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Sample records for modeling linking phenotype

  1. Emerging semantics to link phenotype and environment

    DOE PAGES

    Thessen, Anne E.; Bunker, Daniel E.; Buttigieg, Pier Luigi; ...

    2015-12-14

    Understanding the interplay between environmental conditions and phenotypes is a fundamental goal of biology. Unfortunately, data that include observations on phenotype and environment are highly heterogeneous and thus difficult to find and integrate. One approach that is likely to improve the status quo involves the use of ontologies to standardize and link data about phenotypes and environments. Specifying and linking data through ontologies will allow researchers to increase the scope and flexibility of large-scale analyses aided by modern computing methods. Investments in this area would advance diverse fields such as ecology, phylogenetics, and conservation biology. While several biological ontologies aremore » well-developed, using them to link phenotypes and environments is rare because of gaps in ontological coverage and limits to interoperability among ontologies and disciplines. Lastly, in this manuscript, we present (1) use cases from diverse disciplines to illustrate questions that could be answered more efficiently using a robust linkage between phenotypes and environments, (2) two proof-of-concept analyses that show the value of linking phenotypes to environments in fishes and amphibians, and (3) two proposed example data models for linking phenotypes and environments using the extensible observation ontology (OBOE) and the Biological Collections Ontology (BCO); these provide a starting point for the development of a data model linking phenotypes and environments.« less

  2. Emerging semantics to link phenotype and environment

    SciTech Connect

    Thessen, Anne E.; Bunker, Daniel E.; Buttigieg, Pier Luigi; Cooper, Laurel D.; Dahdul, Wasila M.; Domisch, Sami; Franz, Nico M.; Jaiswal, Pankaj; Lawrence-Dill, Carolyn J.; Midford, Peter E.; Mungall, Christopher J.; Ramirez, Martin J.; Specht, Chelsea D.; Vogt, Lars; Vos, Rutger Aldo; Walls, Ramona L.; White, Jeffrey W.; Zhang, Guanyang; Deans, Andrew R.; Huala, Eva; Lewis, Suzanna E.; Mabee, Paula M.

    2015-12-14

    Understanding the interplay between environmental conditions and phenotypes is a fundamental goal of biology. Unfortunately, data that include observations on phenotype and environment are highly heterogeneous and thus difficult to find and integrate. One approach that is likely to improve the status quo involves the use of ontologies to standardize and link data about phenotypes and environments. Specifying and linking data through ontologies will allow researchers to increase the scope and flexibility of large-scale analyses aided by modern computing methods. Investments in this area would advance diverse fields such as ecology, phylogenetics, and conservation biology. While several biological ontologies are well-developed, using them to link phenotypes and environments is rare because of gaps in ontological coverage and limits to interoperability among ontologies and disciplines. Lastly, in this manuscript, we present (1) use cases from diverse disciplines to illustrate questions that could be answered more efficiently using a robust linkage between phenotypes and environments, (2) two proof-of-concept analyses that show the value of linking phenotypes to environments in fishes and amphibians, and (3) two proposed example data models for linking phenotypes and environments using the extensible observation ontology (OBOE) and the Biological Collections Ontology (BCO); these provide a starting point for the development of a data model linking phenotypes and environments.

  3. Emerging semantics to link phenotype and environment.

    PubMed

    Thessen, Anne E; Bunker, Daniel E; Buttigieg, Pier Luigi; Cooper, Laurel D; Dahdul, Wasila M; Domisch, Sami; Franz, Nico M; Jaiswal, Pankaj; Lawrence-Dill, Carolyn J; Midford, Peter E; Mungall, Christopher J; Ramírez, Martín J; Specht, Chelsea D; Vogt, Lars; Vos, Rutger Aldo; Walls, Ramona L; White, Jeffrey W; Zhang, Guanyang; Deans, Andrew R; Huala, Eva; Lewis, Suzanna E; Mabee, Paula M

    2015-01-01

    Understanding the interplay between environmental conditions and phenotypes is a fundamental goal of biology. Unfortunately, data that include observations on phenotype and environment are highly heterogeneous and thus difficult to find and integrate. One approach that is likely to improve the status quo involves the use of ontologies to standardize and link data about phenotypes and environments. Specifying and linking data through ontologies will allow researchers to increase the scope and flexibility of large-scale analyses aided by modern computing methods. Investments in this area would advance diverse fields such as ecology, phylogenetics, and conservation biology. While several biological ontologies are well-developed, using them to link phenotypes and environments is rare because of gaps in ontological coverage and limits to interoperability among ontologies and disciplines. In this manuscript, we present (1) use cases from diverse disciplines to illustrate questions that could be answered more efficiently using a robust linkage between phenotypes and environments, (2) two proof-of-concept analyses that show the value of linking phenotypes to environments in fishes and amphibians, and (3) two proposed example data models for linking phenotypes and environments using the extensible observation ontology (OBOE) and the Biological Collections Ontology (BCO); these provide a starting point for the development of a data model linking phenotypes and environments.

  4. Emerging semantics to link phenotype and environment

    PubMed Central

    Bunker, Daniel E.; Buttigieg, Pier Luigi; Cooper, Laurel D.; Dahdul, Wasila M.; Domisch, Sami; Franz, Nico M.; Jaiswal, Pankaj; Lawrence-Dill, Carolyn J.; Midford, Peter E.; Mungall, Christopher J.; Ramírez, Martín J.; Specht, Chelsea D.; Vogt, Lars; Vos, Rutger Aldo; Walls, Ramona L.; White, Jeffrey W.; Zhang, Guanyang; Deans, Andrew R.; Huala, Eva; Lewis, Suzanna E.; Mabee, Paula M.

    2015-01-01

    Understanding the interplay between environmental conditions and phenotypes is a fundamental goal of biology. Unfortunately, data that include observations on phenotype and environment are highly heterogeneous and thus difficult to find and integrate. One approach that is likely to improve the status quo involves the use of ontologies to standardize and link data about phenotypes and environments. Specifying and linking data through ontologies will allow researchers to increase the scope and flexibility of large-scale analyses aided by modern computing methods. Investments in this area would advance diverse fields such as ecology, phylogenetics, and conservation biology. While several biological ontologies are well-developed, using them to link phenotypes and environments is rare because of gaps in ontological coverage and limits to interoperability among ontologies and disciplines. In this manuscript, we present (1) use cases from diverse disciplines to illustrate questions that could be answered more efficiently using a robust linkage between phenotypes and environments, (2) two proof-of-concept analyses that show the value of linking phenotypes to environments in fishes and amphibians, and (3) two proposed example data models for linking phenotypes and environments using the extensible observation ontology (OBOE) and the Biological Collections Ontology (BCO); these provide a starting point for the development of a data model linking phenotypes and environments. PMID:26713234

  5. Regulatory mechanisms link phenotypic plasticity to evolvability.

    PubMed

    van Gestel, Jordi; Weissing, Franz J

    2016-04-18

    Organisms have a remarkable capacity to respond to environmental change. They can either respond directly, by means of phenotypic plasticity, or they can slowly adapt through evolution. Yet, how phenotypic plasticity links to evolutionary adaptability is largely unknown. Current studies of plasticity tend to adopt a phenomenological reaction norm (RN) approach, which neglects the mechanisms underlying plasticity. Focusing on a concrete question - the optimal timing of bacterial sporulation - we here also consider a mechanistic approach, the evolution of a gene regulatory network (GRN) underlying plasticity. Using individual-based simulations, we compare the RN and GRN approach and find a number of striking differences. Most importantly, the GRN model results in a much higher diversity of responsive strategies than the RN model. We show that each of the evolved strategies is pre-adapted to a unique set of unseen environmental conditions. The regulatory mechanisms that control plasticity therefore critically link phenotypic plasticity to the adaptive potential of biological populations.

  6. Defining the Social Phenotype in Williams Syndrome: A Model for Linking Gene, the Brain, and Behavior

    PubMed Central

    Järvinen-Pasley, Anna; Bellugi, Ursula; Reilly, Judy; Mills, Debra L.; Galaburda, Albert; Reiss, Allan L.; Korenberg, Julie R.

    2010-01-01

    Research into phenotype-genotype correlations in neurodevelopmental disorders has greatly elucidated the contribution of genetic and neurobiological factors to variations in typical and atypical development. Etiologically relatively homogeneous disorders, such as Williams syndrome (WS), provide unique opportunities for elucidating gene-brain-behavior relationships. WS is a neurogenetic disorder, caused by a hemizygous deletion of approximately 25 genes on chromosome 7q11.23. This results in a cascade of physical, cognitive-behavioral, affective, and neurobiological aberrations. WS is associated with a markedly uneven neurocognitive profile, and the mature state cognitive profile of WS is relatively well developed. Although anecdotally, individuals with WS have been frequently described as unusually friendly and sociable, personality remains a considerably less well-studied area. This paper investigates genetic influences, cognitive-behavioral characteristics, aberrations in brain structure and function, and environmental and biological variables that influence the social outcomes of individuals with WS. We bring together a series of findings across multiple levels of scientific enquiry to examine the social phenotype in WS, reflecting the journey from gene to the brain to behavior. Understanding the complex multilevel scientific perspective in WS has implications for understanding typical social development by identifying important developmental events and markers, as well as helping to define the boundaries of psychopathology. PMID:18211726

  7. Simulating Brain Tumor Heterogeneity with a Multiscale Agent-Based Model: Linking Molecular Signatures, Phenotypes and Expansion Rate

    PubMed Central

    Zhang, Le; Strouthos, Costas G.; Wang, Zhihui; Deisboeck, Thomas S.

    2008-01-01

    We have extended our previously developed 3D multi-scale agent-based brain tumor model to simulate cancer heterogeneity and to analyze its impact across the scales of interest. While our algorithm continues to employ an epidermal growth factor receptor (EGFR) gene-protein interaction network to determine the cells’ phenotype, it now adds an implicit treatment of tumor cell adhesion related to the model’s biochemical microenvironment. We simulate a simplified tumor progression pathway that leads to the emergence of five distinct glioma cell clones with different EGFR density and cell ‘search precisions’. The in silico results show that microscopic tumor heterogeneity can impact the tumor system’s multicellular growth patterns. Our findings further confirm that EGFR density results in the more aggressive clonal populations switching earlier from proliferation-dominated to a more migratory phenotype. Moreover, analyzing the dynamic molecular profile that triggers the phenotypic switch between proliferation and migration, our in silico oncogenomics data display spatial and temporal diversity in documenting the regional impact of tumorigenesis, and thus support the added value of multi-site and repeated assessments in vitro and in vivo. Potential implications from this in silico work for experimental and computational studies are discussed. PMID:20047002

  8. Alternative parameterizations of the multiple-trait random regression model for milk yield and somatic cell score via recursive links between phenotypes.

    PubMed

    Jamrozik, J; Schaeffer, L R

    2011-08-01

    Multiple-trait random regression models with recursive phenotypic link from somatic cell score (SCS) to milk yield on the same test day and with different restrictions on co-variances between these traits were fitted to the first-lactation Canadian Holstein data. Bayesian methods with Gibbs sampling were used to derive inferences about parameters for all models. Bayes factor indicated that the recursive model with uncorrelated environmental effects between traits was the most plausible specification in describing the data. Goodness of fit in terms of a within-trait weighted mean square error and correlation between observed and predicted data was the same for all parameterizations. All recursive models estimated similar negative causal effects from SCS to milk yield (up to -0.4 in 46-115 days in milk in lactation). Estimates of heritabilities, genetic and environmental correlations for the first two regression coefficients (overall level of a trait and lactation persistency) within both traits were similar among models. Genetic correlations between milk and SCS were dependent on the restrictions on genetic co-variances for these traits. Recursive model with uncorrelated system genetic effects between milk and SCS gave estimates of genetic correlations of the opposite sign compared with a regular multiple-trait model. Phenotypic recursion between milk and SCS seemed, however, to be the only source of environmental correlations between these two traits. Rankings of sires for total milk yield in lactation, average daily SCS and persistency for both traits were similar among models. Multiple-trait model with recursive links between milk and SCS and uncorrelated random environmental effects could be an attractive alternative for a regular multiple-trait model in terms of model parsimony and accuracy.

  9. X-Linked Retinoschisis: Phenotypic Variability in a Chinese Family

    PubMed Central

    Xiao, Yangyan; Liu, Xiao; Tang, Luosheng; Wang, Xia; Coursy, Terry; Guo, Xiaojian; Li, Zhuo

    2016-01-01

    X-linked juvenile retinoschisis (XLRS), a leading cause of juvenile macular degeneration, is characterized by a spoke-wheel pattern in the macular region of the retina and splitting of the neurosensory retina. Our study is to describe the clinical characteristics of a four generations of this family (a total of 18 members)with X-linked retinoschisis (XLRS) and detected a novel mutations of c.3G > A (p.M1?) in the initiation codon of the RS1 gene. by direct sequencing.Identification of this mutation in this family provides evidence about potential genetic or environmental factors on its phenotypic variance, as patients presented with different phenotypes regardless of having the same mutation. Importantly, OCT has proven vital for XLRS diagnosis in children. PMID:26823236

  10. Animal models of RLS phenotypes.

    PubMed

    Allen, Richard P; Donelson, Nathan C; Jones, Byron C; Li, Yuqing; Manconi, Mauro; Rye, David B; Sanyal, Subhabrata; Winkelmann, Juliane

    2017-03-01

    Restless legs syndrome (RLS) is a complex disorder that involves sensory and motor systems. The major pathophysiology of RLS is low iron concentration in the substantia nigra containing the cell bodies of dopamine neurons that project to the striatum, an area that is crucial for modulating movement. People who have RLS often present with normal iron values outside the brain; recent studies implicate several genes are involved in the syndrome. Like most complex diseases, animal models usually do not faithfully capture the full phenotypic spectrum of "disease," which is a uniquely human construct. Nonetheless, animal models have proven useful in helping to unravel the complex pathophysiology of diseases such as RLS and suggesting novel treatment paradigms. For example, hypothesis-independent genome-wide association studies (GWAS) have identified several genes as increasing the risk for RLS, including BTBD9. Independently, the murine homolog Btbd9 was identified as a candidate gene for iron regulation in the midbrain in mice. The relevance of the phenotype of another of the GWAS identified genes, MEIS1, has also been explored. The role of Btbd9 in iron regulation and RLS-like behaviors has been further evaluated in mice carrying a null mutation of the gene and in fruit flies when the BTBD9 protein is degraded. The BTBD9 and MEIS1 stories originate from human GWAS research, supported by work in a genetic reference population of mice (forward genetics) and further verified in mice, fish flies, and worms. Finally, the role of genetics is further supported by an inbred mouse strain that displays many of the phenotypic characteristics of RLS. The role of animal models of RLS phenotypes is also extended to include periodic limb movements.

  11. The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data.

    PubMed

    Köhler, Sebastian; Doelken, Sandra C; Mungall, Christopher J; Bauer, Sebastian; Firth, Helen V; Bailleul-Forestier, Isabelle; Black, Graeme C M; Brown, Danielle L; Brudno, Michael; Campbell, Jennifer; FitzPatrick, David R; Eppig, Janan T; Jackson, Andrew P; Freson, Kathleen; Girdea, Marta; Helbig, Ingo; Hurst, Jane A; Jähn, Johanna; Jackson, Laird G; Kelly, Anne M; Ledbetter, David H; Mansour, Sahar; Martin, Christa L; Moss, Celia; Mumford, Andrew; Ouwehand, Willem H; Park, Soo-Mi; Riggs, Erin Rooney; Scott, Richard H; Sisodiya, Sanjay; Van Vooren, Steven; Wapner, Ronald J; Wilkie, Andrew O M; Wright, Caroline F; Vulto-van Silfhout, Anneke T; de Leeuw, Nicole; de Vries, Bert B A; Washingthon, Nicole L; Smith, Cynthia L; Westerfield, Monte; Schofield, Paul; Ruef, Barbara J; Gkoutos, Georgios V; Haendel, Melissa; Smedley, Damian; Lewis, Suzanna E; Robinson, Peter N

    2014-01-01

    The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online.

  12. The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data

    PubMed Central

    Köhler, Sebastian; Doelken, Sandra C.; Mungall, Christopher J.; Bauer, Sebastian; Firth, Helen V.; Bailleul-Forestier, Isabelle; Black, Graeme C. M.; Brown, Danielle L.; Brudno, Michael; Campbell, Jennifer; FitzPatrick, David R.; Eppig, Janan T.; Jackson, Andrew P.; Freson, Kathleen; Girdea, Marta; Helbig, Ingo; Hurst, Jane A.; Jähn, Johanna; Jackson, Laird G.; Kelly, Anne M.; Ledbetter, David H.; Mansour, Sahar; Martin, Christa L.; Moss, Celia; Mumford, Andrew; Ouwehand, Willem H.; Park, Soo-Mi; Riggs, Erin Rooney; Scott, Richard H.; Sisodiya, Sanjay; Vooren, Steven Van; Wapner, Ronald J.; Wilkie, Andrew O. M.; Wright, Caroline F.; Vulto-van Silfhout, Anneke T.; de Leeuw, Nicole; de Vries, Bert B. A.; Washingthon, Nicole L.; Smith, Cynthia L.; Westerfield, Monte; Schofield, Paul; Ruef, Barbara J.; Gkoutos, Georgios V.; Haendel, Melissa; Smedley, Damian; Lewis, Suzanna E.; Robinson, Peter N.

    2014-01-01

    The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online. PMID:24217912

  13. Metabolic phenotype and adipose and liver features in a high-fat Western diet-induced mouse model of obesity-linked NAFLD

    PubMed Central

    Luo, Yuwen; Burrington, Christine M.; Graff, Emily C.; Zhang, Jian; Judd, Robert L.; Suksaranjit, Promporn; Kaewpoowat, Quanhathai; Davenport, Samantha K.; O'Neill, Ann Marie

    2015-01-01

    nonalcoholic fatty liver disease (NAFLD), an obesity and insulin resistance associated clinical condition - ranges from simple steatosis to nonalcoholic steatohepatitis. To model the human condition, a high-fat Western diet that includes liquid sugar consumption has been used in mice. Even though liver pathophysiology has been well characterized in the model, little is known about the metabolic phenotype (e.g., energy expenditure, activity, or food intake). Furthermore, whether the consumption of liquid sugar exacerbates the development of glucose intolerance, insulin resistance, and adipose tissue dysfunction in the model is currently in question. In our study, a high-fat Western diet (HFWD) with liquid sugar [fructose and sucrose (F/S)] induced acute hyperphagia above that observed in HFWD-fed mice, yet without changes in energy expenditure. Liquid sugar (F/S) exacerbated HFWD-induced glucose intolerance and insulin resistance and impaired the storage capacity of epididymal white adipose tissue (eWAT). Hepatic TG, plasma alanine aminotransferase, and normalized liver weight were significantly increased only in HFWD+F/S-fed mice. HFWD+F/S also resulted in increased hepatic fibrosis and elevated collagen 1a2, collagen 3a1, and TGFβ gene expression. Furthermore, HWFD+F/S-fed mice developed more profound eWAT inflammation characterized by adipocyte hypertrophy, macrophage infiltration, a dramatic increase in crown-like structures, and upregulated proinflammatory gene expression. An early hypoxia response in the eWAT led to reduced vascularization and increased fibrosis gene expression in the HFWD+F/S-fed mice. Our results demonstrate that sugary water consumption induces acute hyperphagia, limits adipose tissue expansion, and exacerbates glucose intolerance and insulin resistance, which are associated with NAFLD progression. PMID:26670487

  14. Preferential phenotypic association linked with cooperation in paper wasps.

    PubMed

    Tibbetts, E A; Injaian, A

    2013-11-01

    Animals can influence their social environment by preferentially associating with certain conspecifics. Such preferential association has gained increasing theoretical attention, as it may influence social evolution and population dynamics. However, relatively little empirical work has examined the occurrence of preferential association and its effects on cooperative group formation. Here, we test the factors associated with cooperative group formation in Polistes dominulus nest-founding queen wasps. P. dominulus are a good system to study preferential association, as foundresses can nest alone or in groups and group membership is flexible. We found that both social and environmental factors were associated with partner choice. First, facial patterns were associated with cooperation. Wasps with more similar facial patterns were more likely to cooperate than wasps with less similar facial patterns. This preferential phenotypic association fits the theoretical criteria for the evolution of tag-based cooperation. Season was also associated with cooperation; wasps on early-season nests were more likely to cooperate than wasps on late-season nests. High levels of aggression by nest owners during initial interactions were also correlated with lower probabilities of subsequent cooperation, suggesting that nest owners have some control over group membership. Other factors including body weight, weight similarity and nest productivity were not linked with cooperation. Overall, multiple factors influence cooperation in paper wasps, including facial pattern similarity. The occurrence of preferential phenotypic association in paper wasps is quite interesting and may influence the evolution of cooperation and population divergence in this group.

  15. X-linked dystonia parkinsonism: clinical phenotype, genetics and therapeutics.

    PubMed

    Rosales, Raymond L

    2010-10-01

    The clinical phenotype of X-Linked Dystonia Parkinsonism (XDP) is typically one that involves a Filipino adult male whose ancestry is mostly traced in the Philippine island of Panay. Dystonia usually starts focally in the lower limbs or oromandibular regions, then spreads to become generalized eventually. Parkinsonism sets in later into the disease and usually in combination with dystonia. /DYT3/ and /TAF1/ are the two genes associated with XDP. An SVA retrotransposon insertion in an intron of /TAF1/ may reduce neuron-specific expression of the /TAF1/ isoform in the caudate nucleus, and subsequently interfere with the transcription of many neuronal genes. Polypharmacy with oral benzodiazepines, anticholinergic agents and muscle relaxants leaves much to be desired in terms of efficacy. The medications to date that may appear beneficial, especially in disabling dystonias, are zolpidem, muscle afferent block with lidocaine-ethanol and botulinum toxin type A. Despite the few cases undergoing deep brain stimulation, this functional surgery has shown the greatest promise in XDP. An illustrative case of XDP in a family depicts the variable course of illness, including a bout of "status dystonicus," challenges in therapy, reckoning with the social impact of the disease, and eventual patient demise. Indeed, there remains some gaps in understanding some phenomenological, genetic and treatment aspects of XDP, the areas upon which future research directions may be worthwhile.

  16. Molecular targets that link dioxin exposure to toxicity phenotypes.

    PubMed

    Yoshioka, Wataru; Peterson, Richard E; Tohyama, Chiharu

    2011-10-01

    Many toxicology studies have elucidated health effects associated with exposure to various chemicals, but few have identified the molecular targets that cause specific endpoints of toxicity. Our understanding of the toxicity of dioxins, a group of chemicals capable of causing toxicity at environmentally relevant levels of exposure, is no exception. Dioxins are unique compared to most chemicals that we are exposed to in the environment because they activate a high affinity receptor, aryl hydrocarbon receptor (AhR), that was identified more than three decades ago. In recent years, several lines of experimental evidence have provided clues for opening the "black box" that contains the molecular mechanisms of dioxin action. These clues have emerged by toxicologists beginning to identify the molecular targets that link AhR signaling to tissue-specific toxicity phenotypes. Endpoints of dioxin toxicity for which downstream molecular targets have begun to be elucidated are observed in developmental or tissue regeneration processes, and include impaired prostate development and hydronephrosis in mouse fetuses and pups, reduced midbrain blood flow and jaw malformation in zebrafish embryos, and impaired fin regeneration in larval and adult zebrafish. Significant progress in identifying molecular targets for dioxin-induced hepatotoxicity in adult mice also has occurred. Misregulation of AhR downstream pathways, such as conversion of arachidonic acid to prostanoids via cyclooxygenase-2, and altered Wnt/β-catenin signaling downregulating Sox9, and signaling by receptors for inflammatory cytokines have been implicated in tissue-specific endpoints of dioxin toxicity. These findings may not only begin to clarify the molecular targets of dioxin action but shed light on new molecular events associated with development and disease.

  17. HMG Nuclear Proteins: Linking Chromatin Structure to Cellular Phenotype

    PubMed Central

    Reeves, Raymond

    2009-01-01

    I. Summary Although the three families of mammalian HMG proteins (HMGA, HMGB and HMGN) participate in many of the same nuclear processes, each family plays its own unique role in modulating chromatin structure and regulating genomic function. This review focuses on the similarities and differences in the mechanisms by which the different HMG families impact chromatin structure and influence cellular phenotype. The biological implications of having three architectural transcription factor families with complementary, but partially overlapping, nuclear functions are discussed. PMID:19748605

  18. Obesity and cancer phenotype: Is angiogenesis a missed link?

    PubMed

    Mendonça, Fernando; Soares, Raquel

    2015-10-15

    Obesity remains nowadays one of the main threats to human health, being a problem of worldwide proportions. It is characterized by augmented storage of fatty acids in an enlarged adipose tissue. This process is possible thanks to a rich capillary network, supported by a mechanism that has also a crucial role on cancer: angiogenesis. Given that several studies point obesity as a risk factor for cancer development, angiogenesis may be approached as the missed link between these two pathologies. Understanding the different pathways behind angiogenesis becomes essential to break this link by developing new anti-angiogenic therapies or improving the actual ones. In the first phase, this paper will focus the structural and cellular changes that adipose tissue suffers in obesity. Then, the main pro-angiogenic players will be reviewed, taking into account the pathways that explain their putative role in obesity-cancer link. Finally, the clinical implications of the presented mechanisms will also be regarded, being the main focus on the anti-angiogenic therapies.

  19. Hormones and phenotypic plasticity in an ecological context: linking physiological mechanisms to evolutionary processes.

    PubMed

    Lema, Sean C

    2014-11-01

    Hormones are chemical signaling molecules that regulate patterns of cellular physiology and gene expression underlying phenotypic traits. Hormone-signaling pathways respond to an organism's external environment to mediate developmental stage-specific malleability in phenotypes, so that environmental variation experienced at different stages of development has distinct effects on an organism's phenotype. Studies of hormone-signaling are therefore playing a central role in efforts to understand how plastic phenotypic responses to environmental variation are generated during development. But, how do adaptive, hormonally mediated phenotypes evolve if the individual signaling components (hormones, conversion enzymes, membrane transporters, and receptors) that comprise any hormone-signaling pathway show expressional flexibility in response to environmental variation? What relevance do these components hold as molecular targets for selection to couple or decouple correlated hormonally mediated traits? This article explores how studying the endocrine underpinnings of phenotypic plasticity in an ecologically relevant context can provide insights into these, and other, crucial questions into the role of phenotypic plasticity in evolution, including how plasticity itself evolves. These issues are discussed in the light of investigations into how thyroid hormones mediate morphological plasticity in Death Valley's clade of pupfishes (Cyprinodon spp.). Findings from this work with pupfish illustrate that the study of hormone-signaling from an ecological perspective can reveal how phenotypic plasticity contributes to the generation of phenotypic novelty, as well as how physiological mechanisms developmentally link an organism's phenotype to its environmental experiences.

  20. Linking Post-Translational Modifications and Variation of Phenotypic Traits*

    PubMed Central

    Albertin, Warren; Marullo, Philippe; Bely, Marina; Aigle, Michel; Bourgais, Aurélie; Langella, Olivier; Balliau, Thierry; Chevret, Didier; Valot, Benoît; da Silva, Telma; Dillmann, Christine; de Vienne, Dominique; Sicard, Delphine

    2013-01-01

    Enzymes can be post-translationally modified, leading to isoforms with different properties. The phenotypic consequences of the quantitative variability of isoforms have never been studied. We used quantitative proteomics to dissect the relationships between the abundances of the enzymes and isoforms of alcoholic fermentation, metabolic traits, and growth-related traits in Saccharomyces cerevisiae. Although the enzymatic pool allocated to the fermentation proteome was constant over the culture media and the strains considered, there was variation in abundance of individual enzymes and sometimes much more of their isoforms, which suggests the existence of selective constraints on total protein abundance and trade-offs between isoforms. Variations in abundance of some isoforms were significantly associated to metabolic traits and growth-related traits. In particular, cell size and maximum population size were highly correlated to the degree of N-terminal acetylation of the alcohol dehydrogenase. The fermentation proteome was found to be shaped by human selection, through the differential targeting of a few isoforms for each food-processing origin of strains. These results highlight the importance of post-translational modifications in the diversity of metabolic and life-history traits. PMID:23271801

  1. Linking Dynamic Phenotyping with Metabolite Analysis to Study Natural Variation in Drought Responses of Brachypodium distachyon

    PubMed Central

    Fisher, Lorraine H. C.; Han, Jiwan; Corke, Fiona M. K.; Akinyemi, Aderemi; Didion, Thomas; Nielsen, Klaus K.; Doonan, John H.; Mur, Luis A. J.; Bosch, Maurice

    2016-01-01

    Drought is an important environmental stress limiting the productivity of major crops worldwide. Understanding drought tolerance and possible mechanisms for improving drought resistance is therefore a prerequisite to develop drought-tolerant crops that produce significant yields with reduced amounts of water. Brachypodium distachyon (Brachypodium) is a key model species for cereals, forage grasses, and energy grasses. In this study, initial screening of a Brachypodium germplasm collection consisting of 138 different ecotypes exposed to progressive drought, highlighted the natural variation in morphology, biomass accumulation, and responses to drought stress. A core set of ten ecotypes, classified as being either tolerant, susceptible or intermediate, in response to drought stress, were exposed to mild or severe (respectively, 15 and 0% soil water content) drought stress and phenomic parameters linked to growth and color changes were assessed. When exposed to severe drought stress, phenotypic data and metabolite profiling combined with multivariate analysis revealed a remarkable consistency in separating the selected ecotypes into their different pre-defined drought tolerance groups. Increases in several metabolites, including for the phytohormones jasmonic acid and salicylic acid, and TCA-cycle intermediates, were positively correlated with biomass yield and with reduced yellow pixel counts; suggestive of delayed senescence, both key target traits for crop improvement to drought stress. While metabolite analysis also separated ecotypes into the distinct tolerance groupings after exposure to mild drought stress, similar analysis of the phenotypic data failed to do so, confirming the value of metabolomics to investigate early responses to drought stress. The results highlight the potential of combining the analyses of phenotypic and metabolic responses to identify key mechanisms and markers associated with drought tolerance in both the Brachypodium model plant as

  2. Quantification of private information leakage from phenotype-genotype data: linking attacks.

    PubMed

    Harmanci, Arif; Gerstein, Mark

    2016-03-01

    Studies on genomic privacy have traditionally focused on identifying individuals using DNA variants. In contrast, molecular phenotype data, such as gene expression levels, are generally assumed to be free of such identifying information. Although there is no explicit genotypic information in phenotype data, adversaries can statistically link phenotypes to genotypes using publicly available genotype-phenotype correlations such as expression quantitative trait loci (eQTLs). This linking can be accurate when high-dimensional data (i.e., many expression levels) are used, and the resulting links can then reveal sensitive information (for example, the fact that an individual has cancer). Here we develop frameworks for quantifying the leakage of characterizing information from phenotype data sets. These frameworks can be used to estimate the leakage from large data sets before release. We also present a general three-step procedure for practically instantiating linking attacks and a specific attack using outlier gene expression levels that is simple yet accurate. Finally, we describe the effectiveness of this outlier attack under different scenarios.

  3. Linking trait-based phenotypes to prefrontal cortex activation during inhibitory control.

    PubMed

    Rodrigo, Achala H; Di Domenico, Stefano I; Graves, Bryanna; Lam, Jaeger; Ayaz, Hasan; Bagby, R Michael; Ruocco, Anthony C

    2016-01-01

    Inhibitory control is subserved in part by discrete regions of the prefrontal cortex whose functionality may be altered according to specific trait-based phenotypes. Using a unified model of normal range personality traits, we examined activation within lateral and medial aspects of the prefrontal cortex during a manual go/no-go task. Evoked hemodynamic oxygenation within the prefrontal cortex was measured in 106 adults using a 16-channel continuous-wave functional near-infrared spectroscopy system. Within lateral regions of the prefrontal cortex, greater activation was associated with higher trait levels of extraversion, agreeableness and conscientiousness, and lower neuroticism. Higher agreeableness was also related to more activation in the medial prefrontal cortex during inhibitory control. These results suggest that personality traits reflecting greater emotional stability, extraversion, agreeableness and conscientiousness may be associated with more efficient recruitment of control processes subserved by lateral regions of the prefrontal cortex. These findings highlight key links between trait-based phenotypes and neural activation patterns in the prefrontal cortex underlying inhibitory control.

  4. Linking trait-based phenotypes to prefrontal cortex activation during inhibitory control

    PubMed Central

    Rodrigo, Achala H.; Di Domenico, Stefano I.; Graves, Bryanna; Lam, Jaeger; Ayaz, Hasan; Bagby, R. Michael

    2016-01-01

    Inhibitory control is subserved in part by discrete regions of the prefrontal cortex whose functionality may be altered according to specific trait-based phenotypes. Using a unified model of normal range personality traits, we examined activation within lateral and medial aspects of the prefrontal cortex during a manual go/no-go task. Evoked hemodynamic oxygenation within the prefrontal cortex was measured in 106 adults using a 16-channel continuous-wave functional near-infrared spectroscopy system. Within lateral regions of the prefrontal cortex, greater activation was associated with higher trait levels of extraversion, agreeableness and conscientiousness, and lower neuroticism. Higher agreeableness was also related to more activation in the medial prefrontal cortex during inhibitory control. These results suggest that personality traits reflecting greater emotional stability, extraversion, agreeableness and conscientiousness may be associated with more efficient recruitment of control processes subserved by lateral regions of the prefrontal cortex. These findings highlight key links between trait-based phenotypes and neural activation patterns in the prefrontal cortex underlying inhibitory control. PMID:26163672

  5. "Young at heart": Regenerative potential linked to immature cardiac phenotypes.

    PubMed

    Gomes, Renata S M; Skroblin, Philipp; Munster, Alex B; Tomlins, Hannah; Langley, Sarah R; Zampetaki, Anna; Yin, Xiaoke; Wardle, Fiona C; Mayr, Manuel

    2016-03-01

    The adult human myocardium is incapable of regeneration; yet, the zebrafish (Danio rerio) can regenerate damaged myocardium. Similar to the zebrafish heart, hearts of neonatal, but not adult mice are capable of myocardial regeneration. We performed a proteomics analysis of adult zebrafish hearts and compared their protein expression profile to hearts from neonatal and adult mice. Using difference in-gel electrophoresis (DIGE), there was little overlap between the proteome from adult mouse (>8weeks old) and adult zebrafish (18months old) hearts. Similarly, there was a significant degree of mismatch between the protein expression in neonatal and adult mouse hearts. Enrichment analysis of the selected proteins revealed over-expression of DNA synthesis-related proteins in the cardiac proteome of the adult zebrafish heart similar to neonatal and 4days old mice, whereas in hearts of adult mice there was a mitochondria-related predominance in protein expression. Importantly, we noted pronounced differences in the myofilament composition: the adult zebrafish heart lacks many of the myofilament proteins of differentiated adult cardiomyocytes such as the ventricular isoforms of myosin light chains and nebulette. Instead, troponin I and myozenin 1 were expressed as skeletal isoforms rather than cardiac isoforms. The relative immaturity of the adult zebrafish heart was further supported by cardiac microRNA data. Our assessment of zebrafish and mammalian hearts challenges the assertions on the translational potential of cardiac regeneration in the zebrafish model. The immature myofilament composition of the fish heart may explain why adult mouse and human cardiomyocytes lack this endogenous repair mechanism.

  6. Quantification of Private Information Leakage from Phenotype-Genotype Data: Linking Attacks

    PubMed Central

    Harmanci, Arif; Gerstein, Mark

    2016-01-01

    Studies on genomic privacy have traditionally focused on identifying individuals using DNA variants. In contrast, molecular phenotype data, such as gene expression levels, are generally assumed free of such identifying information. Although there is no explicit genotypic information in them, adversaries can statistically link phenotypes to genotypes using publicly available genotype-phenotype correlations, for instance, expression quantitative trait loci (eQTLs). This linking can be accurate when high-dimensional data (many expression levels) are used, and the resulting links can then reveal sensitive information, for example, an individual having cancer. Here, we develop frameworks for quantifying the leakage of individual characterizing information from phenotype datasets. These can be used for estimating the leakage from large datasets before release. We also present a general three-step procedure for practically instantiating linking attacks and a specific attack using outlier gene-expression levels that is simple yet accurate. Finally, we describe the effectiveness of this outlier attack under different scenarios. PMID:26828419

  7. Sex-linked phenotypic divergence in the hermaphrodite fungus Neurospora tetrasperma

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Here we present a study of the molecular phenotype linked to a large region of suppressed recombination (extending over ~ 7 Mbp and >1,500 genes) surrounding the mating-type (mat) locus of the filamentous ascomycete Neurospora tetrasperma. While the remainder of the genome is largely homoallelic, th...

  8. An enzyme linked immunosorbent assay (ELISA) for the determination of the human haptoglobin phenotype

    PubMed Central

    Levy, Nina S.; Vardi, Moshe; Blum, Shany; Miller-Lotan, Rachel; Afinbinder, Yefim; Cleary, Patricia A.; Paterson, Andrew D.; Bharaj, Bhupinder; Snell-Bergeon, Janet K.; Rewers, Marian J.; Lache, Orit; Levy, Andrew P.

    2013-01-01

    Background Haptoglobin (Hp) is an abundant serum protein which binds extracorpuscular hemoglobin (Hb). Two alleles exist in humans for the Hp gene, denoted 1 and 2. Diabetic individuals with the Hp 2-2 genotype are at increased risk of developing vascular complications including heart attack, stroke, and kidney disease. Recent evidence shows that treatment with vitamin E can reduce the risk of diabetic vascular complications by as much as 50% in Hp 2-2 individuals. We sought to develop a rapid and accurate test for Hp phenotype (which is 100% concordant with the three major Hp genotypes) to facilitate widespread diagnostic testing as well as prospective clinical trials. Methods A monoclonal antibody raised against human Hp was shown to distinguish between the three Hp phenotypes in an enzyme linked immunosorbent assay (ELISA). Hp phenotypes obtained in over 8000 patient samples using this ELISA method were compared with those obtained by polyacrylamide gel electrophoresis or the TaqMan PCR method. Results Our analysis showed that the sensitivity and specificity of the ELISA test for Hp 2-2 phenotype is 99.0% and 98.1%, respectively. The positive predictive value and the negative predictive value for Hp 2-2 phenotype is 97.5% and 99.3%, respectively. Similar results were obtained for Hp 2-1 and Hp 1-1 phenotypes. In addition, the ELISA was determined to be more sensitive and specific than the TaqMan method. Conclusions The Hp ELISA represents a user-friendly, rapid and highly accurate diagnostic tool for determining Hp phenotypes. This test will greatly facilitate the typing of thousands of samples in ongoing clinical studies. PMID:23492570

  9. A novel test of the phenotype-linked fertility hypothesis reveals independent components of fertility.

    PubMed Central

    Pizzari, Tommaso; Jensen, Per; Cornwallis, Charles K.

    2004-01-01

    The phenotype-linked fertility hypothesis predicts that male sexual ornaments signal fertilizing efficiency and that the coevolution of male ornaments and female preference for such ornaments is driven by female pursuit of fertility benefits. In addition, directional testicular asymmetry frequently observed in birds has been suggested to reflect fertilizing efficiency and to covary with ornament expression. However, the idea of a phenotypic relationship between male ornaments and fertilizing efficiency is often tested in populations where environmental effects mask the underlying genetic associations between ornaments and fertilizing efficiency implied by this idea. Here, we adopt a novel design, which increases genetic diversity through the crossing of two divergent populations while controlling for environmental effects, to test: (i) the phenotypic relationship between male ornaments and both, gonadal (testicular mass) and gametic (sperm quality) components of fertilizing efficiency; and (ii) the extent to which these components are phenotypically integrated in the fowl, Gallus gallus. We show that consistent with theory, the testosterone-dependent expression of a male ornament, the comb, predicted testicular mass. However, despite their functional inter-dependence, testicular mass and sperm quality were not phenotypically integrated. Consistent with this result, males of one parental population invested more in testicular and comb mass, whereas males of the other parental population had higher sperm quality. We found no evidence that directional testicular asymmetry covaried with ornament expression. These results shed new light on the evolutionary relationship between male fertilizing efficiency and ornaments. Although testosterone-dependent ornaments may covary with testicular mass and thus reflect sperm production rate, the lack of phenotypic integration between gonadal and gametic traits reveals that the expression of an ornament is unlikely to reflect the

  10. A multiple phenotype predator-prey model with mutation

    NASA Astrophysics Data System (ADS)

    Abernethy, Gavin M.; Mullan, Rory; Glass, David H.; McCartney, Mark

    2017-01-01

    An existing multiple phenotype predator-prey model is expanded to include mutation amongst the predator phenotypes. Two unimodal maps are used for the underlying dynamics of the prey. A predation strategy is also defined which differs for each of the predators in the model. Results show that the introduction of predator mutation enhances predator survival both in terms of the number of phenotypes and total population for a range of values of the predation rate. In general, the dominant predator phenotype is the one which is most focused on the prey phenotype with the largest population.

  11. Coevolution is linked with phenotypic diversification but not speciation in avian brood parasites

    PubMed Central

    Medina, Iliana; Langmore, Naomi E.

