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Sample records for modelling genetic regulation

  1. Nonlinear software sensor for monitoring genetic regulation processes with noise and modeling errors

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    Ibarra-Junquera, V; Rosu, H C; Arguello, G; Collado-Vides, J

    2004-01-01

    Nonlinear control techniques by means of a software sensor that are commonly used in chemical engineering could be also applied to genetic regulation processes. We provide here a realistic formulation of this procedure by introducing an additive white Gaussian noise, which is usually found in experimental data. Besides, we include model errors, meaning that we assume we do not know the nonlinear regulation function of the process. In order to illustrate this procedure, we employ the Goodwin dynamics of the concentrations (1963) in the simple form recently discussed by De Jong (2002), which involves the dynamics of the mRNA a, given protein A, and metabolite K concentrations. However instead of considering their full dynamics, we use only the data of metabolite K and a designed software sensor. We also show, more generally, that it is possible to rebuild the complete set of n concentrations despite the uncertainties in the regulation function and the perturbation due to the additive white Gaussian noise

  2. Dynamics Analysis and Prediction of Genetic Regulation in Glycerol Metabolic Network via Structural Kinetic Modelling

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    Jianxiong Ye

    2015-01-01

    Full Text Available Glycerol can be biologically converted to 1,3-propanediol (1,3-PD by Klebsiella pneumoniae. In the synthesis pathway of 1,3-PD, the accumulation of an intermediary metabolite 3-hydroxypropionaldehyde (3-HPA would cause an irreversible cessation of the dynamic system. Genetic manipulation on the key enzymes which control the formation rate and consumption rate of 3-HPA would decrease the accumulation of 3-HPA, resulting in nonlinear regulation on the dynamic system. The interest of this work is to focus on analyzing the influence of 3-HPA inhibition on the stability of the dynamic system. Due to the lack of intracellular knowledge, structural kinetic modelling is applied. On the basis of statistical account of the dynamical capabilities of the system in the parameter space, we conclude that, under weak or no inhibition to the reaction of 3-HPA consumption, the system is much easier to obtain a stable state, whereas strong inhibition to its formation is in favor of stabilizing the system. In addition, the existence of Hopf bifurcation in this system is also verified. The obtained results are helpful for deeply understanding the metabolic and genetic regulations of glycerol fermentation by Klebsiella pneumoniae.

  3. Stochastic models for inferring genetic regulation from microarray gene expression data.

    Science.gov (United States)

    Tian, Tianhai

    2010-03-01

    Microarray expression profiles are inherently noisy and many different sources of variation exist in microarray experiments. It is still a significant challenge to develop stochastic models to realize noise in microarray expression profiles, which has profound influence on the reverse engineering of genetic regulation. Using the target genes of the tumour suppressor gene p53 as the test problem, we developed stochastic differential equation models and established the relationship between the noise strength of stochastic models and parameters of an error model for describing the distribution of the microarray measurements. Numerical results indicate that the simulated variance from stochastic models with a stochastic degradation process can be represented by a monomial in terms of the hybridization intensity and the order of the monomial depends on the type of stochastic process. The developed stochastic models with multiple stochastic processes generated simulations whose variance is consistent with the prediction of the error model. This work also established a general method to develop stochastic models from experimental information.

  4. Genetic regulation of bone strength: a review of animal model studies.

    Science.gov (United States)

    Adams, Douglas J; Ackert-Bicknell, Cheryl L

    2015-01-01

    Population- and family-based studies have established that fragility fracture risk is heritable; yet, the genome-wide association studies published to date have only accounted for a small fraction of the known variation for fracture risk of either the femur or the lumbar spine. Much work has been carried out using animal models toward finding genetic loci that are associated with bone strength. Studies using animal models overcome some of the issues associated with using patient data, but caution is needed when interpreting the results. In this review, we examine the types of tests that have been used for forward genetics mapping in animal models to identify loci and/or genes that regulate bone strength and discuss the limitations of these test methods. In addition, we present a summary of the quantitative trait loci that have been mapped for bone strength in mice, rats and chickens. The majority of these loci co-map with loci for bone size and/or geometry and thus likely dictate strength via modulating bone size. Differences in bone matrix composition have been demonstrated when comparing inbred strains of mice, and these matrix differences may be associated with differences in bone strength. However, additional work is needed to identify loci that act on bone strength at the materials level.

  5. Nonlinear software sensor for monitoring genetic regulation processes with noise and modeling errors

    Science.gov (United States)

    Ibarra-Junquera, V.; Torres, L. A.; Rosu, H. C.; Argüello, G.; Collado-Vides, J.

    2005-07-01

    Nonlinear control techniques by means of a software sensor that are commonly used in chemical engineering could be also applied to genetic regulation processes. We provide here a realistic formulation of this procedure by introducing an additive white Gaussian noise, which is usually found in experimental data. Besides, we include model errors, meaning that we assume we do not know the nonlinear regulation function of the process. In order to illustrate this procedure, we employ the Goodwin dynamics of the concentrations [B. C. Goodwin, Temporal Oscillations in Cells (Academic, New York, 1963)] in the simple form recently applied to single gene systems and some operon cases [H. De Jong, J. Comput. Biol. 9, 67 (2002)], which involves the dynamics of the mRNA, given protein and metabolite concentrations. Further, we present results for a three gene case in coregulated sets of transcription units as they occur in prokaryotes. However, instead of considering their full dynamics, we use only the data of the metabolites and a designed software sensor. We also show, more generally, that it is possible to rebuild the complete set of nonmeasured concentrations despite the uncertainties in the regulation function or, even more, in the case of not knowing the mRNA dynamics. In addition, the rebuilding of concentrations is not affected by the perturbation due to the additive white Gaussian noise and also we managed to filter the noisy output of the biological system.

  6. Modelling genetic regulation of growth and form in a branching sponge.

    Science.gov (United States)

    Kaandorp, Jaap A; Blom, Joke G; Verhoef, Jozef; Filatov, Max; Postma, M; Müller, Werner E G

    2008-11-22

    We present a mathematical model of the genetic regulation controlling skeletogenesis and the influence of the physical environment on a branching sponge with accretive growth (e.g. Haliclona oculata or Lubomirskia baikalensis). From previous work, it is known that high concentrations of silicate induce spicule formation and upregulate the silicatein gene. The upregulation of this gene activates locally the production of spicules in the sponge and the deposition of the skeleton. Furthermore, it is known that the expression of the gene Iroquois induces the formation of an aquiferous system, consisting of exhalant and inhalant pores. We propose a model of the regulatory network controlling the separation in time and space of the skeletogenesis and the formation of the aquiferous system. The regulatory network is closely linked with environmental influences. In building a skeleton, silicate is absorbed from the environment. In our model, silicate is transported by diffusion through the environment and absorbed at the surface of a geometric model of the sponge, resulting in silicate gradients emerging in the neighbourhood of the sponge. Our model simulations predict sponge morphology and the positioning of the exhalant pores over the surface of the sponge.

  7. Interpreting microarray data to build models of microbial genetic regulation networks

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    Sokhansanj, Bahrad A.; Garnham, Janine B.; Fitch, J. Patrick

    2002-06-01

    Microarrays and DNA chips are an efficient, high-throughput technology for measuring temporal changes in the expression of message RNA (mRNA) from thousands of genes (often the entire genome of an organism) in a single experiment. A crucial drawback of microarray experiments is that results are inherently qualitative: data are generally neither quantitatively repeatable, nor may microarray spot intensities be calibrated to in vivo mRNA concentrations. Nevertheless, microarrays represent by the far the cheapest and fastest way to obtain information about a cell's global genetic regulatory networks. Besides poor signal characteristics, the massive number of data produced by microarray experiments pose challenges for visualization, interpretation and model building. Towards initial model development, we have developed a Java tool for visualizing the spatial organization of gene expression in bacteria. We are also developing an approach to inferring and testing qualitative fuzzy logic models of gene regulation using microarray data. Because we are developing and testing qualitative hypotheses that do not require quantitative precision, our statistical evaluation of experimental data is limited to checking for validity and consistency. Our goals are to maximize the impact of inexpensive microarray technology, bearing in mind that biological models and hypotheses are typically qualitative.

  8. Interpreting Microarray Data to Build Models of Microbial Genetic Regulation Networks

    Energy Technology Data Exchange (ETDEWEB)

    Sokhansanj, B; Garnham, J B; Fitch, J P

    2002-01-23

    Microarrays and DNA chips are an efficient, high-throughput technology for measuring temporal changes in the expression of message RNA (mRNA) from thousands of genes (often the entire genome of an organism) in a single experiment. A crucial drawback of microarray experiments is that results are inherently qualitative: data are generally neither quantitatively repeatable, nor may microarray spot intensities be calibrated to in vivo mRNA concentrations. Nevertheless, microarrays represent by the far the cheapest and fastest way to obtain information about a cells global genetic regulatory networks. Besides poor signal characteristics, the massive number of data produced by microarray experiments poses challenges for visualization, interpretation and model building. Towards initial model development, we have developed a Java tool for visualizing the spatial organization of gene expression in bacteria. We are also developing an approach to inferring and testing qualitative fuzzy logic models of gene regulation using microarray data. Because we are developing and testing qualitative hypotheses that do not require quantitative precision, our statistical evaluation of experimental data is limited to checking for validity and consistency. Our goals are to maximize the impact of inexpensive microarray technology, bearing in mind that biological models and hypotheses are typically qualitative.

  9. Modeling host genetic regulation of influenza pathogenesis in the collaborative cross.

    Directory of Open Access Journals (Sweden)

    Martin T Ferris

    2013-02-01

    Full Text Available Genetic variation contributes to host responses and outcomes following infection by influenza A virus or other viral infections. Yet narrow windows of disease symptoms and confounding environmental factors have made it difficult to identify polymorphic genes that contribute to differential disease outcomes in human populations. Therefore, to control for these confounding environmental variables in a system that models the levels of genetic diversity found in outbred populations such as humans, we used incipient lines of the highly genetically diverse Collaborative Cross (CC recombinant inbred (RI panel (the pre-CC population to study how genetic variation impacts influenza associated disease across a genetically diverse population. A wide range of variation in influenza disease related phenotypes including virus replication, virus-induced inflammation, and weight loss was observed. Many of the disease associated phenotypes were correlated, with viral replication and virus-induced inflammation being predictors of virus-induced weight loss. Despite these correlations, pre-CC mice with unique and novel disease phenotype combinations were observed. We also identified sets of transcripts (modules that were correlated with aspects of disease. In order to identify how host genetic polymorphisms contribute to the observed variation in disease, we conducted quantitative trait loci (QTL mapping. We identified several QTL contributing to specific aspects of the host response including virus-induced weight loss, titer, pulmonary edema, neutrophil recruitment to the airways, and transcriptional expression. Existing whole-genome sequence data was applied to identify high priority candidate genes within QTL regions. A key host response QTL was located at the site of the known anti-influenza Mx1 gene. We sequenced the coding regions of Mx1 in the eight CC founder strains, and identified a novel Mx1 allele that showed reduced ability to inhibit viral replication

  10. Analysis of genetic regulation of chicken spontaneous autoimmune thyroiditis, an animal model of human Hashimoto's thyroiditis.

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    Vasícek, D; Vasícková, K; Kaiser, P; Drozenová, R; Cítek, J; Hala, K

    2001-12-01

    We analyzed the genetic regulation of spontaneous autoimmune thyroiditis (SAT) by means of crosses between Obese strain (OS) chickens with the disease, and healthy inbred chicken of line CB. Mononuclear cell infiltration of the thyroid was used as a criterion for the disease. We confirmed the existence of one recessive gene, regulating the susceptibility of the thyroid gland to autoimmune attack. From the frequency of progeny with the thyroid infiltration in backcross and F2 generations, we presume the existence of one or two additional dominant genes coding for abnormal reactivity of the immune system. The total number of genes regulating SAT is therefore a maximum of three. We attempted to identify disease-specific transcripts responsible for the initiation of the disease using suppression subtractive hybridization of RNA prepared from OS and CB thyroid lobes, obtained from 3-day-old chicks. From forward and reverse subtractions, we recovered a fragment mixture in the range of 300 bp to 1.5 kb. In total, 768 clones were screened and 9 were sequenced. Four of them represent unknown sequences. Two, specific for OS thyroid, correspond to envelope genes of avian endogenous viruses (ev)-1, -3 and -6. The expressed product of an env gene could be iodinated in the thyroid gland and become involved in thyroglobulin metabolism. This may be another possible mechanism driving SAT, as iodine modulates SAT in the chicken. Further experiments will be required to prove this hypothesis. Two thyroid-specific clones had significant alignment to human thyroglobulin, and one clone to human coatomer protein. We analyzed, by RFLP and RNA dot blots, cosegregation between clones for the env gene of endogenous viruses as the most promising candidate for involvement in driving SAT; we did not find differences at the DNA and RNA levels. We can possibly therefore rule out a simple involvement of env genes with the initiation of disease.

  11. The common sense model of self-regulation and psychological adjustment to predictive genetic testing: a prospective study.

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    van Oostrom, Iris; Meijers-Heijboer, Hanne; Duivenvoorden, Hugo J; Bröcker-Vriends, Annette H J T; van Asperen, Christi J; Sijmons, Rolf H; Seynaeve, Caroline; Van Gool, Arthur R; Klijn, Jan G M; Tibben, Aad

    2007-12-01

    This prospective study explored the contribution of illness representations and coping to cancer-related distress in unaffected individuals undergoing predictive genetic testing for an identified mutation in BRCA1/2 (BReast CAncer) or an HNPCC (Hereditary Nonpolyposis Colorectal Cancer)-related gene, based on the common sense model of self-regulation. Coping with hereditary cancer (UCL), illness representations (IPQ-R) and risk perception were assessed in 235 unaffected applicants for genetic testing before test result disclosure. Hereditary cancer distress (IES) and cancer worry (CWS) were assessed before, 2 weeks after and 6 months after result disclosure. Timeline (r = 0.30), consequences (r = 0.25), illness coherence (r = 0.21) and risk perception (r = 0.20) were significantly correlated to passive coping. Passive coping predicted hereditary cancer distress and cancer worry from pre-test (beta = 0.46 and 0.42, respectively) up to 6 months after result disclosure (beta = 0.32 and 0.19, respectively). Illness coherence predicted hereditary cancer distress up to 6 months after result disclosure (beta = 0.24), too. The self-regulatory model may be useful to predict the cognitive and emotional reactions to genetic cancer susceptibility testing. Identifying unhelpful representations and cognitive restructuring may be appropriate interventions to help distressed individuals undergoing genetic susceptibility testing for a BRCA1/2 or a HNPCC-related mutation.

  12. Mechanistic Modeling of Genetic Circuits for ArsR Arsenic Regulation.

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    Berset, Yves; Merulla, Davide; Joublin, Aurélie; Hatzimanikatis, Vassily; van der Meer, Jan R

    2017-02-24

    Bioreporters are living cells that generate an easily measurable signal in the presence of a chemical compound. They acquire their functionality from synthetic gene circuits, the configuration of which defines the response signal and signal-to-noise ratio. Bioreporters based on the Escherichia coli ArsR system have raised significant interest for quantifying arsenic pollution, but they need to be carefully optimized to accurately work in the required low concentration range (1-10 μg arsenite L(-1)). To better understand the general functioning of ArsR-based genetic circuits, we developed a comprehensive mechanistic model that was empirically tested and validated in E. coli carrying different circuit configurations. The model accounts for the different elements in the circuits (proteins, DNA, chemical species), and their detailed affinities and interactions, and predicts the (fluorescent) output from the bioreporter cell as a function of arsenite concentration. The model was parametrized using existing ArsR biochemical data, and then complemented by parameter estimations from the accompanying experimental data using a scatter search algorithm. Model predictions and experimental data were largely coherent for feedback and uncoupled circuit configurations, different ArsR alleles, promoter strengths, and presence or absence of arsenic efflux in the bioreporters. Interestingly, the model predicted a particular useful circuit variant having steeper response at low arsenite concentrations, which was experimentally confirmed and may be useful as arsenic bioreporter in the field. From the extensive validation we expect the mechanistic model to further be a useful framework for detailed modeling of other synthetic circuits.

  13. Genetic regulation of microglia activation, complement expression, and neurodegeneration in a rat model of traumatic brain injury.

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    Bellander, Bo-Michael; Lidman, Olle; Ohlsson, Marcus; Meijer, Britt; Piehl, Fredrik; Svensson, Mikael

    2010-08-01

    Secondary brain damage following traumatic brain injury in part depends on neuroinflammation, a process where genetic factors may play an important role. We examined the response to a standardized cortical contusion in two different inbred rat strains, Dark Agouti (DA) and Piebald Virol Glaxo (PVG). Both are well characterized in models of autoimmune neuroinflammation, where DA is susceptible and PVG resistant. We found that infiltration of polymorphonuclear granulocytes (PMN) at 3-day postinjury was more pronounced in PVG. DA was more infiltrated by T cells at 3-day postinjury, showed an enhanced glial activation at 7-day postinjury and higher expression of C3 complement at 7-day postinjury. Neurodegeneration, assessed by Fluoro-Jade, was also more pronounced in the DA strain at 30-day postinjury. These results demonstrate differences in the response to cortical contusion injury attributable to genetic influences and suggest a link between injury-induced inflammation and neurodegeneration. Genetic factors that regulate inflammation elicited by brain trauma may be important for the development of secondary brain damage.

  14. Modeling Host Genetic Regulation of Influenza Pathogenesis in the Collaborative Cross

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    R.L. Ferris (Robert); D.L. Aylor (David); D. Bottomly (Daniel); A.C. Whitmore (Alan); L.D. Aicher (Lauri); T.A. Bell (Timothy); B. Bradel-Tretheway (Birgit); S. Bryan (Stirling); R.J. Buus (Ryan); L.E. Gralinski (Lisa); B.L. Haagmans (Bart); L. McMillan (Leonard); D.R. Miller (Darla); E. Rosenzweig (Elizabeth); W. Valdar (William); J. Wang (Jinxia); G.A. Churchill (Gary); D.W. Threadgill (David); S.K. McWeeney (Shannon); M.G. Katze (Michael); F. Pardo-Manuel de Villena (Fernando); R. Baric (Ralph); M.T. Heise (Mark)

    2013-01-01

    textabstractGenetic variation contributes to host responses and outcomes following infection by influenza A virus or other viral infections. Yet narrow windows of disease symptoms and confounding environmental factors have made it difficult to identify polymorphic genes that contribute to differenti

  15. In vivo regulation of phenylalanine hydroxylase in the genetic mutant hph-1 mouse model.

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    Gunasekera, Richard S; Hyland, Keith

    2009-11-01

    The hph-1 mouse has low liver activity of GTP cyclohydrolase 1, the rate limiting enzyme in the biosynthesis of tetrahydrobiopterin (BH(4)). BH(4) is the cofactor for phenylalanine hydroxylase (PAH) and in the early stages of life the hph-1 mouse is hyperphenylalaninemic. At approximately 15 days after birth the blood phenylalanine levels normalize. During this period the animals provide an in vivo model which can be used to study the regulatory effects of phenylalanine on PAH, and for related pediatric metabolic disease in humans; from birth to youth. We therefore, examined; liver PAH activity using BH(4) and 6-methyltetrahydropterin (6MPH(4)) as cofactor; PAH total enzyme concentration by Western blotting using the PH8 antibody, and PAH state of phosphorylation using the PH7 antibody from 4 to 18 days after birth. The findings were compared to the wild type animals that are not hyperphenylalaninemic during this period. PAH (6MPH(4)) activity and total protein (PH8 antibody) rose steadily in the hph-1 mice. In control mice, both activity and total protein fluctuated. The degree of phosphorylation of PAH in the mutants and the state of activation (as measured by the 6MPH(4)/BH(4) activity ratio) increased as phenylalanine levels rose, and decreased when they fell. Similar patterns were not seen in the control animals. These studies provide in vivo evidence that phenylalanine concentration regulates the activity of PAH in the hph-1 mouse and that this acts via a mechanism that includes phosphorylation of the PAH molecule. The kinetic values (K(m) and V(max)) for mouse PAH are also reported.

  16. The population genetics of cooperative gene regulation

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    Stewart Alexander J

    2012-09-01

    Full Text Available Abstract Background Changes in gene regulatory networks drive the evolution of phenotypic diversity both within and between species. Rewiring of transcriptional networks is achieved either by changes to transcription factor binding sites or by changes to the physical interactions among transcription factor proteins. It has been suggested that the evolution of cooperative binding among factors can facilitate the adaptive rewiring of a regulatory network. Results We use a population-genetic model to explore when cooperative binding of transcription factors is favored by evolution, and what effects cooperativity then has on the adaptive re-writing of regulatory networks. We consider a pair of transcription factors that regulate multiple targets and overlap in the sets of target genes they regulate. We show that, under stabilising selection, cooperative binding between the transcription factors is favoured provided the amount of overlap between their target genes exceeds a threshold. The value of this threshold depends on several population-genetic factors: strength of selection on binding sites, cost of pleiotropy associated with protein-protein interactions, rates of mutation and population size. Once it is established, we find that cooperative binding of transcription factors significantly accelerates the adaptive rewiring of transcriptional networks under positive selection. We compare our qualitative predictions to systematic data on Saccharomyces cerevisiae transcription factors, their binding sites, and their protein-protein interactions. Conclusions Our study reveals a rich set of evolutionary dynamics driven by a tradeoff between the beneficial effects of cooperative binding at targets shared by a pair of factors, and the detrimental effects of cooperative binding for non-shared targets. We find that cooperative regulation will evolve when transcription factors share a sufficient proportion of their target genes. These findings help to

  17. Systems Genetics as a Tool to Identify Master Genetic Regulators in Complex Disease.

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    Moreno-Moral, Aida; Pesce, Francesco; Behmoaras, Jacques; Petretto, Enrico

    2017-01-01

    Systems genetics stems from systems biology and similarly employs integrative modeling approaches to describe the perturbations and phenotypic effects observed in a complex system. However, in the case of systems genetics the main source of perturbation is naturally occurring genetic variation, which can be analyzed at the systems-level to explain the observed variation in phenotypic traits. In contrast with conventional single-variant association approaches, the success of systems genetics has been in the identification of gene networks and molecular pathways that underlie complex disease. In addition, systems genetics has proven useful in the discovery of master trans-acting genetic regulators of functional networks and pathways, which in many cases revealed unexpected gene targets for disease. Here we detail the central components of a fully integrated systems genetics approach to complex disease, starting from assessment of genetic and gene expression variation, linking DNA sequence variation to mRNA (expression QTL mapping), gene regulatory network analysis and mapping the genetic control of regulatory networks. By summarizing a few illustrative (and successful) examples, we highlight how different data-modeling strategies can be effectively integrated in a systems genetics study.

  18. The common sense model of self-regulation and psychological adjustment to predictive genetic testing : a prospective study

    NARCIS (Netherlands)

    van Oostrom, Iris; Meijers-Heijboer, Hanne; Duivenvoorden, Hugo J.; Broecker-Vriends, Annette H. J. T.; van Asperen, Christi J.; Sijmons, Rolf H.; Seynaeve, Caroline; Van Gool, Arthur R.; Klijn, Jan G. M.; Tibben, Aad

    2007-01-01

    This prospective study explored the contribution of illness representations and coping to cancer-related distress in unaffected individuals undergoing predictive genetic testing for an identified mutation in BRCA1/2 (BReast CAncer) or an HNPCC (Hereditary Nonpolyposis Colorectal Cancer)-related gene

  19. The common sense model of self-regulation and psychological adjustment to predictive genetic testing: a prospective study.

    NARCIS (Netherlands)

    Oostrom, I.I.H. van; Meijers-Heijboer, H.; Duivenvoorden, H.J.; Brocker-Vriends, A.H.; Asperen, C.J. van; Sijmons, R.H.; Seynaeve, C.; Gool, A.R. van; Klijn, J.G.M.; Tibben, A.

    2007-01-01

    This prospective study explored the contribution of illness representations and coping to cancer-related distress in unaffected individuals undergoing predictive genetic testing for an identified mutation in BRCA1/2 (BReast CAncer) or an HNPCC (Hereditary Nonpolyposis Colorectal Cancer)-related gene

  20. Regulation of skeletal muscle growth by the IGF1-Akt/PKB pathway: insights from genetic models

    National Research Council Canada - National Science Library

    Schiaffino, Stefano; Mammucari, Cristina

    2011-01-01

    A highly conserved signaling pathway involving insulin-like growth factor 1 (IGF1), and a cascade of intracellular components that mediate its effects, plays a major role in the regulation of skeletal muscle growth...

  1. Genetic regulation of programmed cell death in Drosophila

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Programmed cell death plays an important role in maintaining homeostasis during animal development, and has been conserved in animals as different as nematodes and humans. Recent studies of Drosophila have provided valuable information toward our understanding of genetic regulation of death. Different signals trigger the novel death regulators rpr, hid, and grim, that utilize the evolutionarily conserved iap and ark genes to modulate caspase function. Subsequent removal of dying cells also appears to be accomplished by conserved mechanisms. The similarity between Drosophila and human in cell death signaling pathways illustrate the promise of fruit flies as a model system to elucidate the mechanisms underlying regulation of programmed cell death.

  2. Graphical models for genetic analyses

    DEFF Research Database (Denmark)

    Lauritzen, Steffen Lilholt; Sheehan, Nuala A.

    2003-01-01

    This paper introduces graphical models as a natural environment in which to formulate and solve problems in genetics and related areas. Particular emphasis is given to the relationships among various local computation algorithms which have been developed within the hitherto mostly separate areas...... of graphical models and genetics. The potential of graphical models is explored and illustrated through a number of example applications where the genetic element is substantial or dominating....

  3. Genetic network models: a comparative study

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    van Someren, Eugene P.; Wessels, Lodewyk F. A.; Reinders, Marcel J. T.

    2001-06-01

    Currently, the need arises for tools capable of unraveling the functionality of genes based on the analysis of microarray measurements. Modeling genetic interactions by means of genetic network models provides a methodology to infer functional relationships between genes. Although a wide variety of different models have been introduced so far, it remains, in general, unclear what the strengths and weaknesses of each of these approaches are and where these models overlap and differ. This paper compares different genetic modeling approaches that attempt to extract the gene regulation matrix from expression data. A taxonomy of continuous genetic network models is proposed and the following important characteristics are suggested and employed to compare the models: inferential power; predictive power; robustness; consistency; stability and computational cost. Where possible, synthetic time series data are employed to investigate some of these properties. The comparison shows that although genetic network modeling might provide valuable information regarding genetic interactions, current models show disappointing results on simple artificial problems. For now, the simplest models are favored because they generalize better, but more complex models will probably prevail once their bias is more thoroughly understood and their variance is better controlled.

  4. Future contributions of crop modelling : from heuristics and supporting decision making to understanding genetic regulation and aiding crop improvement

    NARCIS (Netherlands)

    Hammer, G.L.; Kropff, M.J.; Sinclair, T.R.; Porter, J.R.

    2002-01-01

    Crop modelling has evolved over the last 30 or so years in concert with advances in crop physiology, crop ecology and computing technology. Having reached a respectable degree of acceptance, it is appropriate to review briefly the course of developments in crop modelling and to project what might be

  5. Future contributions of crop modelling : from heuristics and supporting decision making to understanding genetic regulation and aiding crop improvement

    NARCIS (Netherlands)

    Hammer, G.L.; Kropff, M.J.; Sinclair, T.R.; Porter, J.R.

    2002-01-01

    Crop modelling has evolved over the last 30 or so years in concert with advances in crop physiology, crop ecology and computing technology. Having reached a respectable degree of acceptance, it is appropriate to review briefly the course of developments in crop modelling and to project what might be

  6. Investigation of gene effects and epistatic interactions between Akt1 and neuregulin 1 in the regulation of behavioral phenotypes and social functions in genetic mouse models of schizophrenia

    Directory of Open Access Journals (Sweden)

    Ching-Hsun eHuang

    2015-01-01

    Full Text Available Accumulating evidence from human genetic studies has suggested several functional candidate genes that might contribute to susceptibility to schizophrenia, including AKT1 and neuregulin 1 (NRG1. Recent findings also revealed that NRG1 stimulates the PI3-kinase/AKT signaling pathway, which might be involved in the functional outcomes of some schizophrenic patients. The aim of this study was to evaluate the effect of Akt1-deficiency and Nrg1-deficiency alone or in combination in the regulation of behavioral phenotypes, cognition, and social functions using genetically modified mice as a model. Male Akt1+/-, Nrg1+/-, and double mutant mice were bred and compared with their wild-type littermate controls. In experiment 1, general physical examination revealed that all mutant mice displayed a normal profile of body weight during development and a normal brain activity with microPET scan. In experiment 2, no significant genotypic differences were found in our basic behavioral phenotyping, including locomotion, anxiety-like behavior, and sensorimotor gating. However, both Nrg1+/- and double mutant mice exhibited impaired episodic-like memory. Double mutant mice also had impaired sociability. In experiment 3, a synergistic epistasis between Akt1 and Nrg1 was further confirmed in double mutant mice in that they had impaired social interaction compared to the other 3 groups, especially encountering with a novel male or an ovariectomized female. Double mutant and Nrg1+/- mice also emitted fewer female urine-induced ultrasonic vocalization calls. Collectively, our results indicate that double deficiency of Akt1 and Nrg1 can result in the impairment of social cognitive functions, which might be pertinent to the pathogenesis of schizophrenia-related social cognition.

  7. The genetic regulation of the terminating phase of liver regeneration

    DEFF Research Database (Denmark)

    Nygård, Ingvild E.; Mortensen, Kim E.; Hedegaard, Jakob;

    2012-01-01

    Background After partial hepatectomy (PHx), the liver regeneration process terminates when the normal liver-mass/body-weight ratio of 2.5% has been re-established. To investigate the genetic regulation of the terminating phase of liver regeneration, we performed a 60% PHx in a porcine model. Liver...... biopsies were taken at the time of resection, after three weeks and upon termination the sixth week. Gene expression profiles were obtained using porcine oligonucleotide microarrays. Our study reveals the interactions between genes regulating the cell cycle, apoptosis and angiogenesis, and the role...... of Transforming Growth Factor-β (TGF-β) signalling towards the end of liver regeneration. Results Microarray analysis revealed a dominance of genes regulating apoptosis towards the end of regeneration. Caspase Recruitment Domain-Containing Protein 11 (CARD11) was up-regulated six weeks after PHx, suggesting...

  8. Regulating genetic information--exploring the options in legal theory.

    Science.gov (United States)

    2014-12-01

    Ground-breaking genetic discoveries and technological advances have introduced a new world of genetic exploration, and technological advances have facilitated the discovery of the genetic basis of a myriad of diseases. Genetic testing promises to potentially revolutionise health care and offer the potential ofpersonalised medicine. Genetic technology may also offer the means to detect potential future disabilities. In light of rapid advances in genetic science and technology, questions arise as to whether an appropriate framework exists to protect the interests of individuals, prevent the misuse of genetic information by interested third parties, and also to encourage further advances in genetic science. In consideration of rapidly advancing genetic technologies and the ethical and legal concerns that arise, this article examines the regulation of genetic information, primarily from a theoretical perspective. It explores the preferable mode of regulation and choice of regulatory frameworks in legal theory, including non-discrimination, privacy and property.

  9. Genetics of mammalian meiosis: regulation, dynamics and impact on fertility.

    Science.gov (United States)

    Handel, Mary Ann; Schimenti, John C

    2010-02-01

    Meiosis is an essential stage in gamete formation in all sexually reproducing organisms. Studies of mutations in model organisms and of human haplotype patterns are leading to a clearer understanding of how meiosis has adapted from yeast to humans, the genes that control the dynamics of chromosomes during meiosis, and how meiosis is tied to gametic success. Genetic disruptions and meiotic errors have important roles in infertility and the aetiology of developmental defects, especially aneuploidy. An understanding of the regulation of meiosis, coupled with advances in genomics, may ultimately allow us to diagnose the causes of meiosis-based infertilities, more wisely apply assisted reproductive technologies, and derive functional germ cells.

  10. Graphical models for genetic analyses

    DEFF Research Database (Denmark)

    Lauritzen, Steffen Lilholt; Sheehan, Nuala A.

    2003-01-01

    This paper introduces graphical models as a natural environment in which to formulate and solve problems in genetics and related areas. Particular emphasis is given to the relationships among various local computation algorithms which have been developed within the hitherto mostly separate areas...

  11. Genetic Regulation of Phenotypic Plasticity and Canalisation in Yeast Growth

    OpenAIRE

    Yadav, Anupama; Dhole, Kaustubh; Sinha, Himanshu

    2016-01-01

    The ability of a genotype to show diverse phenotypes in different environments is called phenotypic plasticity. Phenotypic plasticity helps populations to evade extinctions in novel environments, facilitates adaptation and fuels evolution. However, most studies focus on understanding the genetic basis of phenotypic regulation in specific environments. As a result, while it’s evolutionary relevance is well established, genetic mechanisms regulating phenotypic plasticity and their overlap with ...

  12. Alternative Splicing Regulation of Cancer-Related Pathways in Caenorhabditis elegans: An In Vivo Model System with a Powerful Reverse Genetics Toolbox

    Directory of Open Access Journals (Sweden)

    Sergio Barberán-Soler

    2013-01-01

    Full Text Available Alternative splicing allows for the generation of protein diversity and fine-tunes gene expression. Several model systems have been used for the in vivo study of alternative splicing. Here we review the use of the nematode Caenorhabditis elegans to study splicing regulation in vivo. Recent studies have shown that close to 25% of genes in the worm genome undergo alternative splicing. A big proportion of these events are functional, conserved, and under strict regulation either across development or other conditions. Several techniques like genome-wide RNAi screens and bichromatic reporters are available for the study of alternative splicing in worms. In this review, we focus, first, on the main studies that have been performed to dissect alternative splicing in this system and later on examples from genes that have human homologs that are implicated in cancer. The significant advancement towards understanding the regulation of alternative splicing and cancer that the C. elegans system has offered is discussed.

  13. Phosphorylation networks regulating JNK activity in diverse genetic backgrounds

    DEFF Research Database (Denmark)

    Bakal, Chris; Linding, Rune; Llense, Flora;

    2008-01-01

    Cellular signaling networks have evolved to enable swift and accurate responses, even in the face of genetic or environmental perturbation. Thus, genetic screens may not identify all the genes that regulate different biological processes. Moreover, although classical screening approaches have suc...

  14. Genetic and Epigenetic Regulation of Aortic Aneurysms

    Science.gov (United States)

    Kim, Ha Won

    2017-01-01

    Aneurysms are characterized by structural deterioration of the vascular wall leading to progressive dilatation and, potentially, rupture of the aorta. While aortic aneurysms often remain clinically silent, the morbidity and mortality associated with aneurysm expansion and rupture are considerable. Over 13,000 deaths annually in the United States are attributable to aortic aneurysm rupture with less than 1 in 3 persons with aortic aneurysm rupture surviving to surgical intervention. Environmental and epidemiologic risk factors including smoking, male gender, hypertension, older age, dyslipidemia, atherosclerosis, and family history are highly associated with abdominal aortic aneurysms, while heritable genetic mutations are commonly associated with aneurysms of the thoracic aorta. Similar to other forms of cardiovascular disease, family history, genetic variation, and heritable mutations modify the risk of aortic aneurysm formation and provide mechanistic insight into the pathogenesis of human aortic aneurysms. This review will examine the relationship between heritable genetic and epigenetic influences on thoracic and abdominal aortic aneurysm formation and rupture. PMID:28116311

  15. [Genetic regulation of plant shoot stem cells].

    Science.gov (United States)

    Al'bert, E V; Ezhova, T A

    2013-02-01

    This article describes the main features of plant stem cells and summarizes the results of studies of the genetic control of stem cell maintenance in the apical meristem of the shoot. It is demonstrated that the WUS-CLV gene system plays a key role in the maintenance of shoot apical stem cells and the formation of adventitious buds and somatic embryos. Unconventional concepts of plant stem cells are considered.

  16. Regulation of transgene expression in genetic immunization

    Directory of Open Access Journals (Sweden)

    Harms J.S.

    1999-01-01

    Full Text Available The use of mammalian gene expression vectors has become increasingly important for genetic immunization and gene therapy as well as basic research. Essential for the success of these vectors in genetic immunization is the proper choice of a promoter linked to the antigen of interest. Many genetic immunization vectors use promoter elements from pathogenic viruses including SV40 and CMV. Lymphokines produced by the immune response to proteins expressed by these vectors could inhibit further transcription initiation by viral promoters. Our objective was to determine the effect of IFN-g on transgene expression driven by viral SV40 or CMV promoter/enhancer and the mammalian promoter/enhancer for the major histocompatibility complex class I (MHC I gene. We transfected the luciferase gene driven by these three promoters into 14 cell lines of many tissues and several species. Luciferase assays of transfected cells untreated or treated with IFN-g indicated that although the viral promoters could drive luciferase production in all cell lines tested to higher or lower levels than the MHC I promoter, treatment with IFN-g inhibited transgene expression in most of the cell lines and amplification of the MHC I promoter-driven transgene expression in all cell lines. These data indicate that the SV40 and CMV promoter/enhancers may not be a suitable choice for gene delivery especially for genetic immunization or cancer cytokine gene therapy. The MHC I promoter/enhancer, on the other hand, may be an ideal transgene promoter for applications involving the immune system.

  17. Genetic regulation of flowering time in annual and perennial plants.

    Science.gov (United States)

    Khan, Muhammad Rehman Gul; Ai, Xiao-Yan; Zhang, Jin-Zhi

    2014-01-01

    Flowering time plays a significant role in the reproductive success of plants. So far, five major pathways to flowering have been characterized in Arabidopsis, including environmental induction through photoperiod, vernalization, and gibberellins and autonomous floral iation, and aging by sequentially operating miRNAs (typically miR156 and miR172) responding to endogenous cues. The balance of signals from these pathways is integrated by a common set of genes (FLOWERING LOCUS C, FLOWERING LOCUS T, LEAFY, and SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1) that determine the flowering time. Recent studies have indicated that epigenetic modification, alternative splicing, antisense RNA and chromatin silencing regulatory mechanisms play an important role in this process by regulating related flowering gene expression. In this review, we discuss the current understanding in genetic regulation of the phase transition from vegetative to reproductive growth by using Arabidopsis as a model. We also describe how this knowledge has been successfully applied for identifying homologous genes from perennial crops. Furthermore, detailed analysis of the similarities and differences between annual and perennial plants flowering will help elucidate the mechanisms of perennial plant maturation and regulation of floral initiation.

  18. Behavior genetic modeling of human fertility

    DEFF Research Database (Denmark)

    Rodgers, J L; Kohler, H P; Kyvik, K O;

    2001-01-01

    Try) and number of children (NumCh). Behavior genetic models were fitted using structural equation modeling and DF analysis. A consistent medium-level additive genetic influence was found for NumCh, equal across genders; a stronger genetic influence was identified for FirstTry, greater for females than for males...

  19. Genetic and Diet-Induced Obesity Increased Intestinal Tumorigenesis in the Double Mutant Mouse Model Multiple Intestinal Neoplasia X Obese via Disturbed Glucose Regulation and Inflammation

    Directory of Open Access Journals (Sweden)

    Ha Thi Ngo

    2015-01-01

    Full Text Available We have studied how spontaneous or carcinogen-induced intestinal tumorigenesis was affected by genetic or diet-induced obesity in C57BL/6J-ApcMin/+ X C57BL/6J-Lepob/+ mice. Obesity was induced by the obese (ob mutation in the lep gene coding for the hormone leptin, or by a 45% fat diet. The effects of obesity were examined on spontaneous intestinal tumors caused by the multiple intestinal neoplasia (Min mutation in the adenomatous polyposis coli (Apc gene and on tumors induced by the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP. F1 ob/ob (homozygous mutated mice had increased body weight (bw and number of spontaneous and PhIP-induced small intestinal tumors (in ApcMin/+ mice, versus ob/wt (heterozygous mutated and wt/wt mice (homozygous wild-type. A 45% fat diet exacerbated bw and spontaneous tumor numbers versus 10% fat, but not PhIP-induced tumors. Except for bw, ob/wt and wt/wt were not significantly different. The obesity caused hyperglucosemia and insulinemia in ob/ob mice. A 45% fat diet further increased glucose, but not insulin. Inflammation was seen as increased TNFα levels in ob/ob mice. Thus the results implicate disturbed glucose regulation and inflammation as mechanisms involved in the association between obesity and intestinal tumorigenesis. Ob/ob mice had shorter lifespan than ob/wt and wt/wt mice.

  20. Ionic regulation in genetic translation systems.

    Science.gov (United States)

    Douzou, P; Maurel, P

    1977-03-01

    The polyelectrolyte theory can provide an interpretation of the interdependence of pH, ionic strength, and polyamines one observes in the activity of ribonuclease acting on RNA. According to this theory: (i) A nucleic acid-enzyme complex and the suspending medium may be considered as two phases in equilibrium, even though within limits, the complex is soluble in water. (ii) The enzymatic catalysis is under tight control of the electrostatic potential generated by the system. Consequently, modification in electrostatic potential will induce a concomitant change in activity. (iii) The electrostatic potential can be modified through action on the system of "modulators", either "external" (ionic strength, pH, temperature, etc.) or "internal" (specific ligands, substrates, protein factors, etc.). Similarities between the reaction of ribonuclease (ribonuclease 3'-pyrimidino-oligonucleotidohydrolase; EC 3.1.4.22) and RNA and those observed with highly organized systems catalyzing DNA, RNA, and protein synthesis suggest that the electrostatic potential also provides an important regulatory mechanism in genetic translation. In this view, an essential function of nucleic acids is to provide their enzyme partners with polyanionic microenvironments within which their catalytic activities are controlled by variation in physicochemical parameters, including the proton concentration induced through "modulation" of the local electrostatic potential.

  1. Adrenal glucocorticoids regulate adipsin gene expression in genetically obese mice.

    Science.gov (United States)

    Spiegelman, B M; Lowell, B; Napolitano, A; Dubuc, P; Barton, D; Francke, U; Groves, D L; Cook, K S; Flier, J S

    1989-01-25

    Adipsin expression at the protein and mRNA levels is greatly reduced in several distinct syndromes of obesity in the mouse: genetic obesity due to the db/db and ob/ob genes, and a chemically induced model secondary to neonatal exposure to monosodium glutamate. We considered first the possibility that the adipsin gene might be identical to the db or ob locus and the lowered expression of this protein might result from a mutation in this gene. We show here that the adipsin structural gene is located on chromosome 10 and hence is physically distinct from any obesity genes so far identified in the mouse. A major role for the adrenal gland and adrenal glucocorticoids in the aberrant regulation of adipsin in these models of obesity is indicated by several experiments. Adrenalectomy of the ob/ob mouse raises the circulating levels of adipsin protein and the amount of this mRNA in epididymal fat pads (5-fold), although neither is increased to the levels seen in lean controls. Exogenous administration of corticosterone completely blocks the effects of adrenalectomy on adipsin, suggesting that the effect of this endocrine ablation is through reduction of adrenal glucocorticoids. Corticosterone administration also causes suppression in the levels of adipsin mRNA and protein in lean mice, although this decrease is never as severe as that seen in obese mice. The effect of exogenous corticosterone in lean mice occurs within 2 days and hence is not secondary to the obesity which these hormones eventually elicit. These results indicate that glucocorticoids can regulate adipsin expression in vivo and strongly suggest that the hyperglucocorticoid state seen in certain obese models plays a significant role in lowering adipsin mRNA and protein levels. Quantitative analysis of these experiments suggests that other as yet unknown neuroendocrine factors also function to suppress adipsin in obesity.

  2. Routine Discovery of Complex Genetic Models using Genetic Algorithms.

    Science.gov (United States)

    Moore, Jason H; Hahn, Lance W; Ritchie, Marylyn D; Thornton, Tricia A; White, Bill C

    2004-02-01

    Simulation studies are useful in various disciplines for a number of reasons including the development and evaluation of new computational and statistical methods. This is particularly true in human genetics and genetic epidemiology where new analytical methods are needed for the detection and characterization of disease susceptibility genes whose effects are complex, nonlinear, and partially or solely dependent on the effects of other genes (i.e. epistasis or gene-gene interaction). Despite this need, the development of complex genetic models that can be used to simulate data is not always intuitive. In fact, only a few such models have been published. We have previously developed a genetic algorithm approach to discovering complex genetic models in which two single nucleotide polymorphisms (SNPs) influence disease risk solely through nonlinear interactions. In this paper, we extend this approach for the discovery of high-order epistasis models involving three to five SNPs. We demonstrate that the genetic algorithm is capable of routinely discovering interesting high-order epistasis models in which each SNP influences risk of disease only through interactions with the other SNPs in the model. This study opens the door for routine simulation of complex gene-gene interactions among SNPs for the development and evaluation of new statistical and computational approaches for identifying common, complex multifactorial disease susceptibility genes.

  3. Genetic regulation of conidiation in Trichoderma hamatun

    Institute of Scientific and Technical Information of China (English)

    Johanna Steyaert; Travis Glare; Alison Stewart; Margaret Carpenter; Hayley Ridgway

    2004-01-01

    @@ Achieving a balance between vegetative growth and spore production is essential for successful biocontrol by fungi. Low sporulation rates in the field can result in poor establishment and survival,whereas failure of conidia to recognise hosts can lead to persistence without efficacy. Commercial biocontrol products involve bulk preparations of conidia, however considerable variability in conidiation rates exists between biocontrol agents, which can restrict choice of strain for production. The majority of studies on Trichoderma conidiation have focused on the species T. viride and T. atroviride.These species form conidia in response to blue and near-UV light and/or nutrient deprivation and conidiation proceeds in a highly co-ordinated fashion, however relatively little is known on the genetic basis of Trichoderrma conidiation. In addition, whilst photoconidiation appears to be a general response detailed studies in other Trichoderma species are absent. In this study, conidiation in the lesser known biocontrol species T. hamatum is being investigated using a combined morphological and molecular approach. In contrast to T. atroviride, conidiation in response to blue-light was weaker and variable and suggested that additional triggers may be required for the T. hamatum photoresponse. A series of comparative photoconidiation assays are currently being undertaken investigating the effect of inoculum type and abiotic factors on timing and intensity of the response.Results will be discussed in relation to the current knowledge on conidial morphogenesis in Trichoderma. In addition to these morphological assays, a selection of genes implicated in sporulation and the blue-light responses are currently being isolated and characterised from T. hamatum. Two genes, phr1 and cmp1 , which were isolated previously from T. atroviride will be used as early and late markers of gene expression during the photoresponse in T. hamatum in order to define time points for harvesting

  4. We see the light: chemical-genetic protein regulation.

    Science.gov (United States)

    Farber, Steven A; Zeituni, Erin M

    2012-03-23

    The challenge of studying complex protein networks in whole animals has driven the development of new methods for manipulating protein function with spatial and temporal precision. A novel combination of chemical and genetic protein regulation (Rodriguez and Wolfgang, in this issue of Chemistry & Biology) achieves levels of control that will revolutionize the study of protein function.

  5. Regulation of Genetically Modified Organisms in the European Union

    NARCIS (Netherlands)

    Grossman, M.R.; Bryan Endres, A.

    2000-01-01

    To be successful, laws that regulate genetically modified organisms (GMOs) must help society decide rationally when to pause and when to proceed in adopting new biotechnological developments. In the context of European Union (EU) institutions and lawmaking procedures, this article examines European

  6. Regulation of Genetically Modified Organisms in the European Union

    NARCIS (Netherlands)

    Grossman, M.R.; Bryan Endres, A.

    2000-01-01

    To be successful, laws that regulate genetically modified organisms (GMOs) must help society decide rationally when to pause and when to proceed in adopting new biotechnological developments. In the context of European Union (EU) institutions and lawmaking procedures, this article examines European

  7. [Genetic variations in energy balance regulation].

    Science.gov (United States)

    Pankov, Iu A

    2010-01-01

    Single nucleotide polymorphism (SNP) near certain genes revealed association of FAT(fat mass and obesity-associated gene), MC4R (melanocortin 4 receptor gene), and other genes with obesity. Participation of the FAT expression products in the regulation of energy balance remains to be clarified. The function of MC4R encoding melanocortin 4 receptor (MC4R) is somewhat better understood. alpha-, beta-, and gamma-MSH encoded by the POMC gene bind to MC4R, reduce food intake, and slow down fat accumulation. Expression of POMC that codes MSH is enhanced by leptin binding to the receptor (LepRb) in hypothalamic neurons. Mutations in human and animal MC4R, POMC, and LEP genes are known to be associated with obesity. More than 60 mutations in MC4R, more than 20 mutations in POMC and fewer LEP mutations have been reported. Nonsense mutations and reading frame shifts block gene expression and thereby disrupt protein synthesis. Missense mutations frequently affect protein folding in endoplasmic reticulum; unfolded or misfolded proteins remain in the cytoplasm and undergo degradation. Certain missence mutations do not interfere with gene expression and folding of proteins but impair their functioning at the periphery. P.S127L mutation in MC4R, p.E206X and p.F144L mutations in POMC as well as other mutations in homozygous and heterozygous forms account for disturbed energy balance in man. The LEP gene has been reported to contain G133fsX15, p.R105X, p.R1O5W, and p.S141C mutations. As a rule, they are associated with obesity and other pathological conditions only in homozygous forms.

  8. Behavior genetic modeling of human fertility

    DEFF Research Database (Denmark)

    Rodgers, J L; Kohler, H P; Kyvik, K O

    2001-01-01

    Try) and number of children (NumCh). Behavior genetic models were fitted using structural equation modeling and DF analysis. A consistent medium-level additive genetic influence was found for NumCh, equal across genders; a stronger genetic influence was identified for FirstTry, greater for females than for males......Behavior genetic designs and analysis can be used to address issues of central importance to demography. We use this methodology to document genetic influence on human fertility. Our data come from Danish twin pairs born from 1953 to 1959, measured on age at first attempt to get pregnant (First...

  9. Genetic Regulation of Phenotypic Plasticity and Canalisation in Yeast Growth.

    Science.gov (United States)

    Yadav, Anupama; Dhole, Kaustubh; Sinha, Himanshu

    2016-01-01

    The ability of a genotype to show diverse phenotypes in different environments is called phenotypic plasticity. Phenotypic plasticity helps populations to evade extinctions in novel environments, facilitates adaptation and fuels evolution. However, most studies focus on understanding the genetic basis of phenotypic regulation in specific environments. As a result, while it's evolutionary relevance is well established, genetic mechanisms regulating phenotypic plasticity and their overlap with the environment specific regulators is not well understood. Saccharomyces cerevisiae is highly sensitive to the environment, which acts as not just external stimulus but also as signalling cue for this unicellular, sessile organism. We used a previously published dataset of a biparental yeast population grown in 34 diverse environments and mapped genetic loci regulating variation in phenotypic plasticity, plasticity QTL, and compared them with environment-specific QTL. Plasticity QTL is one whose one allele exhibits high plasticity whereas the other shows a relatively canalised behaviour. We mapped phenotypic plasticity using two parameters-environmental variance, an environmental order-independent parameter and reaction norm (slope), an environmental order-dependent parameter. Our results show a partial overlap between pleiotropic QTL and plasticity QTL such that while some plasticity QTL are also pleiotropic, others have a significant effect on phenotypic plasticity without being significant in any environment independently. Furthermore, while some plasticity QTL are revealed only in specific environmental orders, we identify large effect plasticity QTL, which are order-independent such that whatever the order of the environments, one allele is always plastic and the other is canalised. Finally, we show that the environments can be divided into two categories based on the phenotypic diversity of the population within them and the two categories have differential regulators of

  10. Genetic regulation of growth from birth to 18 years of age

    DEFF Research Database (Denmark)

    Silventoinen, Karri; Pietiläinen, Kirsi H; Tynelius, Per

    2008-01-01

    birth to age 18. The data were analyzed by two different multivariate variance component models for twin data using the Mx statistical package. At birth and 1 year of age, a substantial part of the variation in length was because of common environment (50 and 57%, respectively) and the effect of genetic...... started to affect height, but also genetic variation affecting height at previous ages remained. These results suggest that genetic regulation of growth is rather uniform, which is encouraging for further efforts to identify genes affecting growth....

  11. Regulation of the genetic code in megakaryocytes and platelets.

    Science.gov (United States)

    Rondina, M T; Weyrich, A S

    2015-06-01

    Platelets are generated from nucleated precursors referred to as megakaryocytes. The formation of platelets is one of the most elegant and unique developmental processes in eukaryotes. Because they enter the circulation without nuclei, platelets are often considered simple, non-complex cells that have limited functions beyond halting blood flow. However, emerging evidence over the past decade demonstrates that platelets are more sophisticated than previously considered. Platelets carry a rich repertoire of messenger RNAs (mRNAs), microRNAs (miRNAs), and proteins that contribute to primary (adhesion, aggregation, secretion) and alternative (immune regulation, RNA transfer, translation) functions. It is also becoming increasingly clear that the 'genetic code' of platelets changes with race, genetic disorders, or disease. Changes in the 'genetic code' can occur at multiple points including megakaryocyte development, platelet formation, or in circulating platelets. This review focuses on regulation of the 'genetic code' in megakaryocytes and platelets and its potential contribution to health and disease. © 2015 International Society on Thrombosis and Haemostasis.

  12. Regulating innovative crop technologies in Canada: the case of regulating genetically modified crops.

    Science.gov (United States)

    Smyth, Stuart; McHughen, Alan

    2008-04-01

    The advent of genetically modified crops in the late 1980s triggered a regulatory response to the relatively new field of plant genetic engineering. Over a 7-year period, a new regulatory framework was created, based on scientific principles that focused on risk mitigation. The process was transparent and deliberately sought the input of those involved in crop development from non-governmental organizations, industry, academia and federal research laboratories. The resulting regulations have now been in place for over a decade, and the resilience of the risk-mitigating regulations is evident as there has been no documented case of damage to either environment or human health.

  13. Genetic diversity and selection regulates evolution of infectious bronchitis virus.

    Science.gov (United States)

    Toro, Haroldo; van Santen, Vicky L; Jackwood, Mark W

    2012-09-01

    Conventional and molecular epidemiologic studies have confirmed the ability of infectious bronchitis virus (IBV) to rapidly evolve and successfully circumvent extensive vaccination programs implemented since the early 1950s. IBV evolution has often been explained as variation in gene frequencies as if evolution were driven by genetic drift alone. However, the mechanisms regulating the evolution of IBV include both the generation of genetic diversity and the selection process. IBV's generation of genetic diversity has been extensively investigated and ultimately involves mutations and recombination events occurring during viral replication. The relevance of the selection process has been further understood more recently by identifying genetic and phenotypic differences between IBV populations prior to, and during, replication in the natural host. Accumulating evidence suggests that multiple environmental forces within the host, including immune responses (or lack thereof) and affinity for cell receptors, as well as physical and biochemical conditions, are responsible for the selection process. Some scientists have used or adopted the related quasispecies frame to explain IBV evolution. The quasispecies frame, while providing a distinct explanation of the dynamics of populations in which mutation is a frequent event, exhibits relevant limitations which are discussed herein. Instead, it seems that IBV populations evolving by the generation of genetic variability and selection on replicons follow the evolutionary mechanisms originally proposed by Darwin. Understanding the mechanisms underlying the evolution of IBV is of basic relevance and, without doubt, essential to appropriately control and prevent the disease.

  14. 76 FR 5780 - Determination of Regulated Status of Alfalfa Genetically Engineered for Tolerance to the...

    Science.gov (United States)

    2011-02-02

    ... Animal and Plant Health Inspection Service Determination of Regulated Status of Alfalfa Genetically... regulated status of alfalfa genetically engineered for tolerance to the herbicide glyphosate based on APHIS... decision and determination on the petition regarding the regulated status of alfalfa genetically engineered...

  15. Versatile RNA-sensing transcriptional regulators for engineering genetic networks.

    Science.gov (United States)

    Lucks, Julius B; Qi, Lei; Mutalik, Vivek K; Wang, Denise; Arkin, Adam P

    2011-05-24

    The widespread natural ability of RNA to sense small molecules and regulate genes has become an important tool for synthetic biology in applications as diverse as environmental sensing and metabolic engineering. Previous work in RNA synthetic biology has engineered RNA mechanisms that independently regulate multiple targets and integrate regulatory signals. However, intracellular regulatory networks built with these systems have required proteins to propagate regulatory signals. In this work, we remove this requirement and expand the RNA synthetic biology toolkit by engineering three unique features of the plasmid pT181 antisense-RNA-mediated transcription attenuation mechanism. First, because the antisense RNA mechanism relies on RNA-RNA interactions, we show how the specificity of the natural system can be engineered to create variants that independently regulate multiple targets in the same cell. Second, because the pT181 mechanism controls transcription, we show how independently acting variants can be configured in tandem to integrate regulatory signals and perform genetic logic. Finally, because both the input and output of the attenuator is RNA, we show how these variants can be configured to directly propagate RNA regulatory signals by constructing an RNA-meditated transcriptional cascade. The combination of these three features within a single RNA-based regulatory mechanism has the potential to simplify the design and construction of genetic networks by directly propagating signals as RNA molecules.

  16. Regulating Intracellular Calcium in Plants: From Molecular Genetics to Physiology

    Energy Technology Data Exchange (ETDEWEB)

    Heven Sze

    2008-06-22

    To grow, develop, adapt, and reproduce, plants have evolved mechanisms to regulate the uptake, translocation and sorting of calcium ions into different cells and subcellular compartments. Yet how plants accomplish this remarkable feat is still poorly understood. The spatial and temporal changes in intracellular [Ca2+] during growth and during responses to hormonal and environmental stimuli indicate that Ca2+ influx and efflux transporters are diverse and tightly regulated in plants. The specific goals were to determine the biological roles of multiple Ca pumps (ECAs) in the model plant Arabidopsis thaliana. We had pioneered the use of K616 yeast strain to functionally express plant Ca pumps, and demonstrated two distinct types of Ca pumps in plants (Sze et al., 2000. Annu Rev Plant Biol. 51,433). ACA2 represented one type that was auto-inhibited by the N-terminal region and stimulated by calmodulin. ECA1 represented another type that was not sensitive to calmodulin and phylogenetically distinct from ACAs. The goal to determine the biological roles of multiple ECA-type Ca pumps in Arabidopsis has been accomplished. Although we demonstrated ECA1 was a Ca pump by functional expression in yeast, the in vivo roles of ECAs was unclear. A few highlights are described. ECA1 and/or ECA4 are Ca/Mn pumps localized to the ER and are highly expressed in all cell types. Using homozygous T-DNA insertional mutants of eca1, we demonstrated that the ER-bound ECA1 supports growth and confers tolerance of plants growing on medium low in Ca or containing toxic levels of Mn. This is the first genetic study to determine the in vivo function of a Ca pump in plants. A phylogenetically distinct ECA3 is also a Ca/Mn pump that is localized to endosome, such as post-Golgi compartments. Although it is expressed at lower levels than ECA1, eca3 mutants are impaired in Ca-dependent root growth and in pollen tube elongation. Increased secretion of wall proteins in mutants suggests that Ca and Mn

  17. Regulating Intracellular Calcium in Plants: From Molecular Genetics to Physiology

    Energy Technology Data Exchange (ETDEWEB)

    Heven Sze

    2008-06-22

    To grow, develop, adapt, and reproduce, plants have evolved mechanisms to regulate the uptake, translocation and sorting of calcium ions into different cells and subcellular compartments. Yet how plants accomplish this remarkable feat is still poorly understood. The spatial and temporal changes in intracellular [Ca2+] during growth and during responses to hormonal and environmental stimuli indicate that Ca2+ influx and efflux transporters are diverse and tightly regulated in plants. The specific goals were to determine the biological roles of multiple Ca pumps (ECAs) in the model plant Arabidopsis thaliana. We had pioneered the use of K616 yeast strain to functionally express plant Ca pumps, and demonstrated two distinct types of Ca pumps in plants (Sze et al., 2000. Annu Rev Plant Biol. 51,433). ACA2 represented one type that was auto-inhibited by the N-terminal region and stimulated by calmodulin. ECA1 represented another type that was not sensitive to calmodulin and phylogenetically distinct from ACAs. The goal to determine the biological roles of multiple ECA-type Ca pumps in Arabidopsis has been accomplished. Although we demonstrated ECA1 was a Ca pump by functional expression in yeast, the in vivo roles of ECAs was unclear. A few highlights are described. ECA1 and/or ECA4 are Ca/Mn pumps localized to the ER and are highly expressed in all cell types. Using homozygous T-DNA insertional mutants of eca1, we demonstrated that the ER-bound ECA1 supports growth and confers tolerance of plants growing on medium low in Ca or containing toxic levels of Mn. This is the first genetic study to determine the in vivo function of a Ca pump in plants. A phylogenetically distinct ECA3 is also a Ca/Mn pump that is localized to endosome, such as post-Golgi compartments. Although it is expressed at lower levels than ECA1, eca3 mutants are impaired in Ca-dependent root growth and in pollen tube elongation. Increased secretion of wall proteins in mutants suggests that Ca and Mn

  18. Adult plant development in triticale (× triticosecale wittmack) is controlled by dynamic genetic patterns of regulation.

    Science.gov (United States)

    Würschum, Tobias; Liu, Wenxin; Alheit, Katharina V; Tucker, Matthew R; Gowda, Manje; Weissmann, Elmar A; Hahn, Volker; Maurer, Hans Peter

    2014-09-18

    Many biologically and agronomically important traits are dynamic and show temporal variation. In this study, we used triticale (× Triticosecale Wittmack) as a model crop to assess the genetic dynamics underlying phenotypic plasticity of adult plant development. To this end, a large mapping population with 647 doubled haploid lines derived from four partially connected families from crosses among six parents was scored for developmental stage at three different time points. Using genome-wide association mapping, we identified main effect and epistatic quantitative trait loci (QTL) at all three time points. Interestingly, some of these QTL were identified at all time points, whereas others appear to only contribute to the genetic architecture at certain developmental stages. Our results illustrate the temporal contribution of QTL to the genetic control of adult plant development and more generally, the temporal genetic patterns of regulation that underlie dynamic traits.

  19. Genetic regulation of feed intake and energy balance in poultry.

    Science.gov (United States)

    Richards, M P

    2003-06-01

    Intensive selection by poultry breeders over many generations for economically important production traits such as growth rate and meat production has been accompanied by significant changes in feed intake and energy balance. For example, the modern commercial broiler, selected for rapid growth and enhanced muscle mass, does not adequately regulate voluntary feed intake to achieve energy balance. When given unrestricted access to feed, broilers exhibit hyperphagia leading to an excessive accumulation of energy (fat) stores, making these birds prone to obesity and other health-related problems. Humoral and neural pathways have been identified and studied in mammals that link appetite and energy balance. A series of highly integrated regulatory mechanisms exists for both of these processes involving complex interactions between peripheral tissues and the central nervous system. Within the central nervous system, the brainstem and the hypothalamus play critical roles in the regulation of feed intake and energy balance. Genes encoding key regulatory factors such as hormones, neuropeptides, receptors, enzymes, transcription factors, and binding/transport proteins constitute the molecular basis for regulatory systems that derive from integrated sensing, signaling, and metabolic pathways. However, we do not yet have a complete understanding of the genetic basis for this regulation in poultry. This review examines what is currently known about the regulation of feed intake and energy balance in poultry. A better understanding of the genes associated with controlling feed intake and energy balance and how their expression is regulated by nutritional and hormonal stimuli will offer new insights into current poultry breeding and management practices.

  20. From biophysics to evolutionary genetics: statistical aspects of gene regulation

    Directory of Open Access Journals (Sweden)

    Lässig Michael

    2007-09-01

    Full Text Available Abstract This is an introductory review on how genes interact to produce biological functions. Transcriptional interactions involve the binding of proteins to regulatory DNA. Specific binding sites can be identified by genomic analysis, and these undergo a stochastic evolution process governed by selection, mutations, and genetic drift. We focus on the links between the biophysical function and the evolution of regulatory elements. In particular, we infer fitness landscapes of binding sites from genomic data, leading to a quantitative evolutionary picture of regulation.

  1. Biosynthesis and Genetic Regulation of Proanthocyanidins in Plants

    Directory of Open Access Journals (Sweden)

    Chang-Qing Duan

    2008-10-01

    Full Text Available Proanthocyanidins (PAs, also known as condensed tannins, are a group of polyphenolic secondary metabolites synthesized in plants as oligomers or polymers of flavan-3-ol units via the flavonoid pathway. Due to their structural complexity and varied composition, only in the recent years has the study on the biosynthesis and regulation of PAs in plants taken off, although some details of the synthetic mechanism remain unclear. This paper aims to summarize the status of research on the structures of PAs in plants, the genes encoding key enzymes of biosynthetic pathway, the transport factors, the transcriptional regulation of PA biosynthesis and the genetic manipulation of PAs. The problems of this field were also discussed, including the nature of the final “enzyme” which catalyzes the polymerization reaction of PAs and the possible mechanism of how the elementary units of flavanols are assembled in vivo.

  2. Genetically Modified Pig Models for Human Diseases

    Institute of Scientific and Technical Information of China (English)

    Nana Fan; Liangxue Lai

    2013-01-01

    Genetically modified animal models are important for understanding the pathogenesis of human disease and developing therapeutic strategies.Although genetically modified mice have been widely used to model human diseases,some of these mouse models do not replicate important disease symptoms or pathology.Pigs are more similar to humans than mice in anatomy,physiology,and genome.Thus,pigs are considered to be better animal models to mimic some human diseases.This review describes genetically modified pigs that have been used to model various diseases including neurological,cardiovascular,and diabetic disorders.We also discuss the development in gene modification technology that can facilitate the generation of transgenic pig models for human diseases.

  3. Regulation of Leaf Senescence and Crop Genetic Improvement

    Institute of Scientific and Technical Information of China (English)

    Xiao-Yuan Wu; Ben-Ke Kuai; Ji-Zeng Jia; Hai-Chun Jing

    2012-01-01

    Leaf senescence can impact crop production by either changing photosynthesis duration,or by modifying the nutrient remobilization efficiency and harvest index.The doubling of the grain yield in major cereals in the last 50 years was primarily achieved through the extension of photosynthesis duration and the increase in crop biomass partitioning,two things that are intrinsically coupled with leaf senescence.In this review,we consider the functionality of a leaf as a function of leaf age,and divide a leaf's life into three phases:the functionality increasing phase at the early growth stage,the full functionality phase,and the senescence and functionality decreasing phase.A genetic framework is proposed to describe gene actions at various checkpoints to regulate leaf development and senescence.Four categories of genes contribute to crop production:those which regulate (Ⅰ) the speed and transition of early leaf growth,(Ⅱ) photosynthesis rate,(Ⅲ) the onset and (Ⅳ) the progression of leaf senescence.Current advances in isolating and characterizing senescence regulatory genes are discussed in the leaf aging and crop production context.We argue that the breeding of crops with leaf senescence ideotypes should be an essential part of further crop genetic improvement.

  4. 75 FR 8299 - Draft Environmental Impact Statement; Determination of Regulated Status of Alfalfa Genetically...

    Science.gov (United States)

    2010-02-24

    ... Regulated Status of Alfalfa Genetically Engineered for Tolerance to the Herbicide Glyphosate AGENCY: Animal... and Forage Genetics International alfalfa lines designated as events J101 and J163 as regulated... determination on the status of the Monsanto Company and Forage Genetics International alfalfa lines designated...

  5. Genetic models of homosexuality: generating testable predictions

    OpenAIRE

    Gavrilets, Sergey; Rice, William R.

    2006-01-01

    Homosexuality is a common occurrence in humans and other species, yet its genetic and evolutionary basis is poorly understood. Here, we formulate and study a series of simple mathematical models for the purpose of predicting empirical patterns that can be used to determine the form of selection that leads to polymorphism of genes influencing homosexuality. Specifically, we develop theory to make contrasting predictions about the genetic characteristics of genes influencing homosexuality inclu...

  6. Quantitative Genetics Identifies Cryptic Genetic Variation Involved in the Paternal Regulation of Seed Development.

    Science.gov (United States)

    Pires, Nuno D; Bemer, Marian; Müller, Lena M; Baroux, Célia; Spillane, Charles; Grossniklaus, Ueli

    2016-01-01

    Embryonic development requires a correct balancing of maternal and paternal genetic information. This balance is mediated by genomic imprinting, an epigenetic mechanism that leads to parent-of-origin-dependent gene expression. The parental conflict (or kinship) theory proposes that imprinting can evolve due to a conflict between maternal and paternal alleles over resource allocation during seed development. One assumption of this theory is that paternal alleles can regulate seed growth; however, paternal effects on seed size are often very low or non-existent. We demonstrate that there is a pool of cryptic genetic variation in the paternal control of Arabidopsis thaliana seed development. Such cryptic variation can be exposed in seeds that maternally inherit a medea mutation, suggesting that MEA acts as a maternal buffer of paternal effects. Genetic mapping using recombinant inbred lines, and a novel method for the mapping of parent-of-origin effects using whole-genome sequencing of segregant bulks, indicate that there are at least six loci with small, paternal effects on seed development. Together, our analyses reveal the existence of a pool of hidden genetic variation on the paternal control of seed development that is likely shaped by parental conflict.

  7. Quantitative Genetics Identifies Cryptic Genetic Variation Involved in the Paternal Regulation of Seed Development.

    Directory of Open Access Journals (Sweden)

    Nuno D Pires

    2016-01-01

    Full Text Available Embryonic development requires a correct balancing of maternal and paternal genetic information. This balance is mediated by genomic imprinting, an epigenetic mechanism that leads to parent-of-origin-dependent gene expression. The parental conflict (or kinship theory proposes that imprinting can evolve due to a conflict between maternal and paternal alleles over resource allocation during seed development. One assumption of this theory is that paternal alleles can regulate seed growth; however, paternal effects on seed size are often very low or non-existent. We demonstrate that there is a pool of cryptic genetic variation in the paternal control of Arabidopsis thaliana seed development. Such cryptic variation can be exposed in seeds that maternally inherit a medea mutation, suggesting that MEA acts as a maternal buffer of paternal effects. Genetic mapping using recombinant inbred lines, and a novel method for the mapping of parent-of-origin effects using whole-genome sequencing of segregant bulks, indicate that there are at least six loci with small, paternal effects on seed development. Together, our analyses reveal the existence of a pool of hidden genetic variation on the paternal control of seed development that is likely shaped by parental conflict.

  8. Quantitative Genetics Identifies Cryptic Genetic Variation Involved in the Paternal Regulation of Seed Development.

    Directory of Open Access Journals (Sweden)

    Nuno D Pires

    2016-01-01

    Full Text Available Embryonic development requires a correct balancing of maternal and paternal genetic information. This balance is mediated by genomic imprinting, an epigenetic mechanism that leads to parent-of-origin-dependent gene expression. The parental conflict (or kinship theory proposes that imprinting can evolve due to a conflict between maternal and paternal alleles over resource allocation during seed development. One assumption of this theory is that paternal alleles can regulate seed growth; however, paternal effects on seed size are often very low or non-existent. We demonstrate that there is a pool of cryptic genetic variation in the paternal control of Arabidopsis thaliana seed development. Such cryptic variation can be exposed in seeds that maternally inherit a medea mutation, suggesting that MEA acts as a maternal buffer of paternal effects. Genetic mapping using recombinant inbred lines, and a novel method for the mapping of parent-of-origin effects using whole-genome sequencing of segregant bulks, indicate that there are at least six loci with small, paternal effects on seed development. Together, our analyses reveal the existence of a pool of hidden genetic variation on the paternal control of seed development that is likely shaped by parental conflict.

  9. Molecular regulation and genetic improvement of seed oil content in Brassica napus L.

    Directory of Open Access Journals (Sweden)

    Wei HUA,Jing LIU,Hanzhong WANG

    2016-09-01

    Full Text Available As an important oil crop and a potential bioenergy crop, Brassica napus L. is becoming a model plant for basic research on seed lipid biosynthesis as well as seed oil content, which has always been the key breeding objective. In this review, we present current progress in understanding of the regulation of oil content in B. napus, including genetics, biosynthesis pathway, transcriptional regulation, maternal effects and QTL analysis. Furthermore, the history of breeding for high oil content in B. napus is summarized and the progress in breeding ultra-high oil content lines is described. Finally, prospects for breeding high oil content B. napus cultivars are outlined.

  10. A review of animal models used to evaluate potential allergenicity of genetically modified organisms (GMOs)

    DEFF Research Database (Denmark)

    Marsteller, Nathan; Bøgh, Katrine Lindholm; Goodman, Richard E.

    2017-01-01

    Food safety regulators request prediction of allergenicity for newly expressed proteins in genetically modified (GM) crops and in novel foods. Some have suggested using animal models to assess potential allergenicity. A variety of animal models have been used in research to evaluate sensitisation...... of genetically modified organisms (GMOs)....

  11. Genetic search feature selection for affective modeling

    DEFF Research Database (Denmark)

    Martínez, Héctor P.; Yannakakis, Georgios N.

    2010-01-01

    Automatic feature selection is a critical step towards the generation of successful computational models of affect. This paper presents a genetic search-based feature selection method which is developed as a global-search algorithm for improving the accuracy of the affective models built...

  12. Threshold-dominated regulation hides genetic variation in gene expression networks

    Directory of Open Access Journals (Sweden)

    Plahte Erik

    2007-12-01

    Full Text Available Abstract Background In dynamical models with feedback and sigmoidal response functions, some or all variables have thresholds around which they regulate themselves or other variables. A mathematical analysis has shown that when the dose-response functions approach binary or on/off responses, any variable with an equilibrium value close to one of its thresholds is very robust to parameter perturbations of a homeostatic state. We denote this threshold robustness. To check the empirical relevance of this phenomenon with response function steepnesses ranging from a near on/off response down to Michaelis-Menten conditions, we have performed a simulation study to investigate the degree of threshold robustness in models for a three-gene system with one downstream gene, using several logical input gates, but excluding models with positive feedback to avoid multistationarity. Varying parameter values representing functional genetic variation, we have analysed the coefficient of variation (CV of the gene product concentrations in the stable state for the regulating genes in absolute terms and compared to the CV for the unregulating downstream gene. The sigmoidal or binary dose-response functions in these models can be considered as phenomenological models of the aggregated effects on protein or mRNA expression rates of all cellular reactions involved in gene expression. Results For all the models, threshold robustness increases with increasing response steepness. The CVs of the regulating genes are significantly smaller than for the unregulating gene, in particular for steep responses. The effect becomes less prominent as steepnesses approach Michaelis-Menten conditions. If the parameter perturbation shifts the equilibrium value too far away from threshold, the gene product is no longer an effective regulator and robustness is lost. Threshold robustness arises when a variable is an active regulator around its threshold, and this function is maintained by

  13. Genetically modified mouse models addressing gonadotropin function.

    Science.gov (United States)

    Ratner, Laura D; Rulli, Susana B; Huhtaniemi, Ilpo T

    2014-03-01

    The development of genetically modified animals has been useful to understand the mechanisms involved in the regulation of the gonadotropin function. It is well known that alterations in the secretion of a single hormone is capable of producing profound reproductive abnormalities. Human chorionic gonadotropin (hCG) is a glycoprotein hormone normally secreted by the human placenta, and structurally and functionally it is related to pituitary LH. LH and hCG bind to the same LH/hCG receptor, and hCG is often used as an analog of LH to boost gonadotropin action. There are many physiological and pathological conditions where LH/hCG levels and actions are elevated. In order to understand how elevated LH/hCG levels may impact on the hypothalamic-pituitary-gonadal axis we have developed a transgenic mouse model with chronic hCG hypersecretion. Female mice develop many gonadal and extragonadal phenotypes including obesity, infertility, hyperprolactinemia, and pituitary and mammary gland tumors. This article summarizes recent findings on the mechanisms involved in pituitary gland tumorigenesis and hyperprolactinemia in the female mice hypersecreting hCG, in particular the relationship of progesterone with the hyperprolactinemic condition of the model. In addition, we describe the role of hyperprolactinemia as the main cause of infertility and the phenotypic abnormalities in these mice, and the use of dopamine agonists bromocriptine and cabergoline to normalize these conditions. Copyright © 2014 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  14. Genetic models of homosexuality: generating testable predictions.

    Science.gov (United States)

    Gavrilets, Sergey; Rice, William R

    2006-12-22

    Homosexuality is a common occurrence in humans and other species, yet its genetic and evolutionary basis is poorly understood. Here, we formulate and study a series of simple mathematical models for the purpose of predicting empirical patterns that can be used to determine the form of selection that leads to polymorphism of genes influencing homosexuality. Specifically, we develop theory to make contrasting predictions about the genetic characteristics of genes influencing homosexuality including: (i) chromosomal location, (ii) dominance among segregating alleles and (iii) effect sizes that distinguish between the two major models for their polymorphism: the overdominance and sexual antagonism models. We conclude that the measurement of the genetic characteristics of quantitative trait loci (QTLs) found in genomic screens for genes influencing homosexuality can be highly informative in resolving the form of natural selection maintaining their polymorphism.

  15. A Mouse Model for Conditional Secretion of Specific Single-Chain Antibodies Provides Genetic Evidence for Regulation of Cortical Plasticity by a Non-cell Autonomous Homeoprotein Transcription Factor.

    Directory of Open Access Journals (Sweden)

    Clémence Bernard

    2016-05-01

    Full Text Available During postnatal life the cerebral cortex passes through critical periods of plasticity allowing its physiological adaptation to the environment. In the visual cortex, critical period onset and closure are influenced by the non-cell autonomous activity of the Otx2 homeoprotein transcription factor, which regulates the maturation of parvalbumin-expressing inhibitory interneurons (PV cells. In adult mice, the maintenance of a non-plastic adult state requires continuous Otx2 import by PV cells. An important source of extra-cortical Otx2 is the choroid plexus, which secretes Otx2 into the cerebrospinal fluid. Otx2 secretion and internalization requires two small peptidic domains that are part of the DNA-binding domain. Thus, mutating these "transfer" sequences also modifies cell autonomous transcription, precluding this approach to obtain a cell autonomous-only mouse. Here, we develop a mouse model with inducible secretion of an anti-Otx2 single-chain antibody to trap Otx2 in the extracellular milieu. Postnatal secretion of this single-chain antibody by PV cells delays PV maturation and reduces plasticity gene expression. Induced adult expression of this single-chain antibody in cerebrospinal fluid decreases Otx2 internalization by PV cells, strongly induces plasticity gene expression and reopens physiological plasticity. We provide the first mammalian genetic evidence for a signaling mechanism involving intercellular transfer of a homeoprotein transcription factor. Our single-chain antibody mouse model is a valid strategy for extracellular neutralization that could be applied to other homeoproteins and signaling molecules within and beyond the nervous system.

  16. Complement regulators in human disease: lessons from modern genetics.

    Science.gov (United States)

    K Liszewski, M; Atkinson, J P

    2015-03-01

    First identified in human serum in the late 19th century as a 'complement' to antibodies in mediating bacterial lysis, the complement system emerged more than a billion years ago probably as the first humoral immune system. The contemporary complement system consists of nearly 60 proteins in three activation pathways (classical, alternative and lectin) and a terminal cytolytic pathway common to all. Modern molecular biology and genetics have not only led to further elucidation of the structure of complement system components, but have also revealed function-altering rare variants and common polymorphisms, particularly in regulators of the alternative pathway, that predispose to human disease by creating 'hyperinflammatory complement phenotypes'. To treat these 'complementopathies', a monoclonal antibody against the initiator of the membrane attack complex, C5, has received approval for use. Additional therapeutic reagents are on the horizon.

  17. Genetically modified organisms in light of domestic and world regulations

    Directory of Open Access Journals (Sweden)

    Nikolić Zorica

    2007-01-01

    Full Text Available At the same time as development and registration of new genetic modification of plant species have intensified, the number of countries in which they are grown has also increased considerably. Genetically modified crops were grown in 22 countries in 2006, six of which were in European Union. Protocol on Biosafety, known as Cartagena protocol was adopted at the international level in February, 2000. Presence, but not growing of GMO in food is allowed in many countries, while in some others labeling of food origination from GMO is obligatory. Labeling is obligatory in European Union, Australia, New Zealand, Japan, Norway, Switzerland and some others. In our country the Law on GMO and sub-law acts were conceived according to EU regulative. The terms for limited use, production, trade of GMO and GMO products have been prescribed. Validation and standardization of GMO testing methods are now being implemented. It is expected that the analytical GMO methods will soon be harmonized at the international level. .

  18. Genomic regulation of type 2 diabetes endophenotypes: Contribution from genetic studies in the Goto-Kakizaki rat.

    Science.gov (United States)

    Bihoreau, Marie-Thérèse; Dumas, Marc-Emmanuel; Lathrop, Mark; Gauguier, Dominique

    2017-08-24

    The inbred Goto-Kakizaki (GK) rat strain is a unique model of spontaneous type 2 diabetes mellitus caused by naturally occurring genetic variants that have been selectively isolated from an outbred colony of Wistar rats. Genetic and genomic studies in experimental crosses and congenic strains of the GK have shed light on the complex etiopathogenesis of diabetes phenotypes in this model. Diabetes-related phenotypes in the GK are under polygenic control and distinct genetic loci regulate glucose tolerance, insulin secretion, β-cell mass and plasma lipids. Metabolome and transcriptome profiling data in GK crosses and congenics, combined with GK genome resequencing, have resulted in a comprehensive landscape of genomic regulations of metabolism that can disentangle causal relationships between GK variants and diabetes phenotypes. Application of systems biology and systems genetics in the GK has contributed to improve our understanding of the fundamental mechanisms regulating metabolism. The wealth of physiological, genetic and genomic information in this strain makes it one of the most powerful model systems to improve our understanding of genetic regulations of metabolism and for testing therapeutic solutions for diabetes. Copyright © 2017. Published by Elsevier B.V.

  19. Genetic models for CNS inflammation

    DEFF Research Database (Denmark)

    Owens, T; Wekerle, H; Antel, J

    2001-01-01

    The use of transgenic technology to over-express or prevent expression of genes encoding molecules related to inflammation has allowed direct examination of their role in experimental disease. This article reviews transgenic and knockout models of CNS demyelinating disease, focusing primarily on ...

  20. Genetic mouse models to study blood–brain barrier development and function

    OpenAIRE

    Sohet, Fabien; Daneman, Richard

    2013-01-01

    The blood–brain barrier (BBB) is a complex physiological structure formed by the blood vessels of the central nervous system (CNS) that tightly regulates the movement of substances between the blood and the neural tissue. Recently, the generation and analysis of different genetic mouse models has allowed for greater understanding of BBB development, how the barrier is regulated during health, and its response to disease. Here we discuss: 1) Genetic mouse models that have been used to study th...

  1. From classical genetics to quantitative genetics to systems biology: modeling epistasis.

    Directory of Open Access Journals (Sweden)

    David L Aylor

    2008-03-01

    Full Text Available Gene expression data has been used in lieu of phenotype in both classical and quantitative genetic settings. These two disciplines have separate approaches to measuring and interpreting epistasis, which is the interaction between alleles at different loci. We propose a framework for estimating and interpreting epistasis from a classical experiment that combines the strengths of each approach. A regression analysis step accommodates the quantitative nature of expression measurements by estimating the effect of gene deletions plus any interaction. Effects are selected by significance such that a reduced model describes each expression trait. We show how the resulting models correspond to specific hierarchical relationships between two regulator genes and a target gene. These relationships are the basic units of genetic pathways and genomic system diagrams. Our approach can be extended to analyze data from a variety of experiments, multiple loci, and multiple environments.

  2. A genetic strategy to measure circulating Drosophila insulin reveals genes regulating insulin production and secretion.

    Science.gov (United States)

    Park, Sangbin; Alfa, Ronald W; Topper, Sydni M; Kim, Grace E S; Kockel, Lutz; Kim, Seung K

    2014-08-01

    Insulin is a major regulator of metabolism in metazoans, including the fruit fly Drosophila melanogaster. Genome-wide association studies (GWAS) suggest a genetic basis for reductions of both insulin sensitivity and insulin secretion, phenotypes commonly observed in humans with type 2 diabetes mellitus (T2DM). To identify molecular functions of genes linked to T2DM risk, we developed a genetic tool to measure insulin-like peptide 2 (Ilp2) levels in Drosophila, a model organism with superb experimental genetics. Our system permitted sensitive quantification of circulating Ilp2, including measures of Ilp2 dynamics during fasting and re-feeding, and demonstration of adaptive Ilp2 secretion in response to insulin receptor haploinsufficiency. Tissue specific dissection of this reduced insulin signaling phenotype revealed a critical role for insulin signaling in specific peripheral tissues. Knockdown of the Drosophila orthologues of human T2DM risk genes, including GLIS3 and BCL11A, revealed roles of these Drosophila genes in Ilp2 production or secretion. Discovery of Drosophila mechanisms and regulators controlling in vivo insulin dynamics should accelerate functional dissection of diabetes genetics.

  3. Genetically engineered mouse models of prostate cancer

    NARCIS (Netherlands)

    Nawijn, Martijn C.; Bergman, Andreas M.; van der Poel, Henk G.

    2008-01-01

    Objectives: Mouse models of prostate cancer are used to test the contribution of individual genes to the transformation process, evaluate the collaboration between multiple genetic lesions observed in a single tumour, and perform preclinical intervention studies in prostate cancer research. Methods:

  4. Adaptive Genetic Algorithm Model for Intrusion Detection

    Directory of Open Access Journals (Sweden)

    K. S. Anil Kumar

    2012-09-01

    Full Text Available Intrusion detection systems are intelligent systems designed to identify and prevent the misuse of computer networks and systems. Various approaches to Intrusion Detection are currently being used, but they are relatively ineffective. Thus the emerging network security systems need be part of the life system and this ispossible only by embedding knowledge into the network. The Adaptive Genetic Algorithm Model - IDS comprising of K-Means clustering Algorithm, Genetic Algorithm and Neural Network techniques. Thetechnique is tested using multitude of background knowledge sets in DARPA network traffic datasets.

  5. Animal Models of Parkinson's Disease: Vertebrate Genetics

    Science.gov (United States)

    Lee, Yunjong; Dawson, Valina L.; Dawson, Ted M.

    2012-01-01

    Parkinson's disease (PD) is a complex genetic disorder that is associated with environmental risk factors and aging. Vertebrate genetic models, especially mice, have aided the study of autosomal-dominant and autosomal-recessive PD. Mice are capable of showing a broad range of phenotypes and, coupled with their conserved genetic and anatomical structures, provide unparalleled molecular and pathological tools to model human disease. These models used in combination with aging and PD-associated toxins have expanded our understanding of PD pathogenesis. Attempts to refine PD animal models using conditional approaches have yielded in vivo nigrostriatal degeneration that is instructive in ordering pathogenic signaling and in developing therapeutic strategies to cure or halt the disease. Here, we provide an overview of the generation and characterization of transgenic and knockout mice used to study PD followed by a review of the molecular insights that have been gleaned from current PD mouse models. Finally, potential approaches to refine and improve current models are discussed. PMID:22960626

  6. Zebra fish: an uncharted behavior genetic model.

    Science.gov (United States)

    Gerlai, Robert

    2003-09-01

    The zebra fish has been a preferred subject of genetic analysis. It produces a large number of offspring that can be kept in small aquaria, it can be easily mutagenized using chemical mutagens (e.g., ethyl nitrosourea [ENU]), and high-resolution genetic maps exist that aid identification of novel genes. Libraries containing large numbers of mutant fish have been generated, and the genetic mechanisms of the development of zebra fish, whose embryo is transparent, have been extensively studied. Given the extensive homology of its genome with that of other vertebrate species including our own and given the available genetic tools, zebra fish has become a popular model organism. Despite this popularity, however, surprisingly little is known about its behavior. It is argued that behavioral analysis is a powerful tool with which the function of the brain may be studied, and the zebra fish will represent an excellent subject of such analysis. The present paper is a proof of concept study that uses pharmacological manipulation (exposure to alcohol) to show that the zebra fish is amenable to the behavioral genetic analysis of aggression and thus may allow us to reveal molecular mechanisms of this behavioral phenomenon relevant to vertebrates.

  7. 75 FR 1585 - Draft Environmental Impact Statement; Determination of Regulated Status of Alfalfa Genetically...

    Science.gov (United States)

    2010-01-12

    ... Regulated Status of Alfalfa Genetically Engineered for Tolerance to the Herbicide Glyphosate AGENCY: Animal... determination on the status of the Monsanto Company and Forage Genetics International alfalfa lines designated... Monsanto/Forage Genetics International (FGI) alfalfa events J101 and J163 were no longer considered...

  8. DMPD: The Lps locus: genetic regulation of host responses to bacteriallipopolysaccharide. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 10669111 The Lps locus: genetic regulation of host responses to bacteriallipopolysa...ccharide. Qureshi ST, Gros P, Malo D. Inflamm Res. 1999 Dec;48(12):613-20. (.png) (.svg) (.html) (.csml) Show The... Lps locus: genetic regulation of host responses to bacteriallipopolysaccharide. PubmedID 10669111 Title The

  9. Practices and ethical concerns regarding preimplantation diagnosis. Who regulates preimplantation genetic diagnosis in Brazil?

    Directory of Open Access Journals (Sweden)

    B.B. Damian

    2015-01-01

    Full Text Available Preimplantation genetic diagnosis (PGD was originally developed to diagnose embryo-related genetic abnormalities for couples who present a high risk of a specific inherited disorder. Because this technology involves embryo selection, the medical, bioethical, and legal implications of the technique have been debated, particularly when it is used to select features that are not related to serious diseases. Although several initiatives have attempted to achieve regulatory harmonization, the diversity of healthcare services available and the presence of cultural differences have hampered attempts to achieve this goal. Thus, in different countries, the provision of PGD and regulatory frameworks reflect the perceptions of scientific groups, legislators, and society regarding this technology. In Brazil, several texts have been analyzed by the National Congress to regulate the use of assisted reproduction technologies. Legislative debates, however, are not conclusive, and limited information has been published on how PGD is specifically regulated. The country requires the development of new regulatory standards to ensure adequate access to this technology and to guarantee its safe practice. This study examined official documents published on PGD regulation in Brazil and demonstrated how little direct oversight of PGD currently exists. It provides relevant information to encourage reflection on a particular regulation model in a Brazilian context, and should serve as part of the basis to enable further reform of the clinical practice of PGD in the country.

  10. Regulating genetic privacy in the online health information era.

    Science.gov (United States)

    Magnusson, Roger S

    2002-01-01

    As the clinical implications of the genetic components of disease come to be better understood, there is likely to be a significant increase in the volume of genetic information held within clinical records. As patient health care records, in turn, come on-line as part of broader health information networks, there is likely to be considerable pressure in favour of special laws protecting genetic privacy. This paper reviews some of the privacy challenges posed by electronic health records, some government initiatives in this area, and notes the impact that developments in genetic testing will have upon the 'genetic content' of e-health records. Despite the sensitivity of genetic information, the paper argues against a policy of 'genetic exceptionalism', and its implications for genetic privacy laws.

  11. The genetic regulation of infant immune responses to vaccination

    Directory of Open Access Journals (Sweden)

    Melanie eNewport

    2015-02-01

    Full Text Available A number of factors are recognised to influence immune responses to vaccinations including age, gender, the dose and quality of the antigen used, the number of doses given, the route of administration and the nutritional status of the recipient. Additionally, several immunogenetic studies have identified associations between polymorphisms in genes encoding immune response proteins, both innate and adaptive, and variation in responses to vaccines. Variants in the genes encoding Toll-like receptors, HLA molecules, cytokines, cytokine receptors have associated with heterogeneity of responses to a wide range of vaccines including measles, hepatitis B, influenza A, BCG, Haemophilus influenzae type b and certain Neisseria meningitidis serotypes, amongst others. However, the vast majority of these studies have been conducted in older children and adults and there are very few data available from studies conducted in infants. This paper reviews the evidence to date that host genes influencing vaccines responses in these older population and identifies a large gap in our understanding of the genetic regulation of responses in early life. . Given the high mortality from infection in early life and the challenges of developing vaccines that generate effective immune responses in the context of the developing immune system further research on infant populations is required.

  12. Genetic Algorithm Based Microscale Vehicle Emissions Modelling

    Directory of Open Access Journals (Sweden)

    Sicong Zhu

    2015-01-01

    Full Text Available There is a need to match emission estimations accuracy with the outputs of transport models. The overall error rate in long-term traffic forecasts resulting from strategic transport models is likely to be significant. Microsimulation models, whilst high-resolution in nature, may have similar measurement errors if they use the outputs of strategic models to obtain traffic demand predictions. At the microlevel, this paper discusses the limitations of existing emissions estimation approaches. Emission models for predicting emission pollutants other than CO2 are proposed. A genetic algorithm approach is adopted to select the predicting variables for the black box model. The approach is capable of solving combinatorial optimization problems. Overall, the emission prediction results reveal that the proposed new models outperform conventional equations in terms of accuracy and robustness.

  13. Genetic regulation of nitrogen fixation in Rhizobium meliloti.

    Science.gov (United States)

    Cebolla, A; Palomares, A J

    1994-12-01

    The soil bacterium Rhizobium meliloti fixes dinitrogen when associated with root nodules formed on its plant host, Medicago sativa (alfalfa). The expression of most of the known genes required for nitrogen fixation (nif and fix genes), including the structural genes for nitrogenase, is induced in response to a decrease in oxygen concentration. Induction of nif and fix gene expression by low oxygen is physiologically relevant because a low-oxygen environment is maintained in root nodules to prevent inactivation of the highly oxygen-sensitive nitrogenase enzyme. The genes responsible for sensing and transducing the low oxygen signal, fixL and fixJ, encode proteins (FixL and FixJ, respectively) that are homologous to a large family of bacterial proteins involved in signal transduction, the two component regulatory system proteins. The two components consist of a sensor protein, to which FixL is homologous, and a response regulator protein, to which FixJ is homologous. The sensor protein respond to an activating signal by autophosphorylating and then transferring the phosphate to its cognate response regulator protein. The phosphorylated response regulator, which is often a transcriptional activator, is then able to activate its target. A cascade model of nif and fix gene regulation in R. meliloti has been proposed, whereby FixL acts as an oxygen sensor as the initial event in the cascade and transmits this information to FixJ. FixJ, which possesses a putative helix-turn-helix DNA-binding motif, then activates transcription of the nifA and fixK genes. The nifA and fixK gene products, are transcriptional activators of at least 14 other nif and fix genes.

  14. Forward Genetic Approaches for Elucidation of Novel Regulators of Lyme Arthritis Severity

    Directory of Open Access Journals (Sweden)

    Kenneth K.C. Bramwell

    2014-06-01

    Full Text Available Patients experiencing natural infection with Borrelia burgdorferi display a spectrum of associated symptoms and severity, strongly implicating the impact of genetically determined host factors in the pathogenesis of Lyme disease. Herein, we provide a summary of the host genetic factors that have been demonstrated to influence the severity and chronicity of Lyme arthritis symptoms, and a review of the resources available, current progress, and added value of a forward genetic approach for identification of novel genetic regulators.

  15. Neural-genetic synthesis for state-space controllers based on linear quadratic regulator design for eigenstructure assignment.

    Science.gov (United States)

    da Fonseca Neto, João Viana; Abreu, Ivanildo Silva; da Silva, Fábio Nogueira

    2010-04-01

    Toward the synthesis of state-space controllers, a neural-genetic model based on the linear quadratic regulator design for the eigenstructure assignment of multivariable dynamic systems is presented. The neural-genetic model represents a fusion of a genetic algorithm and a recurrent neural network (RNN) to perform the selection of the weighting matrices and the algebraic Riccati equation solution, respectively. A fourth-order electric circuit model is used to evaluate the convergence of the computational intelligence paradigms and the control design method performance. The genetic search convergence evaluation is performed in terms of the fitness function statistics and the RNN convergence, which is evaluated by landscapes of the energy and norm, as a function of the parameter deviations. The control problem solution is evaluated in the time and frequency domains by the impulse response, singular values, and modal analysis.

  16. Genetic and epigenetic regulation of YKL-40 in childhood.

    Science.gov (United States)

    Guerra, Stefano; Melén, Erik; Sunyer, Jordi; Xu, Cheng-Jian; Lavi, Iris; Benet, Marta; Bustamante, Mariona; Carsin, Anne-Elie; Dobaño, Carlota; Guxens, Mònica; Tischer, Christina; Vrijheid, Martine; Kull, Inger; Bergström, Anna; Kumar, Ashish; Söderhäll, Cilla; Gehring, Ulrike; Dijkstra, Dorieke J; van der Vlies, Pieter; Wickman, Magnus; Bousquet, Jean; Postma, Dirkje S; Anto, Josep M; Koppelman, Gerard H

    2017-07-21

    Circulating levels of the chitinase-like protein YKL-40 are influenced by genetic variation in its encoding gene (chitinase 3-like 1 [CHI3L1]) and are increased in patients with several diseases, including asthma. Epigenetic regulation of circulating YKL-40 early in life is unknown. We sought to determine (1) whether methylation levels at CHI3L1 CpG sites mediate the association of CHI3L1 single nucleotide polymorphisms (SNPs) with YKL-40 levels in the blood and (2) whether these biomarkers (CHI3L1 SNPs, methylation profiles, and YKL-40 levels) are associated with asthma in early childhood. We used data from up to 2405 participants from the Spanish Infancia y Medio Ambiente; the Swedish Barn/Children, Allergy, Milieu, Stockholm, Epidemiological survey; and the Dutch Prevention and Incidence of Asthma and Mite Allergy birth cohorts. Associations between 68 CHI3L1 SNPs, methylation levels at 14 CHI3L1 CpG sites in whole-blood DNA, and circulating YKL-40 levels at 4 years of age were tested by using correlation analysis, multivariable regression, and mediation analysis. Each of these biomarkers was also tested for association with asthma at 4 years of age by using multivariable logistic regression. YKL-40 levels were significantly associated with 7 SNPs and with methylation at 5 CpG sites. Consistent associations between these 7 SNPs (particularly rs10399931 and rs4950928) and 5 CpG sites were observed. Alleles linked to lower YKL-40 levels were associated with higher methylation levels. Participants with high YKL-40 levels (defined as the highest YKL-40 tertile) had increased odds for asthma compared with subjects with low YKL-40 levels (meta-analyzed adjusted odds ratio, 1.90 [95% CI, 1.08-3.36]). In contrast, neither SNPs nor methylation levels at CpG sites in CHI3L1 were associated with asthma. The effects of CHI3L1 genetic variation on circulating YKL-40 levels are partly mediated by methylation profiles. In our study YKL-40 levels, but not CHI3L1 SNPs or

  17. Modeling resistance to genetic control of insects.

    Science.gov (United States)

    Alphey, Nina; Bonsall, Michael B; Alphey, Luke

    2011-02-07

    The sterile insect technique is an area-wide pest control method that reduces pest populations by releasing mass-reared sterile insects which compete for mates with wild insects. Modern molecular tools have created possibilities for improving and extending the sterile insect technique. As with any new insect control method, questions arise about potential resistance. Genetic RIDL(®)(1) (Release of Insects carrying a Dominant Lethal) technology is a proposed modification of the technique, releasing insects that are homozygous for a repressible dominant lethal genetic construct rather than being sterilized by irradiation. Hypothetical resistance to the lethal mechanism is a potential threat to RIDL strategies' effectiveness. Using population genetic and population dynamic models, we assess the circumstances under which monogenic biochemically based resistance could have a significant impact on the effectiveness of releases for population control. We assume that released insects would be homozygous susceptible to the lethal genetic construct and therefore releases would have a built-in element of resistance dilution. We find that this effect could prevent or limit the spread of resistance to RIDL constructs; the outcomes are subject to competing selective forces deriving from the fitness properties of resistance and the release ratio. Resistance that is spreading and capable of having a significant detrimental impact on population reduction is identifiable, signaling in advance a need for mitigating action.

  18. Evolutionary algorithms in genetic regulatory networks model

    CERN Document Server

    Raza, Khalid

    2012-01-01

    Genetic Regulatory Networks (GRNs) plays a vital role in the understanding of complex biological processes. Modeling GRNs is significantly important in order to reveal fundamental cellular processes, examine gene functions and understanding their complex relationships. Understanding the interactions between genes gives rise to develop better method for drug discovery and diagnosis of the disease since many diseases are characterized by abnormal behaviour of the genes. In this paper we have reviewed various evolutionary algorithms-based approach for modeling GRNs and discussed various opportunities and challenges.

  19. Genetic search feature selection for affective modeling

    DEFF Research Database (Denmark)

    Martínez, Héctor P.; Yannakakis, Georgios N.

    2010-01-01

    Automatic feature selection is a critical step towards the generation of successful computational models of affect. This paper presents a genetic search-based feature selection method which is developed as a global-search algorithm for improving the accuracy of the affective models built....... The method is tested and compared against sequential forward feature selection and random search in a dataset derived from a game survey experiment which contains bimodal input features (physiological and gameplay) and expressed pairwise preferences of affect. Results suggest that the proposed method...

  20. Regulation mechanisms in spatial stochastic development models

    CERN Document Server

    Finkelshtein, Dmitri

    2008-01-01

    The aim of this paper is to analyze different regulation mechanisms in spatial continuous stochastic development models. We describe the density behavior for models with global mortality and local establishment rates. We prove that the local self-regulation via a competition mechanism (density dependent mortality) may suppress a unbounded growth of the averaged density if the competition kernel is superstable.

  1. Inferring modulators of genetic interactions with epistatic nested effects models.

    Science.gov (United States)

    Pirkl, Martin; Diekmann, Madeline; van der Wees, Marlies; Beerenwinkel, Niko; Fröhlich, Holger; Markowetz, Florian

    2017-04-01

    Maps of genetic interactions can dissect functional redundancies in cellular networks. Gene expression profiles as high-dimensional molecular readouts of combinatorial perturbations provide a detailed view of genetic interactions, but can be hard to interpret if different gene sets respond in different ways (called mixed epistasis). Here we test the hypothesis that mixed epistasis between a gene pair can be explained by the action of a third gene that modulates the interaction. We have extended the framework of Nested Effects Models (NEMs), a type of graphical model specifically tailored to analyze high-dimensional gene perturbation data, to incorporate logical functions that describe interactions between regulators on downstream genes and proteins. We benchmark our approach in the controlled setting of a simulation study and show high accuracy in inferring the correct model. In an application to data from deletion mutants of kinases and phosphatases in S. cerevisiae we show that epistatic NEMs can point to modulators of genetic interactions. Our approach is implemented in the R-package 'epiNEM' available from https://github.com/cbg-ethz/epiNEM and https://bioconductor.org/packages/epiNEM/.

  2. Modeling sRNA-Regulated Plasmid Maintenance

    Science.gov (United States)

    Klumpp, Stefan

    2017-01-01

    We study a theoretical model for the toxin-antitoxin (hok/sok) mechanism for plasmid maintenance in bacteria. Toxin-antitoxin systems enforce the maintenance of a plasmid through post-segregational killing of cells that have lost the plasmid. Key to their function is the tight regulation of expression of a protein toxin by an sRNA antitoxin. Here, we focus on the nonlinear nature of the regulatory circuit dynamics of the toxin-antitoxin mechanism. The mechanism relies on a transient increase in protein concentration rather than on the steady state of the genetic circuit. Through a systematic analysis of the parameter dependence of this transient increase, we confirm some known design features of this system and identify new ones: for an efficient toxin-antitoxin mechanism, the synthesis rate of the toxin’s mRNA template should be lower that of the sRNA antitoxin, the mRNA template should be more stable than the sRNA antitoxin, and the mRNA-sRNA complex should be more stable than the sRNA antitoxin. Moreover, a short half-life of the protein toxin is also beneficial to the function of the toxin-antitoxin system. In addition, we study a therapeutic scenario in which a competitor mRNA is introduced to sequester the sRNA antitoxin, causing the toxic protein to be expressed. PMID:28085919

  3. Modeling sRNA-regulated Plasmid Maintenance

    CERN Document Server

    Gong, Chen Chris

    2016-01-01

    We study a theoretical model for the toxin-antitoxin (hok/sok) mechanism for plasmid maintenance in bacteria. Toxin-antitoxin systems enforce the maintenance of a plasmid through post-segregational killing of cells that have lost the plasmid. Key to their function is the tight regulation of expression of a protein toxin by an sRNA antitoxin. Here, we focus on the nonlinear nature of the regulatory circuit dynamics of the toxin-antitoxin mechanism. The mechanism relies on a transient increase in protein concentration rather than on the steady state of the genetic circuit. Through a systematic analysis of the parameter dependence of this transient increase, we confirm some known design features of this system and identify new ones: for an efficient toxin-antitoxin mechanism, the synthesis rate of the toxin's mRNA template should be lower that of the sRNA antitoxin, the mRNA template should be more stable than the sRNA antitoxin, and the mRNA-sRNA complex should be more stable than the sRNA antitoxin. Moreover, ...

  4. Synchronization of Discrete-Time Chaotic Fuzzy Systems by means of Fuzzy Output Regulation Using Genetic Algorithm

    Directory of Open Access Journals (Sweden)

    Tonatiuh Hernández Cortés

    2015-01-01

    Full Text Available The synchronization of chaotic systems, described by discrete-time T-S fuzzy models, is treated by means of fuzzy output regulation theory. The conditions for designing a discrete-time output regulator are given in this paper. Besides, when the system does not fulfill the conditions for exact tracking, a new regulator based on genetic algorithms is considered. The genetic algorithms are used to approximate the adequate membership functions, which allow the adequate combination of local regulators. As a result, the tracking error is significantly reduced. Both the Complete Synchronization and the Generalized Synchronization problem are studied. Some numerical examples are used to illustrate the effectiveness of the proposed approach.

  5. An animal model of differential genetic risk for methamphetamine intake

    Directory of Open Access Journals (Sweden)

    Tamara ePhillips

    2015-09-01

    Full Text Available The question of whether genetic factors contribute to risk for methamphetamine (MA use and dependence has not been intensively investigated. Compared to human populations, genetic animal models offer the advantages of control over genetic family history and drug exposure. Using selective breeding, we created lines of mice that differ in genetic risk for voluntary MA intake and identified the chromosomal addresses of contributory genes. A quantitative trait locus was identified on chromosome 10 that accounts for more than 50% of the genetic variance in MA intake in the selected mouse lines. In addition, behavioral and physiological screening identified differences corresponding with risk for MA intake that have generated hypotheses that are testable in humans. Heightened sensitivity to aversive and certain physiological effects of MA, such as MA-induced reduction in body temperature, are hallmarks of mice bred for low MA intake. Furthermore, unlike MA-avoiding mice, MA-preferring mice are sensitive to rewarding and reinforcing MA effects, and to MA-induced increases in brain extracellular dopamine levels. Gene expression analyses implicate the importance of a network enriched in transcription factor genes, some of which regulate the mu opioid receptor gene, Oprm1, in risk for MA use. Neuroimmune factors appear to play a role in differential response to MA between the mice bred for high and low intake. In addition, chromosome 10 candidate gene studies provide strong support for a trace amine associated receptor 1 gene, Taar1, polymorphism in risk for MA intake. MA is a trace amine-associated receptor 1 (TAAR1 agonist, and a non-functional Taar1 allele segregates with high MA consumption. Thus, reduced TAAR1 function has the potential to increase risk for MA use. Overall, existing findings support the MA drinking lines as a powerful model for identifying genetic factors involved in determining risk for harmful MA use. Future directions include the

  6. Latent spatial models and sampling design for landscape genetics

    Science.gov (United States)

    Hanks, Ephraim M.; Hooten, Mevin B.; Knick, Steven T.; Oyler-McCance, Sara J.; Fike, Jennifer A.; Cross, Todd B.; Schwartz, Michael K.

    2016-01-01

    We propose a spatially-explicit approach for modeling genetic variation across space and illustrate how this approach can be used to optimize spatial prediction and sampling design for landscape genetic data. We propose a multinomial data model for categorical microsatellite allele data commonly used in landscape genetic studies, and introduce a latent spatial random effect to allow for spatial correlation between genetic observations. We illustrate how modern dimension reduction approaches to spatial statistics can allow for efficient computation in landscape genetic statistical models covering large spatial domains. We apply our approach to propose a retrospective spatial sampling design for greater sage-grouse (Centrocercus urophasianus) population genetics in the western United States.

  7. Large genetic animal models of Huntington's Disease.

    Science.gov (United States)

    Morton, A Jennifer; Howland, David S

    2013-01-01

    The dominant nature of the Huntington's disease gene mutation has allowed genetic models to be developed in multiple species, with the mutation causing an abnormal neurological phenotype in all animals in which it is expressed. Many different rodent models have been generated. The most widely used of these, the transgenic R6/2 mouse, carries the mutation in a fragment of the human huntingtin gene and has a rapidly progressive and fatal neurological phenotype with many relevant pathological changes. Nevertheless, their rapid decline has been frequently questioned in the context of a disease that takes years to manifest in humans, and strenuous efforts have been made to make rodent models that are genetically more 'relevant' to the human condition, including full length huntingtin gene transgenic and knock-in mice. While there is no doubt that we have learned, and continue to learn much from rodent models, their usefulness is limited by two species constraints. First, the brains of rodents differ significantly from humans in both their small size and their neuroanatomical organization. Second, rodents have much shorter lifespans than humans. Here, we review new approaches taken to these challenges in the development of models of Huntington's disease in large brained, long-lived animals. We discuss the need for such models, and how they might be used to fill specific niches in preclinical Huntington's disease research, particularly in testing gene-based therapeutics. We discuss the advantages and disadvantages of animals in which the prodromal period of disease extends over a long time span. We suggest that there is considerable 'value added' for large animal models in preclinical Huntington's disease research.

  8. Genetic mouse models for otitis media

    Institute of Scientific and Technical Information of China (English)

    Qingyin Zheng; Ken R Johnson

    2003-01-01

    @@ Genetics of Otitis Media (OM): OM is affected by multiple factors including eustachian tube (ET) structure and function, immune status, innate mucosal defense, genetic susceptibility, and pathogens.

  9. GENETIC-BASED NUTRITION RECOMMENDATION MODEL

    Directory of Open Access Journals (Sweden)

    S. A.A. Fayoumi

    2014-01-01

    Full Text Available Evolutionary computing is the collective name for a range of problem-solving techniques based on principles of biological evolution, such as natural selection and genetic inheritance. These techniques are being widely applied to a variety of problems in many vital fields. Also, Evolutionary Algorithms (EA which applied the principles of Evolutionary computations, such as genetic algorithm, particle swarm, ant colony and bees algorithm and so on play an important role in decision making process. EAs serve a lot of fields which can affect our life directly, such as medicine, engineering, transportations, communications. One of these vital fields is Nutrition which can be viewed from several points of view as medical, physical, social, environmental and psychological point of view. This study, presents a proposed model that shows how evolutionary computing generally and genetic algorithm specifically-as a powerful algorithm of evolutionary algorithms-can be used to recommend an appropriate nutrition style in a medical and physical sides only to each person according to his/her personal and medical measurements.

  10. DMPD: Genetic regulation of macrophage priming/activation: the Lsh gene story. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 1757110 Genetic regulation of macrophage priming/activation: the Lsh gene story. Bl... (.svg) (.html) (.csml) Show Genetic regulation of macrophage priming/activation: the Lsh gene story. Pubmed...ID 1757110 Title Genetic regulation of macrophage priming/activation: the Lsh gen

  11. Medulloblastoma: Molecular Genetics and Animal Models

    Directory of Open Access Journals (Sweden)

    Corey Raffel

    2004-07-01

    Full Text Available Medulloblastoma is a primary brain tumor found in the cerebellum of children. The tumor occurs in association with two inherited cancer syndromes: Turcot syndrome and Gorlin syndrome. Insights into the molecular biology of the tumor have come from looking at alterations in the genes altered in these syndromes, PTC and APC, respectively. Murine models of medulloblastoma have been constructed based on these alterations. Additional murine models that, while mimicking the appearance of the human tumor, seem unrelated to the human tumor's molecular alterations have been made. In this review, the clinical picture, origin, molecular biology, murine models of medulloblastoma are discussed. Although a great deal has been discovered about this tumor, the genetic alterations responsible for tumor development in a majority of patients have yet to be described.

  12. Genetically engineered mouse models and human osteosarcoma

    Directory of Open Access Journals (Sweden)

    Ng Alvin JM

    2012-10-01

    Full Text Available Abstract Osteosarcoma is the most common form of bone cancer. Pivotal insight into the genes involved in human osteosarcoma has been provided by the study of rare familial cancer predisposition syndromes. Three kindreds stand out as predisposing to the development of osteosarcoma: Li-Fraumeni syndrome, familial retinoblastoma and RecQ helicase disorders, which include Rothmund-Thomson Syndrome in particular. These disorders have highlighted the important roles of P53 and RB respectively, in the development of osteosarcoma. The association of OS with RECQL4 mutations is apparent but the relevance of this to OS is uncertain as mutations in RECQL4 are not found in sporadic OS. Application of the knowledge or mutations of P53 and RB in familial and sporadic OS has enabled the development of tractable, highly penetrant murine models of OS. These models share many of the cardinal features associated with human osteosarcoma including, importantly, a high incidence of spontaneous metastasis. The recent development of these models has been a significant advance for efforts to improve our understanding of the genetics of human OS and, more critically, to provide a high-throughput genetically modifiable platform for preclinical evaluation of new therapeutics.

  13. Genetic Algorithms Principles Towards Hidden Markov Model

    Directory of Open Access Journals (Sweden)

    Nabil M. Hewahi

    2011-10-01

    Full Text Available In this paper we propose a general approach based on Genetic Algorithms (GAs to evolve Hidden Markov Models (HMM. The problem appears when experts assign probability values for HMM, they use only some limited inputs. The assigned probability values might not be accurate to serve in other cases related to the same domain. We introduce an approach based on GAs to find
    out the suitable probability values for the HMM to be mostly correct in more cases than what have been used to assign the probability values.

  14. Genetic Programming for Automatic Hydrological Modelling

    Science.gov (United States)

    Chadalawada, Jayashree; Babovic, Vladan

    2017-04-01

    One of the recent challenges for the hydrologic research community is the need for the development of coupled systems that involves the integration of hydrologic, atmospheric and socio-economic relationships. This poses a requirement for novel modelling frameworks that can accurately represent complex systems, given, the limited understanding of underlying processes, increasing volume of data and high levels of uncertainity. Each of the existing hydrological models vary in terms of conceptualization and process representation and is the best suited to capture the environmental dynamics of a particular hydrological system. Data driven approaches can be used in the integration of alternative process hypotheses in order to achieve a unified theory at catchment scale. The key steps in the implementation of integrated modelling framework that is influenced by prior understanding and data, include, choice of the technique for the induction of knowledge from data, identification of alternative structural hypotheses, definition of rules, constraints for meaningful, intelligent combination of model component hypotheses and definition of evaluation metrics. This study aims at defining a Genetic Programming based modelling framework that test different conceptual model constructs based on wide range of objective functions and evolves accurate and parsimonious models that capture dominant hydrological processes at catchment scale. In this paper, GP initializes the evolutionary process using the modelling decisions inspired from the Superflex framework [Fenicia et al., 2011] and automatically combines them into model structures that are scrutinized against observed data using statistical, hydrological and flow duration curve based performance metrics. The collaboration between data driven and physical, conceptual modelling paradigms improves the ability to model and manage hydrologic systems. Fenicia, F., D. Kavetski, and H. H. Savenije (2011), Elements of a flexible approach

  15. Genetic and Environmental Regulation on Longitudinal Change of Metabolic Phenotypes in Danish and Chinese Adult Twins.

    Science.gov (United States)

    Li, Shuxia; Kyvik, Kirsten Ohm; Pang, Zengchang; Zhang, Dongfeng; Duan, Haiping; Tan, Qihua; Hjelmborg, Jacob; Kruse, Torben; Dalgård, Christine

    2016-01-01

    The rate of change in metabolic phenotypes can be highly indicative of metabolic disorders and disorder-related modifications. We analyzed data from longitudinal twin studies on multiple metabolic phenotypes in Danish and Chinese twins representing two populations of distinct ethnic, cultural, social-economic backgrounds and geographical environments. The study covered a relatively large sample of 502 pairs of Danish adult twins followed up for a long period of 12 years with a mean age at intake of 38 years (range: 18-65) and a total of 181 Chinese adult twin pairs traced for about 7 years with a mean baseline age of 39.5 years (range: 23-64). The classical twin models were fitted to the longitudinal change in each phenotype (Δphenotype) to estimate the genetic and environmental contributions to the variation in Δphenotype. Moderate to high contributions by the unique environment were estimated for all phenotypes in both Danish (from 0.51 for low density lipoprotein cholesterol up to 0.72 for triglycerides) and Chinese (from 0.41 for triglycerides up to 0.73 for diastolic blood pressure) twins; low to moderate genetic components were estimated for long-term change in most of the phenotypes in Danish twins except for triglycerides and hip circumference. Compared with Danish twins, the Chinese twins tended to have higher genetic control over the longitudinal changes in lipids (except high density lipoprotein cholesterol) and glucose, higher unique environmental contribution to blood pressure but no genetic contribution to longitudinal change in body mass traits. Our results emphasize the major contribution of unique environment to the observed intra-individual variation in all metabolic phenotypes in both samples, and meanwhile reveal differential patterns of genetic and common environmental regulation on changes over time in metabolic phenotypes across the two samples.

  16. Genetically modified organisms in light of domestic and world regulations

    OpenAIRE

    Nikolić Zorica; Milošević Mirjana; Vujaković Milka; Ignjatov Maja

    2007-01-01

    At the same time as development and registration of new genetic modification of plant species have intensified, the number of countries in which they are grown has also increased considerably. Genetically modified crops were grown in 22 countries in 2006, six of which were in European Union. Protocol on Biosafety, known as Cartagena protocol was adopted at the international level in February, 2000. Presence, but not growing of GMO in food is allowed in many countries, while in some others lab...

  17. Models of genetic counseling and their effects on multicultural genetic counseling.

    Science.gov (United States)

    Lewis, Linwood J

    2002-06-01

    This theoretical paper examines challenges to multicultural genetic counseling, counseling between culturally different clients and counselors, in the context of Kessler's typology of models of genetic counseling (Kessler S (1997) J Genet Counsel 6:287-295). It is suggested that challenges such as resistance to multicultural genetic counseling education may be due to conceptions about genetic counseling as a biomedical field that transcends questions of culture as well as lack of multicultural training or prejudice. Directions for future research and recommendations for multicultural genetic counseling education are briefly explored.

  18. Large animal models of rare genetic disorders: sheep as phenotypically relevant models of human genetic disease.

    Science.gov (United States)

    Pinnapureddy, Ashish R; Stayner, Cherie; McEwan, John; Baddeley, Olivia; Forman, John; Eccles, Michael R

    2015-09-02

    Animals that accurately model human disease are invaluable in medical research, allowing a critical understanding of disease mechanisms, and the opportunity to evaluate the effect of therapeutic compounds in pre-clinical studies. Many types of animal models are used world-wide, with the most common being small laboratory animals, such as mice. However, rodents often do not faithfully replicate human disease, despite their predominant use in research. This discordancy is due in part to physiological differences, such as body size and longevity. In contrast, large animal models, including sheep, provide an alternative to mice for biomedical research due to their greater physiological parallels with humans. Completion of the full genome sequences of many species, and the advent of Next Generation Sequencing (NGS) technologies, means it is now feasible to screen large populations of domesticated animals for genetic variants that resemble human genetic diseases, and generate models that more accurately model rare human pathologies. In this review, we discuss the notion of using sheep as large animal models, and their advantages in modelling human genetic disease. We exemplify several existing naturally occurring ovine variants in genes that are orthologous to human disease genes, such as the Cln6 sheep model for Batten disease. These, and other sheep models, have contributed significantly to our understanding of the relevant human disease process, in addition to providing opportunities to trial new therapies in animals with similar body and organ size to humans. Therefore sheep are a significant species with respect to the modelling of rare genetic human disease, which we summarize in this review.

  19. The genetic and molecular regulation of sleep: from fruit flies to humans

    OpenAIRE

    Cirelli, Chiara

    2009-01-01

    It has been known for a long time that genetic factors affect sleep quantity and quality. Genetic screens identified several mutations that affect sleep across species, pointing to an evolutionary conserved regulation of sleep. Moreover, it has also been recognized that sleep affects the expression of genes. These findings have given valuable clues about the molecular underpinnings of sleep regulation and function that might lead the way to more efficient treatments for sleep disorders.

  20. Warehouse Optimization Model Based on Genetic Algorithm

    Directory of Open Access Journals (Sweden)

    Guofeng Qin

    2013-01-01

    Full Text Available This paper takes Bao Steel logistics automated warehouse system as an example. The premise is to maintain the focus of the shelf below half of the height of the shelf. As a result, the cost time of getting or putting goods on the shelf is reduced, and the distance of the same kind of goods is also reduced. Construct a multiobjective optimization model, using genetic algorithm to optimize problem. At last, we get a local optimal solution. Before optimization, the average cost time of getting or putting goods is 4.52996 s, and the average distance of the same kinds of goods is 2.35318 m. After optimization, the average cost time is 4.28859 s, and the average distance is 1.97366 m. After analysis, we can draw the conclusion that this model can improve the efficiency of cargo storage.

  1. Relationship of disease-associated gene expression to cardiac phenotype is buffered by genetic diversity and chromatin regulation.

    Science.gov (United States)

    Karbassi, Elaheh; Monte, Emma; Chapski, Douglas J; Lopez, Rachel; Rosa Garrido, Manuel; Kim, Joseph; Wisniewski, Nicholas; Rau, Christoph D; Wang, Jessica J; Weiss, James N; Wang, Yibin; Lusis, Aldons J; Vondriska, Thomas M

    2016-08-01

    Expression of a cohort of disease-associated genes, some of which are active in fetal myocardium, is considered a hallmark of transcriptional change in cardiac hypertrophy models. How this transcriptome remodeling is affected by the common genetic variation present in populations is unknown. We examined the role of genetics, as well as contributions of chromatin proteins, to regulate cardiac gene expression and heart failure susceptibility. We examined gene expression in 84 genetically distinct inbred strains of control and isoproterenol-treated mice, which exhibited varying degrees of disease. Unexpectedly, fetal gene expression was not correlated with hypertrophic phenotypes. Unbiased modeling identified 74 predictors of heart mass after isoproterenol-induced stress, but these predictors did not enrich for any cardiac pathways. However, expanded analysis of fetal genes and chromatin remodelers as groups correlated significantly with individual systemic phenotypes. Yet, cardiac transcription factors and genes shown by gain-/loss-of-function studies to contribute to hypertrophic signaling did not correlate with cardiac mass or function in disease. Because the relationship between gene expression and phenotype was strain specific, we examined genetic contribution to expression. Strikingly, strains with similar transcriptomes in the basal heart did not cluster together in the isoproterenol state, providing comprehensive evidence that there are different genetic contributors to physiological and pathological gene expression. Furthermore, the divergence in transcriptome similarity versus genetic similarity between strains is organ specific and genome-wide, suggesting chromatin is a critical buffer between genetics and gene expression.

  2. Molecular and Genetic Analysis of Hormone-Regulated Differential Cell Elongation in Arabidopsis

    Energy Technology Data Exchange (ETDEWEB)

    Ecker, Joseph R.

    2005-09-15

    We have utilized the response of Arabidopsis seedlings to the plant hormone ethylene to identify new genes involved in the regulation of ethylene biosynthesis, perception, signal transduction and differential cell growth. In building a genetic framework for the action of these genes, we have developed a molecular model that has facilitated our understanding of the molecular requirements of ethylene for cell elongation processes. The ethylene response pathway in Arabidopsis appears to be primarily linear and is defined by the genes: ETR1, ETR2, ERS1, ERS2, EIN4, CTR1, EIN2, EIN3, EIN5, EIN6, and EIN. Downstream branches identified by the HLS1, EIR1, and AUX1 genes involve interactions with other hormonal (auxin) signals in the process of differential cell elongation in the hypocotyl hook. Cloning and characterization of HLS1 (and three HLL genes) and ETO1 (and ETOL genes) in my laboratory has been supported under this award. HLS1 is required for differential elongation of cells in the hypocotyl and may act in the establishment of hormone gradients. Also during the previous period, we have identified and characterized a gene that genetically acts upstream of the ethylene receptors. ETO1 encodes negative regulators of ethylene biosynthesis.

  3. Molecular and Genetic Analysis of Hormone-Regulated Differential Cell Elongation in Arabidopsis

    Energy Technology Data Exchange (ETDEWEB)

    Ecker, Joseph R.

    2002-12-03

    The authors have utilized the response of Arabidopsis seedlings to the plant hormone ethylene to identify new genes involved in the regulation of ethylene biosynthesis, perception, signal transduction and differential cell growth. In building a genetic framework for the action of these genes, they developed a molecular model that has facilitated the understanding of the molecular requirements of ethylene for cell elongation processes. The ethylene response pathway in Arabidopsis appears to be primarily linear and is defined by the genes: ETR1, ETR2, ERS1, ERS2, EIN4, CTR1, EIN2, EIN3, EIN5 EIN6, and EIN. Downstream branches identified by the HLS1, EIR1, and AUX1 genes involve interactions with other hormonal (auxin) signals in the process of differential cell elongation in the hypocotyl hook. Cloning and characterization of HLS1 and three HLS1-LIKE genes in the laboratory has been supported under this award. HLS1 is required for differential elongation of cells in the hypocotyl and may act in the establishment of hormone gradients. Also during the award period, they have identified and begun preliminary characterization of two genes that genetically act upstream of the ethylene receptors. ETO1 and RAN1 encode negative regulators of ethylene biosynthesis and signaling respectively. Progress on the analysis of these genes along with HOOKLESS1 is described.

  4. Genetic spectrum assignment model with constraints in cognitive radio networks

    Directory of Open Access Journals (Sweden)

    Fang Ye

    2011-06-01

    Full Text Available The interference constraints of genetic spectrum assignment model in cognitive radio networks are analyzed in this paper. An improved genetic spectrum assignment model is proposed. The population of genetic algorithm is divided into two sets, the feasible spectrum assignment strategies and the randomly updated spectrum assignment strategies. The penalty function is added to the utility function to achieve the spectrum assignment strategy that satisfies the interference constraints and has better fitness. The proposed method is applicable in both the genetic spectrum assignment model and the quantum genetic spectrum assignment mode. It can ensure the randomness of partial chromosomes in the population to some extent, and reduce the computational complexity caused by the constraints-free procedure after the update of population. Simulation results show that the proposed method can achieve better performance than the conventional genetic spectrum assignment model and quantum genetic spectrum assignment model

  5. Dynamic model of gene regulation for the lac operon

    Energy Technology Data Exchange (ETDEWEB)

    Angelova, Maia; Ben-Halim, Asma, E-mail: maia.angelova@northumbria.ac.uk, E-mail: asma.benhalim@northumbria.ac.uk [Intelligent Modelling Lab, School of Computing, Engineering and Information Sciences, Northumbria University, Newcastle upon Tyne NE2 1XE (United Kingdom)

    2011-03-01

    Gene regulatory network is a collection of DNA which interact with each other and with other matter in the cell. The lac operon is an example of a relatively simple genetic network and is one of the best-studied structures in the Escherichia coli bacteria. In this work we consider a deterministic model of the lac operon with a noise term, representing the stochastic nature of the regulation. The model is written in terms of a system of simultaneous first order differential equations with delays. We investigate an analytical and numerical solution and analyse the range of values for the parameters corresponding to a stable solution.

  6. Genetic mouse models of brain ageing and Alzheimer's disease.

    Science.gov (United States)

    Bilkei-Gorzo, Andras

    2014-05-01

    Progression of brain ageing is influenced by a complex interaction of genetic and environmental factors. Analysis of genetically modified animals with uniform genetic backgrounds in a standardised, controlled environment enables the dissection of critical determinants of brain ageing on a molecular level. Human and animal studies suggest that increased load of damaged macromolecules, efficacy of DNA maintenance, mitochondrial activity, and cellular stress defences are critical determinants of brain ageing. Surprisingly, mouse lines with genetic impairment of anti-oxidative capacity generally did not show enhanced cognitive ageing but rather an increased sensitivity to oxidative challenge. Mouse lines with impaired mitochondrial activity had critically short life spans or severe and rapidly progressing neurodegeneration. Strains with impaired clearance in damaged macromolecules or defects in the regulation of cellular stress defences showed alterations in the onset and progression of cognitive decline. Importantly, reduced insulin/insulin-like growth factor signalling generally increased life span but impaired cognitive functions revealing a complex interaction between ageing of the brain and of the body. Brain ageing is accompanied by an increased risk of developing Alzheimer's disease. Transgenic mouse models expressing high levels of mutant human amyloid precursor protein showed a number of symptoms and pathophysiological processes typical for early phase of Alzheimer's disease. Generally, therapeutic strategies effective against Alzheimer's disease in humans were also active in the Tg2576, APP23, APP/PS1 and 5xFAD lines, but a large number of false positive findings were also reported. The 3xtg AD model likely has the highest face and construct validity but further studies are needed. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Controversies about the genetic model of colorectal tumorigenesis.

    Science.gov (United States)

    Waliszewski, P

    1995-01-01

    According to the genetic model, intestinal tumorigenesis is a result of the ordered in time inactivation of tumor suppressor genes and the activation of oncogenes. A tacit assumption is that both genes involved in the regulation of proliferation and growth factor-inducible genes, although inactivated, would not be changed during that process. The model requires that cancer cell population is homogenous, exists in a deterministic environment, and develops in a teleological manner. Meanwhile, tumorigenesis is rather a combination of both deterministic and stochastic molecular phenomena. Therefore, a novel notion of bifurcating point genes is defined as a generalization of the idea of tumor suppressor genes and oncogenes. Alternative stochastic mechanisms of tumorigenesis are discussed such as a decreased expression of intestinal-specific genes in cancer cells, most likely reflecting adaptation to survival within a heterogeneous, and non-equilibrated cellular population.

  8. Model comparisons and genetic and environmental parameter ...

    African Journals Online (AJOL)

    arc

    South African Journal of Animal Science 2005, 35 (1) ... Genetic and environmental parameters were estimated for pre- and post-weaning average daily gain ..... and BWT (and medium maternal genetic correlations) indicates that these traits ...

  9. Mapping the genetic architecture of gene regulation in whole blood.

    Directory of Open Access Journals (Sweden)

    Katharina Schramm

    Full Text Available BACKGROUND: We aimed to assess whether whole blood expression quantitative trait loci (eQTLs with effects in cis and trans are robust and can be used to identify regulatory pathways affecting disease susceptibility. MATERIALS AND METHODS: We performed whole-genome eQTL analyses in 890 participants of the KORA F4 study and in two independent replication samples (SHIP-TREND, N = 976 and EGCUT, N = 842 using linear regression models and Bonferroni correction. RESULTS: In the KORA F4 study, 4,116 cis-eQTLs (defined as SNP-probe pairs where the SNP is located within a 500 kb window around the transcription unit and 94 trans-eQTLs reached genome-wide significance and overall 91% (92% of cis-, 84% of trans-eQTLs were confirmed in at least one of the two replication studies. Different study designs including distinct laboratory reagents (PAXgene™ vs. Tempus™ tubes did not affect reproducibility (separate overall replication overlap: 78% and 82%. Immune response pathways were enriched in cis- and trans-eQTLs and significant cis-eQTLs were partly coexistent in other tissues (cross-tissue similarity 40-70%. Furthermore, four chromosomal regions displayed simultaneous impact on multiple gene expression levels in trans, and 746 eQTL-SNPs have been previously reported to have clinical relevance. We demonstrated cross-associations between eQTL-SNPs, gene expression levels in trans, and clinical phenotypes as well as a link between eQTLs and human metabolic traits via modification of gene regulation in cis. CONCLUSIONS: Our data suggest that whole blood is a robust tissue for eQTL analysis and may be used both for biomarker studies and to enhance our understanding of molecular mechanisms underlying gene-disease associations.

  10. Genetic Algorithm Approaches to Prebiobiotic Chemistry Modeling

    Science.gov (United States)

    Lohn, Jason; Colombano, Silvano

    1997-01-01

    We model an artificial chemistry comprised of interacting polymers by specifying two initial conditions: a distribution of polymers and a fixed set of reversible catalytic reactions. A genetic algorithm is used to find a set of reactions that exhibit a desired dynamical behavior. Such a technique is useful because it allows an investigator to determine whether a specific pattern of dynamics can be produced, and if it can, the reaction network found can be then analyzed. We present our results in the context of studying simplified chemical dynamics in theorized protocells - hypothesized precursors of the first living organisms. Our results show that given a small sample of plausible protocell reaction dynamics, catalytic reaction sets can be found. We present cases where this is not possible and also analyze the evolved reaction sets.

  11. Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol.

    Science.gov (United States)

    Alvarez, Monica I; Glover, Luke C; Luo, Peter; Wang, Liuyang; Theusch, Elizabeth; Oehlers, Stefan H; Walton, Eric M; Tram, Trinh Thi Bich; Kuang, Yu-Lin; Rotter, Jerome I; McClean, Colleen M; Chinh, Nguyen Tran; Medina, Marisa W; Tobin, David M; Dunstan, Sarah J; Ko, Dennis C

    2017-09-12

    Risk, severity, and outcome of infection depend on the interplay of pathogen virulence and host susceptibility. Systematic identification of genetic susceptibility to infection is being undertaken through genome-wide association studies, but how to expeditiously move from genetic differences to functional mechanisms is unclear. Here, we use genetic association of molecular, cellular, and human disease traits and experimental validation to demonstrate that genetic variation affects expression of VAC14, a phosphoinositide-regulating protein, to influence susceptibility to Salmonella enterica serovar Typhi (S Typhi) infection. Decreased VAC14 expression increased plasma membrane cholesterol, facilitating Salmonella docking and invasion. This increased susceptibility at the cellular level manifests as increased susceptibility to typhoid fever in a Vietnamese population. Furthermore, treating zebrafish with a cholesterol-lowering agent, ezetimibe, reduced susceptibility to S Typhi. Thus, coupling multiple genetic association studies with mechanistic dissection revealed how VAC14 regulates Salmonella invasion and typhoid fever susceptibility and may open doors to new prophylactic/therapeutic approaches.

  12. Genetic models of poljes in Sicily

    Science.gov (United States)

    Di Maggio, Cipriano; Madonia, Giuliana; Vattano, Marco; De Waele, Jo

    2016-04-01

    Geomorphological and geological studies have been carried out to contribute to the recognition of controlling causes and to the definition of genetic models for poljes of Sicily. A polje is a kilometric closed depression developed mainly on karst rocks, with a conspicuously flat and alluviated bottom affected by intermittent flooding. A polje is usually characterised by relatively steep slopes enclosing an almost perfectly horizontal floor, caused by lateral solution planation related to flooding events. The origin of a polje is due to dissolution of the land surface, although geological structure generally influences its genesis. These large depressions are often elongated according to the direction of main faults, in consequence of a control due to tectonics or to differential erosion. The performed researches have shown the existence of at least seven poljes located along the north-western (chain zone) and the southern (deformed foredeep zone) areas of Sicily. These large karst depressions are developed on Mesozoic limestone/dolomitic rocks within the chain zone and on Messinian gypsum rocks within the deformed foredeep zone. They are up to 4 km in length, can reach surfaces of 3-8 km2 and are around hundred metres deep, with steep slopes and a flat bottom. Generally, they are open, occasionally active depressions and their genesis seems to be strongly controlled by structure. In particular, the studied poljes occur in two different geological/geomorphological settings: a) in graben-like tectonic depressions, where important fault slopes/scarps border the flat bottom; b) in complex depressions controlled by structure, where wide fault line slopes/scarps or large inclined degraded structural surfaces mark the poljes. Finally, landscape analysis leads to the proposition of two main genetic models in which the development of poljes is primarily due to tectonics or differential erosion followed by dissolution.

  13. Genetic screens in Caenorhabditis elegans models for neurodegenerative diseases

    NARCIS (Netherlands)

    Alvarenga Fernandes Sin, Olga; Michels, Helen; Nollen, Ellen A. A.

    2014-01-01

    Caenorhabditis elegans comprises unique features that make it an attractive model organism in diverse fields of biology. Genetic screens are powerful to identify genes and C. elegans can be customized to forward or reverse genetic screens and to establish gene function. These genetic screens can be

  14. Genetic screens in Caenorhabditis elegans models for neurodegenerative diseases

    NARCIS (Netherlands)

    Alvarenga Fernandes Sin, Olga; Michels, Helen; Nollen, Ellen A. A.

    2014-01-01

    Caenorhabditis elegans comprises unique features that make it an attractive model organism in diverse fields of biology. Genetic screens are powerful to identify genes and C. elegans can be customized to forward or reverse genetic screens and to establish gene function. These genetic screens can be

  15. Transcriptional master regulator analysis in breast cancer genetic networks.

    Science.gov (United States)

    Tovar, Hugo; García-Herrera, Rodrigo; Espinal-Enríquez, Jesús; Hernández-Lemus, Enrique

    2015-12-01

    Gene regulatory networks account for the delicate mechanisms that control gene expression. Under certain circumstances, gene regulatory programs may give rise to amplification cascades. Such transcriptional cascades are events in which activation of key-responsive transcription factors called master regulators trigger a series of gene expression events. The action of transcriptional master regulators is then important for the establishment of certain programs like cell development and differentiation. However, such cascades have also been related with the onset and maintenance of cancer phenotypes. Here we present a systematic implementation of a series of algorithms aimed at the inference of a gene regulatory network and analysis of transcriptional master regulators in the context of primary breast cancer cells. Such studies were performed in a highly curated database of 880 microarray gene expression experiments on biopsy-captured tissue corresponding to primary breast cancer and healthy controls. Biological function and biochemical pathway enrichment analyses were also performed to study the role that the processes controlled - at the transcriptional level - by such master regulators may have in relation to primary breast cancer. We found that transcription factors such as AGTR2, ZNF132, TFDP3 and others are master regulators in this gene regulatory network. Sets of genes controlled by these regulators are involved in processes that are well-known hallmarks of cancer. This kind of analyses may help to understand the most upstream events in the development of phenotypes, in particular, those regarding cancer biology.

  16. Identification of common genetic modifiers of neurodegenerative diseases from an integrative analysis of diverse genetic screens in model organisms

    Directory of Open Access Journals (Sweden)

    Chen Xi

    2012-02-01

    Full Text Available Abstract Background An array of experimental models have been developed in the small model organisms C. elegans, S. cerevisiae and D. melanogaster for the study of various neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and expanded polyglutamine diseases as exemplified by Huntington's disease (HD and related ataxias. Genetic approaches to determine the nature of regulators of the disease phenotypes have ranged from small scale to essentially whole genome screens. The published data covers distinct models in all three organisms and one important question is the extent to which shared genetic factors can be uncovered that affect several or all disease models. Surprisingly it has appeared that there may be relatively little overlap and that many of the regulators may be organism or disease-specific. There is, however, a need for a fully integrated analysis of the available genetic data based on careful comparison of orthologues across the species to determine the real extent of overlap. Results We carried out an integrated analysis using C. elegans as the baseline model organism since this is the most widely studied in this context. Combination of data from 28 published studies using small to large scale screens in all three small model organisms gave a total of 950 identifications of genetic regulators. Of these 624 were separate genes with orthologues in C. elegans. In addition, 34 of these genes, which all had human orthologues, were found to overlap across studies. Of the common genetic regulators some such as chaperones, ubiquitin-related enzymes (including the E3 ligase CHIP which directly links the two pathways and histone deacetylases were involved in expected pathways whereas others such as the peroxisomal acyl CoA-oxidase suggest novel targets for neurodegenerative disease therapy Conclusions We identified a significant number of overlapping regulators of neurodegenerative disease models. Since the diseases

  17. [Molecular biology of biological clock--genetic regulation of circadian rhythm and sleep].

    Science.gov (United States)

    Kume, Kazuhiko

    2006-07-01

    Circadian rhythm is a universal biological property functioning in most living species on the earth from bacteria and plants to animals. The molecular mechanisms creating this rhythm have recently been elucidated and the transcriptional feedback loop regulation of 'clock genes' is regarded as essential for all species studied so far. Both mammals and insects share the similar clock genes, which highlights the long conservation of circadian rhythm at the genetic level. Sleep and arousal cycles in mammals are known to be regulated by both homeostatic and circadian processes, but the genetic machinery for sleep regulation is still unclear. Recently, it has been reported that insects also have sleep-like behavior, and we showed that insects use dopamine as a regulator of their sleep/arousal cycling, which strongly suggests the similarity of arousal regulation between insects and mammals at the molecular level. In this review, these recent advancements of the molecular understanding of circadian rhythm and sleep/arousal regulation are outlined.

  18. Research on Modeling of Genetic Networks Based on Information Measurement

    Institute of Scientific and Technical Information of China (English)

    ZHANG Guo-wei; SHAO Shi-huang; ZHANG Ying; LI Hai-ying

    2006-01-01

    As the basis of network of biology organism, the genetic network is concerned by many researchers.Current modeling methods to genetic network, especially the Boolean networks modeling method are analyzed. For modeling the genetic network, the information theory is proposed to mining the relations between elements in network. Through calculating the values of information entropy and mutual entropy in a case, the effectiveness of the method is verified.

  19. Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus

    Science.gov (United States)

    Johnson, Michael R.; Rossetti, Tiziana; Speed, Doug; Srivastava, Prashant K.; Chadeau-Hyam, Marc; Hajji, Nabil; Dabrowska, Aleksandra; Rotival, Maxime; Razzaghi, Banafsheh; Kovac, Stjepana; Wanisch, Klaus; Grillo, Federico W.; Slaviero, Anna; Langley, Sarah R.; Shkura, Kirill; Roncon, Paolo; De, Tisham; Mattheisen, Manuel; Niehusmann, Pitt; O’Brien, Terence J.; Petrovski, Slave; von Lehe, Marec; Hoffmann, Per; Eriksson, Johan; Coffey, Alison J.; Cichon, Sven; Walker, Matthew; Simonato, Michele; Danis, Bénédicte; Mazzuferi, Manuela; Foerch, Patrik; Schoch, Susanne; De Paola, Vincenzo; Kaminski, Rafal M.; Cunliffe, Vincent T.; Becker, Albert J.; Petretto, Enrico

    2015-01-01

    Gene-regulatory network analysis is a powerful approach to elucidate the molecular processes and pathways underlying complex disease. Here we employ systems genetics approaches to characterize the genetic regulation of pathophysiological pathways in human temporal lobe epilepsy (TLE). Using surgically acquired hippocampi from 129 TLE patients, we identify a gene-regulatory network genetically associated with epilepsy that contains a specialized, highly expressed transcriptional module encoding proconvulsive cytokines and Toll-like receptor signalling genes. RNA sequencing analysis in a mouse model of TLE using 100 epileptic and 100 control hippocampi shows the proconvulsive module is preserved across-species, specific to the epileptic hippocampus and upregulated in chronic epilepsy. In the TLE patients, we map the trans-acting genetic control of this proconvulsive module to Sestrin 3 (SESN3), and demonstrate that SESN3 positively regulates the module in macrophages, microglia and neurons. Morpholino-mediated Sesn3 knockdown in zebrafish confirms the regulation of the transcriptional module, and attenuates chemically induced behavioural seizures in vivo. PMID:25615886

  20. Modeling Performance of Plant Growth Regulators

    Directory of Open Access Journals (Sweden)

    W. C. Kreuser

    2017-03-01

    Full Text Available Growing degree day (GDD models can predict the performance of plant growth regulators (PGRs applied to creeping bentgrass ( L.. The goal of this letter is to describe experimental design strategies and modeling approaches to create PGR models for different PGRs, application rates, and turf species. Results from testing the models indicate that clipping yield should be measured until the growth response has diminished. This is in contrast to reapplication of a PGR at preselected intervals. During modeling, inclusion of an amplitude-dampening coefficient in the sinewave model allows the PGR effect to dissipate with time.

  1. Genetic regulation of the intercellular adhesion locus in staphylococci

    Directory of Open Access Journals (Sweden)

    David R Cue

    2012-03-01

    Full Text Available The formation of biofilms by Staphylococcus aureus and Staphylococcus epidermidis is an important aspect of many staphylococcal infections, most notably endocarditis, osteomyelitis and infections associated with indwelling medical devices. The major constituents of S. aureus biofilms are polysaccharides, such as poly N-acetyl glucosamine (PIA/PNAG, cell surface and secreted bacterial proteins, and extracellular DNA. The exact composition of biofilms often varies considerably between different strains of staphylococci and between different sites of infection by the same strain. PIA/PNAG is synthesized by the products of 4 genes, icaADBC, that are encoded in a single operon. A fifth gene, icaR, is a negative regulator of icaADBC. Expression of icaADBC is tightly regulated, but can often be induced in vitro by growing staphylococci in the presence of high salt, high glucose or ethanol. Regulation of icaADBC is complex and numerous regulatory factors have been implicated in control of icaADBC. Many of these are well known global transcriptional regulatory factors like SarA and sigmaB, whereas other regulators, such as IcaR, seem to affect expression of relatively few genes. Here, we will attempt to summarize how various regulatory factors affect the production of PIA/PNAG in staphylococci.

  2. Genetic Algorithm based PID controller for Frequency Regulation Ancillary services

    Directory of Open Access Journals (Sweden)

    Sandeep Bhongade

    2010-12-01

    Full Text Available In this paper, the parameters of Proportional, Integral and Derivative (PID controller for Automatic Generation Control (AGC suitable in restructured power system is tuned according to Generic Algorithms (GAs based performance indices. The key idea of the proposed method is to use the fitness function based on Area Control Error (ACE. The functioning of the proposed Genetic Algorithm based PID (GAPID controller has been demonstrated on a 75-bus Indian power system network and the results have been compared with those obtained by using Least Square Minimization method.

  3. Genetic regulation of heart valve development: Clinical implications

    Directory of Open Access Journals (Sweden)

    Marc-Phillip Hitz

    2011-12-01

    Full Text Available Cardiac malformations, most commonly valve defects, are some of the predominant causes of cardiovascular morbidity and mortality worldwide. Up to a third of all patients with complex congenital heart defects and numerous syndromic conditions, as well as a significant amount of the general population, exhibit valve defects. These observations have not only major implications in infancy; they also have a major impact on the adult population and the growing number of adults with congenital malformations. Over recent years, a large number of Mendelian inheritance patterns and syndromic causes have been identified, shedding light on the importance of genes encoding components of the extracelluar matrix in valve disease. Nevertheless, we still know little about the genetic origin of sporadic and more complex family traits. It is unclear to what extent genetic variations play a role in disease pathogenesis and influences phenotypes rooted in early development. Such knowledge would be greatly beneficial for counseling and treatment of patients. Therefore, this review summarizes the findings in human non-syndromic and syndromic valve disease with a special focus on extracellular matrix proteins, and discusses them in the context of vertebrate valve development.

  4. The mechanism of functional up-regulation of P2X3 receptors of trigeminal sensory neurons in a genetic mouse model of familial hemiplegic migraine type 1 (FHM-1).

    Science.gov (United States)

    Hullugundi, Swathi K; Ferrari, Michel D; van den Maagdenberg, Arn M J M; Nistri, Andrea

    2013-01-01

    A knock-in (KI) mouse model of FHM-1 expressing the R192Q missense mutation of the Cacna1a gene coding for the α1 subunit of CaV2.1 channels shows, at the level of the trigeminal ganglion, selective functional up-regulation of ATP -gated P2X3 receptors of sensory neurons that convey nociceptive signals to the brainstem. Why P2X3 receptors are constitutively more responsive, however, remains unclear as their membrane expression and TRPV1 nociceptor activity are the same as in wildtype (WT) neurons. Using primary cultures of WT or KI trigeminal ganglia, we investigated whether soluble compounds that may contribute to initiating (or maintaining) migraine attacks, such as TNFα, CGRP, and BDNF, might be responsible for increasing P2X3 receptor responses. Exogenous application of TNFα potentiated P2X3 receptor-mediated currents of WT but not of KI neurons, most of which expressed both the P2X3 receptor and the TNFα receptor TNFR2. However, sustained TNFα neutralization failed to change WT or KI P2X3 receptor currents. This suggests that endogenous TNFα does not regulate P2X3 receptor responses. Nonetheless, on cultures made from both genotypes, exogenous TNFα enhanced TRPV1 receptor-mediated currents expressed by a few neurons, suggesting transient amplification of TRPV1 nociceptor responses. CGRP increased P2X3 receptor currents only in WT cultures, although prolonged CGRP receptor antagonism or BDNF neutralization reduced KI currents to WT levels. Our data suggest that, in KI trigeminal ganglion cultures, constitutive up-regulation of P2X3 receptors probably is already maximal and is apparently contributed by basal CGRP and BDNF levels, thereby rendering these neurons more responsive to extracellular ATP.

  5. The mechanism of functional up-regulation of P2X3 receptors of trigeminal sensory neurons in a genetic mouse model of familial hemiplegic migraine type 1 (FHM-1.

    Directory of Open Access Journals (Sweden)

    Swathi K Hullugundi

    Full Text Available A knock-in (KI mouse model of FHM-1 expressing the R192Q missense mutation of the Cacna1a gene coding for the α1 subunit of CaV2.1 channels shows, at the level of the trigeminal ganglion, selective functional up-regulation of ATP -gated P2X3 receptors of sensory neurons that convey nociceptive signals to the brainstem. Why P2X3 receptors are constitutively more responsive, however, remains unclear as their membrane expression and TRPV1 nociceptor activity are the same as in wildtype (WT neurons. Using primary cultures of WT or KI trigeminal ganglia, we investigated whether soluble compounds that may contribute to initiating (or maintaining migraine attacks, such as TNFα, CGRP, and BDNF, might be responsible for increasing P2X3 receptor responses. Exogenous application of TNFα potentiated P2X3 receptor-mediated currents of WT but not of KI neurons, most of which expressed both the P2X3 receptor and the TNFα receptor TNFR2. However, sustained TNFα neutralization failed to change WT or KI P2X3 receptor currents. This suggests that endogenous TNFα does not regulate P2X3 receptor responses. Nonetheless, on cultures made from both genotypes, exogenous TNFα enhanced TRPV1 receptor-mediated currents expressed by a few neurons, suggesting transient amplification of TRPV1 nociceptor responses. CGRP increased P2X3 receptor currents only in WT cultures, although prolonged CGRP receptor antagonism or BDNF neutralization reduced KI currents to WT levels. Our data suggest that, in KI trigeminal ganglion cultures, constitutive up-regulation of P2X3 receptors probably is already maximal and is apparently contributed by basal CGRP and BDNF levels, thereby rendering these neurons more responsive to extracellular ATP.

  6. Genetic and Epigenetic Regulation of CCR5 Transcription

    OpenAIRE

    2012-01-01

    The chemokine receptor CCR5 regulates trafficking of immune cells of the lymphoid and the myeloid lineage (such as monocytes, macrophages and immature dendritic cells) and microglia. Because of this, there is an increasing recognition of the important role of CCR5 in the pathology of (neuro-) inflammatory diseases such as atherosclerosis and multiple sclerosis. Expression of CCR5 is under the control of a complexly organized promoter region upstream of the gene. The transcription factor cAMP-...

  7. Mechanism of genetic regulation. Comprehensive progress report, 1965-1967

    Energy Technology Data Exchange (ETDEWEB)

    Doi, R H

    1968-04-22

    Research progress is reported for the period 1965 through 1967. In order to obtain a biological system for the study of gene regulation, a study of the phage-bacterium complex and the uninfected host was begun. Accomplishments include the isolation and characterization of phages for B. subtilis for studies on transcriptional and translational controls, the identification of factors which control the functional capacity of transfer RNA, and the analysis of the initiation of protein synthesis in B. subtilis. (ACR)

  8. Effect of Keishibukuryogan on Genetic and Dietary Obesity Models

    Directory of Open Access Journals (Sweden)

    Fengying Gao

    2015-01-01

    Full Text Available Obesity has been recognized as one of the most important risk factors for a variety of chronic diseases, such as diabetes, hypertension/cardiovascular diseases, steatosis/hepatitis, and cancer. Keishibukuryogan (KBG, Gui Zhi Fu Ling Wan in Chinese is a traditional Chinese/Japanese (Kampo medicine that has been known to improve blood circulation and is also known for its anti-inflammatory or scavenging effect. In this study, we evaluated the effect of KBG in two distinct rodent models of obesity driven by either a genetic (SHR/NDmcr-cp rat model or dietary (high-fat diet-induced mouse obesity model mechanism. Although there was no significant effect on the body composition in either the SHR rat or the DIO mouse models, KBG treatment significantly decreased the serum level of leptin and liver TG level in the DIO mouse, but not in the SHR rat model. Furthermore, a lower fat deposition in liver and a smaller size of adipocytes in white adipose tissue were observed in the DIO mice treated with KBG. Importantly, we further found downregulation of genes involved in lipid metabolism in the KBG-treated liver, along with decreased liver TG and cholesterol level. Our present data experimentally support in fact that KBG can be an attractive Kampo medicine to improve obese status through a regulation of systemic leptin level and/or lipid metabolism.

  9. The state of genetically modified crop regulation in Canada

    Science.gov (United States)

    Smyth, Stuart J

    2014-01-01

    Genetically modified (GM) crops were first commercialized in Canada in 1995 and the 2014 crop represents the 20th year of successful production. Prior to the first commercialization of GM crops, Canada reviewed its existing science-based regulatory framework and adapted the existing framework to allow for risk assessments on the new technology to be undertaken in a timely and efficient manner. The result has been the rapid and widespread adoption of GM varieties of canola, corn and soybeans. The first decade of GM crop production precipitated 2 landmark legal cases relating to patent infringement and economic liability, while the second decade witnessed increased political efforts to have GM crops labeled in Canada as well as significant challenges from the low level comingling of GM crops with non-GM commodities. This article reviews the 20 y of GM crop production in Canada from a social science perspective that includes intellectual property, consumer acceptance and low level presence. PMID:25437238

  10. The state of genetically modified crop regulation in Canada.

    Science.gov (United States)

    Smyth, Stuart J

    2014-07-03

    Genetically modified (GM) crops were first commercialized in Canada in 1995 and the 2014 crop represents the 20th year of successful production. Prior to the first commercialization of GM crops, Canada reviewed its existing science-based regulatory framework and adapted the existing framework to allow for risk assessments on the new technology to be undertaken in a timely and efficient manner. The result has been the rapid and widespread adoption of GM varieties of canola, corn and soybeans. The first decade of GM crop production precipitated 2 landmark legal cases relating to patent infringement and economic liability, while the second decade witnessed increased political efforts to have GM crops labeled in Canada as well as significant challenges from the low level comingling of GM crops with non-GM commodities. This article reviews the 20 y of GM crop production in Canada from a social science perspective that includes intellectual property, consumer acceptance and low level presence.

  11. Mathematical Modeling of Intestinal Iron Absorption Using Genetic Programming

    Science.gov (United States)

    Colins, Andrea; Gerdtzen, Ziomara P.; Nuñez, Marco T.; Salgado, J. Cristian

    2017-01-01

    Iron is a trace metal, key for the development of living organisms. Its absorption process is complex and highly regulated at the transcriptional, translational and systemic levels. Recently, the internalization of the DMT1 transporter has been proposed as an additional regulatory mechanism at the intestinal level, associated to the mucosal block phenomenon. The short-term effect of iron exposure in apical uptake and initial absorption rates was studied in Caco-2 cells at different apical iron concentrations, using both an experimental approach and a mathematical modeling framework. This is the first report of short-term studies for this system. A non-linear behavior in the apical uptake dynamics was observed, which does not follow the classic saturation dynamics of traditional biochemical models. We propose a method for developing mathematical models for complex systems, based on a genetic programming algorithm. The algorithm is aimed at obtaining models with a high predictive capacity, and considers an additional parameter fitting stage and an additional Jackknife stage for estimating the generalization error. We developed a model for the iron uptake system with a higher predictive capacity than classic biochemical models. This was observed both with the apical uptake dataset used for generating the model and with an independent initial rates dataset used to test the predictive capacity of the model. The model obtained is a function of time and the initial apical iron concentration, with a linear component that captures the global tendency of the system, and a non-linear component that can be associated to the movement of DMT1 transporters. The model presented in this paper allows the detailed analysis, interpretation of experimental data, and identification of key relevant components for this complex biological process. This general method holds great potential for application to the elucidation of biological mechanisms and their key components in other complex

  12. Quantitative Genetics Identifies Cryptic Genetic Variation Involved in the Paternal Regulation of Seed Development

    NARCIS (Netherlands)

    Pires, Nuno D.; Bemer, Marian; Müller, Lena M.; Baroux, Célia; Spillane, Charles; Grossniklaus, Ueli

    2016-01-01

    Embryonic development requires a correct balancing of maternal and paternal genetic information. This balance is mediated by genomic imprinting, an epigenetic mechanism that leads to parent-of-origin-dependent gene expression. The parental conflict (or kinship) theory proposes that imprinting can

  13. Host genetics and environmental factors regulate ecological succession of the mouse colon tissue-associated microbiota.

    Directory of Open Access Journals (Sweden)

    Philip Smith

    Full Text Available BACKGROUND: The integration of host genetics, environmental triggers and the microbiota is a recognised factor in the pathogenesis of barrier function diseases such as IBD. In order to determine how these factors interact to regulate the host immune response and ecological succession of the colon tissue-associated microbiota, we investigated the temporal interaction between the microbiota and the host following disruption of the colonic epithelial barrier. METHODOLOGY/PRINCIPAL FINDINGS: Oral administration of DSS was applied as a mechanistic model of environmental damage of the colon and the resulting inflammation characterized for various parameters over time in WT and Nod2 KO mice. RESULTS: In WT mice, DSS damage exposed the host to the commensal flora and led to a migration of the tissue-associated bacteria from the epithelium to mucosal and submucosal layers correlating with changes in proinflammatory cytokine profiles and a progressive transition from acute to chronic inflammation of the colon. Tissue-associated bacteria levels peaked at day 21 post-DSS and declined thereafter, correlating with recruitment of innate immune cells and development of the adaptive immune response. Histological parameters, immune cell infiltration and cytokine biomarkers of inflammation were indistinguishable between Nod2 and WT littermates following DSS, however, Nod2 KO mice demonstrated significantly higher tissue-associated bacterial levels in the colon. DSS damage and Nod2 genotype independently regulated the community structure of the colon microbiota. CONCLUSIONS/SIGNIFICANCE: The results of these experiments demonstrate the integration of environmental and genetic factors in the ecological succession of the commensal flora in mammalian tissue. The association of Nod2 genotype (and other host polymorphisms and environmental factors likely combine to influence the ecological succession of the tissue-associated microflora accounting in part for their

  14. Genetic Regulation of Maternal Oxytocin Response and Its Influences on Maternal Behavior

    Directory of Open Access Journals (Sweden)

    Divya Mehta

    2016-01-01

    Full Text Available We interrogated the genetic modulation of maternal oxytocin response and its association with maternal behavior using genetic risk scores within the oxytocin receptor (OXTR gene. We identified a novel SNP, rs968389, to be significantly associated with maternal oxytocin response after a challenging mother-infant interaction task (Still Face Paradigm and maternal separation anxiety from the infant. Performing a multiallelic analysis across OXTR by calculating a cumulative genetic risk score revealed a significant gene-by-environment (G×E interaction, with OXTR genetic risk score interacting with adult separation anxiety to modulate levels of maternal sensitivity. Mothers with higher OXTR genetic risk score and adult separation anxiety showed significantly reduced levels of maternal sensitivity during free play with the infant. The same G×E interaction was also observed for the extended OXTR cumulative genetic risk score that included rs968389. Moreover, the extended cumulative OXTR genetic risk score itself was found to be significantly associated with maternal separation anxiety as it specifically relates to the infant. Our results suggest a complex montage of individual and synergistic genetic mediators of maternal behavior. These findings add to specific knowledge about genetic regulation of maternal oxytocin response in relation to maternal adjustment and infant bonding through the first few months of life.

  15. Genetic Regulation of Maternal Oxytocin Response and Its Influences on Maternal Behavior

    Science.gov (United States)

    Eapen, Valsamma; Kohlhoff, Jane; Mendoza Diaz, Antonio; Barnett, Bryanne; Silove, Derrick; Dadds, Mark R.

    2016-01-01

    We interrogated the genetic modulation of maternal oxytocin response and its association with maternal behavior using genetic risk scores within the oxytocin receptor (OXTR) gene. We identified a novel SNP, rs968389, to be significantly associated with maternal oxytocin response after a challenging mother-infant interaction task (Still Face Paradigm) and maternal separation anxiety from the infant. Performing a multiallelic analysis across OXTR by calculating a cumulative genetic risk score revealed a significant gene-by-environment (G × E) interaction, with OXTR genetic risk score interacting with adult separation anxiety to modulate levels of maternal sensitivity. Mothers with higher OXTR genetic risk score and adult separation anxiety showed significantly reduced levels of maternal sensitivity during free play with the infant. The same G × E interaction was also observed for the extended OXTR cumulative genetic risk score that included rs968389. Moreover, the extended cumulative OXTR genetic risk score itself was found to be significantly associated with maternal separation anxiety as it specifically relates to the infant. Our results suggest a complex montage of individual and synergistic genetic mediators of maternal behavior. These findings add to specific knowledge about genetic regulation of maternal oxytocin response in relation to maternal adjustment and infant bonding through the first few months of life. PMID:27872764

  16. Genetic and Environmental Bases of Reading and Spelling: A Unified Genetic Dual Route Model

    Science.gov (United States)

    Bates, Timothy C.; Castles, Anne; Luciano, Michelle; Wright, Margaret J.; Coltheart, Max; Martin, Nicholas G.

    2007-01-01

    We develop and test a dual-route model of genetic effects on reading aloud and spelling, based on irregular and non-word reading and spelling performance assessed in 1382 monozygotic and dizygotic twins. As in earlier research, most of the variance in reading was due to genetic effects. However, there were three more specific conclusions: the…

  17. Functional-mixed effects models for candidate genetic mapping in imaging genetic studies.

    Science.gov (United States)

    Lin, Ja-An; Zhu, Hongtu; Mihye, Ahn; Sun, Wei; Ibrahim, Joseph G

    2014-12-01

    The aim of this paper is to develop a functional-mixed effects modeling (FMEM) framework for the joint analysis of high-dimensional imaging data in a large number of locations (called voxels) of a three-dimensional volume with a set of genetic markers and clinical covariates. Our FMEM is extremely useful for efficiently carrying out the candidate gene approaches in imaging genetic studies. FMEM consists of two novel components including a mixed effects model for modeling nonlinear genetic effects on imaging phenotypes by introducing the genetic random effects at each voxel and a jumping surface model for modeling the variance components of the genetic random effects and fixed effects as piecewise smooth functions of the voxels. Moreover, FMEM naturally accommodates the correlation structure of the genetic markers at each voxel, while the jumping surface model explicitly incorporates the intrinsically spatial smoothness of the imaging data. We propose a novel two-stage adaptive smoothing procedure to spatially estimate the piecewise smooth functions, particularly the irregular functional genetic variance components, while preserving their edges among different piecewise-smooth regions. We develop weighted likelihood ratio tests and derive their exact approximations to test the effect of the genetic markers across voxels. Simulation studies show that FMEM significantly outperforms voxel-wise approaches in terms of higher sensitivity and specificity to identify regions of interest for carrying out candidate genetic mapping in imaging genetic studies. Finally, FMEM is used to identify brain regions affected by three candidate genes including CR1, CD2AP, and PICALM, thereby hoping to shed light on the pathological interactions between these candidate genes and brain structure and function.

  18. Genetic Regulation of Virulence and Antibiotic Resistance in Acinetobacter baumannii.

    Science.gov (United States)

    Kröger, Carsten; Kary, Stefani C; Schauer, Kristina; Cameron, Andrew D S

    2016-12-28

    Multidrug resistant microorganisms are forecast to become the single biggest challenge to medical care in the 21st century. Over the last decades, members of the genus Acinetobacter have emerged as bacterial opportunistic pathogens, in particular as challenging nosocomial pathogens because of the rapid evolution of antimicrobial resistances. Although we lack fundamental biological insight into virulence mechanisms, an increasing number of researchers are working to identify virulence factors and to study antibiotic resistance. Here, we review current knowledge regarding the regulation of virulence genes and antibiotic resistance in Acinetobacter baumannii. A survey of the two-component systems AdeRS, BaeSR, GacSA and PmrAB explains how each contributes to antibiotic resistance and virulence gene expression, while BfmRS regulates cell envelope structures important for pathogen persistence. A. baumannii uses the transcription factors Fur and Zur to sense iron or zinc depletion and upregulate genes for metal scavenging as a critical survival tool in an animal host. Quorum sensing, nucleoid-associated proteins, and non-classical transcription factors such as AtfA and small regulatory RNAs are discussed in the context of virulence and antibiotic resistance.

  19. Genetic Regulation of Virulence and Antibiotic Resistance in Acinetobacter baumannii

    Directory of Open Access Journals (Sweden)

    Carsten Kröger

    2016-12-01

    Full Text Available Multidrug resistant microorganisms are forecast to become the single biggest challenge to medical care in the 21st century. Over the last decades, members of the genus Acinetobacter have emerged as bacterial opportunistic pathogens, in particular as challenging nosocomial pathogens because of the rapid evolution of antimicrobial resistances. Although we lack fundamental biological insight into virulence mechanisms, an increasing number of researchers are working to identify virulence factors and to study antibiotic resistance. Here, we review current knowledge regarding the regulation of virulence genes and antibiotic resistance in Acinetobacter baumannii. A survey of the two-component systems AdeRS, BaeSR, GacSA and PmrAB explains how each contributes to antibiotic resistance and virulence gene expression, while BfmRS regulates cell envelope structures important for pathogen persistence. A. baumannii uses the transcription factors Fur and Zur to sense iron or zinc depletion and upregulate genes for metal scavenging as a critical survival tool in an animal host. Quorum sensing, nucleoid-associated proteins, and non-classical transcription factors such as AtfA and small regulatory RNAs are discussed in the context of virulence and antibiotic resistance.

  20. Genetic Regulation of Virulence and Antibiotic Resistance in Acinetobacter baumannii

    Science.gov (United States)

    Kröger, Carsten; Kary, Stefani C.; Schauer, Kristina; Cameron, Andrew D. S.

    2016-01-01

    Multidrug resistant microorganisms are forecast to become the single biggest challenge to medical care in the 21st century. Over the last decades, members of the genus Acinetobacter have emerged as bacterial opportunistic pathogens, in particular as challenging nosocomial pathogens because of the rapid evolution of antimicrobial resistances. Although we lack fundamental biological insight into virulence mechanisms, an increasing number of researchers are working to identify virulence factors and to study antibiotic resistance. Here, we review current knowledge regarding the regulation of virulence genes and antibiotic resistance in Acinetobacter baumannii. A survey of the two-component systems AdeRS, BaeSR, GacSA and PmrAB explains how each contributes to antibiotic resistance and virulence gene expression, while BfmRS regulates cell envelope structures important for pathogen persistence. A. baumannii uses the transcription factors Fur and Zur to sense iron or zinc depletion and upregulate genes for metal scavenging as a critical survival tool in an animal host. Quorum sensing, nucleoid-associated proteins, and non-classical transcription factors such as AtfA and small regulatory RNAs are discussed in the context of virulence and antibiotic resistance. PMID:28036056

  1. History and future of genetically engineered food animal regulation: an open request.

    Science.gov (United States)

    Wells, Kevin D

    2016-06-01

    Modern biotechnology resulted from of a series of incremental improvements in the understanding of DNA and the enzymes that nature evolved to manipulate it. As the potential impact of genetic engineering became apparent, scientists began the process of trying to identify the potential unintended consequences. Restrictions to recombinant DNA experimentation were at first self-imposed. Collaborative efforts between scientists and lawyers formalized an initial set of guidelines. These guidelines have been used to promulgate regulations around world. However, the initial guidelines were only intended as a starting point and were motivated by a specific set of concerns. As new data became available, the guidelines and regulations should have been adapted to the new knowledge. Instead, other social drivers drove the development of regulations. For most species and most applications, the framework that was established has slowly allowed some products to reach the market. However, genetically engineered livestock that are intended for food have been left in a regulatory state of limbo. To date, no genetically engineered food animal is available in the marketplace. A short history and a U.S.-based genetic engineer's perspective are presented. In addition, a request to regulatory agencies is presented for consideration as regulation continues to evolve. Regulators appear to have shown preference for the slow, random progression of evolution over the efficiency of intentional design.

  2. Regulation and Genetic Analysis of Leaf Source Capacity in Rice

    Institute of Scientific and Technical Information of China (English)

    CAO Shu-qing; ZHANG Rong-xian; LU Wei; CHEN Guo-xiang; DENG Zhi-rui; TANG Yun-lai; GONG Hong-bing; YANG Tu-nan

    2002-01-01

    The highest value of photosynthetic rate and active photosynthesis duration in flag leaves could be increased in a range of 3.55% and 3 d by dressing N (112.5 kg/ha) at heading stage in hybrid rice variety cv. Shanyou63 compared with control (no dressing N at heading), respectively. This resulted in the 7.93 percentage and 5.70 percentage increases of its leaf source capacity (LSC) and yield, respectively. Furthermore,genetic analysis of LSC was made by 4 × 4 incomplete diallel cross-design with 4 sterility lines and 4 resilience lines. The results showed that hB2 and hN2 in LSC for rice were higher than 70 percentage and 30 percentage,respectively, suggesting that it may be used as an index for selecting varieties with high photosynthetic efficiency in rice breeding. There were the similar effects of the additive and non-additive variations on LSC in hybrid rice. LSC was mainly influenced by sterility line and resilience interactions. The adding effect value of general combining ability for its parents may be used to forecast the phenotype of LSC in hybrid rice.

  3. Commercializing genetically modified crops under EU regulations: objectives and barriers.

    Science.gov (United States)

    Raybould, Alan; Poppy, Guy M

    2012-01-01

    Agriculture faces serious problems in feeding 9 billion people by 2050: production must be increased and ecosystem services maintained under conditions for growing crops that are predicted to worsen in many parts of the world. A proposed solution is sustainable intensification of agriculture, whereby yields are increased on land that is currently cultivated, so sparing land to deliver other ecosystem services. Genetically modified (GM) crops are already contributing to sustainable intensification through higher yields and lower environmental impacts, and have potential to deliver further significant improvements. Despite their widespread successful use elsewhere, the European Union (EU) has been slow to introduce GM crops: decisions on applications to import GM commodities are lengthy, and decision-making on applications to cultivate GM crops has virtually ceased. Delayed import approvals result in economic losses, particularly in the EU itself as a result of higher commodity prices. Failure to grant cultivation approvals costs EU farmers opportunities to reduce inputs, and results in loss of agricultural research and development from the EU to countries such as the United States and China. Delayed decision-making in the EU ostensibly results from scientific uncertainty about the effects of using GM crops; however, scientific uncertainty may be a means to justify a political decision to restrict cultivation of GM crops in the EU. The problems associated with delayed decision-making will not improve until there is clarity about the EU's agricultural policy objectives, and whether the use of GM crops will be permitted to contribute to achieving those objectives.

  4. Preserving Yeast Genetic Heritage through DNA Damage Checkpoint Regulation and Telomere Maintenance

    Directory of Open Access Journals (Sweden)

    Huilin Zhou

    2012-10-01

    Full Text Available In order to preserve genome integrity, extrinsic or intrinsic DNA damages must be repaired before they accumulate in cells and trigger other mutations and genome rearrangements. Eukaryotic cells are able to respond to different genotoxic stresses as well as to single DNA double strand breaks (DSBs, suggesting highly sensitive and robust mechanisms to detect lesions that trigger a signal transduction cascade which, in turn, controls the DNA damage response (DDR. Furthermore, cells must be able to distinguish natural chromosomal ends from DNA DSBs in order to prevent inappropriate checkpoint activation, DDR and chromosomal rearrangements. Since the original discovery of RAD9, the first DNA damage checkpoint gene identified in Saccharomyces cerevisiae, many genes that have a role in this pathway have been identified, including MRC1, MEC3, RAD24, RAD53, DUN1, MEC1 and TEL1. Extensive studies have established most of the genetic basis of the DNA damage checkpoint and uncovered its different functions in cell cycle regulation, DNA replication and repair, and telomere maintenance. However, major questions concerning the regulation and functions of the DNA damage checkpoint remain to be answered. First, how is the checkpoint activity coupled to DNA replication and repair? Second, how do cells distinguish natural chromosome ends from deleterious DNA DSBs? In this review we will examine primarily studies performed using Saccharomyces cerevisiae as a model system.

  5. Animal models for human genetic diseases

    African Journals Online (AJOL)

    Sharif Sons

    organisms are extensively used in applied research in agriculture, industry, and also in medicine, where they are ... in genetic disorder that is critical for embryonic .... by practical limitations and ethical concerns. ..... American journal of medical.

  6. Mitochondria from a mouse model of the human infantile neuroaxonal dystrophy (INAD) with genetic defects in VIA iPLA2 have disturbed Ca(2+) regulation with reduction in Ca(2+) capacity.

    Science.gov (United States)

    Strokin, Mikhail; Reiser, Georg

    2016-10-01

    Mutations in the PLA2G6 gene which encodes Ca(2+)-independent phospholipase A2 (VIA iPLA2) were detected in 85% of cases of the inherited degenerative nervous system disorder INAD (infantile neuroaxonal dystrophy, OMIM #256600). However, molecular mechanisms linking these mutations to the disease progression are unclear. VIA iPLA2 is expressed also in mitochondria. Here, we investigate Ca(2+) handling by brain mitochondria derived from mice with hypomorph Pla2g6 allele. These animals with reduced transcript levels (5% of wild type) represent a suitable model for INAD. We demonstrated significant reduction of Ca(2+) uptake rate and Ca(2+) retention capacity in brain mitochondria isolated from this mutant. This phenotype could be mimicked when in wild-type controls VIA iPLA2 was inhibited by S-BEL. Importantly, the reduction could be ameliorated partly by addition of the VIA iPLA2 product, sn-2 lysophosphatidyl-choline. Furthermore, we demonstrated in situ a reduced mitochondrial potential in neurons from mice deficient in VIA iPLA2, which could cause the reduced Ca(2+) uptake rate via the potential-dependent mitochondrial Ca(2+) uniporter. Thus, the disturbances in mitochondrial potential and the changes in Ca(2+) handling were dependent on VIA iPLA2 activity. Reduced mitochondrial Ca(2+) uptake rate and Ca(2+) retention capacity might result in increased vulnerability of mitochondria to the Ca(2+) overload and in disturbed cellular Ca(2+) signaling during INAD. For VIA iPLA2, non-canonical functions beyond sole phospholipid turnover seem to be important, such as regulation of store-operated Ca(2+) entry in cells. Thus, our findings bring new insight into molecular mechanism affected in INAD and highlight the non-canonical function of VIA iPLA2 in regulation of mitochondrial Ca(2+) handling.

  7. Optimization In Searching Daily Rule Curve At Mosul Regulating Reservoir, North Iraq Using Genetic Algorithms

    Directory of Open Access Journals (Sweden)

    Thair M. Al-Taiee

    2013-05-01

    Full Text Available To obtain optimal operating rules for storage reservoirs, large numbers of simulation and optimization models have been developed over the past several decades, which vary significantly in their mechanisms and applications. Rule curves are guidelines for long term reservoir operation. An efficient technique is required to find the optimal rule curves that can mitigate water shortage in long term operation. The investigation of developed Genetic Algorithm (GA technique, which is an optimization approach base on the mechanics of natural selection, derived from the theory of natural evolution, was carried out to through the application to predict the daily rule curve of  Mosul regulating reservoir in Iraq.  Record daily inflows, outflow, water level in the reservoir for 19 year (1986-1990 and (1994-2007 were used in the developed model for assessing the optimal reservoir operation. The objective function is set to minimize the annual sum of squared deviation from the desired downstream release and desired storage volume in the reservoir. The decision variables are releases, storage volume, water level and outlet (demand from the reservoir. The results of the GA model gave a good agreement during the comparison with the actual rule curve and the designed rating curve of the reservoir. The simulated result shows that GA-derived policies are promising and competitive and can be effectively used for daily reservoir operation in addition to the rational monthly operation and predicting also rating curve of reservoirs.

  8. Genetic regulation of recurrent spontaneous abortion in humans

    Directory of Open Access Journals (Sweden)

    Daniel Vaiman

    2015-02-01

    Full Text Available Recurrent pregnancy loss, defined as a pregnancy failure occurring before 24 weeks of gestation more than two or three times according to most definitions, is a fertility defect encountered in 1-5% of the patients. This defect is of course of multifactorial origin. Among the possible origins of recurrent pregnancy loss are uterine structural defaults, defective ploidy control of the embryo, defective immunological dialog between the embryo (or the fetus and the uterus sometimes in relation with immunological disorders (such as autoimmune diseases, thrombophilia, and free radical metabolism imbalance. Numerous studies attempted to correlate variants of genes supposed to be intervening in the different facets of the early maternal-fetal or maternal-embryonic dialog, and eventually modify the outcome of fertilization, leading to success or failure of post-implantation development. The objective of the present review is to portray the major genes and gene polymorphisms studied for their putative association with recurrent pregnancy loss. Most of these genes have been studied as candidate genes for which strong biological arguments were put forward as to their putative involvement in recurrent pregnancy loss. They were mostly studied by genetic analysis, often in various populations of different ethnic origins, throughout the world. Some of these studies were available only in English as abstracts and were nevertheless used if the information was given with enough detail. With the space being too short to depict all the available literature, different major pathways releva nt to the scientific question are presented without any attempt to hide the fact that discordant views often aroused for a given gene.

  9. [Approach to depressogenic genes from genetic analyses of animal models].

    Science.gov (United States)

    Yoshikawa, Takeo

    2004-01-01

    Human depression or mood disorder is defined as a complex disease, making positional cloning of susceptibility genes a formidable task. We have undertaken genetic analyses of three different animal models for depression, comparing our results with advanced database resources. We first performed quantitative trait loci (QTL) analysis on two mouse models of "despair", namely, the forced swim test (FST) and tail suspension test (TST), and detected multiple chromosomal loci that control immobility time in these tests. Since one QTL detected on mouse chromosome 11 harbors the GABA A receptor subunit genes, we tested these genes for association in human mood disorder patients. We obtained significant associations of the alpha 1 and alpha 6 subunit genes with the disease, particularly in females. This result was striking, because we had previously detected an epistatic interaction between mouse chromosomes 11 and X that regulates immobility time in these animals. Next, we performed genome-wide expression analyses using a rat model of depression, learned helplessness (LH). We found that in the frontal cortex of LH rats, a disease implicated region, the LIM kinase 1 gene (Limk 1) showed greatest alteration, in this case down-regulation. By combining data from the QTL analysis of FST/TST and DNA microarray analysis of mouse frontal cortex, we identified adenylyl cyclase-associated CAP protein 1 (Cap 1) as another candidate gene for depression susceptibility. Both Limk 1 and Cap 1 are key players in the modulation of actin G-F conversion. In summary, our current study using animal models suggests disturbances of GABAergic neurotransmission and actin turnover as potential pathophysiologies for mood disorder.

  10. A Mutation Model from First Principles of the Genetic Code.

    Science.gov (United States)

    Thorvaldsen, Steinar

    2016-01-01

    The paper presents a neutral Codons Probability Mutations (CPM) model of molecular evolution and genetic decay of an organism. The CPM model uses a Markov process with a 20-dimensional state space of probability distributions over amino acids. The transition matrix of the Markov process includes the mutation rate and those single point mutations compatible with the genetic code. This is an alternative to the standard Point Accepted Mutation (PAM) and BLOcks of amino acid SUbstitution Matrix (BLOSUM). Genetic decay is quantified as a similarity between the amino acid distribution of proteins from a (group of) species on one hand, and the equilibrium distribution of the Markov chain on the other. Amino acid data for the eukaryote, bacterium, and archaea families are used to illustrate how both the CPM and PAM models predict their genetic decay towards the equilibrium value of 1. A family of bacteria is studied in more detail. It is found that warm environment organisms on average have a higher degree of genetic decay compared to those species that live in cold environments. The paper addresses a new codon-based approach to quantify genetic decay due to single point mutations compatible with the genetic code. The present work may be seen as a first approach to use codon-based Markov models to study how genetic entropy increases with time in an effectively neutral biological regime. Various extensions of the model are also discussed.

  11. Evolution of proline biosynthesis: enzymology, bioinformatics, genetics, and transcriptional regulation.

    Science.gov (United States)

    Fichman, Yosef; Gerdes, Svetlana Y; Kovács, Hajnalka; Szabados, László; Zilberstein, Aviah; Csonka, Laszlo N

    2015-11-01

    Proline is not only an essential component of proteins but it also has important roles in adaptation to osmotic and dehydration stresses, redox control, and apoptosis. Here, we review pathways of proline biosynthesis in the three domains of life. Pathway reconstruction from genome data for hundreds of eubacterial and dozens of archaeal and eukaryotic organisms revealed evolutionary conservation and variations of this pathway across different taxa. In the most prevalent pathway of proline synthesis, glutamate is phosphorylated to γ-glutamyl phosphate by γ-glutamyl kinase, reduced to γ-glutamyl semialdehyde by γ-glutamyl phosphate reductase, cyclized spontaneously to Δ(1)-pyrroline-5-carboxylate and reduced to proline by Δ(1)-pyrroline-5-carboxylate reductase. In higher plants and animals the first two steps are catalysed by a bi-functional Δ(1) -pyrroline-5-carboxylate synthase. Alternative pathways of proline formation use the initial steps of the arginine biosynthetic pathway to ornithine, which can be converted to Δ(1)-pyrroline-5-carboxylate by ornithine aminotransferase and then reduced to proline or converted directly to proline by ornithine cyclodeaminase. In some organisms, the latter pathways contribute to or could be fully responsible for the synthesis of proline. The conservation of proline biosynthetic enzymes and significance of specific residues for catalytic activity and allosteric regulation are analysed on the basis of protein structural data, multiple sequence alignments, and mutant studies, providing novel insights into proline biosynthesis in organisms. We also discuss the transcriptional control of the proline biosynthetic genes in bacteria and plants.

  12. Genetic architecture and phenotypic plasticity of thermally-regulated traits in an eruptive species, Dendroctonus ponderosae

    Science.gov (United States)

    Barbara J. Bentz; Ryan B. Bracewell; Karen E. Mock; Michael E. Pfrender

    2011-01-01

    Phenotypic plasticity in thermally-regulated traits enables close tracking of changing environmental conditions, and can thereby enhance the potential for rapid population increase, a hallmark of outbreak insect species. In a changing climate, exposure to conditions that exceed the capacity of existing phenotypic plasticity may occur. Combining information on genetic...

  13. (Studies of the genetic regulation of the Thermomonospora cellulase complex)

    Energy Technology Data Exchange (ETDEWEB)

    Wilson, D.B.

    1992-01-01

    The goals of this project are to determine the molecular mechanisms regulating cellulose synthesis in the soil bacterium Thermomonosporafusca and to determine the molecular mechanism by which T.fusca cellulases degrade crystalline cellulose. We have determined a structure for the T.fusca E{sub 2} catalytic subunit (E{sub 2}-30) by x-ray crystallography. This structure is quite similar to that of T.reesei CBHU but there are a number of differences. One is that the E{sub 2} active site is in a cleft while that of CBHII is in a tunnel. This is an expected result since E{sub 2} is an endocellulase. Large amounts of homogenous E{sub 5} catalytic subunit have been prepared and attempts to crystallize it are underway. Crystals of E{sub 2}-30 were soaked in cellobiose and modified crystals detracted well, however difference Fourier analysis showed many changes, so that we could not localize cellobiose in the 3-D structure of E{sub 2}-30. This implies that binding of cellobiose causes a significant change in the structure of E{sub 2}-30. The stereochemistry of the cleavage catalyzed by E{sub l}, E{sub 2} and E{sub 5} was determined in collaboration with Dr. Stephen Withers and E{sub 1} and 2 inverted the glycoside linkage while E{sub 5} does not. The entire E{sub l} and E{sub 4} genes have been induced into Streptomyces lividans where they are expressed at a high level and the E{sub l} and E{sub 4} are completely secreted into the medium. Studies on the synergism between the exocellulase E{sub 3} and the endocellulases E{sub 2} or E{sub 5} show that both exo and endocellulase activities are stimulated when they are assayed together.

  14. Genetics of the ceramide/sphingosine-1-phosphate rheostat in blood pressure regulation and hypertension

    DEFF Research Database (Denmark)

    Fenger, Mogens; Linneberg, Allan; Jørgensen, Torben;

    2011-01-01

    . Recently it has been suggested that components of the sphingolipid metabolism pathways may be of importance in vascular physiology. The basic metabolic network of sphingolipids has been established, but the influence of genetic variations on the blood pressure is not known. In the approach presented here......Several attempts to decipher the genetics of hypertension of unknown causes have been made including large-scale genome-wide association analysis (GWA), but only a few genes have been identified. Unsolved heterogeneity of the regulation of blood pressure and the shortcomings of the prevailing...... monogenic approach to capture genetic effects in a polygenic condition are the main reasons for the modest results. The level of the blood pressure is the consequence of the genotypic state of the presumably vast network of genes involved in regulating the vascular tonus and hence the blood pressure...

  15. Genetic algorithm–based varying parameter linear quadratic regulator control for four-wheel independent steering vehicle

    Directory of Open Access Journals (Sweden)

    Linlin Gao

    2015-11-01

    Full Text Available From the perspective of vehicle dynamics, the four-wheel independent steering vehicle dynamics stability control method is studied, and a four-wheel independent steering varying parameter linear quadratic regulator control system is proposed with the help of expert control method. In the article, a four-wheel independent steering linear quadratic regulator controller for model following purpose is designed first. Then, by analyzing the four-wheel independent steering vehicle dynamic characteristics and the influence of linear quadratic regulator control parameters on control performance, a linear quadratic regulator control parameter adjustment strategy based on vehicle steering state is proposed to achieve the adaptive adjustment of linear quadratic regulator control parameters. In addition, to further improve the control performance, the proposed varying parameter linear quadratic regulator control system is optimized by genetic algorithm. Finally, simulation studies have been conducted by applying the proposed control system to the 8-degree-of-freedom four-wheel independent steering vehicle dynamics model. The simulation results indicate that the proposed control system has better performance and robustness and can effectively improve the stability and steering safety of the four-wheel independent steering vehicle.

  16. Mining protein kinases regulation using graphical models.

    Science.gov (United States)

    Chen, Qingfeng; Chen, Yi-Ping Phoebe

    2011-03-01

    Abnormal kinase activity is a frequent cause of diseases, which makes kinases a promising pharmacological target. Thus, it is critical to identify the characteristics of protein kinases regulation by studying the activation and inhibition of kinase subunits in response to varied stimuli. Bayesian network (BN) is a formalism for probabilistic reasoning that has been widely used for learning dependency models. However, for high-dimensional discrete random vectors the set of plausible models becomes large and a full comparison of all the posterior probabilities related to the competing models becomes infeasible. A solution to this problem is based on the Markov Chain Monte Carlo (MCMC) method. This paper proposes a BN-based framework to discover the dependency correlations of kinase regulation. Our approach is to apply the MCMC method to generate a sequence of samples from a probability distribution, by which to approximate the distribution. The frequent connections (edges) are identified from the obtained sampling graphical models. Our results point to a number of novel candidate regulation patterns that are interesting in biology and include inferred associations that were unknown.

  17. Differential genetic regulation of canine hip dysplasia and osteoarthritis.

    Directory of Open Access Journals (Sweden)

    Zhengkui Zhou

    Full Text Available BACKGROUND: Canine hip dysplasia (HD is a common polygenic trait characterized by hip malformation that results in osteoarthritis (OA. The condition in dogs is very similar to developmental dysplasia of the human hip which also leads to OA. METHODOLOGY/PRINCIPAL FINDINGS: A total of 721 dogs, including both an association and linkage population, were genotyped. The association population included 8 pure breeds (Labrador retriever, Greyhounds, German Shepherd, Newfoundland, Golden retriever, Rottweiler, Border Collie and Bernese Mountain Dog. The linkage population included Labrador retrievers, Greyhounds, and their crosses. Of these, 366 dogs were genotyped at ∼22,000 single nucleotide polymorphism (SNP loci and a targeted screen across 8 chromosomes with ∼3,300 SNPs was performed on 551 dogs (196 dogs were common to both sets. A mixed linear model approach was used to perform an association study on this combined association and linkage population. The study identified 4 susceptibility SNPs associated with HD and 2 SNPs associated with hip OA. CONCLUSION/SIGNIFICANCE: The identified SNPs included those near known genes (PTPRD, PARD3B, and COL15A1 reported to be associated with, or expressed in, OA in humans. This suggested that the canine model could provide a unique opportunity to identify genes underlying natural HD and hip OA, which are common and debilitating conditions in both dogs and humans.

  18. Statistical Inference of Biometrical Genetic Model With Cultural Transmission.

    Science.gov (United States)

    Guo, Xiaobo; Ji, Tian; Wang, Xueqin; Zhang, Heping; Zhong, Shouqiang

    2013-01-01

    Twin and family studies establish the foundation for studying the genetic, environmental and cultural transmission effects for phenotypes. In this work, we make use of the well established statistical methods and theory for mixed models to assess cultural transmission in twin and family studies. Specifically, we address two critical yet poorly understood issues: the model identifiability in assessing cultural transmission for twin and family data and the biases in the estimates when sub-models are used. We apply our models and theory to two real data sets. A simulation is conducted to verify the bias in the estimates of genetic effects when the working model is a sub-model.

  19. [Quantum processes in evolution of regulation of living system (mathematical modelling)].

    Science.gov (United States)

    Menshutkin, V V; Natochin, Iu V

    2011-01-01

    We have developed an imitation model of the appearance of regulation of physiological functions of protocell at the initial stages of evolution of living system. It is based on suggestion of the appearance of signal function in spontaneously formed products of partial hydrolysis of the protocell polypeptides, based on which there appear the regulatory molecules--quanta of regulation. For construction of the model, the mathematical apparatus of final automats and of genetic algorithm is used. The model has demonstrated the positive role of involvement of regulatory peptides in the system of regulation of protocell functions to provide its viability under the changing envelopment conditions.

  20. Transcriptional regulation by the numbers: models.

    Science.gov (United States)

    Bintu, Lacramioara; Buchler, Nicolas E; Garcia, Hernan G; Gerland, Ulrich; Hwa, Terence; Kondev, Jané; Phillips, Rob

    2005-04-01

    The expression of genes is regularly characterized with respect to how much, how fast, when and where. Such quantitative data demands quantitative models. Thermodynamic models are based on the assumption that the level of gene expression is proportional to the equilibrium probability that RNA polymerase (RNAP) is bound to the promoter of interest. Statistical mechanics provides a framework for computing these probabilities. Within this framework, interactions of activators, repressors, helper molecules and RNAP are described by a single function, the "regulation factor". This analysis culminates in an expression for the probability of RNA polymerase binding at the promoter of interest as a function of the number of regulatory proteins in the cell.

  1. Genetic regulation of bone metabolism in the chicken: similarities and differences to Mammalian systems.

    Directory of Open Access Journals (Sweden)

    Martin Johnsson

    2015-05-01

    Full Text Available Birds have a unique bone physiology, due to the demands placed on them through egg production. In particular their medullary bone serves as a source of calcium for eggshell production during lay and undergoes continuous and rapid remodelling. We take advantage of the fact that bone traits have diverged massively during chicken domestication to map the genetic basis of bone metabolism in the chicken. We performed a quantitative trait locus (QTL and expression QTL (eQTL mapping study in an advanced intercross based on Red Junglefowl (the wild progenitor of the modern domestic chicken and White Leghorn chickens. We measured femoral bone traits in 456 chickens by peripheral computerised tomography and femoral gene expression in a subset of 125 females from the cross with microarrays. This resulted in 25 loci for female bone traits, 26 loci for male bone traits and 6318 local eQTL loci. We then overlapped bone and gene expression loci, before checking for an association between gene expression and trait values to identify candidate quantitative trait genes for bone traits. A handful of our candidates have been previously associated with bone traits in mice, but our results also implicate unexpected and largely unknown genes in bone metabolism. In summary, by utilising the unique bone metabolism of an avian species, we have identified a number of candidate genes affecting bone allocation and metabolism. These findings can have ramifications not only for the understanding of bone metabolism genetics in general, but could also be used as a potential model for osteoporosis as well as revealing new aspects of vertebrate bone regulation or features that distinguish avian and mammalian bone.

  2. Numeral eddy current sensor modelling based on genetic neural network

    Institute of Scientific and Technical Information of China (English)

    Yu A-Long

    2008-01-01

    This paper presents a method used to the numeral eddy current sensor modelling based on the genetic neural network to settle its nonlinear problem. The principle and algorithms of genetic neural network are introduced. In this method, the nonlinear model parameters of the numeral eddy current sensor are optimized by genetic neural network (GNN) according to measurement data. So the method remains both the global searching ability of genetic algorithm and the good local searching ability of neural network. The nonlinear model has the advantages of strong robustness,on-line modelling and high precision.The maximum nonlinearity error can be reduced to 0.037% by using GNN.However, the maximum nonlinearity error is 0.075% using the least square method.

  3. Genetic fuzzy system modeling and simulation of vascular behaviour

    DEFF Research Database (Denmark)

    Tang, Jiaowei; Boonen, Harrie C.M.

    in cardiovascular disease and ultimately improve pharmacotherapy. For this purpose, novel computational approaches incorporating adaptive properties, auto-regulatory control and rule sets will be assessed, properties that are commonly lacking in deterministic models based on differential equations. We hypothesize...... in principle for any physiological system that is characterized by auto-regulatory control and adaptation. Methods: Currently, one modeling approach is being investigated, Genetic Fuzzy System (GFS). In Genetic Fuzzy Systems, the model algorithm mimics the biologic genetic evolutionary process to learn...... chromosome or individual to define the fuzzy system. The model is implemented by combining the Matlab Genetic algorithm and Fuzzy system toolboxes, respectively. To test the performance of this method, experimental data sets about calculated pressure change in different blood vessels after several chemical...

  4. Multiple comparisons in genetic association studies: a hierarchical modeling approach.

    Science.gov (United States)

    Yi, Nengjun; Xu, Shizhong; Lou, Xiang-Yang; Mallick, Himel

    2014-02-01

    Multiple comparisons or multiple testing has been viewed as a thorny issue in genetic association studies aiming to detect disease-associated genetic variants from a large number of genotyped variants. We alleviate the problem of multiple comparisons by proposing a hierarchical modeling approach that is fundamentally different from the existing methods. The proposed hierarchical models simultaneously fit as many variables as possible and shrink unimportant effects towards zero. Thus, the hierarchical models yield more efficient estimates of parameters than the traditional methods that analyze genetic variants separately, and also coherently address the multiple comparisons problem due to largely reducing the effective number of genetic effects and the number of statistically "significant" effects. We develop a method for computing the effective number of genetic effects in hierarchical generalized linear models, and propose a new adjustment for multiple comparisons, the hierarchical Bonferroni correction, based on the effective number of genetic effects. Our approach not only increases the power to detect disease-associated variants but also controls the Type I error. We illustrate and evaluate our method with real and simulated data sets from genetic association studies. The method has been implemented in our freely available R package BhGLM (http://www.ssg.uab.edu/bhglm/).

  5. Enterprise Projects Set Risk Element Transmission Chaotic Genetic Model

    Directory of Open Access Journals (Sweden)

    Cunbin Li

    2012-08-01

    Full Text Available In order to research projects set risk transfer process and improve risk management efficiency in projects management, combining chaos theory and genetic algorithm, put forward enterprise projects set risk element transmission chaos genetic model. Using logistic chaos mapping and chebyshev chaos mapping mixture, constructed a hybrid chaotic mapping system. The steps of adopting hybrid chaos mapping for genetic operation include projects set initialization, calculation of fitness, selection, crossover and mutation operators, fitness adjustment and condition judgment. The results showed that the model can simulate enterprise projects set risk transmission process very well and it also provides the basis for the enterprise managers to make decisions.

  6. The Neolithic transition in Europe: archaeological models and genetic evidence

    Directory of Open Access Journals (Sweden)

    Martin Richards

    2003-01-01

    Full Text Available The major pattern in the European gene pool is a southeast-northwest frequency gradient of classic genetic markers such as blood groups, which population geneticists initially attributed to the demographic impact of Neolithic farmers dispersing from the Near East. Molecular genetics has enriched this picture, with analyses of mitochondrial DNA and the Y chromosome allowing a more detailed exploration of alternative models for the spread of the Neolithic into Europe. This paper considers a range of possible models in the light of the detailed information now emerging from genetic studies.

  7. Yarn Strength Modelling Using Genetic Fuzzy Expert System

    Science.gov (United States)

    Banerjee, Debamalya; Ghosh, Anindya; Das, Subhasis

    2013-05-01

    This paper deals with the modelling of cotton yarn strength using genetic fuzzy expert system. Primarily a fuzzy expert system has been developed to model the cotton yarn strength from the constituent fibre parameters such as fibre strength, upper half mean length, fibre fineness and short fibre content. A binary coded genetic algorithm has been used to improve the prediction performance of the fuzzy expert system. The experimental validation confirms that the genetic fuzzy expert system has significantly better prediction accuracy and consistency than that of the fuzzy expert system.

  8. A synthetic framework for modeling the genetic basis of phenotypic plasticity and its costs.

    Science.gov (United States)

    Zhai, Yi; Lv, Yafei; Li, Xin; Wu, Weimiao; Bo, Wenhao; Shen, Dengfeng; Xu, Fang; Pang, Xiaoming; Zheng, Bingsong; Wu, Rongling

    2014-01-01

    The phenotype of an individual is controlled not only by its genes, but also by the environment in which it grows. A growing body of evidence shows that the extent to which phenotypic changes are driven by the environment, known as phenotypic plasticity, is also under genetic control, but an overall picture of genetic variation for phenotypic plasticity remains elusive. Here, we develop a model for mapping quantitative trait loci (QTLs) that regulate environment-induced plastic response. This model enables geneticists to test whether there exist actual QTLs that determine phenotypic plasticity and, if there are, further test how plasticity QTLs control the costs of plastic response by dissecting the genetic correlation of phenotypic plasticity and trait value. The model was used to analyze real data for grain yield of winter wheat (Triticum aestivum), leading to the detection of pleiotropic QTLs and epistatic QTLs that affect phenotypic plasticity and its cost in this crop.

  9. Genetic and Environmental Regulation on Longitudinal Change of Metabolic Phenotypes in Danish and Chinese Adult Twins

    DEFF Research Database (Denmark)

    Li, Shuxia; Kyvik, Kirsten Ohm; Pang, Zengchang

    2016-01-01

    OBJECTIVE: The rate of change in metabolic phenotypes can be highly indicative of metabolic disorders and disorder-related modifications. We analyzed data from longitudinal twin studies on multiple metabolic phenotypes in Danish and Chinese twins representing two populations of distinct ethnic...... environmental contribution to blood pressure but no genetic contribution to longitudinal change in body mass traits. CONCLUSION: Our results emphasize the major contribution of unique environment to the observed intra-individual variation in all metabolic phenotypes in both samples, and meanwhile reveal...... differential patterns of genetic and common environmental regulation on changes over time in metabolic phenotypes across the two samples....

  10. Transmission function models of finite population genetic algorithms

    NARCIS (Netherlands)

    Kemenade, C.H.M. van; Kok, J.N.; La Poutré, J.A.; Thierens, D.

    1998-01-01

    Infinite population models show a deterministic behaviour. Genetic algorithms with finite populations behave non-deterministicly. For small population sizes, the results obtained with these models differ strongly from the results predicted by the infinite population model. When the population size i

  11. A novel genetic mechanism regulates dorsolateral hinge-point formation during zebrafish cranial neurulation.

    Science.gov (United States)

    Nyholm, Molly K; Abdelilah-Seyfried, Salim; Grinblat, Yevgenya

    2009-06-15

    During neurulation, vertebrate embryos form a neural tube (NT), the rudiment of the central nervous system. In mammals and birds, a key step in cranial NT morphogenesis is dorsolateral hinge-point (DLHP) bending, which requires an apical actomyosin network. The mechanism of DLHP formation is poorly understood, although several essential genes have been identified, among them Zic2, which encodes a zinc-finger transcription factor. We found that DLHP formation in the zebrafish midbrain also requires actomyosin and Zic function. Given this conservation, we used the zebrafish to study how genes encoding Zic proteins regulate DLHP formation. We demonstrate that the ventral zic2a expression border predicts DLHP position. Using morpholino (MO) knockdown, we show zic2a and zic5 are required for apical F-actin and active myosin II localization and junction integrity. Furthermore, myosin II activity can function upstream of junction integrity during DLHP formation, and canonical Wnt signaling, an activator of zic gene transcription, is necessary for apical active myosin II localization, junction integrity and DLHP formation. We conclude that zic genes act downstream of Wnt signaling to control cytoskeletal organization, and possibly adhesion, during neurulation. This study identifies zic2a and zic5 as crucial players in the genetic network linking patterned gene expression to morphogenetic changes during neurulation, and strengthens the utility of the zebrafish midbrain as a NT morphogenesis model.

  12. Genetic programming-based chaotic time series modeling

    Institute of Scientific and Technical Information of China (English)

    张伟; 吴智铭; 杨根科

    2004-01-01

    This paper proposes a Genetic Programming-Based Modeling (GPM) algorithm on chaotic time series. GP is used here to search for appropriate model structures in function space, and the Particle Swarm Optimization (PSO) algorithm is used for Nonlinear Parameter Estimation (NPE) of dynamic model structures. In addition, GPM integrates the results of Nonlinear Time Series Analysis (NTSA) to adjust the parameters and takes them as the criteria of established models. Experiments showed the effectiveness of such improvements on chaotic time series modeling.

  13. Genetic Discrimination

    Science.gov (United States)

    ... in Genetics Archive Regulation of Genetic Tests Genetic Discrimination Overview Many Americans fear that participating in research ... I) and employment (Title II). Read more Genetic Discrimination and Other Laws Genetic Discrimination and Other Laws ...

  14. AP-2α regulates migration of GN-11 neurons via a specific genetic programme involving the Axl receptor tyrosine kinase

    Directory of Open Access Journals (Sweden)

    Orso Francesca

    2009-05-01

    Full Text Available Abstract Background Neuronal migration is a crucial process that allows neurons to reach their correct target location to allow the nervous system to function properly. AP-2α is a transcription factor essential for neural crest cell migration and its mutation results in apoptosis within this cell population, as demonstrated by genetic models. Results We down-modulated AP-2α expression in GN-11 neurons by RNA interference and observe reduced neuron migration following the activation of a specific genetic programme including the Adhesion Related Kinase (Axl gene. We prove that Axl is able to coordinate migration per se and by ChIP and promoter analysis we observe that its transcription is directly driven by AP-2α via the binding to one or more functional AP-2α binding sites present in its regulatory region. Analysis of migration in AP-2α null mouse embryo fibroblasts also reveals an essential role for AP-2α in cell movement via the activation of a distinct genetic programme. Conclusion We show that AP-2α plays an essential role in cell movement via the activation of cell-specific genetic programmes. Moreover, we demonstrate that the AP-2α regulated gene Axl is an essential player in GN-11 neuron migration.

  15. Co-regulation of pluripotency and genetic integrity at the genomic level

    Directory of Open Access Journals (Sweden)

    Daniel J. Cooper

    2014-11-01

    Full Text Available The Disposable Soma Theory holds that genetic integrity will be maintained at more pristine levels in germ cells than in somatic cells because of the unique role germ cells play in perpetuating the species. We tested the hypothesis that the same concept applies to pluripotent cells compared to differentiated cells. Analyses of transcriptome and cistrome databases, along with canonical pathway analysis and chromatin immunoprecipitation confirmed differential expression of DNA repair and cell death genes in embryonic stem cells and induced pluripotent stem cells relative to fibroblasts, and predicted extensive direct and indirect interactions between the pluripotency and genetic integrity gene networks in pluripotent cells. These data suggest that enhanced maintenance of genetic integrity is fundamentally linked to the epigenetic state of pluripotency at the genomic level. In addition, these findings demonstrate how a small number of key pluripotency factors can regulate large numbers of downstream genes in a pathway-specific manner.

  16. Classroom Activities to Engage Students and Promote Critical Thinking about Genetic Regulation of Bacterial Quorum Sensing

    Directory of Open Access Journals (Sweden)

    Kimberly Aebli

    2016-05-01

    Full Text Available We developed an interactive activity to mimic bacterial quorum sensing, and a classroom worksheet to promote critical thinking about genetic regulation of the lux operon. The interactive quorum sensing activity engages students and provides a direct visualization of how population density functions to influence light production in bacteria. The worksheet activity consists of practice problems that require students to apply basic knowledge of the lux operon in order to make predictions about genetic complementation experiments, and students must evaluate how genetic mutations in the lux operon affect gene expression and overall phenotype. The worksheet promotes critical thinking and problem solving skills, and emphasizes the roles of diffusible signaling molecules, regulatory proteins, and structural proteins in quorum sensing.

  17. PHYSIOLOGY AND GENETIC ASPECTS OF THE REGULATION OF EXPRESSION MILK PROTEIN GENES

    Directory of Open Access Journals (Sweden)

    Jozef Bulla

    2013-06-01

    Full Text Available For the genetic improvement of milk composition and milk yield, both the typing of different protein variants and knowledge about the regulation of expression of the different milk protein genes are important. Some of the processing properties of milk are dependent on the milk composition. Information about the DNA sequence and genes involved in the expression of the milk protein genes,therefore,is big importance for genetic improvement of these traits in animals breeding programmes.In recent years more data has become available concerning the regulation of expression of the milk protein genes and as might have been expected from the complex multihormonal control of these genes it appears to be rather complex. Although several mammary gland specific factors that play a role in expression of some of these genes have been identified,none of these factors has been shown to be involved in the expression of all or the majority of the milk protein genes.

  18. Genetic and non-genetic animal models for autism spectrum disorders (ASD).

    Science.gov (United States)

    Ergaz, Zivanit; Weinstein-Fudim, Liza; Ornoy, Asher

    2016-09-01

    Autism spectrum disorder (ASD) is associated, in addition to complex genetic factors, with a variety of prenatal, perinatal and postnatal etiologies. We discuss the known animal models, mostly in mice and rats, of ASD that helps us to understand the etiology, pathogenesis and treatment of human ASD. We describe only models where behavioral testing has shown autistic like behaviors. Some genetic models mimic known human syndromes like fragile X where ASD is part of the clinical picture, and others are without defined human syndromes. Among the environmentally induced ASD models in rodents, the most common model is the one induced by valproic acid (VPA) either prenatally or early postnatally. VPA induces autism-like behaviors following single exposure during different phases of brain development, implying that the mechanism of action is via a general biological mechanism like epigenetic changes. Maternal infection and inflammation are also associated with ASD in man and animal models. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. The Ising model in physics and statistical genetics.

    Science.gov (United States)

    Majewski, J; Li, H; Ott, J

    2001-10-01

    Interdisciplinary communication is becoming a crucial component of the present scientific environment. Theoretical models developed in diverse disciplines often may be successfully employed in solving seemingly unrelated problems that can be reduced to similar mathematical formulation. The Ising model has been proposed in statistical physics as a simplified model for analysis of magnetic interactions and structures of ferromagnetic substances. Here, we present an application of the one-dimensional, linear Ising model to affected-sib-pair (ASP) analysis in genetics. By analyzing simulated genetics data, we show that the simplified Ising model with only nearest-neighbor interactions between genetic markers has statistical properties comparable to much more complex algorithms from genetics analysis, such as those implemented in the Allegro and Mapmaker-Sibs programs. We also adapt the model to include epistatic interactions and to demonstrate its usefulness in detecting modifier loci with weak individual genetic contributions. A reanalysis of data on type 1 diabetes detects several susceptibility loci not previously found by other methods of analysis.

  20. A NEW GENETIC SIMULATED ANNEALING ALGORITHM FOR FLOOD ROUTING MODEL

    Institute of Scientific and Technical Information of China (English)

    KANG Ling; WANG Cheng; JIANG Tie-bing

    2004-01-01

    In this paper, a new approach, the Genetic Simulated Annealing (GSA), was proposed for optimizing the parameters in the Muskingum routing model. By integrating the simulated annealing method into the genetic algorithm, the hybrid method could avoid some troubles of traditional methods, such as arduous trial-and-error procedure, premature convergence in genetic algorithm and search blindness in simulated annealing. The principle and implementing procedure of this algorithm were described. Numerical experiments show that the GSA can adjust the optimization population, prevent premature convergence and seek the global optimal result.Applications to the Nanyunhe River and Qingjiang River show that the proposed approach is of higher forecast accuracy and practicability.

  1. GLABROUS INFLORESCENCE STEMS regulates trichome branching by genetically interacting with SIM in Arabidopsis

    Institute of Scientific and Technical Information of China (English)

    Li-li SUN; Zhong-jing ZHOU; Li-jun AN; Yan AN; Yong-qin ZHAO; Xiao-fang MENG; Clare STEELE-KING

    2013-01-01

    Arabidopsis trichomes are large branched single cells that protrude from the epidermis.The first morphological indication of trichome development is an increase in nuclear content resulting from an initial cycle of endoreduplication.Our previous study has shown that the C2H2 zinc finger protein GLABROUS INFLORESCENCE STEMS (GIS) is required for trichome initiation in the inflorescence organ and for trichome branching in response to gibberellic acid signaling,although GIS gene does not play a direct role in regulating trichome cell division.Here,we describe a novel role of GIS,controlling trichome cell division indirectly by interacting genetically with a key endoreduplication regulator SIAMESE (SIM).Our molecular and genetic studies have shown that GIS might indireclty control cell division and trichome branching by acting downstream of SIM.A loss of function mutation of SIM signficantly reduced the expression of GIS.Futhermore,the overexpression of GIS rescued the trichome cluster cell phenotypes of sim mutant.The gain or loss of function of GIS had no significant effect on the expression of SIM.These results suggest that GIS may play an indirect role in regulating trichome cell division by genetically interacting with SIM.

  2. Targeting the myofibroblast genetic switch: inhibitors of myocardin-related transcription factor/serum response factor-regulated gene transcription prevent fibrosis in a murine model of skin injury.

    Science.gov (United States)

    Haak, Andrew J; Tsou, Pei-Suen; Amin, Mohammad A; Ruth, Jeffrey H; Campbell, Phillip; Fox, David A; Khanna, Dinesh; Larsen, Scott D; Neubig, Richard R

    2014-06-01

    Systemic sclerosis (SSc), or scleroderma, similar to many fibrotic disorders, lacks effective therapies. Current trials focus on anti-inflammatory drugs or targeted approaches aimed at one of the many receptor mechanisms initiating fibrosis. In light of evidence that a myocardin-related transcription factor (MRTF)-and serum response factor (SRF)-regulated gene transcriptional program induced by Rho GTPases is essential for myofibroblast activation, we explored the hypothesis that inhibitors of this pathway may represent novel antifibrotics. MRTF/SRF-regulated genes show spontaneously increased expression in primary dermal fibroblasts from patients with diffuse cutaneous SSc. A novel small-molecule inhibitor of MRTF/SRF-regulated transcription (CCG-203971) inhibits expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and collagen 1 (COL1A2) in both SSc fibroblasts and in lysophosphatidic acid (LPA)-and transforming growth factor β (TGFβ)-stimulated fibroblasts. In vivo treatment with CCG-203971 also prevented bleomycin-induced skin thickening and collagen deposition. Thus, targeting the MRTF/SRF gene transcription pathway could provide an efficacious new approach to therapy for SSc and other fibrotic disorders.

  3. Underground water quality model inversion of genetic algorithm

    Institute of Scientific and Technical Information of China (English)

    MA Ruijie; LI Xin

    2009-01-01

    The underground water quality model with non-linear inversion problem is ill-posed, and boils down to solving the minimum of nonlinear function. Genetic algorithms are adopted in a number of individuals of groups by iterative search to find the optimal solution of the problem, the encoding strings as its operational objective, and achieving the iterative calculations by the genetic operators. It is an effective method of inverse problems of groundwater, with incomparable advantages and practical significances.

  4. Modeling evolution of insect resistance to genetically modified crops

    OpenAIRE

    2015-01-01

    Genetically modified crops producing insecticidal proteins from Bacillus thuringiensis (Bt) for insect control have been planted on more than 200 million ha worldwide since 1996 [1]. Evolution of resistance by insect pests threatens the continued success of Bt crops [2, 3]. To delay pest resistance, refuges of non-Bt crops are planted near Bt crops to allow survival of susceptible pests [4, 5]. We used computer simulations of a population genetic model to determine if predictions from the the...

  5. Modelling Proteasome and Proteasome Regulator Activities

    Directory of Open Access Journals (Sweden)

    Juliane Liepe

    2014-06-01

    Full Text Available Proteasomes are key proteases involved in a variety of processes ranging from the clearance of damaged proteins to the presentation of antigens to CD8+ T-lymphocytes. Which cleavage sites are used within the target proteins and how fast these proteins are degraded have a profound impact on immune system function and many cellular metabolic processes. The regulation of proteasome activity involves different mechanisms, such as the substitution of the catalytic subunits, the binding of regulatory complexes to proteasome gates and the proteasome conformational modifications triggered by the target protein itself. Mathematical models are invaluable in the analysis; and potentially allow us to predict the complex interactions of proteasome regulatory mechanisms and the final outcomes of the protein degradation rate and MHC class I epitope generation. The pioneering attempts that have been made to mathematically model proteasome activity, cleavage preference variation and their modification by one of the regulatory mechanisms are reviewed here.

  6. A dynamical model of non regulated markets

    CERN Document Server

    Schaale, A

    1999-01-01

    The main focus of this work is to understand the dynamics of non regulated markets. The present model can describe the dynamics of any market where the pricing is based on supply and demand. It will be applied here, as an example, for the German stock market presented by the Deutscher Aktienindex (DAX), which is a measure for the market status. The duality of the present model consists of the superposition of the two components - the long and the short term behaviour of the market. The long term behaviour is characterised by a stable development which is following a trend for time periods of years or even decades. This long term growth (or decline) is based on the development of fundamental market figures. The short term behaviour is described as a dynamical evaluation (trading) of the market by the participants. The trading process is described as an exchange between supply and demand. In the framework of this model there the trading is modelled by a system of nonlinear differential equations. The model also...

  7. Modeling regulated water utility investment incentives

    Science.gov (United States)

    Padula, S.; Harou, J. J.

    2014-12-01

    This work attempts to model the infrastructure investment choices of privatized water utilities subject to rate of return and price cap regulation. The goal is to understand how regulation influences water companies' investment decisions such as their desire to engage in transfers with neighbouring companies. We formulate a profit maximization capacity expansion model that finds the schedule of new supply, demand management and transfer schemes that maintain the annual supply-demand balance and maximize a companies' profit under the 2010-15 price control process in England. Regulatory incentives for costs savings are also represented in the model. These include: the CIS scheme for the capital expenditure (capex) and incentive allowance schemes for the operating expenditure (opex) . The profit-maximizing investment program (what to build, when and what size) is compared with the least cost program (social optimum). We apply this formulation to several water companies in South East England to model performance and sensitivity to water network particulars. Results show that if companies' are able to outperform the regulatory assumption on the cost of capital, a capital bias can be generated, due to the fact that the capital expenditure, contrarily to opex, can be remunerated through the companies' regulatory capital value (RCV). The occurrence of the 'capital bias' or its entity depends on the extent to which a company can finance its investments at a rate below the allowed cost of capital. The bias can be reduced by the regulatory penalties for underperformances on the capital expenditure (CIS scheme); Sensitivity analysis can be applied by varying the CIS penalty to see how and to which extent this impacts the capital bias effect. We show how regulatory changes could potentially be devised to partially remove the 'capital bias' effect. Solutions potentially include allowing for incentives on total expenditure rather than separately for capex and opex and allowing

  8. A Model of Genetic Variation in Human Social Networks

    CERN Document Server

    Fowler, James H; Christakis, Nicholas A

    2008-01-01

    Social networks influence the evolution of cooperation and they exhibit strikingly systematic patterns across a wide range of human contexts. Both of these facts suggest that variation in the topological attributes of human social networks might have a genetic basis. While genetic variation accounts for a significant portion of the variation in many complex social behaviors, the heritability of egocentric social network attributes is unknown. Here we show that three of these attributes (in-degree, transitivity, and centrality) are heritable. We then develop a "mirror network" method to test extant network models and show that none accounts for observed genetic variation in human social networks. We propose an alternative "attract and introduce" model that generates significant heritability as well as other important network features, and we show that this model with two simple forms of heterogeneity is well suited to the modeling of real social networks in humans. These results suggest that natural selection ...

  9. Multivariate Survival Mixed Models for Genetic Analysis of Longevity Traits

    DEFF Research Database (Denmark)

    Pimentel Maia, Rafael; Madsen, Per; Labouriau, Rodrigo

    2013-01-01

    A class of multivariate mixed survival models for continuous and discrete time with a complex covariance structure is introduced in a context of quantitative genetic applications. The methods introduced can be used in many applications in quantitative genetics although the discussion presented...... concentrates on longevity studies. The framework presented allows to combine models based on continuous time with models based on discrete time in a joint analysis. The continuous time models are approximations of the frailty model in which the hazard function will be assumed to be piece-wise constant....... The discrete time models used are multivariate variants of the discrete relative risk models. These models allow for regular parametric likelihood-based inference by exploring a coincidence of their likelihood functions and the likelihood functions of suitably defined multivariate generalized linear mixed...

  10. Multivariate Survival Mixed Models for Genetic Analysis of Longevity Traits

    DEFF Research Database (Denmark)

    Pimentel Maia, Rafael; Madsen, Per; Labouriau, Rodrigo

    2014-01-01

    A class of multivariate mixed survival models for continuous and discrete time with a complex covariance structure is introduced in a context of quantitative genetic applications. The methods introduced can be used in many applications in quantitative genetics although the discussion presented...... concentrates on longevity studies. The framework presented allows to combine models based on continuous time with models based on discrete time in a joint analysis. The continuous time models are approximations of the frailty model in which the hazard function will be assumed to be piece-wise constant....... The discrete time models used are multivariate variants of the discrete relative risk models. These models allow for regular parametric likelihood-based inference by exploring a coincidence of their likelihood functions and the likelihood functions of suitably defined multivariate generalized linear mixed...

  11. A Genetic Screen To Assess Dopamine Receptor (DopR1 Dependent Sleep Regulation in Drosophila

    Directory of Open Access Journals (Sweden)

    Yiqin Jiang

    2016-12-01

    Full Text Available Sleep is an essential behavioral state of rest that is regulated by homeostatic drives to ensure a balance of sleep and activity, as well as independent arousal mechanisms in the central brain. Dopamine has been identified as a critical regulator of both sleep behavior and arousal. Here, we present results of a genetic screen that selectively restored the Dopamine Receptor (DopR/DopR1/dumb to specific neuroanatomical regions of the adult Drosophila brain to assess requirements for DopR in sleep behavior. We have identified subsets of the mushroom body that utilizes DopR in daytime sleep regulation. These data are supported by multiple examples of spatially restricted genetic rescue data in discrete circuits of the mushroom body, as well as immunohistochemistry that corroborates the localization of DopR protein within mushroom body circuits. Independent loss of function data using an inducible RNAi construct in the same specific circuits also supports a requirement for DopR in daytime sleep. Additional circuit activation of discrete DopR+ mushroom body neurons also suggests roles for these subpopulations in sleep behavior. These conclusions support a new separable function for DopR in daytime sleep regulation within the mushroom body. This daytime regulation is independent of the known role of DopR in nighttime sleep, which is regulated within the Fan-Shaped Body (FSB. This study provides new neuroanatomical loci for exploration of dopaminergic sleep functions in Drosophila, and expands our understanding of sleep regulation during the day vs. night.

  12. Genetics of traffic assignment models for strategic transport planning

    NARCIS (Netherlands)

    Bliemer, M.C.J.; Raadsen, M.P.H.; Brederode, L.J.N.; Bell, M.G.H.; Wismans, Luc Johannes Josephus; Smith, M.J.

    2016-01-01

    This paper presents a review and classification of traffic assignment models for strategic transport planning purposes by using concepts analogous to genetics in biology. Traffic assignment models share the same theoretical framework (DNA), but differ in capability (genes). We argue that all traffic

  13. Genetics of traffic assignment models for strategic transport planning

    NARCIS (Netherlands)

    Bliemer, M.C.J.; Raadsen, M.; Brederode, L.; Bell, M.; Wismans, L.J.J.; Smith, M.

    2016-01-01

    This paper presents a review and classification of traffic assignment models for strategic transport planning purposes by using concepts analogous to genetics in biology. Traffic assignment models share the same theoretical framework (DNA), but differ in capability (genes). We argue that all traffic

  14. Genetic models of absence epilepsy: New concepts and insights

    NARCIS (Netherlands)

    Luijtelaar, E.L.J.M. van; Coenen, A.M.L.

    2009-01-01

    The discovery, development, and use of genetic rodent models of absence epilepsy have led to a new theory about the origin of absence seizures. A focal zone has been identified in the peri-oral region of the somatosensory cortex in WAG/Rij and GAERS – the two most commonly used models – from which

  15. Genetic association in multivariate phenotypic data: power in five models

    NARCIS (Netherlands)

    Minica, C.C.; Boomsma, D.I.; van der Sluis, S.; Dolan, C.V.

    2010-01-01

    This article concerns the power of various data analytic strategies to detect the effect of a single genetic variant (GV) in multivariate data. We simulated exactly fitting monozygotic and dizygotic phenotypic data according to single and two common factor models, and simplex models. We calculated t

  16. Immune System Model Calibration by Genetic Algorithm

    NARCIS (Netherlands)

    Presbitero, A.; Krzhizhanovskaya, V.; Mancini, E.; Brands, R.; Sloot, P.

    2016-01-01

    We aim to develop a mathematical model of the human immune system for advanced individualized healthcare where medication plan is fine-tuned to fit a patient's conditions through monitored biochemical processes. One of the challenges is calibrating model parameters to satisfy existing experimental

  17. Genetic diversity affects the strength of population regulation in a marine fish.

    Science.gov (United States)

    Johnson, D W; Freiwald, J; Bernardi, G

    2016-03-01

    Variation is an essential feature of biological populations, yet much of ecological theory treats individuals as though they are identical. This simplifying assumption is often justified by the perception that variation among individuals does not have significant effects on the dynamics of whole populations. However, this perception may be skewed by a historic focus on studying single populations. A true evaluation of the extent to which among-individual variation affects the dynamics of populations requires the study of multiple populations. In this study, we examined variation in the dynamics of populations of a live-bearing, marine fish (black surfperch; Embiotoca jacksoni). In collaboration with an organization of citizen scientists (Reef Check California), we were able to examine the dynamics of eight populations that were distributed throughout approximately 700 km of coastline, a distance that encompasses much of this species' range. We hypothesized that genetic variation within a local population would be related to the intensity of competition and to the strength of population regulation. To test this hypothesis, we examined whether genetic diversity (measured by the diversity of mitochondrial DNA haplotypes) was related to the strength of population regulation. Low-diversity populations experienced strong density dependence in population growth rates and population sizes were regulated much more tightly than they were in high-diversity populations. Mechanisms that contributed to this pattern include links between genetic diversity, habitat use, and spatial crowding. On average, low-diversity populations used less of the available habitat and exhibited greater spatial clustering (and more intense competition) for a given level of density (measured at the scale of the reef). Although the populations we studied also varied with respect to exogenous characteristics (habitat complexity, densities of predators, and interspecific competitors), none of these

  18. The quantitative genetics of indirect genetic effects: a selective review of modelling issues : Review

    NARCIS (Netherlands)

    Bijma, P.

    2014-01-01

    Indirect genetic effects (IGE) occur when the genotype of an individual affects the phenotypic trait value of another conspecific individual. IGEs can have profound effects on both the magnitude and the direction of response to selection. Models of inheritance and response to selection in traits sub

  19. [Improvement of genetics teaching using literature-based learning model].

    Science.gov (United States)

    Liang, Liang; Shiqian, Liang; Hongyan, Qin; Yong, Ji; Hua, Han

    2015-06-01

    Genetics is one of the most important courses for undergraduate students majoring in life science. In recent years, new knowledge and technologies are continually updated with deeper understanding of life science. However, the teaching model of genetics is still based on theoretical instruction, which makes the abstract principles hard to understand by students and directly affects the teaching effect. Thus, exploring a new teaching model is necessary. We have carried out a new teaching model, literature-based learning, in the course on Microbial Genetics for undergraduate students majoring in biotechnology since 2010. Here we comprehensively analyzed the implementation and application value of this model including pre-course knowledge, how to choose professional literature, how to organize teaching process and the significance of developing this new teaching model for students and teachers. Our literature-based learning model reflects the combination of "cutting-edge" and "classic" and makes book knowledge easy to understand, which improves students' learning effect, stimulates their interests, expands their perspectives and develops their ability. This practice provides novel insight into exploring new teaching model of genetics and cultivating medical talents capable of doing both basic and clinical research in the "precision medicine" era.

  20. Genetic variance of tolerance and the toxicant threshold model.

    Science.gov (United States)

    Tanaka, Yoshinari; Mano, Hiroyuki; Tatsuta, Haruki

    2012-04-01

    A statistical genetics method is presented for estimating the genetic variance (heritability) of tolerance to pollutants on the basis of a standard acute toxicity test conducted on several isofemale lines of cladoceran species. To analyze the genetic variance of tolerance in the case when the response is measured as a few discrete states (quantal endpoints), the authors attempted to apply the threshold character model in quantitative genetics to the threshold model separately developed in ecotoxicology. The integrated threshold model (toxicant threshold model) assumes that the response of a particular individual occurs at a threshold toxicant concentration and that the individual tolerance characterized by the individual's threshold value is determined by genetic and environmental factors. As a case study, the heritability of tolerance to p-nonylphenol in the cladoceran species Daphnia galeata was estimated by using the maximum likelihood method and nested analysis of variance (ANOVA). Broad-sense heritability was estimated to be 0.199 ± 0.112 by the maximum likelihood method and 0.184 ± 0.089 by ANOVA; both results implied that the species examined had the potential to acquire tolerance to this substance by evolutionary change.

  1. Modeling the MagnetoencephaloGram (MEG) Of Epileptic Patients Using Genetic Programming and Minimizing the Derived Models Using Genetic Algorithms

    Science.gov (United States)

    Theofilatos, Konstantinos; Georgopoulos, Efstratios; Likothanassis, Spiridon

    2009-09-01

    In this paper, a variation of traditional Genetic Programming(GP) is used to model the MagnetoencephaloGram(MEG) of Epileptic Patients. This variation is Linear Genetic Programming(LGP). LGP is a particular subset of GP wherein computer programs in population are represented as a sequence of instructions from imperative programming language or machine language. The derived models from this method were simplified using genetic algorithms. The proposed method was used to model the MEG signal of epileptic patients using 6 different datasets. Each dataset uses different number of previous values of MEG to predict the next value. The models were tested in datasets different from the ones which were used to produce them and the results were very promising.

  2. Predicting diabetic nephropathy using a multifactorial genetic model.

    Directory of Open Access Journals (Sweden)

    Ilana Blech

    Full Text Available AIMS: The tendency to develop diabetic nephropathy is, in part, genetically determined, however this genetic risk is largely undefined. In this proof-of-concept study, we tested the hypothesis that combined analysis of multiple genetic variants can improve prediction. METHODS: Based on previous reports, we selected 27 SNPs in 15 genes from metabolic pathways involved in the pathogenesis of diabetic nephropathy and genotyped them in 1274 Ashkenazi or Sephardic Jewish patients with Type 1 or Type 2 diabetes of >10 years duration. A logistic regression model was built using a backward selection algorithm and SNPs nominally associated with nephropathy in our population. The model was validated by using random "training" (75% and "test" (25% subgroups of the original population and by applying the model to an independent dataset of 848 Ashkenazi patients. RESULTS: The logistic model based on 5 SNPs in 5 genes (HSPG2, NOS3, ADIPOR2, AGER, and CCL5 and 5 conventional variables (age, sex, ethnicity, diabetes type and duration, and allowing for all possible two-way interactions, predicted nephropathy in our initial population (C-statistic = 0.672 better than a model based on conventional variables only (C = 0.569. In the independent replication dataset, although the C-statistic of the genetic model decreased (0.576, it remained highly associated with diabetic nephropathy (χ(2 = 17.79, p<0.0001. In the replication dataset, the model based on conventional variables only was not associated with nephropathy (χ(2 = 3.2673, p = 0.07. CONCLUSION: In this proof-of-concept study, we developed and validated a genetic model in the Ashkenazi/Sephardic population predicting nephropathy more effectively than a similarly constructed non-genetic model. Further testing is required to determine if this modeling approach, using an optimally selected panel of genetic markers, can provide clinically useful prediction and if generic models can be

  3. Model-free Estimation of Recent Genetic Relatedness

    Science.gov (United States)

    Conomos, Matthew P.; Reiner, Alexander P.; Weir, Bruce S.; Thornton, Timothy A.

    2016-01-01

    Genealogical inference from genetic data is essential for a variety of applications in human genetics. In genome-wide and sequencing association studies, for example, accurate inference on both recent genetic relatedness, such as family structure, and more distant genetic relatedness, such as population structure, is necessary for protection against spurious associations. Distinguishing familial relatedness from population structure with genotype data, however, is difficult because both manifest as genetic similarity through the sharing of alleles. Existing approaches for inference on recent genetic relatedness have limitations in the presence of population structure, where they either (1) make strong and simplifying assumptions about population structure, which are often untenable, or (2) require correct specification of and appropriate reference population panels for the ancestries in the sample, which might be unknown or not well defined. Here, we propose PC-Relate, a model-free approach for estimating commonly used measures of recent genetic relatedness, such as kinship coefficients and IBD sharing probabilities, in the presence of unspecified structure. PC-Relate uses principal components calculated from genome-screen data to partition genetic correlations among sampled individuals due to the sharing of recent ancestors and more distant common ancestry into two separate components, without requiring specification of the ancestral populations or reference population panels. In simulation studies with population structure, including admixture, we demonstrate that PC-Relate provides accurate estimates of genetic relatedness and improved relationship classification over widely used approaches. We further demonstrate the utility of PC-Relate in applications to three ancestrally diverse samples that vary in both size and genealogical complexity. PMID:26748516

  4. Catching transcriptional regulation by thermostatistical modeling

    Science.gov (United States)

    Frank, Till D.; Cheong, Alex; Okada-Hatakeyama, Mariko; Kholodenko, Boris N.

    2012-08-01

    Gene expression is frequently regulated by multiple transcription factors (TFs). Thermostatistical methods allow for a quantitative description of interactions between TFs, RNA polymerase and DNA, and their impact on the transcription rates. We illustrate three different scales of the thermostatistical approach: the microscale of TF molecules, the mesoscale of promoter energy levels and the macroscale of transcriptionally active and inactive cells in a cell population. We demonstrate versatility of combinatorial transcriptional activation by exemplifying logic functions, such as AND and OR gates. We discuss a metric for cell-to-cell transcriptional activation variability known as Fermi entropy. Suitability of thermostatistical modeling is illustrated by describing the experimental data on transcriptional induction of NFκB and the c-Fos protein.

  5. Genetic Algorithm Modeling with GPU Parallel Computing Technology

    CERN Document Server

    Cavuoti, Stefano; Brescia, Massimo; Pescapé, Antonio; Longo, Giuseppe; Ventre, Giorgio

    2012-01-01

    We present a multi-purpose genetic algorithm, designed and implemented with GPGPU / CUDA parallel computing technology. The model was derived from a multi-core CPU serial implementation, named GAME, already scientifically successfully tested and validated on astrophysical massive data classification problems, through a web application resource (DAMEWARE), specialized in data mining based on Machine Learning paradigms. Since genetic algorithms are inherently parallel, the GPGPU computing paradigm has provided an exploit of the internal training features of the model, permitting a strong optimization in terms of processing performances and scalability.

  6. Current concepts of IgE regulation and impact of genetic determinants.

    Science.gov (United States)

    Potaczek, D P; Kabesch, M

    2012-06-01

    Immunoglobulin E (IgE) mediated immune responses seem to be directed against parasites and neoplasms, but are best known for their involvement in allergies. The IgE network is tightly controlled at different levels as outlined in this review. Genetic determinants were suspected to influence IgE regulation and IgE levels considerably for many years. Linkage and candidate gene studies suggested a number of loci and genes to correlate with total serum IgE levels, and recently genome-wide association studies (GWAS) provided the power to identify genetic determinants for total serum IgE levels: 1q23 (FCER1A), 5q31 (RAD50, IL13, IL4), 12q13 (STAT6), 6p21.3 (HLA-DRB1) and 16p12 (IL4R, IL21R). In this review, we analyse the potential role of these GWAS hits in the IgE network and suggest mechanisms of how genes and genetic variants in these loci may influence IgE regulation.

  7. Genetic variants of methyl metabolizing enzymes and epigenetic regulators: Associations with promoter CpG island hypermethylation in colorectal cancer

    NARCIS (Netherlands)

    Vogel, S. de; Wouters, K.A.D.; Gottschalk, R.W.H.; Schooten, F.J. van; Goeij, A.F.P.M. de; Bruïne, A.P. de; Goldbohm, R.A.; Brandt, P.A. van den; Weijenberg, M.P.; Engeland, M. van

    2009-01-01

    Aberrant DNA methylation affects carcinogenesis of colorectal cancer. Folate metabolizing enzymes may influence the bioavailability of methyl groups, whereas DNA and histone methyltransferases are involved in epigenetic regulation of gene expression. We studied associations of genetic variants of fo

  8. Genetics

    Science.gov (United States)

    ... Inheritance; Heterozygous; Inheritance patterns; Heredity and disease; Heritable; Genetic markers ... The chromosomes are made up of strands of genetic information called DNA. Each chromosome contains sections of ...

  9. Genetic control of lithium sensitivity and regulation of inositol biosynthetic genes.

    Directory of Open Access Journals (Sweden)

    Jason King

    Full Text Available Lithium (Li(+ is a common treatment for bipolar mood disorder, a major psychiatric illness with a lifetime prevalence of more than 1%. Risk of bipolar disorder is heavily influenced by genetic predisposition, but is a complex genetic trait and, to date, genetic studies have provided little insight into its molecular origins. An alternative approach is to investigate the genetics of Li(+ sensitivity. Using the social amoeba Dictyostelium, we previously identified prolyl oligopeptidase (PO as a modulator of Li(+ sensitivity. In a link to the clinic, PO enzyme activity is altered in bipolar disorder patients. Further studies demonstrated that PO is a negative regulator of inositol(1,4,5trisphosphate (IP(3 synthesis, a Li(+ sensitive intracellular signal. However, it was unclear how PO could influence either Li(+ sensitivity or risk of bipolar disorder. Here we show that in both Dictyostelium and cultured human cells PO acts via Multiple Inositol Polyphosphate Phosphatase (Mipp1 to control gene expression. This reveals a novel, gene regulatory network that modulates inositol metabolism and Li(+ sensitivity. Among its targets is the inositol monophosphatase gene IMPA2, which has also been associated with risk of bipolar disorder in some family studies, and our observations offer a cellular signalling pathway in which PO activity and IMPA2 gene expression converge.

  10. Dissecting genetic and environmental mutation signatures with model organisms.

    Science.gov (United States)

    Segovia, Romulo; Tam, Annie S; Stirling, Peter C

    2015-08-01

    Deep sequencing has impacted on cancer research by enabling routine sequencing of genomes and exomes to identify genetic changes associated with carcinogenesis. Researchers can now use the frequency, type, and context of all mutations in tumor genomes to extract mutation signatures that reflect the driving mutational processes. Identifying mutation signatures, however, may not immediately suggest a mechanism. Consequently, several recent studies have employed deep sequencing of model organisms exposed to discrete genetic or environmental perturbations. These studies exploit the simpler genomes and availability of powerful genetic tools in model organisms to analyze mutation signatures under controlled conditions, forging mechanistic links between mutational processes and signatures. We discuss the power of this approach and suggest that many such studies may be on the horizon.

  11. Developmental genetics in emerging rodent models: case studies and perspectives.

    Science.gov (United States)

    Mallarino, Ricardo; Hoekstra, Hopi E; Manceau, Marie

    2016-08-01

    For decades, mammalian developmental genetic studies have focused almost entirely on two laboratory models: Mus and Rattus, species that breed readily in the laboratory and for which a wealth of molecular and genetic resources exist. These species alone, however, do not capture the remarkable diversity of morphological, behavioural and physiological traits seen across rodents, a group that represents >40% of all mammal species. Due to new advances in molecular tools and genomic technologies, studying the developmental events underlying natural variation in a wide range of species for a wide range of traits has become increasingly feasible. Here we review several recent studies and discuss how they not only provided technical resources for newly emerging rodent models in developmental genetics but also are instrumental in further encouraging scientists, from a wide range of research fields, to capitalize on the great diversity in development that has evolved among rodents.

  12. Transcriptome comparison reveals a genetic network regulating the lower temperature limit in fish

    Science.gov (United States)

    Hu, Peng; Liu, Mingli; Liu, Yimeng; Wang, Jinfeng; Zhang, Dong; Niu, Hongbo; Jiang, Shouwen; Wang, Jian; Zhang, Dongsheng; Han, Bingshe; Xu, Qianghua; Chen, Liangbiao

    2016-01-01

    Transcriptional plasticity is a major driver of phenotypic differences between species. The lower temperature limit (LTL), namely the lower end of survival temperature, is an important trait delimiting the geographical distribution of a species, however, the genetic mechanisms are poorly understood. We investigated the inter-species transcriptional diversification in cold responses between zebrafish Danio rerio and tilapia Oreochromis niloticus, which were reared at a common temperature (28 °C) but have distinct LTLs. We identified significant expressional divergence between the two species in the orthologous genes from gills when the temperature cooled to the LTL of tilapia (8 °C). Five KEGG pathways were found sequentially over-represented in the zebrafish/tilapia divergently expressed genes in the duration (12 hour) of 8 °C exposure, forming a signaling cascade from metabolic regulation to apoptosis via FoxO signaling. Consistently, we found differential progression of apoptosis in the gills of the two species in which zebrafish manifested a delayed and milder apoptotic phenotype than tilapia, corresponding with a lower LTL of zebrafish. We identified diverged expression in 25 apoptosis-related transcription factors between the two species which forms an interacting network with diverged factors involving the FoxO signaling and metabolic regulation. We propose a genetic network which regulates LTL in fishes. PMID:27356472

  13. Functional Genomic and Advanced Genetic Studies Reveal Novel Insights into the Metabolism, Regulation, and Biology of Haloferax volcanii

    Directory of Open Access Journals (Sweden)

    Jörg Soppa

    2011-01-01

    Full Text Available The genome sequence of Haloferax volcanii is available and several comparative genomic in silico studies were performed that yielded novel insight for example into protein export, RNA modifications, small non-coding RNAs, and ubiquitin-like Small Archaeal Modifier Proteins. The full range of functional genomic methods has been established and results from transcriptomic, proteomic and metabolomic studies are discussed. Notably, Hfx. volcanii is together with Halobacterium salinarum the only prokaryotic species for which a translatome analysis has been performed. The results revealed that the fraction of translationally-regulated genes in haloarchaea is as high as in eukaryotes. A highly efficient genetic system has been established that enables the application of libraries as well as the parallel generation of genomic deletion mutants. Facile mutant generation is complemented by the possibility to culture Hfx. volcanii in microtiter plates, allowing the phenotyping of mutant collections. Genetic approaches are currently used to study diverse biological questions–from replication to posttranslational modification—and selected results are discussed. Taken together, the wealth of functional genomic and genetic tools make Hfx. volcanii a bona fide archaeal model species, which has enabled the generation of important results in recent years and will most likely generate further breakthroughs in the future.

  14. A Genetic Screen Identifies Hypothalamic Fgf15 as a Regulator of Glucagon Secretion

    Directory of Open Access Journals (Sweden)

    Alexandre Picard

    2016-11-01

    Full Text Available The counterregulatory response to hypoglycemia, which restores normal blood glucose levels to ensure sufficient provision of glucose to the brain, is critical for survival. To discover underlying brain regulatory systems, we performed a genetic screen in recombinant inbred mice for quantitative trait loci (QTL controlling glucagon secretion in response to neuroglucopenia. We identified a QTL on the distal part of chromosome 7 and combined this genetic information with transcriptomic analysis of hypothalami. This revealed Fgf15 as the strongest candidate to control the glucagon response. Fgf15 was expressed by neurons of the dorsomedial hypothalamus and the perifornical area. Intracerebroventricular injection of FGF19, the human ortholog of Fgf15, reduced activation by neuroglucopenia of dorsal vagal complex neurons, of the parasympathetic nerve, and lowered glucagon secretion. In contrast, silencing Fgf15 in the dorsomedial hypothalamus increased neuroglucopenia-induced glucagon secretion. These data identify hypothalamic Fgf15 as a regulator of glucagon secretion.

  15. Genetic programming-based chaotic time series modeling

    Institute of Scientific and Technical Information of China (English)

    张伟; 吴智铭; 杨根科

    2004-01-01

    This paper proposes a Genetic Programming-Based Modeling(GPM)algorithm on chaotic time series. GP is used here to search for appropriate model structures in function space,and the Particle Swarm Optimization(PSO)algorithm is used for Nonlinear Parameter Estimation(NPE)of dynamic model structures. In addition,GPM integrates the results of Nonlinear Time Series Analysis(NTSA)to adjust the parameters and takes them as the criteria of established models.Experiments showed the effectiveness of such improvements on chaotic time series modeling.

  16. Genetic signatures of natural selection in a model invasive ascidian

    Science.gov (United States)

    Lin, Yaping; Chen, Yiyong; Yi, Changho; Fong, Jonathan J.; Kim, Won; Rius, Marc; Zhan, Aibin

    2017-01-01

    Invasive species represent promising models to study species’ responses to rapidly changing environments. Although local adaptation frequently occurs during contemporary range expansion, the associated genetic signatures at both population and genomic levels remain largely unknown. Here, we use genome-wide gene-associated microsatellites to investigate genetic signatures of natural selection in a model invasive ascidian, Ciona robusta. Population genetic analyses of 150 individuals sampled in Korea, New Zealand, South Africa and Spain showed significant genetic differentiation among populations. Based on outlier tests, we found high incidence of signatures of directional selection at 19 loci. Hitchhiking mapping analyses identified 12 directional selective sweep regions, and all selective sweep windows on chromosomes were narrow (~8.9 kb). Further analyses indentified 132 candidate genes under selection. When we compared our genetic data and six crucial environmental variables, 16 putatively selected loci showed significant correlation with these environmental variables. This suggests that the local environmental conditions have left significant signatures of selection at both population and genomic levels. Finally, we identified “plastic” genomic regions and genes that are promising regions to investigate evolutionary responses to rapid environmental change in C. robusta. PMID:28266616

  17. Genetic regulation of the specific and non-specific component of immunity.

    Science.gov (United States)

    Stiffel, C; Ibanez, O M; Ribeiro, O G; Decreusefond, C; Siqueira, M; Mouton, D; Biozzi, G

    1987-12-01

    Bi-directional selective breeding for antibody (Ab) responsiveness to heterologous erythrocytes (Selection I) produced a high (H) and a low (L) responder line of mice which were also remarkably separated for Ab responses to many unrelated natural antigens (Ags) such as heterologous proteins, viruses, bacteria, parasites and haptens carried by these immunogens. The character "quantitative Ab responsiveness" is controlled by several independently segregating loci (polygenic regulation). The major genetic modification is produced at the level of macrophage activities. The Ag is slowly catabolized and persists for a long time on the macrophage membrane of the H line, whereas it is rapidly destroyed in L line macrophages. The bactericidal and bacteriostatic activity of the macrophage is also strong in the L line and weak in the H line. The opposite genetic regulation of Ab responsiveness and macrophage activity is a fundamental phenomenon for understanding natural and vaccination-induced anti-infectious immunity. The L line is more resistant than the H line against the infections due to intracellular microorganisms (Salmonellae, Yersinia, Mycobacteria, Brucellae, Leishmania) where the macrophage plays the dominant defensive barrier. The H line is more resistant than the L line to the extracellular microorganisms which are efficiently counteracted by a strong antibody response (Pneumococcus, Klebsiella, Plasmodia, Trypanosoma). The intensity of T cell-mediated immunity as measured by delayed type hypersensitivity, which is independent of the genetic regulation of antibody responsiveness, is correlated with the degree of nonspecific inflammation produced at the site of the reaction by the Ag injection in non-sensitized mice.(ABSTRACT TRUNCATED AT 250 WORDS)

  18. Unraveling the genetics of chronic kidney disease using animal models

    NARCIS (Netherlands)

    Korstanje, Ron; DiPetrillo, K.

    2004-01-01

    Identifying genes underlying common forms of kidney disease in humans has proven difficult, expensive, and time consuming. Quantitative trait loci (QTL) for several complex traits are concordant among mice, rats, and humans, suggesting that genetic findings from these animal models are relevant to

  19. Noninvasive transcranial direct current stimulation in a genetic absence model

    NARCIS (Netherlands)

    Zobeiri, M.; Luijtelaar, E.L.J.M. van

    2013-01-01

    The proposed area of onset for absence epilepsy characteristic of spontaneously occurring spike and slow-wave discharges (SWDs) in the genetic absence rat model is the subgranular layer of the somatosensory cortex. Modulation of the hyperexcitable cortical foci by bilateral transcranial direct curre

  20. Sparse time series chain graphical models for reconstructing genetic networks

    NARCIS (Netherlands)

    Abegaz, Fentaw; Wit, Ernst

    2013-01-01

    We propose a sparse high-dimensional time series chain graphical model for reconstructing genetic networks from gene expression data parametrized by a precision matrix and autoregressive coefficient matrix. We consider the time steps as blocks or chains. The proposed approach explores patterns of co

  1. Morphological diversity and genetic regulation of inflorescence abscission zones in grasses.

    Science.gov (United States)

    Doust, Andrew N; Mauro-Herrera, Margarita; Francis, Amie D; Shand, Laura C

    2014-10-01

    • Variation in how seeds are dispersed in grasses is ecologically important, and selection for dispersal mechanisms has produced a great variety of dispersal structures (diaspores). Abscission ("shattering") is necessary in wild grasses, but its elimination by selection on nonshattering mutants was a key component of the domestication syndrome in cereal grasses. A key question is whether a common genetic pathway controls abscission in wild grasses, and, if so, what genes in that pathway may have been selected upon during domestication. We summarize morphological and genetic information on abscission zones and disarticulation patterns in grasses and identify hypotheses to test the likelihood of a common genetic pathway.• Morphological data on abscission zones for over 10000 species of grasses were tabulated and analyzed using a tribal phylogeny of the grasses. The genomic location of quantitative trait loci (QTLs) and orthologs of genes controlling shattering were compared across species to ascertain whether the same loci might control shattering in different grass lineages.• The simple trait of nonshattering is derived from a great diversity of shattering phenotypes. Several sets of QTLs from multiple species are syntenic yet many are not. Genes known to be involved in shattering in several species were found to have orthologs that sometimes colocalized with QTLs in different species, adding support to the hypothesis of retention of a common genetic pathway. These results are used to suggest a research plan that could test the common genetic pathway model more thoroughly. © 2014 Botanical Society of America, Inc.

  2. Applying Cystic Fibrosis Transmembrane Conductance Regulator Genetics and CFTR2 Data to Facilitate Diagnoses.

    Science.gov (United States)

    Sosnay, Patrick R; Salinas, Danieli B; White, Terry B; Ren, Clement L; Farrell, Philip M; Raraigh, Karen S; Girodon, Emmanuelle; Castellani, Carlo

    2017-02-01

    As a Mendelian disease, genetics plays an integral role in the diagnosis of cystic fibrosis (CF). The identification of 2 disease-causing mutations in the CF transmembrane conductance regulator (CFTR) in an individual with a phenotype provides evidence that the disease is CF. However, not all variations in CFTR always result in CF. Therefore, for CFTR genotype to provide the same level of evidence of CFTR dysfunction as shown by direct tests such as sweat chloride or nasal potential difference, the mutations identified must be known to always result in CF. The use of CFTR genetics in CF diagnosis, therefore, relies heavily on mutation interpretation. Progress that has been made on mutation interpretation and annotation was reviewed at the recent CF Foundation Diagnosis Consensus Conference. A modified Delphi method was used to identify consensus statements on the use of genetic analysis in CF diagnosis. The largest recent advance in CF genetics has come through the Clinical and Functional Translation of CFTR (CFTR2) project. This undertaking seeks to characterize CFTR mutations from patients with CF around the world. The project also established guidelines for the clinical, functional, and population/penetrance criteria that can be used to interpret mutations not yet included in CFTR2's review. The use of CFTR genetics to aid in diagnosis of CF requires that the mutations identified have a known disease liability. The demonstration of 2 in trans mutations known to always result in CF is satisfactory evidence of CFTR dysfunction. However, if the identified mutations are known to be associated with variable outcomes, or have unknown consequence, that genotype may not result in a CF phenotype. In these cases, other tests of CFTR function may help. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. A genetic algorithm for solving supply chain network design model

    Science.gov (United States)

    Firoozi, Z.; Ismail, N.; Ariafar, S. H.; Tang, S. H.; Ariffin, M. K. M. A.

    2013-09-01

    Network design is by nature costly and optimization models play significant role in reducing the unnecessary cost components of a distribution network. This study proposes a genetic algorithm to solve a distribution network design model. The structure of the chromosome in the proposed algorithm is defined in a novel way that in addition to producing feasible solutions, it also reduces the computational complexity of the algorithm. Computational results are presented to show the algorithm performance.

  4. Genetic Design of an Interval Type-2 Fuzzy Controller for Velocity Regulation in a DC Motor

    Directory of Open Access Journals (Sweden)

    Yazmin Maldonado

    2012-11-01

    Full Text Available This paper proposes the design of a Type‐2 Fuzzy Logic Controller (T2‐FLC using Genetic Algorithms (GAs. The T2‐FLC was tested with different levels of uncertainty to regulate velocity in a Direct Current (DC motor. The T2‐FLC was synthesized in Very High Description Language (VHDL code for a Field‐programmable Gate Array (FPGA, using the Xilinx System Generator (XSG of Xilinx ISE and Matlab‐Simulink. Comparisons were made between the Type‐1 Fuzzy Logic Controller and the T2‐FLC in VHDL code and a Proportional Integral Differential (PID Controller so as to regulate the velocity of a DC motor and evaluate the difference in performance of the three types of controllers, using the t‐student test statistic.

  5. The significance of genetics in pathophysiologic models of premature birth.

    Science.gov (United States)

    Uberos, Jose

    2017-05-31

    Prematurity is a major health problem in all countries, especially in certain ethic groups and increasing recurrence imply the influence of genetic factors. Published genetic polymorphisms are identified in relation to the 4 pathophysiological models of prematurity described: Chorioamniotic-decidual inflammation, premature contraction pathway, decidual haemorrhage and susceptibility to environmental toxins. 240 articles are identified, 52 articles are excluded because they are not original, not written in English or duplicated. From them 125 articles were included in qualitative analysis This review aims to update recent knowledge about genes associated with premature birth.

  6. Allostasis: a model of predictive regulation.

    Science.gov (United States)

    Sterling, Peter

    2012-04-12

    The premise of the standard regulatory model, "homeostasis", is flawed: the goal of regulation is not to preserve constancy of the internal milieu. Rather, it is to continually adjust the milieu to promote survival and reproduction. Regulatory mechanisms need to be efficient, but homeostasis (error-correction by feedback) is inherently inefficient. Thus, although feedbacks are certainly ubiquitous, they could not possibly serve as the primary regulatory mechanism. A newer model, "allostasis", proposes that efficient regulation requires anticipating needs and preparing to satisfy them before they arise. The advantages: (i) errors are reduced in magnitude and frequency; (ii) response capacities of different components are matched -- to prevent bottlenecks and reduce safety factors; (iii) resources are shared between systems to minimize reserve capacities; (iv) errors are remembered and used to reduce future errors. This regulatory strategy requires a dedicated organ, the brain. The brain tracks multitudinous variables and integrates their values with prior knowledge to predict needs and set priorities. The brain coordinates effectors to mobilize resources from modest bodily stores and enforces a system of flexible trade-offs: from each organ according to its ability, to each organ according to its need. The brain also helps regulate the internal milieu by governing anticipatory behavior. Thus, an animal conserves energy by moving to a warmer place - before it cools, and it conserves salt and water by moving to a cooler one before it sweats. The behavioral strategy requires continuously updating a set of specific "shopping lists" that document the growing need for each key component (warmth, food, salt, water). These appetites funnel into a common pathway that employs a "stick" to drive the organism toward filling the need, plus a "carrot" to relax the organism when the need is satisfied. The stick corresponds broadly to the sense of anxiety, and the carrot broadly to

  7. Canalization and symmetry in Boolean models for genetic regulatory networks

    Energy Technology Data Exchange (ETDEWEB)

    Reichhardt, C J Olson [Theoretical Division and Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, NM 87545 (United States); Bassler, Kevin E [Department of Physics, University of Houston, Houston, TX 77204-5005 (United States)

    2007-04-20

    Canalization of genetic regulatory networks has been argued to be favoured by evolutionary processes due to the stability that it can confer to phenotype expression. We explore whether a significant amount of canalization and partial canalization can arise in purely random networks in the absence of evolutionary pressures. We use a mapping of the Boolean functions in the Kauffman N-K model for genetic regulatory networks onto a k-dimensional Ising hypercube (where k = K) to show that the functions can be divided into different classes strictly due to geometrical constraints. The classes can be counted and their properties determined using results from group theory and isomer chemistry. We demonstrate that partially canalizing functions completely dominate all possible Boolean functions, particularly for higher k. This indicates that partial canalization is extremely common, even in randomly chosen networks, and has implications for how much information can be obtained in experiments on native state genetic regulatory networks.

  8. Models and mechanisms of energy balance regulation in the young.

    Science.gov (United States)

    Mercer, Julian G

    2008-11-01

    The proportion of the child and adolescent population that is in appropriate energy balance is declining throughout the developed world, and childhood obesity is a particular problem in the UK relative to other northern European countries. Assessment of the underlying causes of obesity, and the different routes to its development, may assist in the definition of successful intervention strategies. The network of peripheral and central (brain) regulatory systems that underlie energy balance and body weight and composition can, for the most part, only be approached experimentally through the study of appropriate laboratory animal models. This problem is particularly acute when the target is overweight and obesity in the young. Some of the mechanisms underlying the development of energy imbalance and specifically the onset of overweight and obesity in the young, and the metabolic health consequences of obesity, can be addressed by examination of experimental rodent models in which mutation of a single gene causes early-onset extreme obesity, genetic susceptibility to obesity is revealed in an obesogenic environment or early-life nutritional experience programmes susceptibility to obesity or metabolic problems in later life. These studies highlight genes that are essential to normal body-weight regulation in rodents and man, the impact of diet and diet-induced obesity on regulatory systems in the young and the potential sensitivity of developing regulatory systems to nutritional experiences in utero and during early life.

  9. Fuzzy Modelling of Knee Joint with Genetic Optimization

    Directory of Open Access Journals (Sweden)

    B. S. K. K. Ibrahim

    2011-01-01

    Full Text Available Modelling of joint properties of lower limbs in people with spinal cord injury is significantly challenging for researchers due to the complexity of the system. The objective of this study is to develop a knee joint model capable of relating electrical parameters to dynamic joint torque as well as knee angle for functional electrical stimulation application. The joint model consists of a segmental dynamic, time-invariant passive properties and uncertain time-variant active properties. The knee joint model structure comprising optimised equations of motion and fuzzy models to represent the passive viscoelasticity and active muscle properties is formulated. The model thus formulated is optimised using genetic optimization, and validated against experimental data. The developed model can be used for simulation of joint movements as well as for control development. The results show that the model developed gives an accurate dynamic characterisation of the knee joint.

  10. Learning with Admixture: Modeling, Optimization, and Applications in Population Genetics

    DEFF Research Database (Denmark)

    Cheng, Jade Yu

    2016-01-01

    Population genetics is a branch of applied mathematics. It is a translation of scientific observations into mathematical models and their manipulations in order to produce quantitative predictions about evolution. Combining knowledge from genetics, statistics, and computer science, population...... data. Ohana's admixture module is based on classical structure modeling but uses new optimization subroutines through quadratic programming, which outperform the current state-of-the-art software in both speed and accuracy. Ohana presents a new method for phylogenetic tree inference using Gaussian...... the foundation for both CoalHMM and Ohana. Optimization modeling has been the main theme throughout my PhD, and it will continue to shape my work for the years to come. The algorithms and software I developed to study historical admixture and population evolution fall into a larger family of machine learning...

  11. Genetic control of macrophage functions. I. Polygenic regulation of phagocytosis stimulation produced by Glyceryl Trioleate.

    Science.gov (United States)

    Mouton, D; Bouthillier, Y; Feingold, N; Feingold, J; Decreusefond, C; Stiffel, C; Biozzi, G

    1975-02-01

    The phagocytic index K, established from the rate of blood clearance of colloidal carbon, measures the phagocytic activity of RE macrophages in contact with the circulating blood. The intravenous injection of glyceryl trioleate (triolein) produces a marked stimulation of the phagocytic activity of RE macrophages. This response is higher in the female than in the male mice. The phenotypic character "responsiveness of macrophage to triolein" presents large individual variants in population of random bred albinos mice. This character is submitted to polygenic regulation. Starting from a foundation population of 25 males and 25 females random bred albinos, mice, two lines were separated by selective breeding for the character "responsiveness to triolein": a "high" responder line, KTH, and a "low" responder line, KTL. After 26 consecutive generations of selective breeding, KTH mice present a very high response to triolein while KTL mice are almost irresponsive. The heritability of this character (h2) calculated from the interline divergence is of 12% plus or minus 1. This value of h2 indicates that the character investigated is determined by the cumulative effect of a group of about 27 independently segregating loci. The distribution of the character in (KTH plus KTL)F1 and their backcrosses with parental lines suggests that low responsiveness is dominant over high responsiveness. The genetic regulation of responsiveness to triolein is independent from the dose administered. These results are discussed in relation to the importance of genetic factors controlling macrophage functions involved in lipid metabolism and in the specific mechanisms of immunity.

  12. Novel Insights into the Genetic Controls of Primitive and Definitive Hematopoiesis from Zebrafish Models

    Directory of Open Access Journals (Sweden)

    Raman Sood

    2012-01-01

    Full Text Available Hematopoiesis is a dynamic process where initiation and maintenance of hematopoietic stem cells, as well as their differentiation into erythroid, myeloid and lymphoid lineages, are tightly regulated by a network of transcription factors. Understanding the genetic controls of hematopoiesis is crucial as perturbations in hematopoiesis lead to diseases such as anemia, thrombocytopenia, or cancers, including leukemias and lymphomas. Animal models, particularly conventional and conditional knockout mice, have played major roles in our understanding of the genetic controls of hematopoiesis. However, knockout mice for most of the hematopoietic transcription factors are embryonic lethal, thus precluding the analysis of their roles during the transition from embryonic to adult hematopoiesis. Zebrafish are an ideal model organism to determine the function of a gene during embryonic-to-adult transition of hematopoiesis since bloodless zebrafish embryos can develop normally into early larval stage by obtaining oxygen through diffusion. In this review, we discuss the current status of the ontogeny and regulation of hematopoiesis in zebrafish. By providing specific examples of zebrafish morphants and mutants, we have highlighted the contributions of the zebrafish model to our overall understanding of the roles of transcription factors in regulation of primitive and definitive hematopoiesis.

  13. Asymmetrical Damage Partitioning in Bacteria: A Model for the Evolution of Stochasticity, Determinism, and Genetic Assimilation.

    Directory of Open Access Journals (Sweden)

    Lin Chao

    2016-01-01

    Full Text Available Non-genetic phenotypic variation is common in biological organisms. The variation is potentially beneficial if the environment is changing. If the benefit is large, selection can favor the evolution of genetic assimilation, the process by which the expression of a trait is transferred from environmental to genetic control. Genetic assimilation is an important evolutionary transition, but it is poorly understood because the fitness costs and benefits of variation are often unknown. Here we show that the partitioning of damage by a mother bacterium to its two daughters can evolve through genetic assimilation. Bacterial phenotypes are also highly variable. Because gene-regulating elements can have low copy numbers, the variation is attributed to stochastic sampling. Extant Escherichia coli partition asymmetrically and deterministically more damage to the old daughter, the one receiving the mother's old pole. By modeling in silico damage partitioning in a population, we show that deterministic asymmetry is advantageous because it increases fitness variance and hence the efficiency of natural selection. However, we find that symmetrical but stochastic partitioning can be similarly beneficial. To examine why bacteria evolved deterministic asymmetry, we modeled the effect of damage anchored to the mother's old pole. While anchored damage strengthens selection for asymmetry by creating additional fitness variance, it has the opposite effect on symmetry. The difference results because anchored damage reinforces the polarization of partitioning in asymmetric bacteria. In symmetric bacteria, it dilutes the polarization. Thus, stochasticity alone may have protected early bacteria from damage, but deterministic asymmetry has evolved to be equally important in extant bacteria. We estimate that 47% of damage partitioning is deterministic in E. coli. We suggest that the evolution of deterministic asymmetry from stochasticity offers an example of Waddington

  14. Asymmetrical Damage Partitioning in Bacteria: A Model for the Evolution of Stochasticity, Determinism, and Genetic Assimilation.

    Science.gov (United States)

    Chao, Lin; Rang, Camilla Ulla; Proenca, Audrey Menegaz; Chao, Jasper Ubirajara

    2016-01-01

    Non-genetic phenotypic variation is common in biological organisms. The variation is potentially beneficial if the environment is changing. If the benefit is large, selection can favor the evolution of genetic assimilation, the process by which the expression of a trait is transferred from environmental to genetic control. Genetic assimilation is an important evolutionary transition, but it is poorly understood because the fitness costs and benefits of variation are often unknown. Here we show that the partitioning of damage by a mother bacterium to its two daughters can evolve through genetic assimilation. Bacterial phenotypes are also highly variable. Because gene-regulating elements can have low copy numbers, the variation is attributed to stochastic sampling. Extant Escherichia coli partition asymmetrically and deterministically more damage to the old daughter, the one receiving the mother's old pole. By modeling in silico damage partitioning in a population, we show that deterministic asymmetry is advantageous because it increases fitness variance and hence the efficiency of natural selection. However, we find that symmetrical but stochastic partitioning can be similarly beneficial. To examine why bacteria evolved deterministic asymmetry, we modeled the effect of damage anchored to the mother's old pole. While anchored damage strengthens selection for asymmetry by creating additional fitness variance, it has the opposite effect on symmetry. The difference results because anchored damage reinforces the polarization of partitioning in asymmetric bacteria. In symmetric bacteria, it dilutes the polarization. Thus, stochasticity alone may have protected early bacteria from damage, but deterministic asymmetry has evolved to be equally important in extant bacteria. We estimate that 47% of damage partitioning is deterministic in E. coli. We suggest that the evolution of deterministic asymmetry from stochasticity offers an example of Waddington's genetic assimilation

  15. [The emphases and basic procedures of genetic counseling in psychotherapeutic model].

    Science.gov (United States)

    Zhang, Yuan-Zhi; Zhong, Nanbert

    2006-11-01

    The emphases and basic procedures of genetic counseling are all different with those in old models. In the psychotherapeutic model, genetic counseling will not only focus on counselees' genetic disorders and birth defects, but also their psychological problems. "Client-centered therapy" termed by Carl Rogers plays an important role in genetic counseling process. The basic procedures of psychotherapeutic model of genetic counseling include 7 steps: initial contact, introduction, agendas, inquiry of family history, presenting information, closing the session and follow-up.

  16. A unified model of the standard genetic code.

    Science.gov (United States)

    José, Marco V; Zamudio, Gabriel S; Morgado, Eberto R

    2017-03-01

    The Rodin-Ohno (RO) and the Delarue models divide the table of the genetic code into two classes of aminoacyl-tRNA synthetases (aaRSs I and II) with recognition from the minor or major groove sides of the tRNA acceptor stem, respectively. These models are asymmetric but they are biologically meaningful. On the other hand, the standard genetic code (SGC) can be derived from the primeval RNY code (R stands for purines, Y for pyrimidines and N any of them). In this work, the RO-model is derived by means of group actions, namely, symmetries represented by automorphisms, assuming that the SGC originated from a primeval RNY code. It turns out that the RO-model is symmetric in a six-dimensional (6D) hypercube. Conversely, using the same automorphisms, we show that the RO-model can lead to the SGC. In addition, the asymmetric Delarue model becomes symmetric by means of quotient group operations. We formulate isometric functions that convert the class aaRS I into the class aaRS II and vice versa. We show that the four polar requirement categories display a symmetrical arrangement in our 6D hypercube. Altogether these results cannot be attained, neither in two nor in three dimensions. We discuss the present unified 6D algebraic model, which is compatible with both the SGC (based upon the primeval RNY code) and the RO-model.

  17. Genetic variants associated with neurodegenerative Alzheimer disease in natural models.

    Science.gov (United States)

    Salazar, Claudia; Valdivia, Gonzalo; Ardiles, Álvaro O; Ewer, John; Palacios, Adrián G

    2016-02-26

    The use of transgenic models for the study of neurodegenerative diseases has made valuable contributions to the field. However, some important limitations, including protein overexpression and general systemic compensation for the missing genes, has caused researchers to seek natural models that show the main biomarkers of neurodegenerative diseases during aging. Here we review some of these models-most of them rodents, focusing especially on the genetic variations in biomarkers for Alzheimer diseases, in order to explain their relationships with variants associated with the occurrence of the disease in humans.

  18. Identification and genetic mapping of four novel genes that regulate leaf development in Arabidopsis

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Molecular and genetic characterizations of mutants have led to a better understanding of many developmental processes in the model system Arabidopsis thaliana. However, the leaf development that is specific to plants has been little studied. With the aim of contributing to the genetic dissection of leaf development, we have performed a large-scare screening for mutants with abnormal leaves. Among a great number of leaf mutants we have generated by T-DNA and transposon tagging and ethylmethae sulfonate (EMS) mutagenesis, four independent mutant lines have been identified and studied genetically. Phenotypes of these mutant lines represent the defects of four novel nuclear genes designated LL1 (LOTUS LEAF 1), LL2 (LOTUS LEAF 2), URO (UPRIGHT ROSETTE), and EIL (ENVIRONMENTCONDITION INDUCED LESION). The phenotypic analysis indicates that these genes play important roles during leaf development. For the further genetic analysis of these genes and the map-based cloning of LL1 and LL2, we have mapped these genes to chromosome regions with an efficient and rapid mapping method.

  19. Identification and genetic mapping of four novel genes that regulate leaf development in Arabidopsis

    Institute of Scientific and Technical Information of China (English)

    SUNYUE; YingLiGuo; 等

    2000-01-01

    Molecular and genetic characterizations of mutants have led to a better understanding of many developmental processes in the model system Arabidopsis thaliana.However,the leaf development that is specific to plants has been little studies.With the aim of contributing to the genetic dissection of leaf development,we have performed a large-scare screening for mutants with abnormal leaves.Among a great number of leaf mutants we have generated by T-DNA and transposon tagging and ethylmethae sulfonate (EMS) mutagenesis,four independent mutant lines have been identified and studied genetically.Phenotypes of these mutant lines represent the defects of four novel muclear genes designated LL1(LOTUS LEAF 1),LL2(LOTUS LEAF2),URO(UPRIGHT ROSETTE),and EIL(ENVIRONMENT CONDITION INDUCED LESION).The phenotypic analysis indicates that these genes play important roles during leaf development.For the further genetic analysis of these genes and the map-based cloning of LL1 and LL2,we have mapped these genes to chromosome regions with an efficient and rapid mapping method.

  20. A Tri-Part Model for Genetics Literacy: Exploring Undergraduate Student Reasoning about Authentic Genetics Dilemmas

    Science.gov (United States)

    Shea, Nicole A.; Duncan, Ravit Golan; Stephenson, Celeste

    2015-01-01

    Genetics literacy is becoming increasingly important as advancements in our application of genetic technologies such as stem cell research, cloning, and genetic screening become more prevalent. Very few studies examine how genetics literacy is applied when reasoning about authentic genetic dilemmas. However, there is evidence that situational…

  1. A Tri-Part Model for Genetics Literacy: Exploring Undergraduate Student Reasoning about Authentic Genetics Dilemmas

    Science.gov (United States)

    Shea, Nicole A.; Duncan, Ravit Golan; Stephenson, Celeste

    2015-01-01

    Genetics literacy is becoming increasingly important as advancements in our application of genetic technologies such as stem cell research, cloning, and genetic screening become more prevalent. Very few studies examine how genetics literacy is applied when reasoning about authentic genetic dilemmas. However, there is evidence that situational…

  2. Genetic Mouse Models of Huntington's Disease: Focus on Electrophysiological Mechanisms

    Directory of Open Access Journals (Sweden)

    Carlos Cepeda

    2010-03-01

    Full Text Available The discovery of the HD (Huntington's disease gene in 1993 led to the creation of genetic mouse models of the disease and opened the doors for mechanistic studies. In particular, the early changes and progression of the disease could be followed and examined systematically. The present review focuses on the contribution of these genetic mouse models to the understanding of functional changes in neurons as the HD phenotype progresses, and concentrates on two brain areas: the striatum, the site of most conspicuous pathology in HD, and the cortex, a site that is becoming increasingly important in understanding the widespread behavioural abnormalities. Mounting evidence points to synaptic abnormalities in communication between the cortex and striatum and cell-cell interactions as major determinants of HD symptoms, even in the absence of severe neuronal degeneration and death.

  3. Exchange Rate Prediction using Neural – Genetic Model

    Directory of Open Access Journals (Sweden)

    MECHGOUG Raihane

    2012-10-01

    Full Text Available Neural network have successfully used for exchange rate forecasting. However, due to a large number of parameters to be estimated empirically, it is not a simple task to select the appropriate neural network architecture for exchange rate forecasting problem.Researchers often overlook the effect of neural network parameters on the performance of neural network forecasting. The performance of neural network is critically dependant on the learning algorithms, thenetwork architecture and the choice of the control parameters. Even when a suitable setting of parameters (weight can be found, the ability of the resulting network to generalize the data not seen during learning may be far from optimal. For these reasons it seemslogical and attractive to apply genetic algorithms. Genetic algorithms may provide a useful tool for automating the design of neural network. The empirical results on foreign exchange rate prediction indicate that the proposed hybrid model exhibits effectively improved accuracy, when is compared with some other time series forecasting models.

  4. Regulation of excitation-contraction coupling in mouse cardiac myocytes: integrative analysis with mathematical modelling

    Directory of Open Access Journals (Sweden)

    Weckström Matti

    2009-08-01

    Full Text Available Abstract Background The cardiomyocyte is a prime example of inherently complex biological system with inter- and cross-connected feedback loops in signalling, forming the basic properties of intracellular homeostasis. Functional properties of cells and tissues have been studied e.g. with powerful tools of genetic engineering, combined with extensive experimentation. While this approach provides accurate information about the physiology at the endpoint, complementary methods, such as mathematical modelling, can provide more detailed information about the processes that have lead to the endpoint phenotype. Results In order to gain novel mechanistic information of the excitation-contraction coupling in normal myocytes and to analyze sophisticated genetically engineered heart models, we have built a mathematical model of a mouse ventricular myocyte. In addition to the fundamental components of membrane excitation, calcium signalling and contraction, our integrated model includes the calcium-calmodulin-dependent enzyme cascade and the regulation it imposes on the proteins involved in excitation-contraction coupling. With the model, we investigate the effects of three genetic modifications that interfere with calcium signalling: 1 ablation of phospholamban, 2 disruption of the regulation of L-type calcium channels by calcium-calmodulin-dependent kinase II (CaMK and 3 overexpression of CaMK. We show that the key features of the experimental phenotypes involve physiological compensatory and autoregulatory mechanisms that bring the system to a state closer to the original wild-type phenotype in all transgenic models. A drastic phenotype was found when the genetic modification disrupts the regulatory signalling system itself, i.e. the CaMK overexpression model. Conclusion The novel features of the presented cardiomyocyte model enable accurate description of excitation-contraction coupling. The model is thus an applicable tool for further studies of both

  5. Genetic and genomic analysis modeling of germline c-MYC overexpression and cancer susceptibility

    Directory of Open Access Journals (Sweden)

    Nunes Virginia

    2008-01-01

    Full Text Available Abstract Background Germline genetic variation is associated with the differential expression of many human genes. The phenotypic effects of this type of variation may be important when considering susceptibility to common genetic diseases. Three regions at 8q24 have recently been identified to independently confer risk of prostate cancer. Variation at 8q24 has also recently been associated with risk of breast and colorectal cancer. However, none of the risk variants map at or relatively close to known genes, with c-MYC mapping a few hundred kilobases distally. Results This study identifies cis-regulators of germline c-MYC expression in immortalized lymphocytes of HapMap individuals. Quantitative analysis of c-MYC expression in normal prostate tissues suggests an association between overexpression and variants in Region 1 of prostate cancer risk. Somatic c-MYC overexpression correlates with prostate cancer progression and more aggressive tumor forms, which was also a pathological variable associated with Region 1. Expression profiling analysis and modeling of transcriptional regulatory networks predicts a functional association between MYC and the prostate tumor suppressor KLF6. Analysis of MYC/Myc-driven cell transformation and tumorigenesis substantiates a model in which MYC overexpression promotes transformation by down-regulating KLF6. In this model, a feedback loop through E-cadherin down-regulation causes further transactivation of c-MYC. Conclusion This study proposes that variation at putative 8q24 cis-regulator(s of transcription can significantly alter germline c-MYC expression levels and, thus, contribute to prostate cancer susceptibility by down-regulating the prostate tumor suppressor KLF6 gene.

  6. A Building Model Framework for a Genetic Algorithm Multi-objective Model Predictive Control

    DEFF Research Database (Denmark)

    Arendt, Krzysztof; Ionesi, Ana; Jradi, Muhyiddine

    2016-01-01

    implemented only in few buildings. The following difficulties hinder the widespread usage of MPC: (1) significant model development time, (2) limited portability of models, (3) model computational demand. In the present study a new model development framework for an MPC system based on a Genetic Algorithm (GA...

  7. Genetic regulation of spy gene expression in Escherichia coli in the presence of protein unfolding agent ethanol.

    Science.gov (United States)

    Srivastava, Santosh Kumar; Lambadi, Paramesh Ramulu; Ghosh, Tamoghna; Pathania, Ranjana; Navani, Naveen Kumar

    2014-09-10

    In a living cell, folding of proteins is assisted by molecular chaperones and other folding helpers. In Escherichia coli (E. coli), recently an ATP independent chaperon 'Spy' was discovered which is highly up-regulated in the presence of protein unfolding agents like ethanol, butanol and tannic acid. Two response regulators; BaeR and CpxR have been recognized as transcriptional regulators of spy gene. However, the mechanism of genetic regulation of spy under protein denaturants like ethanol has not been studied in detail so far. Based on a combination of genetic, molecular biology and biochemical experimental data, we propose that BaeR protein is the primary regulator of spy gene in response to ethanol stress in E. coli. In addition, we expanded the experimental spectrum and validated that regulation of spy gene in the presence of zinc and copper metal stress is primarily via BaeR and CpxR regulators respectively. We also performed in-silico analysis to identify the homologs of Spy protein and their cognate regulatory elements in bacterial species belonging to enterobacteriaceae family. Based on the unique ATP-independent chaperone nature and genetic regulation of spy we also propose its importance in biosensor development and facilitated production of properly folded recombinant proteins.

  8. Modelling genetic susceptibility to multiple sclerosis with family data.

    Science.gov (United States)

    O'Gorman, Cullen; Lin, Rui; Stankovich, James; Broadley, Simon A

    2013-01-01

    A genetic contribution to susceptibility is well established in multiple sclerosis (MS) and 57 associated genetic loci have been identified. We have undertaken a meta-analysis of familial risk studies with the aims of providing definitive figures for risks to relatives, performing a segregation analysis and estimating the proportion of the overall genetic risk that currently identified genes represent. We have used standard methods of meta-analysis combined with novel approaches to age adjustment to provide directly comparable estimates of lifetime risk. The overall recurrence risk for monozygotic twins was 18.2% and for siblings 2.7%. The recurrence risk for dizygotic twins was significantly higher than for siblings. The overall estimate of sibling relative risk (λ(S)) was 16.8. Risks for older relatives (parents, siblings, aunts, uncles and cousins) show a latitudinal gradient, in line with population risk. No latitudinal gradient for λ(S) was seen. Segregation analysis supports a multiplicative model of one locus of moderate effect with many loci of small effect. The estimated contribution of the 57 known MS loci is 18-24% of λ(S). This meta-analysis supports the notion of MS being in part the result of multiple genetic susceptibility factors and environmental factors.

  9. Mouse models for preeclampsia: disruption of redox-regulated signaling

    Directory of Open Access Journals (Sweden)

    Chambers Anne E

    2009-01-01

    Full Text Available Abstract The concept that oxidative stress contributes to the development of human preeclampsia has never been tested in genetically-defined animal models. Homozygous deletion of catechol-O-methyl transferase (Comt-/- in pregnant mice leads to human preeclampsia-like symptoms (high blood pressure, albuminurea and preterm birth resulting from extensive vasculo-endothelial pathology, primarily at the utero-fetal interface where maternal cardiac output is dramatically increased during pregnancy. Comt converts estradiol to 2-methoxyestradiol 2 (2ME2 which counters angiogenesis by depleting hypoxia inducible factor-1 alpha (HIF-1 alpha at late pregnancy. We propose that in wild type (Comt++ pregnant mice, 2ME2 destabilizes HIF-1 alpha by inhibiting mitochondrial superoxide dismutase (MnSOD. Thus, 2ME2 acts as a pro-oxidant, disrupting redox-regulated signaling which blocks angiogenesis in wild type (WT animals in physiological pregnancy. Further, we suggest that a lack of this inhibition under normoxic conditions in mutant animals (Comt-/- stabilises HIF-1 alpha by inactivating prolyl hydroxlases (PHD. We predict that a lack of inhibition of MnSOD, leading to persistent accumulation of HIF-1 alpha, would trigger inflammatory infiltration and endothelial damage in mutant animals. Critical tests of this hypothesis would be to recreate preeclampsia symptoms by inducing oxidative stress in WT animals or to ameliorate by treating mutant mice with Mn-SOD-catalase mimetics or activators of PHD.

  10. A Software Pattern of the Genetic Algorithm -a Study on Reusable Object Model of Genetic Algorithm

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The Genetic Algorithm (GA) has been a pop research field, butthere is little concern on GA in view of Software Engineering and this result in a serie s of problems. In this paper, we extract a GA's software pattern, draw a model d iagram of the reusable objects, analyze the advantages and disadvantages of the pattern, and give a sample code at the end. We are then able to improve the reus ability and expansibility of GA. The results make it easier to program a new GA code by using some existing successful operators, thereby reducing the difficult ies and workload of programming a GA's code, and facilitate the GA application.

  11. Exploratory Bayesian model selection for serial genetics data.

    Science.gov (United States)

    Zhao, Jing X; Foulkes, Andrea S; George, Edward I

    2005-06-01

    Characterizing the process by which molecular and cellular level changes occur over time will have broad implications for clinical decision making and help further our knowledge of disease etiology across many complex diseases. However, this presents an analytic challenge due to the large number of potentially relevant biomarkers and the complex, uncharacterized relationships among them. We propose an exploratory Bayesian model selection procedure that searches for model simplicity through independence testing of multiple discrete biomarkers measured over time. Bayes factor calculations are used to identify and compare models that are best supported by the data. For large model spaces, i.e., a large number of multi-leveled biomarkers, we propose a Markov chain Monte Carlo (MCMC) stochastic search algorithm for finding promising models. We apply our procedure to explore the extent to which HIV-1 genetic changes occur independently over time.

  12. Hierarchical Stochastic Simulation Algorithm for SBML Models of Genetic Circuits

    Directory of Open Access Journals (Sweden)

    Leandro eWatanabe

    2014-11-01

    Full Text Available This paper describes a hierarchical stochastic simulation algorithm which has been implemented within iBioSim, a tool used to model, analyze, and visualize genetic circuits. Many biological analysis tools flatten out hierarchy before simulation, but there are many disadvantages associated with this approach. First, the memory required to represent the model can quickly expand in the process. Second, the flattening process is computationally expensive. Finally, when modeling a dynamic cellular population within iBioSim, inlining the hierarchy of the model is inefficient since models must grow dynamically over time. This paper discusses a new approach to handle hierarchy on the fly to make the tool faster and more memory-efficient. This approach yields significant performance improvements as compared to the former flat analysis method.

  13. Reverse Genetics of Escherichia coli Glycerol Kinase Allosteric Regulation and Glucose Control of Glycerol Utilization In Vivo

    OpenAIRE

    Holtman, C. Kay; Pawlyk, Aaron C.; Meadow, Norman D.; Pettigrew, Donald W.

    2001-01-01

    Reverse genetics is used to evaluate the roles in vivo of allosteric regulation of Escherichia coli glycerol kinase by the glucose-specific phosphocarrier of the phosphoenolpyruvate:glycose phosphotransferase system, IIAGlc (formerly known as IIIglc), and by fructose 1,6-bisphosphate. Roles have been postulated for these allosteric effectors in glucose control of both glycerol utilization and expression of the glpK gene. Genetics methods based on homologous recombination are used to place glp...

  14. Antioxidant compounds and their bioaccessibility in tomato fruit and puree obtained from a DETIOLATED-1 (DET-1) down-regulated genetically modified genotype.

    Science.gov (United States)

    Talens, P; Mora, L; Bramley, Peter M; Fraser, Paul D

    2016-12-15

    The economic value, the ease of cultivation and processing, and the well-known health-promoting properties of tomato fruit, make the tomato an important target for genetic manipulation to increase its nutritional content. A transgenic variety, down-regulated in the DETIOLATED-1 (DET-1) gene, has been studied in comparison with the parental line, for antioxidant levels in fresh and hot break fruit, as well as the bioaccessibility of antioxidants from puree. Differences in the concentrations of antioxidants between the wild-type and the genetically modified raw tomatoes were confirmed, but antioxidant levels were maintained to a greater extent in the GM puree than in the parent. The bioaccessibility of the compounds, tested using an in vitro digestion model, showed an increase in the genetically modified samples.

  15. Multi-Objective Genetic Programming with Redundancy-Regulations for Automatic Construction of Image Feature Extractors

    Science.gov (United States)

    Watchareeruetai, Ukrit; Matsumoto, Tetsuya; Takeuchi, Yoshinori; Kudo, Hiroaki; Ohnishi, Noboru

    We propose a new multi-objective genetic programming (MOGP) for automatic construction of image feature extraction programs (FEPs). The proposed method was originated from a well known multi-objective evolutionary algorithm (MOEA), i.e., NSGA-II. The key differences are that redundancy-regulation mechanisms are applied in three main processes of the MOGP, i.e., population truncation, sampling, and offspring generation, to improve population diversity as well as convergence rate. Experimental results indicate that the proposed MOGP-based FEP construction system outperforms the two conventional MOEAs (i.e., NSGA-II and SPEA2) for a test problem. Moreover, we compared the programs constructed by the proposed MOGP with four human-designed object recognition programs. The results show that the constructed programs are better than two human-designed methods and are comparable with the other two human-designed methods for the test problem.

  16. Genetic architecture supports mosaic brain evolution and independent brain-body size regulation.

    Science.gov (United States)

    Hager, Reinmar; Lu, Lu; Rosen, Glenn D; Williams, Robert W

    2012-01-01

    The mammalian brain consists of distinct parts that fulfil different functions. Finlay and Darlington have argued that evolution of the mammalian brain is constrained by developmental programs, suggesting that different brain parts are not free to respond individually to selection and evolve independent of other parts or overall brain size. However, comparisons among mammals with matched brain weights often reveal greater differences in brain part size, arguing against strong developmental constraints. Here we test these hypotheses using a quantitative genetic approach involving over 10,000 mice. We identify independent loci for size variation in seven key parts of the brain, and observe that brain parts show low or no phenotypic correlation, as is predicted by a mosaic scenario. We also demonstrate that variation in brain size is independently regulated from body size. The allometric relations seen at higher phylogenetic levels are thus unlikely to be the product of strong developmental constraints.

  17. Syndecan 4 interacts genetically with Vangl2 to regulate neural tube closure and planar cell polarity.

    Science.gov (United States)

    Escobedo, Noelia; Contreras, Osvaldo; Muñoz, Rosana; Farías, Marjorie; Carrasco, Héctor; Hill, Charlotte; Tran, Uyen; Pryor, Sophie E; Wessely, Oliver; Copp, Andrew J; Larraín, Juan

    2013-07-01

    Syndecan 4 (Sdc4) is a cell-surface heparan sulfate proteoglycan (HSPG) that regulates gastrulation, neural tube closure and directed neural crest migration in Xenopus development. To determine whether Sdc4 participates in Wnt/PCP signaling during mouse development, we evaluated a possible interaction between a null mutation of Sdc4 and the loop-tail allele of Vangl2. Sdc4 is expressed in multiple tissues, but particularly in the non-neural ectoderm, hindgut and otic vesicles. Sdc4;Vangl2(Lp) compound mutant mice have defective spinal neural tube closure, disrupted orientation of the stereocilia bundles in the cochlea and delayed wound healing, demonstrating a strong genetic interaction. In Xenopus, co-injection of suboptimal amounts of Sdc4 and Vangl2 morpholinos resulted in a significantly greater proportion of embryos with defective neural tube closure than each individual morpholino alone. To probe the mechanism of this interaction, we overexpressed or knocked down Vangl2 function in HEK293 cells. The Sdc4 and Vangl2 proteins colocalize, and Vangl2, particularly the Vangl2(Lp) mutant form, diminishes Sdc4 protein levels. Conversely, Vangl2 knockdown enhances Sdc4 protein levels. Overall HSPG steady-state levels were regulated by Vangl2, suggesting a molecular mechanism for the genetic interaction in which Vangl2(Lp/+) enhances the Sdc4-null phenotype. This could be mediated via heparan sulfate residues, as Vangl2(Lp/+) embryos fail to initiate neural tube closure and develop craniorachischisis (usually seen only in Vangl2(Lp/Lp)) when cultured in the presence of chlorate, a sulfation inhibitor. These results demonstrate that Sdc4 can participate in the Wnt/PCP pathway, unveiling its importance during neural tube closure in mammalian embryos.

  18. Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

    Directory of Open Access Journals (Sweden)

    Nico Derichs

    2013-03-01

    Full Text Available Cystic fibrosis (CF is caused by genetic mutations that affect the cystic fibrosis transmembrane conductance regulator (CFTR protein. These mutations can impact the synthesis and transfer of the CFTR protein to the apical membrane of epithelial cells, as well as influencing the gating or conductance of chloride and bicarbonate ions through the channel. CFTR dysfunction results in ionic imbalance of epithelial secretions in several organ systems, such as the pancreas, gastrointestinal tract, liver and the respiratory system. Since discovery of the CFTR gene in 1989, research has focussed on targeting the underlying genetic defect to identify a disease-modifying treatment for CF. Investigated management strategies have included gene therapy and the development of small molecules that target CFTR mutations, known as CFTR modulators. CFTR modulators are typically identified by high-throughput screening assays, followed by preclinical validation using cell culture systems. Recently, one such modulator, the CFTR potentiator ivacaftor, was approved as an oral therapy for CF patients with the G551D-CFTR mutation. The clinical development of ivacaftor not only represents a breakthrough in CF care but also serves as a noteworthy example of personalised medicine.

  19. Genetic Aspects of Autism Spectrum Disorders: Insights from Animal Models

    Directory of Open Access Journals (Sweden)

    Swati eBanerjee

    2014-02-01

    Full Text Available Autism spectrum disorders (ASD are a complex neurodevelopmental disorder that display a triad of core behavioral deficits including restricted interests, often accompanied by repetitive behavior, deficits in language and communication, and an inability to engage in reciprocal social interactions. ASD is among the most heritable disorders but is not a simple disorder with a singular pathology and has a rather complex etiology. It is interesting to note that perturbations in synaptic growth, development and stability underlie a variety of neuropsychiatric disorders, including ASD, schizophrenia, epilepsy and intellectual disability. Biological characterization of an increasing repertoire of synaptic mutants in various model organisms indicates synaptic dysfunction as causal in the pathophysiology of ASD. Our understanding of the genes and genetic pathways that contribute towards the formation, stabilization and maintenance of functional synapses coupled with an in-depth phenotypic analysis of the cellular and behavioral characteristics is therefore essential to unraveling the pathogenesis of these disorders. In this review, we discuss the genetic aspects of ASD emphasizing on the well conserved set of genes and genetic pathways implicated in this disorder, many of which contribute to synapse assembly and maintenance across species. We also review how fundamental research using animal models is providing key insights into the various facets of human ASD.

  20. Genetic Programming Modeling and Complexity Analysis of the Magnetoencephalogram of Epileptic Patients

    Science.gov (United States)

    Georgopoulos, Efstratios F.; Adamopoulos, Adam V.; Likothanassis, Spiridon D.

    In this work MagnetoEncephaloGram (MEG) recordings of epileptic patients are modeled using a genetic programming approach. This is the first time that genetic programming is used to model MEG signal. Numerous experiments were conducted giving highly successful results. It is demonstrated that genetic programming can produce very simple nonlinear models that fit with great accuracy the observed data of MEG.

  1. How do students self-regulate?: review of Zimmerman's cyclical model of self-regulated learning

    Directory of Open Access Journals (Sweden)

    Ernesto Panadero

    2014-05-01

    Full Text Available The use of learning strategies is crucial for students' academic performance and promoting deeper learning approaches. The self-regulated learning models offer comprehensive theoretical backgrounds. These enable more holistic approaches to the use of learning strategies. In this paper, Zimmerman's (2000; 2003; Zimmerman & Moylan, 2009 cyclical model of self-regulated learning is described and analysed as one of the most comprehensive. The model is grounded in social cognitive theory and is comprised of three phases (forethought, performance and self-reflection with a special focus on the influences of motivation on self-regulation. The different processes included in the model are analysed here in detail. Zimmerman's framework is considered in relation to other self-regulated learning models in order to recognize its importance in theory and practice.

  2. Modelling and Analysis of a New Piezoelectric Dynamic Balance Regulator

    Directory of Open Access Journals (Sweden)

    Mu-Xun Xu

    2012-11-01

    Full Text Available In this paper, a new piezoelectric dynamic balance regulator, which can be used in motorised spindle systems, is presented. The dynamic balancing adjustment mechanism is driven by an in-plane bending vibration from an annular piezoelectric stator excited by a high-frequency sinusoidal input voltage. This device has different construction, characteristics and operating principles than a conventional balance regulator. In this work, a dynamic model of the regulator is first developed using a detailed analytical method. Thereafter, MATLAB is employed to numerically simulate the relations between the dominant parameters and the characteristics of the regulator based on thedynamic model. Finally, experimental measurements are used to certify the validity of the dynamic model. Consequently, the mathematical model presented and analysed in this paper can be used as a tool for optimising the design of a piezoelectric dynamic balance regulator during steady state operation.

  3. ASCL1 and NEUROD1 Reveal Heterogeneity in Pulmonary Neuroendocrine Tumors and Regulate Distinct Genetic Programs

    Directory of Open Access Journals (Sweden)

    Mark D. Borromeo

    2016-08-01

    Full Text Available Small cell lung carcinoma (SCLC is a high-grade pulmonary neuroendocrine tumor. The transcription factors ASCL1 and NEUROD1 play crucial roles in promoting malignant behavior and survival of human SCLC cell lines. Here, we find that ASCL1 and NEUROD1 identify heterogeneity in SCLC, bind distinct genomic loci, and regulate mostly distinct genes. ASCL1, but not NEUROD1, is present in mouse pulmonary neuroendocrine cells, and only ASCL1 is required in vivo for tumor formation in mouse models of SCLC. ASCL1 targets oncogenic genes including MYCL1, RET, SOX2, and NFIB while NEUROD1 targets MYC. ASCL1 and NEUROD1 regulate different genes that commonly contribute to neuronal function. ASCL1 also regulates multiple genes in the NOTCH pathway including DLL3. Together, ASCL1 and NEUROD1 distinguish heterogeneity in SCLC with distinct genomic landscapes and distinct gene expression programs.

  4. Modelling the genetic risk in age-related macular degeneration.

    Directory of Open Access Journals (Sweden)

    Felix Grassmann

    Full Text Available Late-stage age-related macular degeneration (AMD is a common sight-threatening disease of the central retina affecting approximately 1 in 30 Caucasians. Besides age and smoking, genetic variants from several gene loci have reproducibly been associated with this condition and likely explain a large proportion of disease. Here, we developed a genetic risk score (GRS for AMD based on 13 risk variants from eight gene loci. The model exhibited good discriminative accuracy, area-under-curve (AUC of the receiver-operating characteristic of 0.820, which was confirmed in a cross-validation approach. Noteworthy, younger AMD patients aged below 75 had a significantly higher mean GRS (1.87, 95% CI: 1.69-2.05 than patients aged 75 and above (1.45, 95% CI: 1.36-1.54. Based on five equally sized GRS intervals, we present a risk classification with a relative AMD risk of 64.0 (95% CI: 14.11-1131.96 for individuals in the highest category (GRS 3.44-5.18, 0.5% of the general population compared to subjects with the most common genetic background (GRS -0.05-1.70, 40.2% of general population. The highest GRS category identifies AMD patients with a sensitivity of 7.9% and a specificity of 99.9% when compared to the four lower categories. Modeling a general population around 85 years of age, 87.4% of individuals in the highest GRS category would be expected to develop AMD by that age. In contrast, only 2.2% of individuals in the two lowest GRS categories which represent almost 50% of the general population are expected to manifest AMD. Our findings underscore the large proportion of AMD cases explained by genetics particularly for younger AMD patients. The five-category risk classification could be useful for therapeutic stratification or for diagnostic testing purposes once preventive treatment is available.

  5. Model reduction using the genetic algorithm and routh approximations

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    A new method of model reduction combining the genetic algorithm(GA) with the Routh approximation method is presented. It is suggested that a high-order system can be approximated by a low-order model with a time delay. The denominator parameters of the reduced-order model are determined by the Routh approximation method, then the numerator parameters and time delay are identified by the GA. The reduced-order models obtained by the proposed method will always be stable if the original system is stable and produce a good approximation to the original system in both the frequency domain and time domain. Two numerical examples show that the method is computationally simple and efficient.

  6. Genetic moderation of transactional relations between parenting practices and child self-regulation.

    Science.gov (United States)

    Cho, Junhan; Kogan, Steven M; Brody, Gene H

    2016-10-01

    The present study addressed the ways in which parent and child dopamine D4 receptor (DRD4) genotypes jointly moderate the transactional relations between parenting practices and child self-regulation. African American children (N = 309) and their parents provided longitudinal data spanning child ages 11 to 15 years and a saliva sample from which variation at DRD4 was genotyped. Based on the differential susceptibility perspective, this study examined moderation effects of DRD4 status on (a) the extent to which parenting practices affect child self-regulation and (b) the extent to which child self-regulation, as an environmental influence on the parent, affects parenting behavior. Results indicated that responsive-supportive parenting interacted with children's DRD4 status to influence increases in child self-regulation. Also, child self-regulation interacted with parent's DRD4 status to predict changes in parenting practices. Both Gene × Environment effects conformed to a differential susceptibility model in which parents' and children's DRD4 genes operated to increase environmental sensitivity "for better and for worse." (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  7. Genetic diversity in the SIR model of pathogen evolution.

    Science.gov (United States)

    Gordo, Isabel; Gomes, M Gabriela M; Reis, Daniel G; Campos, Paulo R A

    2009-01-01

    We introduce a model for assessing the levels and patterns of genetic diversity in pathogen populations, whose epidemiology follows a susceptible-infected-recovered model (SIR). We model the population of pathogens as a metapopulation composed of subpopulations (infected hosts), where pathogens replicate and mutate. Hosts transmit pathogens to uninfected hosts. We show that the level of pathogen variation is well predicted by analytical expressions, such that pathogen neutral molecular variation is bounded by the level of infection and increases with the duration of infection. We then introduce selection in the model and study the invasion probability of a new pathogenic strain whose fitness (R(0)(1+s)) is higher than the fitness of the resident strain (R(0)). We show that this invasion probability is given by the relative increment in R(0) of the new pathogen (s). By analyzing the patterns of genetic diversity in this framework, we identify the molecular signatures during the replacement and compare these with those observed in sequences of influenza A.

  8. Genetic diversity in the SIR model of pathogen evolution.

    Directory of Open Access Journals (Sweden)

    Isabel Gordo

    Full Text Available We introduce a model for assessing the levels and patterns of genetic diversity in pathogen populations, whose epidemiology follows a susceptible-infected-recovered model (SIR. We model the population of pathogens as a metapopulation composed of subpopulations (infected hosts, where pathogens replicate and mutate. Hosts transmit pathogens to uninfected hosts. We show that the level of pathogen variation is well predicted by analytical expressions, such that pathogen neutral molecular variation is bounded by the level of infection and increases with the duration of infection. We then introduce selection in the model and study the invasion probability of a new pathogenic strain whose fitness (R(0(1+s is higher than the fitness of the resident strain (R(0. We show that this invasion probability is given by the relative increment in R(0 of the new pathogen (s. By analyzing the patterns of genetic diversity in this framework, we identify the molecular signatures during the replacement and compare these with those observed in sequences of influenza A.

  9. Genetic evaluation of European quails by random regression models

    Directory of Open Access Journals (Sweden)

    Flaviana Miranda Gonçalves

    2012-09-01

    Full Text Available The objective of this study was to compare different random regression models, defined from different classes of heterogeneity of variance combined with different Legendre polynomial orders for the estimate of (covariance of quails. The data came from 28,076 observations of 4,507 female meat quails of the LF1 lineage. Quail body weights were determined at birth and 1, 14, 21, 28, 35 and 42 days of age. Six different classes of residual variance were fitted to Legendre polynomial functions (orders ranging from 2 to 6 to determine which model had the best fit to describe the (covariance structures as a function of time. According to the evaluated criteria (AIC, BIC and LRT, the model with six classes of residual variances and of sixth-order Legendre polynomial was the best fit. The estimated additive genetic variance increased from birth to 28 days of age, and dropped slightly from 35 to 42 days. The heritability estimates decreased along the growth curve and changed from 0.51 (1 day to 0.16 (42 days. Animal genetic and permanent environmental correlation estimates between weights and age classes were always high and positive, except for birth weight. The sixth order Legendre polynomial, along with the residual variance divided into six classes was the best fit for the growth rate curve of meat quails; therefore, they should be considered for breeding evaluation processes by random regression models.

  10. Genetic and systems level analysis of Drosophila sticky/citron kinase and dFmr1 mutants reveals common regulation of genetic networks

    Directory of Open Access Journals (Sweden)

    Zarnescu Daniela C

    2008-11-01

    Full Text Available Abstract Background In Drosophila, the genes sticky and dFmr1 have both been shown to regulate cytoskeletal dynamics and chromatin structure. These genes also genetically interact with Argonaute family microRNA regulators. Furthermore, in mammalian systems, both genes have been implicated in neuronal development. Given these genetic and functional similarities, we tested Drosophila sticky and dFmr1 for a genetic interaction and measured whole genome expression in both mutants to assess similarities in gene regulation. Results We found that sticky mutations can dominantly suppress a dFmr1 gain-of-function phenotype in the developing eye, while phenotypes produced by RNAi knock-down of sticky were enhanced by dFmr1 RNAi and a dFmr1 loss-of-function mutation. We also identified a large number of transcripts that were misexpressed in both mutants suggesting that sticky and dFmr1 gene products similarly regulate gene expression. By integrating gene expression data with a protein-protein interaction network, we found that mutations in sticky and dFmr1 resulted in misexpression of common gene networks, and consequently predicted additional specific phenotypes previously not known to be associated with either gene. Further phenotypic analyses validated these predictions. Conclusion These findings establish a functional link between two previously unrelated genes. Microarray analysis indicates that sticky and dFmr1 are both required for regulation of many developmental genes in a variety of cell types. The diversity of transcripts regulated by these two genes suggests a clear cause of the pleiotropy that sticky and dFmr1 mutants display and provides many novel, testable hypotheses about the functions of these genes. As both of these genes are implicated in the development and function of the mammalian brain, these results have relevance to human health as well as to understanding more general biological processes.

  11. Innovative farmers and regulatory gatekeepers: Genetically modified crops regulation and adoption in developing countries.

    Science.gov (United States)

    Sinebo, Woldeyesus; Maredia, Karim

    2016-01-02

    The regulation of genetically modified (GM) crops is a topical issue in agriculture and environment over the past 2 decades. The objective of this paper is to recount regulatory and adoption practices in some developing countries that have successfully adopted GM crops so that aspiring countries may draw useful lessons and best practices for their biosafatey regulatory regimes. The first 11 mega-GM crops growing countries each with an area of more than one million hectares in 2014 were examined. Only five out of the 11 countries had smooth and orderly adoption of these crops as per the regulatory requirement of each country. In the remaining 6 countries (all developing countries), GM crops were either introduced across borders without official authorization, released prior to regulatory approval or unapproved seeds were sold along with the approved ones in violation to the existing regulations. Rapid expansion of transgenic crops over the past 2 decades in the developing world was a result of an intense desire by farmers to adopt these crops irrespective of regulatory roadblocks. Lack of workable biosafety regulatory system and political will to support GM crops encouraged unauthorized access to GM crop varieties. In certain cases, unregulated access in turn appeared to result in the adoption of substandard or spurious technology which undermined performance and productivity. An optimal interaction among the national agricultural innovation systems, biosafety regulatory bodies, biotech companies and high level policy makers is vital in making a workable regulated progress in the adoption of GM crops. Factoring forgone opportunities to farmers to benefit from GM crops arising from overregulation into biosafety risk analysis and decision making is suggested. Building functional biosafety regulatory systems that balances the needs of farmers to access and utilize the GM technology with the regulatory imperatives to ensure adequate safety to the environment and human

  12. Cysteine and hydrogen sulphide in the regulation of metabolism: insights from genetics and pharmacology.

    Science.gov (United States)

    Carter, Roderick N; Morton, Nicholas M

    2016-01-01

    Obesity and diabetes represent a significant and escalating worldwide health burden. These conditions are characterized by abnormal nutrient homeostasis. One such perturbation is altered metabolism of the sulphur-containing amino acid cysteine. Obesity is associated with elevated plasma cysteine, whereas diabetes is associated with reduced cysteine levels. One mechanism by which cysteine may act is through its enzymatic breakdown to produce hydrogen sulphide (H2S), a gasotransmitter that regulates glucose and lipid homeostasis. Here we review evidence from both pharmacological studies and transgenic models suggesting that cysteine and hydrogen sulphide play a role in the metabolic dysregulation underpinning obesity and diabetes. We then outline the growing evidence that regulation of hydrogen sulphide levels through its catabolism can impact metabolic health. By integrating hydrogen sulphide production and breakdown pathways, we re-assess current hypothetical models of cysteine and hydrogen sulphide metabolism, offering new insight into their roles in the pathogenesis of obesity and diabetes.

  13. Mathematical modelling of steam generator and design of temperature regulator

    Energy Technology Data Exchange (ETDEWEB)

    Bogdanovic, S.S. [EE Institute Nikola Tesla, Belgrade (Yugoslavia)

    1999-07-01

    The paper considers mathematical modelling of once-through power station boiler and numerical algorithm for simulation of the model. Fast and numerically stable algorithm based on the linearisation of model equations and on the simultaneous solving of differential and algebraic equations is proposed. The paper also presents the design of steam temperature regulator by using the method of projective controls. Dynamic behaviour of the system closed with optimal linear quadratic regulator is taken as the reference system. The desired proprieties of the reference system are retained and solutions for superheated steam temperature regulator are determined. (author)

  14. Developmental regulation of planar cell polarity and hair-bundle morphogenesis in auditory hair cells: lessons from human and mouse genetics.

    Science.gov (United States)

    Lu, Xiaowei; Sipe, Conor W

    2016-01-01

    Hearing loss is the most common and costly sensory defect in humans and genetic causes underlie a significant proportion of affected individuals. In mammals, sound is detected by hair cells (HCs) housed in the cochlea of the inner ear, whose function depends on a highly specialized mechanotransduction organelle, the hair bundle. Understanding the factors that regulate the development and functional maturation of the hair bundle is crucial for understanding the pathophysiology of human deafness. Genetic analysis of deafness genes in animal models, together with complementary forward genetic screens and conditional knock-out mutations in essential genes, have provided great insights into the molecular machinery underpinning hair-bundle development and function. In this review, we highlight recent advances in our understanding of hair-bundle morphogenesis, with an emphasis on the molecular pathways governing hair-bundle polarity and orientation. We next discuss the proteins and structural elements important for hair-cell mechanotransduction as well as hair-bundle cohesion and maintenance. In addition, developmental signals thought to regulate tonotopic features of HCs are introduced. Finally, novel approaches that complement classic genetics for studying the molecular etiology of human deafness are presented. WIREs Dev Biol 2016, 5:85-101. doi: 10.1002/wdev.202 For further resources related to this article, please visit the WIREs website.

  15. Gravitational Lens Modeling with Genetic Algorithms and Particle Swarm Optimizers

    CERN Document Server

    Rogers, Adam

    2011-01-01

    Strong gravitational lensing of an extended object is described by a mapping from source to image coordinates that is nonlinear and cannot generally be inverted analytically. Determining the structure of the source intensity distribution also requires a description of the blurring effect due to a point spread function. This initial study uses an iterative gravitational lens modeling scheme based on the semilinear method to determine the linear parameters (source intensity profile) of a strongly lensed system. Our 'matrix-free' approach avoids construction of the lens and blurring operators while retaining the least squares formulation of the problem. The parameters of an analytical lens model are found through nonlinear optimization by an advanced genetic algorithm (GA) and particle swarm optimizer (PSO). These global optimization routines are designed to explore the parameter space thoroughly, mapping model degeneracies in detail. We develop a novel method that determines the L-curve for each solution automa...

  16. In vivo Drosophilia genetic model for calcium oxalate nephrolithiasis.

    Science.gov (United States)

    Hirata, Taku; Cabrero, Pablo; Berkholz, Donald S; Bondeson, Daniel P; Ritman, Erik L; Thompson, James R; Dow, Julian A T; Romero, Michael F

    2012-12-01

    Nephrolithiasis is a major public health problem with a complex and varied etiology. Most stones are composed of calcium oxalate (CaOx), with dietary excess a risk factor. Because of complexity of mammalian system, the details of stone formation remain to be understood. Here we have developed a nephrolithiasis model using the genetic model Drosophila melanogaster, which has a simple, transparent kidney tubule. Drosophilia reliably develops CaOx stones upon dietary oxalate supplementation, and the nucleation and growth of microliths can be viewed in real time. The Slc26 anion transporter dPrestin (Slc26a5/6) is strongly expressed in Drosophilia kidney, and biophysical analysis shows that it is a potent oxalate transporter. When dPrestin is knocked down by RNAi in fly kidney, formation of microliths is reduced, identifying dPrestin as a key player in oxalate excretion. CaOx stone formation is an ancient conserved process across >400 My of divergent evolution (fly and human), and from this study we can conclude that the fly is a good genetic model of nephrolithiasis.

  17. The interplay between genetic and bioelectrical signaling permits a spatial regionalisation of membrane potentials in model multicellular ensembles.

    Science.gov (United States)

    Cervera, Javier; Meseguer, Salvador; Mafe, Salvador

    2016-10-12

    The single cell-centred approach emphasises ion channels as specific proteins that determine individual properties, disregarding their contribution to multicellular outcomes. We simulate the interplay between genetic and bioelectrical signals in non-excitable cells from the local single-cell level to the long range multicellular ensemble. The single-cell genetic regulation is based on mean-field kinetic equations involving the mRNA and protein concentrations. The transcription rate factor is assumed to depend on the absolute value of the cell potential, which is dictated by the voltage-gated cell ion channels and the intercellular gap junctions. The interplay between genetic and electrical signals may allow translating single-cell states into multicellular states which provide spatio-temporal information. The model results have clear implications for biological processes: (i) bioelectric signals can override slightly different genetic pre-patterns; (ii) ensembles of cells initially at the same potential can undergo an electrical regionalisation because of persistent genetic differences between adjacent spatial regions; and (iii) shifts in the normal cell electrical balance could trigger significant changes in the genetic regulation.

  18. Combining comparative proteomics and molecular genetics uncovers regulators of synaptic and axonal stability and degeneration in vivo.

    Directory of Open Access Journals (Sweden)

    Thomas M Wishart

    Full Text Available Degeneration of synaptic and axonal compartments of neurons is an early event contributing to the pathogenesis of many neurodegenerative diseases, but the underlying molecular mechanisms remain unclear. Here, we demonstrate the effectiveness of a novel "top-down" approach for identifying proteins and functional pathways regulating neurodegeneration in distal compartments of neurons. A series of comparative quantitative proteomic screens on synapse-enriched fractions isolated from the mouse brain following injury identified dynamic perturbations occurring within the proteome during both initiation and onset phases of degeneration. In silico analyses highlighted significant clustering of proteins contributing to functional pathways regulating synaptic transmission and neurite development. Molecular markers of degeneration were conserved in injury and disease, with comparable responses observed in synapse-enriched fractions isolated from mouse models of Huntington's disease (HD and spinocerebellar ataxia type 5. An initial screen targeting thirteen degeneration-associated proteins using mutant Drosophila lines revealed six potential regulators of synaptic and axonal degeneration in vivo. Mutations in CALB2, ROCK2, DNAJC5/CSP, and HIBCH partially delayed injury-induced neurodegeneration. Conversely, mutations in DNAJC6 and ALDHA1 led to spontaneous degeneration of distal axons and synapses. A more detailed genetic analysis of DNAJC5/CSP mutants confirmed that loss of DNAJC5/CSP was neuroprotective, robustly delaying degeneration in axonal and synaptic compartments. Our study has identified conserved molecular responses occurring within synapse-enriched fractions of the mouse brain during the early stages of neurodegeneration, focused on functional networks modulating synaptic transmission and incorporating molecular chaperones, cytoskeletal modifiers, and calcium-binding proteins. We propose that the proteins and functional pathways identified in

  19. Combining comparative proteomics and molecular genetics uncovers regulators of synaptic and axonal stability and degeneration in vivo.

    Directory of Open Access Journals (Sweden)

    Thomas M Wishart

    Full Text Available Degeneration of synaptic and axonal compartments of neurons is an early event contributing to the pathogenesis of many neurodegenerative diseases, but the underlying molecular mechanisms remain unclear. Here, we demonstrate the effectiveness of a novel "top-down" approach for identifying proteins and functional pathways regulating neurodegeneration in distal compartments of neurons. A series of comparative quantitative proteomic screens on synapse-enriched fractions isolated from the mouse brain following injury identified dynamic perturbations occurring within the proteome during both initiation and onset phases of degeneration. In silico analyses highlighted significant clustering of proteins contributing to functional pathways regulating synaptic transmission and neurite development. Molecular markers of degeneration were conserved in injury and disease, with comparable responses observed in synapse-enriched fractions isolated from mouse models of Huntington's disease (HD and spinocerebellar ataxia type 5. An initial screen targeting thirteen degeneration-associated proteins using mutant Drosophila lines revealed six potential regulators of synaptic and axonal degeneration in vivo. Mutations in CALB2, ROCK2, DNAJC5/CSP, and HIBCH partially delayed injury-induced neurodegeneration. Conversely, mutations in DNAJC6 and ALDHA1 led to spontaneous degeneration of distal axons and synapses. A more detailed genetic analysis of DNAJC5/CSP mutants confirmed that loss of DNAJC5/CSP was neuroprotective, robustly delaying degeneration in axonal and synaptic compartments. Our study has identified conserved molecular responses occurring within synapse-enriched fractions of the mouse brain during the early stages of neurodegeneration, focused on functional networks modulating synaptic transmission and incorporating molecular chaperones, cytoskeletal modifiers, and calcium-binding proteins. We propose that the proteins and functional pathways identified in

  20. Transcriptional regulation and steady-state modeling of metabolic networks

    DEFF Research Database (Denmark)

    Zelezniak, Aleksej

    understanding underlying the operating principles of metabolic networks. Cellular responses to environmental perturbations and genetic/epigenetic modifications are to a large extent controlled through transcription, which is one of the fundamental mechanism/means of cellular regulation. An important question...... cases, the objective of the regulation appears to be metabolite-oriented as opposed to pathway-oriented. The study thus provides a fundamental and novel view of metabolic network regulation in Saccharomyces cerevisiae. Metabolism is a conserved system across all domains of life. Nowadays, metabolism has......: what are the components of the systems, how are the different components interconnected and how do these networks perform the functions that make the resulting system behavior? Modern analytical technologies allow us to unravel the constituents and interactions happening in a given system; however...

  1. The ontology of genetic susceptibility factors (OGSF) and its application in modeling genetic susceptibility to vaccine adverse events.

    Science.gov (United States)

    Lin, Yu; He, Yongqun

    2014-01-01

    Due to human variations in genetic susceptibility, vaccination often triggers adverse events in a small population of vaccinees. Based on our previous work on ontological modeling of genetic susceptibility to disease, we developed an Ontology of Genetic Susceptibility Factors (OGSF), a biomedical ontology in the domain of genetic susceptibility and genetic susceptibility factors. The OGSF framework was then applied in the area of vaccine adverse events (VAEs). OGSF aligns with the Basic Formal Ontology (BFO). OGSF defines 'genetic susceptibility' as a subclass of BFO:disposition and has a material basis 'genetic susceptibility factor'. The 'genetic susceptibility to pathological bodily process' is a subclasses of 'genetic susceptibility'. A VAE is a type of pathological bodily process. OGSF represents different types of genetic susceptibility factors including various susceptibility alleles (e.g., SNP and gene). A general OGSF design pattern was developed to represent genetic susceptibility to VAE and associated genetic susceptibility factors using experimental results in genetic association studies. To test and validate the design pattern, two case studies were populated in OGSF. In the first case study, human gene allele DBR*15:01 is susceptible to influenza vaccine Pandemrix-induced Multiple Sclerosis. The second case study reports genetic susceptibility polymorphisms associated with systemic smallpox VAEs. After the data of the Case Study 2 were represented using OGSF-based axioms, SPARQL was successfully developed to retrieve the susceptibility factors stored in the populated OGSF. A network of data from the Case Study 2 was constructed by using ontology terms and individuals as nodes and ontology relations as edges. Different social network analys is (SNA) methods were then applied to verify core OGSF terms. Interestingly, a SNA hub analysis verified all susceptibility alleles of SNPs and a SNA closeness analysis verified the susceptibility genes in Case

  2. Genetic Dissection of Cardiac Remodeling in an Isoproterenol-Induced Heart Failure Mouse Model.

    Directory of Open Access Journals (Sweden)

    Jessica Jen-Chu Wang

    2016-07-01

    Full Text Available We aimed to understand the genetic control of cardiac remodeling using an isoproterenol-induced heart failure model in mice, which allowed control of confounding factors in an experimental setting. We characterized the changes in cardiac structure and function in response to chronic isoproterenol infusion using echocardiography in a panel of 104 inbred mouse strains. We showed that cardiac structure and function, whether under normal or stress conditions, has a strong genetic component, with heritability estimates of left ventricular mass between 61% and 81%. Association analyses of cardiac remodeling traits, corrected for population structure, body size and heart rate, revealed 17 genome-wide significant loci, including several loci containing previously implicated genes. Cardiac tissue gene expression profiling, expression quantitative trait loci, expression-phenotype correlation, and coding sequence variation analyses were performed to prioritize candidate genes and to generate hypotheses for downstream mechanistic studies. Using this approach, we have validated a novel gene, Myh14, as a negative regulator of ISO-induced left ventricular mass hypertrophy in an in vivo mouse model and demonstrated the up-regulation of immediate early gene Myc, fetal gene Nppb, and fibrosis gene Lgals3 in ISO-treated Myh14 deficient hearts compared to controls.

  3. Modeling socially anhedonic syndromes: genetic and pharmacological manipulation of opioid neurotransmission in mice.

    Science.gov (United States)

    Cinque, C; Pondiki, S; Oddi, D; Di Certo, M G; Marinelli, S; Troisi, A; Moles, A; D'Amato, F R

    2012-08-28

    Social anhedonia, or the diminished capacity to experience pleasure and reward from social affiliation, is a major symptom of different psychiatric disorders, including some forms of infantile autism and schizophrenia spectrum disorders. The brain opioid hypothesis of social attachment is a promising model for achieving insights into how neurobiological and developmental factors contribute to the regulation of social reward. In this study, genetic knocking-out and naltrexone (NTRX) treatment during the first 4 days of life were used to disrupt opioid neurotransmission in mouse pups and their attachment relationships with the mother. Both permanent (genetic) and transient (pharmacological) manipulations of opioid neurotransmission exerted long-term effects on social affiliation. When juveniles, both μ-opioid receptor knockout mice and NTRX-treated pups showed reduced interest in peers and no preference for socially rewarding environment. These results demonstrate that sociability in juvenile mice is highly dependent on the establishment during infancy of a positive affective relationship with their mothers and that opioid neurotransmission has a major role in the regulation of social hedonic capacity. If the validity of this animal model will be confirmed by future research, translational studies focusing on the interaction between early experience and opioid neurotransmission could provide useful insights for identifying endophenotypes of human psychiatric disorders associated with social anhedonia.

  4. Epidemic Modelling by Ripple-Spreading Network and Genetic Algorithm

    Directory of Open Access Journals (Sweden)

    Jian-Qin Liao

    2013-01-01

    Full Text Available Mathematical analysis and modelling is central to infectious disease epidemiology. This paper, inspired by the natural ripple-spreading phenomenon, proposes a novel ripple-spreading network model for the study of infectious disease transmission. The new epidemic model naturally has good potential for capturing many spatial and temporal features observed in the outbreak of plagues. In particular, using a stochastic ripple-spreading process simulates the effect of random contacts and movements of individuals on the probability of infection well, which is usually a challenging issue in epidemic modeling. Some ripple-spreading related parameters such as threshold and amplifying factor of nodes are ideal to describe the importance of individuals’ physical fitness and immunity. The new model is rich in parameters to incorporate many real factors such as public health service and policies, and it is highly flexible to modifications. A genetic algorithm is used to tune the parameters of the model by referring to historic data of an epidemic. The well-tuned model can then be used for analyzing and forecasting purposes. The effectiveness of the proposed method is illustrated by simulation results.

  5. Mapping of the stochastic Lotka-Volterra model to models of population genetics and game theory

    Science.gov (United States)

    Constable, George W. A.; McKane, Alan J.

    2017-08-01

    The relationship between the M -species stochastic Lotka-Volterra competition (SLVC) model and the M -allele Moran model of population genetics is explored via timescale separation arguments. When selection for species is weak and the population size is large but finite, precise conditions are determined for the stochastic dynamics of the SLVC model to be mappable to the neutral Moran model, the Moran model with frequency-independent selection, and the Moran model with frequency-dependent selection (equivalently a game-theoretic formulation of the Moran model). We demonstrate how these mappings can be used to calculate extinction probabilities and the times until a species' extinction in the SLVC model.

  6. Genetic Diseases and Genetic Determinism Models in French Secondary School Biology Textbooks

    Science.gov (United States)

    Castera, Jeremy; Bruguiere, Catherine; Clement, Pierre

    2008-01-01

    The presentation of genetic diseases in French secondary school biology textbooks is analysed to determine the major conceptions taught in the field of human genetics. References to genetic diseases, and the processes by which they are explained (monogeny, polygeny, chromosomal anomaly and environmental influence) are studied in recent French…

  7. Genetic Diseases and Genetic Determinism Models in French Secondary School Biology Textbooks

    Science.gov (United States)

    Castera, Jeremy; Bruguiere, Catherine; Clement, Pierre

    2008-01-01

    The presentation of genetic diseases in French secondary school biology textbooks is analysed to determine the major conceptions taught in the field of human genetics. References to genetic diseases, and the processes by which they are explained (monogeny, polygeny, chromosomal anomaly and environmental influence) are studied in recent French…

  8. Evidence for host genetic regulation of altered lipid metabolism in experimental toxoplasmosis supported with gene data mining results.

    Science.gov (United States)

    Milovanović, Ivan; Busarčević, Miloš; Trbovich, Alexander; Ivović, Vladimir; Uzelac, Aleksandra; Djurković-Djaković, Olgica

    2017-01-01

    Toxoplasma gondii is one of the most successful parasites on Earth, infecting a wide array of mammals including one third of the global human population. The obligate intracellular protozoon is not capable of synthesizing cholesterol (Chl), and thus depends on uptake of host Chl for its own development. To explore the genetic regulation of previously observed lipid metabolism alterations during acute murine T. gondii infection, we here assessed total Chl and its fractions in serum and selected tissues at the pathophysiological and molecular level, and integrated the observed gene expression of selected molecules relevant for Chl metabolism, including its biosynthetic and export KEGG pathways, with the results of published transcriptomes obtained in similar murine models of T. gondii infection. The serum lipid status as well as the transcript levels of relevant genes in the brain and the liver were assessed in experimental models of acute and chronic toxoplasmosis in wild-type mice. The results showed that acute infection was associated with a decrease in Chl content in both the liver and periphery (brain, peripheral lymphocytes), and a decrease in Chl reverse transport. In contrast, in chronic infection, a return to normal levels of Chl metabolism has been noted. These changes corresponded to the brain and liver gene expression results as well as to data obtained via mining. We propose that the observed changes in Chl metabolism are part of the host defense response. Further insight into the lipid metabolism in T. gondii infection may provide novel targets for therapeutic agents.

  9. Calibration of Uncertainty Analysis of the SWAT Model Using Genetic Algorithms and Bayesian Model Averaging

    Science.gov (United States)

    In this paper, the Genetic Algorithms (GA) and Bayesian model averaging (BMA) were combined to simultaneously conduct calibration and uncertainty analysis for the Soil and Water Assessment Tool (SWAT). In this hybrid method, several SWAT models with different structures are first selected; next GA i...

  10. OXYGEN PRESSURE REGULATOR DESIGN AND ANALYSIS THROUGH FINITE ELEMENT MODELING

    Directory of Open Access Journals (Sweden)

    Asterios KOSMARAS

    2017-05-01

    Full Text Available Oxygen production centers produce oxygen in high pressure that needs to be defused. A regulator is designed and analyzed in the current paper for medical use in oxygen production centers. This study aims to design a new oxygen pressure regulator and perform an analysis using Finite Element Modeling in order to evaluate its working principle. In the design procedure,the main elements and the operating principles of a pressure regulator are taking into account. The regulator is designed and simulations take place in order to assessthe proposed design. Stress analysis results are presented for the main body of the regulator, as well as, flow analysis to determine some important flow characteristics in the inlet and outlet of the regulator.

  11. Constructing the barley model for genetic transformation in Triticeae

    Institute of Scientific and Technical Information of China (English)

    LÜ Bo; WU Jia-jie; FU Dao-lin

    2015-01-01

    Barley (Hordeum vulgare L.) is one of the oldest domesticated crops, showing dramatic adaptation to various climate and environmental conditions. As a major cereal crop, barley ranks the 4th after wheat, maize and rice in terms of planting area and production al over the world. Due to its diploid nature, the cultivated barley is considered as an ideal model to study the polyploid wheat and other Triticeae species. Here, we reviewed the development, optimization, and application of transgenic approaches in barley. The most efifcient and robust genetic transformation has been built on the Agrobacterium-mediated transfer in conjunction with the immature embryo-based regeneration. We then discussed future considerations of using more practical technologies in barley transformation, such as the T-DNA/transposon tagging and the genome editing. As a cereal crop amenable to genetic transformation, barley wil serve as the most valuable carrier for global functional genomics in Triticeae and is becoming the most practical model for generating value-added products.

  12. A Generic Model to Exploit Urban Regulation Knowledge

    Directory of Open Access Journals (Sweden)

    Mickaël Brasebin

    2016-02-01

    Full Text Available The Right to Build is defined by textual elements that determine what an owner can build on a parcel. Such regulations contain elements that can influence the development of territories. Expressed through legal texts, their effects on the territory are difficult to assess because of the documents’ complexity and of the diversity of urban configurations. In this paper, we present a generic and extendable model to represent such  regulations. This model is based on (1 a representation of geographical concepts (attributes, features and relations mentioned in regulations and (2 rules formalized with Object Constraints Language (OCL. We also propose an implementation that allows the handling of formalized rules in order to check if a building configuration proposal respects urban regulations. Many applications are possible in order to assist in the conception of such regulations, land acquisition strategy or territorial evolution studies, in this article, we notably describe a future application dedicated to assist building permit surveyors.

  13. Multiobjective financial planning model for electric-utility rate regulation

    Energy Technology Data Exchange (ETDEWEB)

    Linke, C.M.; Whitford, D.T.

    1983-08-01

    The interests of the three parties to the regulatory process (investors in an electric utility, consumers, and regulators) are often in conflict. Investors are concerned with shareholder wealth maximization, while consumers desire dependable service at low rates. If the desired end product of regulation is to establish rates that balance the interests of consumers and investors, then a financial planning model is needed that accurately reflects the multi-objective nature of the regulatory decision process. This article develops such a multi-objective programming model for examining the efficient trade-offs available to utility regulators in setting rates of return. 8 references, 2 figures, 7 tables.

  14. Integer programming model for optimizing bus timetable using genetic algorithm

    Science.gov (United States)

    Wihartiko, F. D.; Buono, A.; Silalahi, B. P.

    2017-01-01

    Bus timetable gave an information for passengers to ensure the availability of bus services. Timetable optimal condition happened when bus trips frequency could adapt and suit with passenger demand. In the peak time, the number of bus trips would be larger than the off-peak time. If the number of bus trips were more frequent than the optimal condition, it would make a high operating cost for bus operator. Conversely, if the number of trip was less than optimal condition, it would make a bad quality service for passengers. In this paper, the bus timetabling problem would be solved by integer programming model with modified genetic algorithm. Modification was placed in the chromosomes design, initial population recovery technique, chromosomes reconstruction and chromosomes extermination on specific generation. The result of this model gave the optimal solution with accuracy 99.1%.

  15. An Intelligent Model for Pairs Trading Using Genetic Algorithms.

    Science.gov (United States)

    Huang, Chien-Feng; Hsu, Chi-Jen; Chen, Chi-Chung; Chang, Bao Rong; Li, Chen-An

    2015-01-01

    Pairs trading is an important and challenging research area in computational finance, in which pairs of stocks are bought and sold in pair combinations for arbitrage opportunities. Traditional methods that solve this set of problems mostly rely on statistical methods such as regression. In contrast to the statistical approaches, recent advances in computational intelligence (CI) are leading to promising opportunities for solving problems in the financial applications more effectively. In this paper, we present a novel methodology for pairs trading using genetic algorithms (GA). Our results showed that the GA-based models are able to significantly outperform the benchmark and our proposed method is capable of generating robust models to tackle the dynamic characteristics in the financial application studied. Based upon the promising results obtained, we expect this GA-based method to advance the research in computational intelligence for finance and provide an effective solution to pairs trading for investment in practice.

  16. An Intelligent Model for Pairs Trading Using Genetic Algorithms

    Science.gov (United States)

    Hsu, Chi-Jen; Chen, Chi-Chung; Li, Chen-An

    2015-01-01

    Pairs trading is an important and challenging research area in computational finance, in which pairs of stocks are bought and sold in pair combinations for arbitrage opportunities. Traditional methods that solve this set of problems mostly rely on statistical methods such as regression. In contrast to the statistical approaches, recent advances in computational intelligence (CI) are leading to promising opportunities for solving problems in the financial applications more effectively. In this paper, we present a novel methodology for pairs trading using genetic algorithms (GA). Our results showed that the GA-based models are able to significantly outperform the benchmark and our proposed method is capable of generating robust models to tackle the dynamic characteristics in the financial application studied. Based upon the promising results obtained, we expect this GA-based method to advance the research in computational intelligence for finance and provide an effective solution to pairs trading for investment in practice. PMID:26339236

  17. Adaptive Fixation in Two-Locus Models of Stabilizing Selection and Genetic Drift

    OpenAIRE

    Wollstein, Andreas; Stephan, Wolfgang

    2014-01-01

    The relationship between quantitative genetics and population genetics has been studied for nearly a century, almost since the existence of these two disciplines. Here we ask to what extent quantitative genetic models in which selection is assumed to operate on a polygenic trait predict adaptive fixations that may lead to footprints in the genome (selective sweeps). We study two-locus models of stabilizing selection (with and without genetic drift) by simulations and analytically. For symmetr...

  18. Genetically Determined Insulin Resistance is Characterized by Down-Regulation of Mitochondrial Oxidative Metabolism in Human Skeletal Muscle

    DEFF Research Database (Denmark)

    Kristensen, Jonas M; Skov, Vibe; Wojtaszewski, Jørgen

    2010-01-01

    Transcriptional profiling of skeletal muscle from patients with type 2 diabetes and high-risk individuals have demonstrated a co-ordinated down-regulation of oxidative phosphorylation (OxPhos) genes, suggesting a link between insulin resistance and mitochondrial dysfunction. However, whether...... mitochondrial dysfunction is a cause or consequence of insulin resistance remains to be clarified. In the present study, we tested the hypothesis that mitochondrial oxidative metabolism was down-regulated in skeletal muscle of patients with genetically determined insulin resistance. Skeletal muscle biopsies.......02), and complex V (ATP5B; p=0.005). Our data demonstrate that genetically determined insulin resistance is associated with a co-ordinated down-regulation of OxPhos components both at the transcriptional and translational level. These findings suggest that an impaired biological response to insulin in skeletal...

  19. Possible genetic defects in regulation of glycosaminoglycans in patients with diabetic nephropathy

    Energy Technology Data Exchange (ETDEWEB)

    Deckert, T.; Horowitz, I.M.; Kofoed-Enevoldsen, A.; Kjellen, L.; Deckert, M.; Lykkelund, C.; Burcharth, F. (Steno Memorial Hospital, Gentofte (Denmark))

    1991-06-01

    The hypothesis of genetic defects in glycosaminoglycan (GAG) regulation among patients with insulin-dependent diabetes mellitus (IDDM) and nephropathy was assessed by studies in tissue cultures of fibroblasts obtained from 7 patients with normal urinary albumin excretion, 11 patients with diabetic nephropathy, and 6 nondiabetic control subjects. The incorporation of (2H) glucosamine and (35S) sulfate into hyaluronic acid (HA), chondroitin sulfate and dermatan sulfate (CS + DS), and heparan sulfate (HS) was measured in cells, matrix, and medium and related to micrograms of tissue protein. Large interindividual variations were seen in all three groups, and the incorporation of (3H) glucosamine into HA, CS + DS, and HS and (35S) sulfate into CS + DS and HS were not significantly different between the three groups. However, the fractional incorporation of (3H)glucosamine into HS was significantly reduced in diabetic patients with nephropathy compared with control subjects. This was the case not only when related to the total amount of GAGs (P = 0.014) but also when related to HA (P = 0.014). No significant difference was seen between control subjects and normoalbuminuric diabetic patients. The degree of N-sulfation of HS was not significantly different between the experimental groups. The results suggest that patients with diabetic nephropathy may suffer from deficiencies of coordinate regulation in the biosynthesis of GAG in fibroblasts, which may lead to a reduced density of HS in the extracellular matrix. If these changes reflect alterations in the biosynthesis of GAG from endothelial, myomedial, and mesangial cells, this observation may be relevant for the pathogenesis of severe diabetic complications.

  20. Flow regulation in coronary vascular tree: a model study.

    Directory of Open Access Journals (Sweden)

    Xinzhou Xie

    Full Text Available Coronary blood flow can always be matched to the metabolic demand of the myocardium due to the regulation of vasoactive segments. Myocardial compressive forces play an important role in determining coronary blood flow but its impact on flow regulation is still unknown. The purpose of this study was to develop a coronary specified flow regulation model, which can integrate myocardial compressive forces and other identified regulation factors, to further investigate the coronary blood flow regulation behavior.A theoretical coronary flow regulation model including the myogenic, shear-dependent and metabolic responses was developed. Myocardial compressive forces were included in the modified wall tension model. Shear-dependent response was estimated by using the experimental data from coronary circulation. Capillary density and basal oxygen consumption were specified to corresponding to those in coronary circulation. Zero flow pressure was also modeled by using a simplified capillary model.Pressure-flow relations predicted by the proposed model are consistent with previous experimental data. The predicted diameter changes in small arteries are in good agreement with experiment observations in adenosine infusion and inhibition of NO synthesis conditions. Results demonstrate that the myocardial compressive forces acting on the vessel wall would extend the auto-regulatory range by decreasing the myogenic tone at the given perfusion pressure.Myocardial compressive forces had great impact on coronary auto-regulation effect. The proposed model was proved to be consistent with experiment observations and can be employed to investigate the coronary blood flow regulation effect in physiological and pathophysiological conditions.

  1. Modelling synergistic effects of appetite regulating hormones

    DEFF Research Database (Denmark)

    Schmidt, Julie Berg; Ritz, Christian

    2016-01-01

    We briefly reviewed one definition of dose addition, which is applicable within the framework of generalized linear models. We established how this definition of dose addition corresponds to effect addition in case only two doses per compound are considered for evaluating synergistic effects. The....... The link between definitions was exemplified for an appetite study where two appetite hormones were studied....

  2. Tackling intraspecific genetic structure in distribution models better reflects species geographical range.

    Science.gov (United States)

    Marcer, Arnald; Méndez-Vigo, Belén; Alonso-Blanco, Carlos; Picó, F Xavier

    2016-04-01

    Genetic diversity provides insight into heterogeneous demographic and adaptive history across organisms' distribution ranges. For this reason, decomposing single species into genetic units may represent a powerful tool to better understand biogeographical patterns as well as improve predictions of the effects of GCC (global climate change) on biodiversity loss. Using 279 georeferenced Iberian accessions, we used classes of three intraspecific genetic units of the annual plant Arabidopsis thaliana obtained from the genetic analyses of nuclear SNPs (single nucleotide polymorphisms), chloroplast SNPs, and the vernalization requirement for flowering. We used SDM (species distribution models), including climate, vegetation, and soil data, at the whole-species and genetic-unit levels. We compared model outputs for present environmental conditions and with a particularly severe GCC scenario. SDM accuracy was high for genetic units with smaller distribution ranges. Kernel density plots identified the environmental variables underpinning potential distribution ranges of genetic units. Combinations of environmental variables accounted for potential distribution ranges of genetic units, which shrank dramatically with GCC at almost all levels. Only two genetic clusters increased their potential distribution ranges with GCC. The application of SDM to intraspecific genetic units provides a detailed picture on the biogeographical patterns of distinct genetic groups based on different genetic criteria. Our approach also allowed us to pinpoint the genetic changes, in terms of genetic background and physiological requirements for flowering, that Iberian A. thaliana may experience with a GCC scenario applying SDM to intraspecific genetic units.

  3. Exploring Middle School Students' Understanding of Three Conceptual Models in Genetics

    Science.gov (United States)

    Bresler Freidenreich, Hava; Golan Duncan, Ravit; Shea, Nicole

    2011-11-01

    Genetics is the cornerstone of modern biology and a critical aspect of scientific literacy. Research has shown, however, that many high school graduates lack fundamental understandings in genetics necessary to make informed decisions about issues and emerging technologies in this domain, such as genetic screening, genetically modified foods, etc. Genetic literacy entails understanding three interrelated models: a genetic model that describes patterns of genetic inheritance, a meiotic model that describes the process by which genes are segregated into sex cells, and a molecular model that describes the mechanisms that link genotypes to phenotypes within an individual. Currently, much of genetics instruction, especially in terms of the molecular model, occurs at the high school level, and we know little about the ways in which middle school students can reason about these models. Furthermore, we do not know the extent to which carefully designed instruction can help younger students develop coherent and interrelated understandings in genetics. In this paper, we discuss a research study aimed at elucidating middle school students' abilities to reason about the three genetic models. As part of our research, we designed an eight-week inquiry unit that was implemented in a combined sixth- to eighth-grade science classroom. We describe our instructional design and report results based on an analysis of written assessments, clinical interviews, and artifacts of the unit. Our findings suggest that middle school students are able to successfully reason about all three genetic models.

  4. Status of market, regulation and research of genetically modified crops in Chile.

    Science.gov (United States)

    Sánchez, Miguel A; León, Gabriel

    2016-12-25

    Agricultural biotechnology and genetically modified (GM) crops are effective tools to substantially increase productivity, quality, and environmental sustainability in agricultural farming. Furthermore, they may contribute to improving the nutritional content of crops, addressing needs related to public health. Chile has become one of the most important global players for GM seed production for counter-season markets and research purposes. It has a comprehensive regulatory framework to carry out this activity, while at the same time there are numerous regulations from different agencies addressing several aspects related to GM crops. Despite imports of GM food/feed or ingredients for the food industry being allowed without restrictions, Chilean farmers are not using GM seeds for farming purposes because of a lack of clear guidelines. Chile is in a rather contradictory situation about GM crops. The country has invested considerable resources to fund research and development on GM crops, but the lack of clarity in the current regulatory situation precludes the use of such research to develop new products for Chilean farmers. Meanwhile, a larger scientific capacity regarding GM crop research continues to build up in the country. The present study maps and analyses the current regulatory environment for research and production of GM crops in Chile, providing an updated overview of the current status of GM seeds production, research and regulatory issues. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Optimization of the linear quadratic regulator (LQR control quarter car suspension system using genetic algorithm

    Directory of Open Access Journals (Sweden)

    Mahesh Nagarkar

    2016-04-01

    Full Text Available In this paper, a genetic algorithm (GA based in an optimization approach is presented in order to search the optimum weighting matrix parameters of a linear quadratic regulator (LQR. A Macpherson strut quarter car suspension system is implemented for ride control application. Initially, the GA is implemented with the objective of minimizing root mean square (RMS controller force. For single objective optimization, RMS controller force is reduced by 20.42% with slight increase in RMS sprung mass acceleration. Trade-off is observed between controller force and sprung mass acceleration. Further, an analysis is extended to multi-objective optimization with objectives such as minimization of RMS controller force and RMS sprung mass acceleration and minimization of RMS controller force, RMS sprung mass acceleration and suspension space deflection. For multi-objective optimization, Pareto-front gives flexibility in order to choose the optimum solution as per designer’s need.

  6. Genetic regulation of tissue-specific expression of amylase structural genes in Drosophila melanogaster.

    Science.gov (United States)

    Abraham, I; Doane, W W

    1978-01-01

    Laboratory strains of Drosophila melanogaster were screened for spatial variations in adult midgut alpha-amylase (1,4-alpha-D-glucan glucanohydrolase, EC 3.2.1.1) expression. No strain-specific differences were found anteriorly, but three patterns of activity were discerned in the posterior midgut: A, activity throughout most of the region; B, activity in the anterior part of the region; and C, little or no activity. Alleles of a control gene, map, are responsible for this tissue-specific regulation of activity; e.g., mapA homozygotes produce the A pattern and mapC homozygotes the C pattern. The map locus was placed at 2--80 +/- on the genetic map of chromosome 2R, about two crossover units distal to the Amy structural gene region for alpha-amylase. Electrophoretic studies showed that mapA is trans acting in mapA/mapC flies, allowing expression of amylase isozymes coded for by genes on the opposite chromosome. The map gene behaves as a temporal gene that is clearly separable from the tightly linked, duplicated Amy structural genes. Images PMID:100784

  7. Toward a workable biosafety system for regulating genetically modified organisms in Ethiopia: balancing conservation and competitiveness.

    Science.gov (United States)

    Abraham, Adane

    2013-01-01

    On September 9, 2009, Ethiopia enacted a highly restrictive biosafety law firmly based on precautionary principles as a foundation for its GMO regulation system. Its drafting process, led by the country's Environmental Protection Authority, was judged as biased, focusing only on protecting the environment from perceived risks, giving little attention to potential benefits of GMOs. Many of its provisions are very stringent, exceeding those of Cartagena Protocol on Biosafety, while others cannot be fulfilled by applicants, collectively rendering the emerged biosafety system unworkable. These provisions include requirements for advance informed agreement and rigorous socioeconomic assessment in risk evaluation for all GMO transactions, including contained research use-which requires the head of the competent national authority of the exporting country to take full responsibility for GMO-related information provided-and stringent labeling, insurance and monitoring requirements for all GMO activities. Furthermore, there is no provision to establish an independent national biosafety decision-making body(ies). As a result, foreign technology owners that provide highly demanded technologies like Bt cotton declined to work with Ethiopia. There is a fear that the emerged biosafety system might also continue to suppress domestic genetic engineering research and development. Thus, to benefit from GMOs, Ethiopia has to revise its biosafety system, primarily by making changes to some provisions of the law in a way that balances its diverse interests of conserving biodiversity, protecting the environment and enhancing competition in agricultural and other economic sectors.

  8. Development of agribiotechnology and biosafety regulations used to assess safety of genetically modified crops in Bangladesh.

    Science.gov (United States)

    Nasiruddin, Khondoker M; Nasim, Anwar

    2007-01-01

    Bangladesh is on the verge of adopting genetically modified (GM) crops for commercial cultivation and consumption as feed and food. Most of the laboratories are engaged in tissue culture and molecular characterization on plants, whereas some have started living modified organism research with shortages of trained manpower, infrastructure, and funding. Nutritionally improved Golden Rice, biotech brinjal, and late blight-resistant potato are in contained trials in a greenhouse, and potato ring spot virus-resistant papaya is in the process of approval for a field trial. The government has taken some initiative in support of GM organism research, which include the formation of a Biotechnology Department in all institutes and the formation of the apex body, the National Task Force Committee on Biotechnology of Bangladesh under the chairpersonship of the Prime Minister. Biosafety policy guidelines and related aspects of biotechnology issues have been approved, and the laws are in the process of being promulgated. Being a party to the Cartagena Protocol, proper biosafety measures are regulated by the appropriate authority as stated. Although there are no laws made yet directly for biosafety of GM crops/foods, the relevant laws on agriculture, medicine, food, import, trade, environment, etc. may suffice and explain the situation.

  9. Genetic analysis of pathway regulation for enhancing branched-chain amino acid biosynthesis in plants

    KAUST Repository

    Chen, Hao

    2010-08-01

    The branched-chain amino acids (BCAAs) valine, leucine and isoleucine are essential amino acids that play critical roles in animal growth and development. Animals cannot synthesize these amino acids and must obtain them from their diet. Plants are the ultimate source of these essential nutrients, and they synthesize BCAAs through a conserved pathway that is inhibited by its end products. This feedback inhibition has prevented scientists from engineering plants that accumulate high levels of BCAAs by simply over-expressing the respective biosynthetic genes. To identify components critical for this feedback regulation, we performed a genetic screen for Arabidopsis mutants that exhibit enhanced resistance to BCAAs. Multiple dominant allelic mutations in the VALINE-TOLERANT 1 (VAT1) gene were identified that conferred plant resistance to valine inhibition. Map-based cloning revealed that VAT1 encodes a regulatory subunit of acetohydroxy acid synthase (AHAS), the first committed enzyme in the BCAA biosynthesis pathway. The VAT1 gene is highly expressed in young, rapidly growing tissues. When reconstituted with the catalytic subunit in vitro, the vat1 mutant-containing AHAS holoenzyme exhibits increased resistance to valine. Importantly, transgenic plants expressing the mutated vat1 gene exhibit valine tolerance and accumulate higher levels of BCAAs. Our studies not only uncovered regulatory characteristics of plant AHAS, but also identified a method to enhance BCAA accumulation in crop plants that will significantly enhance the nutritional value of food and feed. © 2010 Blackwell Publishing Ltd.

  10. MicroRNA-mediated gene regulation: potential applications for plant genetic engineering.

    Science.gov (United States)

    Zhou, Man; Luo, Hong

    2013-09-01

    Food security is one of the most important issues challenging the world today. Any strategies to solve this problem must include increasing crop yields and quality. MicroRNA-based genetic modification technology (miRNA-based GM tech) can be one of the most promising solutions that contribute to agricultural productivity directly by developing superior crop cultivars with enhanced biotic and abiotic stress tolerance and increased biomass yields. Indirectly, the technology may increase usage of marginal soils and decrease pesticide use, among other benefits. This review highlights the most recent progress of transgenic studies utilizing various miRNAs and their targets for plant trait modifications, and analyzes the potential of miRNA-mediated gene regulation for use in crop improvement. Strategies for manipulating miRNAs and their targets in transgenic plants including constitutive, stress-induced, or tissue-specific expression of miRNAs or their targets, RNA interference, expressing miRNA-resistant target genes, artificial target mimic and artificial miRNAs were discussed. We also discussed potential risks of utilizing miRNA-based GM tech. In general, miRNAs and their targets not only provide an invaluable source of novel transgenes, but also inspire the development of several new GM strategies, allowing advances in breeding novel crop cultivars with agronomically useful characteristics.

  11. Computational modelling elucidates the mechanism of ciliary regulation in health and disease

    Directory of Open Access Journals (Sweden)

    Hundhausen Christian

    2011-09-01

    Full Text Available Abstract Background Ciliary dysfunction leads to a number of human pathologies, including primary ciliary dyskinesia, nephronophthisis, situs inversus pathology or infertility. The mechanism of cilia beating regulation is complex and despite extensive experimental characterization remains poorly understood. We develop a detailed systems model for calcium, membrane potential and cyclic nucleotide-dependent ciliary motility regulation. Results The model describes the intimate relationship between calcium and potassium ionic concentrations inside and outside of cilia with membrane voltage and, for the first time, describes a novel type of ciliary excitability which plays the major role in ciliary movement regulation. Our model describes a mechanism that allows ciliary excitation to be robust over a wide physiological range of extracellular ionic concentrations. The model predicts the existence of several dynamic modes of ciliary regulation, such as the generation of intraciliary Ca2+ spike with amplitude proportional to the degree of membrane depolarization, the ability to maintain stable oscillations, monostable multivibrator regimes, all of which are initiated by variability in ionic concentrations that translate into altered membrane voltage. Conclusions Computational investigation of the model offers several new insights into the underlying molecular mechanisms of ciliary pathologies. According to our analysis, the reported dynamic regulatory modes can be a physiological reaction to alterations in the extracellular environment. However, modification of the dynamic modes, as a result of genetic mutations or environmental conditions, can cause a life threatening pathology.

  12. Clinical models of cardiovascular regulation after weightlessness

    Science.gov (United States)

    Robertson, D.; Jacob, G.; Ertl, A.; Shannon, J.; Mosqueda-Garcia, R.; Robertson, R. M.; Biaggioni, I.

    1996-01-01

    After several days in microgravity, return to earth is attended by alterations in cardiovascular function. The mechanisms underlying these effects are inadequately understood. Three clinical disorders of autonomic function represent possible models of this abnormal cardiovascular function after spaceflight. They are pure autonomic failure, baroreflex failure, and orthostatic intolerance. In pure autonomic failure, virtually complete loss of sympathetic and parasympathetic function occurs along with profound and immediate orthostatic hypotension. In baroreflex failure, various degrees of debuffering of blood pressure occur. In acute and complete baroreflex failure, there is usually severe hypertension and tachycardia, while with less complete and more chronic baroreflex impairment, orthostatic abnormalities may be more apparent. In orthostatic intolerance, blood pressure fall is minor, but orthostatic symptoms are prominent and tachycardia frequently occurs. Only careful autonomic studies of human subjects in the microgravity environment will permit us to determine which of these models most closely reflects the pathophysiology brought on by a period of time in the microgravity environment.

  13. Pluralistic and stochastic gene regulation: examples, models and consistent theory.

    Science.gov (United States)

    Salas, Elisa N; Shu, Jiang; Cserhati, Matyas F; Weeks, Donald P; Ladunga, Istvan

    2016-06-01

    We present a theory of pluralistic and stochastic gene regulation. To bridge the gap between empirical studies and mathematical models, we integrate pre-existing observations with our meta-analyses of the ENCODE ChIP-Seq experiments. Earlier evidence includes fluctuations in levels, location, activity, and binding of transcription factors, variable DNA motifs, and bursts in gene expression. Stochastic regulation is also indicated by frequently subdued effects of knockout mutants of regulators, their evolutionary losses/gains and massive rewiring of regulatory sites. We report wide-spread pluralistic regulation in ≈800 000 tightly co-expressed pairs of diverse human genes. Typically, half of ≈50 observed regulators bind to both genes reproducibly, twice more than in independently expressed gene pairs. We also examine the largest set of co-expressed genes, which code for cytoplasmic ribosomal proteins. Numerous regulatory complexes are highly significant enriched in ribosomal genes compared to highly expressed non-ribosomal genes. We could not find any DNA-associated, strict sense master regulator. Despite major fluctuations in transcription factor binding, our machine learning model accurately predicted transcript levels using binding sites of 20+ regulators. Our pluralistic and stochastic theory is consistent with partially random binding patterns, redundancy, stochastic regulator binding, burst-like expression, degeneracy of binding motifs and massive regulatory rewiring during evolution.

  14. Dynamics of the two process model of human sleep regulation

    Science.gov (United States)

    Kenngott, Max; McKay, Cavendish

    2011-04-01

    We examine the dynamics of the two process model of human sleep regulation. In this model, sleep propensity is governed by the interaction between a periodic threshold (process C) and a saturating growth/decay (process S). We find that the parameter space of this model admits sleep cycles with a wide variety of characteristics, many of which are not observed in normal human sleepers. We also examine the effects of phase dependent feedback on this model.

  15. A time study of cancer genetic counselors using a genetic counselor-only patient care model versus a traditional combined genetic counselor plus medical geneticist care model.

    Science.gov (United States)

    Heald, Brandie; Gustafson, Shanna; Mester, Jessica; Arscott, Patricia; Lynch, Katherine; Moline, Jessica; Eng, Charis

    2013-09-01

    Analyses of time-based effort have determined that clinical genetic services are labor-intensive, although these data derive primarily from studying geneticists' efforts in the pediatric model. No studies have investigated the time and patient care activities of cancer genetic counselors (GCs) in traditional clinics with a medical geneticist (GC/MD) compared with genetic counselor-only (GCO) appointments. In this study, 6 GCs prospectively tracked time spent in patient care activities in both clinical settings. The authors found that overall, GCs' time spent per patient was lower for GCO versus GC/MD visits. No differences were seen in time spent on results disclosure, but differences were noted in case preparation, face-to-face, and follow-up times. Furthermore, no differences were seen in number of case preparation activities or topics covered during a session. These data suggest that GCO visits result in better use of GCs' time, without a trade-off in number of patient-related activities.

  16. Obesity: from animal models to human genetics to practical applications.

    Science.gov (United States)

    Warden, Craig H; Fisler, Janis S

    2010-01-01

    Although many animal models are used in genetic studies, the mouse is most common. Analysis of single-gene mutations, linkage analysis in crossbred strains, and gene targeting are the primary techniques used to associate obesity phenotypes with specific genes or alleles. The orthologous human gene can then be tested, either in linkage studies in families or in genome-wide association studies (GWAS), for effect on the phenotype. Frequent lack of concordance between mouse and human obesity genes may be due to the difference in phenotypes measured in humans (body mass index) versus mouse (fat mass or % body fat), lack of intermediate phenotypes, and the fact that identified genes account for only a small percentage of the heritability of common obesity, suggesting that many genes remain unknown. New technology allows analysis of individual genomes at a reasonable cost, making large-scale obesity genome projects in humans feasible. Such projects could identify common allelic variants that contribute to obesity and to variable individual response to obesity therapy. Currently, family history may be more predictive than genetics for risk of obesity, but individual testing could ultimately guide therapy and, in the aggregate, guide public health policy. The primary limitation to development of genotype-based diets is that successful randomized diet trials of widely ranging macronutrient content, adequately powered for finding rare Mendelian mutations, have not been performed. Copyright © 2010 Elsevier Inc. All rights reserved.

  17. Molecular genetics of cancer and tumorigenesis: Drosophila models

    Institute of Scientific and Technical Information of China (English)

    Wu-Min Deng

    2011-01-01

    Why do some cells not respond to normal control of cell division and become tumorous? Which signals trigger some tumor cells to migrate and colonize other tissues? What genetic factors are responsible for tumorigenesis and cancer development? What environmental factors play a role in cancer formation and progression? In how many ways can our bodies prevent and restrict the growth of cancerous cells?How can we identify and deliver effective drugs to fight cancer? In the fight against cancer,which kills more people than any other disease,these and other questions have long interested researchers from a diverse range of fields.To answer these questions and to fight cancer more effectively,we must increase our understanding of basic cancer biology.Model organisms,including the fruit fly Drosophila melanogaster,have played instrumental roles in our understanding of this devastating disease and the search for effective cures.Drosophila and its highly effective,easy-touse,and ever-expanding genetic tools have contributed toand enriched our knowledge of cancer and tumor formation tremendously.

  18. Structure Refinement for Vulnerability Estimation Models using Genetic Algorithm Based Model Generators

    Directory of Open Access Journals (Sweden)

    2009-01-01

    Full Text Available In this paper, a method for model structure refinement is proposed and applied in estimation of cumulative number of vulnerabilities according to time. Security as a quality characteristic is presented and defined. Vulnerabilities are defined and their importance is assessed. Existing models used for number of vulnerabilities estimation are enumerated, inspecting their structure. The principles of genetic model generators are inspected. Model structure refinement is defined in comparison with model refinement and a method for model structure refinement is proposed. A case study shows how the method is applied and the obtained results.

  19. Estimation of genetic parameters and genetic change for stillbirth in Iranian Holstein cows: a comparison between linear and threshold models

    OpenAIRE

    N.G. HOSSEIN-ZADEH

    2008-01-01

    Data on stillbirth from the Animal Breeding Center of Iran collected from January 1990 to December 2007 and comprising 668810 Holstein calving events from 2506 herds were analyzed. Linear and threshold animal and sire models were used to estimate genetic parameters and genetic trends for stillbirth in the first, second, and third parities. Mean incidence of stillbirth decreased from first to third parities: 23.7%, 22.1%, and 21.8%, respectively. Phenotypic rates of stillbirth decreased from 1...

  20. Diverse Genetic Regulon of the Virulence-Associated Transcriptional Regulator MucR in Brucella abortus 2308

    Science.gov (United States)

    Caswell, Clayton C.; Elhassanny, Ahmed E. M.; Planchin, Emilie E.; Roux, Christelle M.; Weeks-Gorospe, Jenni N.; Ficht, Thomas A.; Dunman, Paul M.

    2013-01-01

    The Ros-type regulator MucR is one of the few transcriptional regulators that have been linked to virulence in Brucella. Here, we show that a Brucella abortus in-frame mucR deletion strain exhibits a pronounced growth defect during in vitro cultivation and, more importantly, that the mucR mutant is attenuated in cultured macrophages and in mice. The genetic basis for the attenuation of Brucella mucR mutants has not been defined previously, but in the present study the genes regulated by MucR in B. abortus have been elucidated using microarray analysis and real-time reverse transcription-PCR (RT-PCR). In B. abortus 2308, MucR regulates a wide variety of genes whose products may function in establishing and maintaining cell envelope integrity, polysaccharide biosynthesis, iron homeostasis, genome plasticity, and transcriptional regulation. Particularly notable among the MucR-regulated genes identified is arsR6 (nolR), which encodes a transcriptional regulator previously linked to virulence in Brucella melitensis 16 M. Importantly, electrophoretic mobility shift assays (EMSAs) determined that a recombinant MucR protein binds directly to the promoter regions of several genes repressed by MucR (including arsR6 [nolR]), and in Brucella, as in other alphaproteobacteria, MucR binds to its own promoter to repress expression of the gene that encodes it. Overall, these studies have uncovered the diverse genetic regulon of MucR in Brucella, and in doing so this work has begun to define the MucR-controlled genetic circuitry whose misregulation contributes to the virulence defect of Brucella mucR mutants. PMID:23319565

  1. Genetics

    DEFF Research Database (Denmark)

    Christensen, Kaare; McGue, Matt

    2016-01-01

    The sequenced genomes of individuals aged ≥80 years, who were highly educated, self-referred volunteers and with no self-reported chronic diseases were compared to young controls. In these data, healthy ageing is a distinct phenotype from exceptional longevity and genetic factors that protect...

  2. Local identification of piecewise deterministic models of genetic networks

    NARCIS (Netherlands)

    Cinquemani, Eugenio; Milias-Argeitis, Andreas; Summers, Sean; Lygeros, John

    2009-01-01

    We address the identification of genetic networks under stationary conditions. A stochastic hybrid description of the genetic interactions is considered and an approximation of it in stationary conditions is derived. Contrary to traditional structure identification methods based on fitting determini

  3. Behavioral phenotypes of genetic mouse models of autism.

    Science.gov (United States)

    Kazdoba, T M; Leach, P T; Crawley, J N

    2016-01-01

    More than a hundred de novo single gene mutations and copy-number variants have been implicated in autism, each occurring in a small subset of cases. Mutant mouse models with syntenic mutations offer research tools to gain an understanding of the role of each gene in modulating biological and behavioral phenotypes relevant to autism. Knockout, knockin and transgenic mice incorporating risk gene mutations detected in autism spectrum disorder and comorbid neurodevelopmental disorders are now widely available. At present, autism spectrum disorder is diagnosed solely by behavioral criteria. We developed a constellation of mouse behavioral assays designed to maximize face validity to the types of social deficits and repetitive behaviors that are central to an autism diagnosis. Mouse behavioral assays for associated symptoms of autism, which include cognitive inflexibility, anxiety, hyperactivity, and unusual reactivity to sensory stimuli, are frequently included in the phenotypic analyses. Over the past 10 years, we and many other laboratories around the world have employed these and additional behavioral tests to phenotype a large number of mutant mouse models of autism. In this review, we highlight mouse models with mutations in genes that have been identified as risk genes for autism, which work through synaptic mechanisms and through the mTOR signaling pathway. Robust, replicated autism-relevant behavioral outcomes in a genetic mouse model lend credence to a causal role for specific gene contributions and downstream biological mechanisms in the etiology of autism.

  4. Ripple-Spreading Network Model Optimization by Genetic Algorithm

    Directory of Open Access Journals (Sweden)

    Xiao-Bing Hu

    2013-01-01

    Full Text Available Small-world and scale-free properties are widely acknowledged in many real-world complex network systems, and many network models have been developed to capture these network properties. The ripple-spreading network model (RSNM is a newly reported complex network model, which is inspired by the natural ripple-spreading phenomenon on clam water surface. The RSNM exhibits good potential for describing both spatial and temporal features in the development of many real-world networks where the influence of a few local events spreads out through nodes and then largely determines the final network topology. However, the relationships between ripple-spreading related parameters (RSRPs of RSNM and small-world and scale-free topologies are not as obvious or straightforward as in many other network models. This paper attempts to apply genetic algorithm (GA to tune the values of RSRPs, so that the RSNM may generate these two most important network topologies. The study demonstrates that, once RSRPs are properly tuned by GA, the RSNM is capable of generating both network topologies and therefore has a great flexibility to study many real-world complex network systems.

  5. Toward Developing Genetic Algorithms to Aid in Critical Infrastructure Modeling

    Energy Technology Data Exchange (ETDEWEB)

    2007-05-01

    Today’s society relies upon an array of complex national and international infrastructure networks such as transportation, telecommunication, financial and energy. Understanding these interdependencies is necessary in order to protect our critical infrastructure. The Critical Infrastructure Modeling System, CIMS©, examines the interrelationships between infrastructure networks. CIMS© development is sponsored by the National Security Division at the Idaho National Laboratory (INL) in its ongoing mission for providing critical infrastructure protection and preparedness. A genetic algorithm (GA) is an optimization technique based on Darwin’s theory of evolution. A GA can be coupled with CIMS© to search for optimum ways to protect infrastructure assets. This includes identifying optimum assets to enforce or protect, testing the addition of or change to infrastructure before implementation, or finding the optimum response to an emergency for response planning. This paper describes the addition of a GA to infrastructure modeling for infrastructure planning. It first introduces the CIMS© infrastructure modeling software used as the modeling engine to support the GA. Next, the GA techniques and parameters are defined. Then a test scenario illustrates the integration with CIMS© and the preliminary results.

  6. THE EUROPEAN MODEL OF STATE REGULATION OF TOURISM ACTIVITIES

    Directory of Open Access Journals (Sweden)

    О. Davydova

    2013-11-01

    Full Text Available In the article the existing model of state regulation of the development of tourism. Expediency of the European model of state regulation of tourism development in Ukraine. It is noted that the European model of state regulation of tourism activities based on the coordination of marketing activities and the development of cooperation between the public and private sectors. The basic forms of public-private partnerships and the advantages of using cluster model of development of tourism, namely, contracts, production sharing agreement, lease, joint venture. Promising areas of application of the PPP identified the transport sector, housing and utilities, energy and tourism sector. The features of cluster formations in the country and the prospects for tourism clusters.

  7. Genetic polymorphisms of the main transcription factors for adiponectin gene promoter in regulation of adiponectin levels: association analysis in three European cohorts.

    Directory of Open Access Journals (Sweden)

    Lyudmyla Kedenko

    Full Text Available Adiponectin serum concentrations are an important biomarker in cardiovascular epidemiology with heritability etimates of 30-70%. However, known genetic variants in the adiponectin gene locus (ADIPOQ account for only 2%-8% of its variance. As transcription factors are thought to play an under-acknowledged role in carrying functional variants, we hypothesized that genetic polymorphisms in genes coding for the main transcription factors for the ADIPOQ promoter influence adiponectin levels. Single nucleotide polymorphisms (SNPs at these genes were selected based on the haplotype block structure and previously published evidence to be associated with adiponectin levels. We performed association analyses of the 24 selected SNPs at forkhead box O1 (FOXO1, sterol-regulatory-element-binding transcription factor 1 (SREBF1, sirtuin 1 (SIRT1, peroxisome-proliferator-activated receptor gamma (PPARG and transcription factor activating enhancer binding protein 2 beta (TFAP2B gene loci with adiponectin levels in three different European cohorts: SAPHIR (n = 1742, KORA F3 (n = 1636 and CoLaus (n = 5355. In each study population, the association of SNPs with adiponectin levels on log-scale was tested using linear regression adjusted for age, sex and body mass index, applying both an additive and a recessive genetic model. A pooled effect size was obtained by meta-analysis assuming a fixed effects model. We applied a significance threshold of 0.0033 accounting for the multiple testing situation. A significant association was only found for variants within SREBF1 applying an additive genetic model (smallest p-value for rs1889018 on log(adiponectin = 0.002, β on original scale = -0.217 µg/ml, explaining ~0.4% of variation of adiponectin levels. Recessive genetic models or haplotype analyses of the FOXO1, SREBF1, SIRT1, TFAPB2B genes or sex-stratified analyses did not reveal additional information on the regulation of adiponectin levels. The role of genetic

  8. Genetic Polymorphisms of the Main Transcription Factors for Adiponectin Gene Promoter in Regulation of Adiponectin Levels: Association Analysis in Three European Cohorts

    Science.gov (United States)

    Kiesslich, Tobias; Kapur, Karen; Bergmann, Sven; Waterworth, Dawn; Heid, Iris M.; Wichmann, H.-Erich; Kedenko, Igor; Kronenberg, Florian; Paulweber, Bernhard

    2012-01-01

    Adiponectin serum concentrations are an important biomarker in cardiovascular epidemiology with heritability etimates of 30–70%. However, known genetic variants in the adiponectin gene locus (ADIPOQ) account for only 2%–8% of its variance. As transcription factors are thought to play an under-acknowledged role in carrying functional variants, we hypothesized that genetic polymorphisms in genes coding for the main transcription factors for the ADIPOQ promoter influence adiponectin levels. Single nucleotide polymorphisms (SNPs) at these genes were selected based on the haplotype block structure and previously published evidence to be associated with adiponectin levels. We performed association analyses of the 24 selected SNPs at forkhead box O1 (FOXO1), sterol-regulatory-element-binding transcription factor 1 (SREBF1), sirtuin 1 (SIRT1), peroxisome-proliferator-activated receptor gamma (PPARG) and transcription factor activating enhancer binding protein 2 beta (TFAP2B) gene loci with adiponectin levels in three different European cohorts: SAPHIR (n = 1742), KORA F3 (n = 1636) and CoLaus (n = 5355). In each study population, the association of SNPs with adiponectin levels on log-scale was tested using linear regression adjusted for age, sex and body mass index, applying both an additive and a recessive genetic model. A pooled effect size was obtained by meta-analysis assuming a fixed effects model. We applied a significance threshold of 0.0033 accounting for the multiple testing situation. A significant association was only found for variants within SREBF1 applying an additive genetic model (smallest p-value for rs1889018 on log(adiponectin) = 0.002, β on original scale = −0.217 µg/ml), explaining ∼0.4% of variation of adiponectin levels. Recessive genetic models or haplotype analyses of the FOXO1, SREBF1, SIRT1, TFAPB2B genes or sex-stratified analyses did not reveal additional information on the regulation of adiponectin levels. The

  9. Identification of Hammerstein Model Based on Quantum Genetic Algorithm

    OpenAIRE

    Zhang Hai Li

    2013-01-01

    Nonlinear system identification is a main topic of modern identification. A new method for nonlinear system identification is presented by using Quantum Genetic Algorithm(QGA).The problems of nonlinear system identification are cast as function optimization overprameter space,and the Quantum Genetic Algorithm is adopted to solve the optimization problem. Simulation experiments show that: compared with the genetic algorithm, quantum genetic algorithm is an effective swarm intelligence algorith...

  10. Genetic analysis of the regulation of TCH gene expression, Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Braam, Janet

    2008-10-28

    multiple XTH::GUS genes suggesting that XTHs may contribute to morphogenesis at every developmental stage and in every plant organ. Different XTHs have remarkably diverse and distinct expression patterns indicating that paralogous genes have evolved differential expression regulation perhaps contributing to the maintenance of the large gene family. Extensive overlap in XTH expression patterns is evident; thus, XTHs may act combinatorially in determining wall properties of specific tissues or organs. Knowledge of gene-specific expression among family members yields evidence of where and when gene products may function and provides insights to guide rational approaches to investigate function through reverse genetics.

  11. Genetic fuzzy system modeling and simulation of vascular behaviour

    DEFF Research Database (Denmark)

    Tang, Jiaowei; Boonen, Harrie C.M.

    and find the optimal parameters in a Fuzzy Control set that can control the fluctuation of physical features in a blood vessel, based on experimental data (training data). Our solution is to create chromosomes or individuals composed of a sequence of parameters in the fuzzy system and find the best...... chromosome or individual to define the fuzzy system. The model is implemented by combining the Matlab Genetic algorithm and Fuzzy system toolboxes, respectively. To test the performance of this method, experimental data sets about calculated pressure change in different blood vessels after several chemical...... treatments are chosen as training and testing data sets. In the simulation, the fuzzy control system is trained by pressure data of one blood vessel and tested with pressure data of other blood vessels. Results: Right now, some rough results show that trained fuzzy control system can be used to predict...

  12. New Genetics

    Science.gov (United States)

    ... Home > Science Education > The New Genetics The New Genetics Living Laboratories Classroom Poster Order a Free Copy ... Piece to a Century-Old Evolutionary Puzzle Computing Genetics Model Organisms RNA Interference The New Genetics is ...

  13. Stress, glucocorticoids and absences in a genetic epilepsy model.

    Science.gov (United States)

    Tolmacheva, Elena A; Oitzl, Melly S; van Luijtelaar, Gilles

    2012-05-01

    Although stress can alter the susceptibility of patients and animal models to convulsive epilepsy, little is known about the role of stress and glucocorticoid hormones in absence epilepsy. We measured the basal and acute stress-induced (foot-shocks: FS) concentrations of corticosterone in WAG/Rij rats, non-epileptic inbred ACI rats and outbred Wistar rats. The WAG/Rij strain is a genetic model for absence epilepsy and comorbidity for depression, which originates from the population of Wistar rats and, therefore, shares their genetic background. In a separate experiment, WAG/Rij rats were exposed to FS on three consecutive days. Electroencephalograms (EEGs) were recorded before and after FS, and the number of absence seizures (spike-wave-discharges, SWDs) was quantified. Both WAG/Rij rats and ACI rats exhibited elevated basal levels of corticosterone and a rapid corticosterone increase in response to acute stress. The WAG/Rij rats also displayed the most rapid normalization of corticosterone during the recovery phase compared to that of ACI and Wistar rats. FS had a biphasic effect on SWDs; an initial suppression was followed by an aggravation of the SWDs. By the third day, this aggravation of seizures was present in the hour preceding FS. This increase in SWDs may arise from anticipatory stress about the upcoming FS. Together, these results suggest that the distinct secretion profile of corticosterone found in WAG/Rij rats may contribute to the severity of the epileptic phenotype. Although the acute stressor results in an initial suppression of SWDs followed by an increase in SWDs, stress prior to a predictable negative event aggravates absences.

  14. A Mathematical Model Accounting for the Organisation in Multiplets of the Genetic Code

    OpenAIRE

    Sciarrino, A.

    2001-01-01

    Requiring stability of genetic code against translation errors, modelised by suitable mathematical operators in the crystal basis model of the genetic code, the main features of the organisation in multiplets of the mitochondrial and of the standard genetic code are explained.

  15. Studying Children's Intrapersonal Emotion Regulation Strategies from the Process Model of Emotion Regulation.

    Science.gov (United States)

    López-Pérez, Belén; Gummerum, Michaela; Wilson, Ellie; Dellaria, Giulia

    2017-01-01

    The authors relied on the Process Model of Emotion Regulation (PMER; J. J. Gross, 2007 ) to investigate children's abilities to regulate their emotions and to assess how distinct emotion regulation strategies are used by children of different ages. In Study 1, 180 parents of children aged between 3 and 8 years old reported about a situation in which their child had been able to change what she or he was feeling. In Study 2, 126 children 3-8 years old answered 2 questions about how they regulate their own emotions. Results from both studies showed age differences in children's reported emotion regulation abilities and the strategies they used. As expected, strategies such as situation selection, situation modification, and cognitive change were used more frequently by 5-6- and 7-8-year-olds, whereas attention deployment was mainly used by 3-4-year-olds. No age differences were found for response modulation. The present research contributes to the existing body of literature on emotion regulation by adding more information about the developmental patterns for each specific emotion regulation strategy.

  16. Genetic mapping of male pheromone response in the European corn borer identifies candidate genes regulating neurogenesis

    Science.gov (United States)

    Dekker, Teun; Heckel, David G.

    2016-01-01

    The sexual pheromone communication system of moths is a model system for studies of the evolution of reproductive isolation. Females emit a blend of volatile components that males detect at a distance. Species differences in female pheromone composition and male response directly reinforce reproductive isolation in nature, because even slight variations in the species-specific pheromone blend are usually rejected by the male. The mechanisms by which a new pheromone signal–response system could evolve are enigmatic, because any deviation from the optimally attractive blend should be selected against. Here we investigate the genetic mechanisms enabling a switch in male response. We used a quantitative trait locus-mapping approach to identify the genetic basis of male response in the two pheromone races of the European corn borer, Ostrinia nubilalis. Male response to a 99:1 vs. a 3:97 ratio of the E and Z isomers of the female pheromone is governed by a single, sex-linked locus. We found that the chromosomal region most tightly linked to this locus contains genes involved in neurogenesis but, in accordance with an earlier study, does not contain the odorant receptors expressed in the male antenna that detect the pheromone. This finding implies that differences in the development of neuronal pathways conveying information from the antenna, not differences in pheromone detection by the odorant receptors, are primarily responsible for the behavioral response differences among the males in this system. Comparison with other moth species reveals a previously unexplored mechanism by which male pheromone response can change in evolution. PMID:27698145

  17. Estimation of genetic parameters and genetic change for stillbirth in Iranian Holstein cows: a comparison between linear and threshold models

    Directory of Open Access Journals (Sweden)

    N.G. HOSSEIN-ZADEH

    2008-12-01

    Full Text Available Data on stillbirth from the Animal Breeding Center of Iran collected from January 1990 to December 2007 and comprising 668810 Holstein calving events from 2506 herds were analyzed. Linear and threshold animal and sire models were used to estimate genetic parameters and genetic trends for stillbirth in the first, second, and third parities. Mean incidence of stillbirth decreased from first to third parities: 23.7%, 22.1%, and 21.8%, respectively. Phenotypic rates of stillbirth decreased from 1993 to 1998, for first, second and third calvings, and then increased from 1998 to 2007 for the first three parities. Direct heritability estimates of stillbirth for parities 1, 2 and 3 ranged from 2.2 to 8.7%, 0.6 to 5.1% and 0.1 to 3.8%, respectively, and maternal heritability estimates of stillbirth for parities 1, 2 and 3 ranged from 1.4 to 6.3%, 0.5 to 4.2% and 0.08 to 2.0%, respectively, using linear and threshold animal models. The threshold sire model estimates of heritabilities for stillbirth in this study were 0.021 to 0.071, while the linear sire model estimates of heritabilities for stillbirth in the current study were from 0.003 to 0.021 over the parities. There was a slightly increasing genetic trend for stillbirth rate in parities 1 and 2 over time with the analysis of linear animal and linear sire models. There was a significant decreasing genetic trend for stillbirth rate in parity 1 and 3 over time with the analysis of threshold animal and threshold sire models, but the genetic trend for stillbirth rate in parity 2 with these models of analysis was significantly positive. The low estimates of heritability obtained in this study implied that much of the improvement in stillbirth could be attained by improvement of production environment rather than genetic selection.;

  18. The integrate model of emotion, thinking and self regulation: an application to the "paradox of aging".

    Science.gov (United States)

    Williams, Leanne M; Gatt, Justine M; Hatch, Ainslie; Palmer, Donna M; Nagy, Marie; Rennie, Christopher; Cooper, Nicholas J; Morris, Charlotte; Grieve, Stuart; Dobson-Stone, Carol; Schofield, Peter; Clark, C Richard; Gordon, Evian; Arns, Martijn; Paul, Robert H

    2008-09-01

    This study was undertaken using the INTEGRATE Model of brain organization, which is based on a temporal continuum of emotion, thinking and self regulation. In this model, the key organizing principle of self adaption is the motivation to minimize danger and maximize reward. This principle drives brain organization across a temporal continuum spanning milliseconds to seconds, minutes and hours. The INTEGRATE Model comprises three distinct processes across this continuum. Emotion is defined by automatic action tendencies triggered by signals that are significant due to their relevance to minimizing danger-maximizing reward (such as abrupt, high contrast stimuli). Thinking represents cognitive functions and feelings that rely on brain and body feedback emerging from around 200 ms post-stimulus onwards. Self regulation is the modulation of emotion, thinking and feeling over time, according to more abstract adaptions to minimize danger-maximize reward. Here, we examined the impact of dispositional factors, age and genetic variation, on this temporal continuum. Brain Resource methodology provided a standardized platform for acquiring genetic, brain and behavioral data in the same 1000 healthy subjects. Results showed a "paradox" of declining function in the "thinking" time scale over the lifespan (6 to 80+ years), but a corresponding preservation or even increase in automatic functions of "emotion" and "self regulation". This paradox was paralleled by a greater loss of grey matter in cortical association areas (assessed using MRI) over age, but a relative preservation of subcortical grey matter. Genetic polymorphisms associated with both healthy function and susceptibility to disorder (including the BDNFVal(66)Met, COMTVal(158/108)Met, MAOA and DRD4 tandem repeat and 5HTT-LPR polymorphisms) made specific contributions to emotion, thinking and self regulatory functions, which also varied according to age.

  19. Experimental Population Genetics in the Introductory Genetics Laboratory Using "Drosophila" as a Model Organism

    Science.gov (United States)

    Johnson, Ronald; Kennon, Tillman

    2009-01-01

    Hypotheses of population genetics are derived and tested by students in the introductory genetics laboratory classroom as they explore the effects of biotic variables (physical traits of fruit flies) and abiotic variables (island size and distance) on fruit fly populations. In addition to this hypothesis-driven experiment, the development of…

  20. Experimental Population Genetics in the Introductory Genetics Laboratory Using "Drosophila" as a Model Organism

    Science.gov (United States)

    Johnson, Ronald; Kennon, Tillman

    2009-01-01

    Hypotheses of population genetics are derived and tested by students in the introductory genetics laboratory classroom as they explore the effects of biotic variables (physical traits of fruit flies) and abiotic variables (island size and distance) on fruit fly populations. In addition to this hypothesis-driven experiment, the development of…

  1. Genetic models for the study of luteinizing hormone receptor function

    Directory of Open Access Journals (Sweden)

    Prema eNarayan

    2015-09-01

    Full Text Available The luteinizing hormone/chorionic gonadotropin receptor, LHCGR, is essential for fertility in men and women. LHCGR binds luteinizing hormone (LH as well as the highly homologous chorionic gonadotropin (CG. Signaling from LHCGR is required for steroidogenesis and gametogenesis in males and females and for sexual differentiation in the male. The importance of LHCGR in reproductive physiology is underscored by the large number of naturally occurring inactivating and activating mutations in the receptor that result in reproductive disorders. Consequently, several genetically modified mouse models have been developed for the study of LHCGR function. They include targeted deletion of LH and LHCGR that mimic inactivating mutations in hormone and receptor, expression of a constitutively active mutant in LHCGR that mimics activating mutations associated with familial male-limited precocious puberty and transgenic models of LH and hCG overexpression. This review summarizes the salient findings from these models and their utility in understanding the physiological and pathological consequences of loss and gain of function in LHCGR signaling.

  2. Cis-Antisense Transcription Gives Rise to Tunable Genetic Switch Behavior: A Mathematical Modeling Approach.

    Science.gov (United States)

    Bordoy, Antoni E; Chatterjee, Anushree

    2015-01-01

    Antisense transcription has been extensively recognized as a regulatory mechanism for gene expression across all kingdoms of life. Despite the broad importance and extensive experimental determination of cis-antisense transcription, relatively little is known about its role in controlling cellular switching responses. Growing evidence suggests the presence of non-coding cis-antisense RNAs that regulate gene expression via antisense interaction. Recent studies also indicate the role of transcriptional interference in regulating expression of neighboring genes due to traffic of RNA polymerases from adjacent promoter regions. Previous models investigate these mechanisms independently, however, little is understood about how cells utilize coupling of these mechanisms in advantageous ways that could also be used to design novel synthetic genetic devices. Here, we present a mathematical modeling framework for antisense transcription that combines the effects of both transcriptional interference and cis-antisense regulation. We demonstrate the tunability of transcriptional interference through various parameters, and that coupling of transcriptional interference with cis-antisense RNA interaction gives rise to hypersensitive switches in expression of both antisense genes. When implementing additional positive and negative feed-back loops from proteins encoded by these genes, the system response acquires a bistable behavior. Our model shows that combining these multiple-levels of regulation allows fine-tuning of system parameters to give rise to a highly tunable output, ranging from a simple-first order response to biologically complex higher-order response such as tunable bistable switch. We identify important parameters affecting the cellular switch response in order to provide the design principles for tunable gene expression using antisense transcription. This presents an important insight into functional role of antisense transcription and its importance towards

  3. Models for financing the regulation of pharmaceutical promotion.

    Science.gov (United States)

    Lexchin, Joel

    2012-07-11

    Pharmaceutical companies spend huge sums promoting their products whereas regulation of promotional activities is typically underfinanced. Any option for financing the monitoring and regulation of promotion should adhere to three basic principles: stability, predictability and lack of (perverse) ties between the level of financing and performance. This paper explores the strengths and weaknesses of six different models. All these six models considered here have positive and negative features and none may necessarily be ideal in any particular country. Different countries may choose to utilize a combination of two or more of these models in order to raise sufficient revenue. Financing of regulation of drug promotion should more than pay for itself through the prevention of unnecessary drug costs and the avoidance of adverse health effects due to inappropriate prescribing. However, it involves an initial outlay of money that is currently not being spent and many national governments, in both rich and poor countries, are unwilling to incur extra costs.

  4. Models for financing the regulation of pharmaceutical promotion

    Directory of Open Access Journals (Sweden)

    Lexchin Joel

    2012-07-01

    Full Text Available Abstract Pharmaceutical companies spend huge sums promoting their products whereas regulation of promotional activities is typically underfinanced. Any option for financing the monitoring and regulation of promotion should adhere to three basic principles: stability, predictability and lack of (perverse ties between the level of financing and performance. This paper explores the strengths and weaknesses of six different models. All these six models considered here have positive and negative features and none may necessarily be ideal in any particular country. Different countries may choose to utilize a combination of two or more of these models in order to raise sufficient revenue. Financing of regulation of drug promotion should more than pay for itself through the prevention of unnecessary drug costs and the avoidance of adverse health effects due to inappropriate prescribing. However, it involves an initial outlay of money that is currently not being spent and many national governments, in both rich and poor countries, are unwilling to incur extra costs.

  5. [Expansive development of the French regulation of the genetic print files after the recent reforms (Part I)].

    Science.gov (United States)

    Etxeberria Guridi, José Francisco

    2003-01-01

    French regulations related to "genetic prints" and its later incorporation to an automatized file in the frame of the penal process, initially deserved (1998) a positive judgement due to the guarantees surrounding such techniques, considering that with its use an interference was made with the freedom and rights of the individual. This primary regulation is watching a legislative evolution that brings serious doubts about the current guarantee system. A couple of legal reforms with security as their main axis (2001 and 2003) give more importance to the "genetic print" file by extending the causes in which it starts functioning going against the proportionality that must be observed when freedoms and rights of the individual can be affected.

  6. On the underlying assumptions of threshold Boolean networks as a model for genetic regulatory network behavior

    Science.gov (United States)

    Tran, Van; McCall, Matthew N.; McMurray, Helene R.; Almudevar, Anthony

    2013-01-01

    Boolean networks (BoN) are relatively simple and interpretable models of gene regulatory networks. Specifying these models with fewer parameters while retaining their ability to describe complex regulatory relationships is an ongoing methodological challenge. Additionally, extending these models to incorporate variable gene decay rates, asynchronous gene response, and synergistic regulation while maintaining their Markovian nature increases the applicability of these models to genetic regulatory networks (GRN). We explore a previously-proposed class of BoNs characterized by linear threshold functions, which we refer to as threshold Boolean networks (TBN). Compared to traditional BoNs with unconstrained transition functions, these models require far fewer parameters and offer a more direct interpretation. However, the functional form of a TBN does result in a reduction in the regulatory relationships which can be modeled. We show that TBNs can be readily extended to permit self-degradation, with explicitly modeled degradation rates. We note that the introduction of variable degradation compromises the Markovian property fundamental to BoN models but show that a simple state augmentation procedure restores their Markovian nature. Next, we study the effect of assumptions regarding self-degradation on the set of possible steady states. Our findings are captured in two theorems relating self-degradation and regulatory feedback to the steady state behavior of a TBN. Finally, we explore assumptions of synchronous gene response and asynergistic regulation and show that TBNs can be easily extended to relax these assumptions. Applying our methods to the budding yeast cell-cycle network revealed that although the network is complex, its steady state is simplified by the presence of self-degradation and lack of purely positive regulatory cycles. PMID:24376454

  7. On the underlying assumptions of threshold Boolean networks as a model for genetic regulatory network behavior

    Directory of Open Access Journals (Sweden)

    Van eTran

    2013-12-01

    Full Text Available Boolean networks (BoN are relatively simple and interpretable models of gene regulatorynetworks. Specifying these models with fewer parameters while retaining their ability to describe complex regulatory relationships is an ongoing methodological challenge. Additionally, extending these models to incorporate variable gene decay rates, asynchronous gene response, and synergistic regulation while maintaining their Markovian nature increases the applicability of these models to genetic regulatory networks.We explore a previously-proposed class of BoNs characterized by linear threshold functions, which we refer to as threshold Boolean networks (TBN. Compared to traditional BoNs with unconstrained transition functions, these models require far fewer parameters and offer a more direct interpretation. However, the functional form of a TBN does result in a reduction in the regulatory relationships which can be modeled.We show that TBNs can be readily extended to permit self-degradation, with explicitly modeled degradation rates. We note that the introduction of variable degradation compromises the Markovian property fundamental to BoN models but show that a simple state augmentation procedure restores their Markovian nature. Next, we study the effect of assumptions regarding self-degradation on the set of possible steady states. Our findings are captured in two theorems relating self-degradation and regulatory feedback to the steady state behavior of a TBN. Finally, we explore assumptions of synchronous gene response and asynergistic regulation and show that TBNs can be easily extended to relax these assumptions.Applying our methods to the budding yeast cell-cycle network revealed that although the network is complex, its steady state is simplified by the presence of self-degradation and lack of purely positive regulatory cycles.

  8. Impaired activity-dependent neural circuit assembly and refinement in autism spectrum disorder genetic models

    Directory of Open Access Journals (Sweden)

    Caleb Andrew Doll

    2014-02-01

    Full Text Available Early-use activity during circuit-specific critical periods refines brain circuitry by the coupled processes of eliminating inappropriate synapses and strengthening maintained synapses. We theorize these activity-dependent developmental processes are specifically impaired in autism spectrum disorders (ASDs. ASD genetic models in both mouse and Drosophila have pioneered our insights into normal activity-dependent neural circuit assembly and consolidation, and how these developmental mechanisms go awry in specific genetic conditions. The monogenic Fragile X syndrome (FXS, a common cause of heritable ASD and intellectual disability, has been particularly well linked to defects in activity-dependent critical period processes. The Fragile X Mental Retardation Protein (FMRP is positively activity-regulated in expression and function, in turn regulates excitability and activity in a negative feedback loop, and appears to be required for the activity-dependent remodeling of synaptic connectivity during early-use critical periods. The Drosophila FXS model has been shown to functionally conserve the roles of human FMRP in synaptogenesis, and has been centrally important in generating our current mechanistic understanding of the FXS disease state. Recent advances in Drosophila optogenetics, transgenic calcium reporters, highly-targeted transgenic drivers for individually-identified neurons, and a vastly improved connectome of the brain are now being combined to provide unparalleled opportunities to both manipulate and monitor activity-dependent processes during critical period brain development in defined neural circuits. The field is now poised to exploit this new Drosophila transgenic toolbox for the systematic dissection of activity-dependent mechanisms in normal versus ASD brain development, particularly utilizing the well-established Drosophila FXS disease model.

  9. The Self-Regulated Learning Model and Music Education

    Directory of Open Access Journals (Sweden)

    Maja Marijan

    2017-02-01

    Full Text Available Self-regulation and self-regulated learning (SRL are important features in music education. In this research self-regulated learning model is presented as a complex, multidimensional structure. SRL starts with the self-regulation. Self-regulation is formed through interaction with the environment, thus self-learning, self-analysis, self-judgment, self-instruction, and self-monitoring are the main functions in self-regulatory structure. Co-regulation is needed, and helps self-regulation to be activated and monitored. In music education, co-regulation refers to the instructions that teacher introduces in the lessons. These instructions have to enhance learning and develop regulation over emotions, cognitive, auditor, and motor skills in students. Learning techniques and learning strategies are core components in music education. Adapting those, students become aware of their learning processes, actions, thoughts, feelings and behaviors that are involved in learning. It is suggested that every teaching methodology has to develop learning techniques, as well as metamemory and metacognition in students, in order to gain expertise. The author has emphasized her attention to every aspect that is believed to belong to SRL. There are not many articles on the SRL in music education, written by musicians, in compare with those written by psychologists and neurologists,. Therefore, the author has suggested that this paper would encourage music teachers and performers to take an advantage in the research of SRL. These researches would help music educational systems and teachers to develop and promote learning techniques and strategies. The results would show improvement in student’s learning and self-regulation.

  10. Smooth-Threshold Multivariate Genetic Prediction with Unbiased Model Selection.

    Science.gov (United States)

    Ueki, Masao; Tamiya, Gen

    2016-04-01

    We develop a new genetic prediction method, smooth-threshold multivariate genetic prediction, using single nucleotide polymorphisms (SNPs) data in genome-wide association studies (GWASs). Our method consists of two stages. At the first stage, unlike the usual discontinuous SNP screening as used in the gene score method, our method continuously screens SNPs based on the output from standard univariate analysis for marginal association of each SNP. At the second stage, the predictive model is built by a generalized ridge regression simultaneously using the screened SNPs with SNP weight determined by the strength of marginal association. Continuous SNP screening by the smooth thresholding not only makes prediction stable but also leads to a closed form expression of generalized degrees of freedom (GDF). The GDF leads to the Stein's unbiased risk estimation (SURE), which enables data-dependent choice of optimal SNP screening cutoff without using cross-validation. Our method is very rapid because computationally expensive genome-wide scan is required only once in contrast to the penalized regression methods including lasso and elastic net. Simulation studies that mimic real GWAS data with quantitative and binary traits demonstrate that the proposed method outperforms the gene score method and genomic best linear unbiased prediction (GBLUP), and also shows comparable or sometimes improved performance with the lasso and elastic net being known to have good predictive ability but with heavy computational cost. Application to whole-genome sequencing (WGS) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) exhibits that the proposed method shows higher predictive power than the gene score and GBLUP methods.

  11. Toward a genetically-informed model of borderline personality disorder.

    Science.gov (United States)

    Livesley, John

    2008-02-01

    This article describes a conceptual framework for describing borderline personality disorder (BPD) based on empirical studies of the phenotypic structure and genetic architecture of personality. The proposed phenotype has 2 components: (1) a description of core self and interpersonal pathology-the defining features of personality disorder-as these features are expressed in the disorder; and (2) a set of traits based on the anxious-dependent or emotional dysregulation factor of the four-factor model of PD. Four kinds of traits are described: emotional (anxiousness, emotional reactivity, emotional intensity, and pessimistic-anhedonia), interpersonal (submissiveness, insecure attachment, social apprehensiveness, and need for approval), cognitive (cognitive dysregulation), and self-harm (behaviors and ideas). Formulation of the phenotype was guided by the conceptualization of personality as a system of interrelated sub-systems. The psychopathology associated with BPD involves most components of the system. The trait structure of the disorder is assumed to reflect the genetic architecture of personality and individual traits are assumed to be based on adaptive mechanisms. It is suggested that borderline traits are organized around the trait of anxiousness and that an important feature of BPD is dysregulation of the threat management system leading to pervasive fearfulness and unstable emotions. The interpersonal traits are assumed to be heritable characteristics that evolved to deal with interpersonal threats that arose as a result of social living. The potential for unstable and conflicted interpersonal relationships that is inherent to the disorder is assumed to result from the interplay between the adaptive structure of personality and psychosocial adversity. The etiology of the disorder is discussed in terms of biological and environmental factors associated with each component of the phenotype.

  12. Genetic versus Non-Genetic Regulation of miR-103, miR-143 and miR-483-3p Expression in Adipose Tissue and Their Metabolic Implications—A Twin Study

    Directory of Open Access Journals (Sweden)

    Jette Bork-Jensen

    2014-07-01

    Full Text Available Murine models suggest that the microRNAs miR-103 and miR-143 may play central roles in the regulation of subcutaneous adipose tissue (SAT and development of type 2 diabetes (T2D. The microRNA miR-483-3p may reduce adipose tissue expandability and cause ectopic lipid accumulation, insulin resistance and T2D. We aimed to explore the genetic and non-genetic factors that regulate these microRNAs in human SAT, and to investigate their impact on metabolism in humans. Levels of miR-103, miR-143 and miR-483-3p were measured in SAT biopsies from 244 elderly monozygotic and dizygotic twins using real-time PCR. Heritability estimates were calculated and multiple regression analyses were performed to study associations between these microRNAs and measures of metabolism, as well as between these microRNAs and possible regulating factors. We found that increased BMI was associated with increased miR-103 expression levels. In addition, the miR-103 levels were positively associated with 2 h plasma glucose levels and hemoglobin A1c independently of BMI. Heritability estimates for all three microRNAs were low. In conclusion, the expression levels of miR-103, miR-143 and miR-483-3p in adipose tissue are primarily influenced by non-genetic factors, and miR-103 may be involved in the development of adiposity and control of glucose metabolism in humans.

  13. Molecular genetics and animal models in autistic disorder.

    Science.gov (United States)

    Andres, Christian

    2002-01-01

    Autistic disorder is a behavioural syndrome beginning before the age of 3 years and lasting over the whole lifetime. It is characterised by impaired communication, impaired social interactions, and repetitive interests and behaviour. The prevalence is about 7/10,000 taking a restrictive definition and more than 1/500 with a broader definition, including all the pervasive developmental disorders. The importance of genetic factors has been highlighted by epidemiological studies showing that autistic disorder is one of the most genetic neuropsychiatric diseases. The relative risk of first relatives is about 100-fold higher than the risk in the normal population and the concordance in monozygotic twin is about 60%. Different strategies have been applied on the track of susceptibility genes. The systematic search of linked loci led to contradictory results, in part due to the heterogeneity of the clinical definitions, to the differences in the DNA markers, and to the different methods of analysis used. An oversimplification of the inferred model is probably also cause of our disappointment. More work is necessary to give a clearer picture. One region emerges more frequently: the long arm of chromosome 7. Several candidate genes have been studied and some gave indications of association: the Reelin gene and the Wnt2 gene. Cytogenetical abnormalities are frequent at 15q11-13, the region of the Angelman and Prader-Willi syndrome. Imprinting plays an important role in this region, no candidate gene has been identified in autism. Biochemical abnormalities have been found in the serotonin system. Association and linkage studies gave no consistent results with some serotonin receptors and in the transporter, although it seems interesting to go further in the biochemical characterisation of the serotonin transporter activity, particularly in platelets, easily accessible. Two monogenic diseases have been associated with autistic disorder: tuberous sclerosis and fragile X. A

  14. Drosophila as a genetic and cellular model for studies on axonal growth

    Directory of Open Access Journals (Sweden)

    Whitington Paul

    2007-05-01

    Full Text Available Abstract One of the most fascinating processes during nervous system development is the establishment of stereotypic neuronal networks. An essential step in this process is the outgrowth and precise navigation (pathfinding of axons and dendrites towards their synaptic partner cells. This phenomenon was first described more than a century ago and, over the past decades, increasing insights have been gained into the cellular and molecular mechanisms regulating neuronal growth and navigation. Progress in this area has been greatly assisted by the use of simple and genetically tractable invertebrate model systems, such as the fruit fly Drosophila melanogaster. This review is dedicated to Drosophila as a genetic and cellular model to study axonal growth and demonstrates how it can and has been used for this research. We describe the various cellular systems of Drosophila used for such studies, insights into axonal growth cones and their cytoskeletal dynamics, and summarise identified molecular signalling pathways required for growth cone navigation, with particular focus on pathfinding decisions in the ventral nerve cord of Drosophila embryos. These Drosophila-specific aspects are viewed in the general context of our current knowledge about neuronal growth.

  15. The Self-Made Puzzle: Integrating Self-Assembly and Pattern Formation Under Non-Random Genetic Regulation

    Science.gov (United States)

    Doursat, René

    On the one hand, research in self-assembling systems, whether natural or artificial, has traditionally focused on pre-existing components endowed with fixed shapes. Biological development, by contrast, dynamically creates new cells that acquire selective adhesion properties through differentiation induced by their neighborhood. On the other hand, pattern formation phenomena are generally construed as orderly states of activity on top of a continuous 2-D or 3-D substrate. Yet, again, the spontaneous patterning of an organism into domains of gene expression arises within a multicellular medium in perpetual expansion and reshaping. Finally, both phenomena are often thought in terms of stochastic events, whether mixed components that randomly collide in self-assembly, or spots and stripes that occur unpredictably from instabilities in pattern formation. Here too, these notions need significant revision if they are to be extended and applied to embryogenesis. Cells are not randomly mixed but pre-positioned where cell division occurs. Genetic identity domains are not randomly distributed but highly regulated in number and position. In this work, I present a computational model of program-mable and reproducible artificial morphogenesis that integrates self-assembly and pattern formation under the control of a nonrandom gene regulatory network. The specialized properties of cells (division, adhesion, migration) are determined by the gene expression domains to which they belong, while at the same time these domains further expand and segment into subdomains due to the self-assembly of specialized cells. Through this model, I also promote a new discipline, embryomorphic engineering to solve the paradox of "meta-designing" decentralized, autonomous systems.

  16. Lessons from the 'Humanitarian Golden Rice' project: regulation prevents development of public good genetically engineered crop products.

    Science.gov (United States)

    Potrykus, Ingo

    2010-11-30

    Compared to a non-Genetically Engineered (GE) variety, the deployment of Golden Rice has suffered from a delay of at least ten years. The cause of this delay is exclusively GE-regulation. Considering the potential impact of Golden Rice on the reduction in vitamin A-malnutrition, this delay is responsible for an unjustifiable loss of millions of lives, mostly children and women. GE-regulation is also responsible for the fact that no public institution can deliver a public good GE-product and that thus we have a de facto monopoly in favour of a few potent industries. Considering the forgone benefits from prevented public good GE-products, GE-regulation is responsible for hundreds of millions of lives, all of them, of course, in developing countries. As there is no scientific justification for present GE-regulation, and as it has, so far, not prevented any harm, our society has the urgent responsibility to reconsider present regulation, which is based on an extreme interpretation of the precautionary principle, and change it to science-based regulation on the basis of traits instead of technology. GE-technology has an unprecedented safety record and is far more precise and predictable than any other 'traditional' and unregulated breeding technology. Not to change GE-regulation to a scientific basis is considered by the author 'a crime against humanity'. Copyright © 2010 Elsevier B.V. All rights reserved.

  17. Identification of Hammerstein Model Based on Quantum Genetic Algorithm

    Directory of Open Access Journals (Sweden)

    Zhang Hai Li

    2013-07-01

    Full Text Available Nonlinear system identification is a main topic of modern identification. A new method for nonlinear system identification is presented by using Quantum Genetic Algorithm(QGA.The problems of nonlinear system identification are cast as function optimization overprameter space,and the Quantum Genetic Algorithm is adopted to solve the optimization problem. Simulation experiments show that: compared with the genetic algorithm, quantum genetic algorithm is an effective swarm intelligence algorithm, its salient features of the algorithm parameters, small population size, and the use of Quantum gate update populations, greatly improving the recognition in the optimization of speed and accuracy. Simulation results show the effectiveness of the proposed method.

  18. Applications of Systems Genetics and Biology for Obesity Using Pig Models

    DEFF Research Database (Denmark)

    Kogelman, Lisette J. A.; Kadarmideen, Haja N.

    2016-01-01

    In many biomedical research areas, animals have been used as a model to increase the understanding of molecular mechanisms involved in human diseases. One of those areas is human obesity, where porcine models are increasingly used. The pig shows genetic and physiological features that are very...... similar to humans and have shown to be an excellent model for human obesity. Using pig populations, many genetic studies have been performed to unravel the genetic architecture of human obesity. Most of them are pinpointing toward single genes, but more and more studies focus on a systems genetics...... approach, a branch of systems biology. In this chapter, we will describe the state of the art of genetic studies on human obesity, using pig populations. We will describe the features of using the pig as a model for human obesity and briefly discuss the genetics of obesity, and we will focus on systems...

  19. Hierarchical linear modeling of longitudinal pedigree data for genetic association analysis.

    Science.gov (United States)

    Tan, Qihua; B Hjelmborg, Jacob V; Thomassen, Mads; Jensen, Andreas Kryger; Christiansen, Lene; Christensen, Kaare; Zhao, Jing Hua; Kruse, Torben A

    2014-01-01

    Genetic association analysis on complex phenotypes under a longitudinal design involving pedigrees encounters the problem of correlation within pedigrees, which could affect statistical assessment of the genetic effects. Approaches have been proposed to integrate kinship correlation into the mixed-effect models to explicitly model the genetic relationship. These have proved to be an efficient way of dealing with sample clustering in pedigree data. Although current algorithms implemented in popular statistical packages are useful for adjusting relatedness in the mixed modeling of genetic effects on the mean level of a phenotype, they are not sufficiently straightforward to handle the kinship correlation on the time-dependent trajectories of a phenotype. We introduce a 2-level hierarchical linear model to separately assess the genetic associations with the mean level and the rate of change of a phenotype, integrating kinship correlation in the analysis. We apply our method to the Genetic Analysis Workshop 18 genome-wide association studies data on chromosome 3 to estimate the genetic effects on systolic blood pressure measured over time in large pedigrees. Our method identifies genetic variants associated with blood pressure with estimated inflation factors of 0.99, suggesting that our modeling of random effects efficiently handles the genetic relatedness in pedigrees. Application to simulated data captures important variants specified in the simulation. Our results show that the method is useful for genetic association studies in related samples using longitudinal design.

  20. Form Follows Function: A Model for Clinical Supervision of Genetic Counseling Students.

    Science.gov (United States)

    Wherley, Colleen; Veach, Patricia McCarthy; Martyr, Meredith A; LeRoy, Bonnie S

    2015-10-01

    Supervision plays a vital role in genetic counselor training, yet models describing genetic counseling supervision processes and outcomes are lacking. This paper describes a proposed supervision model intended to provide a framework to promote comprehensive and consistent clinical supervision training for genetic counseling students. Based on the principle "form follows function," the model reflects and reinforces McCarthy Veach et al.'s empirically derived model of genetic counseling practice - the "Reciprocal Engagement Model" (REM). The REM consists of mutually interactive educational, relational, and psychosocial components. The Reciprocal Engagement Model of Supervision (REM-S) has similar components and corresponding tenets, goals, and outcomes. The 5 REM-S tenets are: Learning and applying genetic information are key; Relationship is integral to genetic counseling supervision; Student autonomy must be supported; Students are capable; and Student emotions matter. The REM-S outcomes are: Student understands and applies information to independently provide effective services, develop professionally, and engage in self-reflective practice. The 16 REM-S goals are informed by the REM of genetic counseling practice and supported by prior literature. A review of models in medicine and psychology confirms the REM-S contains supervision elements common in healthcare fields, while remaining unique to genetic counseling. The REM-S shows promise for enhancing genetic counselor supervision training and practice and for promoting research on clinical supervision. The REM-S is presented in detail along with specific examples and training and research suggestions.

  1. Cyclooxygenase 2: understanding the pathophysiological role through genetically altered mouse models.

    Science.gov (United States)

    Martín Sanz, Paloma; Hortelano, Sonsoles; Bosca, Lisardo; Casado, Marta

    2006-09-01

    Cyclooxygenase (COX) -1 and -2 catalyze the first step in the biosynthesis of prostanoids. COX-1 is constitutively expressed in many tissues and seems to be involved in the housekeeping function of prostanoids. COX-2, the inducible isoform, accounts for the elevated production of prostaglandins in response to various inflammatory stimuli, hormones and growth factors. COX-2 expression has been also associated with cell growth regulation, tissue remodelling and carcinogenesis. More of these characteristics have been elucidate through using COX selective inhibitors. Recent advances in transgenic and gene-targeting approaches allow a sophisticated manipulation of the mouse genome by gene addition, gene deletion or gene modifications. The development of COX-2 genetically altered mice has provided models to elucidate the physiological and pathophysiological roles of this enzyme.

  2. Advances and challenges in logical modeling of cell cycle regulation: perspective for multi-scale, integrative yeast cell models.

    Science.gov (United States)

    Barberis, Matteo; Todd, Robert G; van der Zee, Lucas

    2017-01-01

    The eukaryotic cell cycle is robustly designed, with interacting molecules organized within a definite topology that ensures temporal precision of its phase transitions. Its underlying dynamics are regulated by molecular switches, for which remarkable insights have been provided by genetic and molecular biology efforts. In a number of cases, this information has been made predictive, through computational models. These models have allowed for the identification of novel molecular mechanisms, later validated experimentally. Logical modeling represents one of the youngest approaches to address cell cycle regulation. We summarize the advances that this type of modeling has achieved to reproduce and predict cell cycle dynamics. Furthermore, we present the challenge that this type of modeling is now ready to tackle: its integration with intracellular networks, and its formalisms, to understand crosstalks underlying systems level properties, ultimate aim of multi-scale models. Specifically, we discuss and illustrate how such an integration may be realized, by integrating a minimal logical model of the cell cycle with a metabolic network.

  3. Thermodynamics-based models of transcriptional regulation with gene sequence.

    Science.gov (United States)

    Wang, Shuqiang; Shen, Yanyan; Hu, Jinxing

    2015-12-01

    Quantitative models of gene regulatory activity have the potential to improve our mechanistic understanding of transcriptional regulation. However, the few models available today have been based on simplistic assumptions about the sequences being modeled or heuristic approximations of the underlying regulatory mechanisms. In this work, we have developed a thermodynamics-based model to predict gene expression driven by any DNA sequence. The proposed model relies on a continuous time, differential equation description of transcriptional dynamics. The sequence features of the promoter are exploited to derive the binding affinity which is derived based on statistical molecular thermodynamics. Experimental results show that the proposed model can effectively identify the activity levels of transcription factors and the regulatory parameters. Comparing with the previous models, the proposed model can reveal more biological sense.

  4. MODELING OF NAPHTHA PYROLYSIS WITH USING GENETIC ALGORITM

    Directory of Open Access Journals (Sweden)

    V. K. Bityukov

    2015-01-01

    Full Text Available Summary. In operation of industrial pyrolysis furnaces, the main task is the selection of the optimal mode of thermal decomposition of the feedstock, depending on the yield of the desired products under conditions of technological limitations on the process. To solve this problem for an operating reactor, this paper considers the SRT-VI Large-Capacity industrial Furnace , the mathematical model of the pyrolysis process was constructed, using a kinetic scheme which consists of primary reaction of decomposition of raw materials and secondary elementary reactions of interaction of the considered mixture components, the heat balance equation and hydrodynamics of flow in the coil. The raw material for the selected installation type is naphtha (straight-run petrol. Output parameters of the model are the molar costs of marketable hydrocarbons. The reactor is described by the equation of ideal displacement in the static mode of operation. It is assumed that all reactions have a temperature dependence that follows the Arrhenius law. The activation energies of chemical processes were estimated using the PolanyiSemenov equation and identification of pre-exponential factors was carried out using a genetic algorithm (GA. This task requires solving simultaneous system of differential equations describing the pyrolysis process and a search for a large number of unknown parameters, and therefore it is proposed to modify the GA. Optimal scheme includes Gray encoding arithmetic operators, tournament selection, with tournament ranking more than 4, crossover with partial random choice of alleys, mutations with a high probability of occurring and elitism with competitive global competition. Using the proposed approach, the parametric identification of model process is accomplished. The analysis of the simulation results with the data of operating reactor showed its suitability for use in order to control the pyrolysis process.

  5. PTEN Gene: A Model for Genetic Diseases in Dermatology

    Directory of Open Access Journals (Sweden)

    Corrado Romano

    2012-01-01

    Full Text Available PTEN gene is considered one of the most mutated tumor suppressor genes in human cancer, and it’s likely to become the first one in the near future. Since 1997, its involvement in tumor suppression has smoothly increased, up to the current importance. Germline mutations of PTEN cause the PTEN hamartoma tumor syndrome (PHTS, which include the past-called Cowden, Bannayan-Riley-Ruvalcaba, Proteus, Proteus-like, and Lhermitte-Duclos syndromes. Somatic mutations of PTEN have been observed in glioblastoma, prostate cancer, and brest cancer cell lines, quoting only the first tissues where the involvement has been proven. The negative regulation of cell interactions with the extracellular matrix could be the way PTEN phosphatase acts as a tumor suppressor. PTEN gene plays an essential role in human development. A recent model sees PTEN function as a stepwise gradation, which can be impaired not only by heterozygous mutations and homozygous losses, but also by other molecular mechanisms, such as transcriptional regression, epigenetic silencing, regulation by microRNAs, posttranslational modification, and aberrant localization. The involvement of PTEN function in melanoma and multistage skin carcinogenesis, with its implication in cancer treatment, and the role of front office in diagnosing PHTS are the main reasons why the dermatologist should know about PTEN.

  6. A Model of the Economic Theory of Regulation for Undergraduates.

    Science.gov (United States)

    Wilson, Brooks

    1995-01-01

    Presents a model of the economic theory of regulation and recommends its use in undergraduate economics classes. Describes the use of computer-assisted instruction to teach the theory. Maintains that the approach enables students to gain access to graphs and tables that they produce themselves. (CFR)

  7. STREAM: Static Thermodynamic REgulAtory Model of transcription.

    Science.gov (United States)

    Bauer, Denis C; Bailey, Timothy L

    2008-11-01

    Understanding the transcriptional regulation of a gene in detail is a crucial step towards uncovering and ultimately utilizing the regulatory grammar of the genome. Modeling transcriptional regulation using thermodynamic equations has become an increasingly important approach towards this goal. Here, we present stream, the first publicly available framework for modeling, visualizing and predicting the regulation of the transcription rate of a target gene. Given the concentrations of a set of transcription factors (TFs), the TF binding sites (TFBSs) in a regulatory DNA region, and the transcription rate of the target gene, stream will optimize its parameters to generate a model that best fits the input data. This trained model can then be used to (a) validate that the given set of TFs is able to regulate the target gene and (b) to predict the transcription rate under different conditions (e.g. different tissues, knockout/additional TFs or mutated/missing TFBSs). The platform independent executable of stream, as well as a tutorial and the full documentation, are available at http://bioinformatics.org.au/stream/. stream requires Java version 5 or higher.

  8. A genetic approach for investigating vagal sensory roles in regulation of gastrointestinal function and food intake.

    Science.gov (United States)

    Fox, Edward Alan

    2006-06-30

    Sensory innervation of the gastrointestinal (GI) tract by the vagus nerve plays important roles in regulation of GI function and feeding behavior. This innervation is composed of a large number of sensory pathways, each arising from a different population of sensory receptors. Progress in understanding the functions of these pathways has been impeded by their close association with vagal efferent, sympathetic, and enteric systems, which makes it difficult to selectively label or manipulate them. We suggest that a genetic approach may overcome these barriers. To illustrate the potential value of this strategy, as well as to gain insights into its application, investigations of CNS pathways and peripheral tissues involved in energy balance that benefited from the use of gene manipulations are reviewed. Next, our studies examining the feasibility of using mutations of developmental genes for manipulating individual vagal afferent pathways are reviewed. These experiments characterized mechanoreceptor morphology, density and distribution, and feeding patterns in four viable mutant mouse strains. In each strain a single population of vagal mechanoreceptors innervating the muscle wall of the GI tract was altered, and was associated with selective effects on feeding patterns, thus supporting the feasibility of this strategy. However, two limitations of this approach must be addressed for it to achieve its full potential. First, mutation effects in tissues outside the GI tract can contribute to changes in GI function or feeding. Additionally, knockouts of developmental genes are often lethal, preventing analysis of mature innervation and ingestive behavior. To address these issues, we propose to develop conditional gene knockouts restricted to specific GI tract tissues. Two genes of interest are brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), which are essential for vagal afferent development. Creating conditional knockouts of these genes requires

  9. Genetic regulation of phenazine-1-carboxamide synthesis by Pseudomonas chlororaphis strain PCL1391

    NARCIS (Netherlands)

    Girard, Genevieve

    2006-01-01

    A general overview of regulation of secondary metabolism in Pseudomonas species is given in Chapter 1. Several approaches were combined to identify novel genes involved in the regulation of PCN synthesis and to study their interactions with other regulators. Site-directed mutagenesis was used to tes

  10. Genetically engineered mucin mouse models for inflammation and cancer

    Science.gov (United States)

    Joshi, Suhasini; Kumar, Sushil; Bafna, Sangeeta; Rachagani, Satyanarayana; Wagner, Kay-Uwe; Jain, Maneesh

    2015-01-01

    Mucins are heavily O-glycosylated proteins primarily produced by glandular and ductal epithelial cells, either in membrane-tethered or secretory forms, for providing lubrication and protection from various exogenous and endogenous insults. However, recent studies have linked their aberrant overexpression with infection, inflammation, and cancer that underscores their importance in tissue homeostasis. In this review, we present current status of the existing mouse models that have been developed to gain insights into the functional role(s) of mucins under physiological and pathological conditions. Knockout mouse models for membrane-associated (Muc1 and Muc16) and secretory mucins (Muc2) have helped us to elucidate the role of mucins in providing effective and protective barrier functions against pathological threats, participation in disease progression, and improved our understanding of mucin interaction with biotic and abiotic environmental components. Emphasis is also given to available transgenic mouse models (MUC1 and MUC7), which has been exploited to understand the context-dependent regulation and therapeutic potential of human mucins during inflammation and cancer. PMID:25634251

  11. Modeling of genetic algorithms with a finite population

    NARCIS (Netherlands)

    Kemenade, C.H.M. van

    1997-01-01

    Cross-competition between non-overlapping building blocks can strongly influence the performance of evolutionary algorithms. The choice of the selection scheme can have a strong influence on the performance of a genetic algorithm. This paper describes a number of different genetic algorithms, all in

  12. Modeling of genetic algorithms with a finite population

    NARCIS (Netherlands)

    C.H.M. van Kemenade

    1997-01-01

    textabstractCross-competition between non-overlapping building blocks can strongly influence the performance of evolutionary algorithms. The choice of the selection scheme can have a strong influence on the performance of a genetic algorithm. This paper describes a number of different genetic

  13. The effect of genetic selection for Johne's disease resistance n dairy cattle: Results of a genetic-epidemiological model

    NARCIS (Netherlands)

    Hulzen, van K.J.E.; Koets, A.P.; Nielen, M.; Heuven, H.C.M.; Arendonk, van J.A.M.; Klinkenberg, D.

    2014-01-01

    The objective of this study was to model genetic selection for Johne’s disease resistance and to study the effect of different selection strategies on the prevalence in the dairy cattle population. In the Netherlands, a certification-and-surveillance program is in use to reduce prevalence and presen

  14. EFSA guidance on the submission of applications for authorisation of genetically modified plants under Regulation (EC No 1829/2003

    Directory of Open Access Journals (Sweden)

    European Food Safety Authority

    2013-12-01

    Full Text Available This document provides guidance to applicants for submitting an application for authorisation of genetically modified (GM plants for food and feed uses, import and processing, and/or cultivation in the European Union under Regulation (EC No 1829/2003. The EFSA submission guidance describes the community procedures in the European Union for handling GM plant applications, and provides instructions to applicants on how to prepare and present data in an application. It is supplemented with seven appendices providing templates of data presentation to be followed by applicants, including a completeness checklist. The earlier versions are now updated to account for requirements outlined in Implementing Regulation (EU No 503/2013. Instructions for submission described in this EFSA guidance are applicable to all GM plant applications submitted under Articles 5, 11, 17 and 23 of Regulation (EC No 1829/2003.

  15. A C. elegans model of nicotine-dependent behavior: regulation by TRP-family channels.

    Science.gov (United States)

    Feng, Zhaoyang; Li, Wei; Ward, Alex; Piggott, Beverly J; Larkspur, Erin R; Sternberg, Paul W; Xu, X Z Shawn

    2006-11-03

    Nicotine, the primary addictive substance in tobacco, induces profound behavioral responses in mammals, but the underlying genetic mechanisms are not well understood. Here we develop a C. elegans model of nicotine-dependent behavior. We show that worms exhibit behavioral responses to nicotine that parallel those observed in mammals, including acute response, tolerance, withdrawal, and sensitization. These nicotine responses require nicotinic acetylcholine receptor (nAChR) family genes that are known to mediate nicotine dependence in mammals, suggesting functional conservation of nAChRs in nicotine responses. Importantly, we find that mutant worms lacking TRPC (transient receptor potential canonical) channels are defective in their response to nicotine and that such a defect can be rescued by a human TRPC channel, revealing an unexpected role for TRPC channels in regulating nicotine-dependent behavior. Thus, C. elegans can be used to characterize known genes as well as to identify new genes regulating nicotine responses.

  16. A C. elegans model of nicotine-dependent behavior: regulation by TRP family channels

    Science.gov (United States)

    Feng, Zhaoyang; Li, Wei; Ward, Alex; Piggott, Beverly J.; Larkspur, Erin R.; Sternberg, Paul W.; Shawn Xu, X. Z.

    2010-01-01

    Summary Nicotine, the primary addictive substance in tobacco, induces profound behavioral responses in mammals, but the underlying genetic mechanisms are not well understood. Here we develop a C. elegans model of nicotine-dependent behavior. We show that worms exhibit behavioral responses to nicotine that parallel those observed in mammals, including acute response, tolerance, withdrawal and sensitization. These nicotine responses require nicotinic acetylcholine receptor (nAChR) family genes that are known to mediate nicotine dependence in mammals, suggesting functional conservation of nAChRs in nicotine responses. Importantly, we find that mutant worms lacking TRPC (transient-receptor-potential canonical) channels are defective in response to nicotine and that such a defect can be rescued by a human TRPC channel, revealing an unexpected role for TRPC channels in regulating nicotine-dependent behavior. Thus, C. elegans can be used to characterize known genes as well as to identify new genes regulating nicotine responses. PMID:17081982

  17. Dissecting the role of polarity regulators in cancer through the use of mouse models.

    Science.gov (United States)

    Gödde, Nathan J; Pearson, Helen B; Smith, Lorey K; Humbert, Patrick O

    2014-11-01

    Loss of cell polarity and tissue architecture is a hallmark of aggressive epithelial cancers. In addition to serving as an initial barrier to tumorigenesis, evidence in the literature has pointed towards a highly conserved role for many polarity regulators during tumor formation and progression. Here, we review recent developments in the field that have been driven by genetically engineered mouse models that establish the tumor suppressive and context dependent oncogenic function of cell polarity regulators in vivo. These studies emphasize the complexity of the polarity network during cancer formation and progression, and reveal the need to interpret polarity protein function in a cell-type and tissue specific manner. They also highlight how aberrant polarity signaling could provide a novel route for therapeutic intervention to improve our management of malignancies in the clinic.

  18. The Integration of Cooperation Model and Genetic Algorithm

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    In the photogrammetry,some researchers have applied genetic algorithms in aerial image texture classification and reducing hyper-spectrum remote sensing data.Genetic algorithm can rapidly find the solutions which are close to the optimal solution.But it is not easy to find the optimal solution.In order to solve the problem,a cooperative evolution idea integrating genetic algorithm and ant colony algorithm is presented in this paper.On the basis of the advantages of ant colony algorithm,this paper proposes the method integrating genetic algorithms and ant colony algorithm to overcome the drawback of genetic algorithms.Moreover,the paper takes designing texture classification masks of aerial images as an example to illustrate the integration theory and procedures.

  19. Cat Mammary Tumors: Genetic Models for the Human Counterpart

    Directory of Open Access Journals (Sweden)

    Filomena Adega

    2016-08-01

    Full Text Available The records are not clear, but Man has been sheltering the cat inside his home for over 12,000 years. The close proximity of this companion animal, however, goes beyond sharing the same roof; it extends to the great similarity found at the cellular and molecular levels. Researchers have found a striking resemblance between subtypes of feline mammary tumors and their human counterparts that goes from the genes to the pathways involved in cancer initiation and progression. Spontaneous cat mammary pre-invasive intraepithelial lesions (hyperplasias and neoplasias and malignant lesions seem to share a wide repertoire of molecular features with their human counterparts. In the present review, we tried to compile all the genetics aspects published (i.e., chromosomal alterations, critical cancer genes and their expression regarding cat mammary tumors, which support the cat as a valuable alternative in vitro cell and animal model (i.e., cat mammary cell lines and the spontaneous tumors, respectively, but also to present a critical point of view of some of the issues that really need to be investigated in future research.

  20. Genetic mouse models for behavioral analysis through transgenic RNAi technology.

    Science.gov (United States)

    Delic, S; Streif, S; Deussing, J M; Weber, P; Ueffing, M; Hölter, S M; Wurst, W; Kühn, R

    2008-10-01

    Pharmacological inhibitors and knockout mice have developed into routine tools to analyze the role of specific genes in behavior. Both strategies have limitations like the availability of inhibitors for only a subset of proteins and the large efforts required to construct specific mouse mutants. The recent emergence of RNA interference (RNAi)-mediated gene silencing provides a fast alternative that can be applied to any coding gene. We established an approach for the efficient generation of transgenic knockdown mice by targeted insertion of short hairpin (sh) RNA vectors into a defined genomic locus and studied the efficiency of gene silencing in the adult brain and the utility of such mice for behavioral analysis. We generated shRNA knockdown mice for the corticotropin-releasing hormone receptor type 1 (Crhr1), the leucine-rich repeat kinase 2 (Lrkk2) and the purinergic receptor P2X ligand-gated ion channel 7 (P2rx7) genes and show the ubiquitous expression of shRNA and efficient suppression of the target mRNA and protein in the brain of young and 11-month-old knockdown mice. Knockdown mice for the Crhr1 gene exhibited decreased anxiety-related behavior, an impaired stress response, and thereby recapitulate the phenotype of CRHR1 knockout mice. Our results show the feasibility of gene silencing in the adult brain and validate knockdown mice as new genetic models suitable for behavioral analysis.

  1. Modelling Agro-Met Station Observations Using Genetic Algorithm

    Directory of Open Access Journals (Sweden)

    Prashant Kumar

    2014-01-01

    Full Text Available The present work discusses the development of a nonlinear data-fitting technique based on genetic algorithm (GA for the prediction of routine weather parameters using observations from Agro-Met Stations (AMS. The algorithm produces the equations that best describe the temporal evolutions of daily minimum and maximum near-surface (at 2.5-meter height air temperature and relative humidity and daily averaged wind speed (at 10-meter height at selected AMS locations. These enable the forecasts of these weather parameters, which could have possible use in crop forecast models. The forecast equations developed in the present study use only the past observations of the above-mentioned parameters. This approach, unlike other prediction methods, provides explicit analytical forecast equation for each parameter. The predictions up to 3 days in advance have been validated using independent datasets, unknown to the training algorithm, with impressive results. The power of the algorithm has also been demonstrated by its superiority over persistence forecast used as a benchmark.

  2. Discrete channel modelling based on genetic algorithm and simulated annealing for training hidden Markov model

    Institute of Scientific and Technical Information of China (English)

    Zhao Zhi-Jin; Zheng Shi-Lian; Xu Chun-Yun; Kong Xian-Zheng

    2007-01-01

    Hidden Markov models (HMMs) have been used to model burst error sources of wireless channels. This paper proposes a hybrid method of using genetic algorithm (GA) and simulated annealing (SA) to train HMM for discrete channel modelling. The proposed method is compared with pure GA, and experimental results show that the HMMs trained by the hybrid method can better describe the error sequences due to SA's ability of facilitating hill-climbing at the later stage of the search. The burst error statistics of the HMMs trained by the proposed method and the corresponding error sequences are also presented to validate the proposed method.

  3. Genetic simplex modeling of Eysenck's dimensions of personality in a sample of young Australian twins.

    Science.gov (United States)

    Gillespie, Nathan A; Evans, David E; Wright, Margie M; Martin, Nicholas G

    2004-12-01

    The relative stability and magnitude of genetic and environmental effects underlying major dimensions of adolescent personality across time were investigated. The Junior Eysenck Personality Questionnaire was administered to over 540 twin pairs at ages 12, 14 and 16 years. Their personality scores were analyzed using genetic simplex modeling which explicitly took into account the longitudinal nature of the data. With the exception of the dimension lie, multivariate model fitting results revealed that familial aggregation was entirely explained by additive genetic effects. Results from simplex model fitting suggest that large proportions of the additive genetic variance observed at ages 14 and 16 years could be explained by genetic effects present at the age of 12 years. There was also evidence for smaller but significant genetic innovations at 14 and 16 years of age for male and female neuroticism, at 14 years for male extraversion, at 14 and 16 years for female psychoticism, and at 14 years for male psychoticism.

  4. Reconstructing a Network of Stress-Response Regulators via Dynamic System Modeling of Gene Regulation

    Directory of Open Access Journals (Sweden)

    Wei-Sheng Wu

    2008-01-01

    Full Text Available Unicellular organisms such as yeasts have evolved mechanisms to respond to environmental stresses by rapidly reorganizing the gene expression program. Although many stress-response genes in yeast have been discovered by DNA microarrays, the stress-response transcription factors (TFs that regulate these stress-response genes remain to be investigated. In this study, we use a dynamic system model of gene regulation to describe the mechanism of how TFs may control a gene’s expression. Then, based on the dynamic system model, we develop the Stress Regulator Identification Algorithm (SRIA to identify stress-response TFs for six kinds of stresses. We identified some general stress-response TFs that respond to various stresses and some specific stress-response TFs that respond to one specifi c stress. The biological significance of our findings is validated by the literature. We found that a small number of TFs is probably suffi cient to control a wide variety of expression patterns in yeast under different stresses. Two implications can be inferred from this observation. First, the response mechanisms to different stresses may have a bow-tie structure. Second, there may be regulatory cross-talks among different stress responses. In conclusion, this study proposes a network of stress-response regulators and the details of their actions.

  5. Reconstructing a network of stress-response regulators via dynamic system modeling of gene regulation.

    Science.gov (United States)

    Wu, Wei-Sheng; Li, Wen-Hsiung; Chen, Bor-Sen

    2008-02-10

    Unicellular organisms such as yeasts have evolved mechanisms to respond to environmental stresses by rapidly reorganizing the gene expression program. Although many stress-response genes in yeast have been discovered by DNA microarrays, the stress-response transcription factors (TFs) that regulate these stress-response genes remain to be investigated. In this study, we use a dynamic system model of gene regulation to describe the mechanism of how TFs may control a gene's expression. Then, based on the dynamic system model, we develop the Stress Regulator Identification Algorithm (SRIA) to identify stress-response TFs for six kinds of stresses. We identified some general stress-response TFs that respond to various stresses and some specific stress-response TFs that respond to one specific stress. The biological significance of our findings is validated by the literature. We found that a small number of TFs is probably sufficient to control a wide variety of expression patterns in yeast under different stresses. Two implications can be inferred from this observation. First, the response mechanisms to different stresses may have a bow-tie structure. Second, there may be regulatory cross-talks among different stress responses. In conclusion, this study proposes a network of stress-response regulators and the details of their actions.

  6. Prediction and Research on Vegetable Price Based on Genetic Algorithm and Neural Network Model

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    Considering the complexity of vegetables price forecast,the prediction model of vegetables price was set up by applying the neural network based on genetic algorithm and using the characteristics of genetic algorithm and neural work.Taking mushrooms as an example,the parameters of the model are analyzed through experiment.In the end,the results of genetic algorithm and BP neural network are compared.The results show that the absolute error of prediction data is in the scale of 10%;in the scope that the absolute error in the prediction data is in the scope of 20% and 15%.The accuracy of genetic algorithm based on neutral network is higher than the BP neutral network model,especially the absolute error of prediction data is within the scope of 20%.The accuracy of genetic algorithm based on neural network is obviously better than BP neural network model,which represents the favorable generalization capability of the model.

  7. Factor analysis models for structuring covariance matrices of additive genetic effects: a Bayesian implementation

    Directory of Open Access Journals (Sweden)

    Gianola Daniel

    2007-09-01

    Full Text Available Abstract Multivariate linear models are increasingly important in quantitative genetics. In high dimensional specifications, factor analysis (FA may provide an avenue for structuring (covariance matrices, thus reducing the number of parameters needed for describing (codispersion. We describe how FA can be used to model genetic effects in the context of a multivariate linear mixed model. An orthogonal common factor structure is used to model genetic effects under Gaussian assumption, so that the marginal likelihood is multivariate normal with a structured genetic (covariance matrix. Under standard prior assumptions, all fully conditional distributions have closed form, and samples from the joint posterior distribution can be obtained via Gibbs sampling. The model and the algorithm developed for its Bayesian implementation were used to describe five repeated records of milk yield in dairy cattle, and a one common FA model was compared with a standard multiple trait model. The Bayesian Information Criterion favored the FA model.

  8. Models of Genetic Drift as Limiting Forms of the Lotka-Volterra Competition Model

    Science.gov (United States)

    Constable, George W. A.; McKane, Alan J.

    2015-01-01

    The relationship between the Moran model and stochastic Lotka-Volterra competition (SLVC) model is explored via time scale separation arguments. For neutral systems the two are found to be equivalent at long times. For systems with selective pressure, their behavior differs. It is argued that the SLVC is preferable to the Moran model since in the SLVC population size is regulated by competition, rather than arbitrarily fixed as in the Moran model. As a consequence, ambiguities found in the Moran model associated with the introduction of more complex processes, such as selection, are avoided.

  9. Systems genetics of obesity in an F2 pig model by genome-wide association, genetic network and pathway analyses

    Directory of Open Access Journals (Sweden)

    Lisette J. A. Kogelman

    2014-07-01

    Full Text Available Obesity is a complex condition with world-wide exponentially rising prevalence rates, linked with severe diseases like Type 2 Diabetes. Economic and welfare consequences have led to a raised interest in a better understanding of the biological and genetic background. To date, whole genome investigations focusing on single genetic variants have achieved limited success, and the importance of including genetic interactions is becoming evident. Here, the aim was to perform an integrative genomic analysis in an F2 pig resource population that was constructed with an aim to maximize genetic variation of obesity-related phenotypes and genotyped using the 60K SNP chip. Firstly, Genome Wide Association (GWA analysis was performed on the Obesity Index to locate candidate genomic regions that were further validated using combined Linkage Disequilibrium Linkage Analysis and investigated by evaluation of haplotype blocks. We built Weighted Interaction SNP Hub (WISH and differentially wired (DW networks using genotypic correlations amongst obesity-associated SNPs resulting from GWA analysis. GWA results and SNP modules detected by WISH and DW analyses were further investigated by functional enrichment analyses. The functional annotation of SNPs revealed several genes associated with obesity, e.g. NPC2 and OR4D10. Moreover, gene enrichment analyses identified several significantly associated pathways, over and above the GWA study results, that may influence obesity and obesity related diseases, e.g. metabolic processes. WISH networks based on genotypic correlations allowed further identification of various gene ontology terms and pathways related to obesity and related traits, which were not identified by the GWA study. In conclusion, this is the first study to develop a (genetic obesity index and employ systems genetics in a porcine model to provide important insights into the complex genetic architecture associated with obesity and many biological pathways

  10. Systems genetics of obesity in an F2 pig model by genome-wide association, genetic network, and pathway analyses.

    Science.gov (United States)

    Kogelman, Lisette J A; Pant, Sameer D; Fredholm, Merete; Kadarmideen, Haja N

    2014-01-01

    Obesity is a complex condition with world-wide exponentially rising prevalence rates, linked with severe diseases like Type 2 Diabetes. Economic and welfare consequences have led to a raised interest in a better understanding of the biological and genetic background. To date, whole genome investigations focusing on single genetic variants have achieved limited success, and the importance of including genetic interactions is becoming evident. Here, the aim was to perform an integrative genomic analysis in an F2 pig resource population that was constructed with an aim to maximize genetic variation of obesity-related phenotypes and genotyped using the 60K SNP chip. Firstly, Genome Wide Association (GWA) analysis was performed on the Obesity Index to locate candidate genomic regions that were further validated using combined Linkage Disequilibrium Linkage Analysis and investigated by evaluation of haplotype blocks. We built Weighted Interaction SNP Hub (WISH) and differentially wired (DW) networks using genotypic correlations amongst obesity-associated SNPs resulting from GWA analysis. GWA results and SNP modules detected by WISH and DW analyses were further investigated by functional enrichment analyses. The functional annotation of SNPs revealed several genes associated with obesity, e.g., NPC2 and OR4D10. Moreover, gene enrichment analyses identified several significantly associated pathways, over and above the GWA study results, that may influence obesity and obesity related diseases, e.g., metabolic processes. WISH networks based on genotypic correlations allowed further identification of various gene ontology terms and pathways related to obesity and related traits, which were not identified by the GWA study. In conclusion, this is the first study to develop a (genetic) obesity index and employ systems genetics in a porcine model to provide important insights into the complex genetic architecture associated with obesity and many biological pathways that underlie

  11. [The discussion of the infiltrative model of mathematical knowledge to genetics teaching].

    Science.gov (United States)

    Liu, Jun; Luo, Pei-Gao

    2011-11-01

    Genetics, the core course of biological field, is an importance major-basic course in curriculum of many majors related with biology. Due to strong theoretical and practical as well as abstract of genetics, it is too difficult to study on genetics for many students. At the same time, mathematics is one of the basic courses in curriculum of the major related natural science, which has close relationship with the establishment, development and modification of genetics. In this paper, to establish the intrinsic logistic relationship and construct the integral knowledge network and to help students improving the analytic, comprehensive and logistic abilities, we applied some mathematical infiltrative model genetic knowledge in genetics teaching, which could help students more deeply learn and understand genetic knowledge.

  12. Switched Dynamical Latent Force Models for Modelling Transcriptional Regulation

    CERN Document Server

    López-Lopera, Andrés F

    2015-01-01

    In order to develop statistical approaches for transcription networks, statistical community has proposed several methods to infer activity levels of proteins, from time-series measurements of targets' expression levels. A few number of approaches have been proposed in order to outperform the representation of fast switching time instants, but computational overheads are significant due to complex inference algorithms. Using the theory related to latent force models (LFM), the development of this project provide a switched dynamical hybrid model based on Gaussian processes (GPs). To deal with discontinuities in dynamical systems (or latent driving force), an extension of the single input motif approach is introduced, that switches between different protein concentrations, and different dynamical systems. This creates a versatile representation for transcription networks that can capture discrete changes and non-linearities in the dynamics. The proposed method is evaluated on both simulated data and real data,...

  13. A hybrid model of mammalian cell cycle regulation.

    Directory of Open Access Journals (Sweden)

    Rajat Singhania

    Full Text Available The timing of DNA synthesis, mitosis and cell division is regulated by a complex network of biochemical reactions that control the activities of a family of cyclin-dependent kinases. The temporal dynamics of this reaction network is typically modeled by nonlinear differential equations describing the rates of the component reactions. This approach provides exquisite details about molecular regulatory processes but is hampered by the need to estimate realistic values for the many kinetic constants that determine the reaction rates. It is difficult to estimate these kinetic constants from available experimental data. To avoid this problem, modelers often resort to 'qualitative' modeling strategies, such as Boolean switching networks, but these models describe only the coarsest features of cell cycle regulation. In this paper we describe a hybrid approach that combines the best features of continuous differential equations and discrete Boolean networks. Cyclin abundances are tracked by piecewise linear differential equations for cyclin synthesis and degradation. Cyclin synthesis is regulated by transcription factors whose activities are represented by discrete variables (0 or 1 and likewise for the activities of the ubiquitin-ligating enzyme complexes that govern cyclin degradation. The discrete variables change according to a predetermined sequence, with the times between transitions determined in part by cyclin accumulation and degradation and as well by exponentially distributed random variables. The model is evaluated in terms of flow cytometry measurements of cyclin proteins in asynchronous populations of human cell lines. The few kinetic constants in the model are easily estimated from the experimental data. Using this hybrid approach, modelers can quickly create quantitatively accurate, computational models of protein regulatory networks in cells.

  14. PM Synchronous Motor Dynamic Modeling with Genetic Algorithm ...

    African Journals Online (AJOL)

    Adel

    intelligence like neural network, genetic algorithm, etc (El Shahat and El Shewy, ..... maximum power factor has the most powerful effect on all various machine .... Artificial Intelligence, Renewable Energy, Power System, Control Systems, PV ...

  15. Genetic interaction implicates iRhom2 in the regulation of EGF receptor signalling in mice

    Directory of Open Access Journals (Sweden)

    Owen M. Siggs

    2014-11-01

    Full Text Available iRhoms are closely related to rhomboid intramembrane proteases but lack catalytic activity. In mammals iRhoms are known to regulate the trafficking of TACE, the protease that cleaves the membrane bound inflammatory cytokine TNF. We have mapped a spontaneously occurring mouse mutation with a loss of hair phenotype, curly bare (cub, to the Rhbdf2 locus, which encodes the iRhom2 protein. The cub deletion removes the first 268 amino acids of the iRhom2 protein but is not a loss of function. We have also identified a previously reported suppressor of cub, called Mcub (modifier of curly bare, and find it to be a loss of function allele of the amphiregulin gene (Areg. Amphiregulin is an activating ligand of the epidermal growth factor receptor (EGFR that, like TNF, is released by TACE. Our results therefore imply a regulatory link between iRhoms and EGFR signalling in mammals. We have tested the model that the cub mutation leads to iRhom2 hyperactivity and consequently excess TACE processing of amphiregulin and elevated EGFR signalling. Our results do not support this hypothesis: we find that, compared to wild-type cells, cub mutant embryonic fibroblasts release less amphiregulin, and that the cub mutant form of iRhom2 is less able than wild type to bind to TACE and promote its maturation.

  16. URC Fuzzy Modeling and Simulation of Gene Regulation

    Energy Technology Data Exchange (ETDEWEB)

    Sokhansanj, B A; Fitch, J P

    2001-05-01

    Recent technological advances in high-throughput data collection give biologists the ability to study increasingly complex systems. A new methodology is needed to develop and test biological models based on experimental observations and predict the effect of perturbations of the network (e.g. genetic engineering, pharmaceuticals, gene therapy). Diverse modeling approaches have been proposed, in two general categories: modeling a biological pathway as (a) a logical circuit or (b) a chemical reaction network. Boolean logic models can not represent necessary biological details. Chemical kinetics simulations require large numbers of parameters that are very difficult to accurately measure. Based on the way biologists have traditionally thought about systems, we propose that fuzzy logic is a natural language for modeling biology. The Union Rule Configuration (URC) avoids combinatorial explosion in the fuzzy rule base, allowing complex system models. We demonstrate the fuzzy modeling method on the commonly studied lac operon of E. coli. Our goal is to develop a modeling and simulation approach that can be understood and applied by biologists without the need for experts in other fields or ''black-box'' software.

  17. The retinoblastoma protein regulates hypoxia-inducible genetic programs, tumor cell invasiveness and neuroendocrine differentiation in prostate cancer cells

    Science.gov (United States)

    Labrecque, Mark P.; Takhar, Mandeep K.; Nason, Rebecca; Santacruz, Stephanie; Tam, Kevin J.; Massah, Shabnam; Haegert, Anne; Bell, Robert H.; Altamirano-Dimas, Manuel; Collins, Colin C.; Lee, Frank J.S.; Prefontaine, Gratien G.; Cox, Michael E.; Beischlag, Timothy V.

    2016-01-01

    Loss of tumor suppressor proteins, such as the retinoblastoma protein (Rb), results in tumor progression and metastasis. Metastasis is facilitated by low oxygen availability within the tumor that is detected by hypoxia inducible factors (HIFs). The HIF1 complex, HIF1α and dimerization partner the aryl hydrocarbon receptor nuclear translocator (ARNT), is the master regulator of the hypoxic response. Previously, we demonstrated that Rb represses the transcriptional response to hypoxia by virtue of its association with HIF1. In this report, we further characterized the role Rb plays in mediating hypoxia-regulated genetic programs by stably ablating Rb expression with retrovirally-introduced short hairpin RNA in LNCaP and 22Rv1 human prostate cancer cells. DNA microarray analysis revealed that loss of Rb in conjunction with hypoxia leads to aberrant expression of hypoxia-regulated genetic programs that increase cell invasion and promote neuroendocrine differentiation. For the first time, we have established a direct link between hypoxic tumor environments, Rb inactivation and progression to late stage metastatic neuroendocrine prostate cancer. Understanding the molecular pathways responsible for progression of benign prostate tumors to metastasized and lethal forms will aid in the development of more effective prostate cancer therapies. PMID:27015368

  18. The retinoblastoma protein regulates hypoxia-inducible genetic programs, tumor cell invasiveness and neuroendocrine differentiation in prostate cancer cells.

    Science.gov (United States)

    Labrecque, Mark P; Takhar, Mandeep K; Nason, Rebecca; Santacruz, Stephanie; Tam, Kevin J; Massah, Shabnam; Haegert, Anne; Bell, Robert H; Altamirano-Dimas, Manuel; Collins, Colin C; Lee, Frank J S; Prefontaine, Gratien G; Cox, Michael E; Beischlag, Timothy V

    2016-04-26

    Loss of tumor suppressor proteins, such as the retinoblastoma protein (Rb), results in tumor progression and metastasis. Metastasis is facilitated by low oxygen availability within the tumor that is detected by hypoxia inducible factors (HIFs). The HIF1 complex, HIF1α and dimerization partner the aryl hydrocarbon receptor nuclear translocator (ARNT), is the master regulator of the hypoxic response. Previously, we demonstrated that Rb represses the transcriptional response to hypoxia by virtue of its association with HIF1. In this report, we further characterized the role Rb plays in mediating hypoxia-regulated genetic programs by stably ablating Rb expression with retrovirally-introduced short hairpin RNA in LNCaP and 22Rv1 human prostate cancer cells. DNA microarray analysis revealed that loss of Rb in conjunction with hypoxia leads to aberrant expression of hypoxia-regulated genetic programs that increase cell invasion and promote neuroendocrine differentiation. For the first time, we have established a direct link between hypoxic tumor environments, Rb inactivation and progression to late stage metastatic neuroendocrine prostate cancer. Understanding the molecular pathways responsible for progression of benign prostate tumors to metastasized and lethal forms will aid in the development of more effective prostate cancer therapies.

  19. Mathematical model of galactose regulation and metabolic consumption in yeast.

    Science.gov (United States)

    Mitre, Tina M; Mackey, Michael C; Khadra, Anmar

    2016-10-21

    The galactose network has been extensively studied at the unicellular level to broaden our understanding of the regulatory mechanisms governing galactose metabolism in multicellular organisms. Although the key molecular players involved in the metabolic and regulatory processes of this system have been known for decades, their interactions and chemical kinetics remain incompletely understood. Mathematical models can provide an alternative method to study the dynamics of this network from a quantitative and a qualitative perspective. Here, we employ this approach to unravel the main properties of the galactose network, including equilibrium binary and temporal responses, as a way to decipher its adaptation to actively-changing inputs. We combine its two main components: the genetic branch, which allows for bistable responses, and a metabolic branch, encompassing the relevant metabolic processes that can be repressed by glucose. We use both computational tools to estimate model parameters based on published experimental data, as well as bifurcation analysis to decipher the properties of the system in various parameter regimes. Our model analysis reveals that the interplay between the inducer (galactose) and the repressor (glucose) creates a bistable regime which dictates the temporal responses of the system. Based on the same bifurcation techniques, we explain why the system is robust to genetic mutations and molecular instabilities. These findings may provide experimentalists with a theoretical framework with which they can determine how the galactose network functions under various conditions.

  20. Genetic and genomic analysis of RNases in model cyanobacteria.

    Science.gov (United States)

    Cameron, Jeffrey C; Gordon, Gina C; Pfleger, Brian F

    2015-10-01

    Cyanobacteria are diverse photosynthetic microbes with the ability to convert CO2 into useful products. However, metabolic engineering of cyanobacteria remains challenging because of the limited resources for modifying the expression of endogenous and exogenous biochemical pathways. Fine-tuned control of protein production will be critical to optimize the biological conversion of CO2 into desirable molecules. Messenger RNAs (mRNAs) are labile intermediates that play critical roles in determining the translation rate and steady-state protein concentrations in the cell. The majority of studies on mRNA turnover have focused on the model heterotrophic bacteria Escherichia coli and Bacillus subtilis. These studies have elucidated many RNA modifying and processing enzymes and have highlighted the differences between these Gram-negative and Gram-positive bacteria, respectively. In contrast, much less is known about mRNA turnover in cyanobacteria. We generated a compendium of the major ribonucleases (RNases) and provide an in-depth analysis of RNase III-like enzymes in commonly studied and diverse cyanobacteria. Furthermore, using targeted gene deletion, we genetically dissected the RNases in Synechococcus sp. PCC 7002, one of the fastest growing and industrially attractive cyanobacterial strains. We found that all three cyanobacterial homologs of RNase III and a member of the RNase II/R family are not essential under standard laboratory conditions, while homologs of RNase E/G, RNase J1/J2, PNPase, and a different member of the RNase II/R family appear to be essential for growth. This work will enhance our understanding of native control of gene expression and will facilitate the development of an RNA-based toolkit for metabolic engineering in cyanobacteria.

  1. Advances in behavioral genetics modeling using Mplus: applications of factor mixture modeling to twin data.

    Science.gov (United States)

    Muthén, Bengt; Asparouhov, Tihomir; Rebollo, Irene

    2006-06-01

    This article discusses new latent variable techniques developed by the authors. As an illustration, a new factor mixture model is applied to the monozygotic-dizygotic twin analysis of binary items measuring alcohol-use disorder. In this model, heritability is simultaneously studied with respect to latent class membership and within-class severity dimensions. Different latent classes of individuals are allowed to have different heritability for the severity dimensions. The factor mixture approach appears to have great potential for the genetic analyses of heterogeneous populations. Generalizations for longitudinal data are also outlined.

  2. Precision phenotyping of biomass accumulation in triticale reveals temporal genetic patterns of regulation

    Science.gov (United States)

    Busemeyer, Lucas; Ruckelshausen, Arno; Möller, Kim; Melchinger, Albrecht E.; Alheit, Katharina V.; Maurer, Hans Peter; Hahn, Volker; Weissmann, Elmar A.; Reif, Jochen C.; Würschum, Tobias

    2013-08-01

    To extend agricultural productivity by knowledge-based breeding and tailor varieties adapted to specific environmental conditions, it is imperative to improve our ability to assess the dynamic changes of the phenome of crops under field conditions. To this end, we have developed a precision phenotyping platform that combines various sensors for a non-invasive, high-throughput and high-dimensional phenotyping of small grain cereals. This platform yielded high prediction accuracies and heritabilities for biomass of triticale. Genetic variation for biomass accumulation was dissected with 647 doubled haploid lines derived from four families. Employing a genome-wide association mapping approach, two major quantitative trait loci (QTL) for biomass were identified and the genetic architecture of biomass accumulation was found to be characterized by dynamic temporal patterns. Our findings highlight the potential of precision phenotyping to assess the dynamic genetics of complex traits, especially those not amenable to traditional phenotyping.

  3. Modeling cutinase enzyme regulation in polyethylene terepthalate plastic biodegradation

    Science.gov (United States)

    Apri, M.; Silmi, M.; Heryanto, T. E.; Moeis, M. R.

    2016-04-01

    PET (Polyethylene terephthalate) is a plastic material that is commonly used in our daily life. The high production of PET and others plastics that can be up to three hundred million tons per year, is not matched by its degradation rate and hence leads to environmental pollution. To overcome this problem, we develop a biodegradation system. This system utilizes LC Cutinase enzyme produced by engineered escherichia coli bacteria to degrade PET. To make the system works efficaciously, it is important to understand the mechanism underlying its enzyme regulation. Therefore, we construct a mathematical model to describe the regulation of LC Cutinase production. The stability of the model is analyzed. We show that the designated biodegradation system can give an oscillatory behavior that is very important to control the amount of inclusion body (the miss-folded proteins that reduce the efficiency of the biodegradation system).

  4. Modeling cutinase enzyme regulation in polyethylene terepthalate plastic biodegradation

    Energy Technology Data Exchange (ETDEWEB)

    Apri, M., E-mail: m.apri@math.itb.ac.id; Silmi, M. [Department of Mathematics, Institut Teknologi Bandung, Jalan Ganeca 10 Bandung, 40132 (Indonesia); Heryanto, T. E.; Moeis, M. R. [School of Life Sciences and Technology, Institut Teknologi Bandung, Jalan Ganeca 10 Bandung, 40132 (Indonesia)

    2016-04-06

    PET (Polyethylene terephthalate) is a plastic material that is commonly used in our daily life. The high production of PET and others plastics that can be up to three hundred million tons per year, is not matched by its degradation rate and hence leads to environmental pollution. To overcome this problem, we develop a biodegradation system. This system utilizes LC Cutinase enzyme produced by engineered escherichia coli bacteria to degrade PET. To make the system works efficaciously, it is important to understand the mechanism underlying its enzyme regulation. Therefore, we construct a mathematical model to describe the regulation of LC Cutinase production. The stability of the model is analyzed. We show that the designated biodegradation system can give an oscillatory behavior that is very important to control the amount of inclusion body (the miss-folded proteins that reduce the efficiency of the biodegradation system).

  5. "Hypothesis for the Modern RNA World": A pervasive Non-coding RNA-Based Genetic Regulation is a Prerequisite for the Emergence of Multicellular Complexity

    Science.gov (United States)

    Lozada-Chávez, Irma; Stadler, Peter F.; Prohaska, Sonja J.

    2011-12-01

    The transitions to multicellularity mark the most pivotal and distinctive events in life's history on Earth. Although several transitions to "simple" multicellularity (SM) have been recorded in both bacterial and eukaryotic clades, transitions to complex multicellularity (CM) have only happened a few times in eukaryotes. A large number of cell types (associated with large body size), increased energy consumption per gene expressed, and an increment of non-protein-coding DNA positively correlate with CM. These three factors can indeed be understood as the causes and consequences of the regulation of gene expression. Here, we discuss how a vast expansion of non-protein-coding RNA (ncRNAs) regulators rather than large numbers of novel protein regulators can easily contribute to the emergence of CM. We also propose that the evolutionary advantage of RNA-based gene regulation derives from the robustness of the RNA structure that makes it easy to combine genetic drift with functional exploration. We describe a model which aims to explain how the evolutionary dynamic of ncRNAs becomes dominated by the accessibility of advantageous mutations to innovate regulation in complex multicellular organisms. The information and models discussed here outline the hypothesis that pervasive ncRNA-based regulatory systems, only capable of being expanded and explored in higher eukaryotes, are prerequisite to complex multicellularity. Thereby, regulatory RNA molecules in Eukarya have allowed intensification of morphological complexity by stabilizing critical phenotypes and controlling developmental precision. Although the origin of RNA on early Earth is still controversial, it is becoming clear that once RNA emerged into a protocellular system, its relevance within the evolution of biological systems has been greater than we previously thought.

  6. Genetic regulation of meiosis in polyploid species: new insights into an old question.

    Science.gov (United States)

    Cifuentes, Marta; Grandont, Laurie; Moore, Graham; Chèvre, Anne Marie; Jenczewski, Eric

    2010-04-01

    Precise chromosome segregation is vital for polyploid speciation. Here, we highlight recent findings that revitalize the old question of the genetic control of diploid-like meiosis behaviour in polyploid species. We first review new information on the genetic control of autopolyploid and allopolyploid cytological diploidization, notably in wheat and Brassica. These major advances provide new opportunities for speculating about the adaptation of meiosis during polyploid evolution. Some of these advances are discussed, and it is suggested that research on polyploidy and on meiosis should no longer be unlinked.

  7. A model for family-based case–control studies of genetic imprinting and epistasis

    Science.gov (United States)

    Li, Xin; Sui, Yihan; Liu, Tian; Wang, Jianxin; Li, Yongci; Lin, Zhenwu; Hegarty, John; Koltun, Walter A.; Wang, Zuoheng

    2014-01-01

    Genetic imprinting, or called the parent-of-origin effect, has been recognized to play an important role in the formation and pathogenesis of human diseases. Although the epigenetic mechanisms that establish genetic imprinting have been a focus of many genetic studies, our knowledge about the number of imprinting genes and their chromosomal locations and interactions with other genes is still scarce, limiting precise inference of the genetic architecture of complex diseases. In this article, we present a statistical model for testing and estimating the effects of genetic imprinting on complex diseases using a commonly used case–control design with family structure. For each subject sampled from a case and control population, we not only genotype its own single nucleotide polymorphisms (SNPs) but also collect its parents’ genotypes. By tracing the transmission pattern of SNP alleles from parental to offspring generation, the model allows the characterization of genetic imprinting effects based on Pearson tests of a 2 × 2 contingency table. The model is expanded to test the interactions between imprinting effects and additive, dominant and epistatic effects in a complex web of genetic interactions. Statistical properties of the model are investigated, and its practical usefulness is validated by a real data analysis. The model will provide a useful tool for genome-wide association studies aimed to elucidate the picture of genetic control over complex human diseases. PMID:23887693

  8. Genetic and Environmental Models of Circadian Disruption Link SRC-2 Function to Hepatic Pathology.

    Science.gov (United States)

    Fleet, Tiffany; Stashi, Erin; Zhu, Bokai; Rajapakshe, Kimal; Marcelo, Kathrina L; Kettner, Nicole M; Gorman, Blythe K; Coarfa, Cristian; Fu, Loning; O'Malley, Bert W; York, Brian

    2016-10-01

    Circadian rhythmicity is a fundamental process that synchronizes behavioral cues with metabolic homeostasis. Disruption of daily cycles due to jet lag or shift work results in severe physiological consequences including advanced aging, metabolic syndrome, and even cancer. Our understanding of the molecular clock, which is regulated by intricate positive feedforward and negative feedback loops, has expanded to include an important metabolic transcriptional coregulator, Steroid Receptor Coactivator-2 (SRC-2), that regulates both the central clock of the suprachiasmatic nucleus (SCN) and peripheral clocks including the liver. We hypothesized that an environmental uncoupling of the light-dark phases, termed chronic circadian disruption (CCD), would lead to pathology similar to the genetic circadian disruption observed with loss of SRC-2 We found that CCD and ablation of SRC-2 in mice led to a common comorbidity of metabolic syndrome also found in humans with circadian disruption, non-alcoholic fatty liver disease (NAFLD). The combination of SRC-2(-/-) and CCD results in a more robust phenotype that correlates with human non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) gene signatures. Either CCD or SRC-2 ablation produces an advanced aging phenotype leading to increased mortality consistent with other circadian mutant mouse models. Collectively, our studies demonstrate that SRC-2 provides an essential link between the behavioral activities influenced by light cues and the metabolic homeostasis maintained by the liver.

  9. PEB: thermal oriented architectural modeling for building energy efficiency regulations

    OpenAIRE

    Leclercq, Pierre; Juchmes, Roland; Delfosse, Vincent; Safin, Stéphane; Dawans, Arnaud; Dawans, Adrien

    2011-01-01

    As part of the overhauling of the building energy efficiency regulations (following European directive 2002/91/CE), the Wallonia and Brussels-Capital Region commissioned the LUCID to develop an optional 3D graphic encoding module to be integrated with the core energy efficiency computation engine developed by Altran Europe. Our contribution consisted mostly in analyzing the target users’ needs and representations (ergonomics, UI, interactions) and implementing a bespoke 3D CAD modeler dedicat...

  10. High-fidelity Modelling of Self-regulating Pneumatic Valves

    OpenAIRE

    Pollok, Alexander; Casella, Francesco

    2015-01-01

    In conventional aircraft energy systems, self-regulating pneumatic valves (SRPVs) are used to control the pressure and mass flow of the bleed air. The dynamic behavior of these valves is complex and dependent on several physical phenomena. In some cases, limit cycles can occur, deteriorating performance. This paper presents a complex multiphysical model of SRPVs implemented in Modelica. First, the working-principle is explained, and common challenges in control-system design-problems ...

  11. Development of agricultural biotechnology and biosafety regulations used to assess the safety of genetically modified crops in Iran.

    Science.gov (United States)

    Mousavi, Amir; Malboobi, Mohammad A; Esmailzadeh, Nasrin S

    2007-01-01

    Rapid progress in the application of biotechnological methodologies and development of genetically modified crops in Iran necessitated intensive efforts to establish proper organizations and prepare required rules and regulations at the national level to ensure safe application of biotechnology in all pertinent aspects. Practically, preparation of a national biotechnology strategic plan in the country coincided with development of a national biosafety framework that was the basis for the drafted biosafety law. Although biosafety measures were observed by researchers voluntarily, the establishment of national biosafety organizations since the year 2000 built a great capacity to deal with biosafety issues in the present and future time, particularly with respect to food and agricultural biotechnology.

  12. Pathophysiological, genetic and gene expression features of a novel rodent model of the cardio-metabolic syndrome.

    Directory of Open Access Journals (Sweden)

    Robert H Wallis

    Full Text Available BACKGROUND: Complex etiology and pathogenesis of pathophysiological components of the cardio-metabolic syndrome have been demonstrated in humans and animal models. METHODOLOGY/PRINCIPAL FINDINGS: We have generated extensive physiological, genetic and genome-wide gene expression profiles in a congenic strain of the spontaneously diabetic Goto-Kakizaki (GK rat containing a large region (110 cM, 170 Mb of rat chromosome 1 (RNO1, which covers diabetes and obesity quantitative trait loci (QTL, introgressed onto the genetic background of the normoglycaemic Brown Norway (BN strain. This novel disease model, which by the length of the congenic region closely mirrors the situation of a chromosome substitution strain, exhibits a wide range of abnormalities directly relevant to components of the cardio-metabolic syndrome and diabetes complications, including hyperglycaemia, hyperinsulinaemia, enhanced insulin secretion both in vivo and in vitro, insulin resistance, hypertriglyceridemia and altered pancreatic and renal histological structures. Gene transcription data in kidney, liver, skeletal muscle and white adipose tissue indicate that a disproportionately high number (43-83% of genes differentially expressed between congenic and BN rats map to the GK genomic interval targeted in the congenic strain, which represents less than 5% of the total length of the rat genome. Genotype analysis of single nucleotide polymorphisms (SNPs in strains genetically related to the GK highlights clusters of conserved and strain-specific variants in RNO1 that can assist the identification of naturally occurring variants isolated in diabetic and hypertensive strains when different phenotype selection procedures were applied. CONCLUSIONS: Our results emphasize the importance of rat congenic models for defining the impact of genetic variants in well-characterised QTL regions on in vivo pathophysiological features and cis-/trans- regulation of gene expression. The congenic

  13. Genetic analysis of the regulation of type IV pilus function by the Chp chemosensory system of Pseudomonas aeruginosa.

    Science.gov (United States)

    Bertrand, Jacob J; West, Joyce T; Engel, Joanne N

    2010-02-01

    The virulence of the opportunistic pathogen Pseudomonas aeruginosa involves the coordinate expression of many virulence factors, including type IV pili, which are required for colonization of host tissues and for twitching motility. Type IV pilus function is controlled in part by the Chp chemosensory system, which includes a histidine kinase, ChpA, and two CheY-like response regulators, PilG and PilH. How the Chp components interface with the type IV pilus motor proteins PilB, PilT, and PilU is unknown. We present genetic evidence confirming the role of ChpA, PilG, and PilB in the regulation of pilus extension and the role of PilH and PilT in regulating pilus retraction. Using informative double and triple mutants, we show that (i) ChpA, PilG, and PilB function upstream of PilH, PilT, and PilU; (ii) that PilH enhances PilT function; and (iii) that PilT and PilB retain some activity in the absence of signaling input from components of the Chp system. By site-directed mutagenesis, we demonstrate that the histidine kinase domain of ChpA and the phosphoacceptor sites of both PilG and PilH are required for type IV pilus function, suggesting that they form a phosphorelay system important in the regulation of pilus extension and retraction. Finally, we present evidence suggesting that pilA transcription is regulated by intracellular PilA levels. We show that PilA is a negative regulator of pilA transcription in P. aeruginosa and that the Chp system functionally regulates pilA transcription by controlling PilA import and export.

  14. Mainstreaming cancer genetics: A model integrating germline BRCA testing into routine ovarian cancer clinics.

    Science.gov (United States)

    Kentwell, Maira; Dow, Eryn; Antill, Yoland; Wrede, C David; McNally, Orla; Higgs, Emily; Hamilton, Anne; Ananda, Sumitra; Lindeman, Geoffrey J; Scott, Clare L

    2017-04-01

    Owing to the rapid increase in clinical need, we aimed to implement and review the performance of a mainstreaming model of germline BRCA1/2 genetic testing in eligible women with high grade non-mucinous epithelial ovarian cancer via a Genetic Counselor embedded in the gynecology oncology clinic. The model implemented involved a specialized referral form, weekly genetics-lead multidisciplinary review of referrals, and pre- and post-test genetic counseling provided by an embedded genetic counselor during chemotherapy chair time. Performance and outcomes were retrospectively audited over the following two consecutive one year periods, including survey data on medical specialist comfort with mainstreaming and the model. Sixty-four women underwent mainstreamed BRCA1/2 testing over the two year post-implementation period with a rate of detection of BRCA1/2 pathogenic variants of 17%. The referral rate for eligible women significantly increased to over 90% (pgenetic testing results was less than five months, with >90% of patients receiving results during first line chemotherapy. Genetic counseling time decreased from 120 to 54min. Cancer specialists were comfortable with the model. The mainstreaming model proved effective, increasing uptake of genetic testing in eligible patients to over 90%; it was efficient for patients, genetic counselors and cancer specialists and acceptable to cancer specialists. It facilitated co-location of genetic and oncology service delivery but separation of clinical responsibility for genetic testing to a specialist genetics service, ensuring accurate and robust patient-centred care. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Renegotiating GM crop regulation: Targeted gene-modification technology raises new issues for the oversight of genetically modified crops

    OpenAIRE

    2011-01-01

    Targeted genetic modification, which enables scientists to genetically engineer plants more efficiently and precisely, challenges current process-based regulatory frameworks for genetically modified crops.

  16. EXTERNALITIES AND THE SIX FACETS MODEL OF TECHNOLOGY MANAGEMENT: GENETICALLY MODIFIED ORGANISMS IN AGRIBUSINESS

    OpenAIRE

    STEPHEN R. LUXMORE; CLYDE EIRÍKUR HULL

    2010-01-01

    The Six Facets Model of technology management has previously only been applied to process innovation at the firm and the industry level. In this article, the model is applied to product innovation for the first time. In the context of genetically-modified organisms in the agribusiness industry, we examine radical product innovation through the Six Facets Model. We propose, based on the history of genetically-modified organisms in agribusiness, that when applied to product innovation the Six F...

  17. Yeast Genetics for Delineating Bax/Bcl Pathway of Cell Death Regulation.

    Science.gov (United States)

    1998-07-01

    de Biochimie et Genetique Cellulaires regulatory functions apart from their ability to form chan- Centre National de la Recherche Scientifique nels...8217-TGGAGTGCACCACT- y manipulated in terms of genetic analysis. Re- TGCTAAAG-3’. The resulting PCR product was digested with fly, it has been shown that the

  18. Factors influencing QTL mapping accuracy under complicated genetic models by computer simulation.

    Science.gov (United States)

    Su, C F; Wang, W; Gong, S L; Zuo, J H; Li, S J

    2016-12-19

    The accuracy of quantitative trait loci (QTLs) identified using different sample sizes and marker densities was evaluated in different genetic models. Model I assumed one additive QTL; Model II assumed three additive QTLs plus one pair of epistatic QTLs; and Model III assumed two additive QTLs with opposite genetic effects plus two pairs of epistatic QTLs. Recombinant inbred lines (RILs) (50-1500 samples) were simulated according to the Models to study the influence of different sample sizes under different genetic models on QTL mapping accuracy. RILs with 10-100 target chromosome markers were simulated according to Models I and II to evaluate the influence of marker density on QTL mapping accuracy. Different marker densities did not significantly influence accurate estimation of genetic effects with simple additive models, but influenced QTL mapping accuracy in the additive and epistatic models. The optimum marker density was approximately 20 markers when the recombination fraction between two adjacent markers was 0.056 in the additive and epistatic models. A sample size of 150 was sufficient for detecting simple additive QTLs. Thus, a sample size of approximately 450 is needed to detect QTLs with additive and epistatic models. Sample size must be approximately 750 to detect QTLs with additive, epistatic, and combined effects between QTLs. The sample size should be increased to >750 if the genetic models of the data set become more complicated than Model III. Our results provide a theoretical basis for marker-assisted selection breeding and molecular design breeding.

  19. Splicing factors act as genetic modulators of TDP-43 production in a new autoregulatory TDP-43 Drosophila model.

    Science.gov (United States)

    Pons, Marine; Miguel, Laetitia; Miel, Camille; Avequin, Tracey; Juge, François; Frebourg, Thierry; Campion, Dominique; Lecourtois, Magalie

    2017-09-01

    TDP-43 is a critical RNA-binding factor associated with RNA metabolism. In the physiological state, maintaining normal TDP-43 protein levels is critical for proper physiological functions of the cells. As such, TDP-43 expression is tightly regulated through an autoregulatory negative feedback loop. TDP-43 is a major disease-causing protein in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). Several studies argue for a pathogenic role of elevated TDP-43 levels in these disorders. Modulating the cycle of TDP-43 production might therefore provide a new therapeutic strategy. In this study, we developed a new transgenic Drosophila model mimicking the TDP-43 autoregulatory feedback loop in order to identify genetic modulators of TDP-43 protein steady-state levels in vivo. First, we showed that our TDP-43_TDPBR Drosophila model recapitulates key features of the TDP-43 autoregulatory processes previously described in mammalian and cellular models, namely alternative splicing events, differential usage of polyadenylation sites, nuclear retention of the transcript and a decrease in steady-state mRNA levels. Using this new Drosophila model, we identified several splicing factors, including SF2, Rbp1 and Sf3b1, as genetic modulators of TDP-43 production. Interestingly, our data indicate that these three RNA-binding proteins regulate TDP-43 protein production, at least in part, by controlling mRNA steady-state levels. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  20. State of play in direct-to-consumer genetic testing for lifestyle-related diseases: market, marketing content, user experiences and regulation.

    Science.gov (United States)

    Saukko, Paula

    2013-02-01

    Direct-to-consumer (DTC) genetic tests have aroused controversy. Critics have argued many of the tests are not backed by scientific evidence, misguide their customers and should be regulated more stringently. Proponents suggest that finding out genetic susceptibilities for diseases could encourage healthier behaviours and makes the results of genetics research available to the public. This paper reviews the state of play in DTC genetic testing, focusing on tests identifying susceptibilities for lifestyle-related diseases. It will start with mapping the market for the tests. The paper will review (1) research on the content of the online marketing of DTC tests, (2) studies on the effects of DTC genetic tests on customers and (3) academic and policy proposals on how to regulate the tests. Current studies suggest that the marketing of DTC genetic tests often exaggerates their predictive powers, which could misguide consumers. However, research indicates that the tests do not seem to have major negative effects (worry and confusion) but neither do they engender positive effects (lifestyle change) on current users. Research on regulation of the tests has most commonly suggested regulating the marketing claims of the companies. In conclusion, the risks and benefits of DTC genetic tests are less significant than what has been predicted by critics and proponents, which will be argued reflects broader historical trends transforming health and medicine.

  1. Genetic hotels for the standard genetic code: evolutionary analysis based upon novel three-dimensional algebraic models.

    Science.gov (United States)

    José, Marco V; Morgado, Eberto R; Govezensky, Tzipe

    2011-07-01

    Herein, we rigorously develop novel 3-dimensional algebraic models called Genetic Hotels of the Standard Genetic Code (SGC). We start by considering the primeval RNA genetic code which consists of the 16 codons of type RNY (purine-any base-pyrimidine). Using simple algebraic operations, we show how the RNA code could have evolved toward the current SGC via two different intermediate evolutionary stages called Extended RNA code type I and II. By rotations or translations of the subset RNY, we arrive at the SGC via the former (type I) or via the latter (type II), respectively. Biologically, the Extended RNA code type I, consists of all codons of the type RNY plus codons obtained by considering the RNA code but in the second (NYR type) and third (YRN type) reading frames. The Extended RNA code type II, comprises all codons of the type RNY plus codons that arise from transversions of the RNA code in the first (YNY type) and third (RNR) nucleotide bases. Since the dimensions of remarkable subsets of the Genetic Hotels are not necessarily integer numbers, we also introduce the concept of algebraic fractal dimension. A general decoding function which maps each codon to its corresponding amino acid or the stop signals is also derived. The Phenotypic Hotel of amino acids is also illustrated. The proposed evolutionary paths are discussed in terms of the existing theories of the evolution of the SGC. The adoption of 3-dimensional models of the Genetic and Phenotypic Hotels will facilitate the understanding of the biological properties of the SGC.

  2. The WAG/Rij strain: A genetic animal model of absence epilepsy with comorbidity of depressiony

    NARCIS (Netherlands)

    Sarkisova, K.Y.; Luijtelaar, E.L.J.M. van

    2011-01-01

    A great number of clinical observations show a relationship between epilepsy and depression. Idiopathic generalized epilepsy, including absence epilepsy, has a genetic basis. The review provides evidence that WAG/Rij rats can be regarded as a valid genetic animal model of absence epilepsy with comor

  3. An integrative model of ion regulation in yeast.

    Science.gov (United States)

    Ke, Ruian; Ingram, Piers J; Haynes, Ken

    2013-01-01

    Yeast cells are able to tolerate and adapt to a variety of environmental stresses. An essential aspect of stress adaptation is the regulation of monovalent ion concentrations. Ion regulation determines many fundamental physiological parameters, such as cell volume, membrane potential, and intracellular pH. It is achieved through the concerted activities of multiple cellular components, including ion transporters and signaling molecules, on both short and long time scales. Although each component has been studied in detail previously, it remains unclear how the physiological parameters are maintained and regulated by the concerted action of all components under a diverse range of stress conditions. In this study, we have constructed an integrated mathematical model of ion regulation in Saccharomyces cerevisiae to understand this coordinated adaptation process. Using this model, we first predict that the interaction between phosphorylated Hog1p and Tok1p at the plasma membrane inhibits Tok1p activity and consequently reduces Na(+) influx under NaCl stress. We further characterize the impacts of NaCl, sorbitol, KCl and alkaline pH stresses on the cellular physiology and the differences between the cellular responses to these stresses. We predict that the calcineurin pathway is essential for maintaining a non-toxic level of intracellular Na(+) in the long-term adaptation to NaCl stress, but that its activation is not required for maintaining a low level of Na(+) under other stresses investigated. We provide evidence that, in addition to extrusion of toxic ions, Ena1p plays an important role, in some cases alongside Nha1p, in re-establishing membrane potential after stress perturbation. To conclude, this model serves as a powerful tool for both understanding the complex system-level properties of the highly coordinated adaptation process and generating further hypotheses for experimental investigation.

  4. An integrative model of ion regulation in yeast.

    Directory of Open Access Journals (Sweden)

    Ruian Ke

    Full Text Available Yeast cells are able to tolerate and adapt to a variety of environmental stresses. An essential aspect of stress adaptation is the regulation of monovalent ion concentrations. Ion regulation determines many fundamental physiological parameters, such as cell volume, membrane potential, and intracellular pH. It is achieved through the concerted activities of multiple cellular components, including ion transporters and signaling molecules, on both short and long time scales. Although each component has been studied in detail previously, it remains unclear how the physiological parameters are maintained and regulated by the concerted action of all components under a diverse range of stress conditions. In this study, we have constructed an integrated mathematical model of ion regulation in Saccharomyces cerevisiae to understand this coordinated adaptation process. Using this model, we first predict that the interaction between phosphorylated Hog1p and Tok1p at the plasma membrane inhibits Tok1p activity and consequently reduces Na(+ influx under NaCl stress. We further characterize the impacts of NaCl, sorbitol, KCl and alkaline pH stresses on the cellular physiology and the differences between the cellular responses to these stresses. We predict that the calcineurin pathway is essential for maintaining a non-toxic level of intracellular Na(+ in the long-term adaptation to NaCl stress, but that its activation is not required for maintaining a low level of Na(+ under other stresses investigated. We provide evidence that, in addition to extrusion of toxic ions, Ena1p plays an important role, in some cases alongside Nha1p, in re-establishing membrane potential after stress perturbation. To conclude, this model serves as a powerful tool for both understanding the complex system-level properties of the highly coordinated adaptation process and generating further hypotheses for experimental investigation.

  5. Cystic Fibrosis Transmembrane Conductance Regulator (CFTR): CLOSED AND OPEN STATE CHANNEL MODELS.

    Science.gov (United States)

    Corradi, Valentina; Vergani, Paola; Tieleman, D Peter

    2015-09-18

    The cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the ATP-binding cassette (ABC) transporter superfamily. CFTR controls the flow of anions through the apical membrane of epithelia. Dysfunctional CFTR causes the common lethal genetic disease cystic fibrosis. Transitions between open and closed states of CFTR are regulated by ATP binding and hydrolysis on the cytosolic nucleotide binding domains, which are coupled with the transmembrane (TM) domains forming the pathway for anion permeation. Lack of structural data hampers a global understanding of CFTR and thus the development of "rational" approaches directly targeting defective CFTR. In this work, we explored possible conformational states of the CFTR gating cycle by means of homology modeling. As templates, we used structures of homologous ABC transporters, namely TM(287-288), ABC-B10, McjD, and Sav1866. In the light of published experimental results, structural analysis of the transmembrane cavity suggests that the TM(287-288)-based CFTR model could correspond to a commonly occupied closed state, whereas the McjD-based model could represent an open state. The models capture the important role played by Phe-337 as a filter/gating residue and provide structural information on the conformational transition from closed to open channel.

  6. A tomato (Solanum lycopersicum) APETALA2/ERF gene, SlAP2a, is a negative regulator of fruit ripening

    National Research Council Canada - National Science Library

    Chung, Mi‐Young; Vrebalov, Julia; Alba, Rob; Lee, JeMin; McQuinn, Ryan; Chung, Jae‐Dong; Klein, Patricia; Giovannoni, James

    2010-01-01

    .... Tomato is a model for biology and genetics regulating specific ripening pathways including ethylene, carotenoids and cell wall metabolism in addition to upstream signaling and transcriptional regulators. Ripening...

  7. An implementation of continuous genetic algorithm in parameter estimation of predator-prey model

    Science.gov (United States)

    Windarto

    2016-03-01

    Genetic algorithm is an optimization method based on the principles of genetics and natural selection in life organisms. The main components of this algorithm are chromosomes population (individuals population), parent selection, crossover to produce new offspring, and random mutation. In this paper, continuous genetic algorithm was implemented to estimate parameters in a predator-prey model of Lotka-Volterra type. For simplicity, all genetic algorithm parameters (selection rate and mutation rate) are set to be constant along implementation of the algorithm. It was found that by selecting suitable mutation rate, the algorithms can estimate these parameters well.

  8. Regulation models for district heating. Background report; Denmark; Reguleringsmodeller for fjernvarmen. Baggrundsrapport

    Energy Technology Data Exchange (ETDEWEB)

    2012-02-15

    The background report describes in detail the elements of the analysis: the present regulation, experiences from other countries and sectors, the aim of regulation, and detailed analysis of four regulation models. (LN)

  9. Genetic Model of an Aborted Porphyry-copper System

    Science.gov (United States)

    Papp, D. C.; Nitoi, E.; Szakacs, A.

    2009-05-01

    The Neogene Sturzii shallow intrusion from the East Carpathians (Bargau Mts., Romania), hosted by Paleogene-Miocene sediments of the Transcarpatian Flysch, developed as an immature porphyry copper structure. It consists of small volumes of dacites, andesites and related contact breccias, having a surface exposure of a few km2. Hydrothermal alteration occurred in the inner part of the intrusive body. The related mineralization consists of pyrite and chalcopyrite either as small veins or disseminated within the rock. A genetic model of the intrusive structure has been developed based on an integrated petrographic, geochemical, isotopic, fluid inclusion and geophysical study. The rapidly ascending calc-alkaline magmas that generated the intrusion are mantle-derived and contaminated with lower-crustal material. Pressure estimations for amphibole reveal significant differences between values corresponding to the crystal cores and rims, suggesting that decompression occurred during its crystallization. The occurrence of exploded fluid inclusions, as well as of primary igneous garnet, also indicate decompression regime during magma uplift and/or storage. All fluid inclusions identified in dacites are aqueous; C-N-S species were not detected. The general evolution of the fluids is toward decreasing salinity with decreasing temperature. Early high-T, high salinity fluids, most likely of magmatic origin, were subjected to a boiling event, related to a change of fluid pressure from litho- to hydrostatic, and followed by dilution with meteoric fluids as indicated by low salinities. These characteristics of the fluids suggest the tendency of the intrusion to evolve towards a porphyry copper system. We estimate that the evolution stopped due to decompression that allowed cold and dilute external fluids to enter the system and because of the small size of the intrusion that cooled down rapidly and could not induce extensive and long-lasting fluid circulation. Since there is no

  10. Genetic interaction of two abscisic acid signaling regulators, HY5 and FIERY1, in mediating lateral root formation

    KAUST Repository

    Chen, Hao

    2011-01-01

    Root architecture is continuously shaped in a manner that helps plants to better adapt to the environment. Gene regulation at the transcriptional or post-transcriptional levels largely controls this environmental response. Recently, RNA silencing has emerged as an important player in gene regulation and is involved in many aspects of plant development, including lateral root formation. In a recent study, we found that FIERY1, a bifunctional abiotic stress and abscisic acid (ABA) signaling regulator and an endogenous RNA silencing suppressor, mediates auxin response during lateral root formation in Arabidopsis. We proposed that FRY1 regulates lateral root development through its activity on adenosine 3,5-bisphosphate (PAP), a strong inhibitor of exoribonucleases (XRNs). Interestingly, some of the phenotypes of fry1, such as enhanced response to light in repressing hypocotyl elongation and hypersensitivity to ABA in lateral root growth, are opposite to those of another light- and ABA-signaling mutant, hy5. Here we analyzed the hy5 fry1 double mutant for root and hypocotyl growth. We found that the hy5 mutation can suppress the enhanced light sensitivity in fry1 hypocotyl elongation and restore the lateral root formation. The genetic interaction between HY5 and FRY1 indicates that HY5 and FRY1 may act in overlapping pathways that mediate light signaling and lateral root development. © 2011 Landes Bioscience.

  11. Using genetic mouse models to gain insight into glaucoma: Past results and future possibilities.

    Science.gov (United States)

    Fernandes, Kimberly A; Harder, Jeffrey M; Williams, Pete A; Rausch, Rebecca L; Kiernan, Amy E; Nair, K Saidas; Anderson, Michael G; John, Simon W M; Howell, Gareth R; Libby, Richard T

    2015-12-01

    While all forms of glaucoma are characterized by a specific pattern of retinal ganglion cell death, they are clinically divided into several distinct subclasses, including normal tension glaucoma, primary open angle glaucoma, congenital glaucoma, and secondary glaucoma. For each type of glaucoma there are likely numerous molecular pathways that control susceptibility to the disease. Given this complexity, a single animal model will never precisely model all aspects of all the different types of human glaucoma. Therefore, multiple animal models have been utilized to study glaucoma but more are needed. Because of the powerful genetic tools available to use in the laboratory mouse, it has proven to be a highly useful mammalian system for studying the pathophysiology of human disease. The similarity between human and mouse eyes coupled with the ability to use a combination of advanced cell biological and genetic tools in mice have led to a large increase in the number of studies using mice to model specific glaucoma phenotypes. Over the last decade, numerous new mouse models and genetic tools have emerged, providing important insight into the cell biology and genetics of glaucoma. In this review, we describe available mouse genetic models that can be used to study glaucoma-relevant disease/pathobiology. Furthermore, we discuss how these models have been used to gain insights into ocular hypertension (a major risk factor for glaucoma) and glaucomatous retinal ganglion cell death. Finally, the potential for developing new mouse models and using advanced genetic tools and resources for studying glaucoma are discussed.

  12. A Novel Statistical Model to Estimate Host Genetic Effects Affecting Disease Transmission

    Science.gov (United States)

    Anacleto, Osvaldo; Garcia-Cortés, Luis Alberto; Lipschutz-Powell, Debby; Woolliams, John A.; Doeschl-Wilson, Andrea B.

    2015-01-01

    There is increasing recognition that genetic diversity can affect the spread of diseases, potentially affecting plant and livestock disease control as well as the emergence of human disease outbreaks. Nevertheless, even though computational tools can guide the control of infectious diseases, few epidemiological models can simultaneously accommodate the inherent individual heterogeneity in multiple infectious disease traits influencing disease transmission, such as the frequently modeled propensity to become infected and infectivity, which describes the host ability to transmit the infection to susceptible individuals. Furthermore, current quantitative genetic models fail to fully capture the heritable variation in host infectivity, mainly because they cannot accommodate the nonlinear infection dynamics underlying epidemiological data. We present in this article a novel statistical model and an inference method to estimate genetic parameters associated with both host susceptibility and infectivity. Our methodology combines quantitative genetic models of social interactions with stochastic processes to model the random, nonlinear, and dynamic nature of infections and uses adaptive Bayesian computational techniques to estimate the model parameters. Results using simulated epidemic data show that our model can accurately estimate heritabilities and genetic risks not only of susceptibility but also of infectivity, therefore exploring a trait whose heritable variation is currently ignored in disease genetics and can greatly influence the spread of infectious diseases. Our proposed methodology offers potential impacts in areas such as livestock disease control through selective breeding and also in predicting and controlling the emergence of disease outbreaks in human populations. PMID:26405030

  13. Developing Novel Therapeutic Approaches in Small Cell Lung Carcinoma Using Genetically Engineered Mouse Models and Human Circulating Tumor Cells

    Science.gov (United States)

    2015-10-01

    Using Genetically Engineered Mouse Models and Human Circulating Tumor Cells PRINCIPAL INVESTIGATOR: Jeffrey Engelman MD PhD CONTRACTING...SUBTITLE Developiing Novel Therapeutic Approaches in Small Cell Lung 5a. CONTRACT NUMBER Carcinoma Using Genetically Engineered Mouse Models and 5b...biomarkers. 15. SUBJECT TERMS Small cell lung cancer (SCLC), Genetically engineered mouse model (GEMM), BH3 mimetic, TORC inhibitor, Apoptosis

  14. A parametric model for analyzing anticipation in genetically predisposed families

    DEFF Research Database (Denmark)

    Larsen, Klaus; Petersen, Janne; Bernstein, Inge

    2009-01-01

    Anticipation, i.e. a decreasing age-at-onset in subsequent generations has been observed in a number of genetically triggered diseases. The impact of anticipation is generally studied in affected parent-child pairs. These analyses are restricted to pairs in which both individuals have been affect...

  15. A realistic model under which the genetic code is optimal.

    Science.gov (United States)

    Buhrman, Harry; van der Gulik, Peter T S; Klau, Gunnar W; Schaffner, Christian; Speijer, Dave; Stougie, Leen

    2013-10-01

    The genetic code has a high level of error robustness. Using values of hydrophobicity scales as a proxy for amino acid character, and the mean square measure as a function quantifying error robustness, a value can be obtained for a genetic code which reflects the error robustness of that code. By comparing this value with a distribution of values belonging to codes generated by random permutations of amino acid assignments, the level of error robustness of a genetic code can be quantified. We present a calculation in which the standard genetic code is shown to be optimal. We obtain this result by (1) using recently updated values of polar requirement as input; (2) fixing seven assignments (Ile, Trp, His, Phe, Tyr, Arg, and Leu) based on aptamer considerations; and (3) using known biosynthetic relations of the 20 amino acids. This last point is reflected in an approach of subdivision (restricting the random reallocation of assignments to amino acid subgroups, the set of 20 being divided in four such subgroups). The three approaches to explain robustness of the code (specific selection for robustness, amino acid-RNA interactions leading to assignments, or a slow growth process of assignment patterns) are reexamined in light of our findings. We offer a comprehensive hypothesis, stressing the importance of biosynthetic relations, with the code evolving from an early stage with just glycine and alanine, via intermediate stages, towards 64 codons carrying todays meaning.

  16. Linguini Models of Molecular Genetic Mapping and Fingerprinting.

    Science.gov (United States)

    Thompson, James N., Jr.; Gray, Stanton B.; Hellack, Jenna J.

    1997-01-01

    Presents an exercise using linguini noodles to demonstrate an aspect of DNA fingerprinting. DNA maps that show genetic differences can be produced by digesting a certain piece of DNA with two or more restriction enzymes both individually and in combination. By rearranging and matching linguini fragments, students can recreate the original pattern…

  17. [Mobile genetic element MDG4 (gypsy) in Drosophila melanogaster. Features of structure and regulation of transposition].

    Science.gov (United States)

    Kusulidu, L K; Karpova, N N; Razorenova, O V; Glukhov, I A; Kim, A I; Liubomirskaia, N V; Il'in, Iu V

    2001-12-01

    Distribution of two structural functional variants of the MDG4 (gypsy) mobile genetic element was examined in 44 strains of Drosophila melanogaster. The results obtained suggest that less transpositionally active MDG4 variant is more ancient component of the Drosophila genome. Using Southern blotting, five strains characterized by increased copy number of MDG4 with significant prevalence of the active variant over the less active one were selected for further analysis. Genetic analysis of these strains led to the suggestion that some of them carry factors that mobilize MDG4 independently from the cellular flamenco gene known to be responsible for transposition of this element. Other strains probably contained a suppressor of the flam- mutant allele causing active transpositions of the MDG4. Thus, the material for studying poorly examined relationships between the retrovirus and the host cell genome was obtained.

  18. On the Inclusion of Self Regulating Branching Processes in the Working Paradigm of Evolutionary and Population Genetics

    Directory of Open Access Journals (Sweden)

    Charles J Mode

    2013-02-01

    Full Text Available The principal goal of this methodological paper is to suggest to a generalaudience in the genetics community that the consideration of recentdevelopments of self regulating branching processes may lead to thepossibility of including this class of stochastic processes as part ofworking paradigm of evolutionary and population genetics. This class ofbranching processes is self regulating in the sense that an evolvingpopulation will grow only to a total population size that can be sustainedby the environment. From the mathematical point of view the class processesunder consideration belongs to a subfield of probability and statisticssometimes referred to as computational applied probability and stochasticprocesses. Computer intensive methods based on Monte Carlo simulationprocedures have been used to empirically work out the predictions of aformulation by assigning numerical values to some point in the parameterspace and computing replications of realizations of the process overthousands of generations of evolution. Statistical methods are then used onsuch samples of simulated data to produce informative summarizations of thedata that provide insights into the evolutionary implications of computerexperiments. Briefly, it is also possible to embed deterministic non-lineardifference equations in the stochastic process by using a statisticalprocedure to estimate the sample functions of the process, which hasinteresting methodological implications as to whether stochastic ordeterministic formulations may be applied separately or in combination inthe study of evolution. It is recognized that the literature on populationgenetics contains a substantial number of papers in which Monte Carlosimulation methods have been used. But, this extensive literature is beyondthe scope of this paper, which is focused on potential applications of selfregulating branching processes in evolutionary and population genetics.

  19. Finding model parameters: Genetic algorithms and the numerical modelling of quartz luminescence

    Energy Technology Data Exchange (ETDEWEB)

    Adamiec, Grzegorz [Department of Radioisotopes, Institute of Physics, Silesian University of Technology, ul. Krzywoustego 2, 44-100 Gliwice (Poland)]. E-mail: grzegorz.adamiec@polsl.pl; Bluszcz, Andrzej [Department of Radioisotopes, Institute of Physics, Silesian University of Technology, ul. Krzywoustego 2, 44-100 Gliwice (Poland); Bailey, Richard [Department of Geography, Royal Holloway, University of London, Egham, Surrey, TW20 0EX (United Kingdom); Garcia-Talavera, Marta [LIBRA, Centro I-D, Campus Miguel Delibes, 47011 Valladolid (Spain)

    2006-08-15

    The paper presents an application of genetic algorithms (GAs) to the problem of finding appropriate parameter values for the numerical simulation of quartz thermoluminescence (TL). We show that with the use of GAs it is possible to achieve a very good match between simulated and experimentally measured characteristics of quartz, for example the thermal activation characteristics of fired quartz. The rate equations of charge transport in the numerical model of luminescence in quartz contain a large number of parameters (trap depths, frequency factors, populations, charge capture probabilities, optical detrapping probabilities, and recombination probabilities). Given that comprehensive models consist of over 10 traps, finding model parameters proves a very difficult task. Manual parameter changes are very time consuming and allow only a limited degree of accuracy. GAs provide a semi-automatic way of finding appropriate parameters.

  20. Type-dependent irreversible stochastic spin models for genetic regulatory networks at the level of promotion-inhibition circuitry

    Science.gov (United States)

    Mendonça, J. Ricardo G.; de Oliveira, Mário J.

    2015-12-01

    We describe an approach to model genetic regulatory networks at the level of promotion-inhibition circuitry through a class of stochastic spin models that includes spatial and temporal density fluctuations in a natural way. The formalism can be viewed as an agent-based model formalism with agent behaviour ruled by a classical spin-like pseudo-Hamiltonian playing the role of a local, individual objective function. A particular but otherwise generally applicable choice for the microscopic transition rates of the models also makes them of independent interest. To illustrate the formalism, we investigate (by Monte Carlo simulations) some stationary state properties of the repressilator, a synthetic three-gene network of transcriptional regulators that possesses oscillatory behaviour.

  1. The genetic and enzymic regulation of the synthesis of the A and B determinants in the ABO blood group system.

    Science.gov (United States)

    Watkins, W M; Greenwell, P; Yates, A D

    1981-01-01

    Possible genetic models for the inheritance of the ABO blood groups are discussed in terms of the glycosyltransferase enzymes which complete the synthesis of the A and B determinants. Recent immunologic evidence in support of the allelic status of the ABO genes is reviewed. Results are presented of experiments which demonstrate that the B gene associated alpha-3-D-galactosyltransferase can be used to synthesis blood group A determinants.

  2. Modelling and genetic algorithm based optimisation of inverse supply chain

    Science.gov (United States)

    Bányai, T.

    2009-04-01

    (Recycling of household appliances with emphasis on reuse options). The purpose of this paper is the presentation of a possible method for avoiding the unnecessary environmental risk and landscape use through unprovoked large supply chain of collection systems of recycling processes. In the first part of the paper the author presents the mathematical model of recycling related collection systems (applied especially for wastes of electric and electronic products) and in the second part of the work a genetic algorithm based optimisation method will be demonstrated, by the aid of which it is possible to determine the optimal structure of the inverse supply chain from the point of view economical, ecological and logistic objective functions. The model of the inverse supply chain is based on a multi-level, hierarchical collection system. In case of this static model it is assumed that technical conditions are permanent. The total costs consist of three parts: total infrastructure costs, total material handling costs and environmental risk costs. The infrastructure-related costs are dependent only on the specific fixed costs and the specific unit costs of the operation points (collection, pre-treatment, treatment, recycling and reuse plants). The costs of warehousing and transportation are represented by the material handling related costs. The most important factors determining the level of environmental risk cost are the number of out of time recycled (treated or reused) products, the number of supply chain objects and the length of transportation routes. The objective function is the minimization of the total cost taking into consideration the constraints. However a lot of research work discussed the design of supply chain [8], but most of them concentrate on linear cost functions. In the case of this model non-linear cost functions were used. The non-linear cost functions and the possible high number of objects of the inverse supply chain leaded to the problem of choosing a

  3. Aldehyde dehydrogenase-2 regulates nociception in rodent models of acute inflammatory pain.

    Science.gov (United States)

    Zambelli, Vanessa O; Gross, Eric R; Chen, Che-Hong; Gutierrez, Vanessa P; Cury, Yara; Mochly-Rosen, Daria

    2014-08-27

    Exogenous aldehydes can cause pain in animal models, suggesting that aldehyde dehydrogenase-2 (ALDH2), which metabolizes many aldehydes, may regulate nociception. To test this hypothesis, we generated a knock-in mouse with an inactivating point mutation in ALDH2 (ALDH2*2), which is also present in human ALDH2 of ~540 million East Asians. The ALDH2*1/*2 heterozygotic mice exhibited a larger response to painful stimuli than their wild-type littermates, and this heightened nociception was inhibited by an ALDH2-selective activator (Alda-1). No effect on inflammation per se was observed. Using a rat model, we then showed that nociception tightly correlated with ALDH activity (R(2) = 0.90) and that reduced nociception was associated with less early growth response protein 1 (EGR1) in the spinal cord and less reactive aldehyde accumulation at the insult site (including acetaldehyde and 4-hydroxynonenal). Further, acetaldehyde- and formalin-induced nociceptive behavior was greater in the ALDH2*1/*2 mice than in the wild-type mice. Finally, Alda-1 treatment was even beneficial when given after the inflammatory agent was administered. Our data in rodent models suggest that the mitochondrial enzyme ALDH2 regulates nociception and could serve as a molecular target for pain control, with ALDH2 activators, such as Alda-1, as potential non-narcotic, cardiac-safe analgesics. Furthermore, our results suggest a possible genetic basis for East Asians' apparent lower pain tolerance.

  4. 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.

  5. Genetic feedback regulation of frontal cortical neuronal ensembles through activity-dependent Arc expression and dopaminergic input

    Directory of Open Access Journals (Sweden)

    Surjeet Mastwal

    2016-12-01

    Full Text Available Mental functions involve coordinated activities of specific neuronal ensembles that are embedded in complex brain circuits. Aberrant neuronal ensemble dynamics is thought to form the neurobiological basis of mental disorders. A major challenge in mental health research is to identify these cellular ensembles and determine what molecular mechanisms constrain their emergence and consolidation during development and learning. Here, we provide a perspective based on recent studies that use activity-dependent gene Arc/Arg3.1 as a cellular marker to identify neuronal ensembles and a molecular probe to modulate circuit functions. These studies have demonstrated that the transcription of Arc is activated in selective groups of frontal cortical neurons in response to specific behavioral tasks. Arc expression regulates the persistent firing of individual neurons and predicts the consolidation of neuronal ensembles during repeated learning. Therefore, the Arc pathway represents a prototypical example of activity-dependent genetic feedback regulation of neuronal ensembles. The activation of this pathway in the frontal cortex starts during early postnatal development and requires dopaminergic input. Conversely, genetic disruption of Arc leads to a hypoactive mesofrontal dopamine circuit and its related cognitive deficit. This mutual interaction suggests an auto-regulatory mechanism to amplify the impact of neuromodulators and activity-regulated genes during postnatal development. Such a mechanism may contribute to the association of mutations in dopamine and Arc pathways with neurodevelopmental psychiatric disorders. As the mesofrontal dopamine circuit shows extensive activity-dependent developmental plasticity, activity-guided modulation of dopaminergic projections or Arc ensembles during development may help to repair circuit deficits related to neuropsychiatric disorders.

  6. Progress and Prospects for Genetic Modification of Nonhuman Primate Models in Biomedical Research

    OpenAIRE

    Chan, Anthony W. S.

    2013-01-01

    The growing interest of modeling human diseases using genetically modified (transgenic) nonhuman primates (NHPs) is a direct result of NHPs (rhesus macaque, etc.) close relation to humans. NHPs share similar developmental paths with humans in their anatomy, physiology, genetics, and neural functions; and in their cognition, emotion, and social behavior. The NHP model within biomedical research has played an important role in the development of vaccines, assisted reproductive technologies, and...

  7. 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.

  8. Regulator Loss Functions and Hierarchical Modeling for Safety Decision Making.

    Science.gov (United States)

    Hatfield, Laura A; Baugh, Christine M; Azzone, Vanessa; Normand, Sharon-Lise T

    2017-07-01

    Regulators must act to protect the public when evidence indicates safety problems with medical devices. This requires complex tradeoffs among risks and benefits, which conventional safety surveillance methods do not incorporate. To combine explicit regulator loss functions with statistical evidence on medical device safety signals to improve decision making. In the Hospital Cost and Utilization Project National Inpatient Sample, we select pediatric inpatient admissions and identify adverse medical device events (AMDEs). We fit hierarchical Bayesian models to the annual hospital-level AMDE rates, accounting for patient and hospital characteristics. These models produce expected AMDE rates (a safety target), against which we compare the observed rates in a test year to compute a safety signal. We specify a set of loss functions that quantify the costs and benefits of each action as a function of the safety signal. We integrate the loss functions over the posterior distribution of the safety signal to obtain the posterior (Bayes) risk; the preferred action has the smallest Bayes risk. Using simulation and an analysis of AMDE data, we compare our minimum-risk decisions to a conventional Z score approach for classifying safety signals. The 2 rules produced different actions for nearly half of hospitals (45%). In the simulation, decisions that minimize Bayes risk outperform Z score-based decisions, even when the loss functions or hierarchical models are misspecified. Our method is sensitive to the choice of loss functions; eliciting quantitative inputs to the loss functions from regulators is challenging. A decision-theoretic approach to acting on safety signals is potentially promising but requires careful specification of loss functions in consultation with subject matter experts.

  9. A p-Adic Model of DNA Sequence and Genetic Code

    CERN Document Server

    Dragovich, Branko

    2007-01-01

    Using basic properties of p-adic numbers, we consider a simple new approach to describe main aspects of DNA sequence and genetic code. Central role in our investigation plays an ultrametric p-adic information space which basic elements are nucleotides, codons and genes. We show that a 5-adic model is appropriate for DNA sequence. This 5-adic model, combined with 2-adic distance, is also suitable for genetic code and for a more advanced employment in genomics. We find that genetic code degeneracy is related to the p-adic distance between codons.

  10. New canine models of copper toxicosis: diagnosis, treatment, and genetics.

    Science.gov (United States)

    Fieten, Hille; Penning, Louis C; Leegwater, Peter A J; Rothuizen, Jan

    2014-05-01

    The One Health principle recognizes that human health, animal health, and environmental health are inextricably linked. An excellent example is the study of naturally occurring copper toxicosis in dogs to help understand human disorders of copper metabolism. Besides the Bedlington terrier, where copper toxicosis is caused by a mutation in the COMMD1 gene, more complex hereditary forms of copper-associated hepatitis were recognized recently in other dog breeds. The Labrador retriever is one such breed, where an interplay between genetic susceptibility and exposure to copper lead to clinical copper toxicosis. Purebred dog populations are ideal for gene mapping studies, and because genes involved in copper metabolism are highly conserved across species, newly identified gene mutations in the dog may help unravel the genetic complexity of different human forms of copper toxicosis. Furthermore, increasing knowledge with respect to diagnosis and treatment strategies will benefit both species.

  11. THE PROGRAMED CELL DEATH REGULATORS OF ISOLATED MODEL SYSTEMS

    Directory of Open Access Journals (Sweden)

    D. V. Vatlitsov

    2016-06-01

    Full Text Available The technology evolution creates the prerequisites for the emergence of new informational concept and approaches to the formation of a fundamentally new principles of biological objects understanding. The aim was to study the activators of the programmed cell death in an isolated system model. Cell culture aging parameters were performed on flow cytometer. It had formed the theory that the changes in the concentrations of metal ions and increase their extracellular concentration had formed a negative gradient into the cells.regulation of cell death. It was shown that the metals ions concentrations.

  12. Small-signal, continuous, exact model of PWM voltage regulators

    Science.gov (United States)

    Burkhardt, W.; Maranesi, P.; Varoli, V.

    1985-02-01

    The small-signal time-continuous open-loop response of buck, boost, and buck-boost pulse-width-modulation (PWM) voltage regulators using MOSFET switches in their power stages is modeled, applying a time-domain sampling theorem (Woodward, 1953) to obtain the Fourier open-loop transfer function corresponding to the comb function describing the response at the chopping instants only. The results are presented graphically along with simplified circuit diagrams of the PWM devices, and the accuracy and computational efficiency of the analytical approach are indicated.

  13. [Genetic regulation of T-lymphocyte responsiveness to PHA is independent of culture conditions (author's transl)].

    Science.gov (United States)

    Stiffel, C; Liacopoulos-Briot, M; Decreusefond, C; Lambert, F

    1979-01-01

    A maximal interline separation has been obtained after 10 consecutive generations of selective breeding for the character "quantitative in vitro response of lymph node lymphocytes to the mitogenic effect of phytohaemagglutinin". At the selection limit the difference between high and low responder lines was about 20-fold. A similar interline separation has been demonstrated for the T-mitogen effect of concanavalin A. The identical response to PPD (purified protein derivative of tuberculin), a B mitogen, proved that the genetic selection has only modified the potentialities of T lymphocytes. During the selective breeding, responsiveness to PHA stimulation has been always measured under identical culture conditions. To demonstrate that the interline difference in responsiveness was due essentially to genetic factors independent of environmental effects, a systematic study of various culture conditions has been undertaken. The optimal stimulation was found after two days of culture for high line cells and after three days for low line cells. The difference between maximal responses was only slightly lower than that obtained after a two-day culture as used for the selection test. Increase in cell concentrations produced higher thymidine incorporation. In the two lines, a linear correlation was established between the cell concentration and the response produced. The maximal response given by the highest number of low line lymphocytes was equivalent to that given by a number, 11-fold smaller, of high line cells. Within certain limits, changes in the amount of tritiated thymidine added to the culture did not affect the interline separation. With a thymidine of high specific activity, a sub-evaluation of uptake by high line cells decreased the interline difference. Results in mixed culture of lymph node cells from high and low lines indicated that the low response was not due to the release of inhibiting factors or to the presence of suppressive cells in low responder mice

  14. Assembly and interrogation of Alzheimer's disease genetic networks reveal novel regulators of progression.

    Directory of Open Access Journals (Sweden)

    Soline Aubry

    Full Text Available Alzheimer's disease (AD is a complex multifactorial disorder with poorly characterized pathogenesis. Our understanding of this disease would thus benefit from an approach that addresses this complexity by elucidating the regulatory networks that are dysregulated in the neural compartment of AD patients, across distinct brain regions. Here, we use a Systems Biology (SB approach, which has been highly successful in the dissection of cancer related phenotypes, to reverse engineer the transcriptional regulation layer of human neuronal cells and interrogate it to infer candidate Master Regulators (MRs responsible for disease progression. Analysis of gene expression profiles from laser-captured neurons from AD and controls subjects, using the Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe, yielded an interactome consisting of 488,353 transcription-factor/target interactions. Interrogation of this interactome, using the Master Regulator INference algorithm (MARINa, identified an unbiased set of candidate MRs causally responsible for regulating the transcriptional signature of AD progression. Experimental assays in autopsy-derived human brain tissue showed that three of the top candidate MRs (YY1, p300 and ZMYM3 are indeed biochemically and histopathologically dysregulated in AD brains compared to controls. Our results additionally implicate p53 and loss of acetylation homeostasis in the neurodegenerative process. This study suggests that an integrative, SB approach can be applied to AD and other neurodegenerative diseases, and provide significant novel insight on the disease progression.

  15. Random regressions models to describe the genetic variation of milk yield over multiple parities in Buffaloes

    Directory of Open Access Journals (Sweden)

    H. Tonhati

    2010-02-01

    Full Text Available The objectives of this study were to estimate (covariance functions for additive genetic and permanent environmental effects, as well as the genetic parameters for milk yield over multiple parities, using random regressions models (RRM. Records of 4,757 complete lactations of Murrah breed buffaloes from 12 herds were analyzed. Ages at calving were between 2 and 11 years. The model included the additive genetic and permanent environmental random effects and the fixed effects of contemporary groups (herd, year and calving season and milking frequency (1 or 2. A cubic regression on Legendre orthogonal polynomials of ages was used to model the mean trend. The additive genetic and permanent environmental effects were modeled by Legendre orthogonal polynomials. Residual variances were considered homogenous or heterogeneous, modeled through variance functions or step functions with 5, 7 or 10 classes. Results from Akaike’s and Schwarz’s Bayesian information criterion indicated that a RRM considering a third order polynomial for the additive genetic and permanent environmental effects and a step function with 5 classes for residual variances fitted best. Heritability estimates obtained by this model varied from 0.10 to 0.28. Genetic correlations were high between consecutive ages, but decreased when intervals between ages increased

  16. Using genetically engineered animal models in the postgenomic era to understand gene function in alcoholism.

    Science.gov (United States)

    Reilly, Matthew T; Harris, R Adron; Noronha, Antonio

    2012-01-01

    Over the last 50 years, researchers have made substantial progress in identifying genetic variations that underlie the complex phenotype of alcoholism. Not much is known, however, about how this genetic variation translates into altered biological function. Genetic animal models recapitulating specific characteristics of the human condition have helped elucidate gene function and the genetic basis of disease. In particular, major advances have come from the ability to manipulate genes through a variety of genetic technologies that provide an unprecedented capacity to determine gene function in the living organism and in alcohol-related behaviors. Even newer genetic-engineering technologies have given researchers the ability to control when and where a specific gene or mutation is activated or deleted, allowing investigators to narrow the role of the gene's function to circumscribed neural pathways and across development. These technologies are important for all areas of neuroscience, and several public and private initiatives are making a new generation of genetic-engineering tools available to the scientific community at large. Finally, high-throughput "next-generation sequencing" technologies are set to rapidly increase knowledge of the genome, epigenome, and transcriptome, which, combined with genetically engineered mouse mutants, will enhance insight into biological function. All of these resources will provide deeper insight into the genetic basis of alcoholism.

  17. Empirical valence bond models for reactive potential energy surfaces: a parallel multilevel genetic program approach.

    Science.gov (United States)

    Bellucci, Michael A; Coker, David F

    2011-07-28

    We describe a new method for constructing empirical valence bond potential energy surfaces using a parallel multilevel genetic program (PMLGP). Genetic programs can be used to perform an efficient search through function space and parameter space to find the best functions and sets of parameters that fit energies obtained by ab initio electronic structure calculations. Building on the traditional genetic program approach, the PMLGP utilizes a hierarchy of genetic programming on two different levels. The lower level genetic programs are used to optimize coevolving populations in parallel while the higher level genetic program (HLGP) is used to optimize the genetic operator probabilities of the lower level genetic programs. The HLGP allows the algorithm to dynamically learn the mutation or combination of mutations that most effectively increase the fitness of the populations, causing a significant increase in the algorithm's accuracy and efficiency. The algorithm's accuracy and efficiency is tested against a standard parallel genetic program with a variety of one-dimensional test cases. Subsequently, the PMLGP is utilized to obtain an accurate empirical valence bond model for proton transfer in 3-hydroxy-gamma-pyrone in gas phase and protic solvent.

  18. Thermodynamic analysis of regulation in metabolic networks using constraint-based modeling

    Directory of Open Access Journals (Sweden)

    Mahadevan Radhakrishnan

    2010-05-01

    Full Text Available Abstract Background Geobacter sulfurreducens is a member of the Geobacter species, which are capable of oxidation of organic waste coupled to the reduction of heavy metals and electrode with applications in bioremediation and bioenergy generation. While the metabolism of this organism has been studied through the development of a stoichiometry based genome-scale metabolic model, the associated regulatory network has not yet been well studied. In this manuscript, we report on the implementation of a thermodynamics based metabolic flux model for Geobacter sulfurreducens. We use this updated model to identify reactions that are subject to regulatory control in the metabolic network of G. sulfurreducens using thermodynamic variability analysis. Findings As a first step, we have validated the regulatory sites and bottleneck reactions predicted by the thermodynamic flux analysis in E. coli by evaluating the expression ranges of the corresponding genes. We then identified ten reactions in the metabolic network of G. sulfurreducens that are predicted to be candidates for regulation. We then compared the free energy ranges for these reactions with the corresponding gene expression fold changes under conditions of different environmental and genetic perturbations and show that the model predictions of regulation are consistent with data. In addition, we also identify reactions that operate close to equilibrium and show that the experimentally determined exchange coefficient (a measure of reversibility is significant for these reactions. Conclusions Application of the thermodynamic constraints resulted in identification of potential bottleneck reactions not only from the central metabolism but also from the nucleotide and amino acid subsystems, thereby showing the highly coupled nature of the thermodynamic constraints. In addition, thermodynamic variability analysis serves as a valuable tool in estimating the ranges of ΔrG' of every reaction in the model

  19. Baboons as a model to study genetics and epigenetics of human disease.

    Science.gov (United States)

    Cox, Laura A; Comuzzie, Anthony G; Havill, Lorena M; Karere, Genesio M; Spradling, Kimberly D; Mahaney, Michael C; Nathanielsz, Peter W; Nicolella, Daniel P; Shade, Robert E; Voruganti, Saroja; VandeBerg, John L

    2013-01-01

    A major challenge for understanding susceptibility to common human diseases is determining genetic and environmental factors that influence mechanisms underlying variation in disease-related traits. The most common diseases afflicting the US population are complex diseases that develop as a result of defects in multiple genetically controlled systems in response to environmental challenges. Unraveling the etiology of these diseases is exceedingly difficult because of the many genetic and environmental factors involved. Studies of complex disease genetics in humans are challenging because it is not possible to control pedigree structure and often not practical to control environmental conditions over an extended period of time. Furthermore, access to tissues relevant to many diseases from healthy individuals is quite limited. The baboon is a well-established research model for the study of a wide array of common complex diseases, including dyslipidemia, hypertension, obesity, and osteoporosis. It is possible to acquire tissues from healthy, genetically characterized baboons that have been exposed to defined environmental stimuli. In this review, we describe the genetic and physiologic similarity of baboons with humans, the ability and usefulness of controlling environment and breeding, and current genetic and genomic resources. We discuss studies on genetics of heart disease, obesity, diabetes, metabolic syndrome, hypertension, osteoporosis, osteoarthritis, and intrauterine growth restriction using the baboon as a model for human disease. We also summarize new studies and resources under development, providing examples of potential translational studies for targeted interventions and therapies for human disease.

  20. The two-process model of sleep regulation: a reappraisal.

    Science.gov (United States)

    Borbély, Alexander A; Daan, Serge; Wirz-Justice, Anna; Deboer, Tom

    2016-04-01

    In the last three decades the two-process model of sleep regulation has served as a major conceptual framework in sleep research. It has been applied widely in studies on fatigue and performance and to dissect individual differences in sleep regulation. The model posits that a homeostatic process (Process S) interacts with a process controlled by the circadian pacemaker (Process C), with time-courses derived from physiological and behavioural variables. The model simulates successfully the timing and intensity of sleep in diverse experimental protocols. Electrophysiological recordings from the suprachiasmatic nuclei (SCN) suggest that S and C interact continuously. Oscillators outside the SCN that are linked to energy metabolism are evident in SCN-lesioned arrhythmic animals subjected to restricted feeding or methamphetamine administration, as well as in human subjects during internal desynchronization. In intact animals these peripheral oscillators may dissociate from the central pacemaker rhythm. A sleep/fast and wake/feed phase segregate antagonistic anabolic and catabolic metabolic processes in peripheral tissues. A deficiency of Process S was proposed to account for both depressive sleep disturbances and the antidepressant effect of sleep deprivation. The model supported the development of novel non-pharmacological treatment paradigms in psychiatry, based on manipulating circadian phase, sleep and light exposure. In conclusion, the model remains conceptually useful for promoting the integration of sleep and circadian rhythm research. Sleep appears to have not only a short-term, use-dependent function; it also serves to enforce rest and fasting, thereby supporting the optimization of metabolic processes at the appropriate phase of the 24-h cycle.

  1. Campaign Finance Regulation: the Resilence of the American Model

    Directory of Open Access Journals (Sweden)

    William D. Araiza

    2009-12-01

    Full Text Available

    The current term of the United States Supreme Court, which began this past October, is notable for its concentration of cases testing the permissible scope of federal regulation of business. But if this term’s docket reflects the pressure faced by the American economic model – a model marked by lax regulation, faith in private choices and market outcomes, and toleration of large inequalities in results – then this term will likely also mark a reaffirmation of that model in the context of free expression. In September the Court held a rare off-schedule oral argument in Citizens United v. Federal Election Commission, a case that may result in significant changes in the constitutional status of American campaign finance law.  Citizens United presents the Court’s emerging conservative majority with an opportunity to deregulate corporations’ campaign speech by finding restrictions on that speech to violate the First Amendment. Depending on the breadth of the Court’s holding, Citizens United may well result in the triumph of the American economic model in the context of the political marketplace exactly when that model is coming under severe strain on other fronts.

  2. Genetic dys-regulation of astrocytic glutamate transporter EAAT2 and its implications in neurological disorders and manganese toxicity.

    Science.gov (United States)

    Karki, Pratap; Smith, Keisha; Johnson, James; Aschner, Michael; Lee, Eunsook Y

    2015-02-01

    Astrocytic glutamate transporters, the excitatory amino acid transporter (EAAT) 2 and EAAT1 (glutamate transporter 1 and glutamate aspartate transporter in rodents, respectively), are the main transporters for maintaining optimal glutamate levels in the synaptic clefts by taking up more than 90% of glutamate from extracellular space thus preventing excitotoxic neuronal death. Reduced expression and function of these transporters, especially EAAT2, has been reported in numerous neurological disorders, including amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, schizophrenia and epilepsy. The mechanism of down-regulation of EAAT2 in these diseases has yet to be fully established. Genetic as well as transcriptional dys-regulation of these transporters by various modes, such as single nucleotide polymorphisms and epigenetics, resulting in impairment of their functions, might play an important role in the etiology of neurological diseases. Consequently, there has been an extensive effort to identify molecular targets for enhancement of EAAT2 expression as a potential therapeutic approach. Several pharmacological agents increase expression of EAAT2 via nuclear factor κB and cAMP response element binding protein at the transcriptional level. However, the negative regulatory mechanisms of EAAT2 have yet to be identified. Recent studies, including those from our laboratory, suggest that the transcriptional factor yin yang 1 plays a critical role in the repressive effects of various neurotoxins, such as manganese (Mn), on EAAT2 expression. In this review, we will focus on transcriptional epigenetics and translational regulation of EAAT2.

  3. Genetic dys-regulation of astrocytic glutamate transporter EAAT2 and its implications in neurological disorders and manganese toxicity

    Science.gov (United States)

    Karki, Pratap; Smith, Keisha; Johnson, James; Aschner, Michael; Lee, Eunsook

    2014-01-01

    Astrocytic glutamate transporters, the excitatory amino acid transporter (EAAT) 2 and EAAT1 [glutamate transporter 1 (GLT-1) and glutamate aspartate transporter (GLAST) in rodents, respectively], are the main transporters for maintaining optimal glutamate levels in the synaptic clefts by taking up more than 90% of glutamate from extracellular space thus preventing excitotoxic neuronal death. Reduced expression and function of these transporters, especially EAAT2, has been reported in numerous neurological disorders, including amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, schizophrenia and epilepsy. The mechanism of down-regulation of EAAT2 in these diseases has yet to be fully established. Genetic as well as transcriptional dys-regulation of these transporters by various modes, such as single nucleotide polymorphisms (SNPs) and epigenetics, resulting in impairment of their functions, might play an important role in the etiology of neurological diseases. Consequently, there has been an extensive effort to identify molecular targets for enhancement of EAAT2 expression as a potential therapeutic approach. Several pharmacological agents increase expression of EAAT2 via NF-κB and CREB at the transcriptional level. However, the negative regulatory mechanisms of EAAT2 have yet to be identified. Recent studies, including those from our laboratory, suggest that the transcriptional factor yin yang 1 (YY1) plays a critical role in the repressive effects of various neurotoxins, such as manganese (Mn), on EAAT2 expression. In this review, we will focus on transcriptional epigenetics, and translational regulation of EAAT2. PMID:25064045

  4. Thermodynamic state ensemble models of cis-regulation.

    Directory of Open Access Journals (Sweden)

    Marc S Sherman

    Full Text Available A major goal in computational biology is to develop models that accurately predict a gene's expression from its surrounding regulatory DNA. Here we present one class of such models, thermodynamic state ensemble models. We describe the biochemical derivation of the thermodynamic framework in simple terms, and lay out the mathematical components that comprise each model. These components include (1 the possible states of a promoter, where a state is defined as a particular arrangement of transcription factors bound to a DNA promoter, (2 the binding constants that describe the affinity of the protein-protein and protein-DNA interactions that occur in each state, and (3 whether each state is capable of transcribing. Using these components, we demonstrate how to compute a cis-regulatory function that encodes the probability of a promoter being active. Our intention is to provide enough detail so that readers with little background in thermodynamics can compose their own cis-regulatory functions. To facilitate this goal, we also describe a matrix form of the model that can be easily coded in any programming language. This formalism has great flexibility, which we show by illustrating how phenomena such as competition between transcription factors and cooperativity are readily incorporated into these models. Using this framework, we also demonstrate that Michaelis-like functions, another class of cis-regulatory models, are a subset of the thermodynamic framework with specific assumptions. By recasting Michaelis-like functions as thermodynamic functions, we emphasize the relationship between these models and delineate the specific circumstances representable by each approach. Application of thermodynamic state ensemble models is likely to be an important tool in unraveling the physical basis of combinatorial cis-regulation and in generating formalisms that accurately predict gene expression from DNA sequence.

  5. Modeling classic attenuation regulation of gene expression in bacteria.

    Science.gov (United States)

    Lyubetsky, Vassily A; Pirogov, Sergey A; Rubanov, Lev I; Seliverstov, Alexander V

    2007-02-01

    A model is proposed primarily for the classical RNA attenuation regulation of gene expression through premature transcription termination. The model is based on the concept of the RNA secondary structure macrostate within the regulatory region between the ribosome and RNA-polymerase, on hypothetical equation describing deceleration of RNA-polymerase by a macrostate and on views of transcription and translation initiation and elongation, under different values of the four basic model parameters which were varied. A special effort was made to select adequate model parameters. We first discuss kinetics of RNA folding and define the concept of the macrostate as a specific parentheses structure used to construct a conventional set of hairpins. The originally developed software that realizes the proposed model offers functionality to fully model RNA secondary folding kinetics. Its performance is compared to that of a public server described in Ref. 1. We then describe the delay in RNA-polymerase shifting to the next base or its premature termination caused by an RNA secondary structure or, herefrom, a macrostate. In this description, essential concepts are the basic and excited states of the polymerase first introduced in Ref. 2: the polymerase shifting to the next base can occur only in the basic state, and its detachment from DNA strand - only in excited state. As to the authors' knowledge, such a model incorporating the above-mentioned attenuation characteristics is not published elsewhere. The model was implemented in an application with command line interface for running in batch mode in Windows and Linux environments, as well as a public web server.(3) The model was tested with a conventional Monte Carlo procedure. In these simulations, the estimate of correlation between the premature transcription termination probability p and concentration c of charged amino acyl-tRNA was obtained as function p(c) for many regulatory regions in many bacterial genomes, as well as

  6. Ontology driven modeling for the knowledge of genetic susceptibility to disease.

    Science.gov (United States)

    Lin, Yu; Sakamoto, Norihiro

    2009-05-12

    For the machine helped exploring the relationships between genetic factors and complex diseases, a well-structured conceptual framework of the background knowledge is needed. However, because of the complexity of determining a genetic susceptibility factor, there is no formalization for the knowledge of genetic susceptibility to disease, which makes the interoperability between systems impossible. Thus, the ontology modeling language OWL was used for formalization in this paper. After introducing the Semantic Web and OWL language propagated by W3C, we applied text mining technology combined with competency questions to specify the classes of the ontology. Then, an N-ary pattern was adopted to describe the relationships among these defined classes. Based on the former work of OGSF-DM (Ontology of Genetic Susceptibility Factors to Diabetes Mellitus), we formalized the definition of "Genetic Susceptibility", "Genetic Susceptibility Factor" and other classes by using OWL-DL modeling language; and a reasoner automatically performed the classification of the class "Genetic Susceptibility Factor". The ontology driven modeling is used for formalization the knowledge of genetic susceptibility to complex diseases. More importantly, when a class has been completely formalized in an ontology, the OWL reasoning can automatically compute the classification of the class, in our case, the class of "Genetic Susceptibility Factors". With more types of genetic susceptibility factors obtained from the laboratory research, our ontologies always needs to be refined, and many new classes must be taken into account to harmonize with the ontologies. Using the ontologies to develop the semantic web needs to be applied in the future.

  7. A cell-based computational model of early embryogenesis coupling mechanical behaviour and gene regulation.

    Science.gov (United States)

    Delile, Julien; Herrmann, Matthieu; Peyriéras, Nadine; Doursat, René

    2017-01-23

    The study of multicellular development is grounded in two complementary domains: cell biomechanics, which examines how physical forces shape the embryo, and genetic regulation and molecular signalling, which concern how cells determine their states and behaviours. Integrating both sides into a unified framework is crucial to fully understand the self-organized dynamics of morphogenesis. Here we introduce MecaGen, an integrative modelling platform enabling the hypothesis-driven simulation of these dual processes via the coupling between mechanical and chemical variables. Our approach relies upon a minimal 'cell behaviour ontology' comprising mesenchymal and epithelial cells and their associated behaviours. MecaGen enables the specification and control of complex collective movements in 3D space through a biologically relevant gene regulatory network and parameter space exploration. Three case studies investigating pattern formation, epithelial differentiation and tissue tectonics in zebrafish early embryogenesis, the latter with quantitative comparison to live imaging data, demonstrate the validity and usefulness of our framework.

  8. A cell-based computational model of early embryogenesis coupling mechanical behaviour and gene regulation

    Science.gov (United States)

    Delile, Julien; Herrmann, Matthieu; Peyriéras, Nadine; Doursat, René

    2017-01-01

    The study of multicellular development is grounded in two complementary domains: cell biomechanics, which examines how physical forces shape the embryo, and genetic regulation and molecular signalling, which concern how cells determine their states and behaviours. Integrating both sides into a unified framework is crucial to fully understand the self-organized dynamics of morphogenesis. Here we introduce MecaGen, an integrative modelling platform enabling the hypothesis-driven simulation of these dual processes via the coupling between mechanical and chemical variables. Our approach relies upon a minimal `cell behaviour ontology' comprising mesenchymal and epithelial cells and their associated behaviours. MecaGen enables the specification and control of complex collective movements in 3D space through a biologically relevant gene regulatory network and parameter space exploration. Three case studies investigating pattern formation, epithelial differentiation and tissue tectonics in zebrafish early embryogenesis, the latter with quantitative comparison to live imaging data, demonstrate the validity and usefulness of our framework.

  9. Towards a formal design model based on a genetic design model system

    DEFF Research Database (Denmark)

    Storga, Mario; Andreasen, Mogens Myrup; Marjanovic, Dorian

    2005-01-01

    The research presented in this article is aimed to the investigation of the nature, building and practical role of a Design Ontology as a potential framework for the more efficient product development data-, information- and knowledge- description, -explanation, -understanding and -reusing...... by IEEE, provides us definitions for the most general and universal concepts, that we used in our research for derivation of terms definitions and axioms in the Design Ontology. The Design Ontology was evaluated using the OntoEdit® ontology engineering environment, on a real product example, and based....... In this article, we briefly summarize our experience of converting informal definitions of the concepts from the product development domain based on the existing theoretical background into formal design model. As a main data source for extracting the content of a design ontology, Genetic Design Model System...

  10. Towards a formal design model based on a genetic design model system

    DEFF Research Database (Denmark)

    Storga, Mario; Andreasen, Mogens Myrup; Marjanovic, Dorian

    2005-01-01

    . In this article, we briefly summarize our experience of converting informal definitions of the concepts from the product development domain based on the existing theoretical background into formal design model. As a main data source for extracting the content of a design ontology, Genetic Design Model System......The research presented in this article is aimed to the investigation of the nature, building and practical role of a Design Ontology as a potential framework for the more efficient product development data-, information- and knowledge- description, -explanation, -understanding and -reusing...... by IEEE, provides us definitions for the most general and universal concepts, that we used in our research for derivation of terms definitions and axioms in the Design Ontology. The Design Ontology was evaluated using the OntoEdit® ontology engineering environment, on a real product example, and based...

  11. Modelling the loss of genetic diversity in vole populations in a spatially and temporally varying environment

    DEFF Research Database (Denmark)

    Topping, Christopher John; Østergaard, Siri; Pertoldi, Cino

    2003-01-01

    a genetically explicit individual-based model (IBM) coupled to a dynamic landscape model was used to obtain measures for the genetic status of simulated vole populations. The rate of loss of expected heterozygosity (He) was calculated for simulated populations using two levels of spatial and temporal...... heterogeneity. Results showed that both spatial and temporal heterogeneity exerted an influence on the rate of loss of genetic diversity, but the precise effect was a balance between the effects of population sub-structuring, the frequency of founder effects and population size. These were in turn related...... of heterozygosity was corrected for the harmonic mean of the population size, the rate of loss was almost identical in the four scenarios. Unlike classical genetic models, IBMs are flexible enough to mimic real population processes under a range of environmental and behavioural conditions. We conclude that IBMs...

  12. Two-level mixed modeling of longitudinal pedigree data for genetic association analysis

    DEFF Research Database (Denmark)

    Tan, Q.

    2013-01-01

    assess the genetic associations with the mean level and the rate of change in a phenotype both with kinship correlation integrated in the mixed effect models. We apply our method to longitudinal pedigree data to estimate the genetic effects on systolic blood pressure measured over time in large pedigrees...... of follow-up. Approaches have been proposed to integrate kinship correlation into the mixed effect models to explicitly model the genetic relationship which have been proven as an efficient way for dealing with sample clustering in pedigree data. Although useful for adjusting relatedness in the mixed....... Our results show that the method efficiently handles relatedness in detecting genetic variations that affect the mean level or the rate of change for a phenotype of interest....

  13. Genetic Algorithm Calibration of Probabilistic Cellular Automata for Modeling Mining Permit Activity

    Science.gov (United States)

    Louis, S.J.; Raines, G.L.

    2003-01-01

    We use a genetic algorithm to calibrate a spatially and temporally resolved cellular automata to model mining activity on public land in Idaho and western Montana. The genetic algorithm searches through a space of transition rule parameters of a two dimensional cellular automata model to find rule parameters that fit observed mining activity data. Previous work by one of the authors in calibrating the cellular automaton took weeks - the genetic algorithm takes a day and produces rules leading to about the same (or better) fit to observed data. These preliminary results indicate that genetic algorithms are a viable tool in calibrating cellular automata for this application. Experience gained during the calibration of this cellular automata suggests that mineral resource information is a critical factor in the quality of the results. With automated calibration, further refinements of how the mineral-resource information is provided to the cellular automaton will probably improve our model.

  14. A New Modeling Method Based on Genetic Neural Network for Numeral Eddy Current Sensor

    Institute of Scientific and Technical Information of China (English)

    Along Yu; Zheng Li

    2006-01-01

    In this paper, we present a method used to the numeral eddy current sensor modeling based on genetic neural network to settle its nonlinear problem. The principle and algorithms of genetic neural network are introduced. In this method,the nonlinear model parameters of the numeral eddy current sensor are optimized by genetic neural network (GNN) according to measurement data. So the method remains both the global searching ability of genetic algorithm and the good local searching ability of neural network. The nonlinear model has the advantages of strong robustness, on-line scaling and high precision. The maximum nonlinearity error can be reduced to 0.037% using GNN. However, the maximum nonlinearity error is 0.075% using least square method (LMS).

  15. Model-based problem solving through symbolic regression via pareto genetic programming

    NARCIS (Netherlands)

    Vladislavleva, E.

    2008-01-01

    Pareto genetic programming methodology is extended by additional generic model selection and generation strategies that (1) drive the modeling engine to creation of models of reduced non-linearity and increased generalization capabilities, and (2) improve the effectiveness of the search for robust m

  16. Genetic algorithms and genetic programming for multiscale modeling: Applications in materials science and chemistry and advances in scalability

    Science.gov (United States)

    Sastry, Kumara Narasimha

    2007-03-01

    Effective and efficient rnultiscale modeling is essential to advance both the science and synthesis in a, wide array of fields such as physics, chemistry, materials science; biology, biotechnology and pharmacology. This study investigates the efficacy and potential of rising genetic algorithms for rnultiscale materials modeling and addresses some of the challenges involved in designing competent algorithms that solve hard problems quickly, reliably and accurately. In particular, this thesis demonstrates the use of genetic algorithms (GAs) and genetic programming (GP) in multiscale modeling with the help of two non-trivial case studies in materials science and chemistry. The first case study explores the utility of genetic programming (GP) in multi-timescaling alloy kinetics simulations. In essence, GP is used to bridge molecular dynamics and kinetic Monte Carlo methods to span orders-of-magnitude in simulation time. Specifically, GP is used to regress symbolically an inline barrier function from a limited set of molecular dynamics simulations to enable kinetic Monte Carlo that simulate seconds of real time. Results on a non-trivial example of vacancy-assisted migration on a surface of a face-centered cubic (fcc) Copper-Cobalt (CuxCo 1-x) alloy show that GP predicts all barriers with 0.1% error from calculations for less than 3% of active configurations, independent of type of potentials used to obtain the learning set of barriers via molecular dynamics. The resulting method enables 2--9 orders-of-magnitude increase in real-time dynamics simulations taking 4--7 orders-of-magnitude less CPU time. The second case study presents the application of multiobjective genetic algorithms (MOGAs) in multiscaling quantum chemistry simulations. Specifically, MOGAs are used to bridge high-level quantum chemistry and semiempirical methods to provide accurate representation of complex molecular excited-state and ground-state behavior. Results on ethylene and benzene---two common

  17. Revitalization of a forward genetic screen identifies three new regulators of fungal secondary metabolism in the genus Aspergillus

    Science.gov (United States)

    Brandon T. Pfannenstiel; Xixi Zhao; Jennifer Wortman; Philipp Wiemann; Kurt Throckmorton; Joseph E. Spraker; Alexandra A. Soukup; Xingyu Luo; Daniel L. Lindner; Fang Yun Lim; Benjamin P. Knox; Brian Haas; Gregory J. Fischer; Tsokyi Choera; Robert A. E. Butchko; Jin-Woo Bok; Katharyn J. Affeldt; Nancy P. Keller; Jonathan M. Palmer; B. Gillian Turgeon

    2017-01-01

    The study of aflatoxin in Aspergillus spp. has garnered the attention of many researchers due to aflatoxin's carcinogenic properties and frequency as a food and feed contaminant. Significant progress has been made by utilizing the model organism Aspergillus nidulans to characterize the regulation of sterigmatocystin (ST),...

  18. Genetic Parameters for Milk Yield and Lactation Persistency Using Random Regression Models in Girolando Cattle.

    Science.gov (United States)

    Canaza-Cayo, Ali William; Lopes, Paulo Sávio; da Silva, Marcos Vinicius Gualberto Barbosa; de Almeida Torres, Robledo; Martins, Marta Fonseca; Arbex, Wagner Antonio; Cobuci, Jaime Araujo

    2015-10-01

    A total of 32,817 test-day milk yield (TDMY) records of the first lactation of 4,056 Girolando cows daughters of 276 sires, collected from 118 herds between 2000 and 2011 were utilized to estimate the genetic parameters for TDMY via random regression models (RRM) using Legendre's polynomial functions whose orders varied from 3 to 5. In addition, nine measures of persistency in milk yield (PSi) and the genetic trend of 305-day milk yield (305MY) were evaluated. The fit quality criteria used indicated RRM employing the Legendre's polynomial of orders 3 and 5 for fitting the genetic additive and permanent environment effects, respectively, as the best model. The heritability and genetic correlation for TDMY throughout the lactation, obtained with the best model, varied from 0.18 to 0.23 and from -0.03 to 1.00, respectively. The heritability and genetic correlation for persistency and 305MY varied from 0.10 to 0.33 and from -0.98 to 1.00, respectively. The use of PS7 would be the most suitable option for the evaluation of Girolando cattle. The estimated breeding values for 305MY of sires and cows showed significant and positive genetic trends. Thus, the use of selection indices would be indicated in the genetic evaluation of Girolando cattle for both traits.

  19. Ocean circulation model predicts high genetic structure observed in a long-lived pelagic developer.

    Science.gov (United States)

    Sunday, J M; Popovic, I; Palen, W J; Foreman, M G G; Hart, M W

    2014-10-01

    Understanding the movement of genes and individuals across marine seascapes is a long-standing challenge in marine ecology and can inform our understanding of local adaptation, the persistence and movement of populations, and the spatial scale of effective management. Patterns of gene flow in the ocean are often inferred based on population genetic analyses coupled with knowledge of species' dispersive life histories. However, genetic structure is the result of time-integrated processes and may not capture present-day connectivity between populations. Here, we use a high-resolution oceanographic circulation model to predict larval dispersal along the complex coastline of western Canada that includes the transition between two well-studied zoogeographic provinces. We simulate dispersal in a benthic sea star with a 6-10 week pelagic larval phase and test predictions of this model against previously observed genetic structure including a strong phylogeographic break within the zoogeographical transition zone. We also test predictions with new genetic sampling in a site within the phylogeographic break. We find that the coupled genetic and circulation model predicts the high degree of genetic structure observed in this species, despite its long pelagic duration. High genetic structure on this complex coastline can thus be explained through ocean circulation patterns, which tend to retain passive larvae within 20-50 km of their parents, suggesting a necessity for close-knit design of Marine Protected Area networks. © 2014 John Wiley & Sons Ltd.

  20. Identifying future models for delivering genetic services: a nominal group study in primary care

    Directory of Open Access Journals (Sweden)

    Davies Peter

    2005-04-01

    Full Text Available Background To enable primary care medical practitioners to generate a range of possible service delivery models for genetic counselling services and critically assess their suitability. Methods Modified nominal group technique using in primary care professional development workshops. Results 37 general practitioners in Wales, United Kingdom too part in the nominal group process. The practitioners who attended did not believe current systems were sufficient to meet anticipated demand for genetic services. A wide range of different service models was proposed, although no single option emerged as a clear preference. No argument was put forward for genetic assessment and counselling being central to family practice, neither was there a voice for the view that the family doctor should become skilled at advising patients about predictive genetic testing and be able to counsel patients about the wider implications of genetic testing for patients and their family members, even for areas such as common cancers. Nevertheless, all the preferred models put a high priority on providing the service in the community, and often co-located in primary care, by clinicians who had developed expertise. Conclusion There is a need for a wider debate about how healthcare systems address individual concerns about genetic concerns and risk, especially given the increasing commercial marketing of genetic tests.