contextual Model of Depressive Symptoms in Mexican-Origin Female Adolescents

    Science.gov (United States)

    Bámaca-Colbert, Mayra Y.; Umaña-Taylor, Adriana J.; Gayles, Jochebed G.

    2011-01-01

    The current study tested a developmental-contextual model of depressive symptomatology among early and middle adolescent Mexican-origin females and their mothers. The final sample was comprised of 271 dyads. We examined the interrelations among cultural (i.e., acculturation dissonance), developmental (i.e., pubertal development and autonomy expectation discrepancies), and interpersonal (i.e., mother-daughter conflict and maternal supportive parenting) factors in predicting adolescents’ depressive symptoms. For both early and middle adolescents, maternal support was negatively associated with mother-daughter conflict and depressive symptoms. Importantly, mother-daughter autonomy expectation discrepancies were positively associated with mother-daughter conflict, but this association was found only among early adolescents. Further, mother-daughter acculturation dissonance was positively associated with mother-daughter conflict, but only among middle adolescents. Findings call for concurrently examining the interface of developmental, relational, and cultural factors in predicting female adolescents’ depressive symptomatology and the potential differences by developmental stage (e.g., early vs. middle adolescence) PMID:21967564

  2. Modeling winter moth Operophtera brumata egg phenology: nonlinear effects of temperature and developmental stage on developmental rate

    NARCIS (Netherlands)

    Salis, Lucia; Lof, Marjolein; Van Asch, M.; Visser, Marcel E.

    2016-01-01

    Understanding the relationship between an insect's developmental rate and temperature is crucial to forecast insect phenology under climate change. In the winter moth Operophtera brumata timing of egg-hatching has severe fitness consequences on growth and reproduction as egg-hatching has to match

  3. Different developmental trajectories across feature types support a dynamic field model of visual working memory development.

    Science.gov (United States)

    Simmering, Vanessa R; Miller, Hilary E; Bohache, Kevin

    2015-05-01

    Research on visual working memory has focused on characterizing the nature of capacity limits as "slots" or "resources" based almost exclusively on adults' performance with little consideration for developmental change. Here we argue that understanding how visual working memory develops can shed new light onto the nature of representations. We present an alternative model, the Dynamic Field Theory (DFT), which can capture effects that have been previously attributed either to "slot" or "resource" explanations. The DFT includes a specific developmental mechanism to account for improvements in both resolution and capacity of visual working memory throughout childhood. Here we show how development in the DFT can account for different capacity estimates across feature types (i.e., color and shape). The current paper tests this account by comparing children's (3, 5, and 7 years of age) performance across different feature types. Results showed that capacity for colors increased faster over development than capacity for shapes. A second experiment confirmed this difference across feature types within subjects, but also showed that the difference can be attenuated by testing memory for less familiar colors. Model simulations demonstrate how developmental changes in connectivity within the model-purportedly arising through experience-can capture differences across feature types.

  4. Development of QSAR models using artificial neural network analysis for risk assessment of repeated-dose, reproductive, and developmental toxicities of cosmetic ingredients.

    Science.gov (United States)

    Hisaki, Tomoka; Aiba Née Kaneko, Maki; Yamaguchi, Masahiko; Sasa, Hitoshi; Kouzuki, Hirokazu

    2015-04-01

    Use of laboratory animals for systemic toxicity testing is subject to strong ethical and regulatory constraints, but few alternatives are yet available. One possible approach to predict systemic toxicity of chemicals in the absence of experimental data is quantitative structure-activity relationship (QSAR) analysis. Here, we present QSAR models for prediction of maximum "no observed effect level" (NOEL) for repeated-dose, developmental and reproductive toxicities. NOEL values of 421 chemicals for repeated-dose toxicity, 315 for reproductive toxicity, and 156 for developmental toxicity were collected from Japan Existing Chemical Data Base (JECDB). Descriptors to predict toxicity were selected based on molecular orbital (MO) calculations, and QSAR models employing multiple independent descriptors as the input layer of an artificial neural network (ANN) were constructed to predict NOEL values. Robustness of the models was indicated by the root-mean-square (RMS) errors after 10-fold cross-validation (0.529 for repeated-dose, 0.508 for reproductive, and 0.558 for developmental toxicity). Evaluation of the models in terms of the percentages of predicted NOELs falling within factors of 2, 5 and 10 of the in-vivo-determined NOELs suggested that the model is applicable to both general chemicals and the subset of chemicals listed in International Nomenclature of Cosmetic Ingredients (INCI). Our results indicate that ANN models using in silico parameters have useful predictive performance, and should contribute to integrated risk assessment of systemic toxicity using a weight-of-evidence approach. Availability of predicted NOELs will allow calculation of the margin of safety, as recommended by the Scientific Committee on Consumer Safety (SCCS).

  5. Thyroid Hormone Disruption Effects Lamination of the Neocortex but not the Cerebellum in a Model of Developmental Hypothyroidism and Hypothyroxinemia

    Science.gov (United States)

    Introduction: Research on neurodevelopmental changes resulting from thyroid hormone (TH) disruption has important basic and clinical implications. We previously demonstrated, in a rodent model, that developmental hypothyroidism or hypothyroxinemia can cause ...

  6. Regulatory odour model development: Survey of modelling tools and datasets with focus on building effects

    DEFF Research Database (Denmark)

    Olesen, H. R.; Løfstrøm, P.; Berkowicz, R.

    dispersion models for estimating local concentration levels in general. However, the report focuses on some particular issues, which are relevant for subsequent work on odour due to animal production. An issue of primary concern is the effect that buildings (stables) have on flow and dispersion. The handling...... of building effects is a complicated problem, and a major part of the report is devoted to the treatment of building effects in dispersion models......A project within the framework of a larger research programme, Action Plan for the Aquatic Environment III (VMP III) aims towards improving an atmospheric dispersion model (OML). The OML model is used for regulatory applications in Denmark, and it is the candidate model to be used also in future...

  7. Recommendations for harmonization of data collection and analysis of developmental neurotoxicity endpoints in regulatory guideline studies: Proceedings of workshops presented at Society of Toxicology and joint Teratology Society and Neurobehavioral Teratology Society meetings.

    Science.gov (United States)

    Li, Abby A; Sheets, Larry P; Raffaele, Kathleen; Moser, Virginia; Hofstra, Angela; Hoberman, Alan; Makris, Susan L; Garman, Robert; Bolon, Brad; Kaufmann, Wolfgang; Auer, Roland; Lau, Edmund; Vidmar, Thomas; Bowers, Wayne J

    2017-09-01

    The potential for developmental neurotoxicity (DNT) of environmental chemicals may be evaluated using specific test guidelines from the US Environmental Protection Agency or the Organisation for Economic Cooperation and Development (OECD). These guidelines generate neurobehavioral, neuropathological, and morphometric data that are evaluated by regulatory agencies globally. Data from these DNT guideline studies, or the more recent OECD extended one-generation reproductive toxicity guideline, play a pivotal role in children's health risk assessment in different world areas. Data from the same study may be interpreted differently by regulatory authorities in different countries resulting in inconsistent evaluations that may lead to inconsistencies in risk assessment decisions internationally, resulting in regional differences in public health protection or in commercial trade barriers. These issues of data interpretation and reporting are also relevant to juvenile and pre-postnatal studies conducted more routinely for pharmaceuticals and veterinary medicines. There is a need for development of recommendations geared toward the operational needs of the regulatory scientific reviewers who apply these studies in risk assessments, as well as the scientists who generate DNT data sets. The workshops summarized here draw upon the experience of the authors representing government, industry, contract research organizations, and academia to discuss the scientific issues that have emerged from diverse regulatory evaluations. Although various regulatory bodies have different risk management decisions and labeling requirements that are difficult to harmonize, the workshops provided an opportunity to work toward more harmonized scientific approaches for evaluating DNT data within the context of different regulatory frameworks. Five speakers and their coauthors with neurotoxicology, neuropathology, and regulatory toxicology expertise discussed issues of variability, data reporting

  8. Multilevel linear modelling of the response-contingent learning of young children with significant developmental delays.

    Science.gov (United States)

    Raab, Melinda; Dunst, Carl J; Hamby, Deborah W

    2018-02-27

    The purpose of the study was to isolate the sources of variations in the rates of response-contingent learning among young children with multiple disabilities and significant developmental delays randomly assigned to contrasting types of early childhood intervention. Multilevel, hierarchical linear growth curve modelling was used to analyze four different measures of child response-contingent learning where repeated child learning measures were nested within individual children (Level-1), children were nested within practitioners (Level-2), and practitioners were nested within the contrasting types of intervention (Level-3). Findings showed that sources of variations in rates of child response-contingent learning were associated almost entirely with type of intervention after the variance associated with differences in practitioners nested within groups were accounted for. Rates of child learning were greater among children whose existing behaviour were used as the building blocks for promoting child competence (asset-based practices) compared to children for whom the focus of intervention was promoting child acquisition of missing skills (needs-based practices). The methods of analysis illustrate a practical approach to clustered data analysis and the presentation of results in ways that highlight sources of variations in the rates of response-contingent learning among young children with multiple developmental disabilities and significant developmental delays. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  9. A New Algorithm for Identifying Cis-Regulatory Modules Based on Hidden Markov Model

    Directory of Open Access Journals (Sweden)

    Haitao Guo

    2017-01-01

    Full Text Available The discovery of cis-regulatory modules (CRMs is the key to understanding mechanisms of transcription regulation. Since CRMs have specific regulatory structures that are the basis for the regulation of gene expression, how to model the regulatory structure of CRMs has a considerable impact on the performance of CRM identification. The paper proposes a CRM discovery algorithm called ComSPS. ComSPS builds a regulatory structure model of CRMs based on HMM by exploring the rules of CRM transcriptional grammar that governs the internal motif site arrangement of CRMs. We test ComSPS on three benchmark datasets and compare it with five existing methods. Experimental results show that ComSPS performs better than them.

  10. A New Algorithm for Identifying Cis-Regulatory Modules Based on Hidden Markov Model

    Science.gov (United States)

    2017-01-01

    The discovery of cis-regulatory modules (CRMs) is the key to understanding mechanisms of transcription regulation. Since CRMs have specific regulatory structures that are the basis for the regulation of gene expression, how to model the regulatory structure of CRMs has a considerable impact on the performance of CRM identification. The paper proposes a CRM discovery algorithm called ComSPS. ComSPS builds a regulatory structure model of CRMs based on HMM by exploring the rules of CRM transcriptional grammar that governs the internal motif site arrangement of CRMs. We test ComSPS on three benchmark datasets and compare it with five existing methods. Experimental results show that ComSPS performs better than them. PMID:28497059

  11. Modeling the developmental patterns of auditory evoked magnetic fields in children.

    Directory of Open Access Journals (Sweden)

    Rupesh Kotecha

    Full Text Available BACKGROUND: As magnetoencephalography (MEG is of increasing utility in the assessment of deficits and development delays in brain disorders in pediatrics, it becomes imperative to fully understand the functional development of the brain in children. METHODOLOGY: The present study was designed to characterize the developmental patterns of auditory evoked magnetic responses with respect to age and gender. Sixty children and twenty adults were studied with a 275-channel MEG system. CONCLUSIONS: Three main responses were identified at approximately 46 ms (M50, 71 ms (M70 and 106 ms (M100 in latency for children. The latencies of M70 and M100 shortened with age in both hemispheres; the latency of M50 shortened with age only in the right hemisphere. Analysis of developmental lateralization patterns in children showed that the latency of the right hemispheric evoked responses shortened faster than the corresponding left hemispheric responses. The latency of M70 in the right hemisphere highly correlated to the age of the child. The amplitudes of the M70 responses increased with age and reached their peaks in children 12-14 years of age, after which they decreased with age. The source estimates for the M50 and M70 responses indicated that they were generated in different subareas in the Heschl's gyrus in children, while not localizable in adults. Furthermore, gender also affected developmental patterns. The latency of M70 in the right hemisphere was proposed to be an index of auditory development in children, the modeling equation is 85.72-1.240xAge (yrs. Our results demonstrate that there is a clear developmental pattern in the auditory cortex and underscore the importance of M50 and M70 in the developing brain.

  12. Model for Service Delivery for Developmental Disorders in Low-Income Countries.

    Science.gov (United States)

    Hamdani, Syed Usman; Minhas, Fareed Aslam; Iqbal, Zafar; Rahman, Atif

    2015-12-01

    As in many low-income countries, the treatment gap for developmental disorders in rural Pakistan is near 100%. We integrated social, technological, and business innovations to develop and pilot a potentially sustainable service for children with developmental disorders in 1 rural area. Families with developmental disorders were identified through a mobile phone-based interactive voice response system, and organized into "Family Networks." "Champion" family volunteers were trained in evidence-based interventions. An Avatar-assisted Cascade Training and information system was developed to assist with training, implementation, monitoring, and supervision. In a population of ∼30,000, we successfully established 1 self-sustaining Family Network consisting of 10 trained champion family volunteers working under supervision of specialists, providing intervention to 70 families of children with developmental disorders. Each champion was responsible for training and providing ongoing support to 5 to 7 families from his or her village, and the families supported each other in management of their children. A pre-post evaluation of the program indicated that there was significant improvement in disability and socioemotional difficulties in the child, reduction in stigmatizing experiences, and greater family empowerment to seek services and community resources for the child. There was no change in caregivers' well-being. To replicate this service more widely, a social franchise model has been developed whereby the integrated intervention will be "boxed" up and passed on to others to replicate with appropriate support. Such integrated social, technological, and business innovations have the potential to be applied to other areas of health in low-income countries. Copyright © 2015 by the American Academy of Pediatrics.

  13. Coalescent models for developmental biology and the spatio-temporal dynamics of growing tissues.

    Science.gov (United States)

    Smadbeck, Patrick; Stumpf, Michael P H

    2016-04-01

    Development is a process that needs to be tightly coordinated in both space and time. Cell tracking and lineage tracing have become important experimental techniques in developmental biology and allow us to map the fate of cells and their progeny. A generic feature of developing and homeostatic tissues that these analyses have revealed is that relatively few cells give rise to the bulk of the cells in a tissue; the lineages of most cells come to an end quickly. Computational and theoretical biologists/physicists have, in response, developed a range of modelling approaches, most notably agent-based modelling. These models seem to capture features observed in experiments, but can also become computationally expensive. Here, we develop complementary genealogical models of tissue development that trace the ancestry of cells in a tissue back to their most recent common ancestors. We show that with both bounded and unbounded growth simple, but universal scaling relationships allow us to connect coalescent theory with the fractal growth models extensively used in developmental biology. Using our genealogical perspective, it is possible to study bulk statistical properties of the processes that give rise to tissues of cells, without the need for large-scale simulations. © 2016 The Authors.

  14. QSAR models for reproductive toxicity and endocrine disruption in regulatory use – a preliminary investigation

    DEFF Research Database (Denmark)

    Jensen, Gunde Egeskov; Niemelä, Jay Russell; Wedebye, Eva Bay

    2008-01-01

    the new legislation. This article focuses on a screening exercise by use of our own and commercial QSAR models for identification of possible reproductive toxicants. Three QSAR models were used for reproductive toxicity for the endpoints teratogenic risk to humans (based on animal tests, clinical data...... for humans owing to possible developmental toxic effects: Xn (Harmful) and R63 (Possible risk of harm to the unborn child). The chemicals were also screened in three models for endocrine disruption....

  15. Large-scale modeling of condition-specific gene regulatory networks by information integration and inference.

    Science.gov (United States)

    Ellwanger, Daniel Christian; Leonhardt, Jörn Florian; Mewes, Hans-Werner

    2014-12-01

    Understanding how regulatory networks globally coordinate the response of a cell to changing conditions, such as perturbations by shifting environments, is an elementary challenge in systems biology which has yet to be met. Genome-wide gene expression measurements are high dimensional as these are reflecting the condition-specific interplay of thousands of cellular components. The integration of prior biological knowledge into the modeling process of systems-wide gene regulation enables the large-scale interpretation of gene expression signals in the context of known regulatory relations. We developed COGERE (http://mips.helmholtz-muenchen.de/cogere), a method for the inference of condition-specific gene regulatory networks in human and mouse. We integrated existing knowledge of regulatory interactions from multiple sources to a comprehensive model of prior information. COGERE infers condition-specific regulation by evaluating the mutual dependency between regulator (transcription factor or miRNA) and target gene expression using prior information. This dependency is scored by the non-parametric, nonlinear correlation coefficient η(2) (eta squared) that is derived by a two-way analysis of variance. We show that COGERE significantly outperforms alternative methods in predicting condition-specific gene regulatory networks on simulated data sets. Furthermore, by inferring the cancer-specific gene regulatory network from the NCI-60 expression study, we demonstrate the utility of COGERE to promote hypothesis-driven clinical research. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  16. Preliminary Consideration for the Development of Regulatory Level 2 PSA Model

    International Nuclear Information System (INIS)

    Lee, Chang-Ju

    2006-01-01

    In order to assess the validity of PSA (probabilistic safety assessment) results and to establish regulatory requirements for relevant safety issues most of the regulators want to develop an independent and convenient risk assessment model including Level 2 PSA area. As this model and framework should be implicitly independent on the licensee's PSA model, it has a primary objective directly for applying to the risk-informed regulatory affairs and for supporting those kinds of works. According this, the regulator can take an objective view for the uncertainty of risk information made by the licensee and keep up the capability and decision-making framework for overall risk assessment results. In addition, the regulatory model may be used to verify and validate the operational risk levels of all engineered safety features of nuclear power plants (NPPs). An issue for plant-specific application of safety goals was previously identified in the US NRC's risk-informed regulatory guidance development activities, and discussed in many Commission papers, e. g. SECY-97-287, which identifies the goal for large early release frequency (LERF). LERF defines a containment performance criteria derived from the quantitative health objectives. As we know, the LERF was chosen to assess risk significance in Regulatory Guide 1.174 (2002) again, which provides one measure of the performance of the containment barrier, and represents a surrogate for early health effects

  17. Convective effects in a regulatory and proposed fire model

    International Nuclear Information System (INIS)

    Wix, S.D.; Hohnstreiter, G.F.

    1995-01-01

    Radiation is the dominant mode of heat transfer in large fires. However, convection can be as much as 10 to 20 percent of the total heat transfer to an object in a large fire. The current radioactive material transportation packaging regulations include convection as a mode of heat transfer in the accident condition scenario. The current International Atomic Energy Agency Safety Series 6 packaging regulation states ''the convection coefficient shall be that value which the designer can justify if the package were exposed to the specified fire''. The current Title 10, Code of Federal Regulations, Part 71 (10CFR71) packaging regulation states ''when significant, convection heat input must be included on the basis of still, ambient air at 800 degrees C (1475 degrees F)''. Two questions that can arise in an analysts mind from an examination of the packaging regulations is whether convection is significant and whether convection should be included in the design analysis of a radioactive materials transportation container. The objective of this study is to examine the convective effects on an actual radioactive materials transportation package using a regulatory and a proposed thermal boundary condition

  18. Mutual information and the fidelity of response of gene regulatory models

    International Nuclear Information System (INIS)

    Tabbaa, Omar P; Jayaprakash, C

    2014-01-01

    We investigate cellular response to extracellular signals by using information theory techniques motivated by recent experiments. We present results for the steady state of the following gene regulatory models found in both prokaryotic and eukaryotic cells: a linear transcription-translation model and a positive or negative auto-regulatory model. We calculate both the information capacity and the mutual information exactly for simple models and approximately for the full model. We find that (1) small changes in mutual information can lead to potentially important changes in cellular response and (2) there are diminishing returns in the fidelity of response as the mutual information increases. We calculate the information capacity using Gillespie simulations of a model for the TNF-α-NF-κ B network and find good agreement with the measured value for an experimental realization of this network. Our results provide a quantitative understanding of the differences in cellular response when comparing experimentally measured mutual information values of different gene regulatory models. Our calculations demonstrate that Gillespie simulations can be used to compute the mutual information of more complex gene regulatory models, providing a potentially useful tool in synthetic biology. (paper)

  19. Mining Gene Regulatory Networks by Neural Modeling of Expression Time-Series.

    Science.gov (United States)

    Rubiolo, Mariano; Milone, Diego H; Stegmayer, Georgina

    2015-01-01

    Discovering gene regulatory networks from data is one of the most studied topics in recent years. Neural networks can be successfully used to infer an underlying gene network by modeling expression profiles as times series. This work proposes a novel method based on a pool of neural networks for obtaining a gene regulatory network from a gene expression dataset. They are used for modeling each possible interaction between pairs of genes in the dataset, and a set of mining rules is applied to accurately detect the subjacent relations among genes. The results obtained on artificial and real datasets confirm the method effectiveness for discovering regulatory networks from a proper modeling of the temporal dynamics of gene expression profiles.

  20. The future of genome-scale modeling of yeast through integration of a transcriptional regulatory network

    DEFF Research Database (Denmark)

    Liu, Guodong; Marras, Antonio; Nielsen, Jens

    2014-01-01

    regulatory information is necessary to improve the accuracy and predictive ability of metabolic models. Here we review the strategies for the reconstruction of a transcriptional regulatory network (TRN) for yeast and the integration of such a reconstruction into a flux balance analysis-based metabolic model......Metabolism is regulated at multiple levels in response to the changes of internal or external conditions. Transcriptional regulation plays an important role in regulating many metabolic reactions by altering the concentrations of metabolic enzymes. Thus, integration of the transcriptional....... While many large-scale TRN reconstructions have been reported for yeast, these reconstructions still need to be improved regarding the functionality and dynamic property of the regulatory interactions. In addition, mathematical modeling approaches need to be further developed to efficiently integrate...

  1. A Field Study of Participant Reactions to a Developmental Assessment Centre: Testing an organisational justice model

    Directory of Open Access Journals (Sweden)

    Michael M Harris

    2008-06-01

    Full Text Available Although assessment centres are being increasingly employed for developmental purposes, there has been a dearth of research regarding them. We investigated an organisational justice theory model suggested by Cohen-Charash and Spector (2001 in this relatively novel context. The model included antecedents (e.g., perceived validity, organisational justice perceptions (i.e., distributive justice and procedural justice, and one outcome (i.e., feedback utility perceptions. Most of our hypotheses were supported, suggesting much evidence for this model. The predicted effect for perceived fakability was not supported. Contrary to our hypothesis, distributive justice perceptions were at least as important as procedural justice perceptions in predicting feedback utility perceptions. A direct test of the effect of context on organisational justice theory is recommended.

  2. The Alternative Peer Group: A Developmentally Appropriate Recovery Support Model for Adolescents.

    Science.gov (United States)

    Nash, Angela; Collier, Crystal

    2016-01-01

    Recovery as the goal for substance use disorder treatment has been a key component of the Substance Abuse and Mental Health Services Administration's mission for the past decade. Consistent with their mission, there is a call for research and development of recovery-oriented systems of care to support affected individuals through all stages of the recovery process. Evidence is emerging to support recovery practice and research for adults, but recovery-oriented models for adolescents are scant. The Alternative Peer Group (APG) is a comprehensive adolescent recovery support model that integrates recovering peers and prosocial activities into evidence-based clinical practice. Employing APG participants' own words, this article will describe the essential elements and three theoretical frameworks underlying the APG model to illustrate how the APG serves as a developmentally appropriate recovery support service for adolescents with substance use disorder.

  3. Human Inspired Self-developmental Model of Neural Network (HIM): Introducing Content/Form Computing

    Science.gov (United States)

    Krajíček, Jiří

    This paper presents cross-disciplinary research between medical/psychological evidence on human abilities and informatics needs to update current models in computer science to support alternative methods for computation and communication. In [10] we have already proposed hypothesis introducing concept of human information model (HIM) as cooperative system. Here we continue on HIM design in detail. In our design, first we introduce Content/Form computing system which is new principle of present methods in evolutionary computing (genetic algorithms, genetic programming). Then we apply this system on HIM (type of artificial neural network) model as basic network self-developmental paradigm. Main inspiration of our natural/human design comes from well known concept of artificial neural networks, medical/psychological evidence and Sheldrake theory of "Nature as Alive" [22].

  4. Virtual Embryo: Cell-Agent Based Modeling of Developmental Processes and Toxicities (CSS BOSC)

    Science.gov (United States)

    Spatial regulation of cellular dynamics is fundamental to morphological development. As such, chemical disruption of spatial dynamics is a determinant of developmental toxicity. Incorporating spatial dynamics into AOPs for developmental toxicity is desired but constrained by the ...

  5. Developmental vitamin D deficiency and schizophrenia: the role of animal models.

    Science.gov (United States)

    Schoenrock, S A; Tarantino, L M

    2016-01-01

    Schizophrenia is a debilitating neuropsychiatric disorder that affects 1% of the US population. Based on twin and genome-wide association studies, it is clear that both genetics and environmental factors increase the risk for developing schizophrenia. Moreover, there is evidence that conditions in utero, either alone or in concert with genetic factors, may alter neurodevelopment and lead to an increased risk for schizophrenia. There has been progress in identifying genetic loci and environmental exposures that increase risk, but there are still considerable gaps in our knowledge. Furthermore, very little is known about the specific neurodevelopmental mechanisms upon which genetics and the environment act to increase disposition to developing schizophrenia in adulthood. Vitamin D deficiency during the perinatal period has been hypothesized to increase risk for schizophrenia in humans. The developmental vitamin D (DVD) deficiency hypothesis of schizophrenia arises from the observation that disease risk is increased in individuals who are born in winter or spring, live further from the equator or live in urban vs. rural settings. These environments result in less exposure to sunlight, thereby reducing the initial steps in the production of vitamin D. Rodent models have been developed to characterize the behavioral and developmental effects of DVD deficiency. This review focuses on these animal models and discusses the current knowledge of the role of DVD deficiency in altering behavior and neurobiology relevant to schizophrenia. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  6. [Regulatory effect of Erbao granules on brain-gut peptide in juvenile animal model of anorexia].

    Science.gov (United States)

    Zhang, Y; Du, Y; Wang, S

    2000-10-01

    To study the regulatory effect of Erbao granules (EBG) on central and peripheral brain-gut peptide in juvenile animal model of anorexia. Juvenile rat model of anorexia was established by imitating the major cause of infantile anorexia and treated with EBG. The cholocystokinin-octapeptide (CCK-8) and beta-endorphin (beta-EP) concentration in hypothalamus, antrum pyloricum and peripheral blood were examined by radioimmunoassay. CCK-8 concentration in hypothalamus and plasma in the model rats increased (P anorexia model.

  7. Multivariate Hawkes process models of the occurrence of regulatory elements

    DEFF Research Database (Denmark)

    Carstensen, L; Sandelin, A; Winther, Ole

    2010-01-01

    distribution of the occurrences of these TREs along the genome. RESULTS: We present a model of TRE occurrences known as the Hawkes process. We illustrate the use of this model by analyzing two different publically available data sets. We are able to model, in detail, how the occurrence of one TRE is affected....... For each of the two data sets we provide two results: first, a qualitative description of the dependencies among the occurrences of the TREs, and second, quantitative results on the favored or avoided distances between the different TREs. CONCLUSIONS: The Hawkes process is a novel way of modeling the joint...

  8. Developmental transcriptome of Aplysia californica'

    KAUST Repository

    Heyland, Andreas; Vue, Zer; Voolstra, Christian R.; Medina, Mó nica; Moroz, Leonid L.

    2010-01-01

    developmental transcriptome with similar studies in the zebra fish Danio rerio, the fruit fly Drosophila melanogaster, the nematode Caenorhabditis elegans, and other studies on molluscs suggests an overall highly divergent pattern of gene regulatory mechanisms

  9. Quantitative model analysis with diverse biological data: applications in developmental pattern formation.

    Science.gov (United States)

    Pargett, Michael; Umulis, David M

    2013-07-15

    Mathematical modeling of transcription factor and signaling networks is widely used to understand if and how a mechanism works, and to infer regulatory interactions that produce a model consistent with the observed data. Both of these approaches to modeling are informed by experimental data, however, much of the data available or even acquirable are not quantitative. Data that is not strictly quantitative cannot be used by classical, quantitative, model-based analyses that measure a difference between the measured observation and the model prediction for that observation. To bridge the model-to-data gap, a variety of techniques have been developed to measure model "fitness" and provide numerical values that can subsequently be used in model optimization or model inference studies. Here, we discuss a selection of traditional and novel techniques to transform data of varied quality and enable quantitative comparison with mathematical models. This review is intended to both inform the use of these model analysis methods, focused on parameter estimation, and to help guide the choice of method to use for a given study based on the type of data available. Applying techniques such as normalization or optimal scaling may significantly improve the utility of current biological data in model-based study and allow greater integration between disparate types of data. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Network modeling reveals prevalent negative regulatory relationships between signaling sectors in Arabidopsis immune signaling.

    Directory of Open Access Journals (Sweden)

    Masanao Sato

    Full Text Available Biological signaling processes may be mediated by complex networks in which network components and network sectors interact with each other in complex ways. Studies of complex networks benefit from approaches in which the roles of individual components are considered in the context of the network. The plant immune signaling network, which controls inducible responses to pathogen attack, is such a complex network. We studied the Arabidopsis immune signaling network upon challenge with a strain of the bacterial pathogen Pseudomonas syringae expressing the effector protein AvrRpt2 (Pto DC3000 AvrRpt2. This bacterial strain feeds multiple inputs into the signaling network, allowing many parts of the network to be activated at once. mRNA profiles for 571 immune response genes of 22 Arabidopsis immunity mutants and wild type were collected 6 hours after inoculation with Pto DC3000 AvrRpt2. The mRNA profiles were analyzed as detailed descriptions of changes in the network state resulting from the genetic perturbations. Regulatory relationships among the genes corresponding to the mutations were inferred by recursively applying a non-linear dimensionality reduction procedure to the mRNA profile data. The resulting static network model accurately predicted 23 of 25 regulatory relationships reported in the literature, suggesting that predictions of novel regulatory relationships are also accurate. The network model revealed two striking features: (i the components of the network are highly interconnected; and (ii negative regulatory relationships are common between signaling sectors. Complex regulatory relationships, including a novel negative regulatory relationship between the early microbe-associated molecular pattern-triggered signaling sectors and the salicylic acid sector, were further validated. We propose that prevalent negative regulatory relationships among the signaling sectors make the plant immune signaling network a "sector

  11. Developmental hippocampal neuroplasticity in a model of nicotine replacement therapy during pregnancy and breastfeeding.

    Directory of Open Access Journals (Sweden)

    Ian Mahar

    Full Text Available The influence of developmental nicotine exposure on the brain represents an important health topic in light of the popularity of nicotine replacement therapy (NRT as a smoking cessation method during pregnancy.In this study, we used a model of NRT during pregnancy and breastfeeding to explore the consequences of chronic developmental nicotine exposure on cerebral neuroplasticity in the offspring. We focused on two dynamic lifelong phenomena in the dentate gyrus (DG of the hippocampus that are highly sensitive to the environment: granule cell neurogenesis and long-term potentiation (LTP.Pregnant rats were implanted with osmotic mini-pumps delivering either nicotine or saline solutions. Plasma nicotine and metabolite levels were measured in dams and offspring. Corticosterone levels, DG neurogenesis (cell proliferation, survival and differentiation and glutamatergic electrophysiological activity were measured in pups.Juvenile (P15 and adolescent (P41 offspring exposed to nicotine throughout prenatal and postnatal development displayed no significant alteration in DG neurogenesis compared to control offspring. However, NRT-like nicotine exposure significantly increased LTP in the DG of juvenile offspring as measured in vitro from hippocampal slices, suggesting that the mechanisms underlying nicotine-induced LTP enhancement previously described in adult rats are already functional in pups.These results indicate that synaptic plasticity is disrupted in offspring breastfed by dams passively exposed to nicotine in an NRT-like fashion.

  12. Aspects of Piaget's cognitive developmental psychology and neurobiology of psychotic disorders - an integrative model.

    Science.gov (United States)

    Gebhardt, Stefan; Grant, Phillip; von Georgi, Richard; Huber, Martin T

    2008-09-01

    Psychological, neurobiological and neurodevelopmental approaches have frequently been used to provide pathogenic concepts on psychotic disorders. However, aspects of cognitive developmental psychology have hardly been considered in current models. Using a hypothesis-generating approach an integration of these concepts was conducted. According to Piaget (1896-1980), assimilation and accommodation as forms of maintenance and modification of cognitive schemata represent fundamental processes of the brain. In general, based on the perceived input stimuli, cognitive schemata are developed resulting in a conception of the world, the realistic validity and the actuality of which is still being controlled and modified by cognitive adjustment processes. In psychotic disorders, however, a disproportion of environmental demands and the ability to activate required neuronal adaptation processes occurs. We therefore hypothesize a failure of the adjustment of real and requested output patterns. As a consequence autonomous cognitive schemata are generated, which fail to adjust with reality resulting in psychotic symptomatology. Neurobiological, especially neuromodulatory and neuroplastic processes play a central role in these perceptive and cognitive processes. In conclusion, integration of cognitive developmental psychology into the existing pathogenic concepts of psychotic disorders leads to interesting insights into basic disease mechanisms and also guides future research in the cognitive neuroscience of such disorders.

  13. A Julia set model of field-directed morphogenesis: developmental biology and artificial life.

    Science.gov (United States)

    Levin, M

    1994-04-01

    One paradigm used in understanding the control of morphogenetic events is the concept of positional information, where sub-organismic components (such as cells) act in response to positional cues. It is important to determine what kinds of spatiotemporal patterns may be obtained by such a method, and what the characteristics of such a morphogenetic process might be. This paper presents a computer model of morphogenesis based on gene activity driven by interpreting a positional information field. In this model, the interactions of mutually regulating developmental genes are viewed as a map from R2 to R2, and are modeled by the complex number algebra. Functions in complex variables are used to simulate genetic interactions resulting in position-dependent differentiation. This is shown to be equivalent to computing modified Julia sets, and is seen to be sufficient to produce a very rich set of morphologies which are similar in appearance and several important characteristics to those of real organisms. The properties of this model can be used to study the potential role of fields and positional information as guiding factors in morphogenesis, as the model facilitates the study of static images, time-series (movies) and experimental alterations of the developmental process. It is thus shown that gene interactions can be modeled as a multi-dimensional algebra, and that only two interacting genes are sufficient for (i) complex pattern formation, (ii) chaotic differentiation behavior, and (iii) production of sharp edges from a continuous positional information field. This model is meant to elucidate the properties of the process of positional information-guided biomorphogenesis, not to serve as a simulation of any particular organism's development. Good quantitative data are not currently available on the interplay of gene products in morphogenesis. Thus, no attempt is made to link the images produced with actual pictures of any particular real organism. A brief

  14. Assessing the Quality of Life of Persons with Developmental Disabilities: Description of a New Model, Measuring Instruments, and Initial Findings.

    Science.gov (United States)

    Raphael, Dennis; And Others

    1996-01-01

    A conceptual model of quality of life, developed at the Centre for Health Promotion at the University of Toronto (Canada), and associated instrumentation for collecting data from persons with developmental disabilities are presented. Results from a preliminary study with 41 participants support the reliability and validity of the model's…

  15. Psychometric Characteristics of a Measure of Emotional Dispositions Developed to Test a Developmental Propensity Model of Conduct Disorder

    Science.gov (United States)

    Lahey, Benjamin B.; Applegate, Brooks; Chronis, Andrea M.; Jones, Heather A.; Williams, Stephanie Hall; Loney, Jan; Waldman, Irwin D.

    2008-01-01

    Lahey and Waldman proposed a developmental propensity model in which three dimensions of children's emotional dispositions are hypothesized to transact with the environment to influence risk for conduct disorder, heterogeneity in conduct disorder, and comorbidity with other disorders. To prepare for future tests of this model, a new measure of…

  16. In silico modeling of epigenetic-induced changes in photoreceptor cis-regulatory elements.

    Science.gov (United States)

    Hossain, Reafa A; Dunham, Nicholas R; Enke, Raymond A; Berndsen, Christopher E

    2018-01-01

    DNA methylation is a well-characterized epigenetic repressor of mRNA transcription in many plant and vertebrate systems. However, the mechanism of this repression is not fully understood. The process of transcription is controlled by proteins that regulate recruitment and activity of RNA polymerase by binding to specific cis-regulatory sequences. Cone-rod homeobox (CRX) is a well-characterized mammalian transcription factor that controls photoreceptor cell-specific gene expression. Although much is known about the functions and DNA binding specificity of CRX, little is known about how DNA methylation modulates CRX binding affinity to genomic cis-regulatory elements. We used bisulfite pyrosequencing of human ocular tissues to measure DNA methylation levels of the regulatory regions of RHO , PDE6B, PAX6 , and LINE1 retrotransposon repeats. To describe the molecular mechanism of repression, we used molecular modeling to illustrate the effect of DNA methylation on human RHO regulatory sequences. In this study, we demonstrate an inverse correlation between DNA methylation in regulatory regions adjacent to the human RHO and PDE6B genes and their subsequent transcription in human ocular tissues. Docking of CRX to the DNA models shows that CRX interacts with the grooves of these sequences, suggesting changes in groove structure could regulate binding. Molecular dynamics simulations of the RHO promoter and enhancer regions show changes in the flexibility and groove width upon epigenetic modification. Models also demonstrate changes in the local dynamics of CRX binding sites within RHO regulatory sequences which may account for the repression of CRX-dependent transcription. Collectively, these data demonstrate epigenetic regulation of CRX binding sites in human retinal tissue and provide insight into the mechanism of this mode of epigenetic regulation to be tested in future experiments.

  17. Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities.

    Science.gov (United States)

    Teotia, Pooja; Van Hook, Matthew J; Wichman, Christopher S; Allingham, R Rand; Hauser, Michael A; Ahmad, Iqbal

    2017-11-01

    Glaucoma represents a group of multifactorial diseases with a unifying pathology of progressive retinal ganglion cell (RGC) degeneration, causing irreversible vision loss. To test the hypothesis that RGCs are intrinsically vulnerable in glaucoma, we have developed an in vitro model using the SIX6 risk allele carrying glaucoma patient-specific induced pluripotent stem cells (iPSCs) for generating functional RGCs. Here, we demonstrate that the efficiency of RGC generation by SIX6 risk allele iPSCs is significantly lower than iPSCs-derived from healthy, age- and sex-matched controls. The decrease in the number of RGC generation is accompanied by repressed developmental expression of RGC regulatory genes. The SIX6 risk allele RGCs display short and simple neurites, reduced expression of guidance molecules, and immature electrophysiological signature. In addition, these cells have higher expression of glaucoma-associated genes, CDKN2A and CDKN2B, suggesting an early onset of the disease phenotype. Consistent with the developmental abnormalities, the SIX6 risk allele RGCs display global dysregulation of genes which map on developmentally relevant biological processes for RGC differentiation and signaling pathways such as mammalian target of rapamycin that integrate diverse functions for differentiation, metabolism, and survival. The results suggest that SIX6 influences different stages of RGC differentiation and their survival; therefore, alteration in SIX6 function due to the risk allele may lead to cellular and molecular abnormalities. These abnormalities, if carried into adulthood, may make RGCs vulnerable in glaucoma. Stem Cells 2017;35:2239-2252. © 2017 AlphaMed Press.

  18. Application of the Self-Regulatory Model in Dealing with Encopresis.

    Science.gov (United States)

    Grimes, Lynn

    1983-01-01

    Behavioral techniques along with a self-regulation methodology were used successfully to decrease encopretic behaviors in a 9-year-old male. Kanfer's self-regulatory model appears to be generalizable to any child with the cognitive ability to understand that he or she has a problem and to make decisions about treatment. (Author/PN)

  19. A primer on thermodynamic-based models for deciphering transcriptional regulatory logic.

    Science.gov (United States)

    Dresch, Jacqueline M; Richards, Megan; Ay, Ahmet

    2013-09-01

    A rigorous analysis of transcriptional regulation at the DNA level is crucial to the understanding of many biological systems. Mathematical modeling has offered researchers a new approach to understanding this central process. In particular, thermodynamic-based modeling represents the most biophysically informed approach aimed at connecting DNA level regulatory sequences to the expression of specific genes. The goal of this review is to give biologists a thorough description of the steps involved in building, analyzing, and implementing a thermodynamic-based model of transcriptional regulation. The data requirements for this modeling approach are described, the derivation for a specific regulatory region is shown, and the challenges and future directions for the quantitative modeling of gene regulation are discussed. Copyright © 2013 Elsevier B.V. All rights reserved.

  20. Evaluation of Urban air quality models for regulatory use: Refinement of an approach

    International Nuclear Information System (INIS)

    Downton, M.W.; Dennis, R.L.

    1985-01-01

    Statistical measures for evaluating the performance of urban air quality models have recently been strongly recommended by several investigators. Problems that were encountered in the use of recommended performance measures in an evaluation of three versions of an urban photochemical model are described. The example demonstrates the importance of designing an evaluation to take into account the way in which the model will be used in regulatory practice, and then choosing performance measures on the basis of that design. The evaluation illustrates some limitations and possible pitfalls in the use and interpretation of statistical measures of model performance. Drawing on this experience, a procedure for evaluation of air quality models for regulatory use is suggested

  1. Bayesian error analysis model for reconstructing transcriptional regulatory networks

    OpenAIRE

    Sun, Ning; Carroll, Raymond J.; Zhao, Hongyu

    2006-01-01

    Transcription regulation is a fundamental biological process, and extensive efforts have been made to dissect its mechanisms through direct biological experiments and regulation modeling based on physical–chemical principles and mathematical formulations. Despite these efforts, transcription regulation is yet not well understood because of its complexity and limitations in biological experiments. Recent advances in high throughput technologies have provided substantial amounts and diverse typ...

  2. The European Model Company Act: How to choose an efficient regulatory approach?

    DEFF Research Database (Denmark)

    Cleff, Evelyne Beatrix

    ) on the organization of company laws reflect an interesting paradigm shift. Whereas, previously company law was primarily focused on preventing abuse, there is now a trend towards legislation that promote commerce and satisfy the needs of business. This means that the goal of economic efficiency is having...... an increasing influence on the framing of company legislation, such as the choice between mandatory or default rules. This article introduces the project "European Company Law and the choice of Regulatory Method" which is carried out in collaboration with the European Model Company Act Group. The project aims...... to analyze the appropriateness of different regulatory methods which are available to achieve the regulatory goals.   ...

  3. Canadian and United States regulatory models compared: doses from atmospheric pathways

    International Nuclear Information System (INIS)

    Peterson, S-R.

    1997-01-01

    CANDU reactors sold offshore are licensed primarily to satisfy Canadian Regulations. For radioactive emissions during normal operation, the Canadian Standards Association's CAN/CSA-N288.1-M87 is used. This standard provides guidelines and methodologies for calculating a rate of radionuclide release that exposes a member of the public to the annual dose limit. To calculate doses from air concentrations, either CSA-N288.1 or the Regulatory Guide 1.109 of the United States Nuclear Regulatory Commission, which has already been used to license light-water reactors in these countries, may be used. When dose predictions from CSA-N288.1 are compared with those from the U.S. Regulatory Guides, the differences in projected doses raise questions about the predictions. This report explains differences between the two models for ingestion, inhalation, external and immersion doses

  4. Ontogeny and physiognomy of the epigenetic landscape: A general model to explain developmental systems

    International Nuclear Information System (INIS)

    Tamayo Orrego, Lukas

    2013-01-01

    The epigenetic landscape is a graphic metaphor proposed by Conrad H. Waddington to explain the development of organisms and their parts. it is depicted as a wavy surface with summits and descending valleys, representing the paths followed by cells along their differentiation process, as part of organismal development. Conrad H. Waddington, regarded as the father of epigenetics, stands out for his theoretical contributions that include the notions of genetic assimilation, canalization of development and epi-genotype. These ideas were inspired by experimental works in developmental biology that lead to the discovery of the organizer in bird embryos, as well as environmentally-induced phenocopies in drosophila. In the current essay, I present an interpretation of the epigenetic landscape and related concepts that highlight the heuristic power of this model and its importance for contemporary biology. This work is a tribute to the life of C. H. Waddington, whose work is still of great significance.

  5. Precursors of adolescent substance use from early childhood and early adolescence: testing a developmental cascade model.

    Science.gov (United States)

    Sitnick, Stephanie L; Shaw, Daniel S; Hyde, Luke W

    2014-02-01

    This study examined developmentally salient risk and protective factors of adolescent substance use assessed during early childhood and early adolescence using a sample of 310 low-income boys. Child problem behavior and proximal family risk and protective factors (i.e., parenting and maternal depression) during early childhood, as well as child and family factors and peer deviant behavior during adolescence, were explored as potential precursors to later substance use during adolescence using structural equation modeling. Results revealed that early childhood risk and protective factors (i.e., child externalizing problems, mothers' depressive symptomatology, and nurturant parenting) were indirectly related to substance use at the age of 17 via risk and protective factors during early and middle adolescence (i.e., parental knowledge and externalizing problems). The implications of these findings for early prevention and intervention are discussed.

  6. [Sporulation or competence development? A genetic regulatory network model of cell-fate determination in Bacillus subtilis].

    Science.gov (United States)

    Lu, Zhenghui; Zhou, Yuling; Zhang, Xiaozhou; Zhang, Guimin

    2015-11-01

    Bacillus subtilis is a generally recognized as safe (GRAS) strain that has been widely used in industries including fodder, food, and biological control. In addition, B. subtilis expression system also plays a significant role in the production of industrial enzymes. However, its application is limited by its low sporulation frequency and transformation efficiency. Immense studies have been done on interpreting the molecular mechanisms of sporulation and competence development, whereas only few of them were focused on improving sporulation frequency and transformation efficiency of B. subtilis by genetic modification. The main challenge is that sporulation and competence development, as the two major developmental events in the stationary phase of B. subtilis, are regulated by the complicated intracellular genetic regulatory systems. In addition, mutual regulatory mechanisms also exist in these two developmental events. With the development of genetic and metabolic engineering, constructing genetic regulatory networks is currently one of the most attractive research fields, together with the genetic information of cell growth, metabolism, and development, to guide the industrial application. In this review, the mechanisms of sporulation and competence development of B. subtilis, their interactions, and the genetic regulation of cell growth were interpreted. In addition, the roles of these regulatory networks in guiding basic and applied research of B. subtilis and its related species were discussed.

  7. Phonological deficits in specific language impairment and developmental dyslexia: towards a multidimensional model

    Science.gov (United States)

    Ramus, Franck; Marshall, Chloe R.; Rosen, Stuart

    2013-01-01

    An on-going debate surrounds the relationship between specific language impairment and developmental dyslexia, in particular with respect to their phonological abilities. Are these distinct disorders? To what extent do they overlap? Which cognitive and linguistic profiles correspond to specific language impairment, dyslexia and comorbid cases? At least three different models have been proposed: the severity model, the additional deficit model and the component model. We address this issue by comparing children with specific language impairment only, those with dyslexia-only, those with specific language impairment and dyslexia and those with no impairment, using a broad test battery of language skills. We find that specific language impairment and dyslexia do not always co-occur, and that some children with specific language impairment do not have a phonological deficit. Using factor analysis, we find that language abilities across the four groups of children have at least three independent sources of variance: one for non-phonological language skills and two for distinct sets of phonological abilities (which we term phonological skills versus phonological representations). Furthermore, children with specific language impairment and dyslexia show partly distinct profiles of phonological deficit along these two dimensions. We conclude that a multiple-component model of language abilities best explains the relationship between specific language impairment and dyslexia and the different profiles of impairment that are observed. PMID:23413264

  8. Dual Processes in Decision Making and Developmental Neuroscience: A Fuzzy-Trace Model.

    Science.gov (United States)

    Reyna, Valerie F; Brainerd, Charles J

    2011-09-01

    From Piaget to the present, traditional and dual-process theories have predicted improvement in reasoning from childhood to adulthood, and improvement has been observed. However, developmental reversals-that reasoning biases emerge with development -have also been observed in a growing list of paradigms. We explain how fuzzy-trace theory predicts both improvement and developmental reversals in reasoning and decision making. Drawing on research on logical and quantitative reasoning, as well as on risky decision making in the laboratory and in life, we illustrate how the same small set of theoretical principles apply to typical neurodevelopment, encompassing childhood, adolescence, and adulthood, and to neurological conditions such as autism and Alzheimer's disease. For example, framing effects-that risk preferences shift when the same decisions are phrases in terms of gains versus losses-emerge in early adolescence as gist-based intuition develops. In autistic individuals, who rely less on gist-based intuition and more on verbatim-based analysis, framing biases are attenuated (i.e., they outperform typically developing control subjects). In adults, simple manipulations based on fuzzy-trace theory can make framing effects appear and disappear depending on whether gist-based intuition or verbatim-based analysis is induced. These theoretical principles are summarized and integrated in a new mathematical model that specifies how dual modes of reasoning combine to produce predictable variability in performance. In particular, we show how the most popular and extensively studied model of decision making-prospect theory-can be derived from fuzzy-trace theory by combining analytical (verbatim-based) and intuitive (gist-based) processes.

  9. Dual Processes in Decision Making and Developmental Neuroscience: A Fuzzy-Trace Model

    Science.gov (United States)

    Reyna, Valerie F.; Brainerd, Charles J.

    2011-01-01

    From Piaget to the present, traditional and dual-process theories have predicted improvement in reasoning from childhood to adulthood, and improvement has been observed. However, developmental reversals—that reasoning biases emerge with development —have also been observed in a growing list of paradigms. We explain how fuzzy-trace theory predicts both improvement and developmental reversals in reasoning and decision making. Drawing on research on logical and quantitative reasoning, as well as on risky decision making in the laboratory and in life, we illustrate how the same small set of theoretical principles apply to typical neurodevelopment, encompassing childhood, adolescence, and adulthood, and to neurological conditions such as autism and Alzheimer's disease. For example, framing effects—that risk preferences shift when the same decisions are phrases in terms of gains versus losses—emerge in early adolescence as gist-based intuition develops. In autistic individuals, who rely less on gist-based intuition and more on verbatim-based analysis, framing biases are attenuated (i.e., they outperform typically developing control subjects). In adults, simple manipulations based on fuzzy-trace theory can make framing effects appear and disappear depending on whether gist-based intuition or verbatim-based analysis is induced. These theoretical principles are summarized and integrated in a new mathematical model that specifies how dual modes of reasoning combine to produce predictable variability in performance. In particular, we show how the most popular and extensively studied model of decision making—prospect theory—can be derived from fuzzy-trace theory by combining analytical (verbatim-based) and intuitive (gist-based) processes. PMID:22096268

  10. Developmental stress elicits preference for methamphetamine in the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder.

    Science.gov (United States)

    Womersley, Jacqueline S; Mpeta, Bafokeng; Dimatelis, Jacqueline J; Kellaway, Lauriston A; Stein, Dan J; Russell, Vivienne A

    2016-06-17

    Developmental stress has been hypothesised to interact with genetic predisposition to increase the risk of developing substance use disorders. Here we have investigated the effects of maternal separation-induced developmental stress using a behavioural proxy of methamphetamine preference in an animal model of attention-deficit/hyperactivity disorder, the spontaneously hypertensive rat, versus Wistar Kyoto and Sprague-Dawley comparator strains. Analysis of results obtained using a conditioned place preference paradigm revealed a significant strain × stress interaction with maternal separation inducing preference for the methamphetamine-associated compartment in spontaneously hypertensive rats. Maternal separation increased behavioural sensitization to the locomotor-stimulatory effects of methamphetamine in both spontaneously hypertensive and Sprague-Dawley strains but not in Wistar Kyoto rats. Our findings indicate that developmental stress in a genetic rat model of attention-deficit/hyperactivity disorder may foster a vulnerability to the development of substance use disorders.

  11. An Organismal Model for Gene Regulatory Networks in the Gut-Associated Immune Response

    Directory of Open Access Journals (Sweden)

    Katherine M. Buckley

    2017-10-01

    Full Text Available The gut epithelium is an ancient site of complex communication between the animal immune system and the microbial world. While elements of self-non-self receptors and effector mechanisms differ greatly among animal phyla, some aspects of recognition, regulation, and response are broadly conserved. A gene regulatory network (GRN approach provides a means to investigate the nature of this conservation and divergence even as more peripheral functional details remain incompletely understood. The sea urchin embryo is an unparalleled experimental model for detangling the GRNs that govern embryonic development. By applying this theoretical framework to the free swimming, feeding larval stage of the purple sea urchin, it is possible to delineate the conserved regulatory circuitry that regulates the gut-associated immune response. This model provides a morphologically simple system in which to efficiently unravel regulatory connections that are phylogenetically relevant to immunity in vertebrates. Here, we review the organism-wide cellular and transcriptional immune response of the sea urchin larva. A large set of transcription factors and signal systems, including epithelial expression of interleukin 17 (IL17, are important mediators in the activation of the early gut-associated response. Many of these have homologs that are active in vertebrate immunity, while others are ancient in animals but absent in vertebrates or specific to echinoderms. This larval model provides a means to experimentally characterize immune function encoded in the sea urchin genome and the regulatory interconnections that control immune response and resolution across the tissues of the organism.

  12. TIGER: Toolbox for integrating genome-scale metabolic models, expression data, and transcriptional regulatory networks

    Directory of Open Access Journals (Sweden)

    Jensen Paul A

    2011-09-01

    Full Text Available Abstract Background Several methods have been developed for analyzing genome-scale models of metabolism and transcriptional regulation. Many of these methods, such as Flux Balance Analysis, use constrained optimization to predict relationships between metabolic flux and the genes that encode and regulate enzyme activity. Recently, mixed integer programming has been used to encode these gene-protein-reaction (GPR relationships into a single optimization problem, but these techniques are often of limited generality and lack a tool for automating the conversion of rules to a coupled regulatory/metabolic model. Results We present TIGER, a Toolbox for Integrating Genome-scale Metabolism, Expression, and Regulation. TIGER converts a series of generalized, Boolean or multilevel rules into a set of mixed integer inequalities. The package also includes implementations of existing algorithms to integrate high-throughput expression data with genome-scale models of metabolism and transcriptional regulation. We demonstrate how TIGER automates the coupling of a genome-scale metabolic model with GPR logic and models of transcriptional regulation, thereby serving as a platform for algorithm development and large-scale metabolic analysis. Additionally, we demonstrate how TIGER's algorithms can be used to identify inconsistencies and improve existing models of transcriptional regulation with examples from the reconstructed transcriptional regulatory network of Saccharomyces cerevisiae. Conclusion The TIGER package provides a consistent platform for algorithm development and extending existing genome-scale metabolic models with regulatory networks and high-throughput data.

  13. Transgenic Mouse Models Transferred into the Test Tube: New Perspectives for Developmental Toxicity Testing In Vitro?

    Science.gov (United States)

    Kugler, Josephine; Luch, Andreas; Oelgeschläger, Michael

    2016-10-01

    Despite our increasing understanding of molecular mechanisms controlling embryogenesis, the identification and characterization of teratogenic substances still heavily relies on animal testing. Embryonic development depends on cell-autonomous and non-autonomous processes including spatiotemporally regulated extracellular signaling activities. These have been elucidated in transgenic mouse models harboring easily detectable reporter genes under the control of evolutionarily conserved signaling cascades. We propose combining these transgenic mouse models and cells derived thereof with existing alternative toxicological testing strategies. This would enable the plausibility of in vitro data to be verified in light of in vivo data and, ultimately, facilitate regulatory acceptance of in vitro test methods. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Modeling the autistic cell: iPSCs recapitulate developmental principles of syndromic and nonsyndromic ASD.

    Science.gov (United States)

    Ben-Reuven, Lihi; Reiner, Orly

    2016-06-01

    The opportunity to model autism spectrum disorders (ASD) through generation of patient-derived induced pluripotent stem cells (iPSCs) is currently an emerging topic. Wide-scale research of altered brain circuits in syndromic ASD, including Rett Syndrome, Fragile X Syndrome, Angelman's Syndrome and sporadic Schizophrenia, was made possible through animal models. However, possibly due to species differences, and to the possible contribution of epigenetics in the pathophysiology of these diseases, animal models fail to recapitulate many aspects of ASD. With the advent of iPSCs technology, 3D cultures of patient-derived cells are being used to study complex neuronal phenotypes, including both syndromic and nonsyndromic ASD. Here, we review recent advances in using iPSCs to study various aspects of the ASD neuropathology, with emphasis on the efforts to create in vitro model systems for syndromic and nonsyndromic ASD. We summarize the main cellular activity phenotypes and aberrant genetic interaction networks that were found in iPSC-derived neurons of syndromic and nonsyndromic autistic patients. © 2016 Japanese Society of Developmental Biologists.

  15. Developmental Impact Analysis of an ICT-Enabled Scalable Healthcare Model in BRICS Economies

    Directory of Open Access Journals (Sweden)

    Dhrubes Biswas

    2012-06-01

    Full Text Available This article highlights the need for initiating a healthcare business model in a grassroots, emerging-nation context. This article’s backdrop is a history of chronic anomalies afflicting the healthcare sector in India and similarly placed BRICS nations. In these countries, a significant percentage of populations remain deprived of basic healthcare facilities and emergency services. Community (primary care services are being offered by public and private stakeholders as a panacea to the problem. Yet, there is an urgent need for specialized (tertiary care services at all levels. As a response to this challenge, an all-inclusive health-exchange system (HES model, which utilizes information communication technology (ICT to provide solutions in rural India, has been developed. The uniqueness of the model lies in its innovative hub-and-spoke architecture and its emphasis on affordability, accessibility, and availability to the masses. This article describes a developmental impact analysis (DIA that was used to assess the impact of this model. The article contributes to the knowledge base of readers by making them aware of the healthcare challenges emerging nations are facing and ways to mitigate those challenges using entrepreneurial solutions.

  16. Integrating family work into the treatment of young people with severe and complex depression: a developmentally focused model.

    Science.gov (United States)

    Rice, Simon; Halperin, Stephen; Blaikie, Simon; Monson, Katherine; Stefaniak, Rachel; Phelan, Mark; Davey, Christopher

    2018-04-01

    Although models of family intervention are clearly articulated in the child and early adolescent literature, there is less clarity regarding family intervention approaches in later adolescence and emerging adulthood. This study provides the rationale and intervention framework for a developmentally sensitive model of time-limited family work in the outpatient treatment of complex youth depression (15-25 years). Derived from current practice in the Youth Mood Clinic (YMC) at Orygen Youth Health, Melbourne, a stepped model of family intervention is discussed. YMC aims to provide comprehensive orientation, assessment and education to all families. For some, a family-based intervention, delivered either by the treating team or through the integration of a specialist family worker, offers an important adjunct in supporting the recovery of the young person. Developmental phases and challenges experienced by the young person with respect to family/caregiver involvement are discussed in the context of two case studies. A developmentally sensitive model is presented with particular attention to the developmental needs and preferences of young people. Formal evaluation of this model is required. Evaluation perspectives should include young people, caregivers, the broader family system (i.e. siblings) and the treating team (i.e. case manager, doctor and family worker) incorporating outcome measurement. Such work determines how best to apply a time-limited family-based intervention approach in strengthening family/caregiver relationships as part of the young person's recovery from severe and complex depression. © 2016 John Wiley & Sons Australia, Ltd.

  17. Concentration change of DA, DOPAC, Glu and GABA in brain tissues in schizophrenia developmental model rats induced by MK-801.

    Science.gov (United States)

    Liu, Yong; Tang, Yamei; Pu, Weidan; Zhang, Xianghui; Zhao, Jingping

    2011-08-01

    To explore the related neurobiochemical mechanism by comparing the concentration change of dopamine (DA), dihydroxy-phenyl acetic acid (DOPAC), glutamate (Glu), and γ-aminobutyric acid (GABA) in the brain tissues in schizophrenia (SZ) developmental model rats and chronic medication model rats. A total of 60 neonatal male Spragur-Dawley (SD) rats were randomly assigned to 3 groups at the postnatal day 6: an SZ developmental rat model group (subcutaneous injection with MK-801 at the postnatal day 7-10, 0.1 mg/kg, Bid), a chronic medication model group (intraperitoneal injection at the postnatal day 47-60, 0.2 mg/kg,Qd), and a normal control group (injection with 0.9% normal saline during the corresponding periods). DA, DOPAC, Glu, and GABA of the tissue homogenate from the medial prefrontal cortex (mPFC) and hippocampus were examined with Coularray electrochemic detection by high performance liquid chromatogram technique. The utilization rate of DA and Glu was calculated. Compared with the normal control group, the concentration of DA and DOPAC in the mPFC and the hippocampus in the SZ developmental model group significantly decreased (PGABA concentration and Glu utilization rate in the mPFC also decreased (PGABA system decrease in the mPFC and the DA system function reduces in the hippocampus of SZ developmental rats.

  18. Developmental neurotoxicity of the organophosphorus insecticide chlorpyrifos: from clinical findings to preclinical models and potential mechanisms.

    Science.gov (United States)

    Burke, Richard D; Todd, Spencer W; Lumsden, Eric; Mullins, Roger J; Mamczarz, Jacek; Fawcett, William P; Gullapalli, Rao P; Randall, William R; Pereira, Edna F R; Albuquerque, Edson X

    2017-08-01

    Organophosphorus (OP) insecticides are pest-control agents heavily used worldwide. Unfortunately, they are also well known for the toxic effects that they can trigger in humans. Clinical manifestations of an acute exposure of humans to OP insecticides include a well-defined cholinergic crisis that develops as a result of the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that hydrolyzes the neurotransmitter acetylcholine (ACh). Prolonged exposures to levels of OP insecticides that are insufficient to trigger signs of acute intoxication, which are hereafter referred to as subacute exposures, have also been associated with neurological deficits. In particular, epidemiological studies have reported statistically significant correlations between prenatal subacute exposures to OP insecticides, including chlorpyrifos, and neurological deficits that range from cognitive impairments to tremors in childhood. The primary objectives of this article are: (i) to address the short- and long-term neurological issues that have been associated with acute and subacute exposures of humans to OP insecticides, especially early in life (ii) to discuss the translational relevance of animal models of developmental exposure to OP insecticides, and (iii) to review mechanisms that are likely to contribute to the developmental neurotoxicity of OP insecticides. Most of the discussion will be focused on chlorpyrifos, the top-selling OP insecticide in the United States and throughout the world. These points are critical for the identification and development of safe and effective interventions to counter and/or prevent the neurotoxic effects of these chemicals in the developing brain. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms. © 2017 International Society for Neurochemistry.

  19. Ecological models in support of regulatory risk assessments of pesticides: developing a strategy for the future.

    Science.gov (United States)

    Forbes, Valery E; Hommen, Udo; Thorbek, Pernille; Heimbach, Fred; Van den Brink, Paul J; Wogram, Jörn; Thulke, Hans-Hermann; Grimm, Volker

    2009-01-01

    This brief communication reports on the main findings of the LEMTOX workshop, held from 9 to 12 September 2007, at the Helmholtz Centre for Environmental Research (UFZ) in Leipzig, Germany. The workshop brought together a diverse group of stakeholders from academia, regulatory authorities, contract research organizations, and industry, representing Europe, the United States, and Asia, to discuss the role of ecological modeling in risk assessments of pesticides, particularly under the European regulatory framework. The following questions were addressed: What are the potential benefits of using ecological models in pesticide registration and risk assessment? What obstacles prevent ecological modeling from being used routinely in regulatory submissions? What actions are needed to overcome the identified obstacles? What recommendations should be made to ensure good modeling practice in this context? The workshop focused exclusively on population models, and discussion was focused on those categories of population models that link effects on individuals (e.g., survival, growth, reproduction, behavior) to effects on population dynamics. The workshop participants concluded that the overall benefits of ecological modeling are that it could bring more ecology into ecological risk assessment, and it could provide an excellent tool for exploring the importance of, and interactions among, ecological complexities. However, there are a number of challenges that need to be overcome before such models will receive wide acceptance for pesticide risk assessment, despite having been used extensively in other contexts (e.g., conservation biology). The need for guidance on Good Modeling Practice (on model development, analysis, interpretation, evaluation, documentation, and communication), as well as the need for case studies that can be used to explore the added value of ecological models for risk assessment, were identified as top priorities. Assessing recovery potential of exposed

  20. Neural progenitor cells as models for high-throughput screens of developmental neurotoxicity: State of the science

    NARCIS (Netherlands)

    Breier, J.M.; Gassmann, K.; Kayser, R.; Stegeman, H.; Groot, D.de; Fritsche, E.; Shafer, T.J.

    2010-01-01

    In vitro, high-throughput methods have been widely recommended as an approach to screen chemicals for the potential to cause developmental neurotoxicity and prioritize them for additional testing. The choice of cellular models for such an approach will have important ramifications for the accuracy,

  1. Induced pluripotent stem cell-derived neuron as a human model for testing environmentally induced developmental neurotoxicity

    Science.gov (United States)

    Induced pluripotent stem cell-derived neurons as a human model for testing environmentally induced developmental neurotoxicity Ingrid L. Druwe1, Timothy J. Shafer2, Kathleen Wallace2, Pablo Valdivia3 ,and William R. Mundy2. 1University of North Carolina, Curriculum in Toxicology...

  2. How an Evolution View of Workplace Mentoring Relationships Helps Avoid Negative Experiences: The Developmental Relationship Mentoring Model in Action

    Science.gov (United States)

    Washington, Rhianon; Cox, Elaine

    2016-01-01

    In this paper, we explore how the use of a specific mentoring model focusing on the evolution of the relationship between mentor and mentee, may influence the incidence of failure. In our research we employed a case study methodology to examine a regional public service mentoring scheme in the UK where a developmental relationship mentoring model…

  3. Effects of Video Self-Modeling on Eliminating Public Undressing by Elementary-Aged Students with Developmental Disabilities during Urination

    Science.gov (United States)

    Ohtake, Yoshihisa; Takeuchi, Ai; Watanabe, Kentaro

    2014-01-01

    This study investigated the effectiveness of video self-modeling (VSM) for eliminating the public undressing of two elementary-aged students with developmental disabilities during urination. A multiple-probe design across participants revealed that the degree of exposed body parts decreased immediately after introduction of VSM. However, exposure…

  4. Understanding Random Effects in Group-Based Trajectory Modeling: An Application of Moffitt’s Developmental Taxonomy

    OpenAIRE

    Saunders, Jessica M.

    2010-01-01

    The group-based trajectory modeling approach is a systematic way of categorizing subjects into different groups based on their developmental trajectories using formal and objective statistical criteria. With the recent advancement in methods and statistical software, modeling possibilities are almost limitless; however, parallel advances in theory development have not kept pace. This paper examines some of the modeling options that are becoming more widespread and how they impact both empiric...

  5. The Quick Peek Program: A Model for Developmental Screening within Underserved Communities

    Science.gov (United States)

    Harris, Jill; Norton, Amy

    2016-01-01

    Developmental screening of young children is important in all populations, especially underserved communities with known health care disparities. The American Academy of Pediatrics created guidelines and a toolkit for pediatricians to conduct developmental surveillance and screening, yet these guidelines are not uniformly implemented within…

  6. REGULATORY POLICY AND OPTIMIZATION OF INVESTMENT RESOURCE ALLOCATION IN THE MODEL OF FUNCTIONING OF RECREATION INDUSTRY

    Directory of Open Access Journals (Sweden)

    Hanna Shevchenko

    2017-11-01

    Full Text Available The research objective is the rationale of the theoretical and methodical approach concerning the improvement of regulatory policy as well as the process of distribution of financial investments using the model of the functioning of a recreational sector of the national economy. The methodology of the study includes the use of optimal control theory for the model formation of the functioning of the recreational industry as well as determining the behaviour of regulatory authorities and capabilities to optimize the allocation of investment resources in the recreational sector of the national economy. Results. The issue of equilibration of regulatory policy in the recreational sector of the national economy is actualized, including the question of targeted distribution of state and external financial investments. Also, it is proved that regulatory policy should establish the frameworks that on the one hand, do not allow public authorities to exercise extra influence on the economy of recreation, on the other hand, to keep the behaviour of the recreational business entities within the limits of normal socio-economic activity – on the basis of analysis of the continuum “recreation – work” by means of modified Brennan-Buchanan model. It is revealed that even with the condition of the tax reduction, the situation when the population resting less and works more than in the background of a developed economy is observed. However, according to the optimistic forecast, eventually on condition when the economy is emerging from the shade, we will obtain an official mode of the work in which, while maintaining taxes on proposed more advantageous for the population level, ultimately the ratio leisure and work will be established which is corresponding to the principles of sustainable development. Practical value. On the basis of methodical principles of the theory of optimal control, the model of the functioning of the recreational industry under the

  7. Predicting the distribution of spiral waves from cell properties in a developmental-path model of Dictyostelium pattern formation.

    Directory of Open Access Journals (Sweden)

    Daniel Geberth

    2009-07-01

    Full Text Available The slime mold Dictyostelium discoideum is one of the model systems of biological pattern formation. One of the most successful answers to the challenge of establishing a spiral wave pattern in a colony of homogeneously distributed D. discoideum cells has been the suggestion of a developmental path the cells follow (Lauzeral and coworkers. This is a well-defined change in properties each cell undergoes on a longer time scale than the typical dynamics of the cell. Here we show that this concept leads to an inhomogeneous and systematic spatial distribution of spiral waves, which can be predicted from the distribution of cells on the developmental path. We propose specific experiments for checking whether such systematics are also found in data and thus, indirectly, provide evidence of a developmental path.

  8. Computational modeling identifies key gene regulatory interactions underlying phenobarbital-mediated tumor promotion

    Science.gov (United States)

    Luisier, Raphaëlle; Unterberger, Elif B.; Goodman, Jay I.; Schwarz, Michael; Moggs, Jonathan; Terranova, Rémi; van Nimwegen, Erik

    2014-01-01

    Gene regulatory interactions underlying the early stages of non-genotoxic carcinogenesis are poorly understood. Here, we have identified key candidate regulators of phenobarbital (PB)-mediated mouse liver tumorigenesis, a well-characterized model of non-genotoxic carcinogenesis, by applying a new computational modeling approach to a comprehensive collection of in vivo gene expression studies. We have combined our previously developed motif activity response analysis (MARA), which models gene expression patterns in terms of computationally predicted transcription factor binding sites with singular value decomposition (SVD) of the inferred motif activities, to disentangle the roles that different transcriptional regulators play in specific biological pathways of tumor promotion. Furthermore, transgenic mouse models enabled us to identify which of these regulatory activities was downstream of constitutive androstane receptor and β-catenin signaling, both crucial components of PB-mediated liver tumorigenesis. We propose novel roles for E2F and ZFP161 in PB-mediated hepatocyte proliferation and suggest that PB-mediated suppression of ESR1 activity contributes to the development of a tumor-prone environment. Our study shows that combining MARA with SVD allows for automated identification of independent transcription regulatory programs within a complex in vivo tissue environment and provides novel mechanistic insights into PB-mediated hepatocarcinogenesis. PMID:24464994

  9. A biosocial developmental model of borderline personality: Elaborating and extending Linehan's theory.

    Science.gov (United States)

    Crowell, Sheila E; Beauchaine, Theodore P; Linehan, Marsha M

    2009-05-01

    Over the past several decades, research has focused increasingly on developmental precursors to psychological disorders that were previously assumed to emerge only in adulthood. This change in focus follows from the recognition that complex transactions between biological vulnerabilities and psychosocial risk factors shape emotional and behavioral development beginning at conception. To date, however, empirical research on the development of borderline personality is extremely limited. Indeed, in the decade since M. M. Linehan initially proposed a biosocial model of the development of borderline personality disorder, there have been few attempts to test the model among at-risk youth. In this review, diverse literatures are reviewed that can inform understanding of the ontogenesis of borderline pathology, and testable hypotheses are proposed to guide future research with at-risk children and adolescents. One probable pathway is identified that leads to borderline personality disorder; it begins with early vulnerability, expressed initially as impulsivity and followed by heightened emotional sensitivity. These vulnerabilities are potentiated across development by environmental risk factors that give rise to more extreme emotional, behavioral, and cognitive dysregulation. (PsycINFO Database Record (c) 2009 APA, all rights reserved).

  10. A Biosocial Developmental Model of Borderline Personality: Elaborating and Extending Linehan’s Theory

    Science.gov (United States)

    Crowell, Sheila E.; Beauchaine, Theodore P.; Linehan, Marsha M.

    2009-01-01

    Over the past several decades, research has focused increasingly on developmental precursors to psychological disorders that were previously assumed to emerge only in adulthood. This change in focus follows from the recognition that complex transactions between biological vulnerabilities and psychosocial risk factors shape emotional and behavioral development beginning at conception. To date, however, empirical research on the development of borderline personality is extremely limited. Indeed, in the decade since M. M. Linehan initially proposed a biosocial model of the development of borderline personality disorder, there have been few attempts to test the model among at-risk youth. In this review, diverse literatures are reviewed that can inform understanding of the ontogenesis of borderline pathology, and testable hypotheses are proposed to guide future research with at-risk children and adolescents. One probable pathway is identified that leads to borderline personality disorder; it begins with early vulnerability, expressed initially as impulsivity and followed by heightened emotional sensitivity. These vulnerabilities are potentiated across development by environmental risk factors that give rise to more extreme emotional, behavioral, and cognitive dysregulation. PMID:19379027

  11. Animal models of human anxiety disorders: reappraisal from a developmental psychopathology vantage point.

    Science.gov (United States)

    Lampis, Valentina; Maziade, Michel; Battaglia, Marco

    2011-05-01

    We are witnessing a tremendous expansion of strategies and techniques that derive from basic and preclinical science to study the fine genetic, epigenetic, and proteomic regulation of behavior in the laboratory animal. In this endeavor, animal models of psychiatric illness are becoming the almost exclusive domain of basic researchers, with lesser involvement of clinician researchers in their conceptual design, and transfer into practice of new paradigms. From the side of human behavioral research, the growing interest in gene-environment interplay and the fostering of valid endophenotypes are among the few substantial innovations in the effort of linking common mental disorders to cutting-edge clinical research questions. We argue that it is time for cross-fertilization between these camps. In this article, we a) observe that the "translational divide" can-and should-be crossed by having investigators from both the basic and the clinical sides cowork on simpler, valid "endophenotypes" of neurodevelopmental relevance; b) emphasize the importance of unambiguous physiological readouts, more than behavioral equivalents of human symptoms/syndromes, for animal research; c) indicate and discuss how this could be fostered and implemented in a developmental framework of reference for some common anxiety disorders and ultimately lead to better animal models of human mental disorders.

  12. Development and implementation of the regulatory control of sources in Latin American Model Project countries

    International Nuclear Information System (INIS)

    Ferruz Cruz, P.

    2001-01-01

    After a general assessment of the situation regarding radiation safety and the radiation protection infrastructure in Latin American countries, several of them were invited to participate in a Model Project oriented, in some cases, towards establishing a mechanism for national regulatory control of radiation sources, and in others, towards upgrading their national control programme. All these activities aimed at reaching an effective and sustainable radiation protection infrastructure based on international basic safety standards. The paper presents a general overview of the current situation with regard to radiation protection within the Model Project countries in Latin America after almost five years of activities. It includes: the implementation of regulatory issues; the control of occupational, medical and public exposures; emergency response and waste safety issues. The paper also presents some lessons learned during implementation concerning the numerous activities involved in this interregional project. (author)

  13. Neural model of gene regulatory network: a survey on supportive meta-heuristics.

    Science.gov (United States)

    Biswas, Surama; Acharyya, Sriyankar

    2016-06-01

    Gene regulatory network (GRN) is produced as a result of regulatory interactions between different genes through their coded proteins in cellular context. Having immense importance in disease detection and drug finding, GRN has been modelled through various mathematical and computational schemes and reported in survey articles. Neural and neuro-fuzzy models have been the focus of attraction in bioinformatics. Predominant use of meta-heuristic algorithms in training neural models has proved its excellence. Considering these facts, this paper is organized to survey neural modelling schemes of GRN and the efficacy of meta-heuristic algorithms towards parameter learning (i.e. weighting connections) within the model. This survey paper renders two different structure-related approaches to infer GRN which are global structure approach and substructure approach. It also describes two neural modelling schemes, such as artificial neural network/recurrent neural network based modelling and neuro-fuzzy modelling. The meta-heuristic algorithms applied so far to learn the structure and parameters of neutrally modelled GRN have been reviewed here.

  14. CD4+CD25+ regulatory T cells: II. Origin, disease models and clinical aspects

    DEFF Research Database (Denmark)

    Nielsen, Janne; Holm, Thomas Lindebo; Claesson, Mogens H

    2004-01-01

    Autoimmune diseases afflict approximately 5% of the population and reflect a failure in the immune system to discriminate between self and non-self resulting in the breakdown of self-tolerance. Regulatory CD4+CD25+ T cells (Treg cells) have been shown to play an important role in the maintenance ...... in disease models such as autoimmune gastritis and inflammatory bowel disease. Finally, we will consider some aspects of the therapeutic potential of Treg cells....

  15. A Framework for Organizing Current and Future Electric Utility Regulatory and Business Models

    Energy Technology Data Exchange (ETDEWEB)

    Satchwell, Andrew [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Cappers, Peter [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Schwartz, Lisa [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Fadrhonc, Emily Martin [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2015-06-01

    In this report, we will present a descriptive and organizational framework for incremental and fundamental changes to regulatory and utility business models in the context of clean energy public policy goals. We will also discuss the regulated utility's role in providing value-added services that relate to distributed energy resources, identify the "openness" of customer information and utility networks necessary to facilitate change, and discuss the relative risks, and the shifting of risks, for utilities and customers.

  16. Comorbidities and continuities as ontogenic processes: Toward a developmental spectrum model of externalizing psychopathology

    Science.gov (United States)

    Beauchaine, Theodore P.; McNulty, Tiffany

    2014-01-01

    Research on child and adolescent mental health problems has burgeoned since the inaugural issue of Development and Psychopathology was published in 1989. In the quarter century since, static models of psychopathology have been abandoned in favor of transactional models, following the agenda set by editor Dante Cicchetti and other proponents of the discipline. The transactional approach, which has been applied to autism, depression, self-injury, and delinquency, (a) specifies vulnerabilities and risk factors across multiple levels of analysis spanning genes to cultures, (b) identifies multifinal and equifinal pathways to psychopathology, and (c) transcends traditional disciplinary boundaries. However, as noted by Rutter and Sroufe (2000), specific mechanisms of continuity, discontinuity, and comorbidity of psychopathology must be identified if we wish to understand etiology fully. In this article, we present a model of early-onset externalizing behavior in which comorbidities and continuities are viewed as ontogenic processes: products of complex longitudinal transactions between interdependent individual-level vulnerabilities (e.g., genetic, epigenetic, allostatic) and equally interdependent contextual risk factors (e.g., coercive parenting, deviant peer group affiliations, neighborhood criminality). Through interactions across levels of analysis, some individuals traverse along the externalizing spectrum, beginning with heritable trait impulsivity in preschool and ending in antisociality in adulthood. In describing our model, we note that (a) the approach outlined in the DSM to subtyping externalizing disorders continues to obscure developmental pathways to antisociality, (b) molecular genetics studies will likely not identify meaningful subtypes of externalizing disorder, and (c) ontogenic trait approaches to psychopathology are much more likely to advance the discipline in upcoming years. PMID:24342853

  17. Development of thermal hydraulic models for the reliable regulatory auditing code

    Energy Technology Data Exchange (ETDEWEB)

    Chung, B. D.; Song, C. H.; Lee, Y. J.; Kwon, T. S. [Korea Atomic Energy Research Institute, Taejon (Korea, Republic of)

    2003-04-15

    The objective of this project is to develop thermal hydraulic models for use in improving the reliability of the regulatory auditing codes. The current year fall under the first step of the 3 year project, and the main researches were focused on identifying the candidate thermal hydraulic models for improvement and to develop prototypical model development. During the current year, the verification calculations submitted for the APR 1400 design certification have been reviewed, the experimental data from the MIDAS DVI experiment facility in KAERI have been analyzed and evaluated, candidate thermal hydraulic models for improvement have been identified, prototypical models for the improved thermal hydraulic models have been developed, items for experiment in connection with the model development have been identified, and preliminary design of the experiment has been carried out.

  18. Development of thermal hydraulic models for the reliable regulatory auditing code

    International Nuclear Information System (INIS)

    Chung, B. D.; Song, C. H.; Lee, Y. J.; Kwon, T. S.

    2003-04-01

    The objective of this project is to develop thermal hydraulic models for use in improving the reliability of the regulatory auditing codes. The current year fall under the first step of the 3 year project, and the main researches were focused on identifying the candidate thermal hydraulic models for improvement and to develop prototypical model development. During the current year, the verification calculations submitted for the APR 1400 design certification have been reviewed, the experimental data from the MIDAS DVI experiment facility in KAERI have been analyzed and evaluated, candidate thermal hydraulic models for improvement have been identified, prototypical models for the improved thermal hydraulic models have been developed, items for experiment in connection with the model development have been identified, and preliminary design of the experiment has been carried out

  19. A service-oriented architecture for integrating the modeling and formal verification of genetic regulatory networks

    Directory of Open Access Journals (Sweden)

    Page Michel

    2009-12-01

    Full Text Available Abstract Background The study of biological networks has led to the development of increasingly large and detailed models. Computer tools are essential for the simulation of the dynamical behavior of the networks from the model. However, as the size of the models grows, it becomes infeasible to manually verify the predictions against experimental data or identify interesting features in a large number of simulation traces. Formal verification based on temporal logic and model checking provides promising methods to automate and scale the analysis of the models. However, a framework that tightly integrates modeling and simulation tools with model checkers is currently missing, on both the conceptual and the implementational level. Results We have developed a generic and modular web service, based on a service-oriented architecture, for integrating the modeling and formal verification of genetic regulatory networks. The architecture has been implemented in the context of the qualitative modeling and simulation tool GNA and the model checkers NUSMV and CADP. GNA has been extended with a verification module for the specification and checking of biological properties. The verification module also allows the display and visual inspection of the verification results. Conclusions The practical use of the proposed web service is illustrated by means of a scenario involving the analysis of a qualitative model of the carbon starvation response in E. coli. The service-oriented architecture allows modelers to define the model and proceed with the specification and formal verification of the biological properties by means of a unified graphical user interface. This guarantees a transparent access to formal verification technology for modelers of genetic regulatory networks.

  20. Unifying Speech and Language in a Developmentally Sensitive Model of Production.

    Science.gov (United States)

    Redford, Melissa A

    2015-11-01

    Speaking is an intentional activity. It is also a complex motor skill; one that exhibits protracted development and the fully automatic character of an overlearned behavior. Together these observations suggest an analogy with skilled behavior in the non-language domain. This analogy is used here to argue for a model of production that is grounded in the activity of speaking and structured during language acquisition. The focus is on the plan that controls the execution of fluent speech; specifically, on the units that are activated during the production of an intonational phrase. These units are schemas: temporally structured sequences of remembered actions and their sensory outcomes. Schemas are activated and inhibited via associated goals, which are linked to specific meanings. Schemas may fuse together over developmental time with repeated use to form larger units, thereby affecting the relative timing of sequential action in participating schemas. In this way, the hierarchical structure of the speech plan and ensuing rhythm patterns of speech are a product of development. Individual schemas may also become differentiated during development, but only if subsequences are associated with meaning. The necessary association of action and meaning gives rise to assumptions about the primacy of certain linguistic forms in the production process. Overall, schema representations connect usage-based theories of language to the action of speaking.

  1. Foundation observation of teaching project--a developmental model of peer observation of teaching.

    Science.gov (United States)

    Pattison, Andrew Timothy; Sherwood, Morgan; Lumsden, Colin James; Gale, Alison; Markides, Maria

    2012-01-01

    Peer observation of teaching is important in the development of educators. The foundation curriculum specifies teaching competencies that must be attained. We created a developmental model of peer observation of teaching to help our foundation doctors achieve these competencies and develop as educators. A process for peer observation was created based on key features of faculty development. The project consisted of a pre-observation meeting, the observation, a post-observation debrief, writing of reflective reports and group feedback sessions. The project was evaluated by completion of questionnaires and focus groups held with both foundation doctors and the students they taught to achieve triangulation. Twenty-one foundation doctors took part. All completed reflective reports on their teaching. Participants described the process as useful in their development as educators, citing specific examples of changes to their teaching practice. Medical students rated the sessions as better or much better quality as their usual teaching. The study highlights the benefits of the project to individual foundation doctors, undergraduate medical students and faculty. It acknowledges potential anxieties involved in having teaching observed. A structured programme of observation of teaching can deliver specific teaching competencies required by foundation doctors and provides additional benefits.

  2. Development of PSA audit guideline and regulatory PSA model for SMART

    International Nuclear Information System (INIS)

    Cho, Namchul; Lee, Chang-Ju; Kim, I.S.

    2012-01-01

    SMART is under development for dual purposes of power generation and seawater desalination in Korea. It is an integral reactor type with a thermal power output of 330 MW and employs advanced design features such as a passive system for the removal of residual heat and also the setting of all the components of the primary system inside the reactor pressure vessel. It is essential to develop new probabilistic safety assessment (PSA) validation guidance for SMART. For the purpose of regulatory verification to the risk level of SMART, the insights and key issues on the PSA are identified with referring some worldwide safety guides as well as its design characteristics. Regulatory PSA model under the development for the design confirmation and its preliminary result are also described. (authors)

  3. Inference of gene regulatory networks with sparse structural equation models exploiting genetic perturbations.

    Directory of Open Access Journals (Sweden)

    Xiaodong Cai

    Full Text Available Integrating genetic perturbations with gene expression data not only improves accuracy of regulatory network topology inference, but also enables learning of causal regulatory relations between genes. Although a number of methods have been developed to integrate both types of data, the desiderata of efficient and powerful algorithms still remains. In this paper, sparse structural equation models (SEMs are employed to integrate both gene expression data and cis-expression quantitative trait loci (cis-eQTL, for modeling gene regulatory networks in accordance with biological evidence about genes regulating or being regulated by a small number of genes. A systematic inference method named sparsity-aware maximum likelihood (SML is developed for SEM estimation. Using simulated directed acyclic or cyclic networks, the SML performance is compared with that of two state-of-the-art algorithms: the adaptive Lasso (AL based scheme, and the QTL-directed dependency graph (QDG method. Computer simulations demonstrate that the novel SML algorithm offers significantly better performance than the AL-based and QDG algorithms across all sample sizes from 100 to 1,000, in terms of detection power and false discovery rate, in all the cases tested that include acyclic or cyclic networks of 10, 30 and 300 genes. The SML method is further applied to infer a network of 39 human genes that are related to the immune function and are chosen to have a reliable eQTL per gene. The resulting network consists of 9 genes and 13 edges. Most of the edges represent interactions reasonably expected from experimental evidence, while the remaining may just indicate the emergence of new interactions. The sparse SEM and efficient SML algorithm provide an effective means of exploiting both gene expression and perturbation data to infer gene regulatory networks. An open-source computer program implementing the SML algorithm is freely available upon request.

  4. Differential T cell response against BK virus regulatory and structural antigens: A viral dynamics modelling approach.

    Directory of Open Access Journals (Sweden)

    Arturo Blazquez-Navarro

    2018-05-01

    Full Text Available BK virus (BKV associated nephropathy affects 1-10% of kidney transplant recipients, leading to graft failure in about 50% of cases. Immune responses against different BKV antigens have been shown to have a prognostic value for disease development. Data currently suggest that the structural antigens and regulatory antigens of BKV might each trigger a different mode of action of the immune response. To study the influence of different modes of action of the cellular immune response on BKV clearance dynamics, we have analysed the kinetics of BKV plasma load and anti-BKV T cell response (Elispot in six patients with BKV associated nephropathy using ODE modelling. The results show that only a small number of hypotheses on the mode of action are compatible with the empirical data. The hypothesis with the highest empirical support is that structural antigens trigger blocking of virus production from infected cells, whereas regulatory antigens trigger an acceleration of death of infected cells. These differential modes of action could be important for our understanding of BKV resolution, as according to the hypothesis, only regulatory antigens would trigger a fast and continuous clearance of the viral load. Other hypotheses showed a lower degree of empirical support, but could potentially explain the clearing mechanisms of individual patients. Our results highlight the heterogeneity of the dynamics, including the delay between immune response against structural versus regulatory antigens, and its relevance for BKV clearance. Our modelling approach is the first that studies the process of BKV clearance by bringing together viral and immune kinetics and can provide a framework for personalised hypotheses generation on the interrelations between cellular immunity and viral dynamics.

  5. Differential T cell response against BK virus regulatory and structural antigens: A viral dynamics modelling approach.

    Science.gov (United States)

    Blazquez-Navarro, Arturo; Schachtner, Thomas; Stervbo, Ulrik; Sefrin, Anett; Stein, Maik; Westhoff, Timm H; Reinke, Petra; Klipp, Edda; Babel, Nina; Neumann, Avidan U; Or-Guil, Michal

    2018-05-01

    BK virus (BKV) associated nephropathy affects 1-10% of kidney transplant recipients, leading to graft failure in about 50% of cases. Immune responses against different BKV antigens have been shown to have a prognostic value for disease development. Data currently suggest that the structural antigens and regulatory antigens of BKV might each trigger a different mode of action of the immune response. To study the influence of different modes of action of the cellular immune response on BKV clearance dynamics, we have analysed the kinetics of BKV plasma load and anti-BKV T cell response (Elispot) in six patients with BKV associated nephropathy using ODE modelling. The results show that only a small number of hypotheses on the mode of action are compatible with the empirical data. The hypothesis with the highest empirical support is that structural antigens trigger blocking of virus production from infected cells, whereas regulatory antigens trigger an acceleration of death of infected cells. These differential modes of action could be important for our understanding of BKV resolution, as according to the hypothesis, only regulatory antigens would trigger a fast and continuous clearance of the viral load. Other hypotheses showed a lower degree of empirical support, but could potentially explain the clearing mechanisms of individual patients. Our results highlight the heterogeneity of the dynamics, including the delay between immune response against structural versus regulatory antigens, and its relevance for BKV clearance. Our modelling approach is the first that studies the process of BKV clearance by bringing together viral and immune kinetics and can provide a framework for personalised hypotheses generation on the interrelations between cellular immunity and viral dynamics.

  6. Selection of terrestrial transfer factors for radioecological assessment models and regulatory guides

    International Nuclear Information System (INIS)

    Ng, Y.C.; Hoffman, F.O.

    1983-01-01

    A parameter value for a radioecological assessment model is not a single value but a distribution of values about a central value. The sources that contribute to the variability of transfer factors to predict foodchain transport of radionuclides are enumerated. Knowledge of these sources, judgement in interpreting the available data, consideration of collateral information, and established criteria that specify the desired level of conservatism in the resulting predictions are essential elements when selecting appropriate parameter values for radioecological assessment models and regulatory guides. 39 references, 4 figures, 5 tables

  7. Selection of terrestrial transfer factors for radioecological assessment models and regulatory guides

    Energy Technology Data Exchange (ETDEWEB)

    Ng, Y.C.; Hoffman, F.O.

    1983-01-01

    A parameter value for a radioecological assessment model is not a single value but a distribution of values about a central value. The sources that contribute to the variability of transfer factors to predict foodchain transport of radionuclides are enumerated. Knowledge of these sources, judgement in interpreting the available data, consideration of collateral information, and established criteria that specify the desired level of conservatism in the resulting predictions are essential elements when selecting appropriate parameter values for radioecological assessment models and regulatory guides. 39 references, 4 figures, 5 tables.

  8. A system dynamics model of clinical decision thresholds for the detection of developmental-behavioral disorders

    Directory of Open Access Journals (Sweden)

    R. Christopher Sheldrick

    2016-11-01

    Full Text Available Abstract Background Clinical decision-making has been conceptualized as a sequence of two separate processes: assessment of patients’ functioning and application of a decision threshold to determine whether the evidence is sufficient to justify a given decision. A range of factors, including use of evidence-based screening instruments, has the potential to influence either or both processes. However, implementation studies seldom specify or assess the mechanism by which screening is hypothesized to influence clinical decision-making, thus limiting their ability to address unexpected findings regarding clinicians’ behavior. Building on prior theory and empirical evidence, we created a system dynamics (SD model of how physicians’ clinical decisions are influenced by their assessments of patients and by factors that may influence decision thresholds, such as knowledge of past patient outcomes. Using developmental-behavioral disorders as a case example, we then explore how referral decisions may be influenced by changes in context. Specifically, we compare predictions from the SD model to published implementation trials of evidence-based screening to understand physicians’ management of positive screening results and changes in referral rates. We also conduct virtual experiments regarding the influence of a variety of interventions that may influence physicians’ thresholds, including improved access to co-located mental health care and improved feedback systems regarding patient outcomes. Results Results of the SD model were consistent with recent implementation trials. For example, the SD model suggests that if screening improves physicians’ accuracy of assessment without also influencing decision thresholds, then a significant proportion of children with positive screens will not be referred and the effect of screening implementation on referral rates will be modest—results that are consistent with a large proportion of published

  9. Harmonisation within atmospheric dispersion modelling for regulatory purposes. Proceedings. Vol. 2

    International Nuclear Information System (INIS)

    Suppan, P.

    2004-01-01

    Dispersion modelling has proved to be a very effective tool to assess the environmental impact of human activities on air quality already at the early planning stage. Environmental assessments during planning are required by the EU directive 85/337/EEC. Only models can give detailed information on the distribution of pollutants with high spatial and temporal resolution, while they allow the decision-maker to devise a range of scenarios, in which the various processes determining the environmental impact can be easily simulated and changed. In June 1991, the Joint Research Centre of the European Commission started an initiative on the sharing of information and possible harmonisation of new approaches to atmospheric dispersion modelling and model evaluation. This initiative has fostered a series of conferences that have been concerned with improvement of ''modelling culture'' in Europe. The 9 th International Conference on Harmonisation within atmospheric dispersion modelling for regulatory purposes in Garmisch-Partenkirchen, in Germany/ Bavaria, 1-4 June, 2004, will continue the efforts of the previous conferences. The conference has a role as a forum where users and decision-makers can bring their requirements to the attention of scientists. It is also a natural forum for discussing environmental issues related to the European union enlargement process. The scope of this conference is covered by the following topics: Validation and inter-comparison of models: Model evaluation methodology, experiences with implementation of EU directives; regulatory modelling, short distance dispersion modelling, urban scale and street canyon modelling: Meteorology and air quality, mesoscale meteorology and air quality modelling, environmental impact assessment: Air pollution management and decision support systems. (orig.)

  10. Harmonisation within atmospheric dispersion modelling for regulatory purposes. Proceedings. Vol. 1

    International Nuclear Information System (INIS)

    Suppan, P.

    2004-01-01

    Dispersion modelling has proved to be a very effective tool to assess the environmental impact of human activities to be a very effective tool to assess the environmental impact of human activities on air quality already at the early planning stage. Environmental assessments during planning are required by the EU directive 85/337/EEC. Only models can give detailed information on the distribution of pollutants with high spatial and temporal resolution, while they allow the decision-maker to devise a range of scenarios, in which the various processes determining the environmental impact can be easily simulated and changed. In June 1991, the Joint Research Centre of the European Commission started an initiative on the sharing of information and possible harmonisation of new approaches to atmospheric disperion modelling and model evaluation. This initiative has fostered a series of conferences that have be concerned with improvement of ''modelling culture'' in Europe. The 9th International Conference on Harmonisation within Atmospheric dispersion Modelling for Regulatory Purposes in Garmisch-Partenkirchen, in Germany/Bavaria, 1-4 June, 2004, will continue the efforts of the previous conferences. The conference has a role as a forum where users and decision-makers can bring their requirements to the attention of scientists. It is also a natural forum for discussing environmental issues related to the European Union enlargement process. The scope of this conference is covered by the following topics: 1. Validation and inter-comparison of models: Model evaluation methodology - 2. Experiences with implementation of EU directives: regulatory modelling - 3. Short distance dispersion modelling - 4. Urban scale and street canyon modelling: Meteorology and air quality - 5. Mesoscale meteorology and air quality modelling - 6. Environmental impact assessment: Air pollution management and decision support systems. (orig.)

  11. Developmental toxicity assessment of common excipients using a stem cell-based in vitro morphogenesis model.

    Science.gov (United States)

    Yuan, Chloe J; Marikawa, Yusuke

    2017-11-01

    Various chemical compounds can inflict developmental toxicity when sufficiently high concentrations are exposed to embryos at the critical stages of development. Excipients, such as coloring agents and preservatives, are pharmacologically inactive ingredients that are included in various medications, foods, and cosmetics. However, concentrations that may adversely affect embryo development are largely unknown for most excipients. Here, the lowest observed adverse effect level (LOAEL) to inflict developmental toxicity was assessed for three coloring agents (allura red, brilliant blue, and tartrazine) and three preservatives (butylated hydroxyanisole, metabisulfite, and methylparaben). Adverse impact of a compound exposure was determined using the stem cell-based in vitro morphogenesis model, in which three-dimensional cell aggregates, or embryoid bodies (EBs), recapitulate embryonic processes of body axis elongation and patterning. LOAEL to impair EB morphogenesis was 200 μM for methylparaben, 400 μM for butylated hydroxyanisole, 600 μM for allura red and brilliant blue, and 1000 μM for metabisulfite. Gene expression analyses of excipient-treated EBs revealed that butylated hydroxyanisole and methylparaben significantly altered profiles of developmental regulators involved in axial elongation and patterning of the body. The present study may provide a novel in vitro approach to investigate potential developmental toxicity of common excipients with mechanistic insights. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. The role of mathematical models in understanding pattern formation in developmental biology.

    Science.gov (United States)

    Umulis, David M; Othmer, Hans G

    2015-05-01

    In a Wall Street Journal article published on April 5, 2013, E. O. Wilson attempted to make the case that biologists do not really need to learn any mathematics-whenever they run into difficulty with numerical issues, they can find a technician (aka mathematician) to help them out of their difficulty. He formalizes this in Wilsons Principle No. 1: "It is far easier for scientists to acquire needed collaboration from mathematicians and statisticians than it is for mathematicians and statisticians to find scientists able to make use of their equations." This reflects a complete misunderstanding of the role of mathematics in all sciences throughout history. To Wilson, mathematics is mere number crunching, but as Galileo said long ago, "The laws of Nature are written in the language of mathematics[Formula: see text] the symbols are triangles, circles and other geometrical figures, without whose help it is impossible to comprehend a single word." Mathematics has moved beyond the geometry-based model of Galileo's time, and in a rebuttal to Wilson, E. Frenkel has pointed out the role of mathematics in synthesizing the general principles in science (Both point and counter-point are available in Wilson and Frenkel in Notices Am Math Soc 60(7):837-838, 2013). We will take this a step further and show how mathematics has been used to make new and experimentally verified discoveries in developmental biology and how mathematics is essential for understanding a problem that has puzzled experimentalists for decades-that of how organisms can scale in size. Mathematical analysis alone cannot "solve" these problems since the validation lies at the molecular level, but conversely, a growing number of questions in biology cannot be solved without mathematical analysis and modeling. Herein, we discuss a few examples of the productive intercourse between mathematics and biology.

  13. Abnormal stress responsivity in a rodent developmental disruption model of schizophrenia.

    Science.gov (United States)

    Zimmerman, Eric C; Bellaire, Mark; Ewing, Samuel G; Grace, Anthony A

    2013-10-01

    Although numerous studies have implicated stress in the pathophysiology of schizophrenia, less is known about how the effects of stress interact with genetic, developmental, and/or environmental determinants to promote disease progression. In particular, it has been proposed that in humans, stress exposure in adolescence could combine with a predisposition towards increased stress sensitivity, leading to prodromal symptoms and eventually psychosis. However, the neurobiological substrates for this interaction are not fully characterized. Previous work in our lab has demonstrated that rats born to dams administered with the DNA-methylating agent methylazoxymethanol acetate (MAM) at gestational day 17 exhibit as adults behavioral and anatomical abnormalities consistent with those observed in patients with schizophrenia. Here, we examined behavioral and neuroendocrine responses to stress in the MAM model of schizophrenia. MAM-treated male rats were exposed to acute and repeated footshock stress at prepubertal, peripubteral, and adult ages. Ultrasonic vocalizations (USVs), freezing, and corticosterone responses were quantified. We found that juvenile MAM-treated rats emitted significantly more calls, spent more time vocalizing, emitted calls at a higher rate, and showed more freezing in response to acute footshock stress when compared with their saline (SAL) treated counterparts, and that this difference is not present in older animals. In addition, adolescent MAM-treated animals displayed a blunted HPA axis corticosterone response to acute footshock that did not adapt after 10 days of stress exposure. These data demonstrate abnormal stress responsivity in the MAM model of schizophrenia and suggest that these animals are more sensitive to the effects of stress in youth.

  14. Trisomy 21 and facial developmental instability.

    Science.gov (United States)

    Starbuck, John M; Cole, Theodore M; Reeves, Roger H; Richtsmeier, Joan T

    2013-05-01

    The most common live-born human aneuploidy is trisomy 21, which causes Down syndrome (DS). Dosage imbalance of genes on chromosome 21 (Hsa21) affects complex gene-regulatory interactions and alters development to produce a wide range of phenotypes, including characteristic facial dysmorphology. Little is known about how trisomy 21 alters craniofacial morphogenesis to create this characteristic appearance. Proponents of the "amplified developmental instability" hypothesis argue that trisomy 21 causes a generalized genetic imbalance that disrupts evolutionarily conserved developmental pathways by decreasing developmental homeostasis and precision throughout development. Based on this model, we test the hypothesis that DS faces exhibit increased developmental instability relative to euploid individuals. Developmental instability was assessed by a statistical analysis of fluctuating asymmetry. We compared the magnitude and patterns of fluctuating asymmetry among siblings using three-dimensional coordinate locations of 20 anatomic landmarks collected from facial surface reconstructions in four age-matched samples ranging from 4 to 12 years: (1) DS individuals (n = 55); (2) biological siblings of DS individuals (n = 55); 3) and 4) two samples of typically developing individuals (n = 55 for each sample), who are euploid siblings and age-matched to the DS individuals and their euploid siblings (samples 1 and 2). Identification in the DS sample of facial prominences exhibiting increased fluctuating asymmetry during facial morphogenesis provides evidence for increased developmental instability in DS faces. We found the highest developmental instability in facial structures derived from the mandibular prominence and lowest in facial regions derived from the frontal prominence. Copyright © 2013 Wiley Periodicals, Inc.

  15. Alignment and prediction of cis-regulatory modules based on a probabilistic model of evolution.

    Directory of Open Access Journals (Sweden)

    Xin He

    2009-03-01

    Full Text Available Cross-species comparison has emerged as a powerful paradigm for predicting cis-regulatory modules (CRMs and understanding their evolution. The comparison requires reliable sequence alignment, which remains a challenging task for less conserved noncoding sequences. Furthermore, the existing models of DNA sequence evolution generally do not explicitly treat the special properties of CRM sequences. To address these limitations, we propose a model of CRM evolution that captures different modes of evolution of functional transcription factor binding sites (TFBSs and the background sequences. A particularly novel aspect of our work is a probabilistic model of gains and losses of TFBSs, a process being recognized as an important part of regulatory sequence evolution. We present a computational framework that uses this model to solve the problems of CRM alignment and prediction. Our alignment method is similar to existing methods of statistical alignment but uses the conserved binding sites to improve alignment. Our CRM prediction method deals with the inherent uncertainties of binding site annotations and sequence alignment in a probabilistic framework. In simulated as well as real data, we demonstrate that our program is able to improve both alignment and prediction of CRM sequences over several state-of-the-art methods. Finally, we used alignments produced by our program to study binding site conservation in genome-wide binding data of key transcription factors in the Drosophila blastoderm, with two intriguing results: (i the factor-bound sequences are under strong evolutionary constraints even if their neighboring genes are not expressed in the blastoderm and (ii binding sites in distal bound sequences (relative to transcription start sites tend to be more conserved than those in proximal regions. Our approach is implemented as software, EMMA (Evolutionary Model-based cis-regulatory Module Analysis, ready to be applied in a broad biological context.

  16. MODELLING THE DYNAMICS OF THE ADEQUACY OF BANK’S REGULATORY CAPITAL

    Directory of Open Access Journals (Sweden)

    Leonid Katranzhy

    2018-01-01

    Full Text Available The purpose of the article is to develop scientific and methodological recommendations for modelling the dynamics of the level of capital adequacy for ensuring the financial balance of the bank, sufficient controllability and increasing the efficiency of its activities. The article explores peculiarities of banking regulation and supervision in the process of capital formation. It is shown that the issue of formation of capital by banking institutions is actualized in the context of management reform and target tasks of the development of the banking industry of Ukraine. Given the state of the banking services market and its development trends, the unsettled problem of the capitalization of banks, it becomes important to improve the mechanism of capital formation. In order to improve the efficiency of bank regulation and management of capital formation, recommendations are proposed for modelling the dynamics of the adequacy of regulatory capital on the basis of determining the forecast values of its components. Research methodology: the feasibility of using predictive models with the use of artificial neural networks is substantiated. In contrast to the classic trend, discussed in the article, the models with the architecture of the multilayer perceptron proved to be the most adequate and accurate. In addition to a point forecast of the dynamics of regulatory capital, the overall risk and the amount of the net foreign exchange position, their pessimistic and optimistic forecasts were constructed. The author’s proposals are formalized by appropriate calculation algorithms. Modelling the dynamics of the adequacy of regulatory capital and its components in practice will allow more efficiently manage systemic and individual banking risks.

  17. When the model fits the frame: the impact of regulatory fit on efficacy appraisal and persuasion in health communication.

    Science.gov (United States)

    Bosone, Lucia; Martinez, Frédéric; Kalampalikis, Nikos

    2015-04-01

    In health-promotional campaigns, positive and negative role models can be deployed to illustrate the benefits or costs of certain behaviors. The main purpose of this article is to investigate why, how, and when exposure to role models strengthens the persuasiveness of a message, according to regulatory fit theory. We argue that exposure to a positive versus a negative model activates individuals' goals toward promotion rather than prevention. By means of two experiments, we demonstrate that high levels of persuasion occur when a message advertising healthy dietary habits offers a regulatory fit between its framing and the described role model. Our data also establish that the effects of such internal regulatory fit by vicarious experience depend on individuals' perceptions of response-efficacy and self-efficacy. Our findings constitute a significant theoretical complement to previous research on regulatory fit and contain valuable practical implications for health-promotional campaigns. © 2015 by the Society for Personality and Social Psychology, Inc.

  18. Boolean modelling reveals new regulatory connections between transcription factors orchestrating the development of the ventral spinal cord.

    KAUST Repository

    Lovrics, Anna; Gao, Yu; Juhá sz, Bianka; Bock, Istvá n; Byrne, Helen M; Dinnyé s, Andrá s; Ková cs, Krisztiá n A

    2014-01-01

    with the five known progenitor cell types located in the ventral spinal cord. The revised gene regulatory network reproduced previously observed cell state switches between progenitor cells observed in knock-out animal models or in experiments where

  19. A 3-dimensional human embryonic stem cell (hESC)-derived model to detect developmental neurotoxicity of nanoparticles.

    Science.gov (United States)

    Hoelting, Lisa; Scheinhardt, Benjamin; Bondarenko, Olesja; Schildknecht, Stefan; Kapitza, Marion; Tanavde, Vivek; Tan, Betty; Lee, Qian Yi; Mecking, Stefan; Leist, Marcel; Kadereit, Suzanne

    2013-04-01

    Nanoparticles (NPs) have been shown to accumulate in organs, cross the blood-brain barrier and placenta, and have the potential to elicit developmental neurotoxicity (DNT). Here, we developed a human embryonic stem cell (hESC)-derived 3-dimensional (3-D) in vitro model that allows for testing of potential developmental neurotoxicants. Early central nervous system PAX6(+) precursor cells were generated from hESCs and differentiated further within 3-D structures. The 3-D model was characterized for neural marker expression revealing robust differentiation toward neuronal precursor cells, and gene expression profiling suggested a predominantly forebrain-like development. Altered neural gene expression due to exposure to non-cytotoxic concentrations of the known developmental neurotoxicant, methylmercury, indicated that the 3-D model could detect DNT. To test for specific toxicity of NPs, chemically inert polyethylene NPs (PE-NPs) were chosen. They penetrated deep into the 3-D structures and impacted gene expression at non-cytotoxic concentrations. NOTCH pathway genes such as HES5 and NOTCH1 were reduced in expression, as well as downstream neuronal precursor genes such as NEUROD1 and ASCL1. FOXG1, a patterning marker, was also reduced. As loss of function of these genes results in severe nervous system impairments in mice, our data suggest that the 3-D hESC-derived model could be used to test for Nano-DNT.

  20. Data-driven integration of genome-scale regulatory and metabolic network models

    Science.gov (United States)

    Imam, Saheed; Schäuble, Sascha; Brooks, Aaron N.; Baliga, Nitin S.; Price, Nathan D.

    2015-01-01

    Microbes are diverse and extremely versatile organisms that play vital roles in all ecological niches. Understanding and harnessing microbial systems will be key to the sustainability of our planet. One approach to improving our knowledge of microbial processes is through data-driven and mechanism-informed computational modeling. Individual models of biological networks (such as metabolism, transcription, and signaling) have played pivotal roles in driving microbial research through the years. These networks, however, are highly interconnected and function in concert—a fact that has led to the development of a variety of approaches aimed at simulating the integrated functions of two or more network types. Though the task of integrating these different models is fraught with new challenges, the large amounts of high-throughput data sets being generated, and algorithms being developed, means that the time is at hand for concerted efforts to build integrated regulatory-metabolic networks in a data-driven fashion. In this perspective, we review current approaches for constructing integrated regulatory-metabolic models and outline new strategies for future development of these network models for any microbial system. PMID:25999934

  1. Data-driven integration of genome-scale regulatory and metabolic network models

    Directory of Open Access Journals (Sweden)

    Saheed eImam

    2015-05-01

    Full Text Available Microbes are diverse and extremely versatile organisms that play vital roles in all ecological niches. Understanding and harnessing microbial systems will be key to the sustainability of our planet. One approach to improving our knowledge of microbial processes is through data-driven and mechanism-informed computational modeling. Individual models of biological networks (such as metabolism, transcription and signaling have played pivotal roles in driving microbial research through the years. These networks, however, are highly interconnected and function in concert – a fact that has led to the development of a variety of approaches aimed at simulating the integrated functions of two or more network types. Though the task of integrating these different models is fraught with new challenges, the large amounts of high-throughput data sets being generated, and algorithms being developed, means that the time is at hand for concerted efforts to build integrated regulatory-metabolic networks in a data-driven fashion. In this perspective, we review current approaches for constructing integrated regulatory-metabolic models and outline new strategies for future development of these network models for any microbial system.

  2. Development of thermal hydraulic models for the reliable regulatory auditing code

    Energy Technology Data Exchange (ETDEWEB)

    Chung, B. D.; Song, C. H.; Lee, Y. J.; Kwon, T. S.; Lee, S. W. [Korea Automic Energy Research Institute, Taejon (Korea, Republic of)

    2004-02-15

    The objective of this project is to develop thermal hydraulic models for use in improving the reliability of the regulatory auditing codes. The current year fall under the second step of the 3 year project, and the main researches were focused on the development of downcorner boiling model. During the current year, the bubble stream model of downcorner has been developed and installed in he auditing code. The model sensitivity analysis has been performed for APR1400 LBLOCA scenario using the modified code. The preliminary calculation has been performed for the experimental test facility using FLUENT and MARS code. The facility for air bubble experiment has been installed. The thermal hydraulic phenomena for VHTR and super critical reactor have been identified for the future application and model development.

  3. In vitro to in vivo extrapolation of effective dosimetry in developmental toxicity testing : Application of a generic PBK modelling approach

    NARCIS (Netherlands)

    Fragki, Styliani; Piersma, Aldert H; Rorije, Emiel; Zeilmaker, Marco J

    2017-01-01

    Incorporation of kinetics to quantitative in vitro to in vivo extrapolations (QIVIVE) is a key step for the realization of a non-animal testing paradigm, in the sphere of regulatory toxicology. The use of Physiologically-Based Kinetic (PBK) modelling for determining systemic doses of chemicals at

  4. In vitro to in vivo extrapolation of effective dosimetry in developmental toxicity testing: Application of a generic PBK modelling approach.

    NARCIS (Netherlands)

    Fragki, Styliani; Piersma, Aldert H; Rorije, Emiel; Zeilmaker, Marco J

    2017-01-01

    Incorporation of kinetics to quantitative in vitro to in vivo extrapolations (QIVIVE) is a key step for the realization of a non-animal testing paradigm, in the sphere of regulatory toxicology. The use of Physiologically-Based Kinetic (PBK) modelling for determining systemic doses of chemicals at

  5. Defining social inclusion of people with intellectual and developmental disabilities: an ecological model of social networks and community participation.

    Science.gov (United States)

    Simplican, Stacy Clifford; Leader, Geraldine; Kosciulek, John; Leahy, Michael

    2015-03-01

    Social inclusion is an important goal for people with intellectual and developmental disabilities, families, service providers, and policymakers; however, the concept of social inclusion remains unclear, largely due to multiple and conflicting definitions in research and policy. We define social inclusion as the interaction between two major life domains: interpersonal relationships and community participation. We then propose an ecological model of social inclusion that includes individual, interpersonal, organizational, community, and socio-political factors. We identify four areas of research that our ecological model of social inclusion can move forward: (1) organizational implementation of social inclusion; (2) social inclusion of people with intellectual and developmental disabilities living with their families, (3) social inclusion of people along a broader spectrum of disability, and (4) the potential role of self-advocacy organizations in promoting social inclusion. Copyright © 2014. Published by Elsevier Ltd.

  6. Context analysis for a new regulatory model for electric utilities in Brazil

    International Nuclear Information System (INIS)

    El Hage, Fabio S.; Rufín, Carlos

    2016-01-01

    This article examines what would have to change in the Brazilian regulatory framework in order to make utilities profit from energy efficiency and the integration of resources, instead of doing so from traditional consumption growth, as it happens at present. We argue that the Brazilian integrated electric sector resembles a common-pool resources problem, and as such it should incorporate, in addition to the centralized operation for power dispatch already in place, demand side management, behavioral strategies, and smart grids, attained through a new business and regulatory model for utilities. The paper proposes several measures to attain a more sustainable and productive electricity distribution industry: decoupling revenues from volumetric sales through a fixed maximum load fee, which would completely offset current disincentives for energy efficiency; the creation of a market for negawatts (saved megawatts) using the current Brazilian mechanism of public auctions for the acquisition of wholesale energy; and the integration of technologies, especially through the growth of unregulated products and services. Through these measures, we believe that Brazil could improve both energy security and overall sustainability of its power sector in the long run. - Highlights: • Necessary changes in the Brazilian regulatory framework towards energy efficiency. • How to incorporate demand side management, behavioral strategies, and smart grids. • Proposition of a market for negawatts at public auctions. • Measures to attain a more sustainable electricity distribution industry in Brazil.

  7. Dual diathesis-stressor model of emotional and linguistic contributions to developmental stuttering.

    Science.gov (United States)

    Walden, Tedra A; Frankel, Carl B; Buhr, Anthony P; Johnson, Kia N; Conture, Edward G; Karrass, Jan M

    2012-05-01

    This study assessed emotional and speech-language contributions to childhood stuttering. A dual diathesis-stressor framework guided this study, in which both linguistic requirements and skills, and emotion and its regulation, are hypothesized to contribute to stuttering. The language diathesis consists of expressive and receptive language skills. The emotion diathesis consists of proclivities to emotional reactivity and regulation of emotion, and the emotion stressor consists of experimentally manipulated emotional inductions prior to narrative speaking tasks. Preschool-age children who do and do not stutter were exposed to three emotion-producing overheard conversations-neutral, positive, and angry. Emotion and emotion-regulatory behaviors were coded while participants listened to each conversation and while telling a story after each overheard conversation. Instances of stuttering during each story were counted. Although there was no main effect of conversation type, results indicated that stuttering in preschool-age children is influenced by emotion and language diatheses, as well as coping strategies and situational emotional stressors. Findings support the dual diathesis-stressor model of stuttering.

  8. Evolution in performance assessment modeling as a result of regulatory review

    Energy Technology Data Exchange (ETDEWEB)

    Rowat, J.H.; Dolinar, G.M.; Stephens, M.E. [AECL Chalk River Labs., Ontario (Canada)] [and others

    1995-12-31

    AECL is planning to build the IRUS (Intrusion Resistant Underground Structure) facility for near-surface disposal of LLRW. The PSAR (preliminary safety assessment report) was subject to an initial regulatory review during mid-1992. The regulatory authority provided comments on many aspects of the safety assessment documentation including a number of questions on specific PA (Performance Assessment) modelling assumptions. As a result of these comments as well as a separate detailed review of the IRUS disposal concept, changes were made to the conceptual and mathematical models. The original disposal concept included a non-sorbing vault backfill, with a strong reliance on the wasteform as a barrier. This concept was altered to decrease reliance on the wasteform by replacing the original backfill with a sand/clinoptilolite mix, which is a better sorber of metal cations. This change lead to changes in the PA models which in turn altered the safety case for the facility. This, and other changes that impacted performance assessment modelling are the subject of this paper.

  9. A Framework for Organizing Current and Future Electric Utility Regulatory and Business Models

    Energy Technology Data Exchange (ETDEWEB)

    Satchwell, Andrew [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Cappers, Peter [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Schwartz, Lisa C. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Fadrhonc, Emily Martin [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2015-06-01

    Many regulators, utilities, customer groups, and other stakeholders are reevaluating existing regulatory models and the roles and financial implications for electric utilities in the context of today’s environment of increasing distributed energy resource (DER) penetrations, forecasts of significant T&D investment, and relatively flat or negative utility sales growth. When this is coupled with predictions about fewer grid-connected customers (i.e., customer defection), there is growing concern about the potential for serious negative impacts on the regulated utility business model. Among states engaged in these issues, the range of topics under consideration is broad. Most of these states are considering whether approaches that have been applied historically to mitigate the impacts of previous “disruptions” to the regulated utility business model (e.g., energy efficiency) as well as to align utility financial interests with increased adoption of such “disruptive technologies” (e.g., shareholder incentive mechanisms, lost revenue mechanisms) are appropriate and effective in the present context. A handful of states are presently considering more fundamental changes to regulatory models and the role of regulated utilities in the ownership, management, and operation of electric delivery systems (e.g., New York “Reforming the Energy Vision” proceeding).

  10. The Regulatory Machinery of Neurodegeneration in In Vitro Models of Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Burcin Ikiz

    2015-07-01

    Full Text Available Neurodegenerative phenotypes reflect complex, time-dependent molecular processes whose elucidation may reveal neuronal class-specific therapeutic targets. The current focus in neurodegeneration has been on individual genes and pathways. In contrast, we assembled a genome-wide regulatory model (henceforth, “interactome”, whose unbiased interrogation revealed 23 candidate causal master regulators of neurodegeneration in an in vitro model of amyotrophic lateral sclerosis (ALS, characterized by a loss of spinal motor neurons (MNs. Of these, eight were confirmed as specific MN death drivers in our model of familial ALS, including NF-κB, which has long been considered a pro-survival factor. Through an extensive array of molecular, pharmacological, and biochemical approaches, we have confirmed that neuronal NF-κB drives the degeneration of MNs in both familial and sporadic models of ALS, thus providing proof of principle that regulatory network analysis is a valuable tool for studying cell-specific mechanisms of neurodegeneration.

  11. Root Systems Biology: Integrative Modeling across Scales, from Gene Regulatory Networks to the Rhizosphere1

    Science.gov (United States)

    Hill, Kristine; Porco, Silvana; Lobet, Guillaume; Zappala, Susan; Mooney, Sacha; Draye, Xavier; Bennett, Malcolm J.

    2013-01-01

    Genetic and genomic approaches in model organisms have advanced our understanding of root biology over the last decade. Recently, however, systems biology and modeling have emerged as important approaches, as our understanding of root regulatory pathways has become more complex and interpreting pathway outputs has become less intuitive. To relate root genotype to phenotype, we must move beyond the examination of interactions at the genetic network scale and employ multiscale modeling approaches to predict emergent properties at the tissue, organ, organism, and rhizosphere scales. Understanding the underlying biological mechanisms and the complex interplay between systems at these different scales requires an integrative approach. Here, we describe examples of such approaches and discuss the merits of developing models to span multiple scales, from network to population levels, and to address dynamic interactions between plants and their environment. PMID:24143806

  12. Topsy-Turvy Neo-Developmentalism: An Analysis of the Current Brazilian Model of Development

    Directory of Open Access Journals (Sweden)

    Bruno Milanez

    2015-09-01

    Full Text Available The paper discusses the similarities and differences between neo-developmentalism and neo-extractivism. The evaluation compares Brazil with nine other Latin American countries and is based on a framework that considers both economic policies and their outcomes. On the policy side, it looks at income, monetary, international trade, industrial and mineral resource policies; on the outcome side, it observes the composition of both exports and the Gross Domestic Product. In the end, we argue that neo-developmentalism and neo-extractivism are actually variations of the same development route and may face similar challenges in the long term.

  13. Model checking optimal finite-horizon control for probabilistic gene regulatory networks.

    Science.gov (United States)

    Wei, Ou; Guo, Zonghao; Niu, Yun; Liao, Wenyuan

    2017-12-14

    Probabilistic Boolean networks (PBNs) have been proposed for analyzing external control in gene regulatory networks with incorporation of uncertainty. A context-sensitive PBN with perturbation (CS-PBNp), extending a PBN with context-sensitivity to reflect the inherent biological stability and random perturbations to express the impact of external stimuli, is considered to be more suitable for modeling small biological systems intervened by conditions from the outside. In this paper, we apply probabilistic model checking, a formal verification technique, to optimal control for a CS-PBNp that minimizes the expected cost over a finite control horizon. We first describe a procedure of modeling a CS-PBNp using the language provided by a widely used probabilistic model checker PRISM. We then analyze the reward-based temporal properties and the computation in probabilistic model checking; based on the analysis, we provide a method to formulate the optimal control problem as minimum reachability reward properties. Furthermore, we incorporate control and state cost information into the PRISM code of a CS-PBNp such that automated model checking a minimum reachability reward property on the code gives the solution to the optimal control problem. We conduct experiments on two examples, an apoptosis network and a WNT5A network. Preliminary experiment results show the feasibility and effectiveness of our approach. The approach based on probabilistic model checking for optimal control avoids explicit computation of large-size state transition relations associated with PBNs. It enables a natural depiction of the dynamics of gene regulatory networks, and provides a canonical form to formulate optimal control problems using temporal properties that can be automated solved by leveraging the analysis power of underlying model checking engines. This work will be helpful for further utilization of the advances in formal verification techniques in system biology.

  14. Site-specific parameter values for the Nuclear Regulatory Commission's food pathway dose model

    International Nuclear Information System (INIS)

    Hamby, D.M.

    1992-01-01

    Routine operations at the Savannah River Site (SRS) in Western South Carolina result in radionuclide releases to the atmosphere and to the Savannah River. The resulting radiation doses to the off-site maximum individual and the off-site population within 80 km of the SRS are estimated on a yearly basis. These estimates are currently generated using dose models prescribed for the commercial nuclear power industry by the Nuclear Regulatory Commission (NRC). The NRC provides default values for dose-model parameters for facilities without resources to develop site-specific values. A survey of land- and water-use characteristics for the Savannah River area has been conducted to determine site-specific values for water recreation, consumption, and agricultural parameters used in the NRC Regulatory Guide 1.109 (1977) dosimetric models. These site parameters include local characteristics of meat, milk, and vegetable production; recreational and commercial activities on the Savannah River; and meat, milk, vegetable, and seafood consumption rates. This paper describes how parameter data were obtained at the Savannah River Site and the impacts of such data on off-site dose. Dose estimates using site-specific parameter values are compared to estimates using the NRC default values

  15. Diversity and plasticity of Th cell types predicted from regulatory network modelling.

    Directory of Open Access Journals (Sweden)

    Aurélien Naldi

    Full Text Available Alternative cell differentiation pathways are believed to arise from the concerted action of signalling pathways and transcriptional regulatory networks. However, the prediction of mammalian cell differentiation from the knowledge of the presence of specific signals and transcriptional factors is still a daunting challenge. In this respect, the vertebrate hematopoietic system, with its many branching differentiation pathways and cell types, is a compelling case study. In this paper, we propose an integrated, comprehensive model of the regulatory network and signalling pathways controlling Th cell differentiation. As most available data are qualitative, we rely on a logical formalism to perform extensive dynamical analyses. To cope with the size and complexity of the resulting network, we use an original model reduction approach together with a stable state identification algorithm. To assess the effects of heterogeneous environments on Th cell differentiation, we have performed a systematic series of simulations considering various prototypic environments. Consequently, we have identified stable states corresponding to canonical Th1, Th2, Th17 and Treg subtypes, but these were found to coexist with other transient hybrid cell types that co-express combinations of Th1, Th2, Treg and Th17 markers in an environment-dependent fashion. In the process, our logical analysis highlights the nature of these cell types and their relationships with canonical Th subtypes. Finally, our logical model can be used to explore novel differentiation pathways in silico.

  16. Inflammation, Self-Regulation, and Health: An Immunologic Model of Self-Regulatory Failure.

    Science.gov (United States)

    Shields, Grant S; Moons, Wesley G; Slavich, George M

    2017-07-01

    Self-regulation is a fundamental human process that refers to multiple complex methods by which individuals pursue goals in the face of distractions. Whereas superior self-regulation predicts better academic achievement, relationship quality, financial and career success, and lifespan health, poor self-regulation increases a person's risk for negative outcomes in each of these domains and can ultimately presage early mortality. Given its centrality to understanding the human condition, a large body of research has examined cognitive, emotional, and behavioral aspects of self-regulation. In contrast, relatively little attention has been paid to specific biologic processes that may underlie self-regulation. We address this latter issue in the present review by examining the growing body of research showing that components of the immune system involved in inflammation can alter neural, cognitive, and motivational processes that lead to impaired self-regulation and poor health. Based on these findings, we propose an integrated, multilevel model that describes how inflammation may cause widespread biobehavioral alterations that promote self-regulatory failure. This immunologic model of self-regulatory failure has implications for understanding how biological and behavioral factors interact to influence self-regulation. The model also suggests new ways of reducing disease risk and enhancing human potential by targeting inflammatory processes that affect self-regulation.

  17. Differentiating human NT2/D1 neurospheres as a versatile in vitro 3D model system for developmental neurotoxicity testing

    International Nuclear Information System (INIS)

    Hill, E.J.; Woehrling, E.K.; Prince, M.; Coleman, M.D.

    2008-01-01

    Developmental neurotoxicity is a major issue in human health and may have lasting neurological implications. In this preliminary study we exposed differentiating Ntera2/clone D1 (NT2/D1) cell neurospheres to known human teratogens classed as non-embryotoxic (acrylamide), weakly embryotoxic (lithium, valproic acid) and strongly embryotoxic (hydroxyurea) as listed by European Centre for the Validation of Alternative Methods (ECVAM) and examined endpoints of cell viability and neuronal protein marker expression specific to the central nervous system, to identify developmental neurotoxins. Following induction of neuronal differentiation, valproic acid had the most significant effect on neurogenesis, in terms of reduced viability and decreased neuronal markers. Lithium had least effect on viability and did not significantly alter the expression of neuronal markers. Hydroxyurea significantly reduced cell viability but did not affect neuronal protein marker expression. Acrylamide reduced neurosphere viability but did not affect neuronal protein marker expression. Overall, this NT2/D1-based neurosphere model of neurogenesis, may provide the basis for a model of developmental neurotoxicity in vitro

  18. Mouse model of chromosome mosaicism reveals lineage-specific depletion of aneuploid cells and normal developmental potential.

    Science.gov (United States)

    Bolton, Helen; Graham, Sarah J L; Van der Aa, Niels; Kumar, Parveen; Theunis, Koen; Fernandez Gallardo, Elia; Voet, Thierry; Zernicka-Goetz, Magdalena

    2016-03-29

    Most human pre-implantation embryos are mosaics of euploid and aneuploid cells. To determine the fate of aneuploid cells and the developmental potential of mosaic embryos, here we generate a mouse model of chromosome mosaicism. By treating embryos with a spindle assembly checkpoint inhibitor during the four- to eight-cell division, we efficiently generate aneuploid cells, resulting in embryo death during peri-implantation development. Live-embryo imaging and single-cell tracking in chimeric embryos, containing aneuploid and euploid cells, reveal that the fate of aneuploid cells depends on lineage: aneuploid cells in the fetal lineage are eliminated by apoptosis, whereas those in the placental lineage show severe proliferative defects. Overall, the proportion of aneuploid cells is progressively depleted from the blastocyst stage onwards. Finally, we show that mosaic embryos have full developmental potential, provided they contain sufficient euploid cells, a finding of significance for the assessment of embryo vitality in the clinic.

  19. Imitation, Sign Language Skill and the Developmental Ease of Language Understanding (D-ELU) Model.

    Science.gov (United States)

    Holmer, Emil; Heimann, Mikael; Rudner, Mary

    2016-01-01

    account. These results demonstrate that experience of sign language enhances the ability to imitate manual gestures once representations have been established, and suggest that the inherent motor patterns of lexical manual gestures are better suited for representation than those of non-signs. This set of findings prompts a developmental version of the ELU model, D-ELU.

  20. Imitation, sign language skill and the Developmental Ease of Language Understanding (D-ELU model

    Directory of Open Access Journals (Sweden)

    Emil eHolmer

    2016-02-01

    were taken into account. These results demonstrate that experience of sign language enhances the ability to imitate manual gestures once representations have been established, and suggest that the inherent motor patterns of lexical manual gestures are better suited for representation than those of non-signs. This set of findings prompts a developmental version of the ELU model, D-ELU.

  1. Dual Processes in Decision Making and Developmental Neuroscience: A Fuzzy-Trace Model

    Science.gov (United States)

    Reyna, Valerie F.; Brainerd, Charles J.

    2011-01-01

    From Piaget to the present, traditional and dual-process theories have predicted improvement in reasoning from childhood to adulthood, and improvement has been observed. However, developmental reversals--that reasoning biases emerge with development--have also been observed in a growing list of paradigms. We explain how fuzzy-trace theory predicts…

  2. The Developmental Model of Intercultural Sensitivity: A Tool for Understanding Principals' Cultural Competence

    Science.gov (United States)

    Hernandez, Frank; Kose, Brad W.

    2012-01-01

    Principals' understanding and skills pertaining to diversity are important in leading diverse schools and preparing all students for a democratic and multicultural society. Although educational leadership scholars have theorized about exemplary leadership of and for diversity, a developmental perspective on principals' diversity or cultural…

  3. Handwriting-Based Model for Identification of Developmental Disorders among North Indian Children

    Science.gov (United States)

    Dhall, Jasmine Kaur

    2016-01-01

    Handwriting execution is based on the cognitive, kinesthetic, motor skills, and manual co-ordination skills of an individual. The deterioration in handwriting quality is a common implication of neurological disorders. Difficulty and degradation in handwriting has been attributed to the sensory motor deficits prevalent in developmental disorders.…

  4. A Biosocial Developmental Model of Borderline Personality: Elaborating and Extending Linehan's Theory

    Science.gov (United States)

    Crowell, Sheila E.; Beauchaine, Theodore P.; Linehan, Marsha M.

    2009-01-01

    Over the past several decades, research has focused increasingly on developmental precursors to psychological disorders that were previously assumed to emerge only in adulthood. This change in focus follows from the recognition that complex transactions between biological vulnerabilities and psychosocial risk factors shape emotional and behavioral…

  5. Formal modeling and analysis of ER-α associated Biological Regulatory Network in breast cancer

    Directory of Open Access Journals (Sweden)

    Samra Khalid

    2016-10-01

    Full Text Available Background Breast cancer (BC is one of the leading cause of death among females worldwide. The increasing incidence of BC is due to various genetic and environmental changes which lead to the disruption of cellular signaling network(s. It is a complex disease in which several interlinking signaling cascades play a crucial role in establishing a complex regulatory network. The logical modeling approach of René Thomas has been applied to analyze the behavior of estrogen receptor-alpha (ER-α associated Biological Regulatory Network (BRN for a small part of complex events that leads to BC metastasis. Methods A discrete model was constructed using the kinetic logic formalism and its set of logical parameters were obtained using the model checking technique implemented in the SMBioNet software which is consistent with biological observations. The discrete model was further enriched with continuous dynamics by converting it into an equivalent Petri Net (PN to analyze the logical parameters of the involved entities. Results In-silico based discrete and continuous modeling of ER-α associated signaling network involved in BC provides information about behaviors and gene-gene interaction in detail. The dynamics of discrete model revealed, imperative behaviors represented as cyclic paths and trajectories leading to pathogenic states such as metastasis. Results suggest that the increased expressions of receptors ER-α, IGF-1R and EGFR slow down the activity of tumor suppressor genes (TSGs such as BRCA1, p53 and Mdm2 which can lead to metastasis. Therefore, IGF-1R and EGFR are considered as important inhibitory targets to control the metastasis in BC. Conclusion The in-silico approaches allow us to increase our understanding of the functional properties of living organisms. It opens new avenues of investigations of multiple inhibitory targets (ER-α, IGF-1R and EGFR for wet lab experiments as well as provided valuable insights in the treatment of cancers

  6. Recurrent neural network based hybrid model for reconstructing gene regulatory network.

    Science.gov (United States)

    Raza, Khalid; Alam, Mansaf

    2016-10-01

    One of the exciting problems in systems biology research is to decipher how genome controls the development of complex biological system. The gene regulatory networks (GRNs) help in the identification of regulatory interactions between genes and offer fruitful information related to functional role of individual gene in a cellular system. Discovering GRNs lead to a wide range of applications, including identification of disease related pathways providing novel tentative drug targets, helps to predict disease response, and also assists in diagnosing various diseases including cancer. Reconstruction of GRNs from available biological data is still an open problem. This paper proposes a recurrent neural network (RNN) based model of GRN, hybridized with generalized extended Kalman filter for weight update in backpropagation through time training algorithm. The RNN is a complex neural network that gives a better settlement between biological closeness and mathematical flexibility to model GRN; and is also able to capture complex, non-linear and dynamic relationships among variables. Gene expression data are inherently noisy and Kalman filter performs well for estimation problem even in noisy data. Hence, we applied non-linear version of Kalman filter, known as generalized extended Kalman filter, for weight update during RNN training. The developed model has been tested on four benchmark networks such as DNA SOS repair network, IRMA network, and two synthetic networks from DREAM Challenge. We performed a comparison of our results with other state-of-the-art techniques which shows superiority of our proposed model. Further, 5% Gaussian noise has been induced in the dataset and result of the proposed model shows negligible effect of noise on results, demonstrating the noise tolerance capability of the model. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Implementation, availability and regulatory status of an OECD accepted Reconstructed Human Epidermis model in Brazil

    Directory of Open Access Journals (Sweden)

    Rodrigo De Vecchi

    2018-02-01

    Full Text Available Introduction: In 2014, Brazil has joined the growing list of countries to ban cosmetic products from being tested on animal models. The new legislation comes into force in 2019. As a result, the interest for validated alternative testing methods for safety assessment has been increasing in academia, industry and associations. However, the lack of specific legislation on the use of biological material of human origin for toxicological tests makes the access to alternative in vitro models difficult. Furthermore, importation to Brazil is not possible on timely manner. Method: In this article, we report the implementation process of a Reconstructed Human Epidermis (SkinEthic™ RHE, an alternative model internationally accepted by OECD, through a technology transfer from EPISKIN® Lyon to Brazil. Regulatory evolution has been motivating the implementation and wide use of alternative methods to animal testing in several industry segments including cosmetic and pharmaceutical. Results: Protocol has been shown to be robust and highly reproducible. Quality control parameters (histological analysis, barrier function test and tissue viability were performed on 24 batches assembled in Brazil. SkinEthic™ RHE model use allows the full replacement of animal test methods for skin hazards identification. It has regulatory acceptance for several toxicological endpoints, such as the Draize test for skin irritation and corrosion. It allows the reduction and refining of pre-clinical protocols through tiered strategies. Implementation of SkinEthic™ RHE protocol is just a first and important step towards a new approach of toxicological safety testing in Brazil. Conclusion: The implementation was successfully done and reported here. However, in order to follow completely the new legislation up to 2019, the availability of validated models is essential. Quality control tests done on RHE batches produced in Brazil demonstrate that the model met OECD acceptance

  8. Regulatory activity based risk model identifies survival of stage II and III colorectal carcinoma.

    Science.gov (United States)

    Liu, Gang; Dong, Chuanpeng; Wang, Xing; Hou, Guojun; Zheng, Yu; Xu, Huilin; Zhan, Xiaohui; Liu, Lei

    2017-11-17

    Clinical and pathological indicators are inadequate for prognosis of stage II and III colorectal carcinoma (CRC). In this study, we utilized the activity of regulatory factors, univariate Cox regression and random forest for variable selection and developed a multivariate Cox model to predict the overall survival of Stage II/III colorectal carcinoma in GSE39582 datasets (469 samples). Patients in low-risk group showed a significant longer overall survival and recurrence-free survival time than those in high-risk group. This finding was further validated in five other independent datasets (GSE14333, GSE17536, GSE17537, GSE33113, and GSE37892). Besides, associations between clinicopathological information and risk score were analyzed. A nomogram including risk score was plotted to facilitate the utilization of risk score. The risk score model is also demonstrated to be effective on predicting both overall and recurrence-free survival of chemotherapy received patients. After performing Gene Set Enrichment Analysis (GSEA) between high and low risk groups, we found that several cell-cell interaction KEGG pathways were identified. Funnel plot results showed that there was no publication bias in these datasets. In summary, by utilizing the regulatory activity in stage II and III colorectal carcinoma, the risk score successfully predicts the survival of 1021 stage II/III CRC patients in six independent datasets.

  9. An investment-production-regulatory model for firms in the offshore oil and gas industry

    International Nuclear Information System (INIS)

    Jin Di.

    1991-01-01

    This tripartite study examines the economic consequences of proposed environmental regulations on firms in the OCS oil and gas industry. The background part reviews the major issues associated with OCS oil and gas development and relevant environmental regulatory proposals. In the theoretical part, models are developed using optimal control theory and the theory of nonrenewable resources to analyze the impact of rising compliance cost on firm's behavior in terms of the investment and production rates over time. Finally, in the simulation part, an integrated investment-production-regulatory model is developed to simulate OCS development with and without the proposed environmental regulations. Effects of regulations are measured in terms of an increase in compliance costs and the associated reduction in net profits from oil and gas production. The theoretical results indicate that an increase in compliance costs will alter exploration, development and production rates. The total investments in exploration and development, and oil production will decrease as a result of rising compliance costs for exploration, development and production over the entire planning period

  10. Quantitative developmental transcriptomes of the Mediterranean sea urchin Paracentrotus lividus.

    Science.gov (United States)

    Gildor, Tsvia; Malik, Assaf; Sher, Noa; Avraham, Linor; Ben-Tabou de-Leon, Smadar

    2016-02-01

    Embryonic development progresses through the timely activation of thousands of differentially activated genes. Quantitative developmental transcriptomes provide the means to relate global patterns of differentially expressed genes to the emerging body plans they generate. The sea urchin is one of the classic model systems for embryogenesis and the models of its developmental gene regulatory networks are of the most comprehensive of their kind. Thus, the sea urchin embryo is an excellent system for studies of its global developmental transcriptional profiles. Here we produced quantitative developmental transcriptomes of the sea urchin Paracentrotus lividus (P. lividus) at seven developmental stages from the fertilized egg to prism stage. We generated de-novo reference transcriptome and identified 29,817 genes that are expressed at this time period. We annotated and quantified gene expression at the different developmental stages and confirmed the reliability of the expression profiles by QPCR measurement of a subset of genes. The progression of embryo development is reflected in the observed global expression patterns and in our principle component analysis. Our study illuminates the rich patterns of gene expression that participate in sea urchin embryogenesis and provide an essential resource for further studies of the dynamic expression of P. lividus genes. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. Control of Stochastic Master Equation Models of Genetic Regulatory Networks by Approximating Their Average Behavior

    Science.gov (United States)

    Umut Caglar, Mehmet; Pal, Ranadip

    2010-10-01

    The central dogma of molecular biology states that ``information cannot be transferred back from protein to either protein or nucleic acid.'' However, this assumption is not exactly correct in most of the cases. There are a lot of feedback loops and interactions between different levels of systems. These types of interactions are hard to analyze due to the lack of data in the cellular level and probabilistic nature of interactions. Probabilistic models like Stochastic Master Equation (SME) or deterministic models like differential equations (DE) can be used to analyze these types of interactions. SME models based on chemical master equation (CME) can provide detailed representation of genetic regulatory system, but their use is restricted by the large data requirements and computational costs of calculations. The differential equations models on the other hand, have low calculation costs and much more adequate to generate control procedures on the system; but they are not adequate to investigate the probabilistic nature of interactions. In this work the success of the mapping between SME and DE is analyzed, and the success of a control policy generated by DE model with respect to SME model is examined. Index Terms--- Stochastic Master Equation models, Differential Equation Models, Control Policy Design, Systems biology

  12. Social insect colony as a biological regulatory system: modelling information flow in dominance networks.

    Science.gov (United States)

    Nandi, Anjan K; Sumana, Annagiri; Bhattacharya, Kunal

    2014-12-06

    Social insects provide an excellent platform to investigate flow of information in regulatory systems since their successful social organization is essentially achieved by effective information transfer through complex connectivity patterns among the colony members. Network representation of such behavioural interactions offers a powerful tool for structural as well as dynamical analysis of the underlying regulatory systems. In this paper, we focus on the dominance interaction networks in the tropical social wasp Ropalidia marginata-a species where behavioural observations indicate that such interactions are principally responsible for the transfer of information between individuals about their colony needs, resulting in a regulation of their own activities. Our research reveals that the dominance networks of R. marginata are structurally similar to a class of naturally evolved information processing networks, a fact confirmed also by the predominance of a specific substructure-the 'feed-forward loop'-a key functional component in many other information transfer networks. The dynamical analysis through Boolean modelling confirms that the networks are sufficiently stable under small fluctuations and yet capable of more efficient information transfer compared to their randomized counterparts. Our results suggest the involvement of a common structural design principle in different biological regulatory systems and a possible similarity with respect to the effect of selection on the organization levels of such systems. The findings are also consistent with the hypothesis that dominance behaviour has been shaped by natural selection to co-opt the information transfer process in such social insect species, in addition to its primal function of mediation of reproductive competition in the colony. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

  13. Modeling disease risk through analysis of physical interactions between genetic variants within chromatin regulatory circuitry.

    Science.gov (United States)

    Corradin, Olivia; Cohen, Andrea J; Luppino, Jennifer M; Bayles, Ian M; Schumacher, Fredrick R; Scacheri, Peter C

    2016-11-01

    SNPs associated with disease susceptibility often reside in enhancer clusters, or super-enhancers. Constituents of these enhancer clusters cooperate to regulate target genes and often extend beyond the linkage disequilibrium (LD) blocks containing risk SNPs identified in genome-wide association studies (GWAS). We identified 'outside variants', defined as SNPs in weak LD with GWAS risk SNPs that physically interact with risk SNPs as part of a target gene's regulatory circuitry. These outside variants further explain variation in target gene expression beyond that explained by GWAS-associated SNPs. Additionally, the clinical risk associated with GWAS SNPs is considerably modified by the genotype of outside variants. Collectively, these findings suggest a potential model in which outside variants and GWAS SNPs that physically interact in 3D chromatin collude to influence target transcript levels as well as clinical risk. This model offers an additional hypothesis for the source of missing heritability for complex traits.

  14. Using consensus bayesian network to model the reactive oxygen species regulatory pathway.

    Directory of Open Access Journals (Sweden)

    Liangdong Hu

    Full Text Available Bayesian network is one of the most successful graph models for representing the reactive oxygen species regulatory pathway. With the increasing number of microarray measurements, it is possible to construct the bayesian network from microarray data directly. Although large numbers of bayesian network learning algorithms have been developed, when applying them to learn bayesian networks from microarray data, the accuracies are low due to that the databases they used to learn bayesian networks contain too few microarray data. In this paper, we propose a consensus bayesian network which is constructed by combining bayesian networks from relevant literatures and bayesian networks learned from microarray data. It would have a higher accuracy than the bayesian networks learned from one database. In the experiment, we validated the bayesian network combination algorithm on several classic machine learning databases and used the consensus bayesian network to model the Escherichia coli's ROS pathway.

  15. Modeling the Developmental Patterns of Auditory Evoked Magnetic Fields in Children

    OpenAIRE

    Kotecha, Rupesh; Pardos, Maria; Wang, Yingying; Wu, Ting; Horn, Paul; Brown, David; Rose, Douglas; deGrauw, Ton; Xiang, Jing

    2009-01-01

    BACKGROUND: As magnetoencephalography (MEG) is of increasing utility in the assessment of deficits and development delays in brain disorders in pediatrics, it becomes imperative to fully understand the functional development of the brain in children. METHODOLOGY: The present study was designed to characterize the developmental patterns of auditory evoked magnetic responses with respect to age and gender. Sixty children and twenty adults were studied with a 275-channel MEG system. CONCLUSIONS:...

  16. Developmental Database for Phenology Models: Related Insect and Mite Species Have Similar Thermal Requirements

    Czech Academy of Sciences Publication Activity Database

    Jarošík, Vojtěch; Honěk, A.; Magarey, R. D.; Skuhrovec, J.

    2011-01-01

    Roč. 104, č. 6 (2011), s. 1870-1876 ISSN 0022-0493 R&D Projects: GA MŠk LC06073; GA ČR GA206/09/0563 Grant - others:European Comission(XE) 212459 Program:FP7 Institutional support: RVO:67985939 Keywords : lower developmental threshold * base temperature * rate of development Subject RIV: EH - Ecology, Behaviour OBOR OECD: Ecology Impact factor: 1.699, year: 2011

  17. Abnormal Stress Responsivity in a Rodent Developmental Disruption Model of Schizophrenia

    OpenAIRE

    Zimmerman, Eric C; Bellaire, Mark; Ewing, Samuel G; Grace, Anthony A

    2013-01-01

    Although numerous studies have implicated stress in the pathophysiology of schizophrenia, less is known about how the effects of stress interact with genetic, developmental, and/or environmental determinants to promote disease progression. In particular, it has been proposed that in humans, stress exposure in adolescence could combine with a predisposition towards increased stress sensitivity, leading to prodromal symptoms and eventually psychosis. However, the neurobiological substrates for ...

  18. Is Freedom Contagious? A Self-Regulatory Model of Reactance and Sensitivity to Deviant Peers.

    Science.gov (United States)

    Leander, N Pontus; vanDellen, Michelle R; Rachl-Willberger, Judith; Shah, James Y; Fitzsimons, Gavan J; Chartrand, Tanya L

    2016-12-01

    Psychological reactance is typically assumed to motivate resistance to controlling peer influences and societal prohibitions. However, some peer influences encourage behaviors prohibited by society. We consider whether reactant individuals are sensitive to such opportunities to enhance their autonomy. We specifically propose a self-regulatory perspective on reactance, wherein freedom/autonomy is the superordinate goal, and thus highly reactant individuals will be sensitive to peer influences that could enhance their behavioral freedoms. In two studies, we find that reactant individuals can be cooperative in response to autonomy-supportive peer influences. Participants read a scenario in which a peer's intentions to engage in substance use were manipulated to imply freedom of choice or not. Results indicated that highly reactant participants were sensitive to deviant peers whose own behavior towards alcohol (Study 1, N = 160) or marijuana (Study 2, N = 124) appeared to be motivated by autonomy and thus afforded free choice. Altogether, the results support a self-regulatory model of reactance, wherein deviant peer influence can be a means to pursue autonomy.

  19. The Zebrafish Models to Explore Genetic and Epigenetic Impacts on Evolutionary Developmental Origins of Aging

    Science.gov (United States)

    Kishi, Shuji

    2014-01-01

    Can we reset, reprogram, rejuvenate or reverse the organismal aging process? Certain genetic manipulations could at least reset and reprogram epigenetic dynamics beyond phenotypic plasticity and elasticity in cells, which can be further manipulated into organisms. However, in a whole complex aging organism, how can we rejuvenate intrinsic resources and infrastructures in an intact/noninvasive manner? The incidence of diseases increases exponentially with age, accompanied by progressive deteriorations of physiological functions in organisms. Aging-associated diseases are sporadic but essentially inevitable complications arising from senescence. Senescence is often considered the antithesis of early development, but yet there may be factors and mechanisms in common between these two phenomena to rejuvenate over the dynamic process of aging. The association between early development and late-onset disease with advancing age is thought to come from a consequence of developmental plasticity, the phenomenon by which one genotype can give rise to a range of physiologically and/or morphologically adaptive states based on diverse epigenotypes, in response to intrinsic or extrinsic environmental cues and genetic perturbations. We hypothesized that the future aging process can be predictive based on adaptivity during the early developmental period. Modulating the thresholds and windows of plasticity and its robustness by molecular genetic and chemical epigenetic approaches, we have successfully conducted experiments to isolate zebrafish mutants expressing apparently altered senescence phenotypes during their embryonic and/or larval stages (“embryonic/larval senescence”). Subsequently, at least some of these mutant animals were found to show shortened lifespan, while some others would be expected to live longer in adulthoods. We anticipate that previously uncharacterized developmental genes may mediate the aging process and play a pivotal role in senescence. On the other

  20. Is there room for 'development' in developmental models of information processing biases to threat in children and adolescents?

    Science.gov (United States)

    Field, Andy P; Lester, Kathryn J

    2010-12-01

    Clinical and experimental theories assume that processing biases in attention and interpretation are a causal mechanism through which anxiety develops. Despite growing evidence that these processing biases are present in children and, therefore, develop long before adulthood, these theories ignore the potential role of child development. This review attempts to place information processing biases within a theoretical developmental framework. We consider whether child development has no impact on information processing biases to threat (integral bias model), or whether child development influences information processing biases and if so whether it does so by moderating the expression of an existing bias (moderation model) or by affecting the acquisition of a bias (acquisition model). We examine the extent to which these models fit with existing theory and research evidence and outline some methodological issues that need to be considered when drawing conclusions about the potential role of child development in the information processing of threat stimuli. Finally, we speculate about the developmental processes that might be important to consider in future research.

  1. Using nursing intervention classification in an advance practice registered nurse-led preventive model for adults aging with developmental disabilities.

    Science.gov (United States)

    Hahn, Joan Earle

    2014-09-01

    To describe the most frequently reported and the most central nursing interventions in an advance practice registered nurse (APRN)-led in-home preventive intervention model for adults aging with developmental disabilities using the Nursing Intervention Classification (NIC) system. A descriptive data analysis and a market basket analysis were conducted on de-identified nominal nursing intervention data from two home visits conducted by nurse practitioners (NPs) from October 2010 to June 2012 for 80 community-dwelling adults with developmental disabilities, ages 29 to 68 years. The mean number of NIC interventions was 4.7 in the first visit and 6.0 in the second visit and last visit. NPs reported 45 different intervention types as classified using a standardized language, with 376 in Visit One and 470 in Visit Two. Approximately 85% of the sample received the Health education intervention. The market basket analysis revealed common pairs, triples, and quadruple sets of interventions in this preventive model. The NIC nursing interventions that occurred together repeatedly were: Health education, Weight management, Nutrition management, Health screening, and Behavior management. Five NIC interventions form the basis of an APRN-led preventive intervention model for individuals aging with lifelong disability, with health education as the most common intervention, combined with interventions to manage weight and nutrition, promote healthy behaviors, and encourage routine health screening. Less frequently reported NIC interventions suggest the need to tailor prevention to individual needs, whether acute or chronic. APRNs employing prevention among adults aging with developmental disabilities must anticipate the need to focus on health education strategies for health promotion and prevention as well as tailor and target a patient-centered approach to support self-management of health to promote healthy aging in place. These NIC interventions serve not only as a guide for

  2. Tracking of time-varying genomic regulatory networks with a LASSO-Kalman smoother

    OpenAIRE

    Khan, Jehandad; Bouaynaya, Nidhal; Fathallah-Shaykh, Hassan M

    2014-01-01

    It is widely accepted that cellular requirements and environmental conditions dictate the architecture of genetic regulatory networks. Nonetheless, the status quo in regulatory network modeling and analysis assumes an invariant network topology over time. In this paper, we refocus on a dynamic perspective of genetic networks, one that can uncover substantial topological changes in network structure during biological processes such as developmental growth. We propose a novel outlook on the inf...

  3. Modelling the bioaccumulation of persistent organic pollutants in agricultural food chains for regulatory exposure assessment.

    Science.gov (United States)

    Takaki, Koki; Wade, Andrew J; Collins, Chris D

    2017-02-01

    New models for estimating bioaccumulation of persistent organic pollutants in the agricultural food chain were developed using recent improvements to plant uptake and cattle transfer models. One model named AgriSim was based on K OW regressions of bioaccumulation in plants and cattle, while the other was a steady-state mechanistic model, AgriCom. The two developed models and European Union System for the Evaluation of Substances (EUSES), as a benchmark, were applied to four reported food chain (soil/air-grass-cow-milk) scenarios to evaluate the performance of each model simulation against the observed data. The four scenarios considered were as follows: (1) polluted soil and air, (2) polluted soil, (3) highly polluted soil surface and polluted subsurface and (4) polluted soil and air at different mountain elevations. AgriCom reproduced observed milk bioaccumulation well for all four scenarios, as did AgriSim for scenarios 1 and 2, but EUSES only did this for scenario 1. The main causes of the deviation for EUSES and AgriSim were the lack of the soil-air-plant pathway and the ambient air-plant pathway, respectively. Based on the results, it is recommended that soil-air-plant and ambient air-plant pathway should be calculated separately and the K OW regression of transfer factor to milk used in EUSES be avoided. AgriCom satisfied the recommendations that led to the low residual errors between the simulated and the observed bioaccumulation in agricultural food chain for the four scenarios considered. It is therefore recommended that this model should be incorporated into regulatory exposure assessment tools. The model uncertainty of the three models should be noted since the simulated concentration in milk from 5th to 95th percentile of the uncertainty analysis often varied over two orders of magnitude. Using a measured value of soil organic carbon content was effective to reduce this uncertainty by one order of magnitude.

  4. Mutual inactivation of Notch receptors and ligands facilitates developmental patterning.

    Directory of Open Access Journals (Sweden)

    David Sprinzak

    2011-06-01

    Full Text Available Developmental patterning requires juxtacrine signaling in order to tightly coordinate the fates of neighboring cells. Recent work has shown that Notch and Delta, the canonical metazoan juxtacrine signaling receptor and ligand, mutually inactivate each other in the same cell. This cis-interaction generates mutually exclusive sending and receiving states in individual cells. It generally remains unclear, however, how this mutual inactivation and the resulting switching behavior can impact developmental patterning circuits. Here we address this question using mathematical modeling in the context of two canonical pattern formation processes: boundary formation and lateral inhibition. For boundary formation, in a model motivated by Drosophila wing vein patterning, we find that mutual inactivation allows sharp boundary formation across a broader range of parameters than models lacking mutual inactivation. This model with mutual inactivation also exhibits robustness to correlated gene expression perturbations. For lateral inhibition, we find that mutual inactivation speeds up patterning dynamics, relieves the need for cooperative regulatory interactions, and expands the range of parameter values that permit pattern formation, compared to canonical models. Furthermore, mutual inactivation enables a simple lateral inhibition circuit architecture which requires only a single downstream regulatory step. Both model systems show how mutual inactivation can facilitate robust fine-grained patterning processes that would be difficult to implement without it, by encoding a difference-promoting feedback within the signaling system itself. Together, these results provide a framework for analysis of more complex Notch-dependent developmental systems.

  5. Implications of duplicated cis-regulatory elements in the evolution of metazoans: the DDI model or how simplicity begets novelty.

    Science.gov (United States)

    Jiménez-Delgado, Senda; Pascual-Anaya, Juan; Garcia-Fernàndez, Jordi

    2009-07-01

    The discovery that most regulatory genes were conserved among animals from distant phyla challenged the ideas that gene duplication and divergence of homologous coding sequences were the basis for major morphological changes in metazoan evolution. In recent years, however, the interest for the roles, conservation and changes of non-coding sequences grew-up in parallel with genome sequencing projects. Presently, many independent studies are highlighting the importance that subtle changes in cis-regulatory regions had in the evolution of morphology trough the Animal Kingdom. Here we will show and discuss some of these studies, and underscore the future of cis-Evo-Devo research. Nevertheless, we would also explore how gene duplication, which includes duplication of regulatory regions, may have been critical for spatial or temporal co-option of new regulatory networks, causing the deployment of new transcriptome scenarios, and how these induced morphological changes were critical for the evolution of new forms. Forty years after Susumu Ohno famous sentence 'natural selection merely modifies, while redundancy creates', we suggest the alternative: 'natural selection modifies, while redundancy of cis-regulatory elements innovates', and propose the Duplication-Degeneration-Innovation model to explain the increased evolvability of duplicated cis-regulatory regions. Paradoxically, making regulation simpler by subfunctionalization paved the path for future complexity or, in other words, 'to make it simple to make it complex'.

  6. A fetal whole ovarian culture model for the evaluation of CrVI-induced developmental toxicity during germ cell nest breakdown

    International Nuclear Information System (INIS)

    Stanley, Jone A.; Arosh, Joe A.; Burghardt, Robert C.; Banu, Sakhila K.

    2015-01-01

    Prenatal exposure to endocrine disrupting chemicals (EDCs), including bisphenol A, dioxin, pesticides, and cigarette smoke, has been linked to several ovarian diseases such as premature ovarian failure (POF) and early menopause in women. Hexavalent chromium (CrVI), one of the more toxic heavy metals, is widely used in more than 50 industries. As one of the world's leading producers of Cr compounds, the U.S. is facing growing challenges in protecting human health against adverse effects of CrVI. Our recent findings demonstrated that in vivo CrVI exposure during gestational period caused POF in F1 offspring. Our current research focus is three-fold: (i) to identify the effect of CrVI on critical windows of great vulnerability of fetal ovarian development; (ii) to understand the molecular mechanism of CrVI-induced POF; (iii) to identify potential intervention strategies to mitigate or inhibit CrVI effects. In order to accomplish these goals we used a fetal whole ovarian culture system. Fetuses were removed from the normal pregnant rats on gestational day 13.5. Fetal ovaries were cultured in vitro for 12 days, and treated with or without 0.1 ppm potassium dichromate (CrVI) from culture day 2–8, which recapitulated embryonic day 14.5–20.5, in vivo. Results showed that CrVI increased germ cell/oocyte apoptosis by increasing caspase 3, BAX, p53 and PUMA; decreasing BCL2, BMP15, GDF9 and cKIT; and altering cell cycle regulatory genes and proteins. This model system may serve as a potential tool for high throughput testing of various drugs and/or EDCs in particular to assess developmental toxicity of the ovary. - Highlights: • CrVI (0.1 ppm, a regulatory dose) increased germ cell apoptosis of fetal ovaries. • CrVI (0.1 ppm) increased pro-apoptotic proteins. • CrVI (0.1 ppm) decreased cyclins and CDK1 and cell survival proteins. • CrVI (0.1 ppm) increased oxidative stress during fetal ovarian development. • We propose fetal ovarian culture model for high

  7. A fetal whole ovarian culture model for the evaluation of CrVI-induced developmental toxicity during germ cell nest breakdown

    Energy Technology Data Exchange (ETDEWEB)

    Stanley, Jone A.; Arosh, Joe A.; Burghardt, Robert C.; Banu, Sakhila K., E-mail: skbanu@cvm.tamu.edu

    2015-11-15

    Prenatal exposure to endocrine disrupting chemicals (EDCs), including bisphenol A, dioxin, pesticides, and cigarette smoke, has been linked to several ovarian diseases such as premature ovarian failure (POF) and early menopause in women. Hexavalent chromium (CrVI), one of the more toxic heavy metals, is widely used in more than 50 industries. As one of the world's leading producers of Cr compounds, the U.S. is facing growing challenges in protecting human health against adverse effects of CrVI. Our recent findings demonstrated that in vivo CrVI exposure during gestational period caused POF in F1 offspring. Our current research focus is three-fold: (i) to identify the effect of CrVI on critical windows of great vulnerability of fetal ovarian development; (ii) to understand the molecular mechanism of CrVI-induced POF; (iii) to identify potential intervention strategies to mitigate or inhibit CrVI effects. In order to accomplish these goals we used a fetal whole ovarian culture system. Fetuses were removed from the normal pregnant rats on gestational day 13.5. Fetal ovaries were cultured in vitro for 12 days, and treated with or without 0.1 ppm potassium dichromate (CrVI) from culture day 2–8, which recapitulated embryonic day 14.5–20.5, in vivo. Results showed that CrVI increased germ cell/oocyte apoptosis by increasing caspase 3, BAX, p53 and PUMA; decreasing BCL2, BMP15, GDF9 and cKIT; and altering cell cycle regulatory genes and proteins. This model system may serve as a potential tool for high throughput testing of various drugs and/or EDCs in particular to assess developmental toxicity of the ovary. - Highlights: • CrVI (0.1 ppm, a regulatory dose) increased germ cell apoptosis of fetal ovaries. • CrVI (0.1 ppm) increased pro-apoptotic proteins. • CrVI (0.1 ppm) decreased cyclins and CDK1 and cell survival proteins. • CrVI (0.1 ppm) increased oxidative stress during fetal ovarian development. • We propose fetal ovarian culture model for high

  8. A quantitative and dynamic model of the Arabidopsis flowering time gene regulatory network.

    Directory of Open Access Journals (Sweden)

    Felipe Leal Valentim

    Full Text Available Various environmental signals integrate into a network of floral regulatory genes leading to the final decision on when to flower. Although a wealth of qualitative knowledge is available on how flowering time genes regulate each other, only a few studies incorporated this knowledge into predictive models. Such models are invaluable as they enable to investigate how various types of inputs are combined to give a quantitative readout. To investigate the effect of gene expression disturbances on flowering time, we developed a dynamic model for the regulation of flowering time in Arabidopsis thaliana. Model parameters were estimated based on expression time-courses for relevant genes, and a consistent set of flowering times for plants of various genetic backgrounds. Validation was performed by predicting changes in expression level in mutant backgrounds and comparing these predictions with independent expression data, and by comparison of predicted and experimental flowering times for several double mutants. Remarkably, the model predicts that a disturbance in a particular gene has not necessarily the largest impact on directly connected genes. For example, the model predicts that SUPPRESSOR OF OVEREXPRESSION OF CONSTANS (SOC1 mutation has a larger impact on APETALA1 (AP1, which is not directly regulated by SOC1, compared to its effect on LEAFY (LFY which is under direct control of SOC1. This was confirmed by expression data. Another model prediction involves the importance of cooperativity in the regulation of APETALA1 (AP1 by LFY, a prediction supported by experimental evidence. Concluding, our model for flowering time gene regulation enables to address how different quantitative inputs are combined into one quantitative output, flowering time.

  9. Developmental Science: Past, Present, and Future

    Science.gov (United States)

    Lerner, Richard M.

    2012-01-01

    The goal of developmental science is to describe, explain, and optimize intraindividual changes in adaptive developmental regulations and, as well, interindividual differences in such relations, across life. The history of developmental science is reviewed and its current foci, which are framed by relational developmental systems models that…

  10. Modelling the regulatory system for diabetes mellitus with a threshold window

    Science.gov (United States)

    Yang, Jin; Tang, Sanyi; Cheke, Robert A.

    2015-05-01

    Piecewise (or non-smooth) glucose-insulin models with threshold windows for type 1 and type 2 diabetes mellitus are proposed and analyzed with a view to improving understanding of the glucose-insulin regulatory system. For glucose-insulin models with a single threshold, the existence and stability of regular, virtual, pseudo-equilibria and tangent points are addressed. Then the relations between regular equilibria and a pseudo-equilibrium are studied. Furthermore, the sufficient and necessary conditions for the global stability of regular equilibria and the pseudo-equilibrium are provided by using qualitative analysis techniques of non-smooth Filippov dynamic systems. Sliding bifurcations related to boundary node bifurcations were investigated with theoretical and numerical techniques, and insulin clinical therapies are discussed. For glucose-insulin models with a threshold window, the effects of glucose thresholds or the widths of threshold windows on the durations of insulin therapy and glucose infusion were addressed. The duration of the effects of an insulin injection is sensitive to the variation of thresholds. Our results indicate that blood glucose level can be maintained within a normal range using piecewise glucose-insulin models with a single threshold or a threshold window. Moreover, our findings suggest that it is critical to individualise insulin therapy for each patient separately, based on initial blood glucose levels.

  11. Milestones of critical thinking: a developmental model for medicine and nursing.

    Science.gov (United States)

    Papp, Klara K; Huang, Grace C; Lauzon Clabo, Laurie M; Delva, Dianne; Fischer, Melissa; Konopasek, Lyuba; Schwartzstein, Richard M; Gusic, Maryellen

    2014-05-01

    Critical thinking is essential to a health professional's competence to assess, diagnose, and care for patients. Defined as the ability to apply higher-order cognitive skills (conceptualization, analysis, evaluation) and the disposition to be deliberate about thinking (being open-minded or intellectually honest) that lead to action that is logical and appropriate, critical thinking represents a "meta-competency" that transcends other knowledge, skills, abilities, and behaviors required in health care professions. Despite its importance, the developmental stages of critical thinking have not been delineated for nurses and physicians. As part of a task force of educators who considered different developmental stage theories, the authors have iteratively refined and proposed milestones in critical thinking. The attributes associated with unreflective, beginning, practicing, advanced, accomplished, and challenged critical thinkers are conceived as independent of an individual's level of training. Depending on circumstances and environmental factors, even the most experienced clinician may demonstrate attributes associated with a challenged thinker. The authors use the illustrative case of a patient with abdominal pain to demonstrate how critical thinking may manifest in learners at different stages of development, analyzing how the learner at each stage applies information obtained in the patient interaction to arrive at a differential diagnosis and plan for evaluation. The authors share important considerations and provide this work as a foundation for the development of effective approaches to teaching and promoting critical thinking and to establishing expectations for learners in this essential meta-competency.

  12. Can rational models be good accounts of developmental change? The case of language development at two time scales.

    Science.gov (United States)

    Dawson, Colin R; Gerken, LouAnn

    2012-01-01

    Rational models of human perception and cognition have allowed researchers new ways to look at learning and the ability to make inferences from data. But how good are such models at accounting for developmental change? In this chapter, we address this question in the domain of language development, focusing on the speed with which developmental change takes place, and classifying different types of language development as either fast or slow. From the pattern of fast and slow development observed, we hypothesize that rational learning processes are generally well suited for handling fast processes over small amounts of input data. In contrast, we suggest that associative learning processes are generally better suited to slow development, in which learners accumulate information about what is typical of their language over time. Finally, although one system may be dominant for a particular component of language learning, we speculate that both systems frequently interact, with the associative system providing a source of emergent hypotheses to be evaluated by the rational system and the rational system serving to highlight which aspects of the learner's input need to be processed in greater depth by the associative system.

  13. Stages in the development of a model organism as a platform for mechanistic models in developmental biology: Zebrafish, 1970-2000.

    Science.gov (United States)

    Meunier, Robert

    2012-06-01

    Model organisms became an indispensable part of experimental systems in molecular developmental and cell biology, constructed to investigate physiological and pathological processes. They are thought to play a crucial role for the elucidation of gene function, complementing the sequencing of the genomes of humans and other organisms. Accordingly, historians and philosophers paid considerable attention to various issues concerning this aspect of experimental biology. With respect to the representational features of model organisms, that is, their status as models, the main focus was on generalization of phenomena investigated in such experimental systems. Model organisms have been said to be models for other organisms or a higher taxon. This, however, presupposes a representation of the phenomenon in question. I will argue that prior to generalization, model organisms allow researchers to built generative material models of phenomena - structures, processes or the mechanisms that explain them - through their integration in experimental set-ups that carve out the phenomena from the whole organism and thus represent them. I will use the history of zebrafish biology to show how model organism systems, from around 1970 on, were developed to construct material models of molecular mechanisms explaining developmental or physiological processes. Copyright © 2011 Elsevier Ltd. All rights reserved.

  14. The regulatory system for diabetes mellitus: Modeling rates of glucose infusions and insulin injections

    Science.gov (United States)

    Yang, Jin; Tang, Sanyi; Cheke, Robert A.

    2016-08-01

    Novel mathematical models with open and closed-loop control for type 1 or type 2 diabetes mellitus were developed to improve understanding of the glucose-insulin regulatory system. A hybrid impulsive glucose-insulin model with different frequencies of glucose infusions and insulin injections was analyzed, and the existence and uniqueness of the positive periodic solution for type 1 diabetes, which is globally asymptotically stable, was studied analytically. Moreover, permanence of the system for type 2 diabetes was demonstrated which showed that the glucose concentration level is uniformly bounded above and below. To investigate how to prevent hyperinsulinemia and hyperglycemia being caused by this system, we developed a model involving periodic intakes of glucose with insulin injections applied only when the blood glucose level reached a given critical glucose threshold. In addition, our numerical analysis revealed that the period, the frequency and the dose of glucose infusions and insulin injections are crucial for insulin therapies, and the results provide clinical strategies for insulin-administration practices.

  15. Regulatory Forum commentary: alternative mouse models for future cancer risk assessment.

    Science.gov (United States)

    Morton, Daniel; Sistare, Frank D; Nambiar, Prashant R; Turner, Oliver C; Radi, Zaher; Bower, Nancy

    2014-07-01

    International regulatory and pharmaceutical industry scientists are discussing revision of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) S1 guidance on rodent carcinogenicity assessment of small molecule pharmaceuticals. A weight-of-evidence approach is proposed to determine the need for rodent carcinogenicity studies. For compounds with high human cancer risk, the product may be labeled appropriately without conducting rodent carcinogenicity studies. For compounds with minimal cancer risk, only a 6-month transgenic mouse study (rasH2 mouse or p53+/- mouse) or a 2-year mouse study would be needed. If rodent carcinogenicity testing may add significant value to cancer risk assessment, a 2-year rat study and either a 6-month transgenic mouse or a 2-year mouse study is appropriate. In many cases, therefore, one rodent carcinogenicity study could be sufficient. The rasH2 model predicts neoplastic findings relevant to human cancer risk assessment as well as 2-year rodent models, produces fewer irrelevant neoplastic outcomes, and often will be preferable to a 2-year rodent study. Before revising ICH S1 guidance, a prospective evaluation will be conducted to test the proposed weight-of-evidence approach. This evaluation offers an opportunity for a secondary analysis comparing the value of alternative mouse models and 2-year rodent studies in the proposed ICH S1 weight-of-evidence approach for human cancer risk assessment. © 2014 by The Author(s).

  16. Activation of counter-regulatory mechanisms in a rat renal acute rejection model

    Directory of Open Access Journals (Sweden)

    Salomon Daniel R

    2008-02-01

    Full Text Available Abstract Background Microarray analysis provides a powerful approach to identify gene expression alterations following transplantation. In patients the heterogeneity of graft specimens, co-morbidity, co-medications and the challenges in sample collection and preparation complicate conclusions regarding the underlying mechanisms of graft injury, rejection and immune regulation. Results We used a rat kidney transplantation model with strict transplant and sample preparation procedures to analyze genome wide changes in gene expression four days after syngeneic and allogeneic transplantation. Both interventions were associated with substantial changes in gene expression. After allogeneic transplantation, genes and pathways related to transport and metabolism were predominantly down-regulated consistent with rejection-mediated graft injury and dysfunction. Up-regulated genes were primarily related to the acute immune response including antigen presentation, T-cell receptor signaling, apoptosis, interferon signaling and complement cascades. We observed a cytokine and chemokine expression profile consistent with activation of a Th1-cell response. A novel finding was up-regulation of several regulatory and protective genes after allogeneic transplantation, specifically IL10, Bcl2a1, C4bpa, Ctla4, HO-1 and the SOCS family. Conclusion Our data indicate that in parallel with the predicted activation of immune response and tissue injury pathways, there is simultaneous activation of pathways for counter regulatory and protective mechanisms that would balance and limit the ongoing inflammatory/immune responses. The pathophysiological mechanisms behind and the clinical consequences of alterations in expression of these gene classes in acute rejection, injury and dysfunction vs. protection and immunoregulation, prompt further analyses and open new aspects for therapeutic approaches.

  17. A comparative study of covariance selection models for the inference of gene regulatory networks.

    Science.gov (United States)

    Stifanelli, Patrizia F; Creanza, Teresa M; Anglani, Roberto; Liuzzi, Vania C; Mukherjee, Sayan; Schena, Francesco P; Ancona, Nicola

    2013-10-01

    The inference, or 'reverse-engineering', of gene regulatory networks from expression data and the description of the complex dependency structures among genes are open issues in modern molecular biology. In this paper we compared three regularized methods of covariance selection for the inference of gene regulatory networks, developed to circumvent the problems raising when the number of observations n is smaller than the number of genes p. The examined approaches provided three alternative estimates of the inverse covariance matrix: (a) the 'PINV' method is based on the Moore-Penrose pseudoinverse, (b) the 'RCM' method performs correlation between regression residuals and (c) 'ℓ(2C)' method maximizes a properly regularized log-likelihood function. Our extensive simulation studies showed that ℓ(2C) outperformed the other two methods having the most predictive partial correlation estimates and the highest values of sensitivity to infer conditional dependencies between genes even when a few number of observations was available. The application of this method for inferring gene networks of the isoprenoid biosynthesis pathways in Arabidopsis thaliana allowed to enlighten a negative partial correlation coefficient between the two hubs in the two isoprenoid pathways and, more importantly, provided an evidence of cross-talk between genes in the plastidial and the cytosolic pathways. When applied to gene expression data relative to a signature of HRAS oncogene in human cell cultures, the method revealed 9 genes (p-value<0.0005) directly interacting with HRAS, sharing the same Ras-responsive binding site for the transcription factor RREB1. This result suggests that the transcriptional activation of these genes is mediated by a common transcription factor downstream of Ras signaling. Software implementing the methods in the form of Matlab scripts are available at: http://users.ba.cnr.it/issia/iesina18/CovSelModelsCodes.zip. Copyright © 2013 The Authors. Published by

  18. From Creatures of Habit to Goal-Directed Learners: Tracking the Developmental Emergence of Model-Based Reinforcement Learning.

    Science.gov (United States)

    Decker, Johannes H; Otto, A Ross; Daw, Nathaniel D; Hartley, Catherine A

    2016-06-01

    Theoretical models distinguish two decision-making strategies that have been formalized in reinforcement-learning theory. A model-based strategy leverages a cognitive model of potential actions and their consequences to make goal-directed choices, whereas a model-free strategy evaluates actions based solely on their reward history. Research in adults has begun to elucidate the psychological mechanisms and neural substrates underlying these learning processes and factors that influence their relative recruitment. However, the developmental trajectory of these evaluative strategies has not been well characterized. In this study, children, adolescents, and adults performed a sequential reinforcement-learning task that enabled estimation of model-based and model-free contributions to choice. Whereas a model-free strategy was apparent in choice behavior across all age groups, a model-based strategy was absent in children, became evident in adolescents, and strengthened in adults. These results suggest that recruitment of model-based valuation systems represents a critical cognitive component underlying the gradual maturation of goal-directed behavior. © The Author(s) 2016.

  19. Stochastic Boolean networks: An efficient approach to modeling gene regulatory networks

    Directory of Open Access Journals (Sweden)

    Liang Jinghang

    2012-08-01

    Full Text Available Abstract Background Various computational models have been of interest due to their use in the modelling of gene regulatory networks (GRNs. As a logical model, probabilistic Boolean networks (PBNs consider molecular and genetic noise, so the study of PBNs provides significant insights into the understanding of the dynamics of GRNs. This will ultimately lead to advances in developing therapeutic methods that intervene in the process of disease development and progression. The applications of PBNs, however, are hindered by the complexities involved in the computation of the state transition matrix and the steady-state distribution of a PBN. For a PBN with n genes and N Boolean networks, the complexity to compute the state transition matrix is O(nN22n or O(nN2n for a sparse matrix. Results This paper presents a novel implementation of PBNs based on the notions of stochastic logic and stochastic computation. This stochastic implementation of a PBN is referred to as a stochastic Boolean network (SBN. An SBN provides an accurate and efficient simulation of a PBN without and with random gene perturbation. The state transition matrix is computed in an SBN with a complexity of O(nL2n, where L is a factor related to the stochastic sequence length. Since the minimum sequence length required for obtaining an evaluation accuracy approximately increases in a polynomial order with the number of genes, n, and the number of Boolean networks, N, usually increases exponentially with n, L is typically smaller than N, especially in a network with a large number of genes. Hence, the computational efficiency of an SBN is primarily limited by the number of genes, but not directly by the total possible number of Boolean networks. Furthermore, a time-frame expanded SBN enables an efficient analysis of the steady-state distribution of a PBN. These findings are supported by the simulation results of a simplified p53 network, several randomly generated networks and a

  20. MID1 and MID2 homo- and heterodimerise to tether the rapamycin-sensitive PP2A regulatory subunit, Alpha 4, to microtubules: implications for the clinical variability of X-linked Opitz GBBB syndrome and other developmental disorders

    Directory of Open Access Journals (Sweden)

    Cox Timothy C

    2002-01-01

    Full Text Available Abstract Background Patients with Opitz GBBB syndrome present with a variable array of developmental defects including craniofacial, cardiac, and genital anomalies. Mutations in the X-linked MID1 gene, which encodes a microtubule-binding protein, have been found in ~50% of Opitz GBBB syndrome patients consistent with the genetically heterogeneous nature of the disorder. A protein highly related to MID1, called MID2, has also been described that similarly associates with microtubules. Results To identify protein partners of MID1 and MID2 we undertook two separate yeast two-hybrid screens. Using this system we identified Alpha 4, a regulatory subunit of PP2-type phosphatases and a key component of the rapamycin-sensitive signaling pathway, as a strong interactor of both proteins. Analysis of domain-specific deletions has shown that the B-boxes of both MID1 and MID2 mediate the interaction with Alpha 4, the first demonstration in an RBCC protein of a specific role for the B-box region. In addition, we show that the MID1/2 coiled-coil motifs mediate both homo- and hetero-dimerisation, and that dimerisation is a prerequisite for association of the MID-Alpha 4 complex with microtubules. Conclusions Our findings not only implicate Alpha 4 in the pathogenesis of Opitz GBBB syndrome but also support our earlier hypothesis that MID2 is a modifier of the X-linked phenotype. Of further note is the observation that Alpha 4 maps to Xq13 within the region showing linkage to FG (Opitz-Kaveggia syndrome. Overlap in the clinical features of FG and Opitz GBBB syndromes warrants investigation of Alpha 4 as a candidate for causing FG syndrome.

  1. Development of Off-take Model, Subcooled Boiling Model, and Radiation Heat Transfer Input Model into the MARS Code for a Regulatory Auditing of CANDU Reactors

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, C.; Rhee, B. W.; Chung, B. D. [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of); Ahn, S. H.; Kim, M. W. [Korea Institute of Nuclear Safety, Daejeon (Korea, Republic of)

    2009-05-15

    Korea currently has four operating units of the CANDU-6 type reactor in Wolsong. However, the safety assessment system for CANDU reactors has not been fully established due to a lack of self-reliance technology. Although the CATHENA code had been introduced from AECL, it is undesirable to use a vendor's code for a regulatory auditing analysis. In Korea, the MARS code has been developed for decades and is being considered by KINS as a thermal hydraulic regulatory auditing tool for nuclear power plants. Before this decision, KINS (Korea Institute of Nuclear Safety) had developed the RELAP5/MOD3/CANDU code for CANDU safety analyses by modifying the model of the existing PWR auditing tool, RELAP5/MOD3. The main purpose of this study is to transplant the CANDU models of the RELAP5/MOD3/CANDU code to the MARS code including a quality assurance of the developed models.

  2. Development of Off-take Model, Subcooled Boiling Model, and Radiation Heat Transfer Input Model into the MARS Code for a Regulatory Auditing of CANDU Reactors

    International Nuclear Information System (INIS)

    Yoon, C.; Rhee, B. W.; Chung, B. D.; Ahn, S. H.; Kim, M. W.

    2009-01-01

    Korea currently has four operating units of the CANDU-6 type reactor in Wolsong. However, the safety assessment system for CANDU reactors has not been fully established due to a lack of self-reliance technology. Although the CATHENA code had been introduced from AECL, it is undesirable to use a vendor's code for a regulatory auditing analysis. In Korea, the MARS code has been developed for decades and is being considered by KINS as a thermal hydraulic regulatory auditing tool for nuclear power plants. Before this decision, KINS (Korea Institute of Nuclear Safety) had developed the RELAP5/MOD3/CANDU code for CANDU safety analyses by modifying the model of the existing PWR auditing tool, RELAP5/MOD3. The main purpose of this study is to transplant the CANDU models of the RELAP5/MOD3/CANDU code to the MARS code including a quality assurance of the developed models

  3. Modeling Water Utility Investments and Improving Regulatory Policies using Economic Optimisation in England and Wales

    Science.gov (United States)

    Padula, S.; Harou, J. J.

    2012-12-01

    Water utilities in England and Wales are regulated natural monopolies called 'water companies'. Water companies must obtain periodic regulatory approval for all investments (new supply infrastructure or demand management measures). Both water companies and their regulators use results from least economic cost capacity expansion optimisation models to develop or assess water supply investment plans. This presentation first describes the formulation of a flexible supply-demand planning capacity expansion model for water system planning. The model uses a mixed integer linear programming (MILP) formulation to choose the least-cost schedule of future supply schemes (reservoirs, desalination plants, etc.) and demand management (DM) measures (leakage reduction, water efficiency and metering options) and bulk transfers. Decisions include what schemes to implement, when to do so, how to size schemes and how much to use each scheme during each year of an n-year long planning horizon (typically 30 years). In addition to capital and operating (fixed and variable) costs, the estimated social and environmental costs of schemes are considered. Each proposed scheme is costed discretely at one or more capacities following regulatory guidelines. The model uses a node-link network structure: water demand nodes are connected to supply and demand management (DM) options (represented as nodes) or to other demand nodes (transfers). Yields from existing and proposed are estimated separately using detailed water resource system simulation models evaluated over the historical period. The model simultaneously considers multiple demand scenarios to ensure demands are met at required reliability levels; use levels of each scheme are evaluated for each demand scenario and weighted by scenario likelihood so that operating costs are accurately evaluated. Multiple interdependency relationships between schemes (pre-requisites, mutual exclusivity, start dates, etc.) can be accounted for by

  4. A Model of Yeast Cell-Cycle Regulation Based on a Standard Component Modeling Strategy for Protein Regulatory Networks.

    Directory of Open Access Journals (Sweden)

    Teeraphan Laomettachit

    Full Text Available To understand the molecular mechanisms that regulate cell cycle progression in eukaryotes, a variety of mathematical modeling approaches have been employed, ranging from Boolean networks and differential equations to stochastic simulations. Each approach has its own characteristic strengths and weaknesses. In this paper, we propose a "standard component" modeling strategy that combines advantageous features of Boolean networks, differential equations and stochastic simulations in a framework that acknowledges the typical sorts of reactions found in protein regulatory networks. Applying this strategy to a comprehensive mechanism of the budding yeast cell cycle, we illustrate the potential value of standard component modeling. The deterministic version of our model reproduces the phenotypic properties of wild-type cells and of 125 mutant strains. The stochastic version of our model reproduces the cell-to-cell variability of wild-type cells and the partial viability of the CLB2-dbΔ clb5Δ mutant strain. Our simulations show that mathematical modeling with "standard components" can capture in quantitative detail many essential properties of cell cycle control in budding yeast.

  5. A Heme Oxygenase-1 Transducer Model of Degenerative and Developmental Brain Disorders

    Directory of Open Access Journals (Sweden)

    Hyman M. Schipper

    2015-03-01

    Full Text Available Heme oxygenase-1 (HO-1 is a 32 kDa protein which catalyzes the breakdown of heme to free iron, carbon monoxide and biliverdin. The Hmox1 promoter contains numerous consensus sequences that render the gene exquisitely sensitive to induction by diverse pro-oxidant and inflammatory stimuli. In “stressed” astroglia, HO-1 hyperactivity promotes mitochondrial iron sequestration and macroautophagy and may thereby contribute to the pathological iron deposition and bioenergetic failure documented in Alzheimer disease, Parkinson disease and certain neurodevelopmental conditions. Glial HO-1 expression may also impact neuroplasticity and cell survival by modulating brain sterol metabolism and the proteasomal degradation of neurotoxic proteins. The glial HO-1 response may represent a pivotal transducer of noxious environmental and endogenous stressors into patterns of neural damage and repair characteristic of many human degenerative and developmental CNS disorders.

  6. A multi-Poisson dynamic mixture model to cluster developmental patterns of gene expression by RNA-seq.

    Science.gov (United States)

    Ye, Meixia; Wang, Zhong; Wang, Yaqun; Wu, Rongling

    2015-03-01

    Dynamic changes of gene expression reflect an intrinsic mechanism of how an organism responds to developmental and environmental signals. With the increasing availability of expression data across a time-space scale by RNA-seq, the classification of genes as per their biological function using RNA-seq data has become one of the most significant challenges in contemporary biology. Here we develop a clustering mixture model to discover distinct groups of genes expressed during a period of organ development. By integrating the density function of multivariate Poisson distribution, the model accommodates the discrete property of read counts characteristic of RNA-seq data. The temporal dependence of gene expression is modeled by the first-order autoregressive process. The model is implemented with the Expectation-Maximization algorithm and model selection to determine the optimal number of gene clusters and obtain the estimates of Poisson parameters that describe the pattern of time-dependent expression of genes from each cluster. The model has been demonstrated by analyzing a real data from an experiment aimed to link the pattern of gene expression to catkin development in white poplar. The usefulness of the model has been validated through computer simulation. The model provides a valuable tool for clustering RNA-seq data, facilitating our global view of expression dynamics and understanding of gene regulation mechanisms. © The Author 2014. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  7. The safety, efficacy and regulatory triangle in drug development: Impact for animal models and the use of animals.

    Science.gov (United States)

    van Meer, Peter J K; Graham, Melanie L; Schuurman, Henk-Jan

    2015-07-15

    Nonclinical studies in animals are conducted to demonstrate proof-of-concept, mechanism of action and safety of new drugs. For a large part, in particular safety assessment, studies are done in compliance with international regulatory guidance. However, animal models supporting the initiation of clinical trials have their limitations, related to uncertainty regarding the predictive value for a clinical condition. The 3Rs principles (refinement, reduction and replacement) are better applied nowadays, with a more comprehensive application with respect to the original definition. This regards also regulatory guidance, so that opportunities exist to revise or reduce regulatory guidance with the perspective that the optimal balance between scientifically relevant data and animal wellbeing or a reduction in animal use can be achieved. In this manuscript we review the connections in the triangle between nonclinical efficacy/safety studies and regulatory aspects, with focus on in vivo testing of drugs. These connections differ for different drugs (chemistry-based low molecular weight compounds, recombinant proteins, cell therapy or gene therapy products). Regarding animal models and their translational value we focus on regulatory aspects and indications where scientific outcomes warrant changes, reduction or replacement, like for, e.g., biosimilar evaluation and safety testing of monoclonal antibodies. On the other hand, we present applications where translational value has been clearly demonstrated, e.g., immunosuppressives in transplantation. Especially for drugs of more recent date like recombinant proteins, cell therapy products and gene therapy products, a regulatory approach that allows the possibility to conduct combined efficacy/safety testing in validated animal models should strengthen scientific outcomes and improve translational value, while reducing the numbers of animals necessary. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Animal testing, 3R models and regulatory acceptance : Technology transition in a risk-averse context

    NARCIS (Netherlands)

    Schiffelers, M.J.W.A.

    2016-01-01

    Risk avoidance has resulted in a broad range of regulations to guarantee the safety of products such as pharmaceuticals and chemicals. Many of these regulations rely on animal tests. About 3 million laboratory animals are used annually in Europe to meet such regulatory requirements.Regulatory animal

  9. An extended Kalman filtering approach to modeling nonlinear dynamic gene regulatory networks via short gene expression time series.

    Science.gov (United States)

    Wang, Zidong; Liu, Xiaohui; Liu, Yurong; Liang, Jinling; Vinciotti, Veronica

    2009-01-01

    In this paper, the extended Kalman filter (EKF) algorithm is applied to model the gene regulatory network from gene time series data. The gene regulatory network is considered as a nonlinear dynamic stochastic model that consists of the gene measurement equation and the gene regulation equation. After specifying the model structure, we apply the EKF algorithm for identifying both the model parameters and the actual value of gene expression levels. It is shown that the EKF algorithm is an online estimation algorithm that can identify a large number of parameters (including parameters of nonlinear functions) through iterative procedure by using a small number of observations. Four real-world gene expression data sets are employed to demonstrate the effectiveness of the EKF algorithm, and the obtained models are evaluated from the viewpoint of bioinformatics.

  10. Developmental song learning as a model to understand neural mechanisms that limit and promote the ability to learn.

    Science.gov (United States)

    London, Sarah E

    2017-11-20

    Songbirds famously learn their vocalizations. Some species can learn continuously, others seasonally, and still others just once. The zebra finch (Taeniopygia guttata) learns to sing during a single developmental "Critical Period," a restricted phase during which a specific experience has profound and permanent effects on brain function and behavioral patterns. The zebra finch can therefore provide fundamental insight into features that promote and limit the ability to acquire complex learned behaviors. For example, what properties permit the brain to come "on-line" for learning? How does experience become encoded to prevent future learning? What features define the brain in receptive compared to closed learning states? This piece will focus on epigenomic, genomic, and molecular levels of analysis that operate on the timescales of development and complex behavioral learning. Existing data will be discussed as they relate to Critical Period learning, and strategies for future studies to more directly address these questions will be considered. Birdsong learning is a powerful model for advancing knowledge of the biological intersections of maturation and experience. Lessons from its study not only have implications for understanding developmental song learning, but also broader questions of learning potential and the enduring effects of early life experience on neural systems and behavior. Copyright © 2017. Published by Elsevier B.V.

  11. Regulatory T cell activity in immunosuppresive mice model of pseudomonas aeruginosa pneumonia.

    Science.gov (United States)

    Li, Jun-Lu; Chen, Ting-Sang; Yuan, Cong-Cong; Zhao, Guo-Qiang; Xu, Min; Li, Xiao-Yan; Cao, Jie; Xing, Li-Hua

    2017-08-01

    Pseudomonas aeruginosa (PA) pneumonia is a refractory, even lethal complication in immunosuppressive individuals and immune disturbances may promote the pathological process. We aimed to investigate the regulatory T (Treg) cell activity in an immunosuppressive mice model of PA pneumonia by estimating levels of main transcription factor and the main effector of Treg cells, i.e., Forkhead box protein 3 (FOXP3) and interleukine-10 (IL-10). Seventy-two BALB/c mice were divided into four groups randomly: control (A), PA pneumonia (B), immunosuppression (C) and immunosuppression with PA pneumonia (D). Mice were sacrificed at 4, 8 and 24 h after establishing experimental models. The pathological changes of lung tissue were graded, and the FOXP3 mRNA and serum IL-10 levels were detected. Histological analysis of lung tissues showed there were no significantly pathological changes in groups A and C, but significantly pathological changes were found in groups B and D, especially in group D at 8 h (Ppneumonia in immunosuppressive individuals worsens rapidly, which may be associated with Treg cells function disturbance. And Treg cells may be promising as adjuvant therapeutics for PA pneumonia in immunosuppressive individuals.

  12. Econometric model as a regulatory tool in electricity distribution - Case Network Performance Assessment Model

    International Nuclear Information System (INIS)

    Honkapuro, S.; Lassila, J.; Viljainen, S.; Tahvanainen, K.; Partanen, J.

    2004-01-01

    Electricity distribution companies operate in the state of natural monopolies since building of parallel networks is not cost-effective. Monopoly companies do not have pressure from the open markets to keep their prices and costs at reasonable level. The regulation of these companies is needed to prevent the misuse of the monopoly position. Regulation is usually focused either on the profit of company or on the price of electricity. In this document, the usability of an econometric model in the regulation of electricity distribution companies is evaluated. Regulation method which determines allowed income for each company with generic computation model can be seen as an econometric model. As the special case of an econometric model, the method called Network Performance Assessment Model, NPAM (Naetnyttomodellen in Swedish), is analysed. NPAM is developed by Swedish Energy Agency (STEM) for the regulation of electricity distribution companies. Both theoretical analysis and calculations of an example network area are presented in this document to find the major directing effects of the model. The parameters of NPAM, which are used in the calculations of this research report, were dated on 30th of March 2004. These parameters were most recent available at the time when analysis was done. However, since NPAM is under development, the parameters have been constantly changing. Therefore slightly changes in the results can occur if calculations were made with latest parameters. However, main conclusions are same and do not depend on exact parameters. (orig.)

  13. Econometric model as a regulatory tool in electricity distribution. Case network performance assessment model

    International Nuclear Information System (INIS)

    Honkapuro, S.; Lassila, J.; Viljainen, S.; Tahvanainen, K.; Partanen, J.

    2004-01-01

    Electricity distribution companies operate in the state of natural monopolies since building of parallel networks is not cost- effective. Monopoly companies do not have pressure from the open markets to keep their prices and costs at reasonable level. The regulation of these companies is needed to prevent the misuse of the monopoly position. Regulation is usually focused either on the profit of company or on the price of electricity. Regulation method which determines allowed income for each company with generic computation model can be seen as an econometric model. In this document, the usability of an econometric model in the regulation of electricity distribution companies is evaluated. As the special case of an econometric model, the method called Network Performance Assessment Model, NPAM (Naetnyttomodellen in Swedish), is analysed. NPAM is developed by Swedish Energy Agency (STEM) for the regulation of electricity distribution companies. Both theoretical analysis and calculations of an example network area are presented in this document to find the major directing effects of the model. The parameters of NPAM, which are used in the calculations of this research report, were dated on 30th of March 2004. These parameters were most recent ones available at the time when analysis was done. However, since NPAM have been under development, the parameters have been constantly changing. Therefore slight changes might occur in the numerical results of calculations if they were made with the latest set of parameters. However, main conclusions are same and do not depend on exact parameters

  14. Determinants of dermal exposure relevant for exposure modelling in regulatory risk assessment.

    Science.gov (United States)

    Marquart, J; Brouwer, D H; Gijsbers, J H J; Links, I H M; Warren, N; van Hemmen, J J

    2003-11-01

    Risk assessment of chemicals requires assessment of the exposure levels of workers. In the absence of adequate specific measured data, models are often used to estimate exposure levels. For dermal exposure only a few models exist, which are not validated externally. In the scope of a large European research programme, an analysis of potential dermal exposure determinants was made based on the available studies and models and on the expert judgement of the authors of this publication. Only a few potential determinants appear to have been studied in depth. Several studies have included clusters of determinants into vaguely defined parameters, such as 'task' or 'cleaning and maintenance of clothing'. Other studies include several highly correlated parameters, such as 'amount of product handled', 'duration of task' and 'area treated', and separation of these parameters to study their individual influence is not possible. However, based on the available information, a number of determinants could clearly be defined as proven or highly plausible determinants of dermal exposure in one or more exposure situation. This information was combined with expert judgement on the scientific plausibility of the influence of parameters that have not been extensively studied and on the possibilities to gather relevant information during a risk assessment process. The result of this effort is a list of determinants relevant for dermal exposure models in the scope of regulatory risk assessment. The determinants have been divided into the major categories 'substance and product characteristics', 'task done by the worker', 'process technique and equipment', 'exposure control measures', 'worker characteristics and habits' and 'area and situation'. To account for the complex nature of the dermal exposure processes, a further subdivision was made into the three major processes 'direct contact', 'surface contact' and 'deposition'.

  15. Modeling Skills, Signs and Lettering for Children with Down Syndrome, Autism and Other Severe Developmental Delays by Video Instruction in Classroom Setting

    Science.gov (United States)

    Biederman, G. B.; Freedman, B.

    2007-01-01

    This paper addresses optimal strategies in teaching essential life and communication skills to children with Down syndrome, autism and other developmental delays. Evidence from the literature concerning the relative efficacy of hand-over-hand (self-modeling) in contrast to passive observational teaching techniques (e.g., video modeling) shows the…

  16. Early Childhood Developmental Status in Low- and Middle-Income Countries: National, Regional, and Global Prevalence Estimates Using Predictive Modeling.

    Science.gov (United States)

    McCoy, Dana Charles; Peet, Evan D; Ezzati, Majid; Danaei, Goodarz; Black, Maureen M; Sudfeld, Christopher R; Fawzi, Wafaie; Fink, Günther

    2016-06-01

    The development of cognitive and socioemotional skills early in life influences later health and well-being. Existing estimates of unmet developmental potential in low- and middle-income countries (LMICs) are based on either measures of physical growth or proxy measures such as poverty. In this paper we aim to directly estimate the number of children in LMICs who would be reported by their caregivers to show low cognitive and/or socioemotional development. The present paper uses Early Childhood Development Index (ECDI) data collected between 2005 and 2015 from 99,222 3- and 4-y-old children living in 35 LMICs as part of the Multiple Indicator Cluster Survey (MICS) and Demographic and Health Surveys (DHS) programs. First, we estimate the prevalence of low cognitive and/or socioemotional ECDI scores within our MICS/DHS sample. Next, we test a series of ordinary least squares regression models predicting low ECDI scores across our MICS/DHS sample countries based on country-level data from the Human Development Index (HDI) and the Nutrition Impact Model Study. We use cross-validation to select the model with the best predictive validity. We then apply this model to all LMICs to generate country-level estimates of the prevalence of low ECDI scores globally, as well as confidence intervals around these estimates. In the pooled MICS and DHS sample, 14.6% of children had low ECDI scores in the cognitive domain, 26.2% had low socioemotional scores, and 36.8% performed poorly in either or both domains. Country-level prevalence of low cognitive and/or socioemotional scores on the ECDI was best represented by a model using the HDI as a predictor. Applying this model to all LMICs, we estimate that 80.8 million children ages 3 and 4 y (95% CI 48.1 million, 113.6 million) in LMICs experienced low cognitive and/or socioemotional development in 2010, with the largest number of affected children in sub-Saharan Africa (29.4.1 million; 43.8% of children ages 3 and 4 y), followed by

  17. Early Childhood Developmental Status in Low- and Middle-Income Countries: National, Regional, and Global Prevalence Estimates Using Predictive Modeling.

    Directory of Open Access Journals (Sweden)

    Dana Charles McCoy

    2016-06-01

    Full Text Available The development of cognitive and socioemotional skills early in life influences later health and well-being. Existing estimates of unmet developmental potential in low- and middle-income countries (LMICs are based on either measures of physical growth or proxy measures such as poverty. In this paper we aim to directly estimate the number of children in LMICs who would be reported by their caregivers to show low cognitive and/or socioemotional development.The present paper uses Early Childhood Development Index (ECDI data collected between 2005 and 2015 from 99,222 3- and 4-y-old children living in 35 LMICs as part of the Multiple Indicator Cluster Survey (MICS and Demographic and Health Surveys (DHS programs. First, we estimate the prevalence of low cognitive and/or socioemotional ECDI scores within our MICS/DHS sample. Next, we test a series of ordinary least squares regression models predicting low ECDI scores across our MICS/DHS sample countries based on country-level data from the Human Development Index (HDI and the Nutrition Impact Model Study. We use cross-validation to select the model with the best predictive validity. We then apply this model to all LMICs to generate country-level estimates of the prevalence of low ECDI scores globally, as well as confidence intervals around these estimates. In the pooled MICS and DHS sample, 14.6% of children had low ECDI scores in the cognitive domain, 26.2% had low socioemotional scores, and 36.8% performed poorly in either or both domains. Country-level prevalence of low cognitive and/or socioemotional scores on the ECDI was best represented by a model using the HDI as a predictor. Applying this model to all LMICs, we estimate that 80.8 million children ages 3 and 4 y (95% CI 48.1 million, 113.6 million in LMICs experienced low cognitive and/or socioemotional development in 2010, with the largest number of affected children in sub-Saharan Africa (29.4.1 million; 43.8% of children ages 3 and 4 y

  18. Comparison of the regulatory models assessing off-site radiological dose due to the routine releases of tritium

    International Nuclear Information System (INIS)

    Hwang, W. T.; Kim, E. H.; Han, M. H.; Choi, Y. H.; Lee, H. S.; Lee, C. W.

    2005-01-01

    Methodologies of NEWTRIT model, NRC model and AIRDOS-EPA model, which are off-site dose assessment models for regulatory compliance from routine releases of tritium into the environment, were investigated. Using the domestic data, if available, the predictive results of the models were compared. Among them, recently developed NEWTRIT model considers only doses from organically bounded tritium (OBT) due to environmental releases of tritiated water (HTO). A total dose from all exposure pathways predicted from AIRDOS-EPA model was 1.03 and 2.46 times higher than that from NEWTRIT model and NRC model, respectively. From above result, readers should not have an understanding that a predictive dose from NRC model may be underestimated compared with a realistic dose. It is because of that both mathematical models and corresponding parameter values for regulatory compliance are based on the conservative assumptions. For a dose by food consumption predicted from NEWTRIT model, the contribution of OBT was nearly equivalent to that of HTO due to relatively high consumption of grains in Korean. Although a total dose predicted from NEWTRIT model is similar to that from AIRDOS-EPA model, NEWTRIT model may be have a meaning in the understanding of phenomena for the behavior of HTO released into the environment

  19. Human developmental enhancers conserved between deuterostomes and protostomes.

    Directory of Open Access Journals (Sweden)

    Shoa L Clarke

    Full Text Available The identification of homologies, whether morphological, molecular, or genetic, is fundamental to our understanding of common biological principles. Homologies bridging the great divide between deuterostomes and protostomes have served as the basis for current models of animal evolution and development. It is now appreciated that these two clades share a common developmental toolkit consisting of conserved transcription factors and signaling pathways. These patterning genes sometimes show common expression patterns and genetic interactions, suggesting the existence of similar or even conserved regulatory apparatus. However, previous studies have found no regulatory sequence conserved between deuterostomes and protostomes. Here we describe the first such enhancers, which we call bilaterian conserved regulatory elements (Bicores. Bicores show conservation of sequence and gene synteny. Sequence conservation of Bicores reflects conserved patterns of transcription factor binding sites. We predict that Bicores act as response elements to signaling pathways, and we show that Bicores are developmental enhancers that drive expression of transcriptional repressors in the vertebrate central nervous system. Although the small number of identified Bicores suggests extensive rewiring of cis-regulation between the protostome and deuterostome clades, additional Bicores may be revealed as our understanding of cis-regulatory logic and sample of bilaterian genomes continue to grow.

  20. Statistical approaches to use a model organism for regulatory sequences annotation of newly sequenced species.

    Directory of Open Access Journals (Sweden)

    Pietro Liò

    Full Text Available A major goal of bioinformatics is the characterization of transcription factors and the transcriptional programs they regulate. Given the speed of genome sequencing, we would like to quickly annotate regulatory sequences in newly-sequenced genomes. In such cases, it would be helpful to predict sequence motifs by using experimental data from closely related model organism. Here we present a general algorithm that allow to identify transcription factor binding sites in one newly sequenced species by performing Bayesian regression on the annotated species. First we set the rationale of our method by applying it within the same species, then we extend it to use data available in closely related species. Finally, we generalise the method to handle the case when a certain number of experiments, from several species close to the species on which to make inference, are available. In order to show the performance of the method, we analyse three functionally related networks in the Ascomycota. Two gene network case studies are related to the G2/M phase of the Ascomycota cell cycle; the third is related to morphogenesis. We also compared the method with MatrixReduce and discuss other types of validation and tests. The first network is well known and provides a biological validation test of the method. The two cell cycle case studies, where the gene network size is conserved, demonstrate an effective utility in annotating new species sequences using all the available replicas from model species. The third case, where the gene network size varies among species, shows that the combination of information is less powerful but is still informative. Our methodology is quite general and could be extended to integrate other high-throughput data from model organisms.

  1. A model of the anterior esophagus in snakes, with functional and developmental implications.

    Science.gov (United States)

    Cundall, David; Tuttman, Cassandra; Close, Matthew

    2014-03-01

    The gross anatomy of the mouth of snakes has always been interpreted as an evolutionary response to feeding demands. In most alethinophidian species, their anatomy allows limited functional independence of right and left sides and the roof and floor of the mouth as well as wide separation of the tips of the mandibles. However, locations of the tongue and glottis in snakes suggest extraordinary rearrangement of pharyngeal structures characteristic of all vertebrates. Serial histological sections through the heads of a number of colubroid species show muscularis mucosal smooth muscle fibers appearing in the paratracheal gutter of the lower jaw at varying levels between the eye and ear regions. Incomplete muscularis externa elements appear beneath the paratracheal gutter more caudally but typically at otic levels. Both muscle layers encompass more of the gut wall at more posterior levels, encircling the gut at the level of the atlas or axis. The pattern in snakes suggests developmental dissociation of dorsal and ventral splanchnic derivatives and extensive topological rearrangements of some ventral pharyngeal arch derivatives typical of most tetrapods. When snakes swallow large prey, the effective oral cavity becomes extremely short ventrally. The palatomaxillary arches function as ratchets packing the prey almost directly into the esophagus. Our findings raise questions about germ layer origins and regulation of differentiation of gut regions and derivatives in snakes and suggest that significant aspects of the evolution of lepidosaurs may be difficult to recover from bones or molecular sequence data alone. Copyright © 2014 Wiley Periodicals, Inc.

  2. DEVELOPMENTAL TAXONOMY OF CONDUCT DISORDER

    OpenAIRE

    Jelena Kostić; Milkica Nešić; Jasminka Marković; Miodrag Stanković

    2015-01-01

    Conduct disorder is a heterogeneous disorder in terms of etiology, course and prognosis, and currently, there is no singular model that would describe the development of the disorder. The results of empirical research on males confirm this heterogeneity, as they point out to two possible developmental pathways: childhood-onset and adolescentonset type. This paper presents the basic elements of developmental taxonomic theory which argues that there are two different developmental pathways to c...

  3. Recurrent neural network-based modeling of gene regulatory network using elephant swarm water search algorithm.

    Science.gov (United States)

    Mandal, Sudip; Saha, Goutam; Pal, Rajat Kumar

    2017-08-01

    Correct inference of genetic regulations inside a cell from the biological database like time series microarray data is one of the greatest challenges in post genomic era for biologists and researchers. Recurrent Neural Network (RNN) is one of the most popular and simple approach to model the dynamics as well as to infer correct dependencies among genes. Inspired by the behavior of social elephants, we propose a new metaheuristic namely Elephant Swarm Water Search Algorithm (ESWSA) to infer Gene Regulatory Network (GRN). This algorithm is mainly based on the water search strategy of intelligent and social elephants during drought, utilizing the different types of communication techniques. Initially, the algorithm is tested against benchmark small and medium scale artificial genetic networks without and with presence of different noise levels and the efficiency was observed in term of parametric error, minimum fitness value, execution time, accuracy of prediction of true regulation, etc. Next, the proposed algorithm is tested against the real time gene expression data of Escherichia Coli SOS Network and results were also compared with others state of the art optimization methods. The experimental results suggest that ESWSA is very efficient for GRN inference problem and performs better than other methods in many ways.

  4. Prioritization of chemicals in the aquatic environment based on risk assessment: analytical, modeling and regulatory perspective.

    Science.gov (United States)

    Guillén, D; Ginebreda, A; Farré, M; Darbra, R M; Petrovic, M; Gros, M; Barceló, D

    2012-12-01

    The extensive and intensive use of chemicals in our developed, highly technological society includes more than 100,000 chemical substances. Significant scientific evidence has lead to the recognition that their improper use and release may result in undesirable and harmful side-effects on both the human and ecosystem health. To cope with them, appropriate risk assessment processes and related prioritization schemes have been developed in order to provide the necessary scientific support for regulatory procedures. In the present paper, two of the elements that constitute the core of risk assessment, namely occurrence and hazard effects, have been discussed. Recent advances in analytical chemistry (sample pre-treatment and instrumental equipment, etc.) have allowed for more comprehensive monitoring of environmental pollution reaching limits of detection up to sub ng L(-1). Alternative to analytical measurements, occurrence models can provide risk managers with a very interesting approach for estimating environmental concentrations from real or hypothetical scenarios. The most representative prioritization schemes used for issuing lists of concerning chemicals have also been examined and put in the context of existing environmental policies for protection strategies and regulations. Finally, new challenges in the field of risk-assessment have been outlined, including those posed by new materials (i.e., nanomaterials), transformation products, multi-chemical exposure, or extension of the risk assessment process to the whole ecosystem. Copyright © 2012 Elsevier B.V. All rights reserved.

  5. Aggression, Sibling Antagonism, and Theory-of-Mind During the First Year of Siblinghood: A Developmental Cascade Model

    Science.gov (United States)

    Song, Ju-Hyun; Volling, Brenda L.; Lane, Jonathan D.; Wellman, Henry M.

    2016-01-01

    A developmental cascade model was tested to examine longitudinal associations among firstborn children’s aggression, Theory-of-Mind, and antagonism toward their younger sibling during the first year of siblinghood. Aggression and Theory-of-Mind were assessed before the birth of a sibling, and 4 and 12 months after the birth, and antagonism was examined at 4 and 12 months in a sample of 208 firstborn children (initial M age = 30 months, 56% girls) from primarily European American, middle- class families. Firstborns’ aggression consistently predicted high sibling antagonism both directly and through poorer Theory-of-Mind. Results highlight the importance of examining longitudinal influences across behavioral, social-cognitive, and relational factors that are closely intertwined even from the early years of life. PMID:27096923

  6. Causality analysis detects the regulatory role of maternal effect genes in the early Drosophila embryo

    Directory of Open Access Journals (Sweden)

    Zara Ghodsi

    2017-03-01

    Full Text Available In developmental studies, inferring regulatory interactions of segmentation genetic network play a vital role in unveiling the mechanism of pattern formation. As such, there exists an opportune demand for theoretical developments and new mathematical models which can result in a more accurate illustration of this genetic network. Accordingly, this paper seeks to extract the meaningful regulatory role of the maternal effect genes using a variety of causality detection techniques and to explore whether these methods can suggest a new analytical view to the gene regulatory networks. We evaluate the use of three different powerful and widely-used models representing time and frequency domain Granger causality and convergent cross mapping technique with the results being thoroughly evaluated for statistical significance. Our findings show that the regulatory role of maternal effect genes is detectable in different time classes and thereby the method is applicable to infer the possible regulatory interactions present among the other genes of this network.

  7. Developmental Scaffolding

    DEFF Research Database (Denmark)

    Giorgi, Franco; Bruni, Luis Emilio

    2015-01-01

    . Within the developmental hierarchy, each module yields an inter-level relationship that makes it possible for the scaffolding to mediate the production of selectable variations. Awide range of genetic, cellular and morphological mechanisms allows the scaffolding to integrate these modular variations...... to the complexity of sign recognition proper of a cellular community. In this semiotic perspective, the apparent goal directness of any developmental strategy should no longer be accounted for by a predetermined genetic program, but by the gradual definition of the relationships selected amongst the ones...

  8. Transgenerational developmental programming.

    Science.gov (United States)

    Aiken, Catherine E; Ozanne, Susan E

    2014-01-01

    The concept of developmental programming suggests that the early life environment influences offspring characteristics in later life, including the propensity to develop diseases such as the metabolic syndrome. There is now growing evidence that the effects of developmental programming may also manifest in further generations without further suboptimal exposure. This review considers the evidence, primarily from rodent models, for effects persisting to subsequent generations, and evaluates the mechanisms by which developmental programming may be transmitted to further generations. In particular, we focus on the potential role of the intrauterine environment in contributing to a developmentally programmed phenotype in subsequent generations. The literature was systematically searched at http://pubmed.org and http://scholar.google.com to identify published findings regarding transgenerational (F2 and beyond) developmental programming effects in human populations and animal models. Transmission of programming effects is often viewed as a form of epigenetic inheritance, either via the maternal or paternal line. Evidence exists for both germline and somatic inheritance of epigenetic modifications which may be responsible for phenotypic changes in further generations. However, there is increasing evidence for the role of both extra-genomic components of the zygote and the interaction of the developing conceptus with the intrauterine environment in propagating programming effects. The contribution of a suboptimal reproductive tract environment or maternal adaptations to pregnancy may be critical to inheritance of programming effects via the maternal line. As the effects of age exacerbate the programmed metabolic phenotype, advancing maternal age may increase the likelihood of developmental programming effects being transmitted to further generations. We suggest that developmental programming effects could be propagated through the maternal line de novo in generations

  9. Making Epidermal Bladder Cells Bigger: Developmental- and Salinity-Induced Endopolyploidy in a Model Halophyte.

    Science.gov (United States)

    Barkla, Bronwyn J; Rhodes, Timothy; Tran, Kieu-Nga T; Wijesinghege, Chathura; Larkin, John C; Dassanayake, Maheshi

    2018-06-01

    Endopolyploidy occurs when DNA replication takes place without subsequent mitotic nuclear division, resulting in cell-specific ploidy levels within tissues. In plants, endopolyploidy plays an important role in sustaining growth and development, but only a few studies have demonstrated a role in abiotic stress response. In this study, we investigated the function of ploidy level and nuclear and cell size in leaf expansion throughout development and tracked cell type-specific ploidy in the halophyte Mesembryanthemum crystallinum In addition to developmental endopolyploidy, we examined the effects of salinity stress on ploidy level. We focused specifically on epidermal bladder cells (EBC), which are modified balloon-like trichomes, due to their large size and role in salt accumulation. Our results demonstrate that ploidy increases as the leaves expand in a similar manner for each leaf type, and ploidy levels up to 512C were recorded for nuclei in EBC of leaves of adult plants. Salt treatment led to a significant increase in ploidy levels in the EBC, and these cells showed spatially related differences in their ploidy and nuclear and cell size depending on the positions on the leaf and stem surface. Transcriptome analysis highlighted salinity-induced changes in genes involved in DNA replication, cell cycle, endoreduplication, and trichome development in EBC. The increase in cell size and ploidy observed in M. crystallinum under salinity stress may contribute to salt tolerance by increasing the storage capacity for sodium sequestration brought about by higher metabolic activity driving rapid cell enlargement in the leaf tissue and EBC. © 2018 American Society of Plant Biologists. All rights reserved.

  10. Green Growth - an Illusion? Energy and Climate Risk: Rethinking our Developmental Models

    International Nuclear Information System (INIS)

    Dessus, B.

    2011-01-01

    The years go by and international conferences come and go, with their quota of cries of alarm and calls to action to counter climate change. But in reality few large-scale programmes have been launched anywhere in the world involving concrete action to bring down greenhouse gas emissions. As one who has campaigned for many years for policies of energy consumption control, Benjamin Dessus shows here that the energy challenge is as great as it has ever been in a world of expanding populations in which most peoples aspire to reach the developmental level of the northern countries, despite the fact that our climate probably cannot support such a state of affairs. He argues here against a certain number of common suppositions, such as the idea of focussing exclusively on CO 2 in the fight against global warming, the need for a continuous economic growth on the order of 2% per annum or excessive faith in market mechanisms to bring down greenhouse gas emissions. He also stresses the ambiguities of so-called 'green' growth and compares different energy conservation scenarios. In this way, he shows that, against a relatively dominant line of reasoning based largely on (at times near-utopian) technological solutions and the continuation of sustained economic growth, there are more effective paths based on individual/collective energy sobriety and a serious slowdown of economic growth in the most developed countries, if not indeed a total halt to that growth (though these are more ambitious in that they require a revolution in the behaviour of the most affluent peoples). He concludes by proposing some courses of action for implementing such a programme in a country like France, showing the extent to which modern modes of life are going to have to change and how urgent it now is to debate these matters, if such change is to be achieved without - excessive - pain. (author)

  11. Developmental cascade models linking peer victimization, depression, and academic achievement in Chinese children.

    Science.gov (United States)

    Liu, Junsheng; Bullock, Amanda; Coplan, Robert J; Chen, Xinyin; Li, Dan; Zhou, Ying

    2018-03-01

    This study explored the longitudinal relations among peer victimization, depression, and academic achievement in Chinese primary school students. Participants were N = 945 fourth-grade students (485 boys, 460 girls; M age  = 10.16 years, SD = 2 months) attending elementary schools in Shanghai, People's Republic of China. Three waves of data on peer victimization, depression, and academic achievement were collected from peer nominations, self-reports, and school records, respectively. The results indicated that peer victimization had both direct and indirect effects on later depression and academic achievement. Depression also had both direct and indirect negative effects on later academic achievement, but demonstrated only an indirect effect on later peer victimization. Finally, academic achievement had both direct and indirect negative effects on later peer victimization and depression. The findings show that there are cross-cultural similarities and differences in the various transactions that exist among peer victimization, depression, and academic achievement. Statement of contribution What is already known on this subject? Peer victimization directly and indirectly relates to depression and academic achievement. Depression directly and indirectly relates to academic achievement. Academic achievement directly and indirectly relates to depression. What the present study adds? A developmental cascade approach was used to assess the interrelations among peer victimization, depression, and academic achievement. Academic achievement mediates the relation between peer victimization and depression. Depression is related to peer victimization through academic achievement. Academic achievement directly and indirectly relates to peer victimization. Academic achievement is related to depression through peer victimization. © 2017 The British Psychological Society.

  12. Guinea pig models for translation of the developmental origins of health and disease hypothesis into the clinic.

    Science.gov (United States)

    Morrison, Janna L; Botting, Kimberley J; Darby, Jack R T; David, Anna L; Dyson, Rebecca M; Gatford, Kathryn L; Gray, Clint; Herrera, Emilio A; Hirst, Jonathan J; Kim, Bona; Kind, Karen L; Krause, Bernardo J; Matthews, Stephen G; Palliser, Hannah K; Regnault, Timothy R H; Richardson, Bryan S; Sasaki, Aya; Thompson, Loren P; Berry, Mary J

    2018-04-06

    Over 30 years ago Professor David Barker first proposed the theory that events in early life could explain an individual's risk of non-communicable disease in later life: the developmental origins of health and disease (DOHaD) hypothesis. During the 1990s the validity of the DOHaD hypothesis was extensively tested in a number of human populations and the mechanisms underpinning it characterised in a range of experimental animal models. Over the past decade, researchers have sought to use this mechanistic understanding of DOHaD to develop therapeutic interventions during pregnancy and early life to improve adult health. A variety of animal models have been used to develop and evaluate interventions, each with strengths and limitations. It is becoming apparent that effective translational research requires that the animal paradigm selected mirrors the tempo of human fetal growth and development as closely as possible so that the effect of a perinatal insult and/or therapeutic intervention can be fully assessed. The guinea pig is one such animal model that over the past two decades has demonstrated itself to be a very useful platform for these important reproductive studies. This review highlights similarities in the in utero development between humans and guinea pigs, the strengths and limitations of the guinea pig as an experimental model of DOHaD and the guinea pig's potential to enhance clinical therapeutic innovation to improve human health. © 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.

  13. Implementation of Wolsong Pump Model, Pressure Tube Deformation Model and Off-take Model into MARS Code for Regulatory Auditing of CANDU Reactors

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, C.; Rhee, B. W.; Chung, B. D. [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of); Cho, Y. J.; Kim, M. W. [Korea Institute of Nuclear Safety, Daejeon (Korea, Republic of)

    2008-05-15

    Korea currently has four operating units of the CANDU-6 type reactor in Wolsong. However, the safety assessment system for CANDU reactors has not been fully established due to lack of self-reliance technology. Although the CATHENA code had been introduced from AECL, it is undesirable to use vendor's code for regulatory auditing analysis. In Korea, the MARS code has been developed for decades and is being considered by KINS as a thermal hydraulic regulatory auditing tool for nuclear power plants. Before this decision, KINS (Korea Institute of Nuclear Safety) had developed RELAP5/MOD3/CANDU code for CANDU safety analyses by modifying the model of existing PWR auditing tool, RELAP5/MOD3. The main purpose of this study is to transplant the CANDU models of RELAP5/MOD3/CANDU code to MARS code including quality assurance of the developed models. This first part of the research series presents the implementation and verification of the Wolsong pump model, the pressure tube deformation model, and the off-take model for arbitrary-angled branch pipes.

  14. Implementation of Wolsong Pump Model, Pressure Tube Deformation Model and Off-take Model into MARS Code for Regulatory Auditing of CANDU Reactors

    International Nuclear Information System (INIS)

    Yoon, C.; Rhee, B. W.; Chung, B. D.; Cho, Y. J.; Kim, M. W.

    2008-01-01

    Korea currently has four operating units of the CANDU-6 type reactor in Wolsong. However, the safety assessment system for CANDU reactors has not been fully established due to lack of self-reliance technology. Although the CATHENA code had been introduced from AECL, it is undesirable to use vendor's code for regulatory auditing analysis. In Korea, the MARS code has been developed for decades and is being considered by KINS as a thermal hydraulic regulatory auditing tool for nuclear power plants. Before this decision, KINS (Korea Institute of Nuclear Safety) had developed RELAP5/MOD3/CANDU code for CANDU safety analyses by modifying the model of existing PWR auditing tool, RELAP5/MOD3. The main purpose of this study is to transplant the CANDU models of RELAP5/MOD3/CANDU code to MARS code including quality assurance of the developed models. This first part of the research series presents the implementation and verification of the Wolsong pump model, the pressure tube deformation model, and the off-take model for arbitrary-angled branch pipes

  15. Comparison of three models predicting developmental milestones given environmental and individual variation

    Science.gov (United States)

    Estella Gilbert; James A. Powell; Jesse A. Logan; Barbara J. Bentz

    2004-01-01

    In all organisms, phenotypic variability is an evolutionary stipulation. Because the development of poikilothermic organisms depends directly on the temperature of their habitat, environmental variability is also an integral factor in models of their phenology. In this paper we present two existing phenology models, the distributed delay model and the Sharpe and...

  16. Conceptual and Developmental Analysis of Mental Models: An Example with Complex Change Problems.

    Science.gov (United States)

    Poirier, Louise

    Defining better implicit models of children's actions in a series of situations is of paramount importance to understanding how knowledge is constructed. The objective of this study was to analyze the implicit mental models used by children in complex change problems to understand the stability of the models and their evolution with the child's…

  17. Developmental delay

    Science.gov (United States)

    Nutrition support is essential for the care of the child with developmental delay. After a thorough evaluation, an individualized intervention plan that accounts for the child’s nutrition status, feeding ability, and medical condition may be determined. Nutrition assessments may be performed at leas...

  18. Developmental Work

    DEFF Research Database (Denmark)

    Møller, Niels; Hvid, Helge; Kristensen, Tage Søndergaard

    2003-01-01

    Human Deveoplment and Working Life - Work for Welfare explores whether the development of human resources at company level can improve individuals' quality of life, companies' possibilities of development, and welfare and democracy in society. Chapter two discuss the concept "developmental work...

  19. Regulatory framework and business models for charging plug-in electric vehicles: Infrastructure, agents, and commercial relationships

    International Nuclear Information System (INIS)

    Gomez San Roman, Tomas; Momber, Ilan; Rivier Abbad, Michel; Sanchez Miralles, Alvaro

    2011-01-01

    Electric vehicles (EVs) present efficiency and environmental advantages over conventional transportation. It is expected that in the next decade this technology will progressively penetrate the market. The integration of plug-in electric vehicles in electric power systems poses new challenges in terms of regulation and business models. This paper proposes a conceptual regulatory framework for charging EVs. Two new electricity market agents, the EV charging manager and the EV aggregator, in charge of developing charging infrastructure and providing charging services are introduced. According to that, several charging modes such as EV home charging, public charging on streets, and dedicated charging stations are formulated. Involved market agents and their commercial relationships are analysed in detail. The paper elaborates the opportunities to formulate more sophisticated business models for vehicle-to-grid applications under which the storage capability of EV batteries is used for providing peak power or frequency regulation to support the power system operation. Finally penetration phase dependent policy and regulatory recommendations are given concerning time-of-use pricing, smart meter deployment, stable and simple regulation for reselling energy on private property, roll-out of public charging infrastructure as well as reviewing of grid codes and operational system procedures for interactions between network operators and vehicle aggregators. - Highlights: → A conceptual regulatory framework for charging EVs is proposed. → 2 new agents, EV charging point manager, EV aggregator and their functions are introduced. → Depending on private or public access of charging points, contractual relations change. → A classification of charging scenarios alludes implications on regulatory topics. → EV penetration phase dependent policy and regulatory recommendations are given.

  20. Regulatory framework and business models for charging plug-in electric vehicles: Infrastructure, agents, and commercial relationships

    Energy Technology Data Exchange (ETDEWEB)

    Gomez San Roman, Tomas [Instituto de Investigacion Tecnologica, Universidad Pontificia Comillas, Madrid (Spain); Momber, Ilan, E-mail: ilan.momber@iit.upcomillas.es [Instituto de Investigacion Tecnologica, Universidad Pontificia Comillas, Madrid (Spain); Rivier Abbad, Michel; Sanchez Miralles, Alvaro [Instituto de Investigacion Tecnologica, Universidad Pontificia Comillas, Madrid (Spain)

    2011-10-15

    Electric vehicles (EVs) present efficiency and environmental advantages over conventional transportation. It is expected that in the next decade this technology will progressively penetrate the market. The integration of plug-in electric vehicles in electric power systems poses new challenges in terms of regulation and business models. This paper proposes a conceptual regulatory framework for charging EVs. Two new electricity market agents, the EV charging manager and the EV aggregator, in charge of developing charging infrastructure and providing charging services are introduced. According to that, several charging modes such as EV home charging, public charging on streets, and dedicated charging stations are formulated. Involved market agents and their commercial relationships are analysed in detail. The paper elaborates the opportunities to formulate more sophisticated business models for vehicle-to-grid applications under which the storage capability of EV batteries is used for providing peak power or frequency regulation to support the power system operation. Finally penetration phase dependent policy and regulatory recommendations are given concerning time-of-use pricing, smart meter deployment, stable and simple regulation for reselling energy on private property, roll-out of public charging infrastructure as well as reviewing of grid codes and operational system procedures for interactions between network operators and vehicle aggregators. - Highlights: > A conceptual regulatory framework for charging EVs is proposed. > 2 new agents, EV charging point manager, EV aggregator and their functions are introduced. > Depending on private or public access of charging points, contractual relations change. > A classification of charging scenarios alludes implications on regulatory topics. > EV penetration phase dependent policy and regulatory recommendations are given.

  1. Boolean modelling reveals new regulatory connections between transcription factors orchestrating the development of the ventral spinal cord.

    KAUST Repository

    Lovrics, Anna

    2014-11-14

    We have assembled a network of cell-fate determining transcription factors that play a key role in the specification of the ventral neuronal subtypes of the spinal cord on the basis of published transcriptional interactions. Asynchronous Boolean modelling of the network was used to compare simulation results with reported experimental observations. Such comparison highlighted the need to include additional regulatory connections in order to obtain the fixed point attractors of the model associated with the five known progenitor cell types located in the ventral spinal cord. The revised gene regulatory network reproduced previously observed cell state switches between progenitor cells observed in knock-out animal models or in experiments where the transcription factors were overexpressed. Furthermore the network predicted the inhibition of Irx3 by Nkx2.2 and this prediction was tested experimentally. Our results provide evidence for the existence of an as yet undescribed inhibitory connection which could potentially have significance beyond the ventral spinal cord. The work presented in this paper demonstrates the strength of Boolean modelling for identifying gene regulatory networks.

  2. Regulatory perspectives on model validation in high-level radioactive waste management programs: A joint NRC/SKI white paper

    Energy Technology Data Exchange (ETDEWEB)

    Wingefors, S.; Andersson, J.; Norrby, S. [Swedish Nuclear Power lnspectorate, Stockholm (Sweden). Office of Nuclear Waste Safety; Eisenberg, N.A.; Lee, M.P.; Federline, M.V. [U.S. Nuclear Regulatory Commission, Washington, DC (United States). Office of Nuclear Material Safety and Safeguards; Sagar, B.; Wittmeyer, G.W. [Center for Nuclear Waste Regulatory Analyses, San Antonio, TX (United States)

    1999-03-01

    Validation (or confidence building) should be an important aspect of the regulatory uses of mathematical models in the safety assessments of geologic repositories for the disposal of spent nuclear fuel and other high-level radioactive wastes (HLW). A substantial body of literature exists indicating the manner in which scientific validation of models is usually pursued. Because models for a geologic repository performance assessment cannot be tested over the spatial scales of interest and long time periods for which the models will make estimates of performance, the usual avenue for model validation- that is, comparison of model estimates with actual data at the space-time scales of interest- is precluded. Further complicating the model validation process in HLW programs are the uncertainties inherent in describing the geologic complexities of potential disposal sites, and their interactions with the engineered system, with a limited set of generally imprecise data, making it difficult to discriminate between model discrepancy and inadequacy of input data. A successful strategy for model validation, therefore, should attempt to recognize these difficulties, address their resolution, and document the resolution in a careful manner. The end result of validation efforts should be a documented enhancement of confidence in the model to an extent that the model's results can aid in regulatory decision-making. The level of validation needed should be determined by the intended uses of these models, rather than by the ideal of validation of a scientific theory. This white Paper presents a model validation strategy that can be implemented in a regulatory environment. It was prepared jointly by staff members of the U.S. Nuclear Regulatory Commission and the Swedish Nuclear Power Inspectorate-SKI. This document should not be viewed as, and is not intended to be formal guidance or as a staff position on this matter. Rather, based on a review of the literature and previous

  3. Regulatory perspectives on model validation in high-level radioactive waste management programs: A joint NRC/SKI white paper

    International Nuclear Information System (INIS)

    Wingefors, S.; Andersson, J.; Norrby, S.

    1999-03-01

    Validation (or confidence building) should be an important aspect of the regulatory uses of mathematical models in the safety assessments of geologic repositories for the disposal of spent nuclear fuel and other high-level radioactive wastes (HLW). A substantial body of literature exists indicating the manner in which scientific validation of models is usually pursued. Because models for a geologic repository performance assessment cannot be tested over the spatial scales of interest and long time periods for which the models will make estimates of performance, the usual avenue for model validation- that is, comparison of model estimates with actual data at the space-time scales of interest- is precluded. Further complicating the model validation process in HLW programs are the uncertainties inherent in describing the geologic complexities of potential disposal sites, and their interactions with the engineered system, with a limited set of generally imprecise data, making it difficult to discriminate between model discrepancy and inadequacy of input data. A successful strategy for model validation, therefore, should attempt to recognize these difficulties, address their resolution, and document the resolution in a careful manner. The end result of validation efforts should be a documented enhancement of confidence in the model to an extent that the model's results can aid in regulatory decision-making. The level of validation needed should be determined by the intended uses of these models, rather than by the ideal of validation of a scientific theory. This white Paper presents a model validation strategy that can be implemented in a regulatory environment. It was prepared jointly by staff members of the U.S. Nuclear Regulatory Commission and the Swedish Nuclear Power Inspectorate-SKI. This document should not be viewed as, and is not intended to be formal guidance or as a staff position on this matter. Rather, based on a review of the literature and previous

  4. Constitutive, Institutive and Up-Regulation of Carotenogenesis Regulatory Mechanism via In Vitro Culture Model System and Elicitors

    International Nuclear Information System (INIS)

    Rashidi Othman; Fatimah Azzahra Mohd Zaifuddin; Norazian Mohd Hassan

    2015-01-01

    Phyto hormone abscisic acid (ABA) plays a regulatory role in many physiological processes in plants and is regulated and controlled by specific key factors or genes. Different environmental stress conditions such as water, drought, cold, light, and temperature result in increased amounts of ABA. The action of ABA involves modification of gene expression and analysis of in vitro callus model system cultures revealed several potential of constitutive, institutive and up-regulation acting regulatory mechanisms. Therefore, this study was aimed at establishing in vitro cultures as potential research tools to study the regulatory mechanisms of the carotenoid biosynthesis in selected plant species through a controlled environment. The presence and absence of zeaxanthin and neoxanthin in callus cultures and intact plants could be explained by changes in gene expression in response to stress. Abiotic stress can alter gene expression and trigger cellular metabolism in plants. This study suggested that the key factors which involved in regulatory mechanisms of individual carotenoid biosynthesis in a particular biology system of plants can be either be silenced or activated. Therefore, based on the results in this study environmental stress is made possible for enhancement or enrichment of certain carotenoid of interest in food crops without altering the genes. (author)

  5. Reconstructing gene regulatory networks from knock-out data using Gaussian Noise Model and Pearson Correlation Coefficient.

    Science.gov (United States)

    Mohamed Salleh, Faridah Hani; Arif, Shereena Mohd; Zainudin, Suhaila; Firdaus-Raih, Mohd

    2015-12-01

    A gene regulatory network (GRN) is a large and complex network consisting of interacting elements that, over time, affect each other's state. The dynamics of complex gene regulatory processes are difficult to understand using intuitive approaches alone. To overcome this problem, we propose an algorithm for inferring the regulatory interactions from knock-out data using a Gaussian model combines with Pearson Correlation Coefficient (PCC). There are several problems relating to GRN construction that have been outlined in this paper. We demonstrated the ability of our proposed method to (1) predict the presence of regulatory interactions between genes, (2) their directionality and (3) their states (activation or suppression). The algorithm was applied to network sizes of 10 and 50 genes from DREAM3 datasets and network sizes of 10 from DREAM4 datasets. The predicted networks were evaluated based on AUROC and AUPR. We discovered that high false positive values were generated by our GRN prediction methods because the indirect regulations have been wrongly predicted as true relationships. We achieved satisfactory results as the majority of sub-networks achieved AUROC values above 0.5. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Comparing Service Delivery Models for Children with Developmental Delays in Canada: Adaptive and Maladaptive Behaviours, Parental Perceptions of Stress and of Care

    Science.gov (United States)

    Sladeczek, Ingrid E.; Fontil, Laura; Miodrag, Nancy; Karagiannakis, Anastasia; Amar, Daniel; Amos, Janet

    2017-01-01

    This study compares two service delivery models (community-based and centre-based), examining them in light of children's adaptive and maladaptive behaviours, and parental perceptions of stress and of care. More specifically, parents of 96 children with developmental delays assessed their children's adaptive and maladaptive behaviours and rated…

  7. A Simulation Study of Mutations in the Genetic Regulatory Hierarchy for Butterfly Eyespot Focus Determination

    OpenAIRE

    Marcus, Jeffrey M.; Evans, Travis M.

    2008-01-01

    The color patterns on the wings of butterflies have been an important model system in evolutionary developmental biology. A recent computational model tested genetic regulatory hierarchies hypothesized to underlie the formation of butterfly eyespot foci (Evans and Marcus, 2006). The computational model demonstrated that one proposed hierarchy was incapable of reproducing the known patterns of gene expression associated with eyespot focus determination in wild-type butterflies, but that two sl...

  8. Understanding Chinese American Adolescents' Developmental Outcomes: Insights from the Family Stress Model

    Science.gov (United States)

    Benner, Aprile D.; Kim, Su Yeong

    2010-01-01

    In this brief report, we investigated whether the Family Stress Model could be replicated with a sample of Chinese American families. Path analyses with 444 adolescents and their parents provided support for the model's generalizability. Specifically, mothers' and fathers' reports of economic status (i.e., income, financial, and job instability)…

  9. Kinetic modelling and meta-analysis of the B. subtilis SigA regulatory network during spore germination and outgrowth

    Czech Academy of Sciences Publication Activity Database

    Ramaniuk, Olga; Černý, Martin; Krásný, Libor; Vohradský, Jiří

    2017-01-01

    Roč. 1860, č. 8 (2017), s. 894-904 ISSN 1874-9399 R&D Projects: GA MŠk(CZ) LM2015055; GA ČR GA13-16842S; GA MZd(CZ) NV17-29680A Institutional support: RVO:61388971 Keywords : Sigma A * Kinetic modelling * Regulatory network Subject RIV: EE - Microbiology, Virology OBOR OECD: Microbiology Impact factor: 5.018, year: 2016

  10. Modeling the effector - regulatory T cell cross-regulation reveals the intrinsic character of relapses in Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Torrealdea Javier

    2011-07-01

    Full Text Available Abstract Background The relapsing-remitting dynamics is a hallmark of autoimmune diseases such as Multiple Sclerosis (MS. Although current understanding of both cellular and molecular mechanisms involved in the pathogenesis of autoimmune diseases is significant, how their activity generates this prototypical dynamics is not understood yet. In order to gain insight about the mechanisms that drive these relapsing-remitting dynamics, we developed a computational model using such biological knowledge. We hypothesized that the relapsing dynamics in autoimmunity can arise through the failure in the mechanisms controlling cross-regulation between regulatory and effector T cells with the interplay of stochastic events (e.g. failure in central tolerance, activation by pathogens that are able to trigger the immune system. Results The model represents five concepts: central tolerance (T-cell generation by the thymus, T-cell activation, T-cell memory, cross-regulation (negative feedback between regulatory and effector T-cells and tissue damage. We enriched the model with reversible and irreversible tissue damage, which aims to provide a comprehensible link between autoimmune activity and clinical relapses and active lesions in the magnetic resonances studies in patients with Multiple Sclerosis. Our analysis shows that the weakness in this negative feedback between effector and regulatory T-cells, allows the immune system to generate the characteristic relapsing-remitting dynamics of autoimmune diseases, without the need of additional environmental triggers. The simulations show that the timing at which relapses appear is highly unpredictable. We also introduced targeted perturbations into the model that mimicked immunotherapies that modulate effector and regulatory populations. The effects of such therapies happened to be highly dependent on the timing and/or dose, and on the underlying dynamic of the immune system. Conclusion The relapsing dynamic in MS

  11. Predictive regulatory models in Drosophila melanogaster by integrative inference of transcriptional networks

    Science.gov (United States)

    Marbach, Daniel; Roy, Sushmita; Ay, Ferhat; Meyer, Patrick E.; Candeias, Rogerio; Kahveci, Tamer; Bristow, Christopher A.; Kellis, Manolis

    2012-01-01

    Gaining insights on gene regulation from large-scale functional data sets is a grand challenge in systems biology. In this article, we develop and apply methods for transcriptional regulatory network inference from diverse functional genomics data sets and demonstrate their value for gene function and gene expression prediction. We formulate the network inference problem in a machine-learning framework and use both supervised and unsupervised methods to predict regulatory edges by integrating transcription factor (TF) binding, evolutionarily conserved sequence motifs, gene expression, and chromatin modification data sets as input features. Applying these methods to Drosophila melanogaster, we predict ∼300,000 regulatory edges in a network of ∼600 TFs and 12,000 target genes. We validate our predictions using known regulatory interactions, gene functional annotations, tissue-specific expression, protein–protein interactions, and three-dimensional maps of chromosome conformation. We use the inferred network to identify putative functions for hundreds of previously uncharacterized genes, including many in nervous system development, which are independently confirmed based on their tissue-specific expression patterns. Last, we use the regulatory network to predict target gene expression levels as a function of TF expression, and find significantly higher predictive power for integrative networks than for motif or ChIP-based networks. Our work reveals the complementarity between physical evidence of regulatory interactions (TF binding, motif conservation) and functional evidence (coordinated expression or chromatin patterns) and demonstrates the power of data integration for network inference and studies of gene regulation at the systems level. PMID:22456606

  12. Predictive regulatory models in Drosophila melanogaster by integrative inference of transcriptional networks.

    Science.gov (United States)

    Marbach, Daniel; Roy, Sushmita; Ay, Ferhat; Meyer, Patrick E; Candeias, Rogerio; Kahveci, Tamer; Bristow, Christopher A; Kellis, Manolis

    2012-07-01

    Gaining insights on gene regulation from large-scale functional data sets is a grand challenge in systems biology. In this article, we develop and apply methods for transcriptional regulatory network inference from diverse functional genomics data sets and demonstrate their value for gene function and gene expression prediction. We formulate the network inference problem in a machine-learning framework and use both supervised and unsupervised methods to predict regulatory edges by integrating transcription factor (TF) binding, evolutionarily conserved sequence motifs, gene expression, and chromatin modification data sets as input features. Applying these methods to Drosophila melanogaster, we predict ∼300,000 regulatory edges in a network of ∼600 TFs and 12,000 target genes. We validate our predictions using known regulatory interactions, gene functional annotations, tissue-specific expression, protein-protein interactions, and three-dimensional maps of chromosome conformation. We use the inferred network to identify putative functions for hundreds of previously uncharacterized genes, including many in nervous system development, which are independently confirmed based on their tissue-specific expression patterns. Last, we use the regulatory network to predict target gene expression levels as a function of TF expression, and find significantly higher predictive power for integrative networks than for motif or ChIP-based networks. Our work reveals the complementarity between physical evidence of regulatory interactions (TF binding, motif conservation) and functional evidence (coordinated expression or chromatin patterns) and demonstrates the power of data integration for network inference and studies of gene regulation at the systems level.

  13. Analysis and test of a 16-foot radial rib reflector developmental model

    Science.gov (United States)

    Birchenough, Shawn A.

    1989-01-01

    Analytical and experimental modal tests were performed to determine the vibrational characteristics of a 16-foot diameter radial rib reflector model. Single rib analyses and experimental tests provided preliminary information relating to the reflector. A finite element model predicted mode shapes and frequencies of the reflector. The analyses correlated well with the experimental tests, verifying the modeling method used. The results indicate that five related, characteristic mode shapes form a group. The frequencies of the modes are determined by the relative phase of the radial ribs.

  14. Using satellite observations in performance evaluation for regulatory air quality modeling: Comparison with ground-level measurements

    Science.gov (United States)

    Odman, M. T.; Hu, Y.; Russell, A.; Chai, T.; Lee, P.; Shankar, U.; Boylan, J.

    2012-12-01

    Regulatory air quality modeling, such as State Implementation Plan (SIP) modeling, requires that model performance meets recommended criteria in the base-year simulations using period-specific, estimated emissions. The goal of the performance evaluation is to assure that the base-year modeling accurately captures the observed chemical reality of the lower troposphere. Any significant deficiencies found in the performance evaluation must be corrected before any base-case (with typical emissions) and future-year modeling is conducted. Corrections are usually made to model inputs such as emission-rate estimates or meteorology and/or to the air quality model itself, in modules that describe specific processes. Use of ground-level measurements that follow approved protocols is recommended for evaluating model performance. However, ground-level monitoring networks are spatially sparse, especially for particulate matter. Satellite retrievals of atmospheric chemical properties such as aerosol optical depth (AOD) provide spatial coverage that can compensate for the sparseness of ground-level measurements. Satellite retrievals can also help diagnose potential model or data problems in the upper troposphere. It is possible to achieve good model performance near the ground, but have, for example, erroneous sources or sinks in the upper troposphere that may result in misleading and unrealistic responses to emission reductions. Despite these advantages, satellite retrievals are rarely used in model performance evaluation, especially for regulatory modeling purposes, due to the high uncertainty in retrievals associated with various contaminations, for example by clouds. In this study, 2007 was selected as the base year for SIP modeling in the southeastern U.S. Performance of the Community Multiscale Air Quality (CMAQ) model, at a 12-km horizontal resolution, for this annual simulation is evaluated using both recommended ground-level measurements and non-traditional satellite

  15. Developmental Programming of Cardiovascular Disease Following Intrauterine Growth Restriction: Findings Utilising A Rat Model of Maternal Protein Restriction

    Science.gov (United States)

    Zohdi, Vladislava; Lim, Kyungjoon; Pearson, James T.; Black, M. Jane

    2014-01-01

    Over recent years, studies have demonstrated links between risk of cardiovascular disease in adulthood and adverse events that occurred very early in life during fetal development. The concept that there are embryonic and fetal adaptive responses to a sub-optimal intrauterine environment often brought about by poor maternal diet that result in permanent adverse consequences to life-long health is consistent with the definition of “programming”. The purpose of this review is to provide an overview of the current knowledge of the effects of intrauterine growth restriction (IUGR) on long-term cardiac structure and function, with particular emphasis on the effects of maternal protein restriction. Much of our recent knowledge has been derived from animal models. We review the current literature of one of the most commonly used models of IUGR (maternal protein restriction in rats), in relation to birth weight and postnatal growth, blood pressure and cardiac structure and function. In doing so, we highlight the complexity of developmental programming, with regards to timing, degree of severity of the insult, genotype and the subsequent postnatal phenotype. PMID:25551250

  16. Designing Collaborative Developmental Standards by Refactoring of the Earth Science Models, Libraries, Workflows and Frameworks.

    Science.gov (United States)

    Mirvis, E.; Iredell, M.

    2015-12-01

    The operational (OPS) NOAA National Centers for Environmental Prediction (NCEP) suite, traditionally, consist of a large set of multi- scale HPC models, workflows, scripts, tools and utilities, which are very much depending on the variety of the additional components. Namely, this suite utilizes a unique collection of the in-house developed 20+ shared libraries (NCEPLIBS), certain versions of the 3-rd party libraries (like netcdf, HDF, ESMF, jasper, xml etc.), HPC workflow tool within dedicated (sometimes even vendors' customized) HPC system homogeneous environment. This domain and site specific, accompanied with NCEP's product- driven large scale real-time data operations complicates NCEP collaborative development tremendously by reducing chances to replicate this OPS environment anywhere else. The NOAA/NCEP's Environmental Modeling Center (EMC) missions to develop and improve numerical weather, climate, hydrological and ocean prediction through the partnership with the research community. Realizing said difficulties, lately, EMC has been taken an innovative approach to improve flexibility of the HPC environment by building the elements and a foundation for NCEP OPS functionally equivalent environment (FEE), which can be used to ease the external interface constructs as well. Aiming to reduce turnaround time of the community code enhancements via Research-to-Operations (R2O) cycle, EMC developed and deployed several project sub-set standards that already paved the road to NCEP OPS implementation standards. In this topic we will discuss the EMC FEE for O2R requirements and approaches in collaborative standardization, including NCEPLIBS FEE and models code version control paired with the models' derived customized HPC modules and FEE footprints. We will share NCEP/EMC experience and potential in the refactoring of EMC development processes, legacy codes and in securing model source code quality standards by using combination of the Eclipse IDE, integrated with the

  17. Enhancing the value of psychiatric mouse models; differential expression of developmental behavioral and cognitive profiles in four inbred strains of mice.

    Science.gov (United States)

    Molenhuis, Remco T; de Visser, Leonie; Bruining, Hilgo; Kas, Martien J

    2014-06-01

    The behavioral characterization of animal models of psychiatric disorders is often based upon independent traits measured at adult age. To model the neurodevelopmental aspects of psychiatric pathogenesis, we introduce a novel approach for a developmental behavioral analysis in mice. C57BL/6J (C57) mice were used as a reference strain and compared with 129S1/SvImJ (129Sv), BTBR T+tf/J (BTBR) and A/J (AJ) strains as marker strains for aberrant development. Mice were assessed at pre-adolescence (4 weeks), adolescence (6 weeks), early adulthood (8 weeks) and in adulthood (10-12 weeks) on a series of behavioral tasks measuring general health, neurological reflexes, locomotor activity, anxiety, short- and long-term memory and cognitive flexibility. Developmental delays in short-term object memory were associated with either a hypo-reactive profile in 129Sv mice or a hyper-reactive profile in BTBR mice. Furthermore, BTBR mice showed persistent high levels of repetitive grooming behavior during all developmental stages that was associated with the adult expression of cognitive rigidity. In addition, strain differences in development were observed in puberty onset, touch escape, and body position. These data showed that this longitudinal testing battery provides sufficient behavioral and cognitive resolution during different development stages and offers the opportunity to address the behavioral developmental trajectory in genetic mouse models for neurodevelopmental disorders. Furthermore, the data revealed that the assessment of multiple behavioral and cognitive domains at different developmental stages is critical to determine confounding factors (e.g., impaired motor behavior) that may interfere with the behavioral testing performance in mouse models for brain disorders. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

  18. General developmental health in the VPA-rat model of autism

    DEFF Research Database (Denmark)

    Favre, Mônica R; Rinaldi Barkat, Tania; Lamendola, Deborah

    2013-01-01

    Autism is a neurodevelopmental condition diagnosed by impaired social interaction, abnormal communication and, stereotyped behaviors. While post-mortem and imaging studies have provided good insights into the neurobiological symptomology of autism, animal models can be used to study...... with VPA during early pregnancy show an increased risk for giving birth to an autistic child. In rats, early embryonic exposure, around the time of neural tube closure, leads to autism-like anatomical and behavioral abnormalities in the offspring. Considering the increasing use of the VPA rat model, we...

  19. Finding cis-regulatory modules in Drosophila using phylogenetic hidden Markov models

    DEFF Research Database (Denmark)

    Wong, Wendy S W; Nielsen, Rasmus

    2007-01-01

    MOTIVATION: Finding the regulatory modules for transcription factors binding is an important step in elucidating the complex molecular mechanisms underlying regulation of gene expression. There are numerous methods available for solving this problem, however, very few of them take advantage of th...

  20. Ecological Models in Support of Regulatory Risk Assessments of Pesticides: Developing a Strategy for the Future

    NARCIS (Netherlands)

    Forbes, V.E.; Hommen, U.; Thorbek, P.; Heimbach, F.; Brink, van den P.J.; Wogram, J.; Thulke, H.H.; Grimm, V.

    2009-01-01

    This brief communication reports on the main findings of the LEMTOX workshop, held from 9 to 12 September 2007, at the Helmholtz Centre for Environmental Research (UFZ) in Leipzig, Germany. The workshop brought together a diverse group of stakeholders from academia, regulatory authorities, contract

  1. An Integrative Model for the Study of Developmental Competencies in Minority Children.

    Science.gov (United States)

    Coll, Cynthia Garcia; And Others

    1996-01-01

    Proposes a conceptual model for the study of child development in minority populations in the United States that is anchored within social stratification theory and emphasizes the importance of racism, prejudice, discrimination, oppression, and segregation in the development of minority children and families. (MDM)

  2. Cumulative Risk Disparities in Children's Neurocognitive Functioning: A Developmental Cascade Model

    Science.gov (United States)

    Wade, Mark; Browne, Dillon T.; Plamondon, Andre; Daniel, Ella; Jenkins, Jennifer M.

    2016-01-01

    The current longitudinal study examined the role of cumulative social risk on children's theory of mind (ToM) and executive functioning (EF) across early development. Further, we also tested a cascade model of development in which children's social cognition at 18 months was hypothesized to predict ToM and EF at age 4.5 through intermediary…

  3. A dynamic genetic-hormonal regulatory network model explains multiple cellular behaviors of the root apical meristem of Arabidopsis thaliana.

    Science.gov (United States)

    García-Gómez, Mónica L; Azpeitia, Eugenio; Álvarez-Buylla, Elena R

    2017-04-01

    The study of the concerted action of hormones and transcription factors is fundamental to understand cell differentiation and pattern formation during organ development. The root apical meristem of Arabidopsis thaliana is a useful model to address this. It has a stem cell niche near its tip conformed of a quiescent organizer and stem or initial cells around it, then a proliferation domain followed by a transition domain, where cells diminish division rate before transiting to the elongation zone; here, cells grow anisotropically prior to their final differentiation towards the plant base. A minimal model of the gene regulatory network that underlies cell-fate specification and patterning at the root stem cell niche was proposed before. In this study, we update and couple such network with both the auxin and cytokinin hormone signaling pathways to address how they collectively give rise to attractors that correspond to the genetic and hormonal activity profiles that are characteristic of different cell types along A. thaliana root apical meristem. We used a Boolean model of the genetic-hormonal regulatory network to integrate known and predicted regulatory interactions into alternative models. Our analyses show that, after adding some putative missing interactions, the model includes the necessary and sufficient components and regulatory interactions to recover attractors characteristic of the root cell types, including the auxin and cytokinin activity profiles that correlate with different cellular behaviors along the root apical meristem. Furthermore, the model predicts the existence of activity configurations that could correspond to the transition domain. The model also provides a possible explanation for apparently paradoxical cellular behaviors in the root meristem. For example, how auxin may induce and at the same time inhibit WOX5 expression. According to the model proposed here the hormonal regulation of WOX5 might depend on the cell type. Our results

  4. A dynamic genetic-hormonal regulatory network model explains multiple cellular behaviors of the root apical meristem of Arabidopsis thaliana.

    Directory of Open Access Journals (Sweden)

    Mónica L García-Gómez

    2017-04-01

    Full Text Available The study of the concerted action of hormones and transcription factors is fundamental to understand cell differentiation and pattern formation during organ development. The root apical meristem of Arabidopsis thaliana is a useful model to address this. It has a stem cell niche near its tip conformed of a quiescent organizer and stem or initial cells around it, then a proliferation domain followed by a transition domain, where cells diminish division rate before transiting to the elongation zone; here, cells grow anisotropically prior to their final differentiation towards the plant base. A minimal model of the gene regulatory network that underlies cell-fate specification and patterning at the root stem cell niche was proposed before. In this study, we update and couple such network with both the auxin and cytokinin hormone signaling pathways to address how they collectively give rise to attractors that correspond to the genetic and hormonal activity profiles that are characteristic of different cell types along A. thaliana root apical meristem. We used a Boolean model of the genetic-hormonal regulatory network to integrate known and predicted regulatory interactions into alternative models. Our analyses show that, after adding some putative missing interactions, the model includes the necessary and sufficient components and regulatory interactions to recover attractors characteristic of the root cell types, including the auxin and cytokinin activity profiles that correlate with different cellular behaviors along the root apical meristem. Furthermore, the model predicts the existence of activity configurations that could correspond to the transition domain. The model also provides a possible explanation for apparently paradoxical cellular behaviors in the root meristem. For example, how auxin may induce and at the same time inhibit WOX5 expression. According to the model proposed here the hormonal regulation of WOX5 might depend on the cell

  5. Dynamic RSA: Examining parasympathetic regulatory dynamics via vector-autoregressive modeling of time-varying RSA and heart period.

    Science.gov (United States)

    Fisher, Aaron J; Reeves, Jonathan W; Chi, Cyrus

    2016-07-01

    Expanding on recently published methods, the current study presents an approach to estimating the dynamic, regulatory effect of the parasympathetic nervous system on heart period on a moment-to-moment basis. We estimated second-to-second variation in respiratory sinus arrhythmia (RSA) in order to estimate the contemporaneous and time-lagged relationships among RSA, interbeat interval (IBI), and respiration rate via vector autoregression. Moreover, we modeled these relationships at lags of 1 s to 10 s, in order to evaluate the optimal latency for estimating dynamic RSA effects. The IBI (t) on RSA (t-n) regression parameter was extracted from individual models as an operationalization of the regulatory effect of RSA on IBI-referred to as dynamic RSA (dRSA). Dynamic RSA positively correlated with standard averages of heart rate and negatively correlated with standard averages of RSA. We propose that dRSA reflects the active downregulation of heart period by the parasympathetic nervous system and thus represents a novel metric that provides incremental validity in the measurement of autonomic cardiac control-specifically, a method by which parasympathetic regulatory effects can be measured in process. © 2016 Society for Psychophysiological Research.

  6. Robust variable selection method for nonparametric differential equation models with application to nonlinear dynamic gene regulatory network analysis.

    Science.gov (United States)

    Lu, Tao

    2016-01-01

    The gene regulation network (GRN) evaluates the interactions between genes and look for models to describe the gene expression behavior. These models have many applications; for instance, by characterizing the gene expression mechanisms that cause certain disorders, it would be possible to target those genes to block the progress of the disease. Many biological processes are driven by nonlinear dynamic GRN. In this article, we propose a nonparametric differential equation (ODE) to model the nonlinear dynamic GRN. Specially, we address following questions simultaneously: (i) extract information from noisy time course gene expression data; (ii) model the nonlinear ODE through a nonparametric smoothing function; (iii) identify the important regulatory gene(s) through a group smoothly clipped absolute deviation (SCAD) approach; (iv) test the robustness of the model against possible shortening of experimental duration. We illustrate the usefulness of the model and associated statistical methods through a simulation and a real application examples.

  7. Improving the Enterprise Requirements and Acquisition Model’s Developmental Test and Evaluation Process Fidelity

    Science.gov (United States)

    2014-03-27

    program office. Many of the individuals were identified through snowball sampling . SME Discussion Summary The SME discussions brought to light...adequate sample sizes are collected. With computer modeling and simulation, time is less of a limiting factor as it can be manipulated. Data representing...The DAMS suffers from diverse problems of which only a very small sample were discussed here. However, as diverse as the problems encountered were, a

  8. Computational Modeling and Simulation of Developmental Toxicity: what can we learn from a virtual embryo? (RIVM, Brussels)

    Science.gov (United States)

    Developmental and Reproductive Toxicity (DART) testing is important for assessing the potential consequences of drug and chemical exposure on human health and well-being. Complexity of pregnancy and the reproductive cycle makes DART testing challenging and costly for traditional ...

  9. A model of gene expression based on random dynamical systems reveals modularity properties of gene regulatory networks.

    Science.gov (United States)

    Antoneli, Fernando; Ferreira, Renata C; Briones, Marcelo R S

    2016-06-01

    Here we propose a new approach to modeling gene expression based on the theory of random dynamical systems (RDS) that provides a general coupling prescription between the nodes of any given regulatory network given the dynamics of each node is modeled by a RDS. The main virtues of this approach are the following: (i) it provides a natural way to obtain arbitrarily large networks by coupling together simple basic pieces, thus revealing the modularity of regulatory networks; (ii) the assumptions about the stochastic processes used in the modeling are fairly general, in the sense that the only requirement is stationarity; (iii) there is a well developed mathematical theory, which is a blend of smooth dynamical systems theory, ergodic theory and stochastic analysis that allows one to extract relevant dynamical and statistical information without solving the system; (iv) one may obtain the classical rate equations form the corresponding stochastic version by averaging the dynamic random variables (small noise limit). It is important to emphasize that unlike the deterministic case, where coupling two equations is a trivial matter, coupling two RDS is non-trivial, specially in our case, where the coupling is performed between a state variable of one gene and the switching stochastic process of another gene and, hence, it is not a priori true that the resulting coupled system will satisfy the definition of a random dynamical system. We shall provide the necessary arguments that ensure that our coupling prescription does indeed furnish a coupled regulatory network of random dynamical systems. Finally, the fact that classical rate equations are the small noise limit of our stochastic model ensures that any validation or prediction made on the basis of the classical theory is also a validation or prediction of our model. We illustrate our framework with some simple examples of single-gene system and network motifs. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Turmeric Extract Rescues Ethanol-Induced Developmental Defect in the Zebrafish Model for Fetal Alcohol Spectrum Disorder (FASD).

    Science.gov (United States)

    Muralidharan, Pooja; Connors, Craig T; Mohammed, Arooj S; Sarmah, Swapnalee; Marrs, Kathleen; Marrs, James A; Chism, Grady W

    2017-09-01

    Prenatal ethanol exposure causes the most frequent preventable birth disorder, fetal alcohol spectrum disorder (FASD). The effect of turmeric extracts in rescuing an ethanol-induced developmental defect using zebrafish as a model was determined. Ethanol-induced oxidative stress is one of the major mechanisms underlying FASD. We hypothesize that antioxidant inducing properties of turmeric may alleviate ethanol-induced defects. Curcuminoid content of the turmeric powder extract (5 mg/mL turmeric in ethanol) was determined by UPLC and found to contain Curcumin (124.1 ± 0.2 μg/mL), Desmethoxycurcumin (43.4 ± 0.1 μg/mL), and Bisdemethoxycurcumin (36.6 ± 0.1 μg/mL). Zebrafish embryos were treated with 100 mM (0.6% v/v) ethanol during gastrulation through organogenesis (2 to 48 h postfertilization (hpf)) and supplemented with turmeric extract to obtain total curcuminoid concentrations of 0, 1.16, 1.72, or 2.32 μM. Turmeric supplementation showed significant rescue of the body length at 72 hpf compared to ethanol-treated embryos. The mechanism underlying the rescue remains to be determined. © 2017 Institute of Food Technologists®.

  11. Developmental vitamin D deficiency alters MK 801-induced hyperlocomotion in the adult rat: An animal model of schizophrenia.

    Science.gov (United States)

    Kesby, James P; Burne, Thomas H J; McGrath, John J; Eyles, Darryl W

    2006-09-15

    Developmental vitamin D (DVD) deficiency has been proposed as a risk factor for schizophrenia. The behavioral phenotype of adult rats subjected to transient low prenatal vitamin D is characterized by spontaneous hyperlocomotion but normal prepulse inhibition of acoustic startle (PPI). The aim of this study was to examine the impact of selected psychotropic agents and one well-known antipsychotic agent on the behavioral phenotype of DVD deplete rats. Control versus DVD deplete adult rats were assessed on holeboard, open field and PPI. In the open field, animals were given MK-801 and/or haloperidol. For PPI, the animals were given apomorphine or MK-801. DVD deplete rats had increased baseline locomotion on the holeboard task and increased locomotion in response to MK-801 compared to control rats. At low doses, haloperidol antagonized the MK-801 hyperactivity of DVD deplete rats preferentially and, at a high dose, resulted in a more pronounced reduction in spontaneous locomotion in DVD deplete rats. DVD depletion did not affect either baseline or drug-mediated PPI response. These results suggest that DVD deficiency is associated with a persistent alteration in neuronal systems associated with motor function but not those associated with sensory motor gating. In light of the putative association between low prenatal vitamin D and schizophrenia, the discrete behavioral differences associated with the DVD model may help elucidate the neurobiological correlates of schizophrenia.

  12. Drosophila embryos as model to assess cellular and developmental toxicity of multi-walled carbon nanotubes (MWCNT in living organisms.

    Directory of Open Access Journals (Sweden)

    Boyin Liu

    Full Text Available Different toxicity tests for carbon nanotubes (CNT have been developed to assess their impact on human health and on aquatic and terrestrial animal and plant life. We present a new model, the fruit fly Drosophila embryo offering the opportunity for rapid, inexpensive and detailed analysis of CNTs toxicity during embryonic development. We show that injected DiI labelled multi-walled carbon nanotubes (MWCNTs become incorporated into cells in early Drosophila embryos, allowing the study of the consequences of cellular uptake of CNTs on cell communication, tissue and organ formation in living embryos. Fluorescently labelled subcellular structures showed that MWCNTs remained cytoplasmic and were excluded from the nucleus. Analysis of developing ectodermal and neural stem cells in MWCNTs injected embryos revealed normal division patterns and differentiation capacity. However, an increase in cell death of ectodermal but not of neural stem cells was observed, indicating stem cell-specific vulnerability to MWCNT exposure. The ease of CNT embryo injections, the possibility of detailed morphological and genomic analysis and the low costs make Drosophila embryos a system of choice to assess potential developmental and cellular effects of CNTs and test their use in future CNT based new therapies including drug delivery.

  13. Modeling metabolism and stage-specific growth of Plasmodium falciparum HB3 during the intraerythrocytic developmental cycle.

    Science.gov (United States)

    Fang, Xin; Reifman, Jaques; Wallqvist, Anders

    2014-10-01

    The human malaria parasite Plasmodium falciparum goes through a complex life cycle, including a roughly 48-hour-long intraerythrocytic developmental cycle (IDC) in human red blood cells. A better understanding of the metabolic processes required during the asexual blood-stage reproduction will enhance our basic knowledge of P. falciparum and help identify critical metabolic reactions and pathways associated with blood-stage malaria. We developed a metabolic network model that mechanistically links time-dependent gene expression, metabolism, and stage-specific growth, allowing us to predict the metabolic fluxes, the biomass production rates, and the timing of production of the different biomass components during the IDC. We predicted time- and stage-specific production of precursors and macromolecules for P. falciparum (strain HB3), allowing us to link specific metabolites to specific physiological functions. For example, we hypothesized that coenzyme A might be involved in late-IDC DNA replication and cell division. Moreover, the predicted ATP metabolism indicated that energy was mainly produced from glycolysis and utilized for non-metabolic processes. Finally, we used the model to classify the entire tricarboxylic acid cycle into segments, each with a distinct function, such as superoxide detoxification, glutamate/glutamine processing, and metabolism of fumarate as a byproduct of purine biosynthesis. By capturing the normal metabolic and growth progression in P. falciparum during the IDC, our model provides a starting point for further elucidation of strain-specific metabolic activity, host-parasite interactions, stress-induced metabolic responses, and metabolic responses to antimalarial drugs and drug candidates.

  14. L-leucine partially rescues translational and developmental defects associated with zebrafish models of Cornelia de Lange syndrome.

    Science.gov (United States)

    Xu, Baoshan; Sowa, Nenja; Cardenas, Maria E; Gerton, Jennifer L

    2015-03-15

    Cohesinopathies are human genetic disorders that include Cornelia de Lange syndrome (CdLS) and Roberts syndrome (RBS) and are characterized by defects in limb and craniofacial development as well as mental retardation. The developmental phenotypes of CdLS and other cohesinopathies suggest that mutations in the structure and regulation of the cohesin complex during embryogenesis interfere with gene regulation. In a previous project, we showed that RBS was associated with highly fragmented nucleoli and defects in both ribosome biogenesis and protein translation. l-leucine stimulation of the mTOR pathway partially rescued translation in human RBS cells and development in zebrafish models of RBS. In this study, we investigate protein translation in zebrafish models of CdLS. Our results show that phosphorylation of RPS6 as well as 4E-binding protein 1 (4EBP1) was reduced in nipbla/b, rad21 and smc3-morphant embryos, a pattern indicating reduced translation. Moreover, protein biosynthesis and rRNA production were decreased in the cohesin morphant embryo cells. l-leucine partly rescued protein synthesis and rRNA production in the cohesin morphants and partially restored phosphorylation of RPS6 and 4EBP1. Concomitantly, l-leucine treatment partially improved cohesinopathy embryo development including the formation of craniofacial cartilage. Interestingly, we observed that alpha-ketoisocaproate (α-KIC), which is a keto derivative of leucine, also partially rescued the development of rad21 and nipbla/b morphants by boosting mTOR-dependent translation. In summary, our results suggest that cohesinopathies are caused in part by defective protein synthesis, and stimulation of the mTOR pathway through l-leucine or its metabolite α-KIC can partially rescue development in zebrafish models for CdLS. © The Author 2014. Published by Oxford University Press.

  15. Workshop: Improving the Assessment and Valuation of Climate Change Impacts for Policy and Regulatory Analysis: Modeling Climate Change Impacts and Associated Economic Damages (2010 - part 1)

    Science.gov (United States)

    The purpose of this workshop Improving the Assessment and Valuation of Climate Change Impacts for Policy and Regulatory Analysis. focused on conceptual and methodological issues - integrated assessment modeling and valuation.

  16. Testing Models for the Contributions of Genes and Environment to Developmental Change in Adolescent Depression.

    Science.gov (United States)

    Gillespie, Nathan A; Eaves, Lindon J; Maes, Hermine; Silberg, Judy L

    2015-07-01

    We tested two models to identify the genetic and environmental processes underlying longitudinal changes in depression among adolescents. The first assumes that observed changes in covariance structure result from the unfolding of inherent, random individual differences in the overall levels and rates of change in depression over time (random growth curves). The second assumes that observed changes are due to time-specific random effects (innovations) accumulating over time (autoregressive effects). We found little evidence of age-specific genetic effects or persistent genetic innovations. Instead, genetic effects are consistent with a gradual unfolding in the liability to depression and rates of change with increasing age. Likewise, the environment also creates significant individual differences in overall levels of depression and rates of change. However, there are also time-specific environmental experiences that persist with fidelity. The implications of these differing genetic and environmental mechanisms in the etiology of depression are considered.

  17. Foundational Tests of the Need-Support Model: A Framework for Bridging Regulatory Focus Theory and Self-Determination Theory.

    Science.gov (United States)

    Vaughn, Leigh Ann

    2017-03-01

    This article introduces the need-support model, which proposes that regulatory focus can affect subjective support for the needs proposed by self-determination theory (autonomy, competence, and relatedness), and support of these needs can affect subjective labeling of experiences as promotion-focused and prevention-focused. Three studies tested these hypotheses ( N = 2,114). Study 1 found that people recall more need support in promotion-focused experiences than in prevention-focused experiences, and need support in their day yesterday (with no particular regulatory focus) fell in between. Study 2 found that experiences of higher need support were more likely to be labeled as promotion-focused rather than prevention-focused, and that each need accounted for distinct variance in the labeling of experiences. Study 3 varied regulatory focus within a performance task and found that participants in the promotion condition engaged in need-support inflation, whereas participants in the prevention condition engaged in need-support deflation. Directions for future research are discussed.

  18. Improved bolt models for use in global analyses of storage and transportation casks subject to extra-regulatory loading

    International Nuclear Information System (INIS)

    Kalan, R.J.; Ammerman, D.J.; Gwinn, K.W.

    2004-01-01

    Transportation and storage casks subjected to extra-regulatory loadings may experience large stresses and strains in key structural components. One of the areas susceptible to these large stresses and strains is the bolted joint retaining any closure lid on an overpack or a canister. Modeling this joint accurately is necessary in evaluating the performance of the cask under extreme loading conditions. However, developing detailed models of a bolt in a large cask finite element model can dramatically increase the computational time, making the analysis prohibitive. Sandia National Laboratories used a series of calibrated, detailed, bolt finite element sub-models to develop a modified-beam bolt-model in order to examine the response of a storage cask and closure to severe accident loadings. The initial sub-models were calibrated for tension and shear loading using test data for large diameter bolts. Next, using the calibrated test model, sub-models of the actual joints were developed to obtain force-displacement curves and failure points for the bolted joint. These functions were used to develop a modified beam element representation of the bolted joint, which could be incorporated into the larger cask finite element model. This paper will address the modeling and assumptions used for the development of the initial calibration models, the joint sub-models and the modified beam model

  19. Animal models of allergen-induced tolerance in asthma: are T-regulatory-1 cells (Tr-1) the solution for T-helper-2 cells (Th-2) in asthma?

    Science.gov (United States)

    Tournoy, K G; Hove, C; Grooten, J; Moerloose, K; Brusselle, G G; Joos, G F

    2006-01-01

    Non-specific anti-inflammatory medication is actually the treatment of choice for controlling the T-helper type 2 (Th-2) cell-driven airway inflammation in asthma. The induction of counterbalancing Th-1 cell clones, long considered a promising approach for immunotherapy, has failed to fulfil its promise because of potentially detrimental side-effects. This is therefore probably not a valid option for the treatment of asthma. With the increasing awareness that active immune mechanisms exist to control inflammatory responses, interest rises to investigate whether these can be exploited to control allergen-induced airway disease. The induction of antigen-specific T cells with suppressive characteristics (regulatory T cells) is therefore a potentially interesting approach. These regulatory T cells mediate tolerance in healthy, non-atopic individuals and have the potential of becoming an effective means of preventing allergen-induced airway inflammation and possibly of suppressing ongoing allergic immune responses. Here we review the available knowledge about allergen-induced suppressive immunity obtained from animal models taking into account the different developmental stages of allergic airway disease.

  20. Collective Cellular Decision-Making Gives Developmental Plasticity: A Model of Signaling in Branching Roots

    Science.gov (United States)

    McCleery, W. Tyler; Mohd-Radzman, Nadiatul A.; Grieneisen, Veronica A.

    Cells within tissues can be regarded as autonomous entities that respond to their local environment and signaling from neighbors. Cell coordination is particularly important in plants, where root architecture must strategically invest resources for growth to optimize nutrient acquisition. Thus, root cells are constantly adapting to environmental cues and neighbor communication in a non-linear manner. To explain such plasticity, we view the root as a swarm of coupled multi-cellular structures, ''metamers'', rather than as a continuum of identical cells. These metamers are individually programmed to achieve a local objective - developing a lateral root primordia, which aids in local foraging of nutrients. Collectively, such individual attempts may be halted, structuring root architecture as an emergent behavior. Each metamer's decision to branch is coordinated locally and globally through hormone signaling, including processes of controlled diffusion, active polar transport, and dynamic feedback. We present a physical model of the signaling mechanism that coordinates branching decisions in response to the environment. This work was funded by the European Commission 7th Framework Program, Project No. 601062, SWARM-ORGAN.

  1. Developmental programming of metabolic diseases – a review of studies on experimental animal models

    Directory of Open Access Journals (Sweden)

    Iwona Piotrowska

    2014-06-01

    Full Text Available Growth and development in utero is a complex and dynamic process that requires interaction between the mother organism and the fetus. The delivery of macro – and micronutrients, oxygen and endocrine signals has crucial importance for providing a high level of proliferation, growth and differentiation of cells, and a disruption in food intake not only has an influence on the growth of the fetus, but also has negative consequences for the offspring’s health in the future. Diseases that traditionally are linked to inappropriate life style of adults, such as type 2 diabetes, obesity, and arterial hypertension, can be “programmed” in the early stage of life and the disturbed growth of the fetus leads to the symptoms of the metabolic syndrome. The structural changes of some organs, such as the brain, pancreas and kidney, modifications of the signaling and metabolic pathways in skeletal muscles and in fatty tissue, epigenetic mechanisms and mitochondrial dysfunction are the basis of the metabolic disruptions. The programming of the metabolic disturbances is connected with the disruption in the intrauterine environment experienced in the early and late gestation period. It causes the changes in deposition of triglycerides, activation of the hormonal “stress axis” and disturbances in the offspring’s glucose tolerance. The present review summarizes experimental results that led to the identification of the above-mentioned links and it underlines the role of animal models in the studies of this important concept.

  2. Global developmental gene expression and pathway analysis of normal brain development and mouse models of human neuronal migration defects.

    Directory of Open Access Journals (Sweden)

    Tiziano Pramparo

    2011-03-01

    Full Text Available Heterozygous LIS1 mutations are the most common cause of human lissencephaly, a human neuronal migration defect, and DCX mutations are the most common cause of X-linked lissencephaly. LIS1 is part of a protein complex including NDEL1 and 14-3-3ε that regulates dynein motor function and microtubule dynamics, while DCX stabilizes microtubules and cooperates with LIS1 during neuronal migration and neurogenesis. Targeted gene mutations of Lis1, Dcx, Ywhae (coding for 14-3-3ε, and Ndel1 lead to neuronal migration defects in mouse and provide models of human lissencephaly, as well as aid the study of related neuro-developmental diseases. Here we investigated the developing brain of these four mutants and wild-type mice using expression microarrays, bioinformatic analyses, and in vivo/in vitro experiments to address whether mutations in different members of the LIS1 neuronal migration complex lead to similar and/or distinct global gene expression alterations. Consistent with the overall successful development of the mutant brains, unsupervised clustering and co-expression analysis suggested that cell cycle and synaptogenesis genes are similarly expressed and co-regulated in WT and mutant brains in a time-dependent fashion. By contrast, focused co-expression analysis in the Lis1 and Ndel1 mutants uncovered substantial differences in the correlation among pathways. Differential expression analysis revealed that cell cycle, cell adhesion, and cytoskeleton organization pathways are commonly altered in all mutants, while synaptogenesis, cell morphology, and inflammation/immune response are specifically altered in one or more mutants. We found several commonly dysregulated genes located within pathogenic deletion/duplication regions, which represent novel candidates of human mental retardation and neurocognitive disabilities. Our analysis suggests that gene expression and pathway analysis in mouse models of a similar disorder or within a common pathway can

  3. Comparison of Control Approaches in Genetic Regulatory Networks by Using Stochastic Master Equation Models, Probabilistic Boolean Network Models and Differential Equation Models and Estimated Error Analyzes

    Science.gov (United States)

    Caglar, Mehmet Umut; Pal, Ranadip

    2011-03-01

    Central dogma of molecular biology states that ``information cannot be transferred back from protein to either protein or nucleic acid''. However, this assumption is not exactly correct in most of the cases. There are a lot of feedback loops and interactions between different levels of systems. These types of interactions are hard to analyze due to the lack of cell level data and probabilistic - nonlinear nature of interactions. Several models widely used to analyze and simulate these types of nonlinear interactions. Stochastic Master Equation (SME) models give probabilistic nature of the interactions in a detailed manner, with a high calculation cost. On the other hand Probabilistic Boolean Network (PBN) models give a coarse scale picture of the stochastic processes, with a less calculation cost. Differential Equation (DE) models give the time evolution of mean values of processes in a highly cost effective way. The understanding of the relations between the predictions of these models is important to understand the reliability of the simulations of genetic regulatory networks. In this work the success of the mapping between SME, PBN and DE models is analyzed and the accuracy and affectivity of the control policies generated by using PBN and DE models is compared.

  4. Modeling genome-wide dynamic regulatory network in mouse lungs with influenza infection using high-dimensional ordinary differential equations.

    Science.gov (United States)

    Wu, Shuang; Liu, Zhi-Ping; Qiu, Xing; Wu, Hulin

    2014-01-01

    The immune response to viral infection is regulated by an intricate network of many genes and their products. The reverse engineering of gene regulatory networks (GRNs) using mathematical models from time course gene expression data collected after influenza infection is key to our understanding of the mechanisms involved in controlling influenza infection within a host. A five-step pipeline: detection of temporally differentially expressed genes, clustering genes into co-expressed modules, identification of network structure, parameter estimate refinement, and functional enrichment analysis, is developed for reconstructing high-dimensional dynamic GRNs from genome-wide time course gene expression data. Applying the pipeline to the time course gene expression data from influenza-infected mouse lungs, we have identified 20 distinct temporal expression patterns in the differentially expressed genes and constructed a module-based dynamic network using a linear ODE model. Both intra-module and inter-module annotations and regulatory relationships of our inferred network show some interesting findings and are highly consistent with existing knowledge about the immune response in mice after influenza infection. The proposed method is a computationally efficient, data-driven pipeline bridging experimental data, mathematical modeling, and statistical analysis. The application to the influenza infection data elucidates the potentials of our pipeline in providing valuable insights into systematic modeling of complicated biological processes.

  5. Regulatory activities

    International Nuclear Information System (INIS)

    2001-01-01

    This publication, compiled in 8 chapters, presents the regulatory system developed by the Nuclear Regulatory Authority (NRA) of the Argentine Republic. The following activities and developed topics in this document describe: the evolution of the nuclear regulatory activity in Argentina; the Argentine regulatory system; the nuclear regulatory laws and standards; the inspection and safeguards of nuclear facilities; the emergency systems; the environmental systems; the environmental monitoring; the analysis laboratories on physical and biological dosimetry, prenatal irradiation, internal irradiation, radiation measurements, detection techniques on nuclear testing, medical program on radiation protection; the institutional relations with national and international organization; the training courses and meeting; the technical information

  6. How Adverse Outcome Pathways Can Aid the Development and Use of Computational Prediction Models for Regulatory Toxicology.

    Science.gov (United States)

    Wittwehr, Clemens; Aladjov, Hristo; Ankley, Gerald; Byrne, Hugh J; de Knecht, Joop; Heinzle, Elmar; Klambauer, Günter; Landesmann, Brigitte; Luijten, Mirjam; MacKay, Cameron; Maxwell, Gavin; Meek, M E Bette; Paini, Alicia; Perkins, Edward; Sobanski, Tomasz; Villeneuve, Dan; Waters, Katrina M; Whelan, Maurice

    2017-02-01

    Efforts are underway to transform regulatory toxicology and chemical safety assessment from a largely empirical science based on direct observation of apical toxicity outcomes in whole organism toxicity tests to a predictive one in which outcomes and risk are inferred from accumulated mechanistic understanding. The adverse outcome pathway (AOP) framework provides a systematic approach for organizing knowledge that may support such inference. Likewise, computational models of biological systems at various scales provide another means and platform to integrate current biological understanding to facilitate inference and extrapolation. We argue that the systematic organization of knowledge into AOP frameworks can inform and help direct the design and development of computational prediction models that can further enhance the utility of mechanistic and in silico data for chemical safety assessment. This concept was explored as part of a workshop on AOP-Informed Predictive Modeling Approaches for Regulatory Toxicology held September 24-25, 2015. Examples of AOP-informed model development and its application to the assessment of chemicals for skin sensitization and multiple modes of endocrine disruption are provided. The role of problem formulation, not only as a critical phase of risk assessment, but also as guide for both AOP and complementary model development is described. Finally, a proposal for actively engaging the modeling community in AOP-informed computational model development is made. The contents serve as a vision for how AOPs can be leveraged to facilitate development of computational prediction models needed to support the next generation of chemical safety assessment. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology.

  7. Modeling in the quality by design environment: Regulatory requirements and recommendations for design space and control strategy appointment.

    Science.gov (United States)

    Djuris, Jelena; Djuric, Zorica

    2017-11-30

    Mathematical models can be used as an integral part of the quality by design (QbD) concept throughout the product lifecycle for variety of purposes, including appointment of the design space and control strategy, continual improvement and risk assessment. Examples of different mathematical modeling techniques (mechanistic, empirical and hybrid) in the pharmaceutical development and process monitoring or control are provided in the presented review. In the QbD context, mathematical models are predominantly used to support design space and/or control strategies. Considering their impact to the final product quality, models can be divided into the following categories: high, medium and low impact models. Although there are regulatory guidelines on the topic of modeling applications, review of QbD-based submission containing modeling elements revealed concerns regarding the scale-dependency of design spaces and verification of models predictions at commercial scale of manufacturing, especially regarding real-time release (RTR) models. Authors provide critical overview on the good modeling practices and introduce concepts of multiple-unit, adaptive and dynamic design space, multivariate specifications and methods for process uncertainty analysis. RTR specification with mathematical model and different approaches to multivariate statistical process control supporting process analytical technologies are also presented. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Legacy for ChildrenTM: a pair of randomized controlled trials of a public health model to improve developmental outcomes among children in poverty

    Directory of Open Access Journals (Sweden)

    Perou Ruth

    2012-08-01

    Full Text Available Abstract Background One in five Americans under age 18 lives in a family below the Federal poverty threshold. These more than 15 million children are at increased risk of a wide variety of adverse long-term health and developmental outcomes. The early years of life are critical to short- and long-term health and well-being. The Legacy for ChildrenTM model was developed in response to this need and marries the perspectives of epidemiology and public health to developmental psychology theory in order to better address the needs of children at environmental risk for poor developmental outcomes. Methods/design The Legacy for ChildrenTM group-based parenting intervention model was evaluated as a pair of randomized controlled trials among low-income families in Miami and Los Angeles. The study was designed to allow for site-stratified analysis in order to evaluate each model implementation separately. Evaluation domains include comprehensive assessments of family, maternal, and child characteristics, process outcomes, and prospective programmatic cost. Data collection began prenatally or at birth and continues into school-age. Discussion The societal costs of poor developmental outcomes are substantial. A concerted effort from multiple sectors and disciplines, including public health, is necessary to address these societal concerns. Legacy uses a public health model to engage parents and promote overall child well-being in families in poverty through rigorous evaluation methodologies and evidence-based intervention strategies. This study collects rich and modular information on maternal and child outcomes, process, and cost that will enable a detailed understanding of how Legacy works, how it can be refined and improved, and how it can be translated and disseminated. Taken together, these results will inform public policy and help to address issues of health disparities among at-risk populations. Trial registration NCT00164697

  9. Understanding the psychosocial experiences of adults with mild-moderate hearing loss: An application of Leventhal's self-regulatory model.

    Science.gov (United States)

    Heffernan, Eithne; Coulson, Neil S; Henshaw, Helen; Barry, Johanna G; Ferguson, Melanie A

    2016-07-01

    This study explored the psychosocial experiences of adults with hearing loss using the self-regulatory model as a theoretical framework. The primary components of the model, namely cognitive representations, emotional representations, and coping responses, were examined. Individual semi-structured interviews were conducted. The data were analysed using an established thematic analysis procedure. Twenty-five adults with mild-moderate hearing loss from the UK and nine hearing healthcare professionals from the UK, USA, and Canada were recruited via maximum variation sampling. Cognitive representations: Most participants described their hearing loss as having negative connotations and consequences, although they were not particularly concerned about the progression or controllability/curability of the condition. Opinions differed regarding the benefits of understanding the causes of one's hearing loss in detail. Emotional representations: negative emotions dominated, although some experienced positive emotions or muted emotions. Coping responses: engaged coping (e.g. hearing aids, communication tactics) and disengaged coping (e.g. withdrawal from situations, withdrawal within situations): both had perceived advantages and disadvantages. This novel application of the self-regulatory model demonstrates that it can be used to capture the key psychosocial experiences (i.e. perceptions, emotions, and coping responses) of adults with mild-moderate hearing loss within a single, unifying framework.

  10. Telecommunications Liberalisation in Africa: Proposed Regulatory Model for the SADC Region

    Directory of Open Access Journals (Sweden)

    Z. Ntozintle Jobodwana

    2009-12-01

    Full Text Available The liberalisation of the telecommunication industry in Africa, and the further development of the region’s physical infrastructure was accompanied by the further development of Africa’s information, communication and technology infrastructure. Competition within the industry stimulated heavy economic investment in other sectors of the economy. The outcome of liberalisation also included the establishment of community-based structures that continue to enable communities to manage their own development and gain access to information and communication technologies (ICTs in an unprecedented manner. The telecommunication infrastructure further stimulated the fast development of other related services, for example, e-commerce and mobile commerce (m-commerce, e-government, internet banking, mobile banking etcetera. Latest reports and statistics disclose that in Africa m-commerce is set to even overtake the development of e-commerce, through the popular use and penetration of mobile telephony whilst e-commerce development is constrained by difficulties in rolling out speedily fixed telephone lines. These new methods of communication have so intensified that there is hope that further penetration of mobile telephony would leap-frog economic growth and development in Africa, especially in rural communities. Therefore, innovations and investment in ICT’s are changing the world in a number of ways, resulting in a globally connected digital economy.  However, there are regulatory challenges that need to be addressed as a matter of urgency. Certain sections of the continent’s population, especially those in rural areas, have very limited access to ICT’s. This prevents them from exploiting opportunities offered by ICT’s. The main barriers to ICT access relate to inadequate regimes and their supporting legal frameworks, high cost of internet access, connectivity problems, the lack of technical skills to support

  11. Human dental age estimation using third molar developmental stages: does a Bayesian approach outperform regression models to discriminate between juveniles and adults?

    Science.gov (United States)

    Thevissen, P W; Fieuws, S; Willems, G

    2010-01-01

    Dental age estimation methods based on the radiologically detected third molar developmental stages are implemented in forensic age assessments to discriminate between juveniles and adults considering the judgment of young unaccompanied asylum seekers. Accurate and unbiased age estimates combined with appropriate quantified uncertainties are the required properties for accurate forensic reporting. In this study, a subset of 910 individuals uniformly distributed in age between 16 and 22 years was selected from an existing dataset collected by Gunst et al. containing 2,513 panoramic radiographs with known third molar developmental stages of Belgian Caucasian men and women. This subset was randomly split in a training set to develop a classical regression analysis and a Bayesian model for the multivariate distribution of the third molar developmental stages conditional on age and in a test set to assess the performance of both models. The aim of this study was to verify if the Bayesian approach differentiates the age of maturity more precisely and removes the bias, which disadvantages the systematically overestimated young individuals. The Bayesian model offers the discrimination of subjects being older than 18 years more appropriate and produces more meaningful prediction intervals but does not strongly outperform the classical approaches.

  12. Regulatory Benchmarking

    DEFF Research Database (Denmark)

    Agrell, Per J.; Bogetoft, Peter

    2017-01-01

    Benchmarking methods, and in particular Data Envelopment Analysis (DEA), have become well-established and informative tools for economic regulation. DEA is now routinely used by European regulators to set reasonable revenue caps for energy transmission and distribution system operators. The appli......Benchmarking methods, and in particular Data Envelopment Analysis (DEA), have become well-established and informative tools for economic regulation. DEA is now routinely used by European regulators to set reasonable revenue caps for energy transmission and distribution system operators....... The application of bench-marking in regulation, however, requires specific steps in terms of data validation, model specification and outlier detection that are not systematically documented in open publications, leading to discussions about regulatory stability and economic feasibility of these techniques...

  13. Regulatory Benchmarking

    DEFF Research Database (Denmark)

    Agrell, Per J.; Bogetoft, Peter

    2017-01-01

    Benchmarking methods, and in particular Data Envelopment Analysis (DEA), have become well-established and informative tools for economic regulation. DEA is now routinely used by European regulators to set reasonable revenue caps for energy transmission and distribution system operators. The appli......Benchmarking methods, and in particular Data Envelopment Analysis (DEA), have become well-established and informative tools for economic regulation. DEA is now routinely used by European regulators to set reasonable revenue caps for energy transmission and distribution system operators....... The application of benchmarking in regulation, however, requires specific steps in terms of data validation, model specification and outlier detection that are not systematically documented in open publications, leading to discussions about regulatory stability and economic feasibility of these techniques...

  14. Social Defense: An Evolutionary-Developmental Model of Children's Strategies for Coping with Threat in the Peer Group

    Directory of Open Access Journals (Sweden)

    Meredith J. Martin

    2014-04-01

    Full Text Available Navigating the ubiquitous conflict, competition, and complex group dynamics of the peer group is a pivotal developmental task of childhood. Difficulty negotiating these challenges represents a substantial source of risk for psychopathology. Evolutionary developmental psychology offers a unique perspective with the potential to reorganize the way we think about the role of peer relationships in shaping how children cope with the everyday challenges of establishing a social niche. To address this gap, we utilize the ethological reformulation of the emotional security theory as a guide to developing an evolutionary framework for advancing an understanding of the defense strategies children use to manage antagonistic peer relationships and protect themselves from interpersonal threat (Davies and Sturge-Apple, 2007. In this way, we hope to illustrate the value of an evolutionary developmental lens in generating unique theoretical insight and novel research directions into the role of peer relationships in the development of psychopathology.

  15. Bulimia: A Self-Psychological and Ego-Developmental View.

    Science.gov (United States)

    Brenner-Liss, Deborah

    1986-01-01

    Discusses key clinical issues in the treatment of bulimia with clinical examples from a self-psychological and ego-developmental point of view. Identifies three developmental issues for bulimia: self-regulatory, differentiation, and self-esteem. (Author/ABB)

  16. Evolution and developmental genetics of floral display-A review of progress

    Institute of Scientific and Technical Information of China (English)

    Qing Ma; Wenheng Zhang; Qiu-Yun (Jenny) Xiang

    2017-01-01

    Angiosperms evolved a great diversity of ways to display their flowers for reproductive success by variation in floral color,size,shape,scent,arrangements,and flowering time.The various innovations in floral forms and the aggregation of flowers into different kinds of inflorescences can drive new ecological adaptations,speciation,and angiosperm diversification.Evolutionary developmental biology (evo-devo) seeks to uncover the developmental and genetic basis underlying morphological diversification.Advances in the developmental genetics of floral display have provided a foundation for insights into the genetic basis of floral and inflorescence evolution.A number of regulatory genes controlling floral and inflorescence development have been identified in model plants (e.g.,Arabidopsis thaliana,Antirrhinum majus) using forward genetics and conserved functions of many of these genes across diverse non-model species have been revealed by reverse genetics.Gene-regulatory networks that mediated the developmental progresses of floral and inflorescence development have also been established in some plant species.Meanwhile,phylogeny-based comparative analysis of morphological and genetic character has enabled the identification of key evolutionary events that lead to morphological complexity and diversification.Here we review the recent progress on evo-devo studies of floral display including floral symmetry,petal fusion,floral color,floral scent,and inflorescences.We also review the molecular genetic approaches applied to plant evo-devo studies and highlight the future directions of evo-devo.

  17. Developmental transcriptome of Aplysia californica'

    KAUST Repository

    Heyland, Andreas

    2010-12-06

    Genome-wide transcriptional changes in development provide important insight into mechanisms underlying growth, differentiation, and patterning. However, such large-scale developmental studies have been limited to a few representatives of Ecdysozoans and Chordates. Here, we characterize transcriptomes of embryonic, larval, and metamorphic development in the marine mollusc Aplysia californica and reveal novel molecular components associated with life history transitions. Specifically, we identify more than 20 signal peptides, putative hormones, and transcription factors in association with early development and metamorphic stages-many of which seem to be evolutionarily conserved elements of signal transduction pathways. We also characterize genes related to biomineralization-a critical process of molluscan development. In summary, our experiment provides the first large-scale survey of gene expression in mollusc development, and complements previous studies on the regulatory mechanisms underlying body plan patterning and the formation of larval and juvenile structures. This study serves as a resource for further functional annotation of transcripts and genes in Aplysia, specifically and molluscs in general. A comparison of the Aplysia developmental transcriptome with similar studies in the zebra fish Danio rerio, the fruit fly Drosophila melanogaster, the nematode Caenorhabditis elegans, and other studies on molluscs suggests an overall highly divergent pattern of gene regulatory mechanisms that are likely a consequence of the different developmental modes of these organisms. © 2010 Wiley-Liss, Inc., A Wiley Company.

  18. Regulatory focus and the family-work interface : the role of regulatory fit between cohabiting partners

    NARCIS (Netherlands)

    Demerouti, E.; Bakker, A.B.; Tetrick, L.

    2014-01-01

    The aim of the present study was to examine the impact of regulatory focus in goal pursuit and regulatory fit between marital partners on family conditions and the family–work interface. We hypothesized that when both partners are high on promotion focus (fit) they experience higher developmental

  19. Stigma, explanatory models and unmet needs of caregivers of children with developmental disorders in a low-income African country: a cross-sectional facility-based survey.

    Science.gov (United States)

    Tilahun, Dejene; Hanlon, Charlotte; Fekadu, Abebaw; Tekola, Bethlehem; Baheretibeb, Yonas; Hoekstra, Rosa A

    2016-04-27

    Understanding the perspectives of caregivers of children with developmental disorders living in low-income countries is important to inform intervention programmes. The purpose of this study was to examine the stigma experiences, explanatory models, unmet needs, preferred interventions and coping mechanisms of caregivers of children with developmental disorders in Ethiopia. Participants comprised caregivers (n = 102) of children with developmental disorders attending two child mental health clinics in Addis Ababa. The majority (66.7%; n = 68) had a diagnosis of intellectual disability (ID); 34 children (33.3%) had autism spectrum disorder (ASD) as their primary diagnosis. All caregivers were administered a structured questionnaire via a face-to-face interview, which included an adaptation of the Family Interview Schedule, closed questions about socio-demographic characteristics, explanatory models of illness, type of interventions used or desired and coping strategies, and an open ended question regarding the family's unmet needs. Most caregivers reported experience of stigma: 43.1% worried about being treated differently, 45.1% felt ashamed about their child's condition and 26.7% made an effort to keep their child's condition secret. Stigma did not depend on the type of developmental disorder, the child's age or gender, or on the age or level of education of the caregiver (all p > 0.05). Reported stigma was significantly higher in caregivers who had sought traditional help (p child's condition (p = .02) and in caregivers of Orthodox Christian faith (p = .03). Caregivers gave a mixture of biomedical explanations (e.g. head injury (30.4%) or birth complications (25.5%)) and supernatural explanations (e.g. spirit possession (40.2%) or sinful act (27.5%)) for their child's condition. The biggest reported unmet need was educational provision for their child (74.5%), followed by treatment by a health professional (47.1%), financial support (30.4%) and expert help to

  20. Pharmacodynamic/Pharmacogenomic Modeling of Insulin Resistance Genes in Rat Muscle After Methylprednisolone Treatment: Exploring Regulatory Signaling Cascades

    Directory of Open Access Journals (Sweden)

    Zhenling Yao

    2008-01-01

    Full Text Available Corticosteroids (CS effects on insulin resistance related genes in rat skeletal muscle were studied. In our acute study, adrenalectomized (ADX rats were given single doses of 50 mg/kg methylprednisolone (MPL intravenously. In our chronic study, ADX rats were implanted with Alzet mini-pumps giving zero-order release rates of 0.3 mg/kg/h MPL and sacrificed at various times up to 7 days. Total RNA was extracted from gastrocnemius muscles and hybridized to Affymetrix GeneChips. Data mining and literature searches identified 6 insulin resistance related genes which exhibited complex regulatory pathways. Insulin receptor substrate-1 (IRS-1, uncoupling protein 3 (UCP3, pyruvate dehydrogenase kinase isoenzyme 4 (PDK4, fatty acid translocase (FAT and glycerol-3-phosphate acyltransferase (GPAT dynamic profiles were modeled with mutual effects by calculated nuclear drug-receptor complex (DR(N and transcription factors. The oscillatory feature of endothelin-1 (ET-1 expression was depicted by a negative feedback loop. These integrated models provide test- able quantitative hypotheses for these regulatory cascades.

  1. Computational Modeling and Simulation of Developmental Toxicity. What can we learn from a virtual embryo? (FDA-CFSAN workshop)

    Science.gov (United States)

    SYNOPSIS: The question of how tissues and organs are shaped during development is crucial for understanding human birth defects. Data from high-throughput screening assays on human stem cells may be utilized predict developmental toxicity with reasonable accuracy. Other types of ...

  2. Identifying Subtypes among Children with Developmental Coordination Disorder and Mathematical Learning Disabilities, Using Model-Based Clustering

    Science.gov (United States)

    Pieters, Stefanie; Roeyers, Herbert; Rosseel, Yves; Van Waelvelde, Hilde; Desoete, Annemie

    2015-01-01

    A relationship between motor and mathematical skills has been shown by previous research. However, the question of whether subtypes can be differentiated within developmental coordination disorder (DCD) and/or mathematical learning disability (MLD) remains unresolved. In a sample of children with and without DCD and/or MLD, a data-driven…

  3. Identification of functional elements and regulatory circuits by Drosophila modENCODE.

    Science.gov (United States)

    Roy, Sushmita; Ernst, Jason; Kharchenko, Peter V; Kheradpour, Pouya; Negre, Nicolas; Eaton, Matthew L; Landolin, Jane M; Bristow, Christopher A; Ma, Lijia; Lin, Michael F; Washietl, Stefan; Arshinoff, Bradley I; Ay, Ferhat; Meyer, Patrick E; Robine, Nicolas; Washington, Nicole L; Di Stefano, Luisa; Berezikov, Eugene; Brown, Christopher D; Candeias, Rogerio; Carlson, Joseph W; Carr, Adrian; Jungreis, Irwin; Marbach, Daniel; Sealfon, Rachel; Tolstorukov, Michael Y; Will, Sebastian; Alekseyenko, Artyom A; Artieri, Carlo; Booth, Benjamin W; Brooks, Angela N; Dai, Qi; Davis, Carrie A; Duff, Michael O; Feng, Xin; Gorchakov, Andrey A; Gu, Tingting; Henikoff, Jorja G; Kapranov, Philipp; Li, Renhua; MacAlpine, Heather K; Malone, John; Minoda, Aki; Nordman, Jared; Okamura, Katsutomo; Perry, Marc; Powell, Sara K; Riddle, Nicole C; Sakai, Akiko; Samsonova, Anastasia; Sandler, Jeremy E; Schwartz, Yuri B; Sher, Noa; Spokony, Rebecca; Sturgill, David; van Baren, Marijke; Wan, Kenneth H; Yang, Li; Yu, Charles; Feingold, Elise; Good, Peter; Guyer, Mark; Lowdon, Rebecca; Ahmad, Kami; Andrews, Justen; Berger, Bonnie; Brenner, Steven E; Brent, Michael R; Cherbas, Lucy; Elgin, Sarah C R; Gingeras, Thomas R; Grossman, Robert; Hoskins, Roger A; Kaufman, Thomas C; Kent, William; Kuroda, Mitzi I; Orr-Weaver, Terry; Perrimon, Norbert; Pirrotta, Vincenzo; Posakony, James W; Ren, Bing; Russell, Steven; Cherbas, Peter; Graveley, Brenton R; Lewis, Suzanna; Micklem, Gos; Oliver, Brian; Park, Peter J; Celniker, Susan E; Henikoff, Steven; Karpen, Gary H; Lai, Eric C; MacAlpine, David M; Stein, Lincoln D; White, Kevin P; Kellis, Manolis

    2010-12-24

    To gain insight into how genomic information is translated into cellular and developmental programs, the Drosophila model organism Encyclopedia of DNA Elements (modENCODE) project is comprehensively mapping transcripts, histone modifications, chromosomal proteins, transcription factors, replication proteins and intermediates, and nucleosome properties across a developmental time course and in multiple cell lines. We have generated more than 700 data sets and discovered protein-coding, noncoding, RNA regulatory, replication, and chromatin elements, more than tripling the annotated portion of the Drosophila genome. Correlated activity patterns of these elements reveal a functional regulatory network, which predicts putative new functions for genes, reveals stage- and tissue-specific regulators, and enables gene-expression prediction. Our results provide a foundation for directed experimental and computational studies in Drosophila and related species and also a model for systematic data integration toward comprehensive genomic and functional annotation.

  4. Regulatory acceptance and use of 3R models for pharmaceuticals and chemicals: expert opinions on the state of affairs and the way forward.

    Science.gov (United States)

    Schiffelers, Marie-Jeanne W A; Blaauboer, Bas J; Bakker, Wieger E; Beken, Sonja; Hendriksen, Coenraad F M; Koëter, Herman B W M; Krul, Cyrille

    2014-06-01

    Pharmaceuticals and chemicals are subjected to regulatory safety testing accounting for approximately 25% of laboratory animal use in Europe. This testing meets various objections and has led to the development of a range of 3R models to Replace, Reduce or Refine the animal models. However, these models must overcome many barriers before being accepted for regulatory risk management purposes. This paper describes the barriers and drivers and options to optimize this acceptance process as identified by two expert panels, one on pharmaceuticals and one on chemicals. To untangle the complex acceptance process, the multilevel perspective on technology transitions is applied. This perspective defines influences at the micro-, meso- and macro level which need alignment to induce regulatory acceptance of a 3R model. This paper displays that there are many similar mechanisms within both sectors that prevent 3R models from becoming accepted for regulatory risk assessment and management. Shared barriers include the uncertainty about the value of the new 3R models (micro level), the lack of harmonization of regulatory requirements and acceptance criteria (meso level) and the high levels of risk aversion (macro level). In optimizing the process commitment, communication, cooperation and coordination are identified as critical drivers. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Circular RNA Profiling and Bioinformatic Modeling Identify Its Regulatory Role in Hepatic Steatosis.

    Science.gov (United States)

    Guo, Xing-Ya; He, Chong-Xin; Wang, Yu-Qin; Sun, Chao; Li, Guang-Ming; Su, Qing; Pan, Qin; Fan, Jian-Gao

    2017-01-01

    Circular RNAs (circRNAs) exhibit a wide range of physiological and pathological activities. To uncover their role in hepatic steatosis, we investigated the expression profile of circRNAs in HepG2-based hepatic steatosis induced by high-fat stimulation. Differentially expressed circRNAs were subjected to validation using QPCR and functional analyses using principal component analysis, hierarchical clustering, target prediction, gene ontology (GO), and pathway annotation, respectively. Bioinformatic integration established the circRNA-miRNA-mRNA regulatory network so as to identify the mechanisms underlying circRNAs' metabolic effect. Here we reported that hepatic steatosis was associated with a total of 357 circRNAs. Enrichment of transcription-related GOs, especially GO: 0006355, GO: 004589, GO: 0045944, GO: 0045892, and GO: 0000122, demonstrated their specific actions in transcriptional regulation. Lipin 1 (LPIN1) was recognized to mediate the transcriptional regulatory effect of circRNAs on metabolic pathways. circRNA-miRNA-mRNA network further identified the signaling cascade of circRNA_021412/miR-1972/LPIN1, which was characterized by decreased level of circRNA_021412 and miR-1972-based inhibition of LPIN1. LPIN1-induced downregulation of long chain acyl-CoA synthetases (ACSLs) expression finally resulted in the hepatosteatosis. These findings identify circRNAs to be important regulators of hepatic steatosis. Transcription-dependent modulation of metabolic pathways may underlie their effects, partially by the circRNA_021412/miR-1972/LPIN1 signaling.

  6. A mechano-regulatory bone-healing model incorporating cell-phenotype specific activity

    NARCIS (Netherlands)

    Isaksson, H.E.; Donkelaar, van C.C.; Huiskes, R.; Ito, K.

    2008-01-01

    Phenomenological computational models of tissue regeneration and bone healing have been only partially successful in predicting experimental observations. This may be a result of simplistic modeling of cellular activity. Furthermore, phenomenological models are limited when considering the effects

  7. Developmental dyscalculia.

    Science.gov (United States)

    Kucian, Karin; von Aster, Michael

    2015-01-01

    Numerical skills are essential in our everyday life, and impairments in the development of number processing and calculation have a negative impact on schooling and professional careers. Approximately 3 to 6 % of children are affected from specific disorders of numerical understanding (developmental dyscalculia (DD)). Impaired development of number processing skills in these children is characterized by problems in various aspects of numeracy as well as alterations of brain activation and brain structure. Moreover, DD is assumed to be a very heterogeneous disorder putting special challenges to define homogeneous diagnostic criteria. Finally, interdisciplinary perspectives from psychology, neuroscience and education can contribute to the design for interventions, and although results are still sparse, they are promising and have shown positive effects on behaviour as well as brain function. In the current review, we are going to give an overview about typical and atypical development of numerical abilities at the behavioural and neuronal level. Furthermore, current status and obstacles in the definition and diagnostics of DD are discussed, and finally, relevant points that should be considered to make an intervention as successful as possible are summarized.

  8. Emotion and Cognition: An Intricately Bound Developmental Process

    Science.gov (United States)

    Bell, Martha Ann; Wolfe, Christy D.

    2004-01-01

    Regulatory aspects of development can best be understood by research that conceptualizes relations between cognition and emotion. The neural mechanisms associated with regulatory processes may be the same as those associated with higher order cognitive processes. Thus, from a developmental cognitive neuroscience perspective, emotion and cognition…

  9. A patient-specific model of the biomechanics of hip reduction for neonatal Developmental Dysplasia of the Hip: Investigation of strategies for low to severe grades of Developmental Dysplasia of the Hip.

    Science.gov (United States)

    Huayamave, Victor; Rose, Christopher; Serra, Sheila; Jones, Brendan; Divo, Eduardo; Moslehy, Faissal; Kassab, Alain J; Price, Charles T

    2015-07-16

    A physics-based computational model of neonatal Developmental Dysplasia of the Hip (DDH) following treatment with the Pavlik Harness (PV) was developed to obtain muscle force contribution in order to elucidate biomechanical factors influencing the reduction of dislocated hips. Clinical observation suggests that reduction occurs in deep sleep involving passive muscle action. Consequently, a set of five (5) adductor muscles were identified as mediators of reduction using the PV. A Fung/Hill-type model was used to characterize muscle response. Four grades (1-4) of dislocation were considered, with one (1) being a low subluxation and four (4) a severe dislocation. A three-dimensional model of the pelvis-femur lower limb of a representative 10 week-old female was generated based on CT-scans with the aid of anthropomorphic scaling of anatomical landmarks. The model was calibrated to achieve equilibrium at 90° flexion and 80° abduction. The hip was computationally dislocated according to the grade under investigation, the femur was restrained to move in an envelope consistent with PV restraints, and the dynamic response under passive muscle action and the effect of gravity was resolved. Model results with an anteversion angle of 50° show successful reduction Grades 1-3, while Grade 4 failed to reduce with the PV. These results are consistent with a previous study based on a simplified anatomically-consistent synthetic model and clinical reports of very low success of the PV for Grade 4. However our model indicated that it is possible to achieve reduction of Grade 4 dislocation by hyperflexion and the resultant external rotation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Developmental control of transcriptional and proliferative potency during the evolutionary emergence of animals

    Science.gov (United States)

    Arenas-Mena, Cesar; Coffman, James A.

    2016-01-01

    Summary It is proposed that the evolution of complex animals required repressive genetic mechanisms for controlling the transcriptional and proliferative potency of cells. Unicellular organisms are transcriptionally potent, able to express their full genetic complement as the need arises through their life cycle, whereas differentiated cells of multicellular organisms can only express a fraction of their genomic potential. Likewise, whereas cell proliferation in unicellular organisms is primarily limited by nutrient availability, cell proliferation in multicellular organisms is developmentally regulated. Repressive genetic controls limiting the potency of cells at the end of ontogeny would have stabilized the gene expression states of differentiated cells and prevented disruptive proliferation, allowing the emergence of diverse cell types and functional shapes. We propose that distal cis-regulatory elements represent the primary innovations that set the stage for the evolution of developmental gene regulatory networks and the repressive control of key multipotency and cell-cycle control genes. The testable prediction of this model is that the genomes of extant animals, unlike those of our unicellular relatives, encode gene regulatory circuits dedicated to the developmental control of transcriptional and proliferative potency. PMID:26173445

  11. An essential regulatory role of downstream of kinase-1 in the ovalbumin-induced murine model of asthma.

    Directory of Open Access Journals (Sweden)

    Chang-Min Lee

    Full Text Available The downstream of kinase (DOK-1 is involved in the protein tyrosine kinase (PTK pathway in mast cells, but the role of DOK-1 in the pathogenesis of asthma has not been defined. In this study, we have demonstrated a novel regulatory role of DOK-1 in airway inflammation and physiologic responses in a murine model of asthma using lentiviral vector containing DOK-1 cDNA or DOK-1-specific ShRNA. The OVA-induced inflammatory cells, airway hyperresponsiveness, Th2 cytokine expression, and mucus response were significantly reduced in DOK-1 overexpressing mice compared to OVA-challenged control mice. The transgenic introduction of DOK-1 significantly stimulated the activation and expression of STAT-4 and T-bet, while impressively inhibiting the activation and expression of STAT-6 and GATA-3 in airway epithelial cells. On the other hand, DOK-1 knockdown mice enhanced STAT-6 expression and its nuclear translocation compared to OVA-challenged control mice. When viewed in combination, our studies demonstrate DOK-1 regulates allergen-induced Th2 immune responses by selective stimulation and inhibition of STAT-4 and STAT-6 signaling pathways, respectively. These studies provide a novel insight on the regulatory role of DOK-1 in allergen-induced Th2 inflammation and airway responses, which has therapeutic potential for asthma and other allergic diseases.

  12. Diversity of gut microflora is required for the generation of B cell with regulatory properties in a skin graft model.

    Science.gov (United States)

    Alhabbab, R; Blair, P; Elgueta, R; Stolarczyk, E; Marks, E; Becker, P D; Ratnasothy, K; Smyth, L; Safinia, N; Sharif-Paghaleh, E; O'Connell, S; Noelle, R J; Lord, G M; Howard, J K; Spencer, J; Lechler, R I; Lombardi, G

    2015-06-25

    B cells have been reported to promote graft rejection through alloantibody production. However, there is growing evidence that B cells can contribute to the maintenance of tolerance. Here, we used a mouse model of MHC-class I mismatched skin transplantation to investigate the contribution of B cells to graft survival. We demonstrate that adoptive transfer of B cells prolongs skin graft survival but only when the B cells were isolated from mice housed in low sterility "conventional" (CV) facilities and not from mice housed in pathogen free facilities (SPF). However, prolongation of skin graft survival was lost when B cells were isolated from IL-10 deficient mice housed in CV facilities. The suppressive function of B cells isolated from mice housed in CV facilities correlated with an anti-inflammatory environment and with the presence of a different gut microflora compared to mice maintained in SPF facilities. Treatment of mice in the CV facility with antibiotics abrogated the regulatory capacity of B cells. Finally, we identified transitional B cells isolated from CV facilities as possessing the regulatory function. These findings demonstrate that B cells, and in particular transitional B cells, can promote prolongation of graft survival, a function dependent on licensing by gut microflora.

  13. Diversity of gut microflora is required for the generation of B cell with regulatory properties in a skin graft model

    Science.gov (United States)

    Alhabbab, R.; Blair, P.; Elgueta, R.; Stolarczyk, E.; Marks, E.; Becker, P. D.; Ratnasothy, K.; Smyth, L.; Safinia, N.; Sharif-Paghaleh, E.; O’Connell, S.; Noelle, R. J.; Lord, G. M.; Howard, J. K.; Spencer, J.; Lechler, R. I.; Lombardi, G.

    2015-01-01

    B cells have been reported to promote graft rejection through alloantibody production. However, there is growing evidence that B cells can contribute to the maintenance of tolerance. Here, we used a mouse model of MHC-class I mismatched skin transplantation to investigate the contribution of B cells to graft survival. We demonstrate that adoptive transfer of B cells prolongs skin graft survival but only when the B cells were isolated from mice housed in low sterility “conventional” (CV) facilities and not from mice housed in pathogen free facilities (SPF). However, prolongation of skin graft survival was lost when B cells were isolated from IL-10 deficient mice housed in CV facilities. The suppressive function of B cells isolated from mice housed in CV facilities correlated with an anti-inflammatory environment and with the presence of a different gut microflora compared to mice maintained in SPF facilities. Treatment of mice in the CV facility with antibiotics abrogated the regulatory capacity of B cells. Finally, we identified transitional B cells isolated from CV facilities as possessing the regulatory function. These findings demonstrate that B cells, and in particular transitional B cells, can promote prolongation of graft survival, a function dependent on licensing by gut microflora. PMID:26109230

  14. Psychotherapy with people with developmental disabilities

    Directory of Open Access Journals (Sweden)

    Barbara Zafošnik

    2011-08-01

    Full Text Available People with developmental disabilities can experience any psychological abnormalitiy and psychiatric illness as do people without developmental disabilities. Due to different diagnostic criteria, assessment procedures and instruments, we lack definite prevalence rates for people with developmental disabilities, also suffering from mental health problems, eventhough most studies place the rate at 20 to 40%. One of the possible treatment alternatives for augmenting psychological well-being is psychotherapy, but is extremely rarely used for people with severe and profound disabilities, where speech cannot be the main therapeutic medium. So, those that are included in the psychotherapuetic process are predominantly clients with mild developmental disabilities, and they are mostly in cognitive-behavioral therapy. Recently, two models of (psychotherapy for persons with severe and profound developmental disabilities were developed: developmental-dynamic relationship therapy and attachment-based behaviour therapy for children. Conceptually, they both originate form developmental psychoanalytic theories.

  15. How Adverse Outcome Pathways Can Aid the Development and Use of Computational Prediction Models for Regulatory Toxicology

    Energy Technology Data Exchange (ETDEWEB)

    Wittwehr, Clemens; Aladjov, Hristo; Ankley, Gerald; Byrne, Hugh J.; de Knecht, Joop; Heinzle, Elmar; Klambauer, Günter; Landesmann, Brigitte; Luijten, Mirjam; MacKay, Cameron; Maxwell, Gavin; Meek, M. E. (Bette); Paini, Alicia; Perkins, Edward; Sobanski, Tomasz; Villeneuve, Dan; Waters, Katrina M.; Whelan, Maurice

    2016-12-19

    Efforts are underway to transform regulatory toxicology and chemical safety assessment from a largely empirical science based on direct observation of apical toxicity outcomes in whole organism toxicity tests to a predictive one in which outcomes and risk are inferred from accumulated mechanistic understanding. The adverse outcome pathway (AOP) framework has emerged as a systematic approach for organizing knowledge that supports such inference. We argue that this systematic organization of knowledge can inform and help direct the design and development of computational prediction models that can further enhance the utility of mechanistic and in silico data for chemical safety assessment. Examples of AOP-informed model development and its application to the assessment of chemicals for skin sensitization and multiple modes of endocrine disruption are provided. The role of problem formulation, not only as a critical phase of risk assessment, but also as guide for both AOP and complementary model development described. Finally, a proposal for actively engaging the modeling community in AOP-informed computational model development is made. The contents serve as a vision for how AOPs can be leveraged to facilitate development of computational prediction models needed to support the next generation of chemical safety assessment.

  16. Ciona intestinalis as a Marine Model System to Study Some Key Developmental Genes Targeted by the Diatom-Derived Aldehyde Decadienal

    Directory of Open Access Journals (Sweden)

    Anna Lettieri

    2015-03-01

    Full Text Available The anti-proliferative effects of diatoms, described for the first time in copepods, have also been demonstrated in benthic invertebrates such as polychaetes, sea urchins and tunicates. In these organisms PUAs (polyunsaturated aldehydes induce the disruption of gametogenesis, gamete functionality, fertilization, embryonic mitosis, and larval fitness and competence. These inhibitory effects are due to the PUAs, produced by diatoms in response to physical damage as occurs during copepod grazing. The cell targets of these compounds remain largely unknown. Here we identify some of the genes targeted by the diatom PUA 2-trans-4-trans-decadienal (DD using the tunicate Ciona intestinalis. The tools, techniques and genomic resources available for Ciona, as well as the suitability of Ciona embryos for medium-to high-throughput strategies, are key to their employment as model organisms in different fields, including the investigation of toxic agents that could interfere with developmental processes. We demonstrate that DD can induce developmental aberrations in Ciona larvae in a dose-dependent manner. Moreover, through a preliminary analysis, DD is shown to affect the expression level of genes involved in stress response and developmental processes.

  17. In Vitro Developmental Toxicology Screens: A Report on the Progress of the Methodology and Future Applications.

    Science.gov (United States)

    Zhang, Cindy; Ball, Jonathan; Panzica-Kelly, Julie; Augustine-Rauch, Karen

    2016-04-18

    There has been increasing focus on generation and assessment of in vitro developmental toxicology models for assessing teratogenic liability of chemicals. The driver for this focus has been to find reliable in vitro assays that will reduce or replace the use of in vivo tests for assessing teratogenicity. Such efforts may be eventually applied in testing pharmaceutical agents where a developmental toxicology assay or battery of assays may be incorporated into regulatory testing to replace one of the two species currently used in teratogenic assessment. Such assays may be eventually applied in testing a broader spectrum of chemicals, supporting efforts aligned with Tox21 strategies and responding to REACH legislation. This review describes the developmental toxicology assays that are of focus in these assessments: rodent whole embryo culture, zebrafish embryo assays, and embryonic stem cell assays. Progress on assay development as well as future directions of how these assays are envisioned to be applied for broader safety testing of chemicals are discussed. Altogether, the developmental model systems described in this review provide rich biological systems that can be utilized in better understanding teratogenic mechanisms of action of chemotypes and are promising in providing proactive safety assessment related to developmental toxicity. Continual advancements in refining/optimizing these in vitro assays are anticipated to provide a robust data set to provide thoughtful assessment of how whole animal teratogenicity evaluations can be reduced/refined in the future.

  18. Developmental Changes in the Profiles of Dyscalculia: An Explanation Based on a Double Exact-and-Approximate Number Representation Model.

    Science.gov (United States)

    Noël, Marie-Pascale; Rousselle, Laurence

    2011-01-01

    Studies on developmental dyscalculia (DD) have tried to identify a basic numerical deficit that could account for this specific learning disability. The first proposition was that the number magnitude representation of these children was impaired. However, Rousselle and Noël (2007) brought data showing that this was not the case but rather that these children were impaired when processing the magnitude of symbolic numbers only. Since then, incongruent results have been published. In this paper, we will propose a developmental perspective on this issue. We will argue that the first deficit shown in DD regards the building of an exact representation of numerical value, thanks to the learning of symbolic numbers, and that the reduced acuity of the approximate number magnitude system appears only later and is secondary to the first deficit.

  19. Regulatory acceptance and use of 3R models for pharmaceuticals and chemicals: Expert opinions on the state of affairs and the way forward

    NARCIS (Netherlands)

    Schiffelers, M.J.W.A.; Blaauboer, B.J.; Bakker, W.E.; Beken, S.; Hendriksen, C.F.M.; Koeter, H.; Krul, C.A.M.

    2014-01-01

    Pharmaceuticals and chemicals are subjected to regulatory safety testing accounting for approximately 25% of laboratory animal use in Europe. This testing meets various objections and has led to the development of a range of 3R models to Replace, Reduce or Refine the animal models. However, these

  20. [Neurotransmission in developmental disorders].

    Science.gov (United States)

    Takeuchi, Yoshihiro

    2008-11-01

    Attention deficit/hyperactivity disorder (AD/HD) is a heterogeneous developmental disorder with an etiology that is not fully understood. AD/HD has been considered to occur due to a disturbance in cathecholaminergic neurotransmission, with particular emphasis on dopamine. The neurotransmission of dopamine in subcortical regions such as the basal ganglia and limbic areas is synaptic; on the other hand, dopamine neurotransmission in the frontal cortex is quite different, because there are very few dopamine transporters (DAT) in the frontal cortex that allow dopamine to diffuse away from the dopamine synapse ("volume transmission"). It is now clear that noradrenergic neurons play a key regulatory role in dopaminergic function in the frontal cortex. Furthermore, serotonergic neurons exert an inhibitory effect on midbrain dopamine cell bodies, and they have an influence on dopamine release in terminal regions. There is accumulating neurobiological evidence pointing toward a role of the serotonin system in AD/HD. The etiology of autism spectrum disorders (ASD) is still unclear, but information from genetics, neuropathology, brain imaging, and basic neuroscience has provided insights into the understanding of this developmental disorder. In addition to abnormal circuitry in specific limbic and neocortical areas of the cerebral cortex, impairments in brainstem, cerebellar, thalamic, and basal ganglia connections have been reported. Numerous studies have pointed to abnormalities in serotonin and glutamate neurotransmission. Three important aspects involved in the pathophysiology of ASD have been proposed. The first is cell migration, the second is unbalanced excitatory-inhibitory networks, and the third is synapse formation and pruning, the key factors being reelin, neurexin, and neuroligin. Serotonin is considered to play an important role in all of these aspects of the pathophysiology of ASD. Finally, I would like to emphasize that it is crucial in the field of child

  1. Development of a Combined In Vitro Physiologically Based Kinetic (PBK) and Monte Carlo Modelling Approach to Predict Interindividual Human Variation in Phenol-Induced Developmental Toxicity.

    Science.gov (United States)

    Strikwold, Marije; Spenkelink, Bert; Woutersen, Ruud A; Rietjens, Ivonne M C M; Punt, Ans

    2017-06-01

    With our recently developed in vitro physiologically based kinetic (PBK) modelling approach, we could extrapolate in vitro toxicity data to human toxicity values applying PBK-based reverse dosimetry. Ideally information on kinetic differences among human individuals within a population should be considered. In the present study, we demonstrated a modelling approach that integrated in vitro toxicity data, PBK modelling and Monte Carlo simulations to obtain insight in interindividual human kinetic variation and derive chemical specific adjustment factors (CSAFs) for phenol-induced developmental toxicity. The present study revealed that UGT1A6 is the primary enzyme responsible for the glucuronidation of phenol in humans followed by UGT1A9. Monte Carlo simulations were performed taking into account interindividual variation in glucuronidation by these specific UGTs and in the oral absorption coefficient. Linking Monte Carlo simulations with PBK modelling, population variability in the maximum plasma concentration of phenol for the human population could be predicted. This approach provided a CSAF for interindividual variation of 2.0 which covers the 99th percentile of the population, which is lower than the default safety factor of 3.16 for interindividual human kinetic differences. Dividing the dose-response curve data obtained with in vitro PBK-based reverse dosimetry, with the CSAF provided a dose-response curve that reflects the consequences of the interindividual variability in phenol kinetics for the developmental toxicity of phenol. The strength of the presented approach is that it provides insight in the effect of interindividual variation in kinetics for phenol-induced developmental toxicity, based on only in vitro and in silico testing. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  2. GRNsight: a web application and service for visualizing models of small- to medium-scale gene regulatory networks

    Directory of Open Access Journals (Sweden)

    Kam D. Dahlquist

    2016-09-01

    Full Text Available GRNsight is a web application and service for visualizing models of gene regulatory networks (GRNs. A gene regulatory network (GRN consists of genes, transcription factors, and the regulatory connections between them which govern the level of expression of mRNA and protein from genes. The original motivation came from our efforts to perform parameter estimation and forward simulation of the dynamics of a differential equations model of a small GRN with 21 nodes and 31 edges. We wanted a quick and easy way to visualize the weight parameters from the model which represent the direction and magnitude of the influence of a transcription factor on its target gene, so we created GRNsight. GRNsight automatically lays out either an unweighted or weighted network graph based on an Excel spreadsheet containing an adjacency matrix where regulators are named in the columns and target genes in the rows, a Simple Interaction Format (SIF text file, or a GraphML XML file. When a user uploads an input file specifying an unweighted network, GRNsight automatically lays out the graph using black lines and pointed arrowheads. For a weighted network, GRNsight uses pointed and blunt arrowheads, and colors the edges and adjusts their thicknesses based on the sign (positive for activation or negative for repression and magnitude of the weight parameter. GRNsight is written in JavaScript, with diagrams facilitated by D3.js, a data visualization library. Node.js and the Express framework handle server-side functions. GRNsight’s diagrams are based on D3.js’s force graph layout algorithm, which was then extensively customized to support the specific needs of GRNs. Nodes are rectangular and support gene labels of up to 12 characters. The edges are arcs, which become straight lines when the nodes are close together. Self-regulatory edges are indicated by a loop. When a user mouses over an edge, the numerical value of the weight parameter is displayed. Visualizations can

  3. Manufacturing models permitting roll out/scale out of clinically led autologous cell therapies: regulatory and scientific challenges for comparability.

    Science.gov (United States)

    Hourd, Paul; Ginty, Patrick; Chandra, Amit; Williams, David J

    2014-08-01

    Manufacturing of more-than-minimally manipulated autologous cell therapies presents a number of unique challenges driven by complex supply logistics and the need to scale out production to multiple manufacturing sites or near the patient within hospital settings. The existing regulatory structure in Europe and the United States imposes a requirement to establish and maintain comparability between sites. Under a single market authorization, this is likely to become an unsurmountable burden beyond two or three sites. Unless alternative manufacturing approaches can be found to bridge the regulatory challenge of comparability, realizing a sustainable and investable business model for affordable autologous cell therapy supply is likely to be extremely demanding. Without a proactive approach by the regulators to close this "translational gap," these products may not progress down the development pipeline, threatening patient accessibility to an increasing number of clinician-led autologous cellular therapies that are already demonstrating patient benefits. We propose three prospective manufacturing models for the scale out/roll out of more-than-minimally manipulated clinically led autologous cell therapy products and test their prospects for addressing the challenge of product comparability with a selected expert reference panel of US and UK thought leaders. This paper presents the perspectives and insights of the panel and identifies where operational, technological and scientific improvements should be prioritized. The main purpose of this report is to solicit feedback and seek input from key stakeholders active in the field of autologous cell therapy in establishing a consensus-based manufacturing approach that may permit the roll out of clinically led autologous cell therapies. Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  4. Sparse Additive Ordinary Differential Equations for Dynamic Gene Regulatory Network Modeling.

    Science.gov (United States)

    Wu, Hulin; Lu, Tao; Xue, Hongqi; Liang, Hua

    2014-04-02

    The gene regulation network (GRN) is a high-dimensional complex system, which can be represented by various mathematical or statistical models. The ordinary differential equation (ODE) model is one of the popular dynamic GRN models. High-dimensional linear ODE models have been proposed to identify GRNs, but with a limitation of the linear regulation effect assumption. In this article, we propose a sparse additive ODE (SA-ODE) model, coupled with ODE estimation methods and adaptive group LASSO techniques, to model dynamic GRNs that could flexibly deal with nonlinear regulation effects. The asymptotic properties of the proposed method are established and simulation studies are performed to validate the proposed approach. An application example for identifying the nonlinear dynamic GRN of T-cell activation is used to illustrate the usefulness of the proposed method.

  5. Consistent robustness analysis (CRA) identifies biologically relevant properties of regulatory network models.

    Science.gov (United States)

    Saithong, Treenut; Painter, Kevin J; Millar, Andrew J

    2010-12-16

    A number of studies have previously demonstrated that "goodness of fit" is insufficient in reliably classifying the credibility of a biological model. Robustness and/or sensitivity analysis is commonly employed as a secondary method for evaluating the suitability of a particular model. The results of such analyses invariably depend on the particular parameter set tested, yet many parameter values for biological models are uncertain. Here, we propose a novel robustness analysis that aims to determine the "common robustness" of the model with multiple, biologically plausible parameter sets, rather than the local robustness for a particular parameter set. Our method is applied to two published models of the Arabidopsis circadian clock (the one-loop [1] and two-loop [2] models). The results reinforce current findings suggesting the greater reliability of the two-loop model and pinpoint the crucial role of TOC1 in the circadian network. Consistent Robustness Analysis can indicate both the relative plausibility of different models and also the critical components and processes controlling each model.

  6. Determinants of Dermal Exposure Relevant for Exposure Modelling in Regulatory Risk Assessment

    NARCIS (Netherlands)

    Marquart, J.; Brouwer, D.H.; Gijsbers, J.H.J.; Links, I.H.M.; Warren, N.; Hemmen, J.J. van

    2003-01-01

    Risk assessment of chemicals requires assessment of the exposure levels of workers. In the absence of adequate specific measured data, models are often used to estimate exposure levels. For dermal exposure only a few models exist, which are not validated externally. In the scope of a large European

  7. TREXMO: A Translation Tool to Support the Use of Regulatory Occupational Exposure Models.

    Science.gov (United States)

    Savic, Nenad; Racordon, Dimitri; Buchs, Didier; Gasic, Bojan; Vernez, David

    2016-10-01

    Occupational exposure models vary significantly in their complexity, purpose, and the level of expertise required from the user. Different parameters in the same model may lead to different exposure estimates for the same exposure situation. This paper presents a tool developed to deal with this concern-TREXMO or TRanslation of EXposure MOdels. TREXMO integrates six commonly used occupational exposure models, namely, ART v.1.5, STOFFENMANAGER(®) v.5.1, ECETOC TRA v.3, MEASE v.1.02.01, EMKG-EXPO-TOOL, and EASE v.2.0. By enabling a semi-automatic translation between the parameters of these six models, TREXMO facilitates their simultaneous use. For a given exposure situation, defined by a set of parameters in one of the models, TREXMO provides the user with the most appropriate parameters to use in the other exposure models. Results showed that, once an exposure situation and parameters were set in ART, TREXMO reduced the number of possible outcomes in the other models by 1-4 orders of magnitude. The tool should manage to reduce the uncertain entry or selection of parameters in the six models, improve between-user reliability, and reduce the time required for running several models for a given exposure situation. In addition to these advantages, registrants of chemicals and authorities should benefit from more reliable exposure estimates for the risk characterization of dangerous chemicals under Regulation, Evaluation, Authorisation and restriction of CHemicals (REACH). © The Author 2016. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.

  8. Assessment of in vitro COPD models for tobacco regulatory science: Workshop proceedings, conclusions and paths forward for in vitro model use.

    Science.gov (United States)

    Behrsing, Holger; Raabe, Hans; Manuppello, Joseph; Bombick, Betsy; Curren, Rodger; Sullivan, Kristie; Sethi, Sanjay; Phipps, Richard; Tesfaigzi, Yohannes; Yan, Sherwin; D'Ruiz, Carl; Tarran, Robert; Constant, Samuel; Phillips, Gary; Gaça, Marianna; Hayden, Patrick; Cao, Xuefei; Mathis, Carole; Hoeng, Julia; Braun, Armin; Hill, Erin

    2016-05-01

    The Family Smoking Prevention and Tobacco Control Act of 2009 established the Food and Drug Administration Center for Tobacco Products (FDA-CTP), and gave it regulatory authority over the marketing, manufacture and distribution of tobacco products, including those termed 'modified risk'. On 8-10 December 2014, IIVS organised a workshop conference, entitled Assessment of In Vitro COPD Models for Tobacco Regulatory Science, to bring together stakeholders representing regulatory agencies, academia, industry and animal protection, to address the research priorities articulated by the FDA-CTP. Specific topics were covered to assess the status of current in vitro technologies as they are applied to understanding the adverse pulmonary events resulting from tobacco product exposure, and in particular, the progression of chronic obstructive pulmonary disease (COPD). The four topics covered were: a) Inflammation and Oxidative Stress; b) Ciliary Dysfunction and Ion Transport; c) Goblet Cell Hyperplasia and Mucus Production; and d) Parenchymal/Bronchial Tissue Destruction and Remodelling. The 2.5 day workshop included 18 expert speakers, plus poster sessions, networking and breakout sessions, which identified key findings and provided recommendations to advance the in vitro technologies and assays used to evaluate tobacco-induced disease etiologies. The workshop summary was reported at the 2015 Society of Toxicology Annual Meeting, and the recommendations led to an IIVS-organised technical workshop in June 2015, entitled Goblet Cell Hyperplasia, Mucus Production, and Ciliary Beating Assays, to assess these assays and to conduct a proof-of-principle multi-laboratory exercise to determine their suitability for standardisation. Here, we report on the proceedings, recommendations and outcomes of the December 2014 workshop, including paths forward to continue the development of non-animal methods to evaluate tissue responses that model the disease processes that may lead to COPD, a

  9. Intrinsic dynamics of heart regulatory systems on short timescales: from experiment to modelling

    International Nuclear Information System (INIS)

    Khovanov, I A; Khovanova, N A; McClintock, P V E; Stefanovska, A

    2009-01-01

    We discuss open problems related to the stochastic modelling of cardiac function. The work is based on an experimental investigation of the dynamics of heart rate variability (HRV) in the absence of respiratory perturbations. We consider first the cardiac control system on short timescales via an analysis of HRV within the framework of a random walk approach. Our experiments show that HRV on timescales of less than a minute takes the form of free diffusion, close to Brownian motion, which can be described as a non-stationary process with stationary increments. Secondly, we consider the inverse problem of modelling the state of the control system so as to reproduce the experimentally observed HRV statistics of. We discuss some simple toy models and identify open problems for the modelling of heart dynamics

  10. Computational Genetic Regulatory Networks Evolvable, Self-organizing Systems

    CERN Document Server

    Knabe, Johannes F

    2013-01-01

    Genetic Regulatory Networks (GRNs) in biological organisms are primary engines for cells to enact their engagements with environments, via incessant, continually active coupling. In differentiated multicellular organisms, tremendous complexity has arisen in the course of evolution of life on earth. Engineering and science have so far achieved no working system that can compare with this complexity, depth and scope of organization. Abstracting the dynamics of genetic regulatory control to a computational framework in which artificial GRNs in artificial simulated cells differentiate while connected in a changing topology, it is possible to apply Darwinian evolution in silico to study the capacity of such developmental/differentiated GRNs to evolve. In this volume an evolutionary GRN paradigm is investigated for its evolvability and robustness in models of biological clocks, in simple differentiated multicellularity, and in evolving artificial developing 'organisms' which grow and express an ontogeny starting fr...

  11. Can modeling of health outcomes facilitate regulatory decision making? The benefit-risk tradeoff for rosiglitazone in 1999 vs. 2007.

    Science.gov (United States)

    Cross, J T; Veenstra, D L; Gardner, J S; Garrison, L P

    2011-03-01

    Rosiglitazone was initially approved for type 2 diabetes monotherapy. We tested health-outcomes modeling as an aid to regulatory decision making by quantifying the incremental net benefit (INB) value of rosiglitazone (relative to a comparator), both at the time of first approval (1999) and at the FDA advisory committee review (2007). Using 1999 data, rosiglitazone was projected to provide an additional 0.639 years of life (0.373 quality-adjusted life years (QALYs)) relative to placebo but a loss of 0.312 years (0.173 QALYs) relative to glyburide, with uncertainty in reduction of hemoglobin A(1c) (HbA(1c)) level having the greatest impact on the benefit-risk profile. By 2007, rosiglitazone was projected to provide an additional 0.222 years (0.091 QALYs) vs. glyburide and 0.026 years vs. metformin (0.009 QALYs). Modeling suggested that the use of rosiglitazone as monotherapy was not initially warranted, given the uncertainty with regard to benefit. Despite similar net benefit (NB) as metformin shown in postmarketing data, residual cardiovascular (CV) concerns did not support the use of rosiglitazone as first-line therapy. We adapted a mathematical diabetes model to estimate NB and uncertainty of diabetes monotherapy.

  12. Regulatory Impacts on Distributed Generation and Upstream Transmission Substation Expansion Planning: A Novel Stochastic Bi-level Model

    Directory of Open Access Journals (Sweden)

    F. Misaghi

    2017-06-01

    Full Text Available In this paper, a novel framework is proposed to study impacts of regulatory incentive on distributed generation (DG investment in sub-transmission substations, as well as upgrading of upstream transmission substations. Both conventional and wind power technologies are considered here. Investment incentives are fuel cost, firm contracts, capacity payment and investment subsidy relating to wind power. The problem is modelled as a bi-level stochastic optimization problem, where the upper level consists of investor's decisions maximizing its own profit. Both market clearing and decision on upgrading of transmission substation aiming at minimizing the total cost are considered in the lower level. Due to non-convexity of the lower level and impossibility of converting to single level problem (i.e. mathematical programming with equilibrium constraints (MPEC, an algorithm combing enumeration and mathematical optimization is used to tackle with the non-convexity. For each upgrading strategy of substations, a stochastic MPEC, converted to a mixed integer linear programming (MILP is solved. The proposed model is examined on a six-bus and an actual network. Numerical studies confirm that the proposed model can be used for analysing investment behaviour of DGs and substation expansion.

  13. Virally inactivated human platelet concentrate lysate induces regulatory T cells and immunosuppressive effect in a murine asthma model.

    Science.gov (United States)

    Lee, Yueh-Lun; Lee, Lin-Wen; Su, Chen-Yao; Hsiao, George; Yang, Yi-Yuan; Leu, Sy-Jye; Shieh, Ying-Hua; Burnouf, Thierry

    2013-09-01

    Platelet concentrate lysates (PCLs) are increasingly used in regenerative medicine. We have developed a solvent/detergent (S/D)-treated PCL. The functional properties of this preparation should be unveiled. We hypothesized that, due to transforming growth factor-β1 (TGF-β1) content, PCLs may exert immunosuppressive and anti-inflammatory functions. PCL was prepared by S/D treatment, oil extraction, and hydrophobic interaction chromatography. The content of TGF-β in PCL was determined by enzyme-linked immunosorbent assay. Cultured CD4+ T cells were used to investigate the effects of PCL on expression of transcription factor forkhead box P3 (Foxp3), the inhibition of T-cell proliferation, and cytokine production. The regulatory function of PCL-converted CD4+ T cells was analyzed by suppressive assay. The BALB/c mice were given PCL-converted CD4+ T cells before ovalbumin (OVA) sensitization and challenge using an asthma model. Inflammatory parameters, such as the level of immunoglobulin E (IgE), airway hyperresponsiveness (AHR), bronchial lavage fluid eosinophils, and cytokines were assayed. Recombinant human (rHu) TGF-β1 was used as control. PCL significantly enhanced the development of CD4+Foxp3+-induced regulatory T cells (iTregs). Converted iTregs produced neither Th1 nor Th2 cytokines and inhibited normal T-cell proliferation. PCL- and rHuTGF-β-converted CD4+ T cells prevented OVA-induced asthma. PCL- and rHuTGF-β-modified T cells both significantly reduced expression levels of OVA-specific IgE and significantly inhibited the development of AHR, airway eosinophilia, and Th2 responses in mice. S/D-treated PCL promotes Foxp3+ iTregs and exerts immunosuppressive and anti-inflammatory properties. This finding may help to understand the clinical properties of platelet lysates. © 2013 American Association of Blood Banks.

  14. Developmental Delay’ Reconsidered: The Critical Role of Age-Dependent, Co-variant Development

    Directory of Open Access Journals (Sweden)

    Yonata Levy

    2018-04-01

    Full Text Available In memory of Annette Karmiloff-Smith.This paper reviews recent neurobiological research reporting structural co-variance and temporal dependencies in age-dependent gene expression, parameters of cortical maturation, long range connectivity and interaction of the biological network with the environment. This research suggests that age by size trajectories of brain structures relate to functional properties more than absolute sizes. In line with these findings, recent behavioral studies of typically developing children whose language development was delayed reported long term consequences of such delays. As for neurodevelopmental disorders, disrupted developmental timing and slow acquisitional pace are hallmarks of these populations. It is argued that these behavioral and neuro-biological results highlight the need to commit to a developmental model which will reflect the fact that temporal dependencies overseeing structural co-variance among developmental components are major regulatory factors of typical development of the brain/mind network. Consequently, the concept of ‘developmental delay’ in developmental theorizing needs to be reconsidered.

  15. Developmental programming: the role of growth hormone.

    Science.gov (United States)

    Oberbauer, Anita M

    2015-01-01

    Developmental programming of the fetus has consequences for physiologic responses in the offspring as an adult and, more recently, is implicated in the expression of altered phenotypes of future generations. Some phenotypes, such as fertility, bone strength, and adiposity are highly relevant to food animal production and in utero factors that impinge on those traits are vital to understand. A key systemic regulatory hormone is growth hormone (GH), which has a developmental role in virtually all tissues and organs. This review catalogs the impact of GH on tissue programming and how perturbations early in development influence GH function.

  16. Hybrid models for chemical reaction networks: Multiscale theory and application to gene regulatory systems

    Science.gov (United States)

    Winkelmann, Stefanie; Schütte, Christof

    2017-09-01

    Well-mixed stochastic chemical kinetics are properly modeled by the chemical master equation (CME) and associated Markov jump processes in molecule number space. If the reactants are present in large amounts, however, corresponding simulations of the stochastic dynamics become computationally expensive and model reductions are demanded. The classical model reduction approach uniformly rescales the overall dynamics to obtain deterministic systems characterized by ordinary differential equations, the well-known mass action reaction rate equations. For systems with multiple scales, there exist hybrid approaches that keep parts of the system discrete while another part is approximated either using Langevin dynamics or deterministically. This paper aims at giving a coherent overview of the different hybrid approaches, focusing on their basic concepts and the relation between them. We derive a novel general description of such hybrid models that allows expressing various forms by one type of equation. We also check in how far the approaches apply to model extensions of the CME for dynamics which do not comply with the central well-mixed condition and require some spatial resolution. A simple but meaningful gene expression system with negative self-regulation is analysed to illustrate the different approximation qualities of some of the hybrid approaches discussed. Especially, we reveal the cause of error in the case of small volume approximations.

  17. Hybrid models for chemical reaction networks: Multiscale theory and application to gene regulatory systems.

    Science.gov (United States)

    Winkelmann, Stefanie; Schütte, Christof

    2017-09-21

    Well-mixed stochastic chemical kinetics are properly modeled by the chemical master equation (CME) and associated Markov jump processes in molecule number space. If the reactants are present in large amounts, however, corresponding simulations of the stochastic dynamics become computationally expensive and model reductions are demanded. The classical model reduction approach uniformly rescales the overall dynamics to obtain deterministic systems characterized by ordinary differential equations, the well-known mass action reaction rate equations. For systems with multiple scales, there exist hybrid approaches that keep parts of the system discrete while another part is approximated either using Langevin dynamics or deterministically. This paper aims at giving a coherent overview of the different hybrid approaches, focusing on their basic concepts and the relation between them. We derive a novel general description of such hybrid models that allows expressing various forms by one type of equation. We also check in how far the approaches apply to model extensions of the CME for dynamics which do not comply with the central well-mixed condition and require some spatial resolution. A simple but meaningful gene expression system with negative self-regulation is analysed to illustrate the different approximation qualities of some of the hybrid approaches discussed. Especially, we reveal the cause of error in the case of small volume approximations.

  18. Parenting and the Development of Effortful Control from Early Childhood to Early Adolescence: A Transactional Developmental Model

    Science.gov (United States)

    Capaldi, Deborah M.; Kerr, David C. R.; Bertrand, Maria; Pears, Katherine C.; Owen, Lee

    2016-01-01

    Poor effortful control is a key temperamental factor underlying behavioral problems. The bidirectional association of child effortful control with both positive parenting and negative discipline was examined from ages approximately 3 to 13–14 years, involving 5 time points, and using data from parents and children in the Oregon Youth Study-Three Generational Study (N = 318 children from 150 families). Based on a dynamic developmental systems approach, it was hypothesized that there would be concurrent associations between parenting and child effortful control and bidirectional effects across time from each aspect of parenting to effortful control and from effortful control to each aspect of parenting. It was also hypothesized that associations would be more robust in early childhood, from ages 3 to 7 years, and would diminish as indicated by significantly weaker effects at the older ages, 11–12 to 13–14 years. Longitudinal feedback or mediated effects were also tested. Findings supported (a) stability in each construct over multiple developmental periods; (b) concurrent associations, which were significantly weaker at the older ages; (c) bidirectional effects, consistent with the interpretation that at younger ages children’s effortful control influenced parenting, whereas at older child ages, parenting influenced effortful control; and (d) a transactional effect, such that maternal parenting in late childhood was a mechanism explaining children’s development of effortful control from midchildhood to early adolescence. PMID:27427809

  19. Developmental cascade models of a parenting-focused program for divorced families on mental health problems and substance use in emerging adulthood.

    Science.gov (United States)

    Wolchik, Sharlene A; Tein, Jenn-Yun; Sandler, Irwin N; Kim, Han-Joe

    2016-08-01

    A developmental cascade model from functioning in adolescence to emerging adulthood was tested using data from a 15-year longitudinal follow-up of 240 emerging adults whose families participated in a randomized, experimental trial of a preventive program for divorced families. Families participated in the program or literature control condition when the offspring were ages 9-12. Short-term follow-ups were conducted 3 months and 6 months following completion of the program when the offspring were in late childhood/early adolescence. Long-term follow-ups were conducted 6 years and 15 years after program completion when the offspring were in middle to late adolescence and emerging adulthood, respectively. It was hypothesized that the impact of the program on mental health and substance use outcomes in emerging adulthood would be explained by developmental cascade effects of program effects in adolescence. The results provided support for a cascade effects model. Specifically, academic competence in adolescence had cross-domain effects on internalizing problems and externalizing problems in emerging adulthood. In addition, adaptive coping in adolescence was significantly, negatively related to binge drinking. It was unexpected that internalizing symptoms in adolescence were significantly negatively related to marijuana use and alcohol use. Gender differences occurred in the links between mental health problems and substance use in adolescence and mental health problems and substance use in emerging adulthood.

  20. Predictive modelling of migration from packaging materials into food products for regulatory purposes

    NARCIS (Netherlands)

    Helmroth, E.; Rijk, R.; Dekker, M.; Jongen, W.

    2002-01-01

    Migration of low-molecular weight compounds is one of the most important problems of packaging plastics and other plastics intended to come into contact with food products. Since migration experiments are time consuming and expensive, predictive modelling has been introduced as a promising

  1. Agent-based modeling of autophagy reveals emergent regulatory behavior of spatio-temporal autophagy dynamics.

    Science.gov (United States)

    Börlin, Christoph S; Lang, Verena; Hamacher-Brady, Anne; Brady, Nathan R

    2014-09-10

    Autophagy is a vesicle-mediated pathway for lysosomal degradation, essential under basal and stressed conditions. Various cellular components, including specific proteins, protein aggregates, organelles and intracellular pathogens, are targets for autophagic degradation. Thereby, autophagy controls numerous vital physiological and pathophysiological functions, including cell signaling, differentiation, turnover of cellular components and pathogen defense. Moreover, autophagy enables the cell to recycle cellular components to metabolic substrates, thereby permitting prolonged survival under low nutrient conditions. Due to the multi-faceted roles for autophagy in maintaining cellular and organismal homeostasis and responding to diverse stresses, malfunction of autophagy contributes to both chronic and acute pathologies. We applied a systems biology approach to improve the understanding of this complex cellular process of autophagy. All autophagy pathway vesicle activities, i.e. creation, movement, fusion and degradation, are highly dynamic, temporally and spatially, and under various forms of regulation. We therefore developed an agent-based model (ABM) to represent individual components of the autophagy pathway, subcellular vesicle dynamics and metabolic feedback with the cellular environment, thereby providing a framework to investigate spatio-temporal aspects of autophagy regulation and dynamic behavior. The rules defining our ABM were derived from literature and from high-resolution images of autophagy markers under basal and activated conditions. Key model parameters were fit with an iterative method using a genetic algorithm and a predefined fitness function. From this approach, we found that accurate prediction of spatio-temporal behavior required increasing model complexity by implementing functional integration of autophagy with the cellular nutrient state. The resulting model is able to reproduce short-term autophagic flux measurements (up to 3

  2. Benzimidazoles Promote Anti-TNF Mediated Induction of Regulatory Macrophages and Enhance Therapeutic Efficacy in a Murine Model

    NARCIS (Netherlands)

    Wildenberg, Manon E.; Levin, Alon D.; Ceroni, Alessandro; Guo, Zhen; Koelink, Pim J.; Hakvoort, Theodorus B. M.; Westera, Liset; Bloemendaal, Felicia M.; Brandse, Johannan F.; Simmons, Alison; D'Haens, Geert R.; Ebner, Daniel; van den Brink, Gijs R.

    2017-01-01

    Background and Aims: Regulatory macrophages play a critical role in tissue repair, and we have previously shown that anti-tumour necrosis factor [TNF] antibodies induce these macrophages in vitro and in vivo in IBD patients. The induction of regulatory macrophages can be potentiated using the

  3. 77 FR 50172 - Expert Forum on the Use of Performance-Based Regulatory Models in the U.S. Oil and Gas Industry...

    Science.gov (United States)

    2012-08-20

    ... Transportation, Pipeline and Hazardous Materials Safety Administration (PHMSA) invite interested parties to...] Expert Forum on the Use of Performance-Based Regulatory Models in the U.S. Oil and Gas Industry, Offshore... and gas industry. The meeting will take place at the College of the Mainland, and hosted by the Gulf...

  4. An empirical model of Onecut binding activity at the sea urchin SM50 C-element gene regulatory region.

    Science.gov (United States)

    Otim, Ochan

    2017-01-01

    Studying the formation of endoskeleton in many species is complex and difficult. The sea urchin embryo offers an unparalleled platform for understanding this process because of the ease with which its skeletogenic mesenchyme cells can be manipulated. In this study, preliminary evidence from biochemical studies towards understanding the role of the Onecut transcription factor during sea urchin skeletogenic mesenchyme cell specification is presented. Based on the evidence, an empirical model is proposed showing how Onecut, together with associated co-factors, may be using the C-element of the SM50 gene regulatory region in advance of the sea urchin Strongylocentrotus purpuratus spicule development. In the model, Onecut recognizes and binds the DNA sequence CATCGATCTC in the C-element without temporal restriction. Onecut then utilizes different sets of co-factors to switch from its unknown function early in development (four cell stage to the mesenchyme blastula stage), to its known role in the oral-aboral boundary thereafter. At the writing of this report, definitive evidence as to whether the "early" factors are expressed in all cells except the micromere lineages, or whether the "late" factors are expressed in micromere descendants or ectodermal precursors only are lacking. The former would suggest a possible Onecut repression function for the early co-factors outside the micromere lineages; the latter scenario would suggest a Onecut activation function for the late co-factors in the presumptive ciliary band.

  5. Regulatory T Cell Induced by Poria cocos Bark Exert Therapeutic Effects in Murine Models of Atopic Dermatitis and Food Allergy

    Directory of Open Access Journals (Sweden)

    Min-Jung Bae

    2016-01-01

    Full Text Available The prevalence of allergic disorders including atopic dermatitis (AD and food allergy (FA has increased dramatically in pediatric populations, but there is no effective drug available for their management. Therefore, trials are required for the development of safe therapeutic agents such as herbal medicines. We determined whether orally administered Poria cocos bark (PCB extract could exert immunosuppressive effects on allergic and inflammatory symptoms of AD and FA. For both AD, which was induced using house dust mite extract, and FA, which was induced by exposure to ovalbumin, model mice were orally treated with PCB extract for 62 days and 18 days, respectively. We also investigated the inductive effect of PCB extract on the generation and maintenance of Foxp3+CD4+ regulatory T cells (Tregs. The symptoms of AD and FA were ameliorated by the administration of PCB extract. Furthermore, PCB extract inhibited the Th2-related cytokines and increased the population of Foxp3+CD4+ Tregs in both AD and FA models. In ex vivo experiments, PCB extract promoted the functional differentiation of Foxp3+CD4+ Tregs, which is dependent on aryl hydrocarbon receptor activation. Thus, PCB extract has potential as an oral immune suppressor for the treatment of AD and FA through the generation of Tregs.

  6. A model for genetic and epigenetic regulatory networks identifies rare pathways for transcription factor induced pluripotency

    Science.gov (United States)

    Artyomov, Maxim; Meissner, Alex; Chakraborty, Arup

    2010-03-01

    Most cells in an organism have the same DNA. Yet, different cell types express different proteins and carry out different functions. This is because of epigenetic differences; i.e., DNA in different cell types is packaged distinctly, making it hard to express certain genes while facilitating the expression of others. During development, upon receipt of appropriate cues, pluripotent embryonic stem cells differentiate into diverse cell types that make up the organism (e.g., a human). There has long been an effort to make this process go backward -- i.e., reprogram a differentiated cell (e.g., a skin cell) to pluripotent status. Recently, this has been achieved by transfecting certain transcription factors into differentiated cells. This method does not use embryonic material and promises the development of patient-specific regenerative medicine, but it is inefficient. The mechanisms that make reprogramming rare, or even possible, are poorly understood. We have developed the first computational model of transcription factor-induced reprogramming. Results obtained from the model are consistent with diverse observations, and identify the rare pathways that allow reprogramming to occur. If validated, our model could be further developed to design optimal strategies for reprogramming and shed light on basic questions in biology.

  7. Dispersion modeling in assessing air quality of industrial projects under Indian regulatory regime

    Energy Technology Data Exchange (ETDEWEB)

    Bandyopadhyay, Amitava [Department of Chemical Engineering, University of Calcutta, 92, A.P.C.Road, Kolkata 700 009 (India)

    2010-07-01

    Environmental impact assessment (EIA) studies conducted over the years as a part of obtaining environmental clearance in accordance with Indian regulation have been given significant attention towards carrying out Gaussian dispersion modeling for predicting the ground level concentration (GLC) of pollutants, especially for SO{sub 2}. Making any adhoc decision towards recommending flue gas desulfurization (FGD) system in Indian fossil fuel combustion operations is not realistic considering the usage of fuel with low sulfur content. Thus a predictive modeling is imperative prior to making any conclusive decision. In the light of this finding, dispersion modeling has been accorded in Indian environmental regulations. This article aims at providing approaches to ascertain pollution potential for proposed power plant operation either alone or in presence of other industrial operations under different conditions. In order to assess the performance of the computational work four different cases were analyzed based on worst scenario. Results obtained through predictions were compared with National Ambient Air Quality Standards (NAAQS) of India. One specific case found to overshoot the ambient air quality adversely in respect of SO2 and was therefore, suggested to install a FGD system with at least 80 % SO2 removal efficiency. With this recommendation, the cumulative prediction yielded a very conservative resultant value of 24 hourly maximum GLC of SO2 as against a value that exceeded well above the stipulated value without considering the FGD system. The computational algorithm developed can therefore, be gainfully utilized for the purpose of EIA analysis in Indian condition.

  8. Transcriptional regulatory programs underlying barley germination and regulatory functions of Gibberellin and abscisic acid

    Science.gov (United States)

    2011-01-01

    Background Seed germination is a complex multi-stage developmental process, and mainly accomplished through concerted activities of many gene products and biological pathways that are often subjected to strict developmental regulation. Gibberellins (GA) and abscisic acid (ABA) are two key phytohormones regulating seed germination and seedling growth. However, transcriptional regulatory networks underlying seed germination and its associated biological pathways are largely unknown. Results The studies examined transcriptomes of barley representing six distinct and well characterized germination stages and revealed that the transcriptional regulatory program underlying barley germination was composed of early, late, and post-germination phases. Each phase was accompanied with transcriptional up-regulation of distinct biological pathways. Cell wall synthesis and regulatory components including transcription factors, signaling and post-translational modification components were specifically and transiently up-regulated in early germination phase while histone families and many metabolic pathways were up-regulated in late germination phase. Photosynthesis and seed reserve mobilization pathways were up-regulated in post-germination phase. However, stress related pathways and seed storage proteins were suppressed through the entire course of germination. A set of genes were transiently up-regulated within three hours of imbibition, and might play roles in initiating biological pathways involved in seed germination. However, highly abundant transcripts in dry barley and Arabidopsis seeds were significantly conserved. Comparison with transcriptomes of barley aleurone in response to GA and ABA identified three sets of germination responsive genes that were regulated coordinately by GA, antagonistically by ABA, and coordinately by GA but antagonistically by ABA. Major CHO metabolism, cell wall degradation and protein degradation pathways were up-regulated by both GA and seed

  9. Transcriptional regulatory programs underlying barley germination and regulatory functions of Gibberellin and abscisic acid

    Directory of Open Access Journals (Sweden)

    Lin Li

    2011-06-01

    Full Text Available Abstract Background Seed germination is a complex multi-stage developmental process, and mainly accomplished through concerted activities of many gene products and biological pathways that are often subjected to strict developmental regulation. Gibberellins (GA and abscisic acid (ABA are two key phytohormones regulating seed germination and seedling growth. However, transcriptional regulatory networks underlying seed germination and its associated biological pathways are largely unknown. Results The studies examined transcriptomes of barley representing six distinct and well characterized germination stages and revealed that the transcriptional regulatory program underlying barley germination was composed of early, late, and post-germination phases. Each phase was accompanied with transcriptional up-regulation of distinct biological pathways. Cell wall synthesis and regulatory components including transcription factors, signaling and post-translational modification components were specifically and transiently up-regulated in early germination phase while histone families and many metabolic pathways were up-regulated in late germination phase. Photosynthesis and seed reserve mobilization pathways were up-regulated in post-germination phase. However, stress related pathways and seed storage proteins were suppressed through the entire course of germination. A set of genes were transiently up-regulated within three hours of imbibition, and might play roles in initiating biological pathways involved in seed germination. However, highly abundant transcripts in dry barley and Arabidopsis seeds were significantly conserved. Comparison with transcriptomes of barley aleurone in response to GA and ABA identified three sets of germination responsive genes that were regulated coordinately by GA, antagonistically by ABA, and coordinately by GA but antagonistically by ABA. Major CHO metabolism, cell wall degradation and protein degradation pathways were up

  10. IT Management Model for Financial Report Issuance and Regulatory and Legal Compliance

    Directory of Open Access Journals (Sweden)

    José Rogério Poggio Moreira

    2013-10-01

    Full Text Available The development of information systems for financial report issuance must be adherent to the demands of the law and regulations that regulate the financial market. In order to perform this task, organizations need to implement control in the Information Technology (IT area to maintain their systems´ conformity to laws and regulations. In the development of this work, it was found, through a state-of-art study, that there are no proposals contemplating the solution of this problem in its totality. In order to achieve this goal, in this paper it is presented a model for Information Technology management constituted by COBIT, ITIL and BPM management good practices, together with SOA and XBRL Technologies. This model is composed by 03 layers that aim at structuring the organization IT and business processes, besides defining a process for implementing SOA and integrating its Web services with XBRL language. One can expect this work to contribute to companies to decrease the negative impact coming from the lack of conformity with laws and regulations, through the creation of a corporative and IT environment that is flexible and more adaptable to changes, which may occur in legal demands, as well as improving the quality and reliability of financial report issuance.

  11. Cell model for the study of receptor and regulatory functions of human proHB-EGF

    Directory of Open Access Journals (Sweden)

    N. V. Korotkevych

    2014-08-01

    Full Text Available Developing of new models and approaches, particularly with fluorescent techniques, for investigation of intracellular transport of proHB-EGF and its ligand-receptor complexes is strongly required. In order to create a model for studying proHB-EGF functions the genetic construction pEGFP-N1-proHB-EGF, encoding proHB-EGF-EGFP which is fluorescent-labeled form of proHB-EGF with enhanced green fluorescent protein EGFP in the cytoplasmic terminus of the molecule, was obtained. Eukaryotic cells expressing fusion protein proHB-EGF-EGFP on the cell surface were obtained by transfection with pEGFP-N1-proHB-EGF. Expressed in the Vero cells proHB-EGF-EGFP could bind fluorescent derivative of nontoxic receptor-binding subunit B of diphtheria toxin mCherry-SubB. After stimulation of transfected cells with TPA (12-O-Tetradecanoylphorbol-13-acetate, proHB-EGF-EGFP formed a fluorescentl-labeled C-terminal fragment of the molecule – CTF-EGFP. Thus, the obtained genetic construction pEGFP-N1-proHB-EGF could be helpful in visualization of molecules proHB-EGF and CTF in cells, may open new possibilities for the studying of their functions, such as receptor function of proHB-EGF for diphtheria toxin, intracellular translocation of CTF and provide possibilities for natural proHB-EGF ligands search.

  12. Developmental immunotoxicity testing of 4-methyl anisole.

    Science.gov (United States)

    Tonk, Elisa C M; Verhoef, Aart; Gremmer, Eric R; van Loveren, Henk; Piersma, Aldert H

    2015-07-01

    The developmental immunotoxicity of 4-methyl anisole (4MA) was investigated in the rat. Four study designs were used, with either premating or post-weaning onset of exposure, continued to postnatal day 50, and with or without additional oral gavage of pups from postnatal day 10 onward. Reduced litter size (benchmark dose lower confidence limit (BMDL) 80mg/kg bw/day) was the most sensitive developmental parameter, with pup relative organ weight effects observed at similar BMDLs, in the absence of maternal toxicity. Eosinophil numbers were reduced at lower doses (BMDL 16mg/kg bw/day). KLH challenge resulted in increased IL-13 and TNF-α responses, and variably reduced IgG production (BMDL 27mg/kg bw/day). T4 levels were reduced by 11% at maximum with a BMDL of 73mg/kg bw/day. Differences between exposure cohorts were limited and were considered to be without biological significance. This study shows that 4MA induces developmental immunotoxicity at doses below those inducing developmental and general toxicity. These observations being independent of the study designs applied suggest that the post-weaning period, included in all designs, is the most relevant sensitive period for inducing 4MA mediated developmental immunotoxicity. Moreover, this study stresses the importance of including developmental immunotoxicity testing by default in regulatory toxicology. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Effects of developmental bisphenol A exposure on reproductive-related behaviors in California mice (Peromyscus californicus: a monogamous animal model.

    Directory of Open Access Journals (Sweden)

    Scott A Williams

    Full Text Available Bisphenol A (BPA, a pervasive, endocrine disrupting compound (EDC, acts as a mixed agonist-antagonist with respect to estrogens and other steroid hormones. We hypothesized that sexually selected traits would be particularly sensitive to EDC. Consistent with this concept, developmental exposure of males from the polygynous deer mouse, Peromyscus maniculatus, to BPA resulted in compromised spatial navigational ability and exploratory behaviors, while there was little effect on females. Here, we have examined a related, monogamous species, the California mouse (Peromyscus californicus, where we predicted that males would be less sensitive to BPA in terms of navigational and exploratory behaviors, while displaying other traits related to interactions with females and territorial marking that might be vulnerable to disruption. As in the deer mouse experiments, females were fed either a phytoestrogen-free CTL diet through pregnancy and lactation or the same diet supplemented with BPA (50 mg/kg feed weight or ethinyl estradiol (EE (0.1 part per billion to provide a "pure" estrogen control. After weaning, pups were maintained on CTL diet until they had reached sexual maturity, at which time behaviors were evaluated. In addition, territorial marking was assessed in BPA-exposed males housed alone and when a control male was visible in the testing arena. In contrast to deer mice, BPA and EE exposure had no effect on spatial navigational skills in either male or female California mice. While CTL females exhibited greater exploratory behavior than CTL males, BPA exposure abolished this sex difference. BPA-exposed males, however, engaged in less territorial marking when CTL males were present. These studies demonstrate that developmental BPA exposure can disrupt adult behaviors in a sex- and species-dependent manner and are consistent with the hypothesis that sexually selected traits are particularly vulnerable to endocrine disruption and should be a

  14. Psychological stress on female mice diminishes the developmental potential of oocytes: a study using the predatory stress model.

    Directory of Open Access Journals (Sweden)

    Yu-Xiang Liu

    Full Text Available Although the predatory stress experimental protocol is considered more psychological than the restraint protocol, it has rarely been used to study the effect of psychological stress on reproduction. Few studies exist on the direct effect of psychological stress to a female on developmental competence of her oocytes, and the direct effect of predatory maternal stress on oocytes has not been reported. In this study, a predatory stress system was first established for mice with cats as predators. Beginning 24 h after injection of equine chorionic gonadotropin, female mice were subjected to predatory stress for 24 h. Evaluation of mouse responses showed that the predatory stress system that we established increased anxiety-like behaviors and plasma cortisol concentrations significantly and continuously while not affecting food and water intake of the mice. In vitro experiments showed that whereas oocyte maturation and Sr(2+ activation or fertilization were unaffected by maternal predatory stress, rate of blastocyst formation and number of cells per blastocyst decreased significantly in stressed mice compared to non-stressed controls. In vivo embryo development indicated that both the number of blastocysts recovered per donor mouse and the average number of young per recipient after embryo transfer of blastocysts with similar cell counts were significantly lower in stressed than in unstressed donor mice. It is concluded that the predatory stress system we established was both effective and durative to induce mouse stress responses. Furthermore, predatory stress applied during the oocyte pre-maturation stage significantly impaired oocyte developmental potential while exerting no measurable impact on nuclear maturation, suggesting that cytoplasmic maturation of mouse oocytes was more vulnerable to maternal stress than nuclear maturation.

  15. Model My Watershed - A Robust Online App to Enable Citizen Scientists to Model Watershed Hydrology and Water Quality at Regulatory-Level Standards

    Science.gov (United States)

    Daniels, M.; Kerlin, S.; Arscott, D.

    2017-12-01

    Citizen-based watershed monitoring has historically lacked scientific rigor and geographic scope due to limitation in access to watershed-level data and the high level skills and resources required to adequately model watershed dynamics. Public access to watershed information is currently routed through a variety of governmental data portals and often requires advanced geospatial skills to collect and present in useable forms. At the same time, tremendous financial resources are being invested in watershed restoration and management efforts, and often these resources pass through local stakeholder groups such as conservation NGO, watershed interest groups, and local municipalities without extensive hydrologic knowledge or access to sophisticated modeling resources. Even governmental agencies struggle to understand how to best steer or prioritize restoration investments. A new app, Model My Watershed, was built to improve access to watershed data and modeling capabilities in a fast, accessible, free web-app format. Working across the contiguous United States, the Model My Watershed app provides land cover, soils, aerial imagery and relief, watershed delineation, and stream network delineation. Users can model watersheds or areas of interest and create management scenarios to evaluate implementation of land cover changes and best management practice implementation with both hydrologic and water quality outputs that meet TMDL regulatory standards.

  16. Alternative Payment Models in Radiology: The Legislative and Regulatory Roadmap for Reform.

    Science.gov (United States)

    Silva, Ezequiel; McGinty, Geraldine B; Hughes, Danny R; Duszak, Richard

    2016-10-01

    The Medicare Access and CHIP Reauthorization Act (MACRA) replaces the sustainable growth rate with a payment system based on the Merit-Based Incentive Payment System and incentives for alternative payment model participation. It is important that radiologists understand the statutory requirements of MACRA. This includes the nature of the Merit-Based Incentive Payment System composite performance score and its impact on payments. The timeline for MACRA implementation is fairly aggressive and includes a robust effort to define episode groups, which include radiologic services. A number of organizations, including the ACR, are commenting on the structure of MACRA-directed initiatives. Copyright © 2016 American College of Radiology. Published by Elsevier Inc. All rights reserved.

  17. Interdependent demands, regulatory constraint, and peak-load pricing. [Assessment of Bailey's model

    Energy Technology Data Exchange (ETDEWEB)

    Nguyen, D T; Macgregor-Reid, G J

    1977-06-01

    A model of a regulated firm which includes an analysis of peak-load pricing has been formulated by E. E. Bailey in which three alternative modes of regulation on a profit-maximizing firm are considered. The main conclusion reached is that under a regulation limiting the rate of return on capital investment, price reductions are received solely by peak-users and that when regulation limiting the profit per unit of output or the return on costs is imposed, there are price reductions for all users. Bailey has expressly assumed that the demands in different periods are interdependent but has somehow failed to derive the correct price and welfare implications of this empirically highly relevant assumption. Her conclusions would have been perfectly correct for marginal revenues but are quite incorrect for prices, even if her assumption that price exceeds marginal revenues in every period holds. This present paper derives fully and rigorously the implications of regulation for prices, outputs, capacity, and social welfare for a profit-maximizing firm with interdependent demands. In section II, Bailey's model is reproduced and the optimal conditions are given. In section III, it is demonstrated that under the conditions of interdependent demands assumed by Bailey herself, her often-quoted conclusion concerning the effects of the return-on-investment regulation on the off-peak price is invalid. In section IV, the effects of the return-on-investment regulation on the optimal prices, outputs, capacity, and social welfare both for the case in which the demands in different periods are substitutes and for the case in which they are complements are examined. In section V, the pricing and welfare implications of the return-on-investment regulation are compared with the two other modes of regulation considered by Bailey. Section VI is a summary of all sections. (MCW)

  18. The Domain of Developmental Psychopathology.

    Science.gov (United States)

    Sroufe, L. Alan; Rutter, Michael

    1984-01-01

    Describes how developmental psychopathology differs from related disciplines, including abnormal psychology, psychiatry, clinical child psychology, and developmental psychology. Points out propositions underlying a developmental perspective and discusses implications for research in developmental psychopathology. (Author/RH)

  19. Transcriptional signatures of ancient floral developmental genetics in avocado (Persea americana; Lauraceae).

    Science.gov (United States)

    Chanderbali, André S; Albert, Victor A; Leebens-Mack, Jim; Altman, Naomi S; Soltis, Douglas E; Soltis, Pamela S

    2009-06-02

    The debate on the origin and evolution of flowers has recently entered the field of developmental genetics, with focus on the design of the ancestral floral regulatory program. Flowers can differ dramatically among angiosperm lineages, but in general, male and female reproductive organs surrounded by a sterile perianth of sepals and petals constitute the basic floral structure. However, the basal angiosperm lineages exhibit spectacular diversity in the number, arrangement, and structure of floral organs, whereas the evolutionarily derived monocot and eudicot lineages share a far more uniform floral ground plan. Here we show that broadly overlapping transcriptional programs characterize the floral transcriptome of the basal angiosperm Persea americana (avocado), whereas floral gene expression domains are considerably more organ specific in the model eudicot Arabidopsis thaliana. Our findings therefore support the "fading borders" model for organ identity determination in basal angiosperm flowers and extend it from the action of regulatory genes to downstream transcriptional programs. Furthermore, the declining expression of components of the staminal transcriptome in central and peripheral regions of Persea flowers concurs with elements of a previous hypothesis for developmental regulation in a gymnosperm "floral progenitor." Accordingly, in contrast to the canalized organ-specific regulatory apparatus of Arabidopsis, floral development may have been originally regulated by overlapping transcriptional cascades with fading gradients of influence from focal to bordering organs.

  20. Investigating the state of physiologically based kinetic modelling practices and challenges associated with gaining regulatory acceptance of model applications

    Science.gov (United States)

    Physiologically based kinetic (PBK) models are used widely throughout a number of working sectors, including academia and industry, to provide insight into the dosimetry related to observed adverse health effects in humans and other species. Use of these models has increased over...

  1. Long-term consequences of developmental vascular defects on retinal vessel homeostasis and function in a mouse model of Norrie disease.

    Directory of Open Access Journals (Sweden)

    Susanne C Beck

    Full Text Available Loss of Norrin signalling due to mutations in the Norrie disease pseudoglioma gene causes severe vascular defects in the retina, leading to visual impairment and ultimately blindness. While the emphasis of experimental work so far was on the developmental period, we focus here on disease mechanisms that induce progression into severe adult disease. The goal of this study was the comprehensive analysis of the long-term effects of the absence of Norrin on vascular homeostasis and retinal function. In a mouse model of Norrie disease retinal vascular morphology and integrity were studied by means of in vivo angiography; the vascular constituents were assessed in detailed histological analyses using quantitative retinal morphometry. Finally, electroretinographic analyses were performed to assess the retinal function in adult Norrin deficient animals. We could show that the primary developmental defects not only persisted but developed into further vascular abnormalities and microangiopathies. In particular, the overall vessel homeostasis, the vascular integrity, and also the cellular constituents of the vascular wall were affected in the adult Norrin deficient retina. Moreover, functional analyses indicated to persistent hypoxia in the neural retina which was suggested as one of the major driving forces of disease progression. In summary, our data provide evidence that the key to adult Norrie disease are ongoing vascular modifications, driven by the persistent hypoxic conditions, which are ineffective to compensate for the primary Norrin-dependent defects.

  2. Long-term consequences of developmental vascular defects on retinal vessel homeostasis and function in a mouse model of Norrie disease.

    Science.gov (United States)

    Beck, Susanne C; Feng, Yuxi; Sothilingam, Vithiyanjali; Garcia Garrido, Marina; Tanimoto, Naoyuki; Acar, Niyazi; Shan, Shenliang; Seebauer, Britta; Berger, Wolfgang; Hammes, Hans-Peter; Seeliger, Mathias W

    2017-01-01

    Loss of Norrin signalling due to mutations in the Norrie disease pseudoglioma gene causes severe vascular defects in the retina, leading to visual impairment and ultimately blindness. While the emphasis of experimental work so far was on the developmental period, we focus here on disease mechanisms that induce progression into severe adult disease. The goal of this study was the comprehensive analysis of the long-term effects of the absence of Norrin on vascular homeostasis and retinal function. In a mouse model of Norrie disease retinal vascular morphology and integrity were studied by means of in vivo angiography; the vascular constituents were assessed in detailed histological analyses using quantitative retinal morphometry. Finally, electroretinographic analyses were performed to assess the retinal function in adult Norrin deficient animals. We could show that the primary developmental defects not only persisted but developed into further vascular abnormalities and microangiopathies. In particular, the overall vessel homeostasis, the vascular integrity, and also the cellular constituents of the vascular wall were affected in the adult Norrin deficient retina. Moreover, functional analyses indicated to persistent hypoxia in the neural retina which was suggested as one of the major driving forces of disease progression. In summary, our data provide evidence that the key to adult Norrie disease are ongoing vascular modifications, driven by the persistent hypoxic conditions, which are ineffective to compensate for the primary Norrin-dependent defects.

  3. Developmental changes in reading do not alter the development of visual processing skills: An application of explanatory item response models in grades K-2

    Directory of Open Access Journals (Sweden)

    Kristi L Santi

    2015-02-01

    Full Text Available Visual processing has been widely studied in regard to its impact on a students’ ability to read. A less researched area is the role of reading in the development of visual processing skills. A cohort-sequential, accelerated-longitudinal design was utilized with 932 kindergarten, first, and second grade students to examine the impact of reading acquisition on the processing of various types of visual discrimination and visual motor test items. Students were assessed four times per year on a variety of reading measures and reading precursors and two popular measures of visual processing over a three-year period. Explanatory item response models were used to examine the roles of person and item characteristics on changes in visual processing abilities and changes in item difficulties over time. Results showed different developmental patterns for five types of visual processing test items, but most importantly failed to show consistent effects of learning to read on changes in item difficulty. Thus, the present study failed to find support for the hypothesis that learning to read alters performance on measures of visual processing. Rather, visual processing and reading ability improved together over time with no evidence to suggest cross-domain influences from reading to visual processing. Results are discussed in the context of developmental theories of visual processing and brain-based research on the role of visual skills in learning to read.

  4. Measuring Developmental Students' Mathematics Anxiety

    Science.gov (United States)

    Ding, Yanqing

    2016-01-01

    This study conducted an item-level analysis of mathematics anxiety and examined the dimensionality of mathematics anxiety in a sample of developmental mathematics students (N = 162) by Multi-dimensional Random Coefficients Multinominal Logit Model (MRCMLM). The results indicate a moderately correlated factor structure of mathematics anxiety (r =…

  5. Combination Effect of Regulatory T-Cell Depletion and Ionizing Radiation in Mouse Models of Lung and Colon Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Son, Cheol-Hun [Dongnam Institute of Radiological and Medical Sciences, Busan (Korea, Republic of); Department of Biochemistry, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Bae, Jae-Ho [Department of Biochemistry, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Shin, Dong-Yeok; Lee, Hong-Rae; Jo, Wol-Soon; Yang, Kwangmo [Dongnam Institute of Radiological and Medical Sciences, Busan (Korea, Republic of); Park, You-Soo, E-mail: biotek01@hanmail.net [Dongnam Institute of Radiological and Medical Sciences, Busan (Korea, Republic of)

    2015-06-01

    Purpose: To investigate the potential of low-dose cyclophosphamide (LD-CTX) and anti-CD25 antibody to prevent activation of regulatory T cells (Tregs) during radiation therapy. Methods and Materials: We used LD-CTX and anti-CD25 monoclonal antibody as a means to inhibit Tregs and improve the therapeutic effect of radiation in a mouse model of lung and colon cancer. Mice were irradiated on the tumor mass of the right leg and treated with LD-CTX and anti-CD25 antibody once per week for 3 weeks. Results: Combined treatment of LD-CTX or anti-CD25 antibody with radiation significantly decreased Tregs in the spleen and tumor compared with control and irradiation only in both lung and colon cancer. Combinatorial treatments resulted in a significant increase in the effector T cells, longer survival rate, and suppressed irradiated and distal nonirradiated tumor growth. Specifically, the combinatorial treatment of LD-CTX with radiation resulted in outstanding regression of local and distant tumors in colon cancer, and almost all mice in this group survived until the end of the study. Conclusions: Our results suggest that Treg depletion strategies may enhance radiation-mediated antitumor immunity and further improve outcomes after radiation therapy.

  6. Chimeric Antigen Receptor-Redirected Regulatory T Cells Suppress Experimental Allergic Airway Inflammation, a Model of Asthma

    Directory of Open Access Journals (Sweden)

    Jelena Skuljec

    2017-09-01

    Full Text Available Cellular therapy with chimeric antigen receptor (CAR-redirected cytotoxic T cells has shown impressive efficacy in the treatment of hematologic malignancies. We explored a regulatory T cell (Treg-based therapy in the treatment of allergic airway inflammation, a model for asthma, which is characterized by an airway hyper-reactivity (AHR and a chronic, T helper-2 (Th2 cell-dominated immune response to allergen. To restore the immune balance in the lung, we redirected Tregs by a CAR toward lung epithelia in mice upon experimentally induced allergic asthma, closely mimicking the clinical situation. Adoptively transferred CAR Tregs accumulated in the lung and in tracheobronchial lymph nodes, reduced AHR and diminished eosinophilic airway inflammation, indicated by lower cell numbers in the bronchoalveolar lavage fluid and decreased cell infiltrates in the lung. CAR Treg cells furthermore prevented excessive pulmonary mucus production as well as increase in allergen-specific IgE and Th2 cytokine levels in exposed animals. CAR Tregs were more efficient in controlling asthma than non-modified Tregs, indicating the pivotal role of specific Treg cell activation in the affected organ. Data demonstrate that lung targeting CAR Treg cells ameliorate key features of experimental airway inflammation, paving the way for cell therapy of severe allergic asthma.

  7. Regulatory Anatomy

    DEFF Research Database (Denmark)

    Hoeyer, Klaus

    2015-01-01

    This article proposes the term “safety logics” to understand attempts within the European Union (EU) to harmonize member state legislation to ensure a safe and stable supply of human biological material for transplants and transfusions. With safety logics, I refer to assemblages of discourses, le...... they arise. In short, I expose the regulatory anatomy of the policy landscape....

  8. Regulatory Governance

    DEFF Research Database (Denmark)

    Kjær, Poul F.; Vetterlein, Antje

    2018-01-01

    Regulatory governance frameworks have become essential building blocks of world society. From supply chains to the regimes surrounding international organizations, extensive governance frameworks have emerged which structure and channel a variety of social exchanges, including economic, political...... by the International Transitional Administrations (ITAs) in Kosovo and Iraq as well as global supply chains and their impact on the garment industry in Bangladesh....

  9. DEVELOPMENTAL TAXONOMY OF CONDUCT DISORDER

    Directory of Open Access Journals (Sweden)

    Jelena Kostić

    2015-12-01

    Full Text Available Conduct disorder is a heterogeneous disorder in terms of etiology, course and prognosis, and currently, there is no singular model that would describe the development of the disorder. The results of empirical research on males confirm this heterogeneity, as they point out to two possible developmental pathways: childhood-onset and adolescentonset type. This paper presents the basic elements of developmental taxonomic theory which argues that there are two different developmental pathways to conduct disorder which have different causes and serve as the basis for the current typology of conduct disorders in the classification systems. Such a typology of conduct disorders in the diagnostic classification allows better understanding, prognosis and choice of treatment.

  10. A feedback regulatory model for RifQ-mediated repression of rifamycin export in Amycolatopsis mediterranei.

    Science.gov (United States)

    Lei, Chao; Wang, Jingzhi; Liu, Yuanyuan; Liu, Xinqiang; Zhao, Guoping; Wang, Jin

    2018-01-29

    Due to the important role of rifamycin in curing tuberculosis infection, the study on rifamycin has never been stopped. Although RifZ, which locates within the rifamycin biosynthetic cluster, has recently been characterized as a pathway-specific regulator for rifamycin biosynthesis, little is known about the regulation of rifamycin export. In this work, we proved that the expression of the rifamycin efflux pump (RifP) was regulated by RifQ, a TetR-family transcriptional regulator. Deletion of rifQ had little impact on bacterial growth, but resulted in improved rifamycin production, which was consistent with the reverse transcription PCR results that RifQ negatively regulated rifP's transcription. With electrophoretic mobility shift assay and DNase I Footprinting assay, RifQ was found to directly bind to the promoter region of rifP, and a typical inverted repeat was identified within the RifQ-protected sequences. The transcription initiation site of rifP was further characterized and found to be upstream of the RifQ binding sites, well explaining the RifQ-mediated repression of rifP's transcription in vivo. Moreover, rifamycin B (the end product of rifamycin biosynthesis) remarkably decreased the DNA binding affinity of RifQ, which led to derepression of rifamycin export, reducing the intracellular concentration of rifamycin B as well as its toxicity against the host. Here, we proved that the export of rifamycin B was repressed by RifQ in Amycolatopsis mediterranei, and the RifQ-mediated repression could be specifically relieved by rifamycin B, the end product of rifamycin biosynthesis, based on which a feedback model was proposed for regulation of rifamycin export. With the findings here, one could improve the antibiotic yield by simply inactivating the negative regulator of the antibiotic transporter.

  11. Class I histone deacetylase inhibitor entinostat suppresses regulatory T cells and enhances immunotherapies in renal and prostate cancer models.

    Directory of Open Access Journals (Sweden)

    Li Shen

    Full Text Available Immunosuppressive factors such as regulatory T cells (Tregs limit the efficacy of immunotherapies. Histone deacetylase (HDAC inhibitors have been reported to have antitumor activity in different malignancies and immunomodulatory effects. Herein, we report the Tregs-targeting and immune-promoting effect of a class I specific HDAC inhibitor, entinostat, in combination with either IL-2 in a murine renal cell carcinoma (RENCA model or a survivin-based vaccine therapy (SurVaxM in a castration resistant prostate cancer (CR Myc-CaP model.RENCA or CR Myc-CaP tumors were implanted orthotopically or subcutaneously, respectively. Inoculated mice were randomized into four treatment groups: vehicle, entinostat, cytokine or vaccine, and combination. Tregs in the blood were assessed by FACS analysis. Real time quantitative PCR and Western blot analysis of isolated T cell subpopulations from spleen were performed to determine Foxp3 gene and protein expression. The suppressive function of Tregs was tested by T cell proliferation assay. Low dose (5 mg/kg entinostat reduced Foxp3 levels in Tregs and this was associated with enhanced tumor growth inhibition in combination with either IL-2 or a SurVaxM vaccine. Entinostat down-regulated Foxp3 expression transcriptionally and blocked Tregs suppressive function without affecting T effector cells (Teffs. In vitro low dose entinostat (0.5 µM induced STAT3 acetylation and a specific inhibitor of STAT3 partially rescued entinostat-induced down-regulation of Foxp3, suggesting that STAT3 signaling is involved in Foxp3 down-regulation by entinostat.These results demonstrate a novel immunomodulatory effect of class I HDAC inhibition and provide a rationale for the clinical testing of entinostat to enhance cancer immunotherapy.

  12. Distinguishing epigenetic marks of developmental and imprinting regulation

    Directory of Open Access Journals (Sweden)

    McEwen Kirsten R

    2010-01-01

    Full Text Available Abstract Background The field of epigenetics is developing rapidly, however we are only beginning to comprehend the complexity of its influence on gene regulation. Using genomic imprinting as a model we examine epigenetic profiles associated with different forms of gene regulation. Imprinting refers to the expression of a gene from only one of the chromosome homologues in a parental-origin-specific manner. This is dependent on heritable germline epigenetic control at a cis-acting imprinting control region that influences local epigenetic states. Epigenetic modifications associated with imprinting regulation can be compared to those associated with the more canonical developmental regulation, important for processes such as differentiation and tissue specificity. Here we test the hypothesis that these two mechanisms are associated with different histone modification enrichment patterns. Results Using high-throughput data extraction with subsequent analysis, we have found that particular histone modifications are more likely to be associated with either imprinting repression or developmental repression of imprinted genes. H3K9me3 and H4K20me3 are together enriched at imprinted genes with differentially methylated promoters and do not show a correlation with developmental regulation. H3K27me3 and H3K4me3, however, are more often associated with developmental regulation. We find that imprinted genes are subject to developmental regulation through bivalency with H3K4me3 and H3K27me3 enrichment on the same allele. Furthermore, a specific tri-mark signature comprising H3K4me3, H3K9me3 and H4K20me3 has been identified at all imprinting control regions. Conclusion A large amount of data is produced from whole-genome expression and epigenetic profiling studies of cellular material. We have shown that such publicly available data can be mined and analysed in order to generate novel findings for categories of genes or regulatory elements. Comparing two

  13. Social visual engagement in infants and toddlers with autism: early developmental transitions and a model of pathogenesis.

    Science.gov (United States)

    Klin, Ami; Shultz, Sarah; Jones, Warren

    2015-03-01

    Efforts to determine and understand the causes of autism are currently hampered by a large disconnect between recent molecular genetics findings that are associated with the condition and the core behavioral symptoms that define the condition. In this perspective piece, we propose a systems biology framework to bridge that gap between genes and symptoms. The framework focuses on basic mechanisms of socialization that are highly-conserved in evolution and are early-emerging in development. By conceiving of these basic mechanisms of socialization as quantitative endophenotypes, we hope to connect genes and behavior in autism through integrative studies of neurodevelopmental, behavioral, and epigenetic changes. These changes both lead to and are led by the accomplishment of specific social adaptive tasks in a typical infant's life. However, based on recent research that indicates that infants later diagnosed with autism fail to accomplish at least some of these tasks, we suggest that a narrow developmental period, spanning critical transitions from reflexive, subcortically-controlled visual behavior to interactional, cortically-controlled and social visual behavior be prioritized for future study. Mapping epigenetic, neural, and behavioral changes that both drive and are driven by these early transitions may shed a bright light on the pathogenesis of autism. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. A software tool to model genetic regulatory networks. Applications to the modeling of threshold phenomena and of spatial patterning in Drosophila.

    Directory of Open Access Journals (Sweden)

    Rui Dilão

    Full Text Available We present a general methodology in order to build mathematical models of genetic regulatory networks. This approach is based on the mass action law and on the Jacob and Monod operon model. The mathematical models are built symbolically by the Mathematica software package GeneticNetworks. This package accepts as input the interaction graphs of the transcriptional activators and repressors of a biological process and, as output, gives the mathematical model in the form of a system of ordinary differential equations. All the relevant biological parameters are chosen automatically by the software. Within this framework, we show that concentration dependent threshold effects in biology emerge from the catalytic properties of genes and its associated conservation laws. We apply this methodology to the segment patterning in Drosophila early development and we calibrate the genetic transcriptional network responsible for the patterning of the gap gene proteins Hunchback and Knirps, along the antero-posterior axis of the Drosophila embryo. In this approach, the zygotically produced proteins Hunchback and Knirps do not diffuse along the antero-posterior axis of the embryo of Drosophila, developing a spatial pattern due to concentration dependent thresholds. This shows that patterning at the gap genes stage can be explained by the concentration gradients along the embryo of the transcriptional regulators.

  15. Developmental Change in a Spatial Task of Attentional Capacity: An Essay toward an Integration of Two Working Memory Models.

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    de Ribaupierre, Anik; Bailleux, Christine

    1994-01-01

    Attempts the theoretical rapprochement of two theoretical constructs on working memory, neo-Piagetian models and Baddeley's model. Summarizes both types of models, then discusses their similarities and differences. Presents the results of a longitudinal study that supported the idea that these models might be complementary rather than…

  16. Use of 3D printer model to study vertebral artery anatomy and variations in developmental craniovertebral junction anomalies and as a preoperative tool-an institutional experience.

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    Chhabra, Sachin; Chopra, Sanjeev; Kataria, Rashim; Sinha, Virendra Deo

    2017-12-01

    Spinal instrumentation using rods and screws have become procedure of choice for posterior fixation. Vertebral artery anatomy is highly variable in this region posing challenges during surgery. Our study used 3D printer model to understand the anatomy and variations in vertebral artery in live patients thereby providing an accurate idea about vertebral artery injury risk in these patients preoperatively and to rehearse the whole procedure. Ten patients of developmental craniovertebral junction (CVJ) anomalies who were planned for operative intervention in the Department of Neurosurgery at SMS Hospital from February 2016 to December 2016 were analysed using a 3D printer model. Out of twenty vertebral arteries studied in ten patients, two were hypoplastic and out of these one could not be appreciated on 3D printer model. Out of remaining nineteen, thirteen arteries were found to lie outside the joint, three were in lateral third, one traversed the middle third of joint and one lied in medial third. In one patient, the vertebral artery was stretched and it traversed horizontally over the joint. Out of ten patients studied, nine were having occipitalised atlas and so entry of these vertebral arteries into cranium were classified as given by Wang et al. into four types. By our study, 3D printer model was extremely helpful in analyzing joints and vertebral artery preoperatively and making the surgeon acquainted about the placement and trajectory of the screws accordingly. In our opinion, these models should be included as a basic investigation tool in these patients.

  17. Multilevel risk factors and developmental assets for internalizing symptoms and self-esteem in disadvantaged adolescents: modeling longitudinal trajectories from the Rural Adaptation Project.

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    Smokowski, Paul R; Guo, Shenyang; Rose, Roderick; Evans, Caroline B R; Cotter, Katie L; Bacallao, Martica

    2014-11-01

    The current study filled significant gaps in our knowledge of developmental psychopathology by examining the influence of multilevel risk factors and developmental assets on longitudinal trajectories of internalizing symptoms and self-esteem in an exceptionally culturally diverse sample of rural adolescents. Integrating ecological and social capital theories, we explored if positive microsystem transactions are associated with self-esteem while negative microsystem transactions increase the chances of internalizing problems. Data came from the Rural Adaptation Project, a 5-year longitudinal panel study of more than 4,000 middle school students from 28 public schools in two rural, disadvantaged counties in North Carolina. Three-level hierarchical linear modeling models were estimated to predict internalizing symptoms (e.g., depression, anxiety) and self-esteem. Relative to other students, risk for internalizing problems and low self-esteem was elevated for aggressive adolescents, students who were hassled or bullied at school, and those who were rejected by peers or in conflict with their parents. Internalizing problems were also more common among adolescents from socioeconomically disadvantaged families and neighborhoods, among those in schools with more suspensions, in students who reported being pressured by peers, and in youth who required more teacher support. It is likely that these experiences left adolescents disengaged from developing social capital from ecological microsystems (e.g., family, school, peers). On the positive side, support from parents and friends and optimism about the future were key assets associated with lower internalizing symptoms and higher self-esteem. Self-esteem was also positively related to religious orientation, school satisfaction, and future optimism. These variables show active engagement with ecological microsystems. The implications and limitations were discussed.

  18. Fitness consequences of maternal and embryonic responses to environmental variation: using reptiles as models for studies of developmental plasticity.

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    Warner, Daniel A

    2014-11-01

    Environmental factors strongly influence phenotypic variation within populations. The environment contributes to this variation in two ways: (1) by acting as a determinant of phenotypic variation (i.e., plastic responses) and (2) as an agent of selection that "chooses" among existing phenotypes. Understanding how these two environmental forces contribute to phenotypic variation is a major goal in the field of evolutionary biology and a primary objective of my research program. The objective of this article is to provide a framework to guide studies of environmental sources of phenotypic variation (specifically, developmental plasticity and maternal effects, and their adaptive significance). Two case studies from my research on reptiles are used to illustrate the general approaches I have taken to address these conceptual topics. Some key points for advancing our understanding of environmental influences on phenotypic variation include (1) merging laboratory-based research that identifies specific environmental effects with field studies to validate ecological relevance; (2) using controlled experimental approaches that mimic complex environments found in nature; (3) integrating data across biological fields (e.g., genetics, morphology, physiology, behavior, and ecology) under an evolutionary framework to provide novel insights into the underlying mechanisms that generate phenotypic variation; (4) assessing fitness consequences using measurements of survival and/or reproductive success across ontogeny (from embryos to adults) and under multiple ecologically-meaningful contexts; and (5) quantifying the strength and form of natural selection in multiple populations over multiple periods of time to understand the spatial and temporal consistency of phenotypic selection. Research programs that focus on organisms that are amenable to these approaches will provide the most promise for advancing our understanding of the environmental factors that generate the remarkable

  19. Comparative transcriptional profiling of 3 murine models of SLE nephritis reveals both unique and shared regulatory networks.

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    Ramalingam Bethunaickan

    Full Text Available To define shared and unique features of SLE nephritis in mouse models of proliferative and glomerulosclerotic renal disease.Perfused kidneys from NZB/W F1, NZW/BXSB and NZM2410 mice were harvested before and after nephritis onset. Affymetrix based gene expression profiles of kidney RNA were analyzed using Genomatix Pathway Systems and Ingenuity Pathway Analysis software. Gene expression patterns were confirmed using real-time PCR.955, 1168 and 755 genes were regulated in the kidneys of nephritic NZB/W F1, NZM2410 and NZW/BXSB mice respectively. 263 genes were regulated concordantly in all three strains reflecting immune cell infiltration, endothelial cell activation, complement activation, cytokine signaling, tissue remodeling and hypoxia. STAT3 was the top associated transcription factor, having a binding site in the gene promoter of 60/263 regulated genes. The two strains with proliferative nephritis shared a macrophage/DC infiltration and activation signature. NZB/W and NZM2410 mice shared a mitochondrial dysfunction signature. Dominant T cell and plasma cell signatures in NZB/W mice reflected lymphoid aggregates; this was the only strain with regulatory T cell infiltrates. NZW/BXSB mice manifested tubular regeneration and NZM2410 mice had the most metabolic stress and manifested loss of nephrin, indicating podocyte loss.These findings identify shared inflammatory mechanisms of SLE nephritis that can be therapeutically targeted. Nevertheless, the heterogeneity of effector mechanisms suggests that individualized therapy might need to be based on biopsy findings. Some common mechanisms are shared with non-immune-mediated renal diseases, suggesting that strategies to prevent tissue hypoxia and remodeling may be useful in SLE nephritis.

  20. Simulating molecular mechanisms of the MDM2-mediated regulatory interactions: a conformational selection model of the MDM2 lid dynamics.

    Directory of Open Access Journals (Sweden)

    Gennady M Verkhivker

    Full Text Available Diversity and complexity of MDM2 mechanisms govern its principal function as the cellular antagonist of the p53 tumor suppressor. Structural and biophysical studies have demonstrated that MDM2 binding could be regulated by the dynamics of a pseudo-substrate lid motif. However, these experiments and subsequent computational studies have produced conflicting mechanistic models of MDM2 function and dynamics. We propose a unifying conformational selection model that can reconcile experimental findings and reveal a fundamental role of the lid as a dynamic regulator of MDM2-mediated binding. In this work, structure, dynamics and energetics of apo-MDM2 are studied as a function of posttranslational modifications and length of the lid. We found that the dynamic equilibrium between "closed" and "semi-closed" lid forms may be a fundamental characteristic of MDM2 regulatory interactions, which can be modulated by phosphorylation, phosphomimetic mutation as well as by the lid size. Our results revealed that these factors may regulate p53-MDM2 binding by fine-tuning the thermodynamic equilibrium between preexisting conformational states of apo-MDM2. In agreement with NMR studies, the effect of phosphorylation on MDM2 interactions was more pronounced with the truncated lid variant that favored the thermodynamically dominant closed form. The phosphomimetic mutation S17D may alter the lid dynamics by shifting the thermodynamic equilibrium towards the ensemble of "semi-closed" conformations. The dominant "semi-closed" lid form and weakened dependence on the phosphorylation seen in simulations with the complete lid can provide a rationale for binding of small p53-based mimetics and inhibitors without a direct competition with the lid dynamics. The results suggested that a conformational selection model of preexisting MDM2 states may provide a robust theoretical framework for understanding MDM2 dynamics. Probing biological functions and mechanisms of MDM2

  1. Electricity pricing policy: A neo-institutional, developmental and cross-national policy design map

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    Koundinya, Sridarshan Umesh

    This dissertation explores the role of ideas and ideology in the mental policy design maps of regulators in the US and in India. The research approach is to describe the regulatory design process in the history of the US electric industry from a neo-institutional and developmental perspective. And then to use the insights of such a study to suggest policy options to a sample of Indian experts. A regulatory process model explores the interactions among normative values, regulatory instruments and historical phases in policy design. A spectrum of seven regulatory instruments--subsidized rates, average cost pricing, marginal cost pricing, time-of-use pricing, ramsey pricing, incentive regulation and spot pricing is examined. A neo-institutional perspective characterizes the process of institutionalizing these regulatory instruments as a design process that infuses them with values beyond mere technical requirements. The process model includes normative values such as efficiency, fairness, free choice and political feasibility. These values arise from an analytical classification of various market metaphors debated in the history of economic thought. The theory of development and co-evolution applied to the history of electricity regulation yields a typology of evolutionary phases in the US. The typology describes hierarchically emergent relationships between supply and demand and among the normative values. The theory hypothesizes technologically contingent relationships between pricing policies and normative values in the historical phases of dependence (or rural), independence (or urban) and interdependence (or informational). The contents of this model are represented as related elements in a policy design map that simplifies the process of designing regulatory instruments in the US. This neo-institutional, developmental policy design map was used to design a survey instrument. The survey was conducted among electricity experts in India to test the hypothesized

  2. 20170312 - Computer Simulation of Developmental ...

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    Rationale: Recent progress in systems toxicology and synthetic biology have paved the way to new thinking about in vitro/in silico modeling of developmental processes and toxicities, both for embryological and reproductive impacts. Novel in vitro platforms such as 3D organotypic culture models, engineered microscale tissues and complex microphysiological systems (MPS), together with computational models and computer simulation of tissue dynamics, lend themselves to a integrated testing strategies for predictive toxicology. As these emergent methodologies continue to evolve, they must be integrally tied to maternal/fetal physiology and toxicity of the developing individual across early lifestage transitions, from fertilization to birth, through puberty and beyond. Scope: This symposium will focus on how the novel technology platforms can help now and in the future, with in vitro/in silico modeling of complex biological systems for developmental and reproductive toxicity issues, and translating systems models into integrative testing strategies. The symposium is based on three main organizing principles: (1) that novel in vitro platforms with human cells configured in nascent tissue architectures with a native microphysiological environments yield mechanistic understanding of developmental and reproductive impacts of drug/chemical exposures; (2) that novel in silico platforms with high-throughput screening (HTS) data, biologically-inspired computational models of

  3. Friendship in school-age boys with autism spectrum disorders: A meta-analytic summary and developmental, process-based model.

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    Mendelson, Jenna L; Gates, Jacquelyn A; Lerner, Matthew D

    2016-06-01

    Friendship-making is considered a well-established domain of deficit for children with autism spectrum disorders (ASD; American Psychiatric Association, 2013), with this population sometimes described as incapable of making friends. However, the majority of children with ASD indicate a desire for friends, and many report having friends. To what degree, then, do youth with ASD succeed in achieving friendships with peers? If and when they do succeed, by what means do these friendships emerge relative to models of typically developing (TD) youths' friendships? To address these questions, we first meta-analyzed the descriptive friendship literature (peer-reported sociometrics, self-report, parent-report) among school-age boys with ASD. Using random effects models, we found that youth with ASD do make friends according to peers and parents (Hedges's g > 2.84). However, self-reported friendship quality (Hedges's g = -1.09) and parent- and peer-reported quantity (Hedges's g friendship in TD youth (Hartup & Stevens, 1997). We then present a model that synthesizes these domains through the construct of social information processing speed, and thereby present the first developmental, process-based model of friendship development among youth with ASD. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  4. Low-dose ionizing radiation limitations to seed germination: Results from a model linking physiological characteristics and developmental-dynamics simulation strategy.

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    Liu, Hui; Hu, Dawei; Dong, Chen; Fu, Yuming; Liu, Guanghui; Qin, Youcai; Sun, Yi; Liu, Dianlei; Li, Lei; Liu, Hong

    2017-08-01

    There is much uncertainty about the risks of seed germination after repeated or protracted environmental low-dose ionizing radiation exposure. The purpose of this study is to exp