    2015-01-01

    Coevolution is often invoked as an engine of biological diversity. Avian brood parasites and their hosts provide one of the best-known examples of coevolution. Brood parasites lay their eggs in the nests of other species, selecting for host defences and reciprocal counteradaptations in parasites. In theory, this arms race should promote increased rates of speciation and phenotypic evolution. Here, we use recently developed methods to test whether the three largest avian brood parasitic lineages show changes in rates of phenotypic diversity and speciation relative to non-parasitic lineages. Our results challenge the accepted paradigm, and show that there is little consistent evidence that lineages of brood parasites have higher speciation or extinction rates than non-parasitic species. However, we provide the first evidence that the evolution of brood parasitic behaviour may affect rates of evolution in morphological traits associated with parasitism. Specifically, egg size and the colour and pattern of plumage have evolved up to nine times faster in parasitic than in non-parasitic cuckoos. Moreover, cuckoo clades of parasitic species that are sympatric (and share similar host genera) exhibit higher rates of phenotypic evolution. This supports the idea that competition for hosts may be linked to the high phenotypic diversity found in parasitic cuckoos. PMID:26702044

  12. Genome-wide association and high-resolution phenotyping link Oryza sativa panicle traits to numerous trait-specific QTL clusters

    PubMed Central

    Crowell, Samuel; Korniliev, Pavel; Falcão, Alexandre; Ismail, Abdelbagi; Gregorio, Glenn; Mezey, Jason; McCouch, Susan

    2016-01-01

    Rice panicle architecture is a key target of selection when breeding for yield and grain quality. However, panicle phenotypes are difficult to measure and susceptible to confounding during genetic mapping due to correlation with flowering and subpopulation structure. Here we quantify 49 panicle phenotypes in 242 tropical rice accessions with the imaging platform PANorama. Using flowering as a covariate, we conduct a genome-wide association study (GWAS), detect numerous subpopulation-specific associations, and dissect multi-trait peaks using panicle phenotype covariates. Ten candidate genes in pathways known to regulate plant architecture fall under GWAS peaks, half of which overlap with quantitative trait loci identified in an experimental population. This is the first study to assess inflorescence phenotypes of field-grown material using a high-resolution phenotyping platform. Herein, we establish a panicle morphocline for domesticated rice, propose a genetic model underlying complex panicle traits, and demonstrate subtle links between panicle size and yield performance. PMID:26841834

  13. A pleiotropic model of phenotypic evolution.

    PubMed

    Tanaka, Y

    1998-01-01

    A pleiotropic model is presented for deriving the equilibrium genetic variance by mutation and stabilizing selection and the long-term genetic responses to directional selection in the case where mutations have pleiotropic effects on fitness itself (direct deleterious effect) and on a quantitative trait (phenotypic effect). The equilibrium genetic variance is derived as a general form of the rare-alleles models, i.e., [formula: see text], where n is the number of loci, mu is the per-locus mutation rate, alpha 2 is the variance of new mutations, V(s) is the measure of stabilizing selection, and s(u) is the selection coefficient on mutations by direct deleterious effect. The genetic responses to directional selection is calculated based on the assumption that the genetic variance is kept at an equilibrium by mutation and stabilizing selection but without directional selection, and the directional selection starts to operate on the target trait. The evolutionary rate at the t-th generation after the introduction of the directional selection is [formula: see text], where i is the directional selection intensity, and s(T) is the total selection coefficient on mutations, i.e., [formula: see text]. The selection limit is [formula: see text], where V(m) is the mutational variance (2n mu alpha 2). The pleiotropic effects of genes reduce both the evolutionary rate and the selection limit.

  14. Refined phenotyping identifies links between preeclampsia and related diseases in a Norwegian preeclampsia family cohort

    PubMed Central

    Thomsen, Liv Cecilie V.; Melton, Phillip E.; Tollaksen, Kjersti; Lyslo, Ingvill; Roten, Linda T.; Odland, Maria L.; Strand, Kristin M.; Nygård, Ottar; Sun, Chen; Iversen, Ann-Charlotte; Austgulen, Rigmor; Moses, Eric K.; Bjørge, Line

    2015-01-01

    Objective: Preeclampsia is a complex genetic disease of pregnancy with a heterogenous presentation, unknown cause and potential severe outcomes for both mother and child. Preeclamptic women have increased risk for atherothrombotic cardiovascular disease. We aimed to identify heritabilities and phenotypic correlations of preeclampsia and related conditions in the Norwegian Preeclampsia Family Biobank. Methods: By applying a variance components model, a total of 493 individuals (from 138 families with increased occurrence of preeclampsia) were classified according to 30 disease-related phenotypes. Results: Of parous women, 75.7% (263/338) had experienced preeclampsia and 35.7% of women with and 22.4% without preeclampsia delivered children small for gestational age (SGA). We identified 11 phenotypes as heritable. The increased occurrence of preeclampsia was reflected by the presence [heritability (H2r) = 0.60)] and severity (H2r = 0.15) of preeclampsia and being born in a preeclamptic pregnancy (H2r = 0.25). Other heritable phenotypes identified included SGA (H2r = 0.40), chronic hypertension (H2r = 0.57), severity of atherothrombotic cardiovascular disease (H2r = 0.31), BMI (H2r = 0.60) and pulmonary disease (H2r = 0.91). The heritable phenotype preeclampsia overlapped with SGA (P = 0.03), whereas pulmonary disease was phenotypically correlated with atherothrombotic cardiovascular disease (P < 0.01), SGA (P = 0.02) and BMI (P = 0.02). Conclusion: This is the first study identifying the H2r of a range of health-related conditions in preeclamptic families. Our study demonstrates how refinement of phenotypes leads to better H2r estimation and the identification of a biological relationship between preeclampsia and related traits. PMID:26259119

  15. Exploring Links between Genotypes, Phenotypes, and Clinical Predictors of Response to Early Intensive Behavioral Intervention in Autism Spectrum Disorder

    PubMed Central

    Eapen, Valsamma; Črnčec, Rudi; Walter, Amelia

    2013-01-01

    Autism spectrum disorder (ASD) is amongst the most familial of psychiatric disorders. Twin and family studies have demonstrated a monozygotic concordance rate of 70–90%, dizygotic concordance of around 10%, and more than a 20-fold increase in risk for first-degree relatives. Despite major advances in the genetics of autism, the relationship between different aspects of the behavioral and cognitive phenotype and their underlying genetic liability is still unclear. This is complicated by the heterogeneity of autism, which exists at both genetic and phenotypic levels. Given this heterogeneity, one method to find homogeneous entities and link these with specific genotypes would be to pursue endophenotypes. Evidence from neuroimaging, eye tracking, and electrophysiology studies supports the hypothesis that, building on genetic vulnerability, ASD emerges from a developmental cascade in which a deficit in attention to social stimuli leads to impaired interactions with primary caregivers. This results in abnormal development of the neurocircuitry responsible for social cognition, which in turn adversely affects later behavioral and functional domains dependent on these early processes, such as language development. Such a model begets a heterogeneous clinical phenotype, and is also supported by studies demonstrating better clinical outcomes with earlier treatment. Treatment response following intensive early behavioral intervention in ASD is also distinctly variable; however, relatively little is known about specific elements of the clinical phenotype that may predict response to current behavioral treatments. This paper overviews the literature regarding genotypes, phenotypes, and predictors of response to behavioral intervention in ASD and presents suggestions for future research to explore linkages between these that would enable better identification of, and increased treatment efficacy for, ASD. PMID:24062668

  16. Classifying compound mechanism of action for linking whole cell phenotypes to molecular targets

    PubMed Central

    Bourne, Christina R.; Wakeham, Nancy; Bunce, Richard A.; Berlin, K. Darrell; Barrow, William W.

    2013-01-01

    Drug development programs have proven successful when performed at a whole cell level, thus incorporating solubility and permeability into the primary screen. However, linking those results to the target within the cell has been a major set-back. The Phenotype Microarray system, marketed and sold by Biolog, seeks to address this need by assessing the phenotype in combination with a variety of chemicals with known mechanism of action (MOA). We have evaluated this system for usefulness in deducing the MOA for three test compounds. To achieve this, we constructed a database with 21 known antimicrobials, which served as a comparison for grouping our unknown MOA compounds. Pearson correlation and Ward linkage calculations were used to generate a dendrogram that produced clustering largely by known MOA, although there were exceptions. Of the three unknown compounds, one was definitively placed as an anti-folate. The second and third compounds’ MOA were not clearly identified, likely due to unique MOA not represented within the commercial database. The availability of the database generated in this report for S. aureus ATCC 29213 will increase the accessibility of this technique to other investigators. From our analysis, the Phenotype Microarray system can group compounds with clear MOA, but distinction of unique or broadly acting MOA at this time is less clear. PMID:22434711

  17. Phenotypic variability in X-linked ocular albinism: Relationship to linkage genotypes

    SciTech Connect

    Schnur, R.E. |; Wick, P.A.; Bailey, C.; Rebbeck, T.; Weleber, R.G.; Wagstaff, J.; Grix, A.W.; Pagon, R.A.; Hockey, A.; Edwards, M.J.

    1994-09-01

    One hundred nineteen individuals from 11 families with X-linked ocular albinism (OA1) were studied with respect to both their clinical phenotypes and their linkage genotypes. In a four-generation Australian family, two affected males and an obligatory carrier lacked cutaneous melanin macroglobules (MMGs); ocular features were identical to those of Nettleship-Falls OA1. Four other families had more unusual phenotypic features in addition to OA1. All OA1 families were genotyped at DXS16, DXS85, DXS143, STS, and DXS452 and for a CA-repeat polymorphism at the Kallmann syndrome locus (KAL). Separate two-point linkage analyses were performed for the following: group A, six families with biopsy-proved MMGs in at least one affected male; group B, four families whose biopsy status was not known; and group C, OA-9 only (16 samples), the family without MMGs. At the set of loci closest to OA1, there is no clear evidence in our data set for locus heterogeneity between groups A and C or among the four other families with complex phenotypes. Combined multipoint analysis (LINKMAP) in the 11 families and analysis of individual recombination events confirms that the major locus for OA1 resides within the DXS85-DXS143 interval. The authors suggest that more detailed clinical evaluations of OA1 individuals and families should be performed for future correlation with specific mutations in candidate OA1 genes. 29 refs., 5 figs., 4 tabs.

  18. X-linked MCT8 gene mutations: characterization of the pediatric neurologic phenotype.

    PubMed

    Holden, Kenton R; Zuñiga, Oscar F; May, Melanie M; Su, Humberto; Molinero, Marco R; Rogers, R Curtis; Schwartz, Charles E

    2005-10-01

    We report a family with X-linked mental retardation that has a novel mutation in the monocarboxylate transporter 8 (MCT8) gene associated with a characteristic neurodevelopmental phenotype with early childhood hypotonia that progresses to spasticity and global developmental delays. Affected patients experience moderate to severe psychomotor delays and congenital hypotonia, develop a myopathic facies, have diminished muscle bulk and generalized muscle weakness, develop progressive spasticity and movement disorders, and have limited speech but alert, affable personalities. Acquired microcephaly and abnormal myelination on brain magnetic resonance imaging can be present. Normal monocarboxylate transporter 8 gene functioning appears to be necessary for normal thyroid-associated metabolism in neurons. Abnormal thyroid function tests appear to be a consistent finding in the absence of typical signs of thyroid dysfunction. Although the phenotype appears to be consistent, and although the neurotoxic effects of abnormal central and peripheral neuromuscular system thyroid metabolism might be partly or wholly responsible for the neurologic phenotype reported, the exact mechanism remains unclear.

  19. Reversion of a fungal genetic code alteration links proteome instability with genomic and phenotypic diversification

    PubMed Central

    Bezerra, Ana R.; Simões, João; Lee, Wanseon; Rung, Johan; Weil, Tobias; Gut, Ivo G.; Gut, Marta; Bayés, Mónica; Rizzetto, Lisa; Cavalieri, Duccio; Giovannini, Gloria; Bozza, Silvia; Romani, Luigina; Kapushesky, Misha; Moura, Gabriela R.; Santos, Manuel A. S.

    2013-01-01

    Many fungi restructured their proteomes through incorporation of serine (Ser) at thousands of protein sites coded by the leucine (Leu) CUG codon. How these fungi survived this potentially lethal genetic code alteration and its relevance for their biology are not understood. Interestingly, the human pathogen Candida albicans maintains variable Ser and Leu incorporation levels at CUG sites, suggesting that this atypical codon assignment flexibility provided an effective mechanism to alter the genetic code. To test this hypothesis, we have engineered C. albicans strains to misincorporate increasing levels of Leu at protein CUG sites. Tolerance to the misincorporations was very high, and one strain accommodated the complete reversion of CUG identity from Ser back to Leu. Increasing levels of Leu misincorporation decreased growth rate, but production of phenotypic diversity on a phenotypic array probing various metabolic networks, drug resistance, and host immune cell responses was impressive. Genome resequencing revealed an increasing number of genotype changes at polymorphic sites compared with the control strain, and 80% of Leu misincorporation resulted in complete loss of heterozygosity in a large region of chromosome V. The data unveil unanticipated links between gene translational fidelity, proteome instability and variability, genome diversification, and adaptive phenotypic diversity. They also explain the high heterozygosity of the C. albicans genome and open the door to produce microorganisms with genetic code alterations for basic and applied research. PMID:23776239

  20. Reversion of a fungal genetic code alteration links proteome instability with genomic and phenotypic diversification.

    PubMed

    Bezerra, Ana R; Simões, João; Lee, Wanseon; Rung, Johan; Weil, Tobias; Gut, Ivo G; Gut, Marta; Bayés, Mónica; Rizzetto, Lisa; Cavalieri, Duccio; Giovannini, Gloria; Bozza, Silvia; Romani, Luigina; Kapushesky, Misha; Moura, Gabriela R; Santos, Manuel A S

    2013-07-02

    Many fungi restructured their proteomes through incorporation of serine (Ser) at thousands of protein sites coded by the leucine (Leu) CUG codon. How these fungi survived this potentially lethal genetic code alteration and its relevance for their biology are not understood. Interestingly, the human pathogen Candida albicans maintains variable Ser and Leu incorporation levels at CUG sites, suggesting that this atypical codon assignment flexibility provided an effective mechanism to alter the genetic code. To test this hypothesis, we have engineered C. albicans strains to misincorporate increasing levels of Leu at protein CUG sites. Tolerance to the misincorporations was very high, and one strain accommodated the complete reversion of CUG identity from Ser back to Leu. Increasing levels of Leu misincorporation decreased growth rate, but production of phenotypic diversity on a phenotypic array probing various metabolic networks, drug resistance, and host immune cell responses was impressive. Genome resequencing revealed an increasing number of genotype changes at polymorphic sites compared with the control strain, and 80% of Leu misincorporation resulted in complete loss of heterozygosity in a large region of chromosome V. The data unveil unanticipated links between gene translational fidelity, proteome instability and variability, genome diversification, and adaptive phenotypic diversity. They also explain the high heterozygosity of the C. albicans genome and open the door to produce microorganisms with genetic code alterations for basic and applied research.

  1. Autosomal recessive congenital cataract, intellectual disability phenotype linked to STX3 in a consanguineous Tunisian family.

    PubMed

    Chograni, M; Alkuraya, F S; Ourteni, I; Maazoul, F; Lariani, I; Chaabouni, H B

    2015-09-01

    The aim of this study is to investigate the genetic basis of autosomal recessive congenital cataract and intellectual disability phenotype in a consanguineous Tunisian family. The whole genome scan of the studied family was performed with single nucleotide polymorphisms (SNPs). The resulted runs of homozygosity (ROH) were analyzed through the integrated Systems Tool for Eye gene discovery (iSyTE) in order to prioritize candidate genes associated with congenital cataract. Selected genes were amplified and sequenced. Bioinformatic analysis was conducted to predict the function of the mutant gene. We identified a new specific lens gene named syntaxin 3 linked to the studied phenotype. The direct sequencing of this gene revealed a novel missense mutation c.122A>G which results in p.E41G. Bioinformatic analysis suggested a deleterious effect of this mutation on protein structure and function. Here, we report for the first time a missense mutation of a novel lens specific gene STX3 in a phenotype associating autosomal recessive congenital cataract and intellectual disability.

  2. X-chromosomal inactivation directly influences the phenotypic manifestation of X-linked protoporphyria

    PubMed Central

    Brancaleoni, V.; Balwani, M.; Granata, F.; Graziadei, G.; Missineo, P.; Fiorentino, V.; Fustinoni, S.; Cappellini, M.D.; Naik, H.; Desnick, R.J.; Di Pierro, E.

    2015-01-01

    X-linked protoporphyria (XLP), a rare erythropoietic porphyria, results from terminal exon gain-of-function mutations in the ALAS2 gene causing increased ALAS2 activity and markedly increased erythrocyte protoporphyrin levels. Patients present with severe cutaneous photosensitivity and may develop liver dysfunction. XLP was originally reported as X-linked dominant with 100% penetrance in males and females. We characterized 11 heterozygous females from six unrelated XLP families and show markedly varying phenotypic and biochemical heterogeneity, reflecting the degree of X-chromsomal inactivation of the mutant gene. ALAS2 sequencing identified the specific mutation and confirmed heterozygosity among the females. Clinical history, plasma and erythrocyte protoporphyrin levels were determined. Methylation assays of the androgen receptor and zinc-finger MYM type 3 short tandem repeat polymorphisms estimated each heterozygotes X-chromosomal inactivation pattern. Heterozygotes with equal or increased skewing, favoring expression of the wild-type allele had no clinical symptoms and only slightly increased erythrocyte protoporphyrin concentrations and/or frequency of protoporphyrin-containing peripheral blood fluorocytes. When the wild-type allele was preferentially inactivated, heterozygous females manifested the disease phenotype and had both higher erythrocyte protoporphyrin levels and circulating fluorocytes. These findings confirm that the previous dominant classification of XLP is inappropriate and genetically misleading, as the disorder is more appropriately designated XLP. PMID:25615817

  3. CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes.

    PubMed

    Hackett, Anna; Tarpey, Patrick S; Licata, Andrea; Cox, James; Whibley, Annabel; Boyle, Jackie; Rogers, Carolyn; Grigg, John; Partington, Michael; Stevenson, Roger E; Tolmie, John; Yates, John Rw; Turner, Gillian; Wilson, Meredith; Futreal, Andrew P; Corbett, Mark; Shaw, Marie; Gecz, Jozef; Raymond, F Lucy; Stratton, Michael R; Schwartz, Charles E; Abidi, Fatima E

    2010-05-01

    Mutations of the calcium/calmodulin-dependent serine protein kinase (CASK) gene have recently been associated with X-linked mental retardation (XLMR) with microcephaly, optic atrophy and brainstem and cerebellar hypoplasia, as well as with an X-linked syndrome having some FG-like features. Our group has recently identified four male probands from 358 probable XLMR families with missense mutations (p.Y268H, p.P396S, p.D710G and p.W919R) in the CASK gene. Congenital nystagmus, a rare and striking feature, was present in two of these families. We screened a further 45 probands with either nystagmus or microcephaly and mental retardation (MR), and identified two further mutations, a missense mutation (p.Y728C) and a splice mutation (c.2521-2A>T) in two small families with nystagmus and MR. Detailed clinical examinations of all six families, including an ophthalmological review in four families, were undertaken to further characterise the phenotype. We report on the clinical features of 24 individuals, mostly male, from six families with CASK mutations. The phenotype was variable, ranging from non-syndromic mild MR to severe MR associated with microcephaly and dysmorphic facial features. Carrier females were variably affected. Congenital nystagmus was found in members of four of the families. Our findings reinforce the CASK gene as a relatively frequent cause of XLMR in females and males. We further define the phenotypic spectrum and demonstrate that affected males with missense mutations or in-frame deletions in CASK are frequently associated with congenital nystagmus and XLMR, a striking feature not previously reported.

  4. Phenotype-Genotype Association Analysis of ACTH-Secreting Pituitary Adenoma and Its Molecular Link to Patient Osteoporosis

    PubMed Central

    Wang, Renzhi; Yang, Yakun; Sheng, Miaomiao; Bu, Dechao; Huang, Fengming; Liu, Xiaohai; Zhou, Cuiqi; Dai, Congxin; Sun, Bowen; Zhu, Jindong; Qiao, Yi; Yao, Yong; Zhu, Huijuan; Lu, Lin; Pan, Hui; Feng, Ming; Deng, Kan; Xing, Bing; Lian, Wei; Zhao, Yi; Jiang, Chengyu

    2016-01-01

    Adrenocorticotrophin (ACTH)-secreting pituitary adenoma, also known as Cushing disease (CD), is rare and causes metabolic syndrome, cardiovascular disease and osteoporosis due to hypercortisolism. However, the molecular pathogenesis of CD is still unclear because of a lack of human cell lines and animal models. Here, we study 106 clinical characteristics and gene expression changes from 118 patients, the largest cohort of CD in a single-center. RNA deep sequencing is used to examine genotypic changes in nine paired female ACTH-secreting pituitary adenomas and adjacent nontumorous pituitary tissues (ANPT). We develop a novel analysis linking disease clinical characteristics and whole transcriptomic changes, using Pearson Correlation Coefficient to discover a molecular network mechanism. We report that osteoporosis is distinguished from the phenotype and genotype analysis. A cluster of genes involved in osteoporosis is identified using Pearson correlation coefficient analysis. Most of the genes are reported in the bone related literature, confirming the feasibility of phenotype-genotype association analysis, which could be used in the analysis of almost all diseases. Secreted phosphoprotein 1 (SPP1), collagen type I α 1 chain (COL1A1), 5′-nucleotidase ecto (NT5E), HtrA serine peptidase 1 (HTRA1) and angiopoietin 1 (ANGPT1) and their signalling pathways are shown to be involved in osteoporosis in CD patients. Our discoveries provide a molecular link for osteoporosis in CD patients, and may open new potential avenues for osteoporosis intervention and treatment. PMID:27690016

  5. Multitrait mixed modeling and categorical data analyses of phenotypic variances

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Quantitative and categorical data were digitally recorded, measured or scored on whole canopies; single plants, leaves, and siliques; and on random seed samples of 224 genotypes in a phenotyping nursery of Brassica napus. They were used to (1) develop a pyramiding phenotyping model based on multitra...

  6. Phenotypic characterization of X-linked retinoschisis: Clinical, electroretinography, and optical coherence tomography variables

    PubMed Central

    Neriyanuri, Srividya; Dhandayuthapani, Sudha; Arunachalam, Jayamuruga Pandian; Raman, Rajiv

    2016-01-01

    Aims: To study the phenotypic characteristics of X-linked retinoschisis (XLRS) and report the clinical, electroretinogram (ERG), and optical coherence tomography (OCT) variables in Indian eyes. Design: A retrospective study. Materials and Methods: Medical records of 21 patients with retinoschisis who were genetically confirmed to have RS1 mutation were reviewed. The phenotype characterization included the age of onset, best-corrected visual acuity, refractive error, fundus findings, OCT, and ERG. Statistical Analysis Used: Data from both the eyes were used for analysis. A P < 0.05 was set as statistical significance. Data were not normally distributed (P < 0.05, Shapiro wilk); hence, nonparametric tests were used for statistical analysis. Results: All were males whose mean age of presentation was 9 years. Visual acuity was moderately impaired (median 0.6 logMAR, interquartile range: 0.47, 1) in these eyes with a hyperopic refractive error of median +1.75 Ds (interquartile range: +0.50 Ds, +4.25 Ds). About 54.7% of the eyes had both foveal and peripheral schisis, isolated foveal schisis was seen in 28.5% of the eyes, and schisis with retinal detachment was seen in 16.6% of the eyes. The inner nuclear layer was found to be commonly involved in the schisis, followed by outer nuclear and plexiform layers as evident on OCT. On ERG, a- and b-wave amplitudes were significantly reduced in eyes with foveal and peripheral schisis when compared to the eyes with only foveal schisis (P < 0.05). Conclusions: XLRS has phenotypic heterogeneity as evident on OCT, ERG, and clinical findings. PMID:27609164

  7. Mutations in the gene for X-linked adrenoleukodystrophy in patients with different clinical phenotypes

    SciTech Connect

    Braun, A.; Ambach, H.; Kammerer, S.; Rolinski, B.; Roscher, A.; Rabl, W.; Stoeckler, S.; Gaertner, J.; Zierz, S.

    1995-04-01

    Recently, the gene for the most common peroxisomal disorder, X-linked adrenoleukodystrophy (X-ALD), has been described encoding a peroxisomal membrane transporter protein. We analyzed the entire protein-coding sequence of this gene by reverse-transcription PCR, SSCP, and DNA sequencing in five patients with different clinical expressions were cerebral childhood ALD, adrenomyecloneuropathy (AMN), and {open_quotes}Addison disease only{close_quotes} (AD) phenotype. In the three patients exhibiting the classical picture of severe childhood ALD we identified in the 5{prime} portion of the X-ALD gene a 38-bp deletion that causes a frameshift mutation, a 3-bp deletion leading to a deletion of an amino acid in the ATP-binding domain of the ALD protein, and a missense mutation. In the patient with the clinical phenotype of AMN, a nonsense mutation in codon 212, along with a second site mutation at codon 178, was observed. Analysis of the patient with the ADO phenotype revealed a further missense mutation at a highly conserved position in the ALDP/PMP70 comparison. The disruptive nature of two mutations (i.e., the frameshift and the nonsense mutation) in patients with biochemically proved childhood ALD and AMN further strongly supports the hypothesis that alterations in this gene play a crucial role in the pathogenesis of X-ALD. Since the current biochemical techniques for X-ALD carrier detection in affected families lack sufficient reliability, our procedure described for systematic mutation scanning is also capable of improving genetic counseling and prenatal diagnosis. 19 refs., 6 figs., 3 tabs.

  8. Females with a disorder phenotypically identical to X-linked agammaglobulinemia

    SciTech Connect

    Conley, M.E. ); Sweinberg, S.K. )

    1992-03-01

    Clinical and laboratory findings in two girls with a disorder phenotypically indistinguishable from typical X-linked agammaglobulinemia (XLA) are described. To examine the possibility that subtle defects in the X chromosome might explain the findings, detailed genetic studies were performed on one of these patients. Cytogenetic studies showed a normal 46XX karyotype. Southern blot analysis of her DNA showed that she had inherited a maternal and a paternal allele at sites flanking the locus for typical XLA at Xq22, making a microdeletion or uniparental disomy unlikely. To determine whether both of her X chromosomes could function as the active X, somatic-cell hybrids that selectively retained the active X were produced from her activated T cells. A normal random pattern of X inactivation was seen. Of 21 T-cell hybrids, 3 retained both X chromosomes, 7 had one X as the active X, and 11 had the other X as the active X. The authors have interpreted these studies as indicating that there is an autosomal recessive disorder that is phenotypically identical to XLA.

  9. Genetic analysis and clinical phenotype of two Indian families with X-linked choroideremia

    PubMed Central

    Battu, Rajani; Jeyabalan, Nallathambi; Murthy, Praveen; Reddy, Kavita S; Schouten, Jan SAG; Webers, Caroll A

    2016-01-01

    Purpose: This study aims to describe the phenotype and genotype of two Indian families affected with X-linked choroideremia (CHM). Materials and Methods: In these two families, the affected individuals and unaffected family members underwent a comprehensive ophthalmic examination including an optical coherence tomography (OCT) and electroretinogram. Blood samples were collected from the families for genetic analysis. Next generation sequencing (NGS) was done using a panel of 184 genes, which covered previously associated genes with retinal dystrophies. Sequencing data were analyzed for the CHM, RPGR, and RP2 genes that have been implicated in CHM and X-linked retinitis pigmentosa (XLRP), respectively. The identified variants were confirmed by Sanger sequencing in available individuals and unrelated controls. Results: In two unrelated male patients, NGS analysis revealed a previously reported 3’-splice site change c.820-1G>C in the CHM gene in the first family and hemizygous mutation c.653G>C (p.Ser218X) in the second family. The asymptomatic family members were carriers for these mutations. Spectral domain-OCT showed loss of outer retina, preservation of the inner retina, and choroidal thinning in the affected males and retinal pigment epithelial changes in the asymptomatic carriers. The identified mutations were not present in 100 controls of Indian origin. There were no potential mutations found in XLRP-associated (RPGR and RP2) genes. Conclusion: This report describes the genotype and phenotype findings in patients with CHM from India. The identified genetic mutation leads to lack of Rab escort protein-1 (REP-1) or affects the production of a REP-1 protein that is likely to cause retinal abnormalities in patients. PMID:28112135

  10. A multi-phenotypic cancer model with cell plasticity.

    PubMed

    Zhou, Da; Wang, Yue; Wu, Bin

    2014-09-21

    The conventional cancer stem cell (CSC) theory indicates a hierarchy of CSCs and non-stem cancer cells (NSCCs), that is, CSCs can differentiate into NSCCs but not vice versa. However, an alternative paradigm of CSC theory with reversible cell plasticity among cancer cells has received much attention very recently. Here we present a generalized multi-phenotypic cancer model by integrating cell plasticity with the conventional hierarchical structure of cancer cells. We prove that under very weak assumption, the nonlinear dynamics of multi-phenotypic proportions in our model has only one stable steady state and no stable limit cycle. This result theoretically explains the phenotypic equilibrium phenomena reported in various cancer cell lines. Furthermore, according to the transient analysis of our model, it is found that cancer cell plasticity plays an essential role in maintaining the phenotypic diversity in cancer especially during the transient dynamics. Two biological examples with experimental data show that the phenotypic conversions from NCSSs to CSCs greatly contribute to the transient growth of CSCs proportion shortly after the drastic reduction of it. In particular, an interesting overshooting phenomenon of CSCs proportion arises in three-phenotypic example. Our work may pave the way for modeling and analyzing the multi-phenotypic cell population dynamics with cell plasticity.

  11. Modeling the Autism Spectrum Disorder Phenotype

    PubMed Central

    McCray, Alexa T.; Trevvett, Philip; Frost, H. Robert

    2013-01-01

    Background Autism Spectrum Disorder (ASD) is highly heritable, and although there has been active research in an attempt to discover the genetic factors underlying ASD, diagnosis still depends heavily on behavioral assessments. Recently, several large-scale initiatives, including those of the Autism Consortium, have contributed to the collection of extensive information from families affected by ASD. Purpose Our goal was to develop an ontology that can be used 1) to provide improved access to the data collected by those who study ASD and other neurodevelopmental disorders, and 2) to assess and compare the characteristics of the instruments that are used in the assessment of ASD. Materials and Methods We analyzed two dozen instruments used to assess ASD, studying the nature of the questions asked and items assessed, the method of delivery, and the overall scope of the content. These data together with the extensive literature on ASD contributed to our iterative development of an ASD phenotype ontology. Results The final ontology comprises 283 concepts distributed across three high-level classes, ‘Personal Traits’, ‘Social Competence’, and ‘Medical History’. The ontology is fully integrated with the Autism Consortium database, allowing researchers to pose ontology-based questions. The ontology also allows researchers to assess the degree of overlap among a set of candidate instruments according to several objective criteria. Conclusions The ASD phenotype ontology has promise for use in research settings where extensive phenotypic data have been collected, allowing a concept-based approach to identifying behavioral features of importance and for correlating these with genotypic data. PMID:24163114

  12. Mixture model for sub-phenotyping in GWAS.

    PubMed

    Warde-Farley, David; Brudno, Michael; Morris, Quaid; Goldenberg, Anna

    2012-01-01

    Genome Wide Association (GWA) studies resulted in discovery of genetic variants underlying several complex diseases including Chron's disease and age-related macular degeneration (AMD). Still geneticists find that in majority of studies the size of the effect even if it is significant tends to be very small. There are several factors contributing to this problem such as rare variants, complex relationships among SNPs (epistatic effect), and heterogeneity of the phenotype. In this work we focus on addressing phenotypic heterogeneity. We introduce the problem of identifying, from GWAS data, separate genotypic markers from overlapping mixtures of clinically indistinguishable phenotypes. We propose a generative model for this scenario and derive an expectation-maximization (EM) procedure to fit the model to data, as well as a novel screening procedure designed to identify skew specific to certain phenotypic regimes. We present results on several simulated datasets as well as preliminary findings in applying the model to type 2 diabetes dataset.

  13. Contribution of Post-translational Phosphorylation to Sarcomere-Linked Cardiomyopathy Phenotypes

    PubMed Central

    Westfall, Margaret V.

    2016-01-01

    Secondary shifts develop in post-translational phosphorylation of sarcomeric proteins in multiple animal models of inherited cardiomyopathy. These signaling alterations together with the primary mutation are predicted to contribute to the overall cardiac phenotype. As a result, identification and integration of post-translational myofilament signaling responses are identified as priorities for gaining insights into sarcomeric cardiomyopathies. However, significant questions remain about the nature and contribution of post-translational phosphorylation to structural remodeling and cardiac dysfunction in animal models and human patients. This perspective essay discusses specific goals for filling critical gaps about post-translational signaling in response to these inherited mutations, especially within sarcomeric proteins. The discussion focuses primarily on pre-clinical analysis of animal models and defines challenges and future directions in this field. PMID:27683560

  14. Large-scale phenotyping links adult hippocampal neurogenesis to the reaction to novelty.

    PubMed

    van Dijk, R Maarten; Lazic, Stanley E; Slomianka, Lutz; Wolfer, David P; Amrein, Irmgard

    2016-05-01

    The discovery of adult-born neurons in the hippocampus has triggered a wide range of studies that link the new neurons to various behavioral functions. However, the role of new neurons in behavior is still equivocal. Conflicting results may be due to the difficulty in manipulating neurogenesis without off-target effects as well as the statistical approach used, which fail to account for neurogenesis-independent effects of experimental manipulations on behavior. In this study, we apply a more comprehensive statistical and conceptual approach. Instead of between-group analyses, we consider the within-group relationships between neurogenesis and behavior (ANCOVA and mediation analysis) in a large-scale experiment, in which distinct age- (3 and 5 months) and strain- (DBA and C57) related differences in basal levels of neurogenesis in mice are compared with a large number (∼1,500) of behavioral read outs. The analysis failed to detect any association between anxiety and motor impulsivity with neurogenesis. However, within-group adult hippocampal neurogenesis is associated with the reaction to novelty. Specifically, more neurogenesis is associated with a longer latency to explore and a lower frequency of exploratory actions, overall indicative of a phenotype where animals with more neurogenesis were slower to explore a novel environment. This effect is observed in 5-months-old, but not in 3-months-old mice of both strains. An association between the reaction to novelty and adult neurogenesis can have a major impact on results from previous studies using classical behavioral experiments, in which animals are tested in a--for the animal--novel experimental set-up. The neurogenesis-novelty association found here is also a necessary link in the relation that has been suggested to exist between neurogenesis and psychiatric disorders marked by a failure to cope with novelty.

  15. Semantically linking in silico cancer models.

    PubMed

    Johnson, David; Connor, Anthony J; McKeever, Steve; Wang, Zhihui; Deisboeck, Thomas S; Quaiser, Tom; Shochat, Eliezer

    2014-01-01

    Multiscale models are commonplace in cancer modeling, where individual models acting on different biological scales are combined within a single, cohesive modeling framework. However, model composition gives rise to challenges in understanding interfaces and interactions between them. Based on specific domain expertise, typically these computational models are developed by separate research groups using different methodologies, programming languages, and parameters. This paper introduces a graph-based model for semantically linking computational cancer models via domain graphs that can help us better understand and explore combinations of models spanning multiple biological scales. We take the data model encoded by TumorML, an XML-based markup language for storing cancer models in online repositories, and transpose its model description elements into a graph-based representation. By taking such an approach, we can link domain models, such as controlled vocabularies, taxonomic schemes, and ontologies, with cancer model descriptions to better understand and explore relationships between models. The union of these graphs creates a connected property graph that links cancer models by categorizations, by computational compatibility, and by semantic interoperability, yielding a framework in which opportunities for exploration and discovery of combinations of models become possible.

  16. Multikernel linear mixed models for complex phenotype prediction

    PubMed Central

    Weissbrod, Omer; Geiger, Dan; Rosset, Saharon

    2016-01-01

    Linear mixed models (LMMs) and their extensions have recently become the method of choice in phenotype prediction for complex traits. However, LMM use to date has typically been limited by assuming simple genetic architectures. Here, we present multikernel linear mixed model (MKLMM), a predictive modeling framework that extends the standard LMM using multiple-kernel machine learning approaches. MKLMM can model genetic interactions and is particularly suitable for modeling complex local interactions between nearby variants. We additionally present MKLMM-Adapt, which automatically infers interaction types across multiple genomic regions. In an analysis of eight case-control data sets from the Wellcome Trust Case Control Consortium and more than a hundred mouse phenotypes, MKLMM-Adapt consistently outperforms competing methods in phenotype prediction. MKLMM is as computationally efficient as standard LMMs and does not require storage of genotypes, thus achieving state-of-the-art predictive power without compromising computational feasibility or genomic privacy. PMID:27302636

  17. Correlation between connexin 32 gene mutations and clinical phenotype in X-linked dominant Charcot-Marie-Tooth neuropathy

    SciTech Connect

    Ionasescu, V.; Ionasescu, R.; Searby, C.

    1996-06-14

    We studied the relationship between the genotype and clinical phenotype in 27 families with dominant X-linked Charcot-Marie-Tooth (CMTX1) neuropathy. Twenty-two families showed mutations in the coding region of the connexin32 (cx32) gene. The mutations include four nonsense mutations, eight missense mutations, two medium size deletions, and one insertion. Most missense mutations showed a mild clinical phenotype (five out of eight), whereas all nonsense mutations, the larger of the two deletions, and the insertion that produced frameshifts showed severe phenotypes. Five CMTX1 families with mild clinical phenotype showed no point mutations of the cx32 gene coding region. Three of these families showed positive genetic linkage with the markers of the Xq13.1 region. The genetic linkage of the remaining two families could not be evaluated because of their small size. 25 refs., 1 fig., 1 tab.

  18. Infections associated with chronic granulomatous disease: linking genetics to phenotypic expression.

    PubMed

    Ben-Ari, Josef; Wolach, Ofir; Gavrieli, Ronit; Wolach, Baruch

    2012-08-01

    Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency characterized by the absence or malfunction of the NADPH oxidase in phagocytic cells. As a result, there is an impaired ability to generate superoxide anions and the subsequent reactive oxygen intermediates. Consequently, CGD patients suffer from two clinical manifestations: recurrent, life-threatening bacterial and fungal infections and excessive inflammatory reactions leading to granulomatous lesions. Although the genotype of CGD was linked to the phenotypic expression of the disease, this connection is still controversial and poorly understood. Certain correlations were reported, but the clinical expression of the disease is usually unpredictable, regardless of the pattern of inheritance. CGD mainly affects the lungs, lymph nodes, skin, GI tract and liver. Patients are particularly susceptible to catalase-positive microorganisms, including Staphyloccocus aureus, Nocardia spp. and Gram-negative bacteria, such as Serratia marcescens, Burkholderia cepacea and Salmonella spp. Unusually, catalase-negative microorganisms were reported as well. New antibacterial and antimycotic agents considerably improved the prognosis of CGD. Therapy with IFN-γ is still controversial. Bone marrow stem cell transplantation is currently the only curative treatment and gene therapy needs further development. In this article, the authors discuss the genetic, functional and molecular aspects of CGD and their impact on the clinical expression, infectious complications and the hyperinflammatory state.

  19. Mitochondrial genetics and hearing loss: the missing link between genotype and phenotype.

    PubMed

    Fischel-Ghodsian, N

    1998-05-01

    Mitochondrial DNA mutations have been implicated in a great variety of diseases, including such common ones as diabetes, Parkinson's disease and Alzheimer's, but the pathophysiological pathway leading from a specific mutation to a specific phenotype has remained elusive. Individuals with the same mutation can fall along a clinical spectrum ranging from asymptomatic to severely affected, and can even have completely different diseases. Much of this phenotypic heterogeneity has been attributed to the heteroplasmic nature of mitochondrial mutations, with both normal and mutated mitochondrial chromosomes being present in different proportions and tissue distributions. Isolated hearing loss is one of the only mitochondrial disorders that can be caused by homoplasmic mutations (e.g., only mutated mitochondrial mutations are present in all tissues). This review will outline the relationship between mitochondrial mutations and hearing loss while showing that even in a homoplasmic model, the two basic questions of mitochondrial genetics, penetrance and tissue specificity, remain unanswered: Why does the same mutation cause severe hearing loss in some family members but not in others, and why is the ear the only organ affected?

  20. Optical Performance Models for FDDI Links

    NASA Astrophysics Data System (ADS)

    Kimball, Robert M.

    1990-01-01

    A loss budget model to predict optical performance of Fiber Distributed Data Interface (FDDI) type networks in the premises distribution environment has been developed. This model tailors existing statistical loss budget models to the FDDI standard. It is expected that as FDDI becomes popular, fiber based distribution systems will become common. When designing a fiber distribution system it is important to understand the constraints placed on link performance by the cable plant. To determine these constraints, the model is examined numerically using a large range of initial conditions. The total link length is used as the dependent variable. This set of initial conditions corresponds to an ensemble of possible link configurations. These link configurations are studied in the context of the premises distribution environment. The model is extended to include the use of optical bypass switches. Laboratory measurement data is presented to verify the accuracy of the bypass switch model. The extended model, including the bypass switch, is examined numerically for a similar set of initial conditions. These constraints are applied to the use of bypass switches in wiring closets, between floors, and at the work location. Distance limitations are determined for FDDI links utilizing optical bypass switches.

  1. Modeling phenotypic plasticity in growth trajectories: a statistical framework.

    PubMed

    Wang, Zhong; Pang, Xiaoming; Wu, Weimiao; Wang, Jianxin; Wang, Zuoheng; Wu, Rongling

    2014-01-01

    Phenotypic plasticity, that is multiple phenotypes produced by a single genotype in response to environmental change, has been thought to play an important role in evolution and speciation. Historically, knowledge about phenotypic plasticity has resulted from the analysis of static traits measured at a single time point. New insight into the adaptive nature of plasticity can be gained by an understanding of how organisms alter their developmental processes in a range of environments. Recent advances in statistical modeling of functional data and developmental genetics allow us to construct a dynamic framework of plastic response in developmental form and pattern. Under this framework, development, genetics, and evolution can be synthesized through statistical bridges to better address how evolution results from phenotypic variation in the process of development via genetic alterations.

  2. Nav 1.5 mutations linked to dilated cardiomyopathy phenotypes: Is the gating pore current the missing link?

    PubMed

    Gosselin-Badaroudine, Pascal; Moreau, Adrien; Chahine, Mohamed

    2014-01-01

    Nav 1.5 dysfunctions are commonly linked to rhythms disturbances that include type 3 long QT syndrome (LQT3), Brugada syndrome (BrS), sick sinus syndrome (SSS) and conduction defects. Recently, this channel protein has been also linked to structural heart diseases such as dilated cardiomyopathy (DCM).

  3. Artery Buckling: New Phenotypes, Models, and Applications

    PubMed Central

    Han, Hai-Chao; Chesnutt, Jennifer K. W.; Garcia, Justin R.; Liu, Qin; Wen, Qi

    2012-01-01

    Arteries are under significant mechanical loads from blood pressure, flow, tissue tethering, and body movement. It is critical that arteries remain patent and stable under these loads. This review summarizes the common forms of buckling that occur in blood vessels including cross-sectional collapse, longitudinal twist buckling, and bent buckling. The phenomena, model analyses, experimental measurements, effects on blood flow, and clinical relevance are discussed. It is concluded that mechanical buckling is an important issue for vasculature, in addition to wall stiffness and strength, and requires further studies to address the challenges. Studies of vessel buckling not only enrich vascular biomechanics but also have important clinical applications. PMID:23192265

  4. Linking genotypes database with locus-specific database and genotype-phenotype correlation in phenylketonuria.

    PubMed

    Wettstein, Sarah; Underhaug, Jarl; Perez, Belen; Marsden, Brian D; Yue, Wyatt W; Martinez, Aurora; Blau, Nenad

    2015-03-01

    The wide range of metabolic phenotypes in phenylketonuria is due to a large number of variants causing variable impairment in phenylalanine hydroxylase function. A total of 834 phenylalanine hydroxylase gene variants from the locus-specific database PAHvdb and genotypes of 4181 phenylketonuria patients from the BIOPKU database were characterized using FoldX, SIFT Blink, Polyphen-2 and SNPs3D algorithms. Obtained data was correlated with residual enzyme activity, patients' phenotype and tetrahydrobiopterin responsiveness. A descriptive analysis of both databases was compiled and an interactive viewer in PAHvdb database was implemented for structure visualization of missense variants. We found a quantitative relationship between phenylalanine hydroxylase protein stability and enzyme activity (r(s) = 0.479), between protein stability and allelic phenotype (r(s) = -0.458), as well as between enzyme activity and allelic phenotype (r(s) = 0.799). Enzyme stability algorithms (FoldX and SNPs3D), allelic phenotype and enzyme activity were most powerful to predict patients' phenotype and tetrahydrobiopterin response. Phenotype prediction was most accurate in deleterious genotypes (≈ 100%), followed by homozygous (92.9%), hemizygous (94.8%), and compound heterozygous genotypes (77.9%), while tetrahydrobiopterin response was correctly predicted in 71.0% of all cases. To our knowledge this is the largest study using algorithms for the prediction of patients' phenotype and tetrahydrobiopterin responsiveness in phenylketonuria patients, using data from the locus-specific and genotypes database.

  5. Structural Modeling Insights into Human VKORC1 Phenotypes

    PubMed Central

    Czogalla, Katrin J.; Watzka, Matthias; Oldenburg, Johannes

    2015-01-01

    Vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) catalyses the reduction of vitamin K and its 2,3-epoxide essential to sustain γ-carboxylation of vitamin K-dependent proteins. Two different phenotypes are associated with mutations in human VKORC1. The majority of mutations cause resistance to 4-hydroxycoumarin- and indandione-based vitamin K antagonists (VKA) used in the prevention and therapy of thromboembolism. Patients with these mutations require greater doses of VKA for stable anticoagulation than patients without mutations. The second phenotype, a very rare autosomal-recessive bleeding disorder caused by combined deficiency of vitamin K dependent clotting factors type 2 (VKCFD2) arises from a homozygous Arg98Trp mutation. The bleeding phenotype can be corrected by vitamin K administration. Here, we summarize published experimental data and in silico modeling results in order to rationalize the mechanisms of VKA resistance and VKCFD2. PMID:26287237

  6. Meta-analysis of global metabolomics and proteomics data to link alterations with phenotype

    DOE PAGES

    Patti, Gary J.; Tautenhahn, Ralf; Fonslow, Bryan R.; ...

    2011-01-01

    Global metabolomics has emerged as a powerful tool to interrogate cellular biochemistry at the systems level by tracking alterations in the levels of small molecules. One approach to define cellular dynamics with respect to this dysregulation of small molecules has been to consider metabolic flux as a function of time. While flux measurements have proven effective for model organisms, acquiring multiple time points at appropriate temporal intervals for many sample types (e.g., clinical specimens) is challenging. As an alternative, meta-analysis provides another strategy for delineating metabolic cause and effect perturbations. That is, the combination of untargeted metabolomic data from multiplemore » pairwise comparisons enables the association of specific changes in small molecules with unique phenotypic alterations. We recently developed metabolomic software called metaXCMS to automate these types of higher order comparisons. Here we discuss the potential of metaXCMS for analyzing proteomic datasets and highlight the biological value of combining meta-results from both metabolomic and proteomic analyses. The combined meta-analysis has the potential to facilitate efforts in functional genomics and the identification of metabolic disruptions related to disease pathogenesis.« less

  7. GABAergic Signaling Is Linked to a Hypermigratory Phenotype in Dendritic Cells Infected by Toxoplasma gondii

    PubMed Central

    Kumar Mendu, Suresh; Jin, Zhe; Wallin, Robert P. A.; Rethi, Bence; Birnir, Bryndis; Barragan, Antonio

    2012-01-01

    During acute infection in human and animal hosts, the obligate intracellular protozoan Toxoplasma gondii infects a variety of cell types, including leukocytes. Poised to respond to invading pathogens, dendritic cells (DC) may also be exploited by T. gondii for spread in the infected host. Here, we report that human and mouse myeloid DC possess functional γ-aminobutyric acid (GABA) receptors and the machinery for GABA biosynthesis and secretion. Shortly after T. gondii infection (genotypes I, II and III), DC responded with enhanced GABA secretion in vitro. We demonstrate that GABA activates GABAA receptor-mediated currents in T. gondii-infected DC, which exhibit a hypermigratory phenotype. Inhibition of GABA synthesis, transportation or GABAA receptor blockade in T. gondii-infected DC resulted in impaired transmigration capacity, motility and chemotactic response to CCL19 in vitro. Moreover, exogenous GABA or supernatant from infected DC restored the migration of infected DC in vitro. In a mouse model of toxoplasmosis, adoptive transfer of infected DC pre-treated with GABAergic inhibitors reduced parasite dissemination and parasite loads in target organs, e.g. the central nervous system. Altogether, we provide evidence that GABAergic signaling modulates the migratory properties of DC and that T. gondii likely makes use of this pathway for dissemination. The findings unveil that GABA, the principal inhibitory neurotransmitter in the brain, has activation functions in the immune system that may be hijacked by intracellular pathogens. PMID:23236276

  8. Animal Models of Cystic Fibrosis Pathology: Phenotypic Parallels and Divergences

    PubMed Central

    McElvaney, Noel G.

    2016-01-01

    Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The resultant characteristic ion transport defect results in decreased mucociliary clearance, bacterial colonisation, and chronic neutrophil-dominated inflammation. Much knowledge surrounding the pathophysiology of the disease has been gained through the generation of animal models, despite inherent limitations in each. The failure of certain mouse models to recapitulate the phenotypic manifestations of human disease has initiated the generation of larger animals in which to study CF, including the pig and the ferret. This review will summarise the basic phenotypes of three animal models and describe the contributions of such animal studies to our current understanding of CF. PMID:27340661

  9. Behavioral phenotypes of genetic mouse models of autism.

    PubMed

    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.

  10. Behavioral phenotypes of genetic mouse models of autism

    PubMed Central

    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. PMID:26403076

  11. Tumor and reproductive traits are linked by RNA metabolism genes in the mouse ovary: a transcriptome-phenotype association analysis

    PubMed Central

    2010-01-01

    Background The link between reproductive life history and incidence of ovarian tumors is well known. Periods of reduced ovulations may confer protection against ovarian cancer. Using phenotypic data available for mouse, a possible association between the ovarian transcriptome, reproductive records and spontaneous ovarian tumor rates was investigated in four mouse inbred strains. NIA15k-DNA microarrays were employed to obtain expression profiles of BalbC, C57BL6, FVB and SWR adult ovaries. Results Linear regression analysis with multiple-test control (adjusted p ≤ 0.05) resulted in ovarian tumor frequency (OTF) and number of litters (NL) as the top-correlated among five tested phenotypes. Moreover, nearly one-hundred genes were coincident between these two traits and were decomposed in 76 OTF(–) NL(+) and 20 OTF(+) NL(–) genes, where the plus/minus signs indicate the direction of correlation. Enriched functional categories were RNA-binding/mRNA-processing and protein folding in the OTF(–) NL(+) and the OTF(+) NL(–) subsets, respectively. In contrast, no associations were detected between OTF and litter size (LS), the latter a measure of ovulation events in a single estrous cycle. Conclusion Literature text-mining pointed to post-transcriptional control of ovarian processes including oocyte maturation, folliculogenesis and angiogenesis as possible causal relationships of observed tumor and reproductive phenotypes. We speculate that repetitive cycling instead of repetitive ovulations represent the actual link between ovarian tumorigenesis and reproductive records. PMID:21210965

  12. Animal models of the polycystic ovary syndrome phenotype

    PubMed Central

    Veiga-Lopez, Almudena

    2013-01-01

    The etiology of the polycystic ovary syndrome (PCOS) remains unclear, despite its high prevalence among infertility disorders in women of reproductive age. Although there is evidence for a genetic component of the disorder, other causes, such as prenatal insults are considered among the potential factors that may contribute to the development of the syndrome. Over the past few decades, several animal models have been developed in an attempt to understand the potential contribution of exposure to excess steroids on the development of this syndrome. The current review summarizes the phenotypes of current animal models exposed to excess steroid during the prenatal and early postnatal period and how they compare with the phenotype seen in women with PCOS. PMID:23701728

  13. Naturally Occurring Animal Models with Outer Retina Phenotypes

    PubMed Central

    Baehr, Wolfgang; Frederick, Jeanne M.

    2009-01-01

    Naturally occurring and laboratory generated animal models serve as powerful tools with which to investigate the etiology of human retinal degenerations, especially retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), cone dystrophies (CD) and macular degeneration (MD). Much progress has been made in elucidating gene defects underlying disease, in understanding mechanisms leading to disease, and in designing molecules for translational research and gene-based therapy to interfere with the progression of disease. Key to this progress has been study of naturally occurring murine and canine retinal degeneration mutants. This article will review the history, phenotypes and gene defects of select animal models with outer retina (photoreceptor and retinal pigment epithelium) degeneration phenotypes. PMID:19375447

  14. A prenatal nicotine exposure mouse model of methylphenidate responsive ADHD-associated cognitive phenotypes.

    PubMed

    Zhu, Jinmin; Fan, Fangfang; McCarthy, Deirdre M; Zhang, Lin; Cannon, Elisa N; Spencer, Thomas J; Biederman, Joseph; Bhide, Pradeep G

    2017-02-04

    Prenatal exposure to nicotine via cigarette smoke or other forms of tobacco use is a significant environmental risk factor for attention deficit hyperactivity disorder (ADHD). The neurobiological mechanisms underlying the link between prenatal nicotine exposure (PNE) and ADHD are not well understood. Animal models, especially rodent models, are beginning to bridge this gap in knowledge. Although ADHD is characterized by hyperactivity, inattention, impulsivity and working memory deficits, the majority of the animal models are based on only one or two ADHD associated phenotypes, in particular, hyperactivity or inattention. We report a PNE mouse model that displays the full range of ADHD associated behavioral phenotypes including working memory deficit, attention deficit and impulsive-like behavior. All of the ADHD-associated phenotypes respond to a single administration of a therapeutic equivalent dose of methylphenidate. In an earlier study, we showed that PNE produces hyperactivity, frontal cortical hypodopaminergic state and thinning of the cingulate cortex. Collectively, these data suggest that the PNE mouse model recapitulates key features of ADHD and may be a suitable preclinical model for ADHD research.

  15. Phenotypic Analysis Reveals that the 2010 Haiti Cholera Epidemic Is Linked to a Hypervirulent Strain

    PubMed Central

    Jones, Christopher J.; Wong, Jennifer; Queen, Jessica; Agarwal, Shivani; Yildiz, Fitnat H.

    2016-01-01

    Vibrio cholerae O1 El Tor strains have been responsible for pandemic cholera since 1961. These strains have evolved over time, spreading globally in three separate waves. Wave 3 is caused by altered El Tor (AET) variant strains, which include the strain with the signature ctxB7 allele that was introduced in 2010 into Haiti, where it caused a devastating epidemic. In this study, we used phenotypic analysis to compare an early isolate from the Haiti epidemic to wave 1 El Tor isolates commonly used for research. It is demonstrated that the Haiti isolate has increased production of cholera toxin (CT) and hemolysin, increased motility, and a reduced ability to form biofilms. This strain also outcompetes common wave 1 El Tor isolates for colonization of infant mice, indicating that it has increased virulence. Monitoring of CT production and motility in additional wave 3 isolates revealed that this phenotypic variation likely evolved over time rather than in a single genetic event. Analysis of available whole-genome sequences and phylogenetic analyses suggested that increased virulence arose from positive selection for mutations found in known and putative regulatory genes, including hns and vieA, diguanylate cyclase genes, and genes belonging to the lysR and gntR regulatory families. Overall, the studies presented here revealed that V. cholerae virulence potential can evolve and that the currently prevalent wave 3 AET strains are both phenotypically distinct from and more virulent than many El Tor isolates. PMID:27297393

  16. Phenotypic Analysis Reveals that the 2010 Haiti Cholera Epidemic Is Linked to a Hypervirulent Strain.

    PubMed

    Satchell, Karla J F; Jones, Christopher J; Wong, Jennifer; Queen, Jessica; Agarwal, Shivani; Yildiz, Fitnat H

    2016-09-01

    Vibrio cholerae O1 El Tor strains have been responsible for pandemic cholera since 1961. These strains have evolved over time, spreading globally in three separate waves. Wave 3 is caused by altered El Tor (AET) variant strains, which include the strain with the signature ctxB7 allele that was introduced in 2010 into Haiti, where it caused a devastating epidemic. In this study, we used phenotypic analysis to compare an early isolate from the Haiti epidemic to wave 1 El Tor isolates commonly used for research. It is demonstrated that the Haiti isolate has increased production of cholera toxin (CT) and hemolysin, increased motility, and a reduced ability to form biofilms. This strain also outcompetes common wave 1 El Tor isolates for colonization of infant mice, indicating that it has increased virulence. Monitoring of CT production and motility in additional wave 3 isolates revealed that this phenotypic variation likely evolved over time rather than in a single genetic event. Analysis of available whole-genome sequences and phylogenetic analyses suggested that increased virulence arose from positive selection for mutations found in known and putative regulatory genes, including hns and vieA, diguanylate cyclase genes, and genes belonging to the lysR and gntR regulatory families. Overall, the studies presented here revealed that V. cholerae virulence potential can evolve and that the currently prevalent wave 3 AET strains are both phenotypically distinct from and more virulent than many El Tor isolates.

  17. Phenotypic constraints and community structure: linking trade-offs within and among species.

    PubMed

    Angert, Amy L; Kimball, Sarah; Peterson, Megan; Huxman, Travis E; Venable, David L

    2014-11-01

    Trade-offs are central to many topics in biology, from the evolution of life histories to ecological mechanisms of species coexistence. Trade-offs observed among species may reflect pervasive constraints on phenotypes that are achievable given biophysical and resource limitations. If so, then among-species trade-offs should be consistent with trade-offs within species. Alternatively, trait variation among co-occurring species may reflect historical contingencies during community assembly rather than within-species constraints. Here, we test whether a key trade-off between relative growth rate (RGR) and water-use efficiency (WUE) among Sonoran Desert winter annual plants is apparent within four species representing different strategies in the system. We grew progeny of maternal families from multiple populations in a greenhouse common garden. One species, Pectocarya recurvata, displayed the expected RGR-WUE trade-off among families within populations. For other species, although RGR and WUE often varied clinally among populations, among-family variation within populations was lacking, implicating a role for past selection on these traits. Our results suggest that a combination of limited genetic variation in single traits and negative trait correlations could pose constraints on the evolution of a high-RGR and high-WUE phenotype within species, providing a microevolutionary explanation for phenotypes that influence community-level patterns of abundance and coexistence.

  18. A phenotypic model recapitulating the neuropathology of Parkinson's disease.

    PubMed

    Ferris, Craig F; Marella, Mathieu; Smerkers, Brian; Barchet, Thomas M; Gershman, Benjamin; Matsuno-Yagi, Akemi; Yagi, Takao

    2013-07-01

    This study was undertaken to develop a phenotypic model recapitulating the neuropathology of Parkinson's disease (PD). Such a model would show loss of dopamine in the basal ganglia, appearance of Lewy bodies, and the early stages of motor dysfunction. The model was developed by subcutaneously injecting biodegradable microspheres of rotenone, a complex I inhibitor in 8-9 month old, ovariectomized Long-Evans rats. Animals were observed for changes in body weight and motor activity. At the end of 11-12 weeks animals were euthanized and the brains examined for histopathological changes. Rotenone treated animals gain weight and appear normal and healthy as compared to controls but showed modest hypokinesia around 5-6 weeks posttreatment. Animals showed loss of dopaminergic (DA) neurons and the appearance of putative Lewy bodies in the substantia nigra. Neuroinflammation and oxidative stress were evidenced by the appearance of activated microglia, iron precipitates, and 8-oxo-2'-deoxyguanosine a major product of DNA oxidation. The dorsal striatum, the projection site of midbrain DA neurons, showed a significant reduction in tyrosine hydroxylase immunostaining, together with an increase in reactive astrocytes, an early sign of DA nerve terminal damage. Levels of vesicular monoamine transporter 2 (VMAT2) were significantly reduced in the dorsal striatum; however, there was an unexpected increase in dopamine transporter (DAT) levels. Old, ovariectomized females treated with rotenone microspheres present with normal weight gain and good health but a modest hypokinesia. Accompanying this behavioral phenotype are a constellation of neuropathologies characteristic of PD that include loss of DA neurons, microglia activation, oxidative damage to nuclear DNA, iron deposition, and appearance of putative Lewy bodies. This phenotypic model recapitulating the neuropathology of Parkinson's disease could provide insight into early mechanisms of pathogenesis and could aid in the

  19. Mutations in chromatin regulators functionally link Cornelia de Lange syndrome and clinically overlapping phenotypes.

    PubMed

    Parenti, Ilaria; Teresa-Rodrigo, María E; Pozojevic, Jelena; Ruiz Gil, Sara; Bader, Ingrid; Braunholz, Diana; Bramswig, Nuria C; Gervasini, Cristina; Larizza, Lidia; Pfeiffer, Lutz; Ozkinay, Ferda; Ramos, Feliciano; Reiz, Benedikt; Rittinger, Olaf; Strom, Tim M; Watrin, Erwan; Wendt, Kerstin; Wieczorek, Dagmar; Wollnik, Bernd; Baquero-Montoya, Carolina; Pié, Juan; Deardorff, Matthew A; Gillessen-Kaesbach, Gabriele; Kaiser, Frank J

    2017-03-01

    The coordinated tissue-specific regulation of gene expression is essential for the proper development of all organisms. Mutations in multiple transcriptional regulators cause a group of neurodevelopmental disorders termed "transcriptomopathies" that share core phenotypical features including growth retardation, developmental delay, intellectual disability and facial dysmorphism. Cornelia de Lange syndrome (CdLS) belongs to this class of disorders and is caused by mutations in different subunits or regulators of the cohesin complex. Herein, we report on the clinical and molecular characterization of seven patients with features overlapping with CdLS who were found to carry mutations in chromatin regulators previously associated to other neurodevelopmental disorders that are frequently considered in the differential diagnosis of CdLS. The identified mutations affect the methyltransferase-encoding genes KMT2A and SETD5 and different subunits of the SWI/SNF chromatin-remodeling complex. Complementary to this, a patient with Coffin-Siris syndrome was found to carry a missense substitution in NIPBL. Our findings indicate that mutations in a variety of chromatin-associated factors result in overlapping clinical phenotypes, underscoring the genetic heterogeneity that should be considered when assessing the clinical and molecular diagnosis of neurodevelopmental syndromes. It is clear that emerging molecular mechanisms of chromatin dysregulation are central to understanding the pathogenesis of these clinically overlapping genetic disorders.

  20. Environmental metabolomics links genotype to phenotype and predicts genotype abundance in wild plant populations.

    PubMed

    Field, Katie J; Lake, Janice A

    2011-08-01

    'The Holy Grail' of plant ecology is to uncover rules that associate species and traits with environmental constraints, community composition and subsequent ecosystem functioning. These aims have been crystallized in recent years within the context of global climate change and environmental pollution, increasing the urgency of the need to predict how vegetation will respond across spatial scales. We investigated whether genetic diversity is associated with the way in which phenotypic plasticity within plant populations is realized and whether this is related to genotype abundance. We used environmental metabolomics to demonstrate biochemical variation between co-occurring genotypes of Carex caryophyllea L. A novel combined metabolomic/functional trait analysis was used to test the functionality of this variation in governing plasticity to variation in edaphic conditions, with particular reference to metabolic pathways that play important roles in growth-related traits. We show that genetic diversity within a wild C. caryophyllea population relates to differences in metabolic composition and functional traits in response to soil nutrient variation, influencing genotype abundance within a community. Our findings highlight the vital role genetic diversity plays within a population in facilitating plant phenotypic plasticity and the potential usefulness of environmental metabolomics to future ecological studies.

  1. Healthy Volunteers Can Be Phenotyped Using Cutaneous Sensitization Pain Models

    PubMed Central

    Rowbotham, Michael C.; Dahl, Jørgen B.

    2013-01-01

    Background Human experimental pain models leading to development of secondary hyperalgesia are used to estimate efficacy of analgesics and antihyperalgesics. The ability to develop an area of secondary hyperalgesia varies substantially between subjects, but little is known about the agreement following repeated measurements. The aim of this study was to determine if the areas of secondary hyperalgesia were consistently robust to be useful for phenotyping subjects, based on their pattern of sensitization by the heat pain models. Methods We performed post-hoc analyses of 10 completed healthy volunteer studies (n = 342 [409 repeated measurements]). Three different models were used to induce secondary hyperalgesia to monofilament stimulation: the heat/capsaicin sensitization (H/C), the brief thermal sensitization (BTS), and the burn injury (BI) models. Three studies included both the H/C and BTS models. Results Within-subject compared to between-subject variability was low, and there was substantial strength of agreement between repeated induction-sessions in most studies. The intraclass correlation coefficient (ICC) improved little with repeated testing beyond two sessions. There was good agreement in categorizing subjects into ‘small area’ (1st quartile [<25%]) and ‘large area’ (4th quartile [>75%]) responders: 56–76% of subjects consistently fell into same ‘small-area’ or ‘large-area’ category on two consecutive study days. There was moderate to substantial agreement between the areas of secondary hyperalgesia induced on the same day using the H/C (forearm) and BTS (thigh) models. Conclusion Secondary hyperalgesia induced by experimental heat pain models seem a consistent measure of sensitization in pharmacodynamic and physiological research. The analysis indicates that healthy volunteers can be phenotyped based on their pattern of sensitization by the heat [and heat plus capsaicin] pain models. PMID:23671631

  2. Grocery Store Genetics: A PCR-Based Genetics Lab that Links Genotype to Phenotype

    ERIC Educational Resources Information Center

    Briju, Betsy J.; Wyatt, Sarah E.

    2015-01-01

    Instructors often present Mendelian genetics and molecular biology separately. As a result, students often fail to connect the two topics in a tangible manner. We have adopted a simple experiment to help link these two important topics in a basic biology course, using red and white onions bought from a local grocery store. A lack of red coloration…

  3. Response to Drs. Shastry and Trese: Phenotype-genotype correlations in X-linked retinitis pigmentosa

    SciTech Connect

    Kaplan, J.; Munnich, A.

    1996-11-11

    Shastry and Trese recently reported on a large kindred with X-linked retinitis pigmentosa (XLRP) characterized by a loss of central vision and preserved peripheral function. In their report, the disease had an early onset with severe myopia and a loss of central vision, while night blindness occurred later. Genetic analysis suggested that the disease was linked to the RP2 locus, and the authors raised the question of whether other cases linked to RP2 could display a similar loss of central vision. Three years ago, we reported on 4 large XLRP pedigrees with a very early onset with severe myopia and early loss of visual acuity, while in 5 other families the disease started later with night blindness. We showed that the first clinical form was linked to RP2, while the second was linked to RP3. Thus, the major difference between the two forms concerns the initial symptom, information which can be obtained from the parents and patients after careful questioning. By contrast, in adult life, no difference in either severity of disease or aspect of the fundus was observed in our series, regardless of the clinical subtype of XLRP. Some months later, Jacobson et al. reported on a pedigree with an RP2 genotype, and their data support the notion that in XLRP of RP2 type 1, cone dysfunction takes place first, and as the disease advances both rods and cones are affected. We were very happy, therefore, to read that the study of Shastry and Trese fully confirmed our previous findings. 3 refs.

  4. Mutant IDH: a targetable driver of leukemic phenotypes linking metabolism, epigenetics and transcriptional regulation.

    PubMed

    Garrett-Bakelman, Francine E; Melnick, Ari M

    2016-07-01

    Aberrant epigenomic programming is a hallmark of acute myeloid leukemia. This is partially due to somatic mutations that perturb cytosine methylation, histone post-translational modifications and transcription factors. Remarkably, mutations in the IDH1 and IDH2 genes perturb the epigenome through all three of these mechanisms. Mutant IDH enzymes produce high levels of the oncometabolite (R)-2-hydroxyglutarate that competitively inhibits dioxygenase enzymes that modify methylcytosine to hydroxymethylcytosine and histone tail methylation. The development of IDH mutant specific inhibitors may now enable the therapeutic reprogramming of both layers of the epigenome spontaneously to revert the malignant phenotype of these leukemias and improve clinical outcome for acute myeloid leukemia patients with IDH mutations.

  5. Abrupt transitions to tumor extinction: a phenotypic quasispecies model.

    PubMed

    Sardanyés, Josep; Martínez, Regina; Simó, Carles; Solé, Ricard

    2016-10-06

    The dynamics of heterogeneous tumor cell populations competing with healthy cells is an important topic in cancer research with deep implications in biomedicine. Multitude of theoretical and computational models have addressed this issue, especially focusing on the nature of the transitions governing tumor clearance as some relevant model parameters are tuned. In this contribution, we analyze a mathematical model of unstable tumor progression using the quasispecies framework. Our aim is to define a minimal model incorporating the dynamics of competition between healthy cells and a heterogeneous population of cancer cell phenotypes involving changes in replication-related genes (i.e., proto-oncogenes and tumor suppressor genes), in genes responsible for genomic stability, and in house-keeping genes. Such mutations or loss of genes result into different phenotypes with increased proliferation rates and/or increased genomic instabilities. Despite bifurcations in the classical deterministic quasispecies model are typically given by smooth, continuous shifts (i.e., transcritical bifurcations), we here identify a novel type of bifurcation causing an abrupt transition to tumor extinction. Such a bifurcation, named as trans-heteroclinic, is characterized by the exchange of stability between two distant fixed points (that do not collide) involving tumor persistence and tumor clearance. The increase of mutation and/or the decrease of the replication rate of tumor cells involves this catastrophic shift of tumor cell populations. The transient times near bifurcation thresholds are also characterized, showing a power law dependence of exponent [Formula: see text] of the transients as mutation is changed near the bifurcation value. These results are discussed in the context of targeted cancer therapy as a possible therapeutic strategy to force a catastrophic shift by simultaneously delivering mutagenic and cytotoxic drugs inside tumor cells.

  6. Common data link (CDL) interference model

    NASA Astrophysics Data System (ADS)

    Cerasoli, Caramen; Zhao, Wiley; Santapietro, John J.; McAlinden, R. E.; Smith, B. F.; Jacyk, P. A.

    2002-07-01

    The increasing use of airwaves for military communication and surveillance and commercial applications places burdens on spectrum use. This crowding of the spectrum presents two broad problem categories. The first is "co-site interference" where numerous transmitters and receivers are physically located in a small area and share a given portion of the spectrum. Under these conditions, a receiver can be "victim" to a co-located transmitter. The second category involves numerous transmitters (typically airborne) well separated from each other but communicating to receivers placed in a relatively small area. The Common Data Link (CDL) refers to a standard protocol for military data delivery and communication. Surveillance platforms such as Tactical Unmanned Aerial Vehicles (TUAV), JSTARS, U2's, Global Hawks will stream high rate surveillance data (radar, visual and/or infrared imagery, etc.) down to ground terminals. As such, bandwidths are wide (100's MHz) and the potential exists for ground receivers to be victim to signals from airborne transmitters other than its desired source. MITRE has developed a CDL Interference Model to assess potential problems in realistic tactical surveillance scenarios. This paper documents the physical basis of the CDL Interference Model as well as the visualization software architecture that integrates the model with ModSAF/OneSAF.

  7. Behavioural and Psychiatric Phenotypes in Men and Boys with X-Linked Ichthyosis: Evidence from a Worldwide Online Survey

    PubMed Central

    Chatterjee, Sohini; Humby, Trevor; Davies, William

    2016-01-01

    Background X-linked ichthyosis (XLI) is a rare dermatological condition arising from deficiency for the enzyme steroid sulfatase (STS). Preliminary evidence in boys with XLI, and animal model studies, suggests that individuals lacking STS are at increased risk of developmental disorders and associated traits. However, the behavioural profile of children with XLI is poorly-characterised, and the behavioural profile of adults with XLI has not yet been documented at all. Materials and Methods Using an online survey, advertised worldwide, we collected detailed self- or parent-reported information on behaviour in adult (n = 58) and younger (≤18yrs, n = 24) males with XLI for comparison to data from their non-affected brothers, and age/gender-matched previously-published normative data. The survey comprised demographic and background information (including any prior clinical diagnoses) and validated questionnaires assaying phenotypes of particular interest (Adult ADHD Self-Report Scale v1.1, Barrett Impulsiveness Scale-11, adult and adolescent Autism Quotient, Kessler Psychological Distress Scales, and Disruptive Behaviour Disorder Rating Scale). Results Individuals with XLI generally exhibited normal sensory function. Boys with XLI were at increased risk of developmental disorder, whilst adults with the condition were at increased risk of both developmental and mood disorders. Both adult and younger XLI groups scored significantly more highly than male general population norms on measures of inattention, impulsivity, autism-related traits, psychological distress and disruptive behavioural traits. Conclusions These findings indicate that both adult and younger males with XLI exhibit personality profiles that are distinct from those of males within the general population, and suggest that individuals with XLI may be at heightened risk of psychopathology. The data are consistent with the notion that STS is important in neurodevelopment and ongoing brain function, and

  8. A model for phenotype change in a stochastic framework.

    PubMed

    Wake, Graeme; Pleasants, Anthony; Beedle, Alan; Gluckman, Peter

    2010-07-01

    In some species, an inducible secondary phenotype will develop some time after the environmental change that evokes it. Nishimura (2006) [4] showed how an individual organism should optimize the time it takes to respond to an environmental change ("waiting time''). If the optimal waiting time is considered to act over the population, there are implications for the expected value of the mean fitness in that population. A stochastic predator-prey model is proposed in which the prey have a fixed initial energy budget. Fitness is the product of survival probability and the energy remaining for non-defensive purposes. The model is placed in the stochastic domain by assuming that the waiting time in the population is a normally distributed random variable because of biological variance inherent in mounting the response. It is found that the value of the mean waiting time that maximises fitness depends linearly on the variance of the waiting time.

  9. Linking childhood allergic asthma phenotypes with endotype through integrated systems biology: current evidence and research needs.

    PubMed

    Choi, Hyunok; Song, Won-Min; Zhang, Bin

    2017-03-01

    Asthma and other complex diseases results from a complex web of interactions involving inflammation, immunity, cell cycle, apoptosis, and metabolic perturbations across multiple organ systems. The extent to which various degrees of the age at onset, symptom severity, and the natural progression of the disease reflect multiple disease subtypes, influenced by unique process of development remains unknown. One of the most critical challenges to our understanding stems from incomplete understanding of the mechanisms. Within this review, we focus on the phenotypes of childhood allergic asthma as the basis to better understand the endotype for quantitative define subtypes of asthma. We highlight some of the known mechanistic pathways associated with the key hallmark events before the asthma onset. In particular, we examine how the recent advent of multiaxial -omics technologies and systems biology could help to clarify our current understanding of the pathway. We review how a large volume of molecular, genomic data generated by multiaxial technologies could be digested to identify cogent pathophysiologic molecular networks. We highlight some recent successes in application of these technologies within the context of other disease conditions for therapeutic interventions. We conclude by summarizing the research needs for the predictive value of preclinical biomarkers.

  10. Signaling pathways in mammalian preimplantation development: Linking cellular phenotypes to lineage decisions.

    PubMed

    Menchero, Sergio; Rayon, Teresa; Andreu, Maria Jose; Manzanares, Miguel

    2017-04-01

    The first stages of mammalian development, before implantation of the embryo in the maternal uterus, result in the establishment of three cell populations in the blastocyst: trophectoderm, epiblast, and primitive endoderm. These events involve only a small number of cells, and are initiated by morphological differences among them related to cell adhesion and polarity. Much attention has been paid to the master transcription factors that are critical for establishing and maintaining early lineage choices. Nevertheless, a large body of work also reveals that additional molecular mechanisms are involved. Here, we provide an updated view of the role of different signaling pathways in the first stages of mouse development, and how their cross-talk and interplay determine the initial lineage decisions occurring in the blastocyst. We will also discuss how these pathways are critical for translating cellular phenotypes, the product of the morphogenetic events occurring at these stages, into transcriptional responses and expression of lineage-specifying transcription factors. Developmental Dynamics 246:245-261, 2017. © 2016 Wiley Periodicals, Inc.

  11. p16 overexpression and 9p21 deletion are linked to unfavorable tumor phenotype in breast cancer.

    PubMed

    Lebok, Patrick; Roming, Magdalena; Kluth, Martina; Koop, Christina; Özden, Cansu; Taskin, Berivan; Hussein, Khakan; Lebeau, Annette; Witzel, Isabell; Wölber, Linn; Geist, Stefan; Paluchowski, Peter; Wilke, Christian; Heilenkötter, Uwe; Müller, Volkmar; Schmalfeldt, Barbara; Simon, Ronald; Sauter, Guido; Terracciano, Luigi; Krech, Rainer Horst; von der Assen, Albert; Burandt, Eike

    2016-12-06

    Overexpression of the p16 tumor suppressor, but also deletion of its gene locus 9p21, is linked to unfavorable tumor phenotype and poor prognosis in breast cancer. To better understand these contradictory observations, and to clarify the prognostic impact of p16 expression and 9p21 deletion, a tissue microarray (TMA) with 2,197 breast cancers was analyzed by fluorescence in-situ hybridization and immunohistochemistry (FISH) for 9p21 deletion and p16 expression. p16 immunostaining was weak in 25.6%, moderate in 7.1%, and strong in 12.7% of 1,684 evaluable cancers. Strong p16 staining was linked to advanced tumor stage (p = 0.0003), high-grade (p < 0.0001), high tumor cell proliferation (p < 0.0001), negative hormone receptor (ER/PR) status (p < 0.0001 each), and shorter overall survival (p = 0.0038). 9p21 deletion was found in 15.3% of 1,089 analyzable breast cancers, including 1.7% homozygous and 13.6% heterozygous deletions. 9p21 deletion was linked to adverse tumor features, including high-grade (p < 0.0001) and nodal positive cancers (p = 0.0063), high cell proliferation (p < 0.0001), negative hormone receptor (ER/PR) status (p ≤ 0.0006), and HER2 amplification (p = 0.0078). Patient outcome was worse in 9p21 deleted than in undeleted cancers (p = 0.0720). p16 expression was absent in cancers harboring homozygous 9p21 deletions, but no difference in p16 expression was found between cancers with (59.2% p16 positive) and without heterozygous 9p21 deletion (51.3% p16 positive, p = 0.0256). In summary, p16 expression is unrelated to partial 9p21 deletion, but both alterations are linked to aggressive breast cancer phenotype. High-level p16 expression is a strong predictor of unfavorable disease course in breast cancer.

  12. Medial prefrontal cortex: genes linked to bipolar disorder and schizophrenia have altered expression in the highly social maternal phenotype.

    PubMed

    Eisinger, Brian E; Driessen, Terri M; Zhao, Changjiu; Gammie, Stephen C

    2014-01-01

    The transition to motherhood involves CNS changes that modify sociability and affective state. However, these changes also put females at risk for post-partum depression and psychosis, which impairs parenting abilities and adversely affects children. Thus, changes in expression and interactions in a core subset of genes may be critical for emergence of a healthy maternal phenotype, but inappropriate changes of the same genes could put women at risk for post-partum disorders. This study evaluated microarray gene expression changes in medial prefrontal cortex (mPFC), a region implicated in both maternal behavior and psychiatric disorders. Post-partum mice were compared to virgin controls housed with females and isolated for identical durations. Using the Modular Single-set Enrichment Test (MSET), we found that the genetic landscape of maternal mPFC bears statistical similarity to gene databases associated with schizophrenia (5 of 5 sets) and bipolar disorder (BPD, 3 of 3 sets). In contrast to previous studies of maternal lateral septum (LS) and medial preoptic area (MPOA), enrichment of autism and depression-linked genes was not significant (2 of 9 sets, 0 of 4 sets). Among genes linked to multiple disorders were fatty acid binding protein 7 (Fabp7), glutamate metabotropic receptor 3 (Grm3), platelet derived growth factor, beta polypeptide (Pdgfrb), and nuclear receptor subfamily 1, group D, member 1 (Nr1d1). RT-qPCR confirmed these gene changes as well as FMS-like tyrosine kinase 1 (Flt1) and proenkephalin (Penk). Systems-level methods revealed involvement of developmental gene networks in establishing the maternal phenotype and indirectly suggested a role for numerous microRNAs and transcription factors in mediating expression changes. Together, this study suggests that a subset of genes involved in shaping the healthy maternal brain may also be dysregulated in mental health disorders and put females at risk for post-partum psychosis with aspects of schizophrenia

  13. Behavioral phenotyping of mouse models of Parkinson's Disease

    PubMed Central

    Taylor, Tonya N.; Greene, James G.; Miller, Gary W.

    2010-01-01

    Parkinson's disease (PD) is a common neurodegenerative movement disorder afflicting millions of people in the United States. The advent of transgenic technologies has contributed to the development of several new mouse models, many of which recapitulate some aspects of the disease; however, no model has been demonstrated to faithfully reproduce the full constellation of symptoms seen in human PD. This may be due in part to the narrow focus on the dopamine-mediated motor deficits. As current research continues to unmask PD as a multi-system disorder, animal models should similarly evolve to include the non-motor features of the disease. This requires that typically cited behavioral test batteries be expanded. The major non-motor symptoms observed in PD patients include hyposmia, sleep disturbances, gastrointestinal dysfunction, autonomic dysfunction, anxiety, depression, and cognitive decline. Mouse behavioral tests exist for all of these symptoms and while some models have begun to be reassessed for the prevalence of this broader behavioral phenotype, the majority has not. Moreover, all behavioral paradigms should be tested for their responsiveness to L-DOPA so these data can be compared to patient response and help elucidate which symptoms are likely not dopamine-mediated. Here, we suggest an extensive, yet feasible, battery of behavioral tests for mouse models of PD aimed to better assess both non-motor and motor deficits associated with the disease. PMID:20211655

  14. Phenotypic Variation in Dentinogenesis Imperfecta/Dentin Dysplasia Linked to 4q21

    PubMed Central

    Beattie, M.L.; Kim, J.-W.; Gong, S.-G.; Murdoch-Kinch, C.A.; Simmer, J.P.; Hu, J.C.-C.

    2008-01-01

    Dentinogenesis imperfecta (DGI) and dentin dysplasia (DD) are allelic disorders that primarily affect the formation of tooth dentin. Both conditions are autosomal-dominant and can be caused by mutations in the dentin sialophospho-protein gene (DSPP, 4q21.3). We recruited 23 members of a four-generation kindred, including ten persons with dentin defects, and tested the hypothesis that these defects are linked to DSPP. The primary dentition showed amber discoloration, pulp obliteration, and severe attrition. The secondary dentition showed either pulp obliteration with bulbous crowns and gray discoloration or thistle-tube pulp configurations, normal crowns, and mild gray discoloration. Haplotype analyses showed no recombination between three 4q21-q24 markers and the disease locus. Mutational analyses identified no coding or intron junction sequence variations associated with affection status in DMP1, MEPE, or the DSP portion of DSPP. The defects in the permanent dentition were typically mild and consistent with a diagnosis of DD-II, but some dental features associated with DGI-II were also present. We conclude that DD-II and DGI-II are milder and more severe forms, respectively, of the same disease. PMID:16567553

  15. Phenotypic differences among patients with Bardet-Biedl syndrome linked to three different chromosome loci

    SciTech Connect

    Carmi, R.; Elbedour, K.; Stone, E.M.; Sheffield, V.C.

    1995-11-06

    Bardet-Biedl syndrome (BBS) is an autosomal-recessive disorder of mental retardation, obesity, retinal dystrophy, polydactyly, and hypogenitalism. Renal and cardiac abnormalities are also frequent in this disorder. Previous clinical suggestions of heterogeneity of BBS were confirmed recently by the identification of four different chromosome loci linked to the disease. In this study we compared clinical manifestations of the syndrome in patients form 3 unrelated, extended Arab-Bedouin kindreds which were used for the linkage mapping of the BBS loci to chromosomes 3, 15, and 16. The observed differences included the limb distribution of the postaxial polydactyly and the extent and age-association of obesity. It appears that the chromosome 3 locus is associated with polydactyly of all four limbs, while polydactyly of the chromosome 15 type is mostly confined to the hands. On the other hand, the chromosome 15 type is associated with early-onset morbid obesity, while the chromosome 16 type appears to present the {open_quotes}leanest{close_quotes} form of BBS. Future cloning of the various BB genes will contribute to the understanding of the molecular basis of limb development and the identification of human obesity-related genes. 22 refs., 1 fig., 4 tabs.

  16. From integrative genomics to systems genetics in the rat to link genotypes to phenotypes

    PubMed Central

    Moreno-Moral, Aida

    2016-01-01

    ABSTRACT Complementary to traditional gene mapping approaches used to identify the hereditary components of complex diseases, integrative genomics and systems genetics have emerged as powerful strategies to decipher the key genetic drivers of molecular pathways that underlie disease. Broadly speaking, integrative genomics aims to link cellular-level traits (such as mRNA expression) to the genome to identify their genetic determinants. With the characterization of several cellular-level traits within the same system, the integrative genomics approach evolved into a more comprehensive study design, called systems genetics, which aims to unravel the complex biological networks and pathways involved in disease, and in turn map their genetic control points. The first fully integrated systems genetics study was carried out in rats, and the results, which revealed conserved trans-acting genetic regulation of a pro-inflammatory network relevant to type 1 diabetes, were translated to humans. Many studies using different organisms subsequently stemmed from this example. The aim of this Review is to describe the most recent advances in the fields of integrative genomics and systems genetics applied in the rat, with a focus on studies of complex diseases ranging from inflammatory to cardiometabolic disorders. We aim to provide the genetics community with a comprehensive insight into how the systems genetics approach came to life, starting from the first integrative genomics strategies [such as expression quantitative trait loci (eQTLs) mapping] and concluding with the most sophisticated gene network-based analyses in multiple systems and disease states. Although not limited to studies that have been directly translated to humans, we will focus particularly on the successful investigations in the rat that have led to primary discoveries of genes and pathways relevant to human disease. PMID:27736746

  17. Comparison of Liver Cell Models Using the Basel Phenotyping Cocktail

    PubMed Central

    Berger, Benjamin; Donzelli, Massimiliano; Maseneni, Swarna; Boess, Franziska; Roth, Adrian; Krähenbühl, Stephan; Haschke, Manuel

    2016-01-01

    Currently used hepatocyte cell systems for in vitro assessment of drug metabolism include hepatoma cell lines and primary human hepatocyte (PHH) cultures. We investigated the suitability of the validated in vivo Basel phenotyping cocktail (caffeine [CYP1A2], efavirenz [CYP2B6], losartan [CYP2C9], omeprazole [CYP2C19], metoprolol [CYP2D6], midazolam [CYP3A4]) in vitro and characterized four hepatocyte cell systems (HepG2 cells, HepaRG cells, and primary cryopreserved human hepatocytes in 2-dimensional [2D] culture or in 3D-spheroid co-culture) regarding basal metabolism and CYP inducibility. Under non-induced conditions, all CYP activities could be determined in 3D-PHH, CYP2B6, CYP2C19, CYP2D6, and CYP3A4 in 2D-PHH and HepaRG, and CYP2C19 and CYP3A4 in HepG2 cells. The highest non-induced CYP activities were observed in 3D-PHH and HepaRG cells. mRNA expression was at least four-fold higher for all CYPs in 3D-PHH compared to the other cell systems. After treatment with 20 μM rifampicin, mRNA increased 3- to 50-fold for all CYPs except CYP1A2 and 2D6 for HepaRG and 3D-PHH, 4-fold (CYP2B6) and 17-fold (CYP3A4) for 2D-PHH and four-fold (CYP3A4) for HepG2. In 3D-PHH at least a two-fold increase in CYP activity was observed for all inducible CYP isoforms while CYP1A2 and CYP2C9 activity did not increase in 2D-PHH and HepaRG. CYP inducibility assessed in vivo using the same phenotyping probes was also best reflected by the 3D-PHH model. Our studies show that 3D-PHH and (with some limitations) HepaRG are suitable cell systems for assessing drug metabolism and CYP induction in vitro. HepG2 cells are less suited to assess CYP induction of the 2C and 3A family. The Basel phenotyping cocktail is suitable for the assessment of CYP activity and induction also in vitro. PMID:27917125

  18. Modeling psychiatric disorders: from genomic findings to cellular phenotypes

    PubMed Central

    Falk, A; Heine, V M; Harwood, A J; Sullivan, P F; Peitz, M; Brüstle, O; Shen, S; Sun, Y-M; Glover, J C; Posthuma, D; Djurovic, S

    2016-01-01

    Major programs in psychiatric genetics have identified >150 risk loci for psychiatric disorders. These loci converge on a small number of functional pathways, which span conventional diagnostic criteria, suggesting a partly common biology underlying schizophrenia, autism and other psychiatric disorders. Nevertheless, the cellular phenotypes that capture the fundamental features of psychiatric disorders have not yet been determined. Recent advances in genetics and stem cell biology offer new prospects for cell-based modeling of psychiatric disorders. The advent of cell reprogramming and induced pluripotent stem cells (iPSC) provides an opportunity to translate genetic findings into patient-specific in vitro models. iPSC technology is less than a decade old but holds great promise for bridging the gaps between patients, genetics and biology. Despite many obvious advantages, iPSC studies still present multiple challenges. In this expert review, we critically review the challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes. PMID:27240529

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

    PubMed

    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.

  20. Modeling Phenotypes of Tuberous Sclerosis in the Mouse

    DTIC Science & Technology

    2006-02-01

    other proteins in this pathological progression, and to evaluate relevant therapeutic interventions such as rapamycin. 15. SUBJECT TERMS MOUSE...whether rapamycin treatment corrects this dysregulation, and whether phenotypes seen in the mice are abrogated by breeding pertinent MMP knockout...induction by doxycycline (Figure 7), this approach did not yield a phenotype, at least after 6 months of doxycycline treatment . Thus, as our

  1. Monogenic mouse models of autism spectrum disorders: Common mechanisms and missing links.

    PubMed

    Hulbert, S W; Jiang, Y-H

    2016-05-03

    Autism spectrum disorders (ASDs) present unique challenges in the fields of genetics and neurobiology because of the clinical and molecular heterogeneity underlying these disorders. Genetic mutations found in ASD patients provide opportunities to dissect the molecular and circuit mechanisms underlying autistic behaviors using animal models. Ongoing studies of genetically modified models have offered critical insight into possible common mechanisms arising from different mutations, but links between molecular abnormalities and behavioral phenotypes remain elusive. The challenges encountered in modeling autism in mice demand a new analytic paradigm that integrates behavioral assessment with circuit-level analysis in genetically modified models with strong construct validity.

  2. Genome-wide modeling of complex phenotypes in Caenorhabditis elegans and Drosophila melanogaster

    PubMed Central

    2013-01-01

    Background The genetic and molecular basis for many intermediate and end stage phenotypes in model systems such as C. elegans and D. melanogaster has long been known to involve pleiotropic effects and complex multigenic interactions. Gene sets are groups of genes that contribute to multiple biological or molecular phenomena. They have been used in the analysis of large molecular datasets such as microarray data, Next Generation sequencing, and other genomic datasets to reveal pleiotropic and multigenic contributions to phenotypic outcomes. Many model systems lack species specific organized phenotype based gene sets to enable high throughput analysis of large molecular datasets. Results and discussion Here, we describe two novel collections of gene sets in C. elegans and D. melanogaster that are based exclusively on genetically determined phenotypes and use a controlled phenotypic ontology. We use these collections to build genome-wide models of thousands of defined phenotypes in both model species. In addition, we demonstrate the utility of these gene sets in systems analysis and in analysis of gene expression-based molecular datasets and show how they are useful in analysis of genomic datasets connecting multigenic gene inputs to complex phenotypes. Conclusions Phenotypic based gene sets in both C. elegans and D. melanogaster are developed, characterized, and shown to be useful in the analysis of large scale species-specific genomic datasets. These phenotypic gene set collections will contribute to the understanding of complex phenotypic outcomes in these model systems. PMID:23984798

  3. Predicting complex phenotype-genotype interactions to enable yeast engineering: Saccharomyces cerevisiae as a model organism and a cell factory.

    PubMed

    Dikicioglu, Duygu; Pir, Pınar; Oliver, Stephen G

    2013-09-01

    There is an increasing use of systems biology approaches in both "red" and "white" biotechnology in order to enable medical, medicinal, and industrial applications. The intricate links between genotype and phenotype may be explained through the use of the tools developed in systems biology, synthetic biology, and evolutionary engineering. Biomedical and biotechnological research are among the fields that could benefit most from the elucidation of this complex relationship. Researchers have studied fitness extensively to explain the phenotypic impacts of genetic variations. This elaborate network of dependencies and relationships so revealed are further complicated by the influence of environmental effects that present major challenges to our achieving an understanding of the cellular mechanisms leading to healthy or diseased phenotypes or optimized production yields. An improved comprehension of complex genotype-phenotype interactions and their accurate prediction should enable us to more effectively engineer yeast as a cell factory and to use it as a living model of human or pathogen cells in intelligent screens for new drugs. This review presents different methods and approaches undertaken toward improving our understanding and prediction of the growth phenotype of the yeast Saccharomyces cerevisiae as both a model and a production organism.

  4. “Young at heart”: Regenerative potential linked to immature cardiac phenotypes

    PubMed Central

    Gomes, Renata S.M.; Skroblin, Philipp; Munster, Alex B.; Tomlins, Hannah; Langley, Sarah R.; Zampetaki, Anna; Yin, Xiaoke; Wardle, Fiona C.; Mayr, Manuel

    2016-01-01

    The adult human myocardium is incapable of regeneration; yet, the zebrafish (Danio rerio) can regenerate damaged myocardium. Similar to the zebrafish heart, hearts of neonatal, but not adult mice are capable of myocardial regeneration. We performed a proteomics analysis of adult zebrafish hearts and compared their protein expression profile to hearts from neonatal and adult mice. Using difference in-gel electrophoresis (DIGE), there was little overlap between the proteome from adult mouse (> 8 weeks old) and adult zebrafish (18 months old) hearts. Similarly, there was a significant degree of mismatch between the protein expression in neonatal and adult mouse hearts. Enrichment analysis of the selected proteins revealed over-expression of DNA synthesis-related proteins in the cardiac proteome of the adult zebrafish heart similar to neonatal and 4 days old mice, whereas in hearts of adult mice there was a mitochondria-related predominance in protein expression. Importantly, we noted pronounced differences in the myofilament composition: the adult zebrafish heart lacks many of the myofilament proteins of differentiated adult cardiomyocytes such as the ventricular isoforms of myosin light chains and nebulette. Instead, troponin I and myozenin 1 were expressed as skeletal isoforms rather than cardiac isoforms. The relative immaturity of the adult zebrafish heart was further supported by cardiac microRNA data. Our assessment of zebrafish and mammalian hearts challenges the assertions on the translational potential of cardiac regeneration in the zebrafish model. The immature myofilament composition of the fish heart may explain why adult mouse and human cardiomyocytes lack this endogenous repair mechanism. PMID:26827899

  5. Mouse Genome Database: From sequence to phenotypes and disease models

    PubMed Central

    Richardson, Joel E.; Kadin, James A.; Smith, Cynthia L.; Blake, Judith A.; Bult, Carol J.

    2015-01-01

    Summary The Mouse Genome Database (MGD, www.informatics.jax.org) is the international scientific database for genetic, genomic, and biological data on the laboratory mouse to support the research requirements of the biomedical community. To accomplish this goal, MGD provides broad data coverage, serves as the authoritative standard for mouse nomenclature for genes, mutants, and strains, and curates and integrates many types of data from literature and electronic sources. Among the key data sets MGD supports are: the complete catalog of mouse genes and genome features, comparative homology data for mouse and vertebrate genes, the authoritative set of Gene Ontology (GO) annotations for mouse gene functions, a comprehensive catalog of mouse mutations and their phenotypes, and a curated compendium of mouse models of human diseases. Here, we describe the data acquisition process, specifics about MGD's key data areas, methods to access and query MGD data, and outreach and user help facilities. genesis 53:458–473, 2015. © 2015 The Authors. Genesis Published by Wiley Periodicals, Inc. PMID:26150326

  6. A Splice Defect in the EDA Gene in Dogs with an X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED) Phenotype

    PubMed Central

    Waluk, Dominik P.; Zur, Gila; Kaufmann, Ronnie; Welle, Monika M.; Jagannathan, Vidhya; Drögemüller, Cord; Müller, Eliane J.; Leeb, Tosso; Galichet, Arnaud

    2016-01-01

    X-linked hypohidrotic ectodermal dysplasia (XLHED) caused by variants in the EDA gene represents the most common ectodermal dysplasia in humans. We investigated three male mixed-breed dogs with an ectodermal dysplasia phenotype characterized by marked hypotrichosis and multifocal complete alopecia, almost complete absence of sweat and sebaceous glands, and altered dentition with missing and abnormally shaped teeth. Analysis of SNP chip genotypes and whole genome sequence data from the three affected dogs revealed that the affected dogs shared the same haplotype on a large segment of the X-chromosome, including the EDA gene. Unexpectedly, the whole genome sequence data did not reveal any nonsynonymous EDA variant in the affected dogs. We therefore performed an RNA-seq experiment on skin biopsies to search for changes in the transcriptome. This analysis revealed that the EDA transcript in the affected dogs lacked 103 nucleotides encoded by exon 2. We speculate that this exon skipping is caused by a genetic variant located in one of the large introns flanking this exon, which was missed by whole genome sequencing with the illumina short read technology. The altered EDA transcript splicing most likely causes the observed ectodermal dysplasia in the affected dogs. These dogs thus offer an excellent opportunity to gain insights into the complex splicing processes required for expression of the EDA gene, and other genes with large introns. PMID:27449516

  7. X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations.

    PubMed

    Savige, Judith; Storey, Helen; Il Cheong, Hae; Gyung Kang, Hee; Park, Eujin; Hilbert, Pascale; Persikov, Anton; Torres-Fernandez, Carmen; Ars, Elisabet; Torra, Roser; Hertz, Jens Michael; Thomassen, Mads; Shagam, Lev; Wang, Dongmao; Wang, Yanyan; Flinter, Frances; Nagel, Mato

    2016-01-01

    Alport syndrome results from mutations in the COL4A5 (X-linked) or COL4A3/COL4A4 (recessive) genes. This study examined 754 previously- unpublished variants in these genes from individuals referred for genetic testing in 12 accredited diagnostic laboratories worldwide, in addition to all published COL4A5, COL4A3 and COL4A4 variants in the LOVD databases. It also determined genotype-phenotype correlations for variants where clinical data were available. Individuals were referred for genetic testing where Alport syndrome was suspected clinically or on biopsy (renal failure, hearing loss, retinopathy, lamellated glomerular basement membrane), variant pathogenicity was assessed using currently-accepted criteria, and variants were examined for gene location, and age at renal failure onset. Results were compared using Fisher's exact test (DNA Stata). Altogether 754 new DNA variants were identified, an increase of 25%, predominantly in people of European background. Of the 1168 COL4A5 variants, 504 (43%) were missense mutations, 273 (23%) splicing variants, 73 (6%) nonsense mutations, 169 (14%) short deletions and 76 (7%) complex or large deletions. Only 135 of the 432 Gly residues in the collagenous sequence were substituted (31%), which means that fewer than 10% of all possible variants have been identified. Both missense and nonsense mutations in COL4A5 were not randomly distributed but more common at the 70 CpG sequences (p<10-41 and p<0.001 respectively). Gly>Ala substitutions were underrepresented in all three genes (p< 0.0001) probably because of an association with a milder phenotype. The average age at end-stage renal failure was the same for all mutations in COL4A5 (24.4 ±7.8 years), COL4A3 (23.3 ± 9.3) and COL4A4 (25.4 ± 10.3) (COL4A5 and COL4A3, p = 0.45; COL4A5 and COL4A4, p = 0.55; COL4A3 and COL4A4, p = 0.41). For COL4A5, renal failure occurred sooner with non-missense than missense variants (p<0.01). For the COL4A3 and COL4A4 genes, age at renal failure

  8. X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations

    PubMed Central

    Savige, Judith; Storey, Helen; Il Cheong, Hae; Gyung Kang, Hee; Park, Eujin; Hilbert, Pascale; Persikov, Anton; Torres-Fernandez, Carmen; Ars, Elisabet; Torra, Roser; Hertz, Jens Michael; Thomassen, Mads; Shagam, Lev; Wang, Dongmao; Wang, Yanyan; Flinter, Frances; Nagel, Mato

    2016-01-01

    Alport syndrome results from mutations in the COL4A5 (X-linked) or COL4A3/COL4A4 (recessive) genes. This study examined 754 previously- unpublished variants in these genes from individuals referred for genetic testing in 12 accredited diagnostic laboratories worldwide, in addition to all published COL4A5, COL4A3 and COL4A4 variants in the LOVD databases. It also determined genotype-phenotype correlations for variants where clinical data were available. Individuals were referred for genetic testing where Alport syndrome was suspected clinically or on biopsy (renal failure, hearing loss, retinopathy, lamellated glomerular basement membrane), variant pathogenicity was assessed using currently-accepted criteria, and variants were examined for gene location, and age at renal failure onset. Results were compared using Fisher’s exact test (DNA Stata). Altogether 754 new DNA variants were identified, an increase of 25%, predominantly in people of European background. Of the 1168 COL4A5 variants, 504 (43%) were missense mutations, 273 (23%) splicing variants, 73 (6%) nonsense mutations, 169 (14%) short deletions and 76 (7%) complex or large deletions. Only 135 of the 432 Gly residues in the collagenous sequence were substituted (31%), which means that fewer than 10% of all possible variants have been identified. Both missense and nonsense mutations in COL4A5 were not randomly distributed but more common at the 70 CpG sequences (p<10−41 and p<0.001 respectively). Gly>Ala substitutions were underrepresented in all three genes (p< 0.0001) probably because of an association with a milder phenotype. The average age at end-stage renal failure was the same for all mutations in COL4A5 (24.4 ±7.8 years), COL4A3 (23.3 ± 9.3) and COL4A4 (25.4 ± 10.3) (COL4A5 and COL4A3, p = 0.45; COL4A5 and COL4A4, p = 0.55; COL4A3 and COL4A4, p = 0.41). For COL4A5, renal failure occurred sooner with non-missense than missense variants (p<0.01). For the COL4A3 and COL4A4 genes, age at renal

  9. Characterization of X-linked Hypohidrotic Ectodermal Dysplasia (XL-HED) Hair and Sweat Gland Phenotypes Using Phototrichogram Analysis and Live Confocal Imaging

    PubMed Central

    Jones, Kyle B.; Goodwin, Alice F.; Landan, Maya; Seidel, Kerstin; Tran, Dong-Kha; Hogue, Jacob; Chavez, Miquella; Fete, Mary; Yu, Wenli; Hussein, Tarek; Johnson, Ramsey; Huttner, Kenneth; Jheon, Andrew H.; Klein, Ophir D.

    2015-01-01

    Hypohidrotic ectodermal dysplasia (HED) is the most common type of ectodermal dysplasia (ED), which encompasses a large group of syndromes that share several phenotypic features such as missing or malformed ectodermal structures, including skin, hair, sweat glands, and teeth. X-linked hypohidrotic ectodermal dysplasia (XL-HED) is associated with mutations in ectodysplasin (EDA1). Hypohidrosis due to hypoplastic sweat glands and thin, sparse hair are phenotypic features that significantly affect the daily lives of XL-HED individuals and therefore require systematic analysis. We sought to determine the quality of life of individuals with XL-HED and to quantify sweat duct and hair phenotypes using confocal imaging, pilocarpine iontophoresis, and phototrichogram analysis. Using these highly sensitive and non-invasive techniques, we demonstrated that 11/12 XL-HED individuals presented with a complete absence of sweat ducts and that none produced sweat. We determined that the thin hair phenotype observed in XL-HED was due to multiple factors, such as fewer terminal hairs with decreased thickness and slower growth rate, as well as fewer follicular units and fewer hairs per unit. The precise characterization of XL-HED phenotypes using sensitive and non-invasive techniques presented in our study will improve upon larger genotype-phenotype studies and in the assessment of future therapies in XL-HED. PMID:23687000

  10. Pex gene deletions in Gy and Hyp mice provide mouse models for X-linked hypophosphatemia.

    PubMed

    Strom, T M; Francis, F; Lorenz, B; Böddrich, A; Econs, M J; Lehrach, H; Meitinger, T

    1997-02-01

    X-linked hypophosphatemic rickets in humans is caused by mutations in the PEX gene which codes for a protein homologous to neutral endopeptidases. Hyp and Gy mice both have X-linked hypophosphatemic rickets, although genetic data and the different phenotypic spectra observed have previously suggested that two different genes are mutated. In addition to the metabolic disorder observed in Hyp mice, male Gy mice are sterile and show circling behavior and reduced viability. We now report the cloning of the mouse homolog of PEX which is highly conserved between man and mouse. The 3' end of this gene is deleted in Hyp mice. In Gy mice, the first three exons and the promotor region are deleted. Thus, Hyp and Gy are allelic mutations and both provide mouse models for X-linked hypophosphatemia.

  11. Model Invariance across Genders of the Broad Autism Phenotype Questionnaire

    ERIC Educational Resources Information Center

    Broderick, Neill; Wade, Jordan L.; Meyer, J. Patrick; Hull, Michael; Reeve, Ronald E.

    2015-01-01

    ASD is one of the most heritable neuropsychiatric disorders, though comprehensive genetic liability remains elusive. To facilitate genetic research, researchers employ the concept of the broad autism phenotype (BAP), a milder presentation of traits in undiagnosed relatives. Research suggests that the BAP Questionnaire (BAPQ) demonstrates…

  12. A VGI data integration framework based on linked data model

    NASA Astrophysics Data System (ADS)

    Wan, Lin; Ren, Rongrong

    2015-12-01

    This paper aims at the geographic data integration and sharing method for multiple online VGI data sets. We propose a semantic-enabled framework for online VGI sources cooperative application environment to solve a target class of geospatial problems. Based on linked data technologies - which is one of core components of semantic web, we can construct the relationship link among geographic features distributed in diverse VGI platform by using linked data modeling methods, then deploy these semantic-enabled entities on the web, and eventually form an interconnected geographic data network to support geospatial information cooperative application across multiple VGI data sources. The mapping and transformation from VGI sources to RDF linked data model is presented to guarantee the unique data represent model among different online social geographic data sources. We propose a mixed strategy which combined spatial distance similarity and feature name attribute similarity as the measure standard to compare and match different geographic features in various VGI data sets. And our work focuses on how to apply Markov logic networks to achieve interlinks of the same linked data in different VGI-based linked data sets. In our method, the automatic generating method of co-reference object identification model according to geographic linked data is discussed in more detail. It finally built a huge geographic linked data network across loosely-coupled VGI web sites. The results of the experiment built on our framework and the evaluation of our method shows the framework is reasonable and practicable.

  13. COMPARING AND LINKING PLUMES ACROSS MODELING APPROACHES

    EPA Science Inventory

    River plumes carry many pollutants, including microorganisms, into lakes and the coastal ocean. The physical scales of many stream and river plumes often lie between the scales for mixing zone plume models, such as the EPA Visual Plumes model, and larger-sized grid scales for re...

  14. Design and modelling of a link monitoring mechanism for the Common Data Link (CDL)

    NASA Astrophysics Data System (ADS)

    Eichelberger, John W., III

    1994-09-01

    The Common Data Link (CDL) is a full duplex, point-to-point microwave communications system used in imagery and signals intelligence collection systems. It provides a link between two remote Local Area Networks (LAN's) aboard collection and surface platforms. In a hostile environment, there is an overwhelming need to dynamically monitor the link and thus, limit the impact of jamming. This work describes steps taken to design, model, and evaluate a link monitoring system suitable for the CDL. The monitoring system is based on features and monitoring constructs of the Link Control Protocol (LCP) in the Point-to-Point Protocol (PPP) suite. The CDL model is based on a system of two remote Fiber Distributed Data Interface (FDDI) LAN's. In particular, the policies and mechanisms associated with monitoring are described in detail. An implementation of the required mechanisms using the OPNET network engineering tool is described. Performance data related to monitoring parameters is reported. Finally, integration of the FDDI-CDL model with the OPNET Internet model is described.

  15. Feasibility of using Clinical Element Models (CEM) to standardize phenotype variables in the database of genotypes and phenotypes (dbGaP).

    PubMed

    Lin, Ko-Wei; Tharp, Melissa; Conway, Mike; Hsieh, Alexander; Ross, Mindy; Kim, Jihoon; Kim, Hyeon-Eui

    2013-01-01

    The database of Genotypes and Phenotypes (dbGaP) contains various types of data generated from genome-wide association studies (GWAS). These data can be used to facilitate novel scientific discoveries and to reduce cost and time for exploratory research. However, idiosyncrasies and inconsistencies in phenotype variable names are a major barrier to reusing these data. We addressed these challenges in standardizing phenotype variables by formalizing their descriptions using Clinical Element Models (CEM). Designed to represent clinical data, CEMs were highly expressive and thus were able to represent a majority (77.5%) of the 215 phenotype variable descriptions. However, their high expressivity also made it difficult to directly apply them to research data such as phenotype variables in dbGaP. Our study suggested that simplification of the template models makes it more straightforward to formally represent the key semantics of phenotype variables.

  16. Shuttle/TDRSS modelling and link simulation study

    NASA Technical Reports Server (NTRS)

    Braun, W. R.; Mckenzie, T. M.; Biederman, L.; Lindsey, W. C.

    1979-01-01

    A Shuttle/TDRSS S-band and Ku-band link simulation package called LinCsim was developed for the evaluation of link performance for specific Shuttle signal designs. The link models were described in detail and the transmitter distortion parameters or user constraints were carefully defined. The overall link degradation (excluding hardware degradations) relative to an ideal BPSK channel were given for various sets of user constraint values. The performance sensitivity to each individual user constraint was then illustrated. The effect of excessive Spacelab clock jitter on the return link BER performance was also investigated as was the problem of subcarrier recovery for the K-band Shuttle return link signal.

  17. Cookie-Ases: Interactive Models for Teaching Genotype-Phenotype Relationships

    ERIC Educational Resources Information Center

    Seipelt, Rebecca L.

    2006-01-01

    Several hands-on and wet laboratory activities have been proposed to model the genetic concepts of genotypes and phenotypes and their relationship. The exercise presented in this article is a novel, time effective, student-centered, role-playing activity in which students learn about the intricate connection between genotype and phenotype by…

  18. Multi-Scale Modeling of Cross-Linked Nanotube Materials

    NASA Technical Reports Server (NTRS)

    Frankland, S. J. V.; Odegard, G. M.; Herzog, M. N.; Gates, T. S.; Fay, C. C.

    2005-01-01

    The effect of cross-linking single-walled carbon nanotubes on the Young's modulus of a nanotube-reinforced composite is modeled with a multi-scale method. The Young's modulus is predicted as a function of nanotube volume fraction and cross-link density. In this method, the constitutive properties of molecular representative volume elements are determined using molecular dynamics simulation and equivalent-continuum modeling. The Young's modulus is subsequently calculated for cross-linked nanotubes in a matrix which consists of the unreacted cross-linking agent. Two different cross-linking agents are used in this study, one that is short and rigid (Molecule A), and one that is long and flexible (Molecule B). Direct comparisons between the predicted elastic constants are made for the models in which the nanotubes are either covalently bonded or not chemically bonded to the cross-linking agent. At a nanotube volume fraction of 10%, the Young's modulus of Material A is not affected by nanotube crosslinking, while the Young's modulus of Material B is reduced by 64% when the nanotubes are cross-linked relative to the non-cross-linked material with the same matrix.

  19. Extended model of restricted beam for FSO links

    NASA Astrophysics Data System (ADS)

    Poliak, Juraj; Wilfert, Otakar

    2012-10-01

    Modern wireless optical communication systems in many aspects overcome wire or radio communications. Their advantages are license-free operation and broad bandwidth that they offer. The medium in free-space optical (FSO) links is the atmosphere. Operation of outdoor FSO links struggles with many atmospheric phenomena that deteriorate phase and amplitude of the transmitted optical beam. This beam originates in the transmitter and is affected by its individual parts, especially by the lens socket and the transmitter aperture, where attenuation and diffraction effects take place. Both of these phenomena unfavourable influence the beam and cause degradation of link availability, or its total malfunction. Therefore, both of these phenomena should be modelled and simulated, so that one can judge the link function prior to the realization of the system. Not only the link availability and reliability are concerned, but also economic aspects. In addition, the transmitted beam is not, generally speaking, circularly symmetrical, what makes the link simulation more difficult. In a comprehensive model, it is necessary to take into account the ellipticity of the beam that is restricted by circularly symmetrical aperture where then the attenuation and diffraction occur. General model is too computationally extensive; therefore simplification of the calculations by means of analytical and numerical approaches will be discussed. Presented model is not only simulated using computer, but also experimentally proven. One can then deduce the ability of the model to describe the reality and to estimate how far can one go with approximations, i.e. limitations of the model are discussed.

  20. Manipulators with flexible links: A simple model and experiments

    NASA Technical Reports Server (NTRS)

    Shimoyama, Isao; Oppenheim, Irving J.

    1989-01-01

    A simple dynamic model proposed for flexible links is briefly reviewed and experimental control results are presented for different flexible systems. A simple dynamic model is useful for rapid prototyping of manipulators and their control systems, for possible application to manipulator design decisions, and for real time computation as might be applied in model based or feedforward control. Such a model is proposed, with the further advantage that clear physical arguments and explanations can be associated with its simplifying features and with its resulting analytical properties. The model is mathematically equivalent to Rayleigh's method. Taking the example of planar bending, the approach originates in its choice of two amplitude variables, typically chosen as the link end rotations referenced to the chord (or the tangent) motion of the link. This particular choice is key in establishing the advantageous features of the model, and it was used to support the series of experiments reported.

  1. Metabolic parameters linked by Phenotype MicroArray to acid resistance profiles of poultry-associated Salmonella enterica

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Phenotype microarrays were analyzed for 51 datasets derived from Salmonella enterica. The top 4 serovars associated with poultry products and one associated with turkey, respectively Typhimurium, Enteritidis, Heidelberg, Infantis and Senftenberg, were represented. Datasets were clustered into two ...

  2. Characterizing nanoparticle interactions: Linking models to experiments

    SciTech Connect

    Ramakrishnan, S.; Zukoski, C. F.

    2000-07-15

    Self-assembly of nanoparticles involves manipulating particle interactions such that attractions are on the order of the average thermal energy in the system. If the self-assembly is to result in an ordered packing, an understanding of their phase behavior is necessary. Here we test the ability of simple pair potentials to characterize the interactions and phase behavior of silico tungstic acid (STA), a 1.2 nm particle. The strength of interaction is controlled by dispersing STA in different background salt concentrations. The experimental variables used in characterizing the interactions are the osmotic compressibility (d{pi}/d{rho}), the second virial coefficient (B{sub 2}), relative solution viscosity ({eta}/{eta}{sub c}), and the solubility ({rho}{sigma}{sup 3}){sub sat}. Various techniques are then developed to extract the parameters of square well, the adhesive hard sphere (AHS), and the Yukawa pair potentials that best describe the experimental data. The AHS model describes the solution thermodynamic behavior only where the system is weakly attractive but, as would be expected, fails when long range repulsions or nonmonotonic pair potentials become important. Model free representations are presented which offer the opportunity to extract pair potential parameters. (c) 2000 American Institute of Physics.

  3. Phenotype and genotype of deaf patients with combined genomic and mitochondrial inheritance models.

    PubMed

    Huang, Shasha; Wang, Guojian; Jiang, Yi; Yuan, Yongyi; Han, Dongyi; Song, Yueshuai; Dai, Pu

    2013-11-01

    In most studies, sensorineural hearing loss is reported as a single-gene disease with autosomal dominant or autosomal recessive or with X-linked or maternal inheritance. It is uncommon that the hearing impairment is caused by a combined inheritance model including genomic and mitochondrial models. Here, we report six patients with sensorineural hearing loss caused by co-existing mutations in GJB2 or SLC26A4 and the mitochondrial gene. And there was no significant difference in hearing phenotypes between the six patients and the controls. The results indicate the complicated genetic etiology of, and may impact the diagnostic strategy for, hereditary hearing impairment. All patient siblings will carry mitochondrial DNA A1555G or C1494T mutations, and 25% of siblings may carry the same homozygous or compound heterozygote mutations in GJB2 or SLC26A4. Although this combined inheritance is not common in the Chinese deaf population (0.10%), our findings will have great impact in genetic counseling and risk prediction for deafness.

  4. Advances in biotechnology and informatics to link variation in the genome to phenotypes in plants and animals.

    PubMed

    Appels, R; Barrero, R; Bellgard, M

    2013-03-01

    Advances in our understanding of genome structure provide consistent evidence for the existence of a core genome representing species classically defined by phenotype, as well as conditionally dispensable components of the genome that shows extensive variation between individuals of a given species. Generally, conservation of phenotypic features between species reflects conserved features of the genome; however, this is evidently not necessarily always the case as demonstrated by the analysis of the tunicate chordate Oikopleura dioica. In both plants and animals, the methylation activity of DNA and histones continues to present new variables for modifying (eventually) the phenotype of an organism and provides for structural variation that builds on the point mutations, rearrangements, indels, and amplification of retrotransposable elements traditionally considered. The translation of the advances in the structure/function analysis of the genome to industry is facilitated through the capture of research outputs in "toolboxes" that remain accessible in the public domain.

  5. Link Prediction in Weighted Networks: A Weighted Mutual Information Model

    PubMed Central

    Zhu, Boyao; Xia, Yongxiang

    2016-01-01

    The link-prediction problem is an open issue in data mining and knowledge discovery, which attracts researchers from disparate scientific communities. A wealth of methods have been proposed to deal with this problem. Among these approaches, most are applied in unweighted networks, with only a few taking the weights of links into consideration. In this paper, we present a weighted model for undirected and weighted networks based on the mutual information of local network structures, where link weights are applied to further enhance the distinguishable extent of candidate links. Empirical experiments are conducted on four weighted networks, and results show that the proposed method can provide more accurate predictions than not only traditional unweighted indices but also typical weighted indices. Furthermore, some in-depth discussions on the effects of weak ties in link prediction as well as the potential to predict link weights are also given. This work may shed light on the design of algorithms for link prediction in weighted networks. PMID:26849659

  6. Linking knowledge and action through mental models of sustainable agriculture.

    PubMed

    Hoffman, Matthew; Lubell, Mark; Hillis, Vicken

    2014-09-09

    Linking knowledge to action requires understanding how decision-makers conceptualize sustainability. This paper empirically analyzes farmer "mental models" of sustainability from three winegrape-growing regions of California where local extension programs have focused on sustainable agriculture. The mental models are represented as networks where sustainability concepts are nodes, and links are established when a farmer mentions two concepts in their stated definition of sustainability. The results suggest that winegrape grower mental models of sustainability are hierarchically structured, relatively similar across regions, and strongly linked to participation in extension programs and adoption of sustainable farm practices. We discuss the implications of our findings for the debate over the meaning of sustainability, and the role of local extension programs in managing knowledge systems.

  7. Intermittent fasting alleviates the neuropathic phenotype in a mouse model of Charcot-Marie-Tooth disease.

    PubMed

    Madorsky, Irina; Opalach, Katherine; Waber, Amanda; Verrier, Jonathan D; Solmo, Chelsea; Foster, Thomas; Dunn, William A; Notterpek, Lucia

    2009-04-01

    Charcot-Marie-Tooth type 1A (CMT1A) neuropathies linked to the misexpression of peripheral myelin protein 22 (PMP22) are progressive demyelinating disorders of the peripheral nervous system. In this study we asked whether dietary restriction by intermittent fasting (IF) could alleviate the neuropathic phenotype in the Trembler J (TrJ) mouse model of CMT1A. Our results show that neuropathic mice kept on a five month long IF regimen had improved locomotor performance compared to ad libitum (AL) fed littermates. The functional benefits of this dietary intervention are associated with an increased expression of myelin proteins combined with a thicker myelin sheath, less redundant basal lamina, and a reduction in aberrant Schwann cell proliferation. These morphological improvements are accompanied by a decrease in PMP22 protein aggregates, and enhanced expression of cytosolic chaperones and constituents of the autophagy-lysosomal pathway. These results indicate that dietary restriction is beneficial for peripheral nerve function in TrJ neuropathic mice, as it promotes the maintenance of locomotor performance.

  8. Intermittent fasting alleviates the neuropathic phenotype in a mouse model of Charcot-Marie-Tooth disease

    PubMed Central

    Madorsky, Irina; Opalach, Katherine; Waber, Amanda; Verrier, Jonathan D.; Solmo, Chelsea; Foster, Thomas; Dunn, William A; Notterpek, Lucia

    2009-01-01

    Charcot-Marie-Tooth type 1A (CMT1A) neuropathies linked to the misexpression of peripheral myelin protein 22 (PMP22) are progressive demyelinating disorders of the peripheral nervous system. In this study we asked whether dietary restriction by intermittent fasting (IF) could alleviate the neuropathic phenotype in the Trembler J (TrJ) mouse model of CMT1A. Our results show that neuropathic mice kept on a five month long IF regimen had improved locomotor performance compared to ad libitum (AL) fed littermates. The functional benefits of this dietary intervention are associated with an increased expression of myelin proteins combined with a thicker myelin sheath, less redundant basal lamina, and a reduction in aberrant Schwann cell proliferation. These morphological improvements are accompanied by a decrease in PMP22 protein aggregates, and enhanced expression of cytosolic chaperones and constituents of the autophagy-lysosomal pathway. These results indicate that dietary restriction is beneficial for peripheral nerve function in TrJ neuropathic mice, as it promotes the maintenance of locomotor performance. PMID:19320048

  9. Beyond the Central Dogma: Model-Based Learning of How Genes Determine Phenotypes

    ERIC Educational Resources Information Center

    Reinagel, Adam; Speth, Elena Bray

    2016-01-01

    In an introductory biology course, we implemented a learner-centered, model-based pedagogy that frequently engaged students in building conceptual models to explain how genes determine phenotypes. Model-building tasks were incorporated within case studies and aimed at eliciting students' understanding of 1) the origin of variation in a population…

  10. Link performance model for filter bank based multicarrier systems

    NASA Astrophysics Data System (ADS)

    Petrov, Dmitry; Oborina, Alexandra; Giupponi, Lorenza; Stitz, Tobias Hidalgo

    2014-12-01

    This paper presents a complete link level abstraction model for link quality estimation on the system level of filter bank multicarrier (FBMC)-based networks. The application of mean mutual information per coded bit (MMIB) approach is validated for the FBMC systems. The considered quality measure of the resource element for the FBMC transmission is the received signal-to-noise-plus-distortion ratio (SNDR). Simulation results of the proposed link abstraction model show that the proposed approach is capable of estimating the block error rate (BLER) accurately, even when the signal is propagated through the channels with deep and frequent fades, as it is the case for the 3GPP Hilly Terrain (3GPP-HT) and Enhanced Typical Urban (ETU) models. The FBMC-related results of link level simulations are compared with cyclic prefix orthogonal frequency division multiplexing (CP-OFDM) analogs. Simulation results are also validated through the comparison to reference publicly available results. Finally, the steps of link level abstraction algorithm for FBMC are formulated and its application for system level simulation of a professional mobile radio (PMR) network is discussed.

  11. Computational evaluation of exome sequence data using human and model organism phenotypes improves diagnostic efficiency

    PubMed Central

    Bone, William P.; Washington, Nicole L.; Buske, Orion J.; Adams, David R.; Davis, Joie; Draper, David; Flynn, Elise D.; Girdea, Marta; Godfrey, Rena; Golas, Gretchen; Groden, Catherine; Jacobsen, Julius; Köhler, Sebastian; Lee, Elizabeth M. J.; Links, Amanda E.; Markello, Thomas C.; Mungall, Christopher J.; Nehrebecky, Michele; Robinson, Peter N.; Sincan, Murat; Soldatos, Ariane G.; Tifft, Cynthia J.; Toro, Camilo; Trang, Heather; Valkanas, Elise; Vasilevsky, Nicole; Wahl, Colleen; Wolfe, Lynne A.; Boerkoel, Cornelius F.; Brudno, Michael; Haendel, Melissa A.; Gahl, William A.; Smedley, Damian

    2016-01-01

    Purpose: Medical diagnosis and molecular or biochemical confirmation typically rely on the knowledge of the clinician. Although this is very difficult in extremely rare diseases, we hypothesized that the recording of patient phenotypes in Human Phenotype Ontology (HPO) terms and computationally ranking putative disease-associated sequence variants improves diagnosis, particularly for patients with atypical clinical profiles. Genet Med 18 6, 608–617. Methods: Using simulated exomes and the National Institutes of Health Undiagnosed Diseases Program (UDP) patient cohort and associated exome sequence, we tested our hypothesis using Exomiser. Exomiser ranks candidate variants based on patient phenotype similarity to (i) known disease–gene phenotypes, (ii) model organism phenotypes of candidate orthologs, and (iii) phenotypes of protein–protein association neighbors. Genet Med 18 6, 608–617. Results: Benchmarking showed Exomiser ranked the causal variant as the top hit in 97% of known disease–gene associations and ranked the correct seeded variant in up to 87% when detectable disease–gene associations were unavailable. Using UDP data, Exomiser ranked the causative variant(s) within the top 10 variants for 11 previously diagnosed variants and achieved a diagnosis for 4 of 23 cases undiagnosed by clinical evaluation. Genet Med 18 6, 608–617. Conclusion: Structured phenotyping of patients and computational analysis are effective adjuncts for diagnosing patients with genetic disorders. Genet Med 18 6, 608–617. PMID:26562225

  12. Linking knowledge and action through mental models of sustainable agriculture

    PubMed Central

    Hoffman, Matthew; Lubell, Mark; Hillis, Vicken

    2014-01-01

    Linking knowledge to action requires understanding how decision-makers conceptualize sustainability. This paper empirically analyzes farmer “mental models” of sustainability from three winegrape-growing regions of California where local extension programs have focused on sustainable agriculture. The mental models are represented as networks where sustainability concepts are nodes, and links are established when a farmer mentions two concepts in their stated definition of sustainability. The results suggest that winegrape grower mental models of sustainability are hierarchically structured, relatively similar across regions, and strongly linked to participation in extension programs and adoption of sustainable farm practices. We discuss the implications of our findings for the debate over the meaning of sustainability, and the role of local extension programs in managing knowledge systems. PMID:25157158

  13. Linking Academic Entitlement and Student Incivility Using Latent Means Modeling

    ERIC Educational Resources Information Center

    Kopp, Jason P.; Finney, Sara J.

    2013-01-01

    Academic entitlement has been theoretically linked with uncivil student behavior; however, this relationship has not been tested. To address this gap in the literature, the authors used latent means modeling to estimate the relationship between the Academic Entitlement Questionnaire and uncivil student behavior. The authors gathered scores on the…

  14. Model selection for athermal cross-linked fiber networks.

    PubMed

    Shahsavari, A; Picu, R C

    2012-07-01

    Athermal random fiber networks are usually modeled by representing each fiber as a truss, a Euler-Bernoulli or a Timoshenko beam, and, in the case of cross-linked networks, each cross-link as a pinned, rotating, or welded joint. In this work we study the effect of these various modeling options on the dependence of the overall network stiffness on system parameters. We conclude that Timoshenko beams can be used for the entire range of density and beam stiffness parameters, while the Euler-Bernoulli model can be used only at relatively low network densities. In the high density-high bending stiffness range, strain energy is stored predominantly in the axial and shear deformation modes, while in the other extreme range of parameters, the energy is stored in the bending mode. The effect of the model size on the network stiffness is also discussed.

  15. Boolean Network Model Predicts Knockout Mutant Phenotypes of Fission Yeast

    PubMed Central

    Davidich, Maria I.; Bornholdt, Stefan

    2013-01-01

    Boolean networks (or: networks of switches) are extremely simple mathematical models of biochemical signaling networks. Under certain circumstances, Boolean networks, despite their simplicity, are capable of predicting dynamical activation patterns of gene regulatory networks in living cells. For example, the temporal sequence of cell cycle activation patterns in yeasts S. pombe and S. cerevisiae are faithfully reproduced by Boolean network models. An interesting question is whether this simple model class could also predict a more complex cellular phenomenology as, for example, the cell cycle dynamics under various knockout mutants instead of the wild type dynamics, only. Here we show that a Boolean network model for the cell cycle control network of yeast S. pombe correctly predicts viability of a large number of known mutants. So far this had been left to the more detailed differential equation models of the biochemical kinetics of the yeast cell cycle network and was commonly thought to be out of reach for models as simplistic as Boolean networks. The new results support our vision that Boolean networks may complement other mathematical models in systems biology to a larger extent than expected so far, and may fill a gap where simplicity of the model and a preference for an overall dynamical blueprint of cellular regulation, instead of biochemical details, are in the focus. PMID:24069138

  16. Single photon time transfer link model for GNSS satellites

    NASA Astrophysics Data System (ADS)

    Vacek, Michael; Michalek, Vojtech; Peca, Marek; Prochazka, Ivan; Blazej, Josef

    2015-05-01

    The importance of optical time transfer serving as a complement to traditional microwave links, has been attested for GNSSes and for scientific missions. Single photon time transfer (SPTT) is a process, allowing to compare (subtract) time readings of two distant clocks. Such a comparison may be then used to synchronize less accurate clock to a better reference, to perform clock characterization and calibration, to calculate mean time out of ensemble of several clocks, displaced in space. The single-photon time transfer is well established in field of space geodesy, being supported by passive retro-reflectors within space segment of five known GNSSes. A truly two-way, active terminals work aboard of Jason-2 (T2L2) - multiphoton operation, GNSS Beidou (Compass) - SPTT, and are going to be launched within recent ACES project (ELT) - SPTT, and GNSS GLONASS - multiphoton operation. However, there is still missing comprehensive theoretical model of two-way (using satellite receiver and retroreflector) SPTT link incorporating all crucial parameters of receiver (both ground and space segment receivers), transmitter, atmosphere effects on uplink and downlink path, influence of retroreflector. The input to calculation of SPTT link performance will be among others: link budget (distance, power, apertures, beam divergence, attenuation, scattering), propagating medium (atmosphere scintillation, beam wander, etc.), mutual Tx/Rx velocity, wavelength. The SPTT model will be evaluated without the properties of real components. These will be added in the further development. The ground-to-space SPTT link performance of typical scenarios are modeled. This work is a part of the ESA study "Comparison of optical time-transfer links."

  17. A continuous phenotype space model of cancer evolution

    NASA Astrophysics Data System (ADS)

    Masip, David; Korobeinikiov, Andrei

    2017-02-01

    It was suggested that the ability of cancer to avoid immune response pressure (that should be expected to be capable to annihilate cancer at its early stage) can be attributed to the ability of the cancer cells to evolve. The goal of this notice is to illustrate this possibility by the means of mathematical modelling. In this notice, we construct a simple mechanistic model of cancer evolution, which is based upon a classical model of cancer-immune response interaction. Numerical simulations confirm the hypothesis that if cancer mutates fast enough and if immune response is not sufficiently strong, then cancer is able to avoid immune response pressure by evolution.

  18. A mathematical model of N-linked glycoform biosynthesis.

    PubMed

    Umaña, P; Bailey, J E

    1997-09-20

    Metabolic engineering of N-linked oligosaccharide biosynthesis to produce novel glycoforms or glycoform distributions of a recombinant glycoprotein can potentially lead to an improved therapeutic performance of the glycoprotein product. Effective engineering of this pathway to maximize the fractions of beneficial glycoforms within the glycoform population of a target glycoprotein can be aided by a mathematical model of the N-linked glycosylation process. A mathematical model is presented here, whose main function is to calculate the expected qualitative trends in the N-linked oligosaccharide distribution resulting from changes in the levels of one or more enzymes involved in the network of enzyme-catalyzed reactions that accomplish N-linked oligosaccharide biosynthesis. It consists of mass balances for 33 different oligosaccharide species N-linked to a specified protein that is being transported through the different compartments of the Golgi complex. Values of the model parameters describing Chinese hamster ovary (CHO) cells were estimated from literature information. A basal set of kinetic parameters for the enzyme-catalyzed reactions acting on free oligosaccharide substrates was also obtained from the literature. The solution of the system for this basal set of parameters gave a glycoform distribution consisting mainly of complex-galactosylated oligosaccharides distributed in structures with different numbers of antennae in a fashion similar to that observed for various recombinant proteins produced in CHO cells. Other simulations indicate that changes in the oligosaccharide distribution could easily result from alteration in glycoprotein productivity within the range currently attainable in industry. The overexpression of N-acetylglucosaminyltransferase III in CHO cells was simulated under different conditions to test the main function of the model. These simulations allow a comparison of different strategies, such as simultaneous overexpression of several

  19. Phenotypic characterization of recessive gene knockout rat models of Parkinson's disease.

    PubMed

    Dave, Kuldip D; De Silva, Shehan; Sheth, Niketa P; Ramboz, Sylvie; Beck, Melissa J; Quang, Changyu; Switzer, Robert C; Ahmad, Syed O; Sunkin, Susan M; Walker, Dan; Cui, Xiaoxia; Fisher, Daniel A; McCoy, Aaron M; Gamber, Kevin; Ding, Xiaodong; Goldberg, Matthew S; Benkovic, Stanley A; Haupt, Meredith; Baptista, Marco A S; Fiske, Brian K; Sherer, Todd B; Frasier, Mark A

    2014-10-01

    Recessively inherited loss-of-function mutations in the PTEN-induced putative kinase 1(Pink1), DJ-1 (Park7) and Parkin (Park2) genes are linked to familial cases of early-onset Parkinson's disease (PD). As part of its strategy to provide more tools for the research community, The Michael J. Fox Foundation for Parkinson's Research (MJFF) funded the generation of novel rat models with targeted disruption ofPink1, DJ-1 or Parkin genes and determined if the loss of these proteins would result in a progressive PD-like phenotype. Pathological, neurochemical and behavioral outcome measures were collected at 4, 6 and 8months of age in homozygous KO rats and compared to wild-type (WT) rats. Both Pink1 and DJ-1 KO rats showed progressive nigral neurodegeneration with about 50% dopaminergic cell loss observed at 8 months of age. ThePink1 KO and DJ-1 KO rats also showed a two to three fold increase in striatal dopamine and serotonin content at 8 months of age. Both Pink1 KO and DJ-1 KO rats exhibited significant motor deficits starting at 4months of age. However, Parkin KO rats displayed normal behaviors with no neurochemical or pathological changes. These results demonstrate that inactivation of the Pink1 or DJ-1 genes in the rat produces progressive neurodegeneration and early behavioral deficits, suggesting that these recessive genes may be essential for the survival of dopaminergic neurons in the substantia nigra (SN). These MJFF-generated novel rat models will assist the research community to elucidate the mechanisms by which these recessive genes produce PD pathology and potentially aid in therapeutic development.

  20. De novo loss-of-function mutations in X-linked SMC1A cause severe ID and therapy-resistant epilepsy in females: expanding the phenotypic spectrum.

    PubMed

    Jansen, S; Kleefstra, T; Willemsen, M H; de Vries, P; Pfundt, R; Hehir-Kwa, J Y; Gilissen, C; Veltman, J A; de Vries, B B A; Vissers, L E L M

    2016-11-01

    De novo missense mutations and in-frame coding deletions in the X-linked gene SMC1A (structural maintenance of chromosomes 1A), encoding part of the cohesin complex, are known to cause Cornelia de Lange syndrome in both males and females. For a long time, loss-of-function (LoF) mutations in SMC1A were considered incompatible with life, as such mutations had not been reported in neither male nor female patients. However, recently, the authors and others reported LoF mutations in females with intellectual disability (ID) and epilepsy. Here we present the detailed phenotype of two females with de novo LoF mutations in SMC1A, including a de novo mutation of single base deletion [c.2364del, p.(Asn788Lysfs*10)], predicted to result in a frameshift, and a de novo deletion of exon 16, resulting in an out-of-frame mRNA splice product [p.(Leu808Argfs*6)]. By combining our patients with the other recently reported females carrying SMC1A LoF mutations, we ascertained a phenotypic spectrum of (severe) ID, therapy-resistant epilepsy, absence/delay of speech, hypotonia and small hands and feet. Our data show the existence of a novel phenotypic entity - distinct from CdLS - and caused by de novo SMC1A LoF mutations.

  1. Individual Consistency and Phenotypic Plasticity in Rockhopper Penguins: Female but Not Male Body Mass Links Environmental Conditions to Reproductive Investment

    PubMed Central

    Dehnhard, Nina; Eens, Marcel; Demongin, Laurent; Quillfeldt, Petra; Poisbleau, Maud

    2015-01-01

    In marine habitats, increasing ocean temperatures due to global climate change may distinctly reduce nutrient and consequently food availability for seabirds. Food availability is a known driver of body mass and reproductive investment in birds, but these traits may also depend on individual effects. Penguins show extreme intra-annual body mass variation and rely on accumulated body reserves for successful breeding. However, no study so far has tested individual consistency and phenotypic responses in body mass and reproductive investment in this taxon. Using a unique dataset on individually marked female and male southern rockhopper penguins (Eudyptes chrysocome chrysocome) across six years, we investigated 1) the individual consistency in body mass (measured at egg laying), body condition and reproductive investment across years, subsequently 2) identified the best-explanatory temperature-related environmental variables for female and male body mass, and 3) tested the effect of female and male body mass on reproductive investment. Body mass, body condition and reproductive investment were all highly repeatable. As body condition should control for the structural size of the birds, the similarly high repeatability estimates for body mass and body condition suggested that the consistent between-individual body mass differences were independent of structural size. This supported the use of body mass for the subsequent analyses. Body mass was higher under colder environmental conditions (positive Southern Annular Mode), but the overall phenotypic response appeared limited. Reproductive investment increased with female but not male body mass. While environmental effects on body mass in our study period were rather small, one can expect that ongoing global climate change will lead to a deterioration of food availability and we might therefore in the long-term expect a phenotypical decline in body mass and reproductive investment. PMID:26030824

  2. Individual consistency and phenotypic plasticity in rockhopper penguins: female but not male body mass links environmental conditions to reproductive investment.

    PubMed

    Dehnhard, Nina; Eens, Marcel; Demongin, Laurent; Quillfeldt, Petra; Poisbleau, Maud

    2015-01-01

    In marine habitats, increasing ocean temperatures due to global climate change may distinctly reduce nutrient and consequently food availability for seabirds. Food availability is a known driver of body mass and reproductive investment in birds, but these traits may also depend on individual effects. Penguins show extreme intra-annual body mass variation and rely on accumulated body reserves for successful breeding. However, no study so far has tested individual consistency and phenotypic responses in body mass and reproductive investment in this taxon. Using a unique dataset on individually marked female and male southern rockhopper penguins (Eudyptes chrysocome chrysocome) across six years, we investigated 1) the individual consistency in body mass (measured at egg laying), body condition and reproductive investment across years, subsequently 2) identified the best-explanatory temperature-related environmental variables for female and male body mass, and 3) tested the effect of female and male body mass on reproductive investment. Body mass, body condition and reproductive investment were all highly repeatable. As body condition should control for the structural size of the birds, the similarly high repeatability estimates for body mass and body condition suggested that the consistent between-individual body mass differences were independent of structural size. This supported the use of body mass for the subsequent analyses. Body mass was higher under colder environmental conditions (positive Southern Annular Mode), but the overall phenotypic response appeared limited. Reproductive investment increased with female but not male body mass. While environmental effects on body mass in our study period were rather small, one can expect that ongoing global climate change will lead to a deterioration of food availability and we might therefore in the long-term expect a phenotypical decline in body mass and reproductive investment.

  3. Model updating in flexible-link multibody systems

    NASA Astrophysics Data System (ADS)

    Belotti, R.; Caneva, G.; Palomba, I.; Richiedei, D.; Trevisani, A.

    2016-09-01

    The dynamic response of flexible-link multibody systems (FLMSs) can be predicted through nonlinear models based on finite elements, to describe the coupling between rigid- body and elastic behaviour. Their accuracy should be as high as possible to synthesize controllers and observers. Model updating based on experimental measurements is hence necessary. By taking advantage of the experimental modal analysis, this work proposes a model updating procedure for FLMSs and applies it experimentally to a planar robot. Indeed, several peculiarities of the model of FLMS should be carefully tackled. On the one hand, nonlinear models of a FLMS should be linearized about static equilibrium configurations. On the other, the experimental mode shapes should be corrected to be consistent with the elastic displacements represented in the model, which are defined with respect to a fictitious moving reference (the equivalent rigid link system). Then, since rotational degrees of freedom are also represented in the model, interpolation of the experimental data should be performed to match the model displacement vector. Model updating has been finally cast as an optimization problem in the presence of bounds on the feasible values, by also adopting methods to improve the numerical conditioning and to compute meaningful updated inertial and elastic parameters.

  4. The lek mating system of the worm pipefish (Nerophis lumbriciformis): a molecular maternity analysis and test of the phenotype-linked fertility hypothesis.

    PubMed

    Monteiro, N M; Carneiro, D; Antunes, A; Queiroz, N; Vieira, M N; Jones, A G

    2016-11-19

    The origin and maintenance of mating preferences continues to be an important and controversial topic in sexual selection research. Leks and lek-like mating systems, where individuals gather in particular spots for the sole purpose of mate choice, are particularly puzzling, because the strong directional selection imposed by mate choice should erode genetic variation among competing individuals and negate any benefit for the choosing sex. Here, we take advantage of the lek-like mating system of the worm pipefish (Nerophis lumbriciformis) to test the phenotype-linked fertility hypothesis for the maintenance of mating preferences. We use microsatellite markers to perform a parentage analysis, along with a mark-recapture study, to confirm that the worm pipefish has an unusual mating system that strongly resembles a female lek, where females display and males visit the lek to choose mates. Our results show that the most highly ornamented females occupy positions near the centre of the breeding area, and males mating with these females receive fuller broods with larger eggs compared to males mating with less-ornamented females. We also conduct a laboratory experiment to show that female ornaments are condition-dependent and honestly signal reproductive potential. Overall, these results are consistent with the predictions of a sex-independent version of the phenotype-linked fertility hypothesis, as male preference for female ornaments correlates with fertility benefits.

  5. UAS Modeling of the Communication Links Study Results

    NASA Technical Reports Server (NTRS)

    Birr, Richard B.; Girgis, Nancy; Murray, Jennifer

    2011-01-01

    The Federal Aviation Administration (FAA) is the authority that grants access into, and operations within, the National Airspace System (NAS) for all aircraft, including Unmanned Aircraft Systems (UAS). The safe operation of UAS in the NAS must be assured if the full potential of UAS is to be realized and supported by the public and Congress. This report analyzed the communication systems that are needed for the safe operations of UAS in the NAS. Safe operations can be defined as the availability of the required links to carry the information to control the UAS and the return links to allow controllers to know where the UAS is at any given moment as well as how it is performing. This report is the end result of work performed jointly between the FAA and National Aeronautics and Space Administration (NASA)/Kennedy Space Center (NASA KSC). The work was done in support of the Radio Technical Commission for Aeronautics (RTCA) Special Committee 203 (SC-203) Control and Communications Working Group. The RTCA is a federal advisory committee to the FAA. Though the work was not under the direction of the working group, a large part of the specific values used in the simulations came from the working group. Specifically, all of the radio links were modeled based on the formulation completed by the working group. This report analyzed three scenarios from RTCA SC-203 that represent how a UAS would operate in the NAS. Each scenario was created using the Satellite Tool Kit (STK) modeling and simulation tool. The flight paths of the UAS were generated and the UAS dynamics were likewise modeled. Then each communication asset such as transmitters, receivers, and antennas were modeled and placed on the appropriate UAS, satellite, or Control Station (CS). After that, the radio links were analyzed for signal strength and antenna blockage, and the overall link performance was analyzed in detail. The goal was to obtain 99.9% availability on all of the radio communication links. In order

  6. How to consistently link extraversion and intelligence to the catechol-O-methyltransferase (COMT) gene: on defining and measuring psychological phenotypes in neurogenetic research.

    PubMed

    Wacker, Jan; Mueller, Erik M; Hennig, Jürgen; Stemmler, Gerhard

    2012-02-01

    The evidence for associations between genetic polymorphisms and complex behavioral/psychological phenotypes (traits) has thus far been weak and inconsistent. Using the well-studied Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene as an example, we demonstrate that using theoretical models to guide phenotype definition and measuring the phenotypes of interest with a high degree of specificity reveals strong gene-behavior associations that are consistent with prior work and that would have otherwise gone unnoticed. Only after statistically controlling for irrelevant portions of phenotype variance did we observe strong (Cohen's d = 0.33-0.70) and significant associations between COMT Val158Met and both cognitive and affective traits in a healthy male sample (N = 201) in Study 1: Carriers of the Met allele scored higher in fluid intelligence (reasoning) but lower in both crystallized intelligence (general knowledge) and the agency facet of extraversion. In Study 2, we conceptually replicated the association of COMT Val158Met with the agency facet of extraversion after partialing irrelevant phenotype variance in a female sample (N = 565). Finally, through reanalysis of a large published data set we showed that Met allele carriers also scored higher in indicators of fluid intelligence after partialing verbal fluency. Because the Met allele codes for a less efficient variant of the enzyme COMT, resulting in higher levels of extrasynaptic prefrontal dopamine, these observations provide further support for a role for dopamine in both intelligence and extraversion. More importantly, the present findings have important implications for the definition of psychological phenotypes in neurogenetic research.

  7. Mutual information model for link prediction in heterogeneous complex networks

    PubMed Central

    Shakibian, Hadi; Moghadam Charkari, Nasrollah

    2017-01-01

    Recently, a number of meta-path based similarity indices like PathSim, HeteSim, and random walk have been proposed for link prediction in heterogeneous complex networks. However, these indices suffer from two major drawbacks. Firstly, they are primarily dependent on the connectivity degrees of node pairs without considering the further information provided by the given meta-path. Secondly, most of them are required to use a single and usually symmetric meta-path in advance. Hence, employing a set of different meta-paths is not straightforward. To tackle with these problems, we propose a mutual information model for link prediction in heterogeneous complex networks. The proposed model, called as Meta-path based Mutual Information Index (MMI), introduces meta-path based link entropy to estimate the link likelihood and could be carried on a set of available meta-paths. This estimation measures the amount of information through the paths instead of measuring the amount of connectivity between the node pairs. The experimental results on a Bibliography network show that the MMI obtains high prediction accuracy compared with other popular similarity indices. PMID:28344326

  8. Achondrogenesis type IB: agenesis of cartilage interterritorial matrix as the link between gene defect and pathological skeletal phenotype.

    PubMed

    Corsi, A; Riminucci, M; Fisher, L W; Bianco, P

    2001-10-01

    Achondrogenesis type IB is a lethal osteochondrodysplasia caused by mutations in the diastrophic dysplasia sulfate transporter gene. How these mutations lead to the skeletal phenotype is not known. Histology of plastic-embedded skeletal fetal achondrogenesis type IB samples suggested that interterritorial epiphyseal cartilage matrix was selectively missing. Cartilage was organized in "chondrons" separated by cleft spaces; chondrocyte seriation, longitudinal septa, and, in turn, mineralized cartilaginous septa were absent. Agenesis of interterritorial matrix as the key histologic change was confirmed by immunohistology using specific markers of territorial and interterritorial matrix. Biglycan-enriched territorial matrix was preserved; decorin-enriched interterritorial areas were absent, although immunostaining was observed within chondrocytes. Thus, in achondrogenesis type IB: (1) a complex derangement in cartilage matrix assembly lies downstream of the deficient sulfate transporter activity; (2) the severely impaired decorin deposition participates in the changes in matrix organization with lack of development of normal interterritorial matrix; and (3) this change determines the lack of the necessary structural substrate for proper endochondral bone formation and explains the severe skeletal phenotype.

  9. Beyond the Central Dogma: Model-Based Learning of How Genes Determine Phenotypes.

    PubMed

    Reinagel, Adam; Bray Speth, Elena

    2016-01-01

    In an introductory biology course, we implemented a learner-centered, model-based pedagogy that frequently engaged students in building conceptual models to explain how genes determine phenotypes. Model-building tasks were incorporated within case studies and aimed at eliciting students' understanding of 1) the origin of variation in a population and 2) how genes/alleles determine phenotypes. Guided by theory on hierarchical development of systems-thinking skills, we scaffolded instruction and assessment so that students would first focus on articulating isolated relationships between pairs of molecular genetics structures and then integrate these relationships into an explanatory network. We analyzed models students generated on two exams to assess whether students' learning of molecular genetics progressed along the theoretical hierarchical sequence of systems-thinking skills acquisition. With repeated practice, peer discussion, and instructor feedback over the course of the semester, students' models became more accurate, better contextualized, and more meaningful. At the end of the semester, however, more than 25% of students still struggled to describe phenotype as an output of protein function. We therefore recommend that 1) practices like modeling, which require connecting genes to phenotypes; and 2) well-developed case studies highlighting proteins and their functions, take center stage in molecular genetics instruction.

  10. Beyond the Central Dogma: Model-Based Learning of How Genes Determine Phenotypes

    PubMed Central

    Reinagel, Adam; Bray Speth, Elena

    2016-01-01

    In an introductory biology course, we implemented a learner-centered, model-based pedagogy that frequently engaged students in building conceptual models to explain how genes determine phenotypes. Model-building tasks were incorporated within case studies and aimed at eliciting students’ understanding of 1) the origin of variation in a population and 2) how genes/alleles determine phenotypes. Guided by theory on hierarchical development of systems-thinking skills, we scaffolded instruction and assessment so that students would first focus on articulating isolated relationships between pairs of molecular genetics structures and then integrate these relationships into an explanatory network. We analyzed models students generated on two exams to assess whether students’ learning of molecular genetics progressed along the theoretical hierarchical sequence of systems-thinking skills acquisition. With repeated practice, peer discussion, and instructor feedback over the course of the semester, students’ models became more accurate, better contextualized, and more meaningful. At the end of the semester, however, more than 25% of students still struggled to describe phenotype as an output of protein function. We therefore recommend that 1) practices like modeling, which require connecting genes to phenotypes; and 2) well-developed case studies highlighting proteins and their functions, take center stage in molecular genetics instruction. PMID:26903496

  11. Discovering novel phenotypes with automatically inferred dynamic models: a partial melanocyte conversion in Xenopus

    NASA Astrophysics Data System (ADS)

    Lobo, Daniel; Lobikin, Maria; Levin, Michael

    2017-01-01

    Progress in regenerative medicine requires reverse-engineering cellular control networks to infer perturbations with desired systems-level outcomes. Such dynamic models allow phenotypic predictions for novel perturbations to be rapidly assessed in silico. Here, we analyzed a Xenopus model of conversion of melanocytes to a metastatic-like phenotype only previously observed in an all-or-none manner. Prior in vivo genetic and pharmacological experiments showed that individual animals either fully convert or remain normal, at some characteristic frequency after a given perturbation. We developed a Machine Learning method which inferred a model explaining this complex, stochastic all-or-none dataset. We then used this model to ask how a new phenotype could be generated: animals in which only some of the melanocytes converted. Systematically performing in silico perturbations, the model predicted that a combination of altanserin (5HTR2 inhibitor), reserpine (VMAT inhibitor), and VP16-XlCreb1 (constitutively active CREB) would break the all-or-none concordance. Remarkably, applying the predicted combination of three reagents in vivo revealed precisely the expected novel outcome, resulting in partial conversion of melanocytes within individuals. This work demonstrates the capability of automated analysis of dynamic models of signaling networks to discover novel phenotypes and predictively identify specific manipulations that can reach them.

  12. Discovering novel phenotypes with automatically inferred dynamic models: a partial melanocyte conversion in Xenopus

    PubMed Central

    Lobo, Daniel; Lobikin, Maria; Levin, Michael

    2017-01-01

    Progress in regenerative medicine requires reverse-engineering cellular control networks to infer perturbations with desired systems-level outcomes. Such dynamic models allow phenotypic predictions for novel perturbations to be rapidly assessed in silico. Here, we analyzed a Xenopus model of conversion of melanocytes to a metastatic-like phenotype only previously observed in an all-or-none manner. Prior in vivo genetic and pharmacological experiments showed that individual animals either fully convert or remain normal, at some characteristic frequency after a given perturbation. We developed a Machine Learning method which inferred a model explaining this complex, stochastic all-or-none dataset. We then used this model to ask how a new phenotype could be generated: animals in which only some of the melanocytes converted. Systematically performing in silico perturbations, the model predicted that a combination of altanserin (5HTR2 inhibitor), reserpine (VMAT inhibitor), and VP16-XlCreb1 (constitutively active CREB) would break the all-or-none concordance. Remarkably, applying the predicted combination of three reagents in vivo revealed precisely the expected novel outcome, resulting in partial conversion of melanocytes within individuals. This work demonstrates the capability of automated analysis of dynamic models of signaling networks to discover novel phenotypes and predictively identify specific manipulations that can reach them. PMID:28128301

  13. Phenotype-Specific CpG Island Methylation Events in a Murine Model of Prostate Cancer

    PubMed Central

    Camoriano, Marta; Morey Kinney, Shannon R.; Moser, Michael T.; Foster, Barbara A.; Mohler, James L.; Trump, Donald L.; Karpf, Adam R.; Smiraglia, Dominic J.

    2010-01-01

    Aberrant DNA methylation plays a significant role in nearly all human cancers and may contribute to disease progression to advanced phenotypes. Study of advanced prostate cancer phenotypes in the human disease is hampered by limited availability of tissues. We therefore took advantage of the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model to study whether three different phenotypes of TRAMP tumors (PRIM, late-stage primary tumors; AIP, androgen-independent primary tumors; and MET, metastases) displayed specific patterns of CpG island hypermethylation using Restriction Landmark Genomic Scanning. Each tumor phenotype displayed numerous hypermethylation events, with the most homogeneous methylation pattern in AIP and the most heterogeneous pattern in MET. Several loci displayed a phenotype-specific methylation pattern; the most striking pattern being loci methylated at high frequency in PRIM and AIP but rarely in MET. Examination of the mRNA expression of three genes, BC058385, Goosecoid, and Neurexin 2, which exhibited nonpromoter methylation, revealed increased expression associated with downstream methylation. Only methylated samples showed mRNA expression, in which tumor phenotype was a key factor determining the level of expression. The CpG island in the human orthologue of BC058385 was methylated in human AIP but not in primary androgen-stimulated prostate cancer or benign prostate. The clinical data show a proof-of-principle that the TRAMP model can be used to identify targets of aberrant CpG island methylation relevant to human disease. In conclusion, phenotype-specific hypermethylation events were associated with the overexpression of different genes and may provide new markers of prostate tumorigenesis. PMID:18519676

  14. An evaluation of the NQF Quality Data Model for representing Electronic Health Record driven phenotyping algorithms.

    PubMed

    Thompson, William K; Rasmussen, Luke V; Pacheco, Jennifer A; Peissig, Peggy L; Denny, Joshua C; Kho, Abel N; Miller, Aaron; Pathak, Jyotishman

    2012-01-01

    The development of Electronic Health Record (EHR)-based phenotype selection algorithms is a non-trivial and highly iterative process involving domain experts and informaticians. To make it easier to port algorithms across institutions, it is desirable to represent them using an unambiguous formal specification language. For this purpose we evaluated the recently developed National Quality Forum (NQF) information model designed for EHR-based quality measures: the Quality Data Model (QDM). We selected 9 phenotyping algorithms that had been previously developed as part of the eMERGE consortium and translated them into QDM format. Our study concluded that the QDM contains several core elements that make it a promising format for EHR-driven phenotyping algorithms for clinical research. However, we also found areas in which the QDM could be usefully extended, such as representing information extracted from clinical text, and the ability to handle algorithms that do not consist of Boolean combinations of criteria.

  15. Modeling the Transitions between Collective and Solitary Migration Phenotypes in Cancer Metastasis

    PubMed Central

    Huang, Bin; Jolly, Mohit Kumar; Lu, Mingyang; Tsarfaty, Ilan; Ben-Jacob, Eshel; Onuchic, Jose’ N

    2015-01-01

    Cellular plasticity during cancer metastasis is a major clinical challenge. Two key cellular plasticity mechanisms —Epithelial-to-Mesenchymal Transition (EMT) and Mesenchymal-to-Amoeboid Transition (MAT) – have been carefully investigated individually, yet a comprehensive understanding of their interconnections remains elusive. Previously, we have modeled the dynamics of the core regulatory circuits for both EMT (miR-200/ZEB/miR-34/SNAIL) and MAT (Rac1/RhoA). We now extend our previous work to study the coupling between these two core circuits by considering the two microRNAs (miR-200 and miR-34) as external signals to the core MAT circuit. We show that this coupled circuit enables four different stable steady states (phenotypes) that correspond to hybrid epithelial/mesenchymal (E/M), mesenchymal (M), amoeboid (A) and hybrid amoeboid/mesenchymal (A/M) phenotypes. Our model recapitulates the metastasis-suppressing role of the microRNAs even in the presence of EMT-inducing signals like Hepatocyte Growth Factor (HGF). It also enables mapping the microRNA levels to the transitions among various cell migration phenotypes. Finally, it offers a mechanistic understanding for the observed phenotypic transitions among different cell migration phenotypes, specifically the Collective-to-Amoeboid Transition (CAT). PMID:26627083

  16. Building predictive models for mechanism-of-action classification from phenotypic assay data sets.

    PubMed

    Berg, Ellen L; Yang, Jian; Polokoff, Mark A

    2013-12-01

    Compound mechanism-of-action information can be critical for drug development decisions but is often challenging for phenotypic drug discovery programs. One concern is that compounds selected by phenotypic screening will have a previously known but undesirable target mechanism. Here we describe a useful method for assigning mechanism class to compounds and bioactive agents using an 84-feature signature from a panel of primary human cell systems (BioMAP systems). For this approach, a reference data set of well-characterized compounds was used to develop predictive models for 28 mechanism classes using support vector machines. These mechanism classes encompass safety and efficacy-related mechanisms, include both target-specific and pathway-based classes, and cover the most common mechanisms identified in phenotypic screens, such as inhibitors of mitochondrial and microtubule function, histone deacetylase, and cAMP elevators. Here we describe the performance and the application of these predictive models in a decision scheme for triaging phenotypic screening hits using a previously published data set of 309 environmental chemicals tested as part of the Environmental Protection Agency's ToxCast program. By providing quantified membership in specific mechanism classes, this approach is suitable for identification of off-target toxicity mechanisms as well as enabling target deconvolution of phenotypic drug discovery hits.

  17. Modeling the Transitions between Collective and Solitary Migration Phenotypes in Cancer Metastasis

    NASA Astrophysics Data System (ADS)

    Huang, Bin; Jolly, Mohit Kumar; Lu, Mingyang; Tsarfaty, Ilan; Ben-Jacob, Eshel; Onuchic, Jose' N.

    2015-12-01

    Cellular plasticity during cancer metastasis is a major clinical challenge. Two key cellular plasticity mechanisms —Epithelial-to-Mesenchymal Transition (EMT) and Mesenchymal-to-Amoeboid Transition (MAT) - have been carefully investigated individually, yet a comprehensive understanding of their interconnections remains elusive. Previously, we have modeled the dynamics of the core regulatory circuits for both EMT (miR-200/ZEB/miR-34/SNAIL) and MAT (Rac1/RhoA). We now extend our previous work to study the coupling between these two core circuits by considering the two microRNAs (miR-200 and miR-34) as external signals to the core MAT circuit. We show that this coupled circuit enables four different stable steady states (phenotypes) that correspond to hybrid epithelial/mesenchymal (E/M), mesenchymal (M), amoeboid (A) and hybrid amoeboid/mesenchymal (A/M) phenotypes. Our model recapitulates the metastasis-suppressing role of the microRNAs even in the presence of EMT-inducing signals like Hepatocyte Growth Factor (HGF). It also enables mapping the microRNA levels to the transitions among various cell migration phenotypes. Finally, it offers a mechanistic understanding for the observed phenotypic transitions among different cell migration phenotypes, specifically the Collective-to-Amoeboid Transition (CAT).

  18. Metabolic phenotyping guidelines: assessing glucose homeostasis in rodent models.

    PubMed

    Bowe, James E; Franklin, Zara J; Hauge-Evans, Astrid C; King, Aileen J; Persaud, Shanta J; Jones, Peter M

    2014-09-01

    The pathophysiology of diabetes as a disease is characterised by an inability to maintain normal glucose homeostasis. In type 1 diabetes, this is due to autoimmune destruction of the pancreatic β-cells and subsequent lack of insulin production, and in type 2 diabetes it is due to a combination of both insulin resistance and an inability of the β-cells to compensate adequately with increased insulin release. Animal models, in particular genetically modified mice, are increasingly being used to elucidate the mechanisms underlying both type 1 and type 2 diabetes, and as such the ability to study glucose homeostasis in vivo has become an essential tool. Several techniques exist for measuring different aspects of glucose tolerance and each of these methods has distinct advantages and disadvantages. Thus the appropriate methodology may vary from study to study depending on the desired end-points, the animal model, and other practical considerations. This review outlines the most commonly used techniques for assessing glucose tolerance in rodents and details the factors that should be taken into account in their use. Representative scenarios illustrating some of the practical considerations of designing in vivo experiments for the measurement of glucose homeostasis are also discussed.

  19. The mouse genome database: genotypes, phenotypes, and models of human disease.

    PubMed

    Bult, Carol J; Eppig, Janan T; Blake, Judith A; Kadin, James A; Richardson, Joel E

    2013-01-01

    The laboratory mouse is the premier animal model for studying human biology because all life stages can be accessed experimentally, a completely sequenced reference genome is publicly available and there exists a myriad of genomic tools for comparative and experimental research. In the current era of genome scale, data-driven biomedical research, the integration of genetic, genomic and biological data are essential for realizing the full potential of the mouse as an experimental model. The Mouse Genome Database (MGD; http://www.informatics.jax.org), the community model organism database for the laboratory mouse, is designed to facilitate the use of the laboratory mouse as a model system for understanding human biology and disease. To achieve this goal, MGD integrates genetic and genomic data related to the functional and phenotypic characterization of mouse genes and alleles and serves as a comprehensive catalog for mouse models of human disease. Recent enhancements to MGD include the addition of human ortholog details to mouse Gene Detail pages, the inclusion of microRNA knockouts to MGD's catalog of alleles and phenotypes, the addition of video clips to phenotype images, providing access to genotype and phenotype data associated with quantitative trait loci (QTL) and improvements to the layout and display of Gene Ontology annotations.

  20. Molecular modeling indicates distinct classes of missense variants with mild and severe XLRS phenotypes.

    PubMed

    Sergeev, Yuri V; Vitale, Susan; Sieving, Paul A; Vincent, Ajoy; Robson, Anthony G; Moore, Anthony T; Webster, Andrew R; Holder, Graham E

    2013-12-01

    X-linked retinoschisis (XLRS) is a vitreo-retinal degeneration caused by mutations in the RS1 gene which encodes the protein retinoschisin (RS1), required for the structural and functional integrity of the retina. Data are presented from a group of 38 XLRS patients from Moorfields Eye Hospital (London, UK) who had one of 18 missense mutations in RS1. Patients were grouped based on mutation severity predicted by molecular modeling: mild (class I), moderate (intermediate) and severe (class II). Most patients had an electronegative scotopic bright flash electroretinogram (ERG) (reduced b/a-wave ratio) in keeping with predominant inner retinal dysfunction. An association between the type of structural RS1 alterations and the severity of b/a-wave reduction was found in all but the oldest group of patients, significant in patients aged 15-30 years. Severe RS1 missense changes were associated with a lower ERG b/a ratio than were mild changes, suggesting that the extent of inner retinal dysfunction is influenced by the effect of the mutations on protein structure. The majority of class I mutations showed no changes involving cysteine residues. Class II mutations caused severe perturbations due to the removal or insertion of cysteine residues or due to changes in the hydrophobic core. The ERG b/a ratio in intermediate cases was abnormal but showed significant variability, possibly related to the role of proline or arginine residues. We also conducted a second study, using a completely independent cohort, to indicate a genotype-ERG phenotype correlation.

  1. Design Space Toolbox V2: Automated Software Enabling a Novel Phenotype-Centric Modeling Strategy for Natural and Synthetic Biological Systems

    PubMed Central

    Lomnitz, Jason G.; Savageau, Michael A.

    2016-01-01

    Mathematical models of biochemical systems provide a means to elucidate the link between the genotype, environment, and phenotype. A subclass of mathematical models, known as mechanistic models, quantitatively describe the complex non-linear mechanisms that capture the intricate interactions between biochemical components. However, the study of mechanistic models is challenging because most are analytically intractable and involve large numbers of system parameters. Conventional methods to analyze them rely on local analyses about a nominal parameter set and they do not reveal the vast majority of potential phenotypes possible for a given system design. We have recently developed a new modeling approach that does not require estimated values for the parameters initially and inverts the typical steps of the conventional modeling strategy. Instead, this approach relies on architectural features of the model to identify the phenotypic repertoire and then predict values for the parameters that yield specific instances of the system that realize desired phenotypic characteristics. Here, we present a collection of software tools, the Design Space Toolbox V2 based on the System Design Space method, that automates (1) enumeration of the repertoire of model phenotypes, (2) prediction of values for the parameters for any model phenotype, and (3) analysis of model phenotypes through analytical and numerical methods. The result is an enabling technology that facilitates this radically new, phenotype-centric, modeling approach. We illustrate the power of these new tools by applying them to a synthetic gene circuit that can exhibit multi-stability. We then predict values for the system parameters such that the design exhibits 2, 3, and 4 stable steady states. In one example, inspection of the basins of attraction reveals that the circuit can count between three stable states by transient stimulation through one of two input channels: a positive channel that increases the count

  2. Design Space Toolbox V2: Automated Software Enabling a Novel Phenotype-Centric Modeling Strategy for Natural and Synthetic Biological Systems.

    PubMed

    Lomnitz, Jason G; Savageau, Michael A

    2016-01-01

    Mathematical models of biochemical systems provide a means to elucidate the link between the genotype, environment, and phenotype. A subclass of mathematical models, known as mechanistic models, quantitatively describe the complex non-linear mechanisms that capture the intricate interactions between biochemical components. However, the study of mechanistic models is challenging because most are analytically intractable and involve large numbers of system parameters. Conventional methods to analyze them rely on local analyses about a nominal parameter set and they do not reveal the vast majority of potential phenotypes possible for a given system design. We have recently developed a new modeling approach that does not require estimated values for the parameters initially and inverts the typical steps of the conventional modeling strategy. Instead, this approach relies on architectural features of the model to identify the phenotypic repertoire and then predict values for the parameters that yield specific instances of the system that realize desired phenotypic characteristics. Here, we present a collection of software tools, the Design Space Toolbox V2 based on the System Design Space method, that automates (1) enumeration of the repertoire of model phenotypes, (2) prediction of values for the parameters for any model phenotype, and (3) analysis of model phenotypes through analytical and numerical methods. The result is an enabling technology that facilitates this radically new, phenotype-centric, modeling approach. We illustrate the power of these new tools by applying them to a synthetic gene circuit that can exhibit multi-stability. We then predict values for the system parameters such that the design exhibits 2, 3, and 4 stable steady states. In one example, inspection of the basins of attraction reveals that the circuit can count between three stable states by transient stimulation through one of two input channels: a positive channel that increases the count

  3. Towards a reference plant trait ontology for modeling knowledge of plant traits and phenotypes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ontology engineering and knowledge modeling for the plant sciences is expected to contribute to the understanding of the basis of plant traits that determine phenotypic expression in a given environment. Several crop- or clade-specific plant trait ontologies have been developed to describe plant tr...

  4. Improving nonlinear modeling capabilities of functional link adaptive filters.

    PubMed

    Comminiello, Danilo; Scarpiniti, Michele; Scardapane, Simone; Parisi, Raffaele; Uncini, Aurelio

    2015-09-01

    The functional link adaptive filter (FLAF) represents an effective solution for online nonlinear modeling problems. In this paper, we take into account a FLAF-based architecture, which separates the adaptation of linear and nonlinear elements, and we focus on the nonlinear branch to improve the modeling performance. In particular, we propose a new model that involves an adaptive combination of filters downstream of the nonlinear expansion. Such combination leads to a cooperative behavior of the whole architecture, thus yielding a performance improvement, particularly in the presence of strong nonlinearities. An advanced architecture is also proposed involving the adaptive combination of multiple filters on the nonlinear branch. The proposed models are assessed in different nonlinear modeling problems, in which their effectiveness and capabilities are shown.

  5. A rat tail temporary static compression model reproduces different stages of intervertebral disc degeneration with decreased notochordal cell phenotype.

    PubMed

    Hirata, Hiroaki; Yurube, Takashi; Kakutani, Kenichiro; Maeno, Koichiro; Takada, Toru; Yamamoto, Junya; Kurakawa, Takuto; Akisue, Toshihiro; Kuroda, Ryosuke; Kurosaka, Masahiro; Nishida, Kotaro

    2014-03-01

    The intervertebral disc nucleus pulposus (NP) has two phenotypically distinct cell types-notochordal cells (NCs) and non-notochordal chondrocyte-like cells. In human discs, NCs are lost during adolescence, which is also when discs begin to show degenerative signs. However, little evidence exists regarding the link between NC disappearance and the pathogenesis of disc degeneration. To clarify this, a rat tail disc degeneration model induced by static compression at 1.3 MPa for 0, 1, or 7 days was designed and assessed for up to 56 postoperative days. Radiography, MRI, and histomorphology showed degenerative disc findings in response to the compression period. Immunofluorescence displayed that the number of DAPI-positive NP cells decreased with compression; particularly, the decrease was notable in larger, vacuolated, cytokeratin-8- and galectin-3-co-positive cells, identified as NCs. The proportion of TUNEL-positive cells, which predominantly comprised non-NCs, increased with compression. Quantitative PCR demonstrated isolated mRNA up-regulation of ADAMTS-5 in the 1-day loaded group and MMP-3 in the 7-day loaded group. Aggrecan-1 and collagen type 2α-1 mRNA levels were down-regulated in both groups. This rat tail temporary static compression model, which exhibits decreased NC phenotype, increased apoptotic cell death, and imbalanced catabolic and anabolic gene expression, reproduces different stages of intervertebral disc degeneration.

  6. XGAP: a uniform and extensible data model and software platform for genotype and phenotype experiments.

    PubMed

    Swertz, Morris A; Velde, K Joeri van der; Tesson, Bruno M; Scheltema, Richard A; Arends, Danny; Vera, Gonzalo; Alberts, Rudi; Dijkstra, Martijn; Schofield, Paul; Schughart, Klaus; Hancock, John M; Smedley, Damian; Wolstencroft, Katy; Goble, Carole; de Brock, Engbert O; Jones, Andrew R; Parkinson, Helen E; Jansen, Ritsert C

    2010-01-01

    We present an extensible software model for the genotype and phenotype community, XGAP. Readers can download a standard XGAP (http://www.xgap.org) or auto-generate a custom version using MOLGENIS with programming interfaces to R-software and web-services or user interfaces for biologists. XGAP has simple load formats for any type of genotype, epigenotype, transcript, protein, metabolite or other phenotype data. Current functionality includes tools ranging from eQTL analysis in mouse to genome-wide association studies in humans.

  7. XGAP: a uniform and extensible data model and software platform for genotype and phenotype experiments

    PubMed Central

    2010-01-01

    We present an extensible software model for the genotype and phenotype community, XGAP. Readers can download a standard XGAP (http://www.xgap.org) or auto-generate a custom version using MOLGENIS with programming interfaces to R-software and web-services or user interfaces for biologists. XGAP has simple load formats for any type of genotype, epigenotype, transcript, protein, metabolite or other phenotype data. Current functionality includes tools ranging from eQTL analysis in mouse to genome-wide association studies in humans. PMID:20214801

  8. Expanding phenotype of p.Ala140Val mutation in MECP2 in a 4 generation family with X-linked intellectual disability and spasticity.

    PubMed

    Lambert, Sophie; Maystadt, Isabelle; Boulanger, Sébastien; Vrielynck, Pascal; Destrée, Anne; Lederer, Damien; Moortgat, Stéphanie

    2016-10-01

    Mutations in MECP2 (MIM #312750), located on Xq28 and encoding a methyl CpG binding protein, are classically associated with Rett syndrome in female patients, with a lethal effect in hemizygous males. However, MECP2 mutations have already been reported in surviving males with severe neonatal-onset encephalopathy, or with X-linked intellectual disability associated with psychosis, pyramidal signs, parkinsonian features and macro-orchidism (PPM-X syndrome; MIM3 #300055). Here we report on the identification of the p.Ala140Val mutation in the MECP2 gene in 4 males and 3 females of a large Caucasian family affected with X-linked intellectual disability. Females present with mild cognitive impairment and speech difficulties. Males have moderate intellectual disability, impaired language development, friendly behavior, slowly progressive spastic paraparesis and dystonic movements of the hands. Two of them show microcephaly. The p.Ala140Val mutation is recurrent, as it was already described in 4 families with X-linked mental retardation and in three sporadic male patients with intellectual disability. We further delineate the phenotype associated with the p.Ala140Val mutation, illustrating a variable expressivity even within a given family, and we compare our patients with previous reported cases in the literature.

  9. The Immature Fiber Mutant Phenotype of Cotton (Gossypium hirsutum) Is Linked to a 22-bp Frame-Shift Deletion in a Mitochondria Targeted Pentatricopeptide Repeat Gene

    PubMed Central

    Thyssen, Gregory N.; Fang, David D.; Zeng, Linghe; Song, Xianliang; Delhom, Christopher D.; Condon, Tracy L.; Li, Ping; Kim, Hee Jin

    2016-01-01

    Cotton seed trichomes are the most important source of natural fibers globally. The major fiber thickness properties influence the price of the raw material, and the quality of the finished product. The recessive immature fiber (im) gene reduces the degree of fiber cell wall thickening by a process that was previously shown to involve mitochondrial function in allotetraploid Gossypium hirsutum. Here, we present the fine genetic mapping of the im locus, gene expression analysis of annotated proteins near the locus, and association analysis of the linked markers. Mapping-by-sequencing identified a 22-bp deletion in a pentatricopeptide repeat (PPR) gene that is completely linked to the immature fiber phenotype in 2837 F2 plants, and is absent from all 163 cultivated varieties tested, although other closely linked marker polymorphisms are prevalent in the diversity panel. This frame-shift mutation results in a transcript with two long open reading frames: one containing the N-terminal transit peptide that targets mitochondria, the other containing only the RNA-binding PPR domains, suggesting that a functional PPR protein cannot be targeted to mitochondria in the im mutant. Taken together, these results suggest that PPR gene Gh_A03G0489 is involved in the cotton fiber wall thickening process, and is a promising candidate gene at the im locus. Our findings expand our understanding of the molecular mechanisms that modulate cotton fiber fineness and maturity, and may facilitate the development of cotton varieties with superior fiber attributes. PMID:27172184

  10. Imaging techniques for visualizing and phenotyping congenital heart defects in murine models.

    PubMed

    Liu, Xiaoqin; Tobita, Kimimasa; Francis, Richard J B; Lo, Cecilia W

    2013-06-01

    Mouse model is ideal for investigating the genetic and developmental etiology of congenital heart disease. However, cardiovascular phenotyping for the precise diagnosis of structural heart defects in mice remain challenging. With rapid advances in imaging techniques, there are now high throughput phenotyping tools available for the diagnosis of structural heart defects. In this review, we discuss the efficacy of four different imaging modalities for congenital heart disease diagnosis in fetal/neonatal mice, including noninvasive fetal echocardiography, micro-computed tomography (micro-CT), micro-magnetic resonance imaging (micro-MRI), and episcopic fluorescence image capture (EFIC) histopathology. The experience we have gained in the use of these imaging modalities in a large-scale mouse mutagenesis screen have validated their efficacy for congenital heart defect diagnosis in the tiny hearts of fetal and newborn mice. These cutting edge phenotyping tools will be invaluable for furthering our understanding of the developmental etiology of congenital heart disease.

  11. Histiocytoid cardiomyopathy and microphthalmia with linear skin defects syndrome: phenotypes linked by truncating variants in NDUFB11

    PubMed Central

    Rea, Gillian; Homfray, Tessa; Till, Jan; Roses-Noguer, Ferran; Buchan, Rachel J.; Wilkinson, Sam; Wilk, Alicja; Walsh, Roddy; John, Shibu; McKee, Shane; Stewart, Fiona J.; Murday, Victoria; Taylor, Robert W.; Ashworth, Michael; Baksi, A. John; Daubeney, Piers; Prasad, Sanjay; Barton, Paul J.R.; Cook, Stuart A.; Ware, James S.

    2017-01-01

    Variants in NDUFB11, which encodes a structural component of complex I of the mitochondrial respiratory chain (MRC), were recently independently reported to cause histiocytoid cardiomyopathy (histiocytoid CM) and microphthalmia with linear skin defects syndrome (MLS syndrome). Here we report an additional case of histiocytoid CM, which carries a de novo nonsense variant in NDUFB11 (ENST00000276062.8: c.262C > T; p.[Arg88*]) identified using whole-exome sequencing (WES) of a family trio. An identical variant has been previously reported in association with MLS syndrome. The case we describe here lacked the diagnostic features of MLS syndrome, but a detailed clinical comparison of the two cases revealed significant phenotypic overlap. Heterozygous variants in HCCS (which encodes an important mitochondrially targeted protein) and COX7B, which, like NDUFB11, encodes a protein of the MRC, have also previously been identified in MLS syndrome including a case with features of both MLS syndrome and histiocytoid CM. However, a systematic review of WES data from previously published histiocytoid CM cases, alongside four additional cases presented here for the first time, did not identify any variants in these genes. We conclude that NDUFB11 variants play a role in the pathogenesis of both histiocytoid CM and MLS and that these disorders are allelic (genetically related). PMID:28050600

  12. Par1b links lumen polarity with LGN–NuMA positioning for distinct epithelial cell division phenotypes

    PubMed Central

    Lázaro-Diéguez, Francisco; Cohen, David; Fernandez, Dawn; Hodgson, Louis; van IJzendoorn, Sven C.D.

    2013-01-01

    Columnar epithelia establish their luminal domains and their mitotic spindles parallel to the basal surface and undergo symmetric cell divisions in which the cleavage furrow bisects the apical domain. Hepatocyte lumina interrupt the lateral domain of neighboring cells perpendicular to two basal domains and their cleavage furrow rarely bifurcates the luminal domains. We determine that the serine/threonine kinase Par1b defines lumen position in concert with the position of the astral microtubule anchoring complex LGN–NuMA to yield the distinct epithelial division phenotypes. Par1b signaling via the extracellular matrix (ECM) in polarizing cells determined RhoA/Rho-kinase activity at cell–cell contact sites. Columnar MDCK and Par1b-depleted hepatocytic HepG2 cells featured high RhoA activity that correlated with robust LGN–NuMA recruitment to the metaphase cortex, spindle alignment with the substratum, and columnar organization. Reduced RhoA activity at the metaphase cortex in HepG2 cells and Par1b-overexpressing MDCK cells correlated with a single or no LGN–NuMA crescent, tilted spindles, and the development of lateral lumen polarity. PMID:24165937

  13. A FAULT MODEL FOR ONTOLOGY MAPPING, ALIGNMENT, AND LINKING SYSTEMS

    PubMed Central

    JOHNSON, HELEN L.; COHEN, K. BRETONNEL; HUNTER, LAWRENCE

    2008-01-01

    There has been much work devoted to the mapping, alignment, and linking of ontologies (MALO), but little has been published about how to evaluate systems that do this. A fault model for conducting fine-grained evaluations of MALO systems is proposed, and its application to the system described in Johnson et al. [15] is illustrated. Two judges categorized errors according to the model, and inter-judge agreement was calculated by error category. Overall inter-judge agreement was 98% after dispute resolution, suggesting that the model is consistently applicable. The results of applying the model to the system described in [15] reveal the reason for a puzzling set of results in that paper, and also suggest a number of avenues and techniques for improving the state of the art in MALO, including the development of biomedical domain specific language processing tools, filtering of high frequency matching results, and word sense disambiguation. PMID:17990495

  14. A QTL model to map the common genetic basis for correlative phenotypic plasticity.

    PubMed

    Zhou, Tao; Lyu, Yafei; Xu, Fang; Bo, Wenhao; Zhai, Yi; Zhang, Jian; Pang, Xiaoming; Zheng, Bingsong; Wu, Rongling

    2015-01-01

    As an important mechanism for adaptation to heterogeneous environment, plastic responses of correlated traits to environmental alteration may also be genetically correlated, but less is known about the underlying genetic basis. We describe a statistical model for mapping specific quantitative trait loci (QTLs) that control the interrelationship of phenotypic plasticity between different traits. The model is constructed by a bivariate mixture setting, implemented with the EM algorithm to estimate the genetic effects of QTLs on correlative plastic response. We provide a series of procedure that test (1) how a QTL controls the phenotypic plasticity of a single trait; and (2) how the QTL determines the correlation of environment-induced changes of different traits. The model is readily extended to test how epistatic interactions among QTLs play a part in the correlations of different plastic traits. The model was validated through computer simulation and used to analyse multi-environment data of genetic mapping in winter wheat, showing its utilization in practice.

  15. Modeling of Long-Range Atmospheric Lasercom Links Between Static and Mobile Platforms

    SciTech Connect

    Scharlemann, E T; Breitfeller, E F; Henderson, J R; Kallman, J S; Morris, J R; Ruggiero, A J

    2003-07-29

    We describe modeling and simulation of long-range terrestrial laser communications links between static and mobile platforms. Atmospheric turbulence modeling, along with pointing, tracking and acquisition models are combined to provide an overall capability to estimate communications link performance.

  16. Father-offspring phenotypic correlations suggest intralocus sexual conflict for a fitness-linked trait in a wild sexually dimorphic mammal.

    PubMed

    Mainguy, Julien; Côté, Steeve D; Festa-Bianchet, Marco; Coltman, David W

    2009-11-22

    In sexually dimorphic and polygynous mammals, sexual selection often favours large males with well-developed weaponry, as these secondary sexual characters confer advantages in intrasexual competition and are often preferred by females. Little is known, however, about the effects of sexually selected paternal traits on offspring phenotype in wild mammals, especially when considering that shared phenotypic traits and selection can also differ greatly between genders. Here, we conducted molecular parentage analyses in a long-term study population of mountain goats (Oreamnos americanus), an ungulate exhibiting high sexual dimorphism in mass, to first assess the determinants of yearly reproductive success (YRS) in males. We then examined the effects of paternal characteristics on offspring mass at 1 year of age. Paternity was highly skewed, with 9 per cent of 57 males siring 51 per cent of 96 offspring assigned over 12 years. Male YRS increased with age until apparent reproductive senescence at 9 years, but mass was a stronger determinant of siring success than age, horn length or social rank. Mass of sons increased with paternal mass, but the mass of daughters was negatively related to that of their father, a finding consistent with recent theory on intralocus sexual conflict. Because early differences in mass persisted to early adulthood, sex-specific effects of paternal mass can have important fitness consequences, as adult mass is positively linked with reproduction in both sexes. Divergent father-offspring phenotypic correlations may partly explain the maintenance of sexual dimorphism in mountain goats and the large variance observed for this homologous trait within each gender in polygynous mammals.

  17. miR-199a Links MeCP2 with mTOR Signaling and Its Dysregulation Leads to Rett Syndrome Phenotypes.

    PubMed

    Tsujimura, Keita; Irie, Koichiro; Nakashima, Hideyuki; Egashira, Yoshihiro; Fukao, Yoichiro; Fujiwara, Masayuki; Itoh, Masayuki; Uesaka, Masahiro; Imamura, Takuya; Nakahata, Yasukazu; Yamashita, Yui; Abe, Takaya; Takamori, Shigeo; Nakashima, Kinichi

    2015-09-22

    Rett syndrome (RTT) is a neurodevelopmental disorder caused by MECP2 mutations. Although emerging evidence suggests that MeCP2 deficiency is associated with dysregulation of mechanistic target of rapamycin (mTOR), which functions as a hub for various signaling pathways, the mechanism underlying this association and the molecular pathophysiology of RTT remain elusive. We show here that MeCP2 promotes the posttranscriptional processing of particular microRNAs (miRNAs) as a component of the microprocessor Drosha complex. Among the MeCP2-regulated miRNAs, we found that miR-199a positively controls mTOR signaling by targeting inhibitors for mTOR signaling. miR-199a and its targets have opposite effects on mTOR activity, ameliorating and inducing RTT neuronal phenotypes, respectively. Furthermore, genetic deletion of miR-199a-2 led to a reduction of mTOR activity in the brain and recapitulated numerous RTT phenotypes in mice. Together, these findings establish miR-199a as a critical downstream target of MeCP2 in RTT pathogenesis by linking MeCP2 with mTOR signaling.

  18. The Hairless Stem Phenotype of Cotton (Gossypium barbadense) Is Linked to a Copia-Like Retrotransposon Insertion in a Homeodomain-Leucine Zipper Gene (HD1).

    PubMed

    Ding, Mingquan; Ye, Wuwei; Lin, Lifeng; He, Shae; Du, Xiongming; Chen, Aiqun; Cao, Yuefen; Qin, Yuan; Yang, Fen; Jiang, Yurong; Zhang, Hua; Wang, Xiyin; Paterson, Andrew H; Rong, Junkang

    2015-09-01

    Cotton (Gossypium) stem trichomes are mostly single cells that arise from stem epidermal cells. In this study, a homeodomain-leucine zipper gene (HD1) was found to cosegregate with the dominant trichome locus previously designated as T1 and mapped to chromosome 6. Characterization of HD1 orthologs revealed that the absence of stem trichomes in modern Gossypium barbadense varieties is linked to a large retrotransposon insertion in the ninth exon, 2565 bp downstream from the initial codon in the At subgenome HD1 gene (At-GbHD1). In both the At and Dt subgenomes, reduced transcription of GbHD1 genes is caused by this insertion. The disruption of At-HD1 further affects the expression of downstream GbMYB25 and GbHOX3 genes. Analyses of primitive cultivated accessions identified another retrotransposon insertion event in the sixth exon of At-GbHD1 that might predate the previously identified retrotransposon in modern varieties. Although both retrotransposon insertions results in similar phenotypic changes, the timing of these two retrotransposon insertion events fits well with our current understanding of the history of cotton speciation and dispersal. Taken together, the results of genetics mapping, gene expression and association analyses suggest that GbHD1 is an important component that controls stem trichome development and is a promising candidate gene for the T1 locus. The interspecific phenotypic difference in stem trichome traits also may be attributable to HD1 inactivation associated with retrotransposon insertion.

  19. X-linked borderline mental retardation with prominent behavioral disturbance: Phenotype, genetic localization, and evidence for disturbed monoamine metabolism

    SciTech Connect

    Brunner, H.G.; Nelen, M.R.; Zandvoort, P. van; Abeling, N.G.G.M.; Gennip, A.H. van; Ropers, H.H.; Oost, B.A. van ); Wolters, E.C.; Kuiper, M.A. )

    1993-06-01

    The authors have identified a large Dutch kindred with a new form of X-linked nondysmorphic mild mental retardation. All affected males in this family show very characteristic abnormal behavior, in particular aggressive and sometimes violent behavior. Other types of impulsive behavior include arson, attempted rape, and exhibitionism. Attempted suicide has been reported in a single case. The locus for this disorder could be assigned to the Xp11-21 interval between DXS7 and DXS77 by linkage analysis using markers spanning the X chromosome. A maximal multipoint lod score of 3.69 was obtained at the monoamine oxidase type A (MAOA) monoamine metabolism. These data are compatible with a primary defect in the structural gene for MAOA and/or monoamine oxidase type B (MAOB). Normal platelet MAOB activity suggests that the unusual behavior pattern in this family may be caused by isolated MAOA deficiency. 34 refs., 4 figs., 4 tabs.

  20. Stochastic modeling and experimental analysis of phenotypic switching and survival of cancer cells under stress

    NASA Astrophysics Data System (ADS)

    Zamani Dahaj, Seyed Alireza; Kumar, Niraj; Sundaram, Bala; Celli, Jonathan; Kulkarni, Rahul

    The phenotypic heterogeneity of cancer cells is critical to their survival under stress. A significant contribution to heterogeneity of cancer calls derives from the epithelial-mesenchymal transition (EMT), a conserved cellular program that is crucial for embryonic development. Several studies have investigated the role of EMT in growth of early stage tumors into invasive malignancies. Also, EMT has been closely associated with the acquisition of chemoresistance properties in cancer cells. Motivated by these studies, we analyze multi-phenotype stochastic models of the evolution of cancers cell populations under stress. We derive analytical results for time-dependent probability distributions that provide insights into the competing rates underlying phenotypic switching (e.g. during EMT) and the corresponding survival of cancer cells. Experimentally, we evaluate these model-based predictions by imaging human pancreatic cancer cell lines grown with and without cytotoxic agents and measure growth kinetics, survival, morphological changes and (terminal evaluation of) biomarkers with associated epithelial and mesenchymal phenotypes. The results derived suggest approaches for distinguishing between adaptation and selection scenarios for survival in the presence of external stresses.

  1. Curing critical links in oscillator networks as power flow models

    NASA Astrophysics Data System (ADS)

    Rohden, Martin; Witthaut, Dirk; Timme, Marc; Meyer-Ortmanns, Hildegard

    2017-01-01

    Modern societies crucially depend on the robust supply with electric energy so that blackouts of power grids can have far reaching consequences. Typically, large scale blackouts take place after a cascade of failures: the failure of a single infrastructure component, such as a critical transmission line, results in several subsequent failures that spread across large parts of the network. Improving the robustness of a network to prevent such secondary failures is thus key for assuring a reliable power supply. In this article we analyze the nonlocal rerouting of power flows after transmission line failures for a simplified AC power grid model and compare different strategies to improve network robustness. We identify critical links in the grid and compute alternative pathways to quantify the grid’s redundant capacity and to find bottlenecks along the pathways. Different strategies are developed and tested to increase transmission capacities to restore stability with respect to transmission line failures. We show that local and nonlocal strategies typically perform alike: one can equally well cure critical links by providing backup capacities locally or by extending the capacities of bottleneck links at remote locations.

  2. Linking the Weather Generator with Regional Climate Model

    NASA Astrophysics Data System (ADS)

    Dubrovsky, Martin; Farda, Ales; Skalak, Petr; Huth, Radan

    2013-04-01

    One of the downscaling approaches, which transform the raw outputs from the climate models (GCMs or RCMs) into data with more realistic structure, is based on linking the stochastic weather generator with the climate model output. The present contribution, in which the parametric daily surface weather generator (WG) M&Rfi is linked to the RCM output, follows two aims: (1) Validation of the new simulations of the present climate (1961-1990) made by the ALADIN-Climate Regional Climate Model at 25 km resolution. The WG parameters are derived from the RCM-simulated surface weather series and compared to those derived from weather series observed in 125 Czech meteorological stations. The set of WG parameters will include statistics of the surface temperature and precipitation series (including probability of wet day occurrence). (2) Presenting a methodology for linking the WG with RCM output. This methodology, which is based on merging information from observations and RCM, may be interpreted as a downscaling procedure, whose product is a gridded WG capable of producing realistic synthetic multivariate weather series for weather-ungauged locations. In this procedure, WG is calibrated with RCM-simulated multi-variate weather series in the first step, and the grid specific WG parameters are then de-biased by spatially interpolated correction factors based on comparison of WG parameters calibrated with gridded RCM weather series and spatially scarcer observations. The quality of the weather series produced by the resultant gridded WG will be assessed in terms of selected climatic characteristics (focusing on characteristics related to variability and extremes of surface temperature and precipitation). Acknowledgements: The present experiment is made within the frame of projects ALARO-Climate (project P209/11/2405 sponsored by the Czech Science Foundation), WG4VALUE (project LD12029 sponsored by the Ministry of Education, Youth and Sports of CR) and VALUE (COST ES 1102

  3. Mouse models of frontotemporal dementia: A comparison of phenotypes with clinical symptomatology.

    PubMed

    Ahmed, Rebekah M; Irish, Muireann; van Eersel, Janet; Ittner, Arne; Ke, Yazi D; Volkerling, Alexander; van der Hoven, Julia; Tanaka, Kimi; Karl, Tim; Kassiou, Michael; Kril, Jillian J; Piguet, Olivier; Götz, Jürgen; Kiernan, Matthew C; Halliday, Glenda M; Hodges, John R; Ittner, Lars M

    2017-03-01

    Frontotemporal dementia (FTD) is the second most common cause of young onset dementia. It is increasingly recognized that there is a clinical continuum between FTD and amyotrophic lateral sclerosis (ALS). At a clinical, pathological and genetic level there is much heterogeneity in FTD, meaning that our understanding of this condition, pathophysiology and development of treatments has been limited. A number of mouse models focusing predominantly on recapitulating neuropathological and molecular changes of disease have been developed, with most transgenic lines expressing a single specific protein or genetic mutation. Together with the species-typical presentation of functional deficits, this makes the direct translation of results from these models to humans difficult. However, understanding the phenotypical presentations in mice and how they relate to clinical symptomology in humans is essential for advancing translation. Here we review current mouse models in FTD and compare their phenotype to the clinical presentation in patients.

  4. Dynamic root growth and architecture responses to limiting nutrient availability: linking physiological models and experimentation.

    PubMed

    Postma, Johannes A; Schurr, Ulrich; Fiorani, Fabio

    2014-01-01

    In recent years the study of root phenotypic plasticity in response to sub-optimal environmental factors and the genetic control of these responses have received renewed attention. As a path to increased productivity, in particular for low fertility soils, several applied research projects worldwide target the improvement of crop root traits both in plant breeding and biotechnology contexts. To assist these tasks and address the challenge of optimizing root growth and architecture for enhanced mineral resource use, the development of realistic simulation models is of great importance. We review this research field from a modeling perspective focusing particularly on nutrient acquisition strategies for crop production on low nitrogen and low phosphorous soils. Soil heterogeneity and the dynamics of nutrient availability in the soil pose a challenging environment in which plants have to forage efficiently for nutrients in order to maintain their internal nutrient homeostasis throughout their life cycle. Mathematical models assist in understanding plant growth strategies and associated root phenes that have potential to be tested and introduced in physiological breeding programs. At the same time, we stress that it is necessary to carefully consider model assumptions and development from a whole plant-resource allocation perspective and to introduce or refine modules simulating explicitly root growth and architecture dynamics through ontogeny with reference to key factors that constrain root growth. In this view it is important to understand negative feedbacks such as plant-plant competition. We conclude by briefly touching on available and developing technologies for quantitative root phenotyping from lab to field, from quantification of partial root profiles in the field to 3D reconstruction of whole root systems. Finally, we discuss how these approaches can and should be tightly linked to modeling to explore the root phenome.

  5. Genetic and Environmental Models of Circadian Disruption Link SRC-2 Function to Hepatic Pathology.

    PubMed

    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.

  6. The Zebrafish Model Organism Database: new support for human disease models, mutation details, gene expression phenotypes and searching.

    PubMed

    Howe, Douglas G; Bradford, Yvonne M; Eagle, Anne; Fashena, David; Frazer, Ken; Kalita, Patrick; Mani, Prita; Martin, Ryan; Moxon, Sierra Taylor; Paddock, Holly; Pich, Christian; Ramachandran, Sridhar; Ruzicka, Leyla; Schaper, Kevin; Shao, Xiang; Singer, Amy; Toro, Sabrina; Van Slyke, Ceri; Westerfield, Monte

    2017-01-04

    The Zebrafish Model Organism Database (ZFIN; http://zfin.org) is the central resource for zebrafish (Danio rerio) genetic, genomic, phenotypic and developmental data. ZFIN curators provide expert manual curation and integration of comprehensive data involving zebrafish genes, mutants, transgenic constructs and lines, phenotypes, genotypes, gene expressions, morpholinos, TALENs, CRISPRs, antibodies, anatomical structures, models of human disease and publications. We integrate curated, directly submitted, and collaboratively generated data, making these available to zebrafish research community. Among the vertebrate model organisms, zebrafish are superbly suited for rapid generation of sequence-targeted mutant lines, characterization of phenotypes including gene expression patterns, and generation of human disease models. The recent rapid adoption of zebrafish as human disease models is making management of these data particularly important to both the research and clinical communities. Here, we describe recent enhancements to ZFIN including use of the zebrafish experimental conditions ontology, 'Fish' records in the ZFIN database, support for gene expression phenotypes, models of human disease, mutation details at the DNA, RNA and protein levels, and updates to the ZFIN single box search.

  7. The Zebrafish Model Organism Database: new support for human disease models, mutation details, gene expression phenotypes and searching

    PubMed Central

    Howe, Douglas G.; Bradford, Yvonne M.; Eagle, Anne; Fashena, David; Frazer, Ken; Kalita, Patrick; Mani, Prita; Martin, Ryan; Moxon, Sierra Taylor; Paddock, Holly; Pich, Christian; Ramachandran, Sridhar; Ruzicka, Leyla; Schaper, Kevin; Shao, Xiang; Singer, Amy; Toro, Sabrina; Van Slyke, Ceri; Westerfield, Monte

    2017-01-01

    The Zebrafish Model Organism Database (ZFIN; http://zfin.org) is the central resource for zebrafish (Danio rerio) genetic, genomic, phenotypic and developmental data. ZFIN curators provide expert manual curation and integration of comprehensive data involving zebrafish genes, mutants, transgenic constructs and lines, phenotypes, genotypes, gene expressions, morpholinos, TALENs, CRISPRs, antibodies, anatomical structures, models of human disease and publications. We integrate curated, directly submitted, and collaboratively generated data, making these available to zebrafish research community. Among the vertebrate model organisms, zebrafish are superbly suited for rapid generation of sequence-targeted mutant lines, characterization of phenotypes including gene expression patterns, and generation of human disease models. The recent rapid adoption of zebrafish as human disease models is making management of these data particularly important to both the research and clinical communities. Here, we describe recent enhancements to ZFIN including use of the zebrafish experimental conditions ontology, ‘Fish’ records in the ZFIN database, support for gene expression phenotypes, models of human disease, mutation details at the DNA, RNA and protein levels, and updates to the ZFIN single box search. PMID:27899582

  8. A mathematical model of N-linked glycosylation.

    PubMed

    Krambeck, Frederick J; Betenbaugh, Michael J

    2005-12-20

    Metabolic engineering of N-linked oligosaccharide biosynthesis to produce novel glycoforms or glycoform distributions of a recombinant glycoprotein can potentially lead to an improved therapeutic performance of the glycoprotein product. A mathematical model for the initial stages of this process, up to the first galactosylation of an oligosaccharide, was previously developed by Umana and Bailey (1997) (UB1997). Building on this work, an extended model is developed to include further galactosylation, fucosylation, extension of antennae by N-acetyllactosamine repeats, and sialylation. This allows many more structural features to be predicted. A number of simplifying assumptions are also relaxed to incorporate more variables for the control of glycoforms. The full model generates 7565 oligosaccharide structures in a network of 22,871 reactions. Methods for solving the model for the complete product distribution and adjusting the parameters to match experimental data are also developed. A basal set of kinetic parameters for the enzyme-catalyzed reactions acting on free oligosaccharide substrates is obtained from the previous model and existing literature. Enzyme activities are adjusted to match experimental glycoform distributions for Chinese Hamster Ovary (CHO). The model is then used to predict the effect of increasing expression of a target glycoprotein on the product glycoform distribution and evaluate appropriate metabolic engineering strategies to return the glycoform profile to its original distribution pattern. This model may find significant utility in the future to predict glycosylation patterns and direct glycoengineering projects to optimize glycoform distributions.

  9. Spontaneous shaker rat mutant – a new model for X-linked tremor/ataxia

    PubMed Central

    Figueroa, Karla P.; Paul, Sharan; Calì, Tito; Lopreiato, Raffaele; Karan, Sukanya; Frizzarin, Martina; Ames, Darren; Zanni, Ginevra; Brini, Marisa; Dansithong, Warunee; Milash, Brett; Scoles, Daniel R.; Carafoli, Ernesto; Pulst, Stefan M.

    2016-01-01

    ABSTRACT The shaker rat is an X-linked recessive spontaneous model of progressive Purkinje cell (PC) degeneration exhibiting a shaking ataxia and wide stance. Generation of Wistar Furth (WF)/Brown Norwegian (BN) F1 hybrids and genetic mapping of F2 sib-sib offspring using polymorphic markers narrowed the candidate gene region to 26 Mbp denoted by the last recombinant genetic marker DXRat21 at 133 Mbp to qter (the end of the long arm). In the WF background, the shaker mutation has complete penetrance, results in a stereotypic phenotype and there is a narrow window for age of disease onset; by contrast, the F2 hybrid phenotype was more varied, with a later age of onset and likely non-penetrance of the mutation. By deep RNA-sequencing, five variants were found in the candidate region; four were novel without known annotation. One of the variants caused an arginine (R) to cysteine (C) change at codon 35 of the ATPase, Ca2+ transporting, plasma membrane 3 (Atp2b3) gene encoding PMCA3 that has high expression in the cerebellum. The variant was well supported by hundreds of overlapping reads, and was found in 100% of all affected replicas and 0% of the wild-type (WT) replicas. The mutation segregated with disease in all affected animals and the amino acid change was found in an evolutionarily conserved region of PMCA3. Despite strong genetic evidence for pathogenicity, in vitro analyses of PMCA3R35C function did not show any differences to WT PMCA3. Because Atp2b3 mutation leads to congenital ataxia in humans, the identified Atp2b3 missense change in the shaker rat presents a good candidate for the shaker rat phenotype based on genetic criteria, but cannot yet be considered a definite pathogenic variant owing to lack of functional changes. PMID:27013529

  10. Delineation of the KIAA2022 mutation phenotype: two patients with X-linked intellectual disability and distinctive features.

    PubMed

    Kuroda, Yukiko; Ohashi, Ikuko; Naruto, Takuya; Ida, Kazumi; Enomoto, Yumi; Saito, Toshiyuki; Nagai, Jun-Ichi; Wada, Takahito; Kurosawa, Kenji

    2015-06-01

    Next-generation sequencing has enabled the screening for a causative mutation in X-linked intellectual disability (XLID). We identified KIAA2022 mutations in two unrelated male patients by targeted sequencing. We selected 13 Japanese male patients with severe intellectual disability (ID), including four sibling patients and nine sporadic patients. Two of thirteen had a KIAA2022 mutation. Patient 1 was a 3-year-old boy. He had severe ID with autistic behavior and hypotonia. Patient 2 was a 5-year-old boy. He also had severe ID with autistic behavior, hypotonia, central hypothyroidism, and steroid-dependent nephrotic syndrome. Both patients revealed consistent distinctive features, including upswept hair, narrow forehead, downslanting eyebrows, wide palpebral fissures, long nose, hypoplastic alae nasi, open mouth, and large ears. De novo KIAA2022 mutations (p.Q705X in Patient 1, p.R322X in Patient 2) were detected by targeted sequencing and confirmed by Sanger sequencing. KIAA2022 mutations and alterations have been reported in only four families with nonsyndromic ID and epilepsy. KIAA2022 is highly expressed in the fetal and adult brain and plays a crucial role in neuronal development. These additional patients support the evidence that KIAA2022 is a causative gene for XLID.

  11. Redefining the Pediatric Phenotype of X-Linked Monocarboxylate Transporter 8 (MCT8) Deficiency: Implications for Diagnosis and Therapies.

    PubMed

    Matheus, Maria Gisele; Lehman, Rebecca K; Bonilha, Leonardo; Holden, Kenton R

    2015-10-01

    X-linked monocarboxylate transporter 8 (MCT8) deficiency results from a loss-of-function mutation in the monocarboxylate transporter 8 gene, located on chromosome Xq13.2 (Allan-Herndon-Dudley syndrome). Affected boys present early in life with neurodevelopment delays but have pleasant dispositions and commonly have elevated serum triiodothyronine. They also have marked axial hypotonia and quadriparesis but surprisingly little spasticity early in their disease course. They do, however, have subtle involuntary movements, most often dystonia. The combination of hypotonia and dystonia presents a neurorehabilitation challenge and explains why spasticity-directed therapies have commonly produced suboptimal responses. Our aim was to better define the spectrum of motor disability and to elucidate the neuroanatomic basis of the motor impairments seen in MCT8 deficiency using clinical observation and brain magnetic resonance imaging (MRI) in a cohort of 6 affected pediatric patients. Our findings identified potential imaging biomarkers and suggest that rehabilitation efforts targeting dystonia may be more beneficial than those targeting spasticity in the prepubertal pediatric MCT8 deficiency population.

  12. Modeling lineage and phenotypic diversification in the New World monkey (Platyrrhini, Primates) radiation.

    PubMed

    Aristide, Leandro; Rosenberger, Alfred L; Tejedor, Marcelo F; Perez, S Ivan

    2015-01-01

    Adaptive radiations that have taken place in the distant past can now be more thoroughly studied with the availability of large molecular phylogenies and comparative data drawn from extant and fossil species. Platyrrhines are a good example of a major mammalian evolutionary radiation confined to a single continent, involving a relatively large temporal scale and documented by a relatively small but informative fossil record. Here, we present comparative evidence using data on extant and fossil species to explore alternative evolutionary models in an effort to better understand the process of platyrrhine lineage and phenotypic diversification. Specifically, we compare the likelihood of null models of lineage and phenotypic diversification versus various models of adaptive evolution. Moreover, we statistically explore the main ecological dimension behind the platyrrhine diversification. Contrary to the previous proposals, our study did not find evidence of a rapid lineage accumulation in the phylogenetic tree of extant platyrrhine species. However, the fossil-based diversity curve seems to show a slowdown in diversification rates toward present times. This also suggests an early high rate of extinction among lineages within crown Platyrrhini. Finally, our analyses support the hypothesis that the platyrrhine phenotypic diversification appears to be characterized by an early and profound differentiation in body size related to a multidimensional niche model, followed by little subsequent change (i.e., stasis).

  13. Model of Atmospheric Links on Optical Communications from High Altitude

    NASA Technical Reports Server (NTRS)

    Subich, Christopher

    2004-01-01

    Optical communication links have the potential to solve many of the problems of current radio and microwave links to satellites and high-altitude aircraft. The higher frequency involved in optical systems allows for significantly greater signal bandwidth, and thus information transfer rate, in excess of 10 Gbps, and the highly directional nature of laser-based signals eliminates the need for frequency-division multiplexing seen in radio and microwave links today. The atmosphere, however, distorts an optical signal differently than a microwave signal. While the ionosphere is one of the most significant sources of noise and distortion in a microwave or radio signal, the lower atmosphere affects an optical signal more significantly. Refractive index fluctuations, primarily caused by changes in atmospheric temperature and density, distort the incoming signal in both deterministic and nondeterministic ways. Additionally, suspended particles, such as those in haze or rain, further corrupt the transmitted signal. To model many of the atmospheric effects on the propagating beam, we use simulations based on the beam-propagation method. This method, developed both for simulation of signals in waveguides and propagation in atmospheric turbulence, separates the propagation into a diffraction and refraction problem. The diffraction step is an exact solution, within the limits of numerical precision, to the problem of propagation in free space, and the refraction step models the refractive index variances over a segment of the propagation path. By applying refraction for a segment of the propagation path, then diffracting over that same segment, this method forms a good approximation to true propagation through the atmospheric medium. Iterating over small segments of the total propagation path gives a good approximation to the problem of propagation over the entire path. Parameters in this model, such as initial beam profile and atmospheric constants, are easily modified in a

  14. Pharmacological HIF2α inhibition improves VHL disease-associated phenotypes in zebrafish model.

    PubMed

    Metelo, Ana Martins; Noonan, Haley R; Li, Xiang; Jin, Youngnam; Baker, Rania; Kamentsky, Lee; Zhang, Yiyun; van Rooijen, Ellen; Shin, Jordan; Carpenter, Anne E; Yeh, Jing-Ruey; Peterson, Randall T; Iliopoulos, Othon

    2015-05-01

    Patients with a germline mutation in von Hippel-Lindau (VHL) develop renal cell cancers and hypervascular tumors of the brain, adrenal glands, and pancreas as well as erythrocytosis. These phenotypes are driven by aberrant expression of HIF2α, which induces expression of genes involved in cell proliferation, angiogenesis, and red blood cell production. Currently, there are no effective treatments available for VHL disease. Here, using an animal model of VHL, we report a marked improvement of VHL-associated phenotypes following treatment with HIF2α inhibitors. Inactivation of vhl in zebrafish led to constitutive activation of HIF2α orthologs and modeled several aspects of the human disease, including erythrocytosis, pathologic angiogenesis in the brain and retina, and aberrant kidney and liver proliferation. Treatment of vhl(-/-) mutant embryos with HIF2α-specific inhibitors downregulated Hif target gene expression in a dose-dependent manner, improved abnormal hematopoiesis, and substantially suppressed erythrocytosis and angiogenic sprouting. Moreover, pharmacologic inhibition of HIF2α reversed the compromised cardiac contractility of vhl(-/-) embryos and partially rescued early lethality. This study demonstrates that small-molecule targeting of HIF2α improves VHL-related phenotypes in a vertebrate animal model and supports further exploration of this strategy for treating VHL disease.

  15. Pharmacological HIF2α inhibition improves VHL disease–associated phenotypes in zebrafish model

    PubMed Central

    Metelo, Ana Martins; Noonan, Haley R.; Li, Xiang; Jin, Youngnam; Baker, Rania; Kamentsky, Lee; Zhang, Yiyun; van Rooijen, Ellen; Shin, Jordan; Carpenter, Anne E.; Yeh, Jing-Ruey; Peterson, Randall T.; Iliopoulos, Othon

    2015-01-01

    Patients with a germline mutation in von Hippel-Lindau (VHL) develop renal cell cancers and hypervascular tumors of the brain, adrenal glands, and pancreas as well as erythrocytosis. These phenotypes are driven by aberrant expression of HIF2α, which induces expression of genes involved in cell proliferation, angiogenesis, and red blood cell production. Currently, there are no effective treatments available for VHL disease. Here, using an animal model of VHL, we report a marked improvement of VHL-associated phenotypes following treatment with HIF2α inhibitors. Inactivation of vhl in zebrafish led to constitutive activation of HIF2α orthologs and modeled several aspects of the human disease, including erythrocytosis, pathologic angiogenesis in the brain and retina, and aberrant kidney and liver proliferation. Treatment of vhl–/– mutant embryos with HIF2α-specific inhibitors downregulated Hif target gene expression in a dose-dependent manner, improved abnormal hematopoiesis, and substantially suppressed erythrocytosis and angiogenic sprouting. Moreover, pharmacologic inhibition of HIF2α reversed the compromised cardiac contractility of vhl–/– embryos and partially rescued early lethality. This study demonstrates that small-molecule targeting of HIF2α improves VHL-related phenotypes in a vertebrate animal model and supports further exploration of this strategy for treating VHL disease. PMID:25866969

  16. Generating Phenotypical Erroneous Human Behavior to Evaluate Human-automation Interaction Using Model Checking

    PubMed Central

    Bolton, Matthew L.; Bass, Ellen J.; Siminiceanu, Radu I.

    2012-01-01

    Breakdowns in complex systems often occur as a result of system elements interacting in unanticipated ways. In systems with human operators, human-automation interaction associated with both normative and erroneous human behavior can contribute to such failures. Model-driven design and analysis techniques provide engineers with formal methods tools and techniques capable of evaluating how human behavior can contribute to system failures. This paper presents a novel method for automatically generating task analytic models encompassing both normative and erroneous human behavior from normative task models. The generated erroneous behavior is capable of replicating Hollnagel’s zero-order phenotypes of erroneous action for omissions, jumps, repetitions, and intrusions. Multiple phenotypical acts can occur in sequence, thus allowing for the generation of higher order phenotypes. The task behavior model pattern capable of generating erroneous behavior can be integrated into a formal system model so that system safety properties can be formally verified with a model checker. This allows analysts to prove that a human-automation interactive system (as represented by the model) will or will not satisfy safety properties with both normative and generated erroneous human behavior. We present benchmarks related to the size of the statespace and verification time of models to show how the erroneous human behavior generation process scales. We demonstrate the method with a case study: the operation of a radiation therapy machine. A potential problem resulting from a generated erroneous human action is discovered. A design intervention is presented which prevents this problem from occurring. We discuss how our method could be used to evaluate larger applications and recommend future paths of development. PMID:23105914

  17. Microglial phenotypes in Parkinson's disease and animal models of the disease.

    PubMed

    Joers, Valerie; Tansey, Malú G; Mulas, Giovanna; Carta, Anna R

    2016-04-20

    Over the last decade the important concept has emerged that microglia, similar to other tissue macrophages, assume different phenotypes and serve several effector functions, generating the theory that activated microglia can be organized by their pro-inflammatory or anti-inflammatory and repairing functions. Importantly, microglia exist in a heterogenous population and their phenotypes are not permanently polarized into two categories; they exist along a continuum where they acquire different profiles based on their local environment. In Parkinson's disease (PD), neuroinflammation and microglia activation are considered neuropathological hallmarks, however their precise role in relation to disease progression is not clear, yet represent a critical challenge in the search of disease-modifying strategies. This review will critically address current knowledge on the activation states of microglia as well as microglial phenotypes found in PD and in animal models of PD, focusing on the expression of surface molecules as well as pro-inflammatory and anti-inflammatory cytokine production during the disease process. While human studies have reported an elevation of both pro- or anti-inflammatory markers in the serum and CSF of PD patients, animal models have provided insights on dynamic changes of microglia phenotypes in relation to disease progression especially prior to the development of motor deficits. We also review recent evidence of malfunction at multiple steps of NFκB signaling that may have a causal interrelationship with pathological microglia activation in animal models of PD. Finally, we discuss the immune-modifying strategies that have been explored regarding mechanisms of chronic microglial activation.

  18. MiR-21-5p Links Epithelial-Mesenchymal Transition Phenotype with Stem-Like Cell Signatures via AKT Signaling in Keloid Keratinocytes

    PubMed Central

    Yan, Li; Cao, Rui; Liu, YuanBo; Wang, LianZhao; Pan, Bo; Lv, XiaoYan; Jiao, Hu; Zhuang, Qiang; Sun, XueJian; Xiao, Ran

    2016-01-01

    Keloid is the abnormal wound healing puzzled by the aggressive growth and high recurrence rate due to its unrevealed key pathogenic mechanism. MicroRNAs contribute to a series of biological processes including epithelial-mesenchymal transition (EMT) and cells stemness involved in fibrotic disease. Here, using microRNAs microarray analysis we found mir-21-5p was significantly up-regulated in keloid epidermis. To investigate the role of miR-21-5p in keloid pathogenesis, we transfected miR-21-5p mimic or inhibitor in keloid keratinocytes and examined the abilities of cell proliferation, apoptosis, migration and invasion, the expressions of EMT-related markers vimentin and E-cadherin and stem-like cells-associated markers CD44 and ALDH1, and the involvement of PTEN and the signaling of AKT and ERK. Our results demonstrated that up-regulation or knockdown of miR-21-5p significantly increased or decreased the migration, invasion and sphere-forming abilities of keloid keratinocytes, and the phenotype of EMT and cells stemness were enhanced or reduced as well. Furthermore, PTEN and p-AKT were shown to participate in the regulation of miR-21-5p on EMT phenotypes and stemness signatures of keloid keratinocytes, which might account for the invasion and recurrence of keloids. This molecular mechanism of miR-21-5p on keloid keratinocytes linked EMT with cells stemness and implicated novel therapeutic targets for keloids. PMID:27596120

  19. Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance

    PubMed Central

    Kaiser, Frank J.; Ansari, Morad; Braunholz, Diana; Concepción Gil-Rodríguez, María; Decroos, Christophe; Wilde, Jonathan J.; Fincher, Christopher T.; Kaur, Maninder; Bando, Masashige; Amor, David J.; Atwal, Paldeep S.; Bahlo, Melanie; Bowman, Christine M.; Bradley, Jacquelyn J.; Brunner, Han G.; Clark, Dinah; Del Campo, Miguel; Di Donato, Nataliya; Diakumis, Peter; Dubbs, Holly; Dyment, David A.; Eckhold, Juliane; Ernst, Sarah; Ferreira, Jose C.; Francey, Lauren J.; Gehlken, Ulrike; Guillén-Navarro, Encarna; Gyftodimou, Yolanda; Hall, Bryan D.; Hennekam, Raoul; Hudgins, Louanne; Hullings, Melanie; Hunter, Jennifer M.; Yntema, Helger; Innes, A. Micheil; Kline, Antonie D.; Krumina, Zita; Lee, Hane; Leppig, Kathleen; Lynch, Sally Ann; Mallozzi, Mark B.; Mannini, Linda; Mckee, Shane; Mehta, Sarju G.; Micule, Ieva; Mohammed, Shehla; Moran, Ellen; Mortier, Geert R.; Moser, Joe-Ann S.; Noon, Sarah E.; Nozaki, Naohito; Nunes, Luis; Pappas, John G.; Penney, Lynette S.; Pérez-Aytés, Antonio; Petersen, Michael B.; Puisac, Beatriz; Revencu, Nicole; Roeder, Elizabeth; Saitta, Sulagna; Scheuerle, Angela E.; Schindeler, Karen L.; Siu, Victoria M.; Stark, Zornitza; Strom, Samuel P.; Thiese, Heidi; Vater, Inga; Willems, Patrick; Williamson, Kathleen; Wilson, Louise C.; Hakonarson, Hakon; Quintero-Rivera, Fabiola; Wierzba, Jolanta; Musio, Antonio; Gillessen-Kaesbach, Gabriele; Ramos, Feliciano J.; Jackson, Laird G.; Shirahige, Katsuhiko; Pié, Juan; Christianson, David W.; Krantz, Ian D.; Fitzpatrick, David R.; Deardorff, Matthew A.

    2014-01-01

    Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS. PMID:24403048

  20. The Linked Dual Representation model of vocal perception and production

    PubMed Central

    Hutchins, Sean; Moreno, Sylvain

    2013-01-01

    The voice is one of the most important media for communication, yet there is a wide range of abilities in both the perception and production of the voice. In this article, we review this range of abilities, focusing on pitch accuracy as a particularly informative case, and look at the factors underlying these abilities. Several classes of models have been posited describing the relationship between vocal perception and production, and we review the evidence for and against each class of model. We look at how the voice is different from other musical instruments and review evidence about both the association and the dissociation between vocal perception and production abilities. Finally, we introduce the Linked Dual Representation (LDR) model, a new approach which can account for the broad patterns in prior findings, including trends in the data which might seem to be countervailing. We discuss how this model interacts with higher-order cognition and examine its predictions about several aspects of vocal perception and production. PMID:24204360

  1. Using Model Organisms in an Undergraduate Laboratory to Link Genotype, Phenotype, and the Environment

    ERIC Educational Resources Information Center

    Jacobs-McDaniels, Nicole L.; Maine, Eleanor M.; Albertson, R. Craig; Wiles, Jason R.

    2013-01-01

    We developed laboratory exercises using zebrafish ("Danio rerio") and nematodes ("Caenorhabditis elegans") for a sophomore-level Integrative Biology Laboratory course. Students examined live wildtype zebrafish at different stages of development and noted shifts occurring in response to "fgf8a" deficiency. Students were introduced to development in…

  2. Ultrasonic vocalizations: a tool for behavioural phenotyping of mouse models of neurodevelopmental disorders

    PubMed Central

    Scattoni, Maria Luisa; Crawley, Jacqueline; Ricceri, Laura

    2009-01-01

    In neonatal mice ultrasonic vocalizations have been studied both as an early communicative behavior of the pup-mother dyad and as a sign of an aversive affective state. Adult mice of both sexes produce complex ultrasonic vocalization patterns in different experimental/social contexts. All these vocalizations are becoming an increasingly valuable assay for behavioral phenotyping throughout the mouse life-span and alterations of the ultrasound patterns have been reported in several mouse models of neurodevelopmental disorders. Here we also show that the modulation of vocalizations by maternal cues (maternal potentiation paradigm) – originally identified and investigated in rats - can be measured in C57Bl/6 mouse pups with appropriate modifications of the rat protocol and can likely be applied to mouse behavioral phenotyping. In addition we suggest that a detailed qualitative evaluation of neonatal calls together with analysis of adult mouse vocalization patterns in both sexes in social settings, may lead to a greater understanding of the communication value of vocalizations in mice. Importantly, both neonatal and adult USV altered patterns can be determined during the behavioural phenotyping of mouse models of human neurodevelopmental and neuropsychiatric disorders, starting from those in which deficits in communication are a primary symptom. PMID:18771687

  3. Age-dependent phenotypic characteristics of a triple transgenic mouse model of Alzheimer disease.

    PubMed

    Pietropaolo, Susanna; Feldon, Joram; Yee, Benjamin K

    2008-08-01

    The triple-transgenic mouse line (3 x Tg-AD) harboring PS1M146V, APPSwe, and taup301L transgenes represents the only transgenic model for Alzheimer's disease (AD) to date capturing both beta-amyloid and tau neuropathology. The present study provides an extensive behavioral characterization of the 3 x Tg-AD mouse line, evaluating the emergence of noncognitive and cognitive AD-like symptoms at two ages corresponding to the early (6-7 months) and advanced (12-13 months) stages of AD-pathology. Enhanced responsiveness to aversive stimulation was detected in mutant mice at both ages: the 3 x Tg-AD genotype enhanced acoustic startle response and facilitated performance in the cued-version of the water maze. These noncognitive phenotypes were accompanied by hyperactivity and reduced locomotor habituation in the open field at the older age. Signs of cognitive aberrations were also detected at both ages, but they were limited to associative learning. The present study suggests that this popular transgenic mouse model of AD has clear phenotypes beyond the cognitive domain, and their potential relationship to the cognitive phenotypes should be further explored.

  4. Relationship of childhood adversity and neighborhood violence to a proinflammatory phenotype in emerging adult African American men: An epigenetic link.

    PubMed

    Janusek, Linda Witek; Tell, Dina; Gaylord-Harden, Noni; Mathews, Herbert L

    2017-02-01

    African American men (AAM) who are exposed to trauma and adversity during their early life are at greater risk for poor health over their lifespan. Exposure to adversity during critical developmental windows may embed an epigenetic signature that alters expression of genes that regulate stress response systems, including those genes that regulate the inflammatory response to stress. Such an epigenetic signature may increase risk for diseases exacerbated by inflammation, and may contribute to health disparity. The purpose of this study was to evaluate the extent to which exposure to early life adversity influences the psychological, cortisol, and proinflammatory response to acute stress (Trier Social Stress Test - TSST) in emerging adult AAM, ages 18-25years (N=34). Hierarchical linear modeling was used to examine the cortisol and IL-6 pattern of response to the TSST with respect to childhood adversity factors and DNA methylation of the IL-6 promoter. Findings revealed that in response to the TSST, greater levels of childhood trauma and indirect exposure to neighborhood violence were associated with a greater TSST-induced IL-6 response, and a blunted cortisol response. Reduced methylation of the IL6 promoter was related to increased exposure to childhood trauma and greater TSST-induced IL-6 levels. These results support the concept that exposure to childhood adversity amplifies the adult proinflammatory response to stress, which is related to epigenetic signature.

  5. Effects of linking a soil-water-balance model with a groundwater-flow model

    USGS Publications Warehouse

    Stanton, Jennifer S.; Ryter, Derek W.; Peterson, Steven M.

    2013-01-01

    A previously published regional groundwater-flow model in north-central Nebraska was sequentially linked with the recently developed soil-water-balance (SWB) model to analyze effects to groundwater-flow model parameters and calibration results. The linked models provided a more detailed spatial and temporal distribution of simulated recharge based on hydrologic processes, improvement of simulated groundwater-level changes and base flows at specific sites in agricultural areas, and a physically based assessment of the relative magnitude of recharge for grassland, nonirrigated cropland, and irrigated cropland areas. Root-mean-squared (RMS) differences between the simulated and estimated or measured target values for the previously published model and linked models were relatively similar and did not improve for all types of calibration targets. However, without any adjustment to the SWB-generated recharge, the RMS difference between simulated and estimated base-flow target values for the groundwater-flow model was slightly smaller than for the previously published model, possibly indicating that the volume of recharge simulated by the SWB code was closer to actual hydrogeologic conditions than the previously published model provided. Groundwater-level and base-flow hydrographs showed that temporal patterns of simulated groundwater levels and base flows were more accurate for the linked models than for the previously published model at several sites, particularly in agricultural areas.

  6. Eco-evolutionary Model of Rapid Phenotypic Diversification in Species-Rich Communities.

    PubMed

    Villa Martín, Paula; Hidalgo, Jorge; Rubio de Casas, Rafael; Muñoz, Miguel A

    2016-10-01

    Evolutionary and ecosystem dynamics are often treated as different processes -operating at separate timescales- even if evidence reveals that rapid evolutionary changes can feed back into ecological interactions. A recent long-term field experiment has explicitly shown that communities of competing plant species can experience very fast phenotypic diversification, and that this gives rise to enhanced complementarity in resource exploitation and to enlarged ecosystem-level productivity. Here, we build on progress made in recent years in the integration of eco-evolutionary dynamics, and present a computational approach aimed at describing these empirical findings in detail. In particular we model a community of organisms of different but similar species evolving in time through mechanisms of birth, competition, sexual reproduction, descent with modification, and death. Based on simple rules, this model provides a rationalization for the emergence of rapid phenotypic diversification in species-rich communities. Furthermore, it also leads to non-trivial predictions about long-term phenotypic change and ecological interactions. Our results illustrate that the presence of highly specialized, non-competing species leads to very stable communities and reveals that phenotypically equivalent species occupying the same niche may emerge and coexist for very long times. Thus, the framework presented here provides a simple approach -complementing existing theories, but specifically devised to account for the specificities of the recent empirical findings for plant communities- to explain the collective emergence of diversification at a community level, and paves the way to further scrutinize the intimate entanglement of ecological and evolutionary processes, especially in species-rich communities.

  7. Eco-evolutionary Model of Rapid Phenotypic Diversification in Species-Rich Communities

    PubMed Central

    Villa Martín, Paula; Rubio de Casas, Rafael; Muñoz, Miguel A.

    2016-01-01

    Evolutionary and ecosystem dynamics are often treated as different processes –operating at separate timescales– even if evidence reveals that rapid evolutionary changes can feed back into ecological interactions. A recent long-term field experiment has explicitly shown that communities of competing plant species can experience very fast phenotypic diversification, and that this gives rise to enhanced complementarity in resource exploitation and to enlarged ecosystem-level productivity. Here, we build on progress made in recent years in the integration of eco-evolutionary dynamics, and present a computational approach aimed at describing these empirical findings in detail. In particular we model a community of organisms of different but similar species evolving in time through mechanisms of birth, competition, sexual reproduction, descent with modification, and death. Based on simple rules, this model provides a rationalization for the emergence of rapid phenotypic diversification in species-rich communities. Furthermore, it also leads to non-trivial predictions about long-term phenotypic change and ecological interactions. Our results illustrate that the presence of highly specialized, non-competing species leads to very stable communities and reveals that phenotypically equivalent species occupying the same niche may emerge and coexist for very long times. Thus, the framework presented here provides a simple approach –complementing existing theories, but specifically devised to account for the specificities of the recent empirical findings for plant communities– to explain the collective emergence of diversification at a community level, and paves the way to further scrutinize the intimate entanglement of ecological and evolutionary processes, especially in species-rich communities. PMID:27736874

  8. A large animal model of Spinal Muscular Atrophy and correction of phenotype

    PubMed Central

    Duque, Sandra I.; Arnold, W. David; Odermatt, Philipp; Li, Xiaohui; Porensky, Paul N.; Schmelzer, Leah; Meyer, Kathrin; Kolb, Stephen J.; Schümperli, Daniel; Kaspar, Brian K.; Burghes, Arthur H. M.

    2015-01-01

    Objectives Spinal muscular atrophy (SMA) is caused by reduced levels of SMN which results in motoneuron loss. Therapeutic strategies to increase SMN levels including drug compounds, antisense oligonucleotides or scAAV9 gene therapy have proved effective in mice. We wished to determine whether reduction of SMN in postnatal motoneurons resulted in SMA in a large animal model, whether SMA could be corrected after development of muscle weakness and the response of clinically relevant biomarkers. Methods Using intrathecal delivery of scAAV9 expressing a shRNA targeting pig SMN1, SMN was knocked down in motoneurons postnatally to SMA levels. This resulted in an SMA phenotype representing the first large animal model of SMA. Restoration of SMN was performed at different time points with scAAV9 expressing human SMN (scAAV9-SMN) and electrophysiology measures and pathology were performed. Results Knockdown of SMN in postnatal motoneurons results in overt proximal weakness, fibrillations on electromyography (EMG) indicating active denervation, and reduced compound muscle action potential (CMAP) and motor unit number estimates (MUNE), like human SMA. Neuropathology showed loss of motoneurons and motor axons. Pre-symptomatic delivery of scAAV9-SMN prevented SMA symptoms indicating all changes are SMN dependent. Delivery of scAAV9-SMN after symptom onset had a marked impact on phenotype, electrophysiological measures and pathology. Interpretation High SMN levels are critical in postnatal motoneurons and reduction of SMN results in a SMA phenotype which is SMN dependent. Importantly, clinically relevant biomarkers including CMAP and MUNE are responsive to SMN restoration and abrogation of phenotype can be achieved even after symptom onset. PMID:25516063

  9. Linking GIS and storm water modeling for emergency risk assessment

    SciTech Connect

    Newkirk, R.T.

    1995-12-31

    Many emergencies involve the deposition of chemical contaminants on land either as a direct event or as a secondary byproduct. GIS can be useful in estimating the initial deposition area. Chemical product attribute data bases can be accessed to determine the degree that the contaminants might be transportable in a water medium. An important issue is to estimate the potential impact of the deposition on surface and subsurface water flows. This particularly important since millions of people rely on subsurface ground water as their main source of potable water. Thus, a modeling system is needed by planners and emergency managers to assess the potential for short and long term risks to communities due to storm water transport of deposited contaminants. GIS itself cannot provide the complete analysis. A prototype system to assist in estimating the flows of contaminants related to an emergency has been developed by linking an Arc/Info database, Digital Terrain Model, and SWMM the storm water management modeling system. This system also has important planning applications in assessing alternative land development plans for their impact on ground water recharge and management of storm water.

  10. Linking Geomechanical Models with Observations of Microseismicity during CCS Operations

    NASA Astrophysics Data System (ADS)

    Verdon, J.; Kendall, J.; White, D.

    2012-12-01

    During CO2 injection for the purposes of carbon capture and storage (CCS), injection-induced fracturing of the overburden represents a key risk to storage integrity. Fractures in a caprock provide a pathway along which buoyant CO2 can rise and escape the storage zone. Therefore the ability to link field-scale geomechanical models with field geophysical observations is of paramount importance to guarantee secure CO2 storage. Accurate location of microseismic events identifies where brittle failure has occurred on fracture planes. This is a manifestation of the deformation induced by CO2 injection. As the pore pressure is increased during injection, effective stress is decreased, leading to inflation of the reservoir and deformation of surrounding rocks, which creates microseismicity. The deformation induced by injection can be simulated using finite-element mechanical models. Such a model can be used to predict when and where microseismicity is expected to occur. However, typical elements in a field scale mechanical models have decameter scales, while the rupture size for microseismic events are typically of the order of 1 square meter. This means that mapping modeled stress changes to predictions of microseismic activity can be challenging. Where larger scale faults have been identified, they can be included explicitly in the geomechanical model. Where movement is simulated along these discrete features, it can be assumed that microseismicity will occur. However, microseismic events typically occur on fracture networks that are too small to be simulated explicitly in a field-scale model. Therefore, the likelihood of microseismicity occurring must be estimated within a finite element that does not contain explicitly modeled discontinuities. This can be done in a number of ways, including the utilization of measures such as closeness on the stress state to predetermined failure criteria, either for planes with a defined orientation (the Mohr-Coulomb criteria) for

  11. A Model-Based Joint Identification of Differentially Expressed Genes and Phenotype-Associated Genes

    PubMed Central

    Seo, Minseok; Shin, Su-kyung; Kwon, Eun-Young; Kim, Sung-Eun; Bae, Yun-Jung; Lee, Seungyeoun; Sung, Mi-Kyung; Choi, Myung-Sook; Park, Taesung

    2016-01-01

    Over the last decade, many analytical methods and tools have been developed for microarray data. The detection of differentially expressed genes (DEGs) among different treatment groups is often a primary purpose of microarray data analysis. In addition, association studies investigating the relationship between genes and a phenotype of interest such as survival time are also popular in microarray data analysis. Phenotype association analysis provides a list of phenotype-associated genes (PAGs). However, it is sometimes necessary to identify genes that are both DEGs and PAGs. We consider the joint identification of DEGs and PAGs in microarray data analyses. The first approach we used was a naïve approach that detects DEGs and PAGs separately and then identifies the genes in an intersection of the list of PAGs and DEGs. The second approach we considered was a hierarchical approach that detects DEGs first and then chooses PAGs from among the DEGs or vice versa. In this study, we propose a new model-based approach for the joint identification of DEGs and PAGs. Unlike the previous two-step approaches, the proposed method identifies genes simultaneously that are DEGs and PAGs. This method uses standard regression models but adopts different null hypothesis from ordinary regression models, which allows us to perform joint identification in one-step. The proposed model-based methods were evaluated using experimental data and simulation studies. The proposed methods were used to analyze a microarray experiment in which the main interest lies in detecting genes that are both DEGs and PAGs, where DEGs are identified between two diet groups and PAGs are associated with four phenotypes reflecting the expression of leptin, adiponectin, insulin-like growth factor 1, and insulin. Model-based approaches provided a larger number of genes, which are both DEGs and PAGs, than other methods. Simulation studies showed that they have more power than other methods. Through analysis of

  12. Linking geophysics and soil function modelling - two examples

    NASA Astrophysics Data System (ADS)

    Krüger, J.; Franko, U.; Werban, U.; Dietrich, P.; Behrens, T.; Schmidt, K.; Fank, J.; Kroulik, M.

    2011-12-01

    iSOIL - "Interactions between soil related sciences - Linking geophysics, soil science and digital soil mapping" is a Collaborative Project (Grant Agreement number 211386) co-funded by the Research DG of the European Commission within the RTD activities of the FP7 Thematic Priority Environment. The iSOIL project aims at reliable mapping of soil properties and soil functions with various methods including geophysical, spectroscopic and monitoring techniques. The general procedure contains three steps (i) geophysical monitoring, (ii) generation of soil property maps and (iii) process modelling. The objective of this work is to demonstrate the methodological procedure on two different examples. Example A focuses on the turnover conditions for soil organic matter (SOM) since many soil functions in a direct or indirect way depend on SOM and SOM depletion is amongst the worst soil threats. Example B deals with the dynamics of soil water and the direct influence on crop biomass production. The applied CANDY model (Franko et al. 1995) was developed to describe dynamics of soil organic matter and mineral nitrogen as well as soil water and temperature. The new module PLUS extends CANDY to simulate crop biomass production based on environmental influences (Krüger et al. 2011). The methodological procedure of example A illustrates a model application for a field site in the Czech Republic using generated soil maps from combined geophysical data. Modelling requires a complete set of soil parameters. Combining measured soil properties and data of geophysical measurements (electrical conductivity and gamma spectrometry) is the basis for digital soil mapping which provided data about clay, silt and sand as well as SOC content. With these data pedotransfer functions produce detailed soil input data (e.g. bulk and particle density, field capacity, wilting point, saturated conductivity) for the rooted soil profile. CANDY calculated different indicators for SOM and gave hints about

  13. X-linked Charcot-Marie-Tooth (CMT) neuropathies (CMTX1, CMTX2, CMTX3) show different clinical phenotype and molecular genetics

    SciTech Connect

    Ionasescu, V.V.; Searby, C.C.; Ionasescu, R.

    1994-09-01

    The purpose of this study was to compare the X-linked dominant type CMTX1 (20 families) with X-linked recessive types CMTX2 and CMTX3 (2 families). The clinical phenotype was consistent with CMT peripheral neuropathy in all cases including distal weakness, atrophy and sensory loss, pes cavus and areflexia. Additional clinicial involvement of the central nervous system was present in one family with CMTX2 (mental retardation) and one family with CMTX3 (spastic paraparesis). Tight genetic linkage to Xq13.1 was present in 20 families with CMTX1 (Z=34.07 at {theta}=0) for the marker DXS453. Fifteen of the CMTX1 families showed point mutations of the connexin 32 coding region (5 nonsense mutations, 8 missense mutations, 2 deletions). Five CMTX1 neuropathy families showed no evidence of point mutations of the CX32 coding sequence. These findings suggest that the CMTX1 neuropathy genotype in these families may be the result of promoter mutations, 3{prime}-untranslated region mutations or exon/intron splice site mutations or a mutation with a different type of connexin but which has close structural similarities to CX32. No mutations of the CX32 coding region were found in the CMTX2 or CMTX3 families. Linkage to Xq13.1 was excluded in both families. Genetic linkage to Xp22.2 was present in the CMTX2 family (Z=3.54 at {theta}=0) for the markers DXS987 and DXS999. Suggestion of linkage to Xq26 (Z=1.81 at {theta}=0) for the marker DXS86 was present in the CMTX3 family.

  14. Linking genes to communities and ecosystems: Daphnia as an ecogenomic model.

    PubMed

    Miner, Brooks E; De Meester, Luc; Pfrender, Michael E; Lampert, Winfried; Hairston, Nelson G

    2012-05-22

    How do genetic variation and evolutionary change in critical species affect the composition and functioning of populations, communities and ecosystems? Illuminating the links in the causal chain from genes up to ecosystems is a particularly exciting prospect now that the feedbacks between ecological and evolutionary changes are known to be bidirectional. Yet to fully explore phenomena that span multiple levels of the biological hierarchy requires model organisms and systems that feature a comprehensive triad of strong ecological interactions in nature, experimental tractability in diverse contexts and accessibility to modern genomic tools. The water flea Daphnia satisfies these criteria, and genomic approaches capitalizing on the pivotal role Daphnia plays in the functioning of pelagic freshwater food webs will enable investigations of eco-evolutionary dynamics in unprecedented detail. Because its ecology is profoundly influenced by both genetic polymorphism and phenotypic plasticity, Daphnia represents a model system with tremendous potential for developing a mechanistic understanding of the relationship between traits at the genetic, organismal and population levels, and consequences for community and ecosystem dynamics. Here, we highlight the combination of traits and ecological interactions that make Daphnia a definitive model system, focusing on the additional power and capabilities enabled by recent molecular and genomic advances.

  15. The central nervous system phenotype of X-linked Charcot-Marie-Tooth disease: a transient disorder of children and young adults.

    PubMed

    Al-Mateen, Majeed; Craig, Alexa Kanwit; Chance, Phillip F

    2014-03-01

    We describe 2 patients with X-linked Charcot-Marie-Tooth disease, type 1 (CMTX1) disease and central nervous system manifestations and review 19 cases from the literature. Our first case had not been previously diagnosed with Charcot-Marie-Tooth disease, and the second case, although known to have Charcot-Marie-Tooth disease, was suspected of having CMTX1 after presentation with central nervous system manifestations. The most common central nervous system manifestations were transient and included dysarthria, ataxia, hemiparesis, and tetraparesis resembling periodic paralysis. Of the 21 patients, 19 presented at 21 years of age or younger, implicating CMTX1 with transient central nervous system manifestations as a disorder that predominantly affects children and adolescents. CMTX1 should be included in the differential diagnosis of patients who present with transient central nervous system phenomena, including stroke-like episodes, tetraparesis suggestive of periodic paralysis, dysarthria, ataxia, or combinations of these deficits. Reversible, bilateral, nonenhancing white matter lesions and restricted diffusion on magnetic resonance imaging are characteristic features of the central nervous system phenotype of CMTX1.

  16. Immune response phenotype of allergic versus clinically tolerant pigs in a neonatal swine model of allergy.

    PubMed

    Schmied, Julie; Rupa, Prithy; Garvie, Sarah; Wilkie, Bruce

    2013-07-15

    The prevalence of childhood food allergy and the duration of these allergies, particularly those considered to be transient, like egg and milk allergy, are increasing. The identification of allergic individuals using minimally invasive, non-anaphylaxis-threatening methods is therefore of increasing importance. In this experiment, correlates were sought of an allergic immune response (IR) phenotype in pigs. Using pigs pre-treated with heat-killed bacteria or bacterial components before allergic sensitization with the egg white protein ovomucoid (Ovm), differences were determined in IR phenotype of pigs in the categories treated-allergic, treated-tolerant, control-allergic (CA) and control-tolerant. Phenotype was established by measuring immunoglobulin (Ig)-associated antibody activity (AbA), cytokine profiles and the proportion of blood T-regulatory cells (T-regs) and observing late-phase allergen-specific skin tests (ST). Although 100% of pigs became sensitized to Ovm, only 33% of pigs had clinical signs of allergy after oral challenge with egg white. Pigs without clinical signs were classified as clinically tolerant. Sixty-seven percent of allergic pigs had a positive, late-phase ST classified as very strong or strong, while 84% of clinically tolerant pigs did not have late-phase ST. Treated-allergic pigs and CA pigs had greater total antibody IgG (H+L), IgE and IgG1 AbA than clinically tolerant pigs. Cytokine profiles of allergic pigs and the proportion of circulating T-regs, did not differ significantly between allergic and clinically tolerant pigs. Therefore, measurement of allergen-specific IgG, IgG1 and/or IgE activity and evaluation of late-phase ID ST may be useful in identifying allergic IR phenotypes in swine models of food allergy, which may be extended toward human use.

  17. Implementation of a vibrationally linked chemical reaction model for DSMC

    NASA Technical Reports Server (NTRS)

    Carlson, A. B.; Bird, Graeme A.

    1994-01-01

    A new procedure closely linking dissociation and exchange reactions in air to the vibrational levels of the diatomic molecules has been implemented in both one- and two-dimensional versions of Direct Simulation Monte Carlo (DSMC) programs. The previous modeling of chemical reactions with DSMC was based on the continuum reaction rates for the various possible reactions. The new method is more closely related to the actual physics of dissociation and is more appropriate to the particle nature of DSMC. Two cases are presented: the relaxation to equilibrium of undissociated air initially at 10,000 K, and the axisymmetric calculation of shuttle forebody heating during reentry at 92.35 km and 7500 m/s. Although reaction rates are not used in determining the dissociations or exchange reactions, the new method produces rates which agree astonishingly well with the published rates derived from experiment. The results for gas properties and surface properties also agree well with the results produced by earlier DSMC models, equilibrium air calculations, and experiment.

  18. Linking Geomagentic Data to Dynamo Models via Variational Data Assimilation

    NASA Astrophysics Data System (ADS)

    Dimitrova, L. L.; Egbert, G. D.; Kuang, W.; Jiang, W.; Tangborn, A.

    2011-12-01

    The increased resolution and accuracy of both the geomagnetic field models and observations in recent years has resulted in increased efforts to link theory to data via data assimilation (DA) techniques similar to those previously developed in the atmospheric and oceanic communities . If applied to the geomagnetic field, DA has potential to improve both models and observations: geodynamics models can be assessed and improved based on observational constraints to better understand the physics of the core dynamics; the improved models can then be used to (1)constrain "hidden" components of the state of the geodynamo that are not directly observable, (2)more accurately forecast the geomagnetic fields and (3) hindcast and improve past geomagnetic field models. DA methods can be broadly divided into two approaches: sequential and variational. In sequential DA, observations are combined with the current model state to produce a new state estimate, which is then used as the initial state for the next model forecast. As such, sequential DA leads to discontinuous model state, and observations can influence only the future model state. Variational DA differs from sequential DA in that the goal is a global adjustment of the model trajectory to fit simultaneously all the data. Thus in the variational approach, observations at a later time could influence the model solution at an earlier time. Both sequential and variational DA has been applied to simplified dynamic models (e.g.Sun et al. [2007], Fournier et al. [2007]), and sequential DA has been applied to full dynamo models (e.g. Liu et al. [2007], Kuang et al. [2008]). However, since the best data is from recent years, sequential schemes can't readily project this data backwards in time. We present an update to our ongoing efforts to implement modern variational DA methods (based on theory of representers, potentially allowing for weak constraint DA) for the Modular Scalable Self-consistent Three-dimensional (Mo

  19. Exosomes from adipose-derived stem cells ameliorate phenotype of Huntington's disease in vitro model.

    PubMed

    Lee, Mijung; Liu, Tian; Im, Wooseok; Kim, Manho

    2016-08-01

    Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by the aggregation of mutant Huntingtin (mHtt). Adipose-derived stem cells (ASCs) have a potential for use in the treatment of incurable disorders, including HD. ASCs secrete various neurotrophic factors and microvesicles, and modulate hostile microenvironments affected by disease through paracrine mechanisms. Exosomes are small vesicles that transport nucleic acid and protein between cells. Here, we investigated the therapeutic role of exosomes from ASCs (ASC-exo) using in vitro HD model by examining pathological phenotypes of this model. Immunocytochemistry result showed that ASC-exo significantly decreases mHtt aggregates in R6/2 mice-derived neuronal cells. Western blot result further confirmed the reduction in mHtt aggregates level by ASC-exo treatment. ASC-exo up-regulates PGC-1, phospho-CREB and ameliorates abnormal apoptotic protein level in an in vitro HD model. In addition, MitoSOX Red, JC-1 and cell viability assay showed that ASC-exo reduces mitochondrial dysfunction and cell apoptosis of in vitro HD model. These findings suggest that ASC-exo has a therapeutic potential for treating HD by modulating representative cellular phenotypes of HD.

  20. A communications model for an ISAS to NASA span link

    NASA Technical Reports Server (NTRS)

    Green, James L.; Mcguire, Robert E.; Lopez-Swafford, Brian

    1987-01-01

    The authors propose that an initial computer-to-computer communication link use the public packet switched networks (PPSN) Venus-P in Japan and TELENET in the U.S. When the traffic warrants it, this link would then be upgraded to a dedicated leased line that directly connects into the Space Physics Analysis Network (SPAN). The proposed system of hardware and software will easily support migration to such a dedicated link. It therefore provides a cost effective approach to the network problem. Once a dedicated line becomes operation it is suggested that the public networks link and continue to coexist, providing a backup capability.

  1. FSO and radio link attenuation: meteorological models verified by experiment

    NASA Astrophysics Data System (ADS)

    Brazda, Vladimir; Fiser, Ondrej; Svoboda, Jaroslav

    2011-09-01

    Institute of Atmospheric Physics of Czech Academy measures atmospheric attenuation on 60 m experimental FSO link on 830 and 1550 nm for more than three years. Visibility sensors and two 3D sonic anemometers on both transmitting and receiving site, rain gauge and many sensors enabling the refractivity index computation are spaced along the optical link. Meteorological visibility, wind turbulent energy, sonic temperature, structure index and rain rate are correlated with measured attenuation. FSO link attenuation dependence on the above mentioned parameters is analyzed. The paper shows also basic statistical behavior of the long-term FSO signal level and also the simulation of hybrid link techniques.

  2. A phenotypic in vitro model for the main determinants of human whole heart function

    PubMed Central

    Stancescu, Maria; Molnar, Peter; McAleer, Christopher W.; McLamb, William; Long, Christopher J.; Oleaga, Carlota; Prot, Jean-Matthieu; Hickman, James J.

    2015-01-01

    This article details the construction and testing of a phenotypic assay system that models in vivo cardiac function in a parallel in vitro environment with human stem cell derived cardiomyocytes. The major determinants of human whole-heart function were experimentally modeled by integrating separate 2D cellular systems with BioMicroelectromechanical Systems (BioMEMS) constructs. The model featured a serum-free defined medium to enable both acute and chronic evaluation of drugs and toxins. The integration of data from both systems produced biologically relevant predictions of cardiac function in response to varying concentrations of selected drugs. Sotalol, norepinephrine and verapamil were shown to affect the measured parameters according to their specific mechanism of action, in agreement with clinical data. This system is applicable for cardiac side effect assessment, general toxicology, efficacy studies, and evaluation of in vitro cellular disease models in body-on-a-chip systems. PMID:25978005

  3. Qualitative Dynamical Modelling Can Formally Explain Mesoderm Specification and Predict Novel Developmental Phenotypes

    PubMed Central

    Gustafson, E. Hilary; Ciglar, Lucia; Junion, Guillaume; Gonzalez, Aitor; Girardot, Charles; Perrin, Laurent; Furlong, Eileen E. M.; Thieffry, Denis

    2016-01-01

    Given the complexity of developmental networks, it is often difficult to predict the effect of genetic perturbations, even within coding genes. Regulatory factors generally have pleiotropic effects, exhibit partially redundant roles, and regulate highly interconnected pathways with ample cross-talk. Here, we delineate a logical model encompassing 48 components and 82 regulatory interactions involved in mesoderm specification during Drosophila development, thereby providing a formal integration of all available genetic information from the literature. The four main tissues derived from mesoderm correspond to alternative stable states. We demonstrate that the model can predict known mutant phenotypes and use it to systematically predict the effects of over 300 new, often non-intuitive, loss- and gain-of-function mutations, and combinations thereof. We further validated several novel predictions experimentally, thereby demonstrating the robustness of model. Logical modelling can thus contribute to formally explain and predict regulatory outcomes underlying cell fate decisions. PMID:27599298

  4. A phenotypic in vitro model for the main determinants of human whole heart function.

    PubMed

    Stancescu, Maria; Molnar, Peter; McAleer, Christopher W; McLamb, William; Long, Christopher J; Oleaga, Carlota; Prot, Jean-Matthieu; Hickman, James J

    2015-08-01

    This article details the construction and testing of a phenotypic assay system that models in vivo cardiac function in a parallel in vitro environment with human stem cell derived cardiomyocytes. The major determinants of human whole-heart function were experimentally modeled by integrating separate 2D cellular systems with BioMicroelectromechanical Systems (BioMEMS) constructs. The model features a serum-free defined medium to enable both acute and chronic evaluation of drugs and toxins. The integration of data from both systems produced biologically relevant predictions of cardiac function in response to varying concentrations of selected drugs. Sotalol, norepinephrine and verapamil were shown to affect the measured parameters according to their specific mechanism of action, in agreement with clinical data. This system is applicable for cardiac side effect assessment, general toxicology, efficacy studies, and evaluation of in vitro cellular disease models in body-on-a-chip systems.

  5. Relationship between the monosomy X phenotype and Y-linked ribosomal protein S4 (Rps4) in several species of mammals: A molecular evolutionary analysis of Rps4 homologs

    SciTech Connect

    Omoe, Katsuhiko; Endo, Akira

    1996-01-01

    Two isoforms of the human ribosomal protein S4 gene, RPS4X and RPS4Y, are located on the X and Y chromsomes. It has been postulated and haploinsufficiency of these genes may contribute to Turner syndrome. We show here that several animal species that show the Turner-like phenotype on monosomy X have no Y-linked Rps4 homolog. There may be another gene(s) that contributes to abnormal phenotypes of monosomy X. Molecular evolutionary analysis shows that the Y-linked and RPS4X-related homologs diverged prior to the radiation of placental mammals and evolved independently. Furthermore, the functional constraints against the RPS4X-related homologs are much stronger than those against the Y-linked homologs. 37 refs., 3 figs., 1 tab.

  6. Assessment of ataxia phenotype in a new mouse model of galactose-1 phosphate uridylyltransferase (GALT) deficiency.

    PubMed

    Chen, Wyman; Caston, Rose; Balakrishnan, Bijina; Siddiqi, Anwer; Parmar, Kamalpreet; Tang, Manshu; Feng, Merry; Lai, Kent

    2017-01-01

    Despite adequate dietary management, patients with classic galactosemia continue to have increased risks of cognitive deficits, speech dyspraxia, primary ovarian insufficiency, and abnormal motor development. A recent evaluation of a new galactose-1 phosphate uridylyltransferase (GALT)-deficient mouse model revealed reduced fertility and growth restriction. These phenotypes resemble those seen in human patients. In this study, we further assess the fidelity of this new mouse model by examining the animals for the manifestation of a common neurological sequela in human patients: cerebellar ataxia. The balance, grip strength, and motor coordination of GALT-deficient and wild-type mice were tested using a modified rotarod. The results were compared to composite phenotype scoring tests, typically used to evaluate neurological and motor impairment. The data demonstrated abnormalities with varying severity in the GALT-deficient mice. Mice of different ages were used to reveal the progressive nature of motor impairment. The varying severity and age-dependent impairments seen in the animal model agree with reports on human patients. Finally, measurements of the cerebellar granular and molecular layers suggested that mutant mice experience cerebellar hypoplasia, which could have resulted from the down-regulation of the PI3K/Akt signaling pathway.

  7. Time series modeling of live-cell shape dynamics for image-based phenotypic profiling.

    PubMed

    Gordonov, Simon; Hwang, Mun Kyung; Wells, Alan; Gertler, Frank B; Lauffenburger, Douglas A; Bathe, Mark

    2016-01-01

    Live-cell imaging can be used to capture spatio-temporal aspects of cellular responses that are not accessible to fixed-cell imaging. As the use of live-cell imaging continues to increase, new computational procedures are needed to characterize and classify the temporal dynamics of individual cells. For this purpose, here we present the general experimental-computational framework SAPHIRE (Stochastic Annotation of Phenotypic Individual-cell Responses) to characterize phenotypic cellular responses from time series imaging datasets. Hidden Markov modeling is used to infer and annotate morphological state and state-switching properties from image-derived cell shape measurements. Time series modeling is performed on each cell individually, making the approach broadly useful for analyzing asynchronous cell populations. Two-color fluorescent cells simultaneously expressing actin and nuclear reporters enabled us to profile temporal changes in cell shape following pharmacological inhibition of cytoskeleton-regulatory signaling pathways. Results are compared with existing approaches conventionally applied to fixed-cell imaging datasets, and indicate that time series modeling captures heterogeneous dynamic cellular responses that can improve drug classification and offer additional important insight into mechanisms of drug action. The software is available at http://saphire-hcs.org.

  8. From stem cells to bone: phenotype acquisition, stabilization, and tissue engineering in animal models.

    PubMed

    Gordeladze, Jan O; Reseland, Janne E; Duroux-Richard, Isabelle; Apparailly, Florence; Jorgensen, Christian

    2009-01-01

    The regeneration of bone tissue depends on the concerted actions of a plethora of signals that recruit mesenchymal stem cells for lineage-specific differentiation, with cellular phenotypes serving various functions throughout their life span. The signals are conveyed in hormones, growth factors, and mechanical forces, all of which ensure proper modeling and remodeling. Both processes are secured by indigenous and programmed metabolism in osteoblasts/osteocytes as well as in other stem cell (SC)-derived cell types (e.g., osteoclasts, bone lining cells) involved in the remodeling of the subject tissue. The focus of this review is the concerted action of these signals as well as the regulatory and/or stabilizing control circuits exhibited by a class of small RNAs, designated microRNAs. We discuss an in vitro approach for ensuring proper phenotype acquisition as well as the choice of scaffolds and animal models for in vivo tissue repair. This approach includes selection of SC niches to optimize bone formation in vivo, transcription factors important for osteoblastogenesis, the Wnt and Notch pathways of signaling, selection of delivery systems for gene therapy, use of appropriate matrices and scaffolds, in vivo mechanostimulation, choice of lesions to be repaired, and type of animal to use. We also discuss Wnt-related and SC-based treatment of osteoporosis. Throughout, we offer considerations for the selection of model systems and parameters to assess the entire procedure from initial SC selection to final bone repair, and conclude with a table summarizing our recommendations.

  9. A cell-based model system links chromothripsis with hyperploidy

    PubMed Central

    Mardin, Balca R; Drainas, Alexandros P; Waszak, Sebastian M; Weischenfeldt, Joachim; Isokane, Mayumi; Stütz, Adrian M; Raeder, Benjamin; Efthymiopoulos, Theocharis; Buccitelli, Christopher; Segura-Wang, Maia; Northcott, Paul; Pfister, Stefan M; Lichter, Peter; Ellenberg, Jan; Korbel, Jan O

    2015-01-01

    A remarkable observation emerging from recent cancer genome analyses is the identification of chromothripsis as a one-off genomic catastrophe, resulting in massive somatic DNA structural rearrangements (SRs). Largely due to lack of suitable model systems, the mechanistic basis of chromothripsis has remained elusive. We developed an integrative method termed “complex alterations after selection and transformation (CAST),” enabling efficient in vitro generation of complex DNA rearrangements including chromothripsis, using cell perturbations coupled with a strong selection barrier followed by massively parallel sequencing. We employed this methodology to characterize catastrophic SR formation processes, their temporal sequence, and their impact on gene expression and cell division. Our in vitro system uncovered a propensity of chromothripsis to occur in cells with damaged telomeres, and in particular in hyperploid cells. Analysis of primary medulloblastoma cancer genomes verified the link between hyperploidy and chromothripsis in vivo. CAST provides the foundation for mechanistic dissection of complex DNA rearrangement processes. PMID:26415501

  10. Optical coherence tomography for live phenotypic analysis of embryonic ocular structures in mouse models

    NASA Astrophysics Data System (ADS)

    Larina, Irina V.; Syed, Saba H.; Sudheendran, Narendran; Overbeek, Paul A.; Dickinson, Mary E.; Larin, Kirill V.

    2012-08-01

    Mouse models of ocular diseases provide a powerful resource for exploration of molecular regulation of eye development and pre-clinical studies. Availability of a live high-resolution imaging method for mouse embryonic eyes would significantly enhance longitudinal analyses and high-throughput morphological screening. We demonstrate that optical coherence tomography (OCT) can be used for live embryonic ocular imaging throughout gestation. At all studied stages, the whole eye is within the imaging distance of the system and there is a good optical contrast between the structures. We also performed OCT eye imaging in the embryonic retinoblastoma mouse model Pax6-SV40 T-antigen, which spontaneously forms lens and retinal lesions, and demonstrate that OCT allows us to clearly differentiate between the mutant and wild type phenotypes. These results demonstrate that OCTin utero imaging is a potentially useful tool to study embryonic ocular diseases in mouse models.

  11. Linking the M&Rfi Weather Generator with Agrometeorological Models

    NASA Astrophysics Data System (ADS)

    Dubrovsky, Martin; Trnka, Miroslav

    2015-04-01

    Realistic meteorological inputs (representing the present and/or future climates) for the agrometeorological model simulations are often produced by stochastic weather generators (WGs). This contribution presents some methodological issues and results obtained in our recent experiments. We also address selected questions raised in the synopsis of this session. The input meteorological time series for our experiments are produced by the parametric single site weather generator (WG) Marfi, which is calibrated from the available observational data (or interpolated from surrounding stations). To produce meteorological series representing the future climate, the WG parameters are modified by climate change scenarios, which are prepared by the pattern scaling method: the standardised scenarios derived from Global or Regional Climate Models are multiplied by the change in global mean temperature (ΔTG) determined by the simple climate model MAGICC. The presentation will address following questions: (i) The dependence of the quality of the synthetic weather series and impact results on the WG settings. An emphasis will be put on an effect of conditioning the daily WG on monthly WG (presently being one of our hot topics), which aims at improvement of the reproduction of the low-frequency weather variability. Comparison of results obtained with various WG settings is made in terms of climatic and agroclimatic indices (including extreme temperature and precipitation characteristics and drought indices). (ii) Our methodology accounts for the uncertainties coming from various sources. We will show how the climate change impact results are affected by 1. uncertainty in climate modelling, 2. uncertainty in ΔTG, and 3. uncertainty related to the complexity of the climate change scenario (focusing on an effect of inclusion of changes in variability into the climate change scenarios). Acknowledgements: This study was funded by project "Building up a multidisciplinary scientific

  12. Toward a nonhuman primate model of fetal programming: phenotypic plasticity of the common marmoset fetoplacental complex.

    PubMed

    Rutherford, Julienne N

    2012-11-01

    Nonhuman primates offer unique opportunities as animal models in the study of developmental programming and the role of the placenta in developmental processes. All primates share fundamental similarities in life history and reproductive biology. Thus, insights gleaned from studies of nonhuman primates have a higher degree of biological salience to human biology than do studies of rodents or agricultural animals. The common marmoset monkey is a small-bodied primate from South America that produces litters of dizygotic fetuses that share a single placental mass. This natural variation allows us to model different intrauterine conditions and associated fetoplacental phenotypes. The marmoset placenta is phenotypically plastic according to litter size. Triplet litters are characterized by low individual fetal weights and significantly more efficient placentas and attendant alterations to the microscopic architecture and endocrine function, thus modeling a nutrient restricted intrauterine environment. Consistent with this model, triplet neonates experience a higher risk of perinatal mortality and an increased likelihood of elevated adult weight. Recent evidence has shown that the intrauterine experience of females has an impact on their own pregnancy outcomes in adulthood: triplet females experience significantly greater pregnancy loss than do twin females. The marmoset monkey thus represents a potential powerful nonhuman primate model of multiple pregnancies, restrictive prenatal experiences, and differential reproductive outcomes in adulthood, which may have important implications for studying the impact of in vitro fertilization on adult reproductive health. It is still too early to determine exactly what developmental pathways lead to this disparity or what specific role the placenta plays; future work on this front will be critical to establish the marmoset as an important model of fetal programming of reproductive function in adulthood and across generations.

  13. Sex differences in mania phenotype and ethanol consumption in the lateral hypothalamic kindled rat model

    PubMed Central

    Abulseoud, O A; Gawad, N A; Mohamed, K; Vadnie, C; Camsari, U M; Karpyak, V; Frye, M A; Choi, D-S

    2015-01-01

    Sex differences have been observed in mania phenotypes in humans. However the mechanisms underlying this difference are poorly understood. Activating the lateral hypothalamus is implicated in manic-like behaviors in rodents. Using newly established lateral hypothalamus kindled (LHK) rat mania model, we investigated sex differences of manic-like behaviors and its correlation with voluntary ethanol intake. We stimulated the lateral hypothalamus bilaterally in the male and female Wistar rats over five consecutive days. We recorded and quantified kindling-induced behaviors for each individual animal. We also assessed ethanol consumption using a two-bottle choice ethanol drinking as well as circadian locomotor activity counts daily throughout the experiment. We found notable sex differences in several aspects of manic-like behaviors during kindling. Males exhibited a significantly increased locomotor activity during the light phase, and reduced rest interval. On the other hand, females displayed significantly higher ethanol consumption and more frequent rearing behavior. However, no sex differences were present in the duration of sexual, feeding or grooming behaviors or in dark-phase activity counts. The excessive alcohol intake in LHK female rats is reminiscent of clinically reported sex differences in bipolar patients while the other phenotypic sex differences such as rearing and locomotor activity are less clearly described in clinical studies. Overall, our results lend further evidence for the validity of the LHK rat as a useful model to study brain region-specific molecular changes during mania and its correlation with alcohol use disorders. PMID:25803497

  14. Plant Phenotyping using Probabilistic Topic Models: Uncovering the Hyperspectral Language of Plants.

    PubMed

    Wahabzada, Mirwaes; Mahlein, Anne-Katrin; Bauckhage, Christian; Steiner, Ulrike; Oerke, Erich-Christian; Kersting, Kristian

    2016-03-09

    Modern phenotyping and plant disease detection methods, based on optical sensors and information technology, provide promising approaches to plant research and precision farming. In particular, hyperspectral imaging have been found to reveal physiological and structural characteristics in plants and to allow for tracking physiological dynamics due to environmental effects. In this work, we present an approach to plant phenotyping that integrates non-invasive sensors, computer vision, as well as data mining techniques and allows for monitoring how plants respond to stress. To uncover latent hyperspectral characteristics of diseased plants reliably and in an easy-to-understand way, we "wordify" the hyperspectral images, i.e., we turn the images into a corpus of text documents. Then, we apply probabilistic topic models, a well-established natural language processing technique that identifies content and topics of documents. Based on recent regularized topic models, we demonstrate that one can track automatically the development of three foliar diseases of barley. We also present a visualization of the topics that provides plant scientists an intuitive tool for hyperspectral imaging. In short, our analysis and visualization of characteristic topics found during symptom development and disease progress reveal the hyperspectral language of plant diseases.

  15. Plant Phenotyping using Probabilistic Topic Models: Uncovering the Hyperspectral Language of Plants

    PubMed Central

    Wahabzada, Mirwaes; Mahlein, Anne-Katrin; Bauckhage, Christian; Steiner, Ulrike; Oerke, Erich-Christian; Kersting, Kristian

    2016-01-01

    Modern phenotyping and plant disease detection methods, based on optical sensors and information technology, provide promising approaches to plant research and precision farming. In particular, hyperspectral imaging have been found to reveal physiological and structural characteristics in plants and to allow for tracking physiological dynamics due to environmental effects. In this work, we present an approach to plant phenotyping that integrates non-invasive sensors, computer vision, as well as data mining techniques and allows for monitoring how plants respond to stress. To uncover latent hyperspectral characteristics of diseased plants reliably and in an easy-to-understand way, we “wordify” the hyperspectral images, i.e., we turn the images into a corpus of text documents. Then, we apply probabilistic topic models, a well-established natural language processing technique that identifies content and topics of documents. Based on recent regularized topic models, we demonstrate that one can track automatically the development of three foliar diseases of barley. We also present a visualization of the topics that provides plant scientists an intuitive tool for hyperspectral imaging. In short, our analysis and visualization of characteristic topics found during symptom development and disease progress reveal the hyperspectral language of plant diseases. PMID:26957018

  16. Disease phenotype of a ferret CFTR-knockout model of cystic fibrosis

    PubMed Central

    Sun, Xingshen; Sui, Hongshu; Fisher, John T.; Yan, Ziying; Liu, Xiaoming; Cho, Hyung-Ju; Joo, Nam Soo; Zhang, Yulong; Zhou, Weihong; Yi, Yaling; Kinyon, Joann M.; Lei-Butters, Diana C.; Griffin, Michelle A.; Naumann, Paul; Luo, Meihui; Ascher, Jill; Wang, Kai; Frana, Timothy; Wine, Jeffrey J.; Meyerholz, David K.; Engelhardt, John F.

    2010-01-01

    Cystic fibrosis (CF) is a recessive disease that affects multiple organs. It is caused by mutations in CFTR. Animal modeling of this disease has been challenging, with species- and strain-specific differences in organ biology and CFTR function influencing the emergence of disease pathology. Here, we report the phenotype of a CFTR-knockout ferret model of CF. Neonatal CFTR-knockout ferrets demonstrated many of the characteristics of human CF disease, including defective airway chloride transport and submucosal gland fluid secretion; variably penetrant meconium ileus (MI); pancreatic, liver, and vas deferens disease; and a predisposition to lung infection in the early postnatal period. Severe malabsorption by the gastrointestinal (GI) tract was the primary cause of death in CFTR-knockout kits that escaped MI. Elevated liver function tests in CFTR-knockout kits were corrected by oral administration of ursodeoxycholic acid, and the addition of an oral proton-pump inhibitor improved weight gain and survival. To overcome the limitations imposed by the severe intestinal phenotype, we cloned 4 gut-corrected transgenic CFTR-knockout kits that expressed ferret CFTR specifically in the intestine. One clone passed feces normally and demonstrated no detectable ferret CFTR expression in the lung or liver. The animals described in this study are likely to be useful tools for dissecting CF disease pathogenesis and developing treatments. PMID:20739752

  17. Predicting the functional, molecular, and phenotypic consequences of amino acid substitutions using hidden Markov models.

    PubMed

    Shihab, Hashem A; Gough, Julian; Cooper, David N; Stenson, Peter D; Barker, Gary L A; Edwards, Keith J; Day, Ian N M; Gaunt, Tom R

    2013-01-01

    The rate at which nonsynonymous single nucleotide polymorphisms (nsSNPs) are being identified in the human genome is increasing dramatically owing to advances in whole-genome/whole-exome sequencing technologies. Automated methods capable of accurately and reliably distinguishing between pathogenic and functionally neutral nsSNPs are therefore assuming ever-increasing importance. Here, we describe the Functional Analysis Through Hidden Markov Models (FATHMM) software and server: a species-independent method with optional species-specific weightings for the prediction of the functional effects of protein missense variants. Using a model weighted for human mutations, we obtained performance accuracies that outperformed traditional prediction methods (i.e., SIFT, PolyPhen, and PANTHER) on two separate benchmarks. Furthermore, in one benchmark, we achieve performance accuracies that outperform current state-of-the-art prediction methods (i.e., SNPs&GO and MutPred). We demonstrate that FATHMM can be efficiently applied to high-throughput/large-scale human and nonhuman genome sequencing projects with the added benefit of phenotypic outcome associations. To illustrate this, we evaluated nsSNPs in wheat (Triticum spp.) to identify some of the important genetic variants responsible for the phenotypic differences introduced by intense selection during domestication. A Web-based implementation of FATHMM, including a high-throughput batch facility and a downloadable standalone package, is available at http://fathmm.biocompute.org.uk.

  18. Determining the potential link between irrigation water quality and the microbiological quality of onions by phenotypic and genotypic characterization of Escherichia coli isolates.

    PubMed

    du Plessis, Erika M; Duvenage, Francois; Korsten, Lise

    2015-04-01

    , respectively. Phenotypic (antimicrobial) and genotypic (virulence gene prevalence, DNA fingerprinting) analyses showed a link between river, dam, irrigation pivot point, and onion E. coli isolates.

  19. Improving Power System Modeling. A Tool to Link Capacity Expansion and Production Cost Models

    SciTech Connect

    Diakov, Victor; Cole, Wesley; Sullivan, Patrick; Brinkman, Gregory; Margolis, Robert

    2015-11-01

    Capacity expansion models (CEM) provide a high-level long-term view at the prospects of the evolving power system. In simulating the possibilities of long-term capacity expansion, it is important to maintain the viability of power system operation in the short-term (daily, hourly and sub-hourly) scales. Production-cost models (PCM) simulate routine power system operation on these shorter time scales using detailed load, transmission and generation fleet data by minimizing production costs and following reliability requirements. When based on CEM 'predictions' about generating unit retirements and buildup, PCM provide more detailed simulation for the short-term system operation and, consequently, may confirm the validity of capacity expansion predictions. Further, production cost model simulations of a system that is based on capacity expansion model solution are 'evolutionary' sound: the generator mix is the result of logical sequence of unit retirement and buildup resulting from policy and incentives. The above has motivated us to bridge CEM with PCM by building a capacity expansion - to - production cost model Linking Tool (CEPCoLT). The Linking Tool is built to onset capacity expansion model prescriptions onto production cost model inputs. NREL's ReEDS and Energy Examplar's PLEXOS are the capacity expansion and the production cost models, respectively. Via the Linking Tool, PLEXOS provides details of operation for the regionally-defined ReEDS scenarios.

  20. Modeling the population dynamics and community impacts of Ambystoma tigrinum: A case study of phenotype plasticity.

    PubMed

    McCarthy, Maeve L; Wallace, Dorothy; Whiteman, Howard H; Rheingold, Evan T; Dunham, Ann M; Prosper, Olivia; Chen, Michelle; Hu-Wang, Eileen

    2017-02-24

    Phenotypic plasticity is the ability of an organism to change its phenotype in response to changes in the environment. General mathematical descriptions of the phenomenon rely on an abstract measure of "viability" that, in this study, is instantiated in the case of the Tiger Salamander, Ambystoma tigrinum. This organism has a point in its development when, upon maturing, it may take two very different forms. One is a terrestrial salamander (metamorph)that visits ponds to reproduce and eat, while the other is an aquatic form (paedomorph) that remains in the pond to breed and which consumes a variety of prey including its own offspring. A seven dimensional nonlinear system of ordinary differential equations is developed, incorporating small (Z) and large (B) invertebrates, Ambystoma young of the year (Y), juveniles (J), terrestrial metamorphs (A) and aquatic paedomorphs (P). One parameter in the model controls the proportion of juveniles maturing into A versus P. Solutions are shown to remain non-negative. Every effort was made to justify parameters biologically through studies reported in the literature. A sensitivity analysis and equilibrium analysis of model parameters demonstrate that morphological choice is critical to the overall composition of the Ambystoma population. Various population viability measures were used to select optimal percentages of juveniles maturing into metamorphs, with optimal choices differing considerably depending on the viability measure. The model suggests that the criteria for viability for this organism vary, both from location to location and also in time. Thus, optimal responses change with spatiotemporal variation, which is consistent with other phenotypically plastic systems. Two competing hypotheses for the conditions under which metamorphosis occurs are examined in light of the model and data from an Ambystoma tigrinum population at Mexican Cut, Colorado. The model clearly supports one of these over the other for this data set

  1. MTO1-Deficient Mouse Model Mirrors the Human Phenotype Showing Complex I Defect and Cardiomyopathy

    PubMed Central

    Becker, Lore; Kling, Eva; Schiller, Evelyn; Zeh, Ramona; Schrewe, Anja; Hölter, Sabine M.; Mossbrugger, Ilona; Calzada-Wack, Julia; Strecker, Valentina; Wittig, Ilka; Dumitru, Iulia; Wenz, Tina; Bender, Andreas; Aichler, Michaela; Janik, Dirk; Neff, Frauke; Walch, Axel; Quintanilla-Fend, Leticia; Floss, Thomas; Bekeredjian, Raffi; Gailus-Durner, Valérie; Fuchs, Helmut; Wurst, Wolfgang; Meitinger, Thomas; Prokisch, Holger; de Angelis, Martin Hrabě; Klopstock, Thomas

    2014-01-01

    Recently, mutations in the mitochondrial translation optimization factor 1 gene (MTO1) were identified as causative in children with hypertrophic cardiomyopathy, lactic acidosis and respiratory chain defect. Here, we describe an MTO1-deficient mouse model generated by gene trap mutagenesis that mirrors the human phenotype remarkably well. As in patients, the most prominent signs and symptoms were cardiovascular and included bradycardia and cardiomyopathy. In addition, the mutant mice showed a marked worsening of arrhythmias during induction and reversal of anaesthesia. The detailed morphological and biochemical workup of murine hearts indicated that the myocardial damage was due to complex I deficiency and mitochondrial dysfunction. In contrast, neurological examination was largely normal in Mto1-deficient mice. A translational consequence of this mouse model may be to caution against anaesthesia-related cardiac arrhythmias which may be fatal in patients. PMID:25506927

  2. Verification of Geometric Model-Based Plant Phenotyping Methods for Studies of Xerophytic Plants.

    PubMed

    Drapikowski, Paweł; Kazimierczak-Grygiel, Ewa; Korecki, Dominik; Wiland-Szymańska, Justyna

    2016-06-27

    This paper presents the results of verification of certain non-contact measurement methods of plant scanning to estimate morphological parameters such as length, width, area, volume of leaves and/or stems on the basis of computer models. The best results in reproducing the shape of scanned objects up to 50 cm in height were obtained with the structured-light DAVID Laserscanner. The optimal triangle mesh resolution for scanned surfaces was determined with the measurement error taken into account. The research suggests that measuring morphological parameters from computer models can supplement or even replace phenotyping with classic methods. Calculating precise values of area and volume makes determination of the S/V (surface/volume) ratio for cacti and other succulents possible, whereas for classic methods the result is an approximation only. In addition, the possibility of scanning and measuring plant species which differ in morphology was investigated.

  3. A novel early onset phenotype in a zebrafish model of merosin deficient congenital muscular dystrophy

    PubMed Central

    Smith, Sarah J.; Wang, Jeffrey C.; Gupta, Vandana A.; Dowling, James J.

    2017-01-01

    Merosin deficient congenital muscular dystrophy (MDC1A) is a severe neuromuscular disorder with onset in infancy that is associated with severe morbidities (particularly wheelchair dependence) and early mortality. It is caused by recessive mutations in the LAMA2 gene that encodes a subunit of the extracellular matrix protein laminin 211. At present, there are no treatments for this disabling disease. The zebrafish has emerged as a powerful model system for the identification of novel therapies. However, drug discovery in the zebrafish is largely dependent on the identification of phenotypes suitable for chemical screening. Our goal in this study was to elucidate novel, early onset abnormalities in the candyfloss (caf) zebrafish, a model of MDC1A. We uncovered and characterize abnormalities in spontaneous coiling, the earliest motor movement in the zebrafish, as a fully penetrant change specific to caf mutants that is ideal for future drug testing. PMID:28241031

  4. Morphological Evolution of Physical Robots through Model-Free Phenotype Development

    PubMed Central

    Brodbeck, Luzius; Hauser, Simon; Iida, Fumiya

    2015-01-01

    Artificial evolution of physical systems is a stochastic optimization method in which physical machines are iteratively adapted to a target function. The key for a meaningful design optimization is the capability to build variations of physical machines through the course of the evolutionary process. The optimization in turn no longer relies on complex physics models that are prone to the reality gap, a mismatch between simulated and real-world behavior. We report model-free development and evaluation of phenotypes in the artificial evolution of physical systems, in which a mother robot autonomously designs and assembles locomotion agents. The locomotion agents are automatically placed in the testing environment and their locomotion behavior is analyzed in the real world. This feedback is used for the design of the next iteration. Through experiments with a total of 500 autonomously built locomotion agents, this article shows diversification of morphology and behavior of physical robots for the improvement of functionality with limited resources. PMID:26091255

  5. Verification of Geometric Model-Based Plant Phenotyping Methods for Studies of Xerophytic Plants

    PubMed Central

    Drapikowski, Paweł; Kazimierczak-Grygiel, Ewa; Korecki, Dominik; Wiland-Szymańska, Justyna

    2016-01-01

    This paper presents the results of verification of certain non-contact measurement methods of plant scanning to estimate morphological parameters such as length, width, area, volume of leaves and/or stems on the basis of computer models. The best results in reproducing the shape of scanned objects up to 50 cm in height were obtained with the structured-light DAVID Laserscanner. The optimal triangle mesh resolution for scanned surfaces was determined with the measurement error taken into account. The research suggests that measuring morphological parameters from computer models can supplement or even replace phenotyping with classic methods. Calculating precise values of area and volume makes determination of the S/V (surface/volume) ratio for cacti and other succulents possible, whereas for classic methods the result is an approximation only. In addition, the possibility of scanning and measuring plant species which differ in morphology was investigated. PMID:27355949

  6. Modeling Rice Metabolism: From Elucidating Environmental Effects on Cellular Phenotype to Guiding Crop Improvement

    PubMed Central

    Lakshmanan, Meiyappan; Cheung, C. Y. Maurice; Mohanty, Bijayalaxmi; Lee, Dong-Yup

    2016-01-01

    Crop productivity is severely limited by various biotic and abiotic stresses. Thus, it is highly needed to understand the underlying mechanisms of environmental stress response and tolerance in plants, which could be addressed by systems biology approach. To this end, high-throughput omics profiling and in silico modeling can be considered to explore the environmental effects on phenotypic states and metabolic behaviors of rice crops at the systems level. Especially, the advent of constraint-based metabolic reconstruction and analysis paves a way to characterize the plant cellular physiology under various stresses by combining the mathematical network models with multi-omics data. Rice metabolic networks have been reconstructed since 2013 and currently six such networks are available, where five are at genome-scale. Since their publication, these models have been utilized to systematically elucidate the rice abiotic stress responses and identify agronomic traits for crop improvement. In this review, we summarize the current status of the existing rice metabolic networks and models with their applications. Furthermore, we also highlight future directions of rice modeling studies, particularly stressing how these models can be used to contextualize the affluent multi-omics data that are readily available in the public domain. Overall, we envisage a number of studies in the future, exploiting the available metabolic models to enhance the yield and quality of rice and other food crops. PMID:27965696

  7. Phenotypic distribution models corroborate species distribution models: A shift in the role and prevalence of a dominant prairie grass in response to climate change.

    PubMed

    Smith, Adam B; Alsdurf, Jacob; Knapp, Mary; Baer, Sara G; Johnson, Loretta C

    2017-02-17

    Phenotypic distribution within species can vary widely across environmental gradients but forecasts of species' responses to environmental change often assume species respond homogenously across their ranges. We compared predictions from species and phenotype distribution models under future climate scenarios for Andropogon gerardii, a widely distributed, dominant grass found throughout the central United States. Phenotype data on aboveground biomass, height, leaf width, and chlorophyll content were obtained from 33 populations spanning a ~1000 km gradient that encompassed the majority of the species' environmental range. Species and phenotype distribution models were trained using current climate conditions and projected to future climate scenarios. We used permutation procedures to infer the most important variable for each model. The species-level response to climate was most sensitive to maximum temperature of the hottest month, but phenotypic variables were most sensitive to mean annual precipitation. The phenotype distribution models predict that A. gerardii could be largely functionally eliminated from where this species currently dominates, with biomass and height declining by up to ~60% and leaf width by ~20%. By the 2070s, the core area of highest suitability for A. gerardii is projected to shift up to ~700 km northeastward. Further, short-statured phenotypes found in the present-day short grass prairies on the western periphery of the species' range will become favored in the current core ~800 km eastward of their current location. Combined, species and phenotype models predict this currently dominant prairie grass will decline in prevalence and stature. Thus, sourcing plant material for grassland restoration and forage should consider changes in the phenotype that will be favored under future climate conditions. Phenotype distribution models account for the role of intraspecific variation in determining responses to anticipated climate change and

  8. Reversible pathologic and cognitive phenotypes in an inducible model of Alzheimer-amyloidosis

    PubMed Central

    Melnikova, Tatiana; Fromholt, Susan; Kim, HyunSu; Lee, Deidre; Xu, Guilian; Price, Ashleigh; Moore, Brenda D.; Golde, Todd E.; Felsenstein, Kevin M.; Savonenko, Alena; Borchelt, David R.

    2013-01-01

    Transgenic mice that express mutant amyloid precursor protein (APPsi) using tet-Off vector systems provide an alternative model for assessing short- and long-term effects of Aβ-targeting therapies on phenotypes related to the deposition of Alzheimer-type amyloid. Here we use such a model, termed APPsi:tTA, to determine what phenotypes persist in mice with high amyloid burden after new production of APP/Aβ has been suppressed. We find that 12-13 month old APPsi:tTA mice are impaired in cognitive tasks that assess short- and long-term memories. Acutely suppressing new APPsi/Aβ production produced highly significant improvements in performance short-term spatial memory tasks; which upon continued suppression translated to superior performance in more demanding tasks that assess long-term spatial memory and working memory. Deficits in episodic-like memory and cognitive flexibility, however, were more persistent. Arresting mutant APPsi production caused a rapid decline in the brain levels of soluble APP ectodomains, full-length APP, and APP C-terminal fragments. As expected, amyloid deposits persisted after new APP/Aβ production was inhibited whereas, unexpectedly, we detected persistent pools of solubilizable, relatively mobile, Aβ42. Additionally, we observed persistent levels of Aβ immunoreactive entities that were of a size consistent with SDS-resistant oligomeric assemblies. Thus, in this model with significant amyloid pathology, a rapid amelioration of cognitive deficits was observed despite persistent levels of oligomeric Aβ assemblies and low, but detectable solubilizable Aβ42 peptides. These findings implicate complex relationships between accumulating Aβ and activities of APP, soluble APP ectodomains, and/or APP CTFs in mediating cognitive deficits in this model of amyloidosis. PMID:23447589

  9. Reversible pathologic and cognitive phenotypes in an inducible model of Alzheimer-amyloidosis.

    PubMed

    Melnikova, Tatiana; Fromholt, Susan; Kim, HyunSu; Lee, Deidre; Xu, Guilian; Price, Ashleigh; Moore, Brenda D; Golde, Todd E; Felsenstein, Kevin M; Savonenko, Alena; Borchelt, David R

    2013-02-27

    Transgenic mice that express mutant amyloid precursor protein (APPsi) using tet-Off vector systems provide an alternative model for assessing short- and long-term effects of Aβ-targeting therapies on phenotypes related to the deposition of Alzheimer-type amyloid. Here we use such a model, termed APPsi:tTA, to determine what phenotypes persist in mice with high amyloid burden after new production of APP/Aβ has been suppressed. We find that 12- to 13-month-old APPsi:tTA mice are impaired in cognitive tasks that assess short- and long-term memories. Acutely suppressing new APPsi/Aβ production produced highly significant improvements in performing short-term spatial memory tasks, which upon continued suppression translated to superior performance in more demanding tasks that assess long-term spatial memory and working memory. Deficits in episodic-like memory and cognitive flexibility, however, were more persistent. Arresting mutant APPsi production caused a rapid decline in the brain levels of soluble APP ectodomains, full-length APP, and APP C-terminal fragments. As expected, amyloid deposits persisted after new APP/Aβ production was inhibited, whereas, unexpectedly, we detected persistent pools of solubilizable, relatively mobile, Aβ42. Additionally, we observed persistent levels of Aβ-immunoreactive entities that were of a size consistent with SDS-resistant oligomeric assemblies. Thus, in this model with significant amyloid pathology, a rapid amelioration of cognitive deficits was observed despite persistent levels of oligomeric Aβ assemblies and low, but detectable solubilizable Aβ42 peptides. These findings implicate complex relationships between accumulating Aβ and activities of APP, soluble APP ectodomains, and/or APP C-terminal fragments in mediating cognitive deficits in this model of amyloidosis.

  10. Tracing the sources of human salmonellosis: a multi-model comparison of phenotyping and genotyping methods.

    PubMed

    Mughini-Gras, Lapo; Smid, Joost; Enserink, Remko; Franz, Eelco; Schouls, Leo; Heck, Max; van Pelt, Wilfrid

    2014-12-01

    Salmonella source attribution is usually performed using frequency-matched models, such as the (modified) Dutch and Hald models, based on phenotyping data, i.e. serotyping, phage typing, and antimicrobial resistance profiling. However, for practical and economic reasons, genotyping methods such as Multi-locus Variable Number of Tandem Repeats Analysis (MLVA) are gradually replacing traditional phenotyping of salmonellas beyond the serovar level. As MLVA-based source attribution of human salmonellosis using frequency-matched models is problematic due to the high variability of the genetic targets investigated, other models need to be explored. Using a comprehensive data set from the Netherlands in 2005-2013, this study aimed at attributing sporadic and domestic cases of Salmonella Typhimurium/4,[5],12:i:- and Salmonella Enteritidis to four putative food-producing animal sources (pigs, cattle, broilers, and layers/eggs) using the modified Dutch and Hald models (based on sero/phage typing data) in comparison with a widely applied population genetics model - the asymmetric island model (AIM) - supplied with MLVA data. This allowed us to compare model outcomes and to corroborate whether MLVA-based Salmonella source attribution using the AIM is able to provide sound, comparable results. All three models provided very similar results, confirming once more that most S. Typhimurium/4,[5],12:i:- and S. Enteritidis cases are attributable to pigs and layers/eggs, respectively. We concluded that MLVA-based source attribution using the AIM is a feasible option, at least for S. Typhimurium/4,[5],12:i:- and S. Enteritidis. Enough information seems to be contained in the MLVA profiles to trace the sources of human salmonellosis even in presence of imperfect temporal overlap between human and source isolates. Besides Salmonella, the AIM might also be applicable to other pathogens that do not always comply to clonal models. This would add further value to current surveillance

  11. Morphological and functional reversal of phenotypes in a mouse model of Rett syndrome.

    PubMed

    Robinson, Lianne; Guy, Jacky; McKay, Leanne; Brockett, Emma; Spike, Rosemary C; Selfridge, Jim; De Sousa, Dina; Merusi, Cara; Riedel, Gernot; Bird, Adrian; Cobb, Stuart R

    2012-09-01

    Rett syndrome is a neurological disorder caused by mutation of the X-linked MECP2 gene. Mice lacking functional Mecp2 display a spectrum of Rett syndrome-like signs, including disturbances in motor function and abnormal patterns of breathing, accompanied by structural defects in central motor areas and the brainstem. Although routinely classified as a neurodevelopmental disorder, many aspects of the mouse phenotype can be effectively reversed by activation of a quiescent Mecp2 gene in adults. This suggests that absence of Mecp2 during brain development does not irreversibly compromise brain function. It is conceivable, however, that deep-seated neurological defects persist in mice rescued by late activation of Mecp2. To test this possibility, we have quantitatively analysed structural and functional plasticity of the rescued adult male mouse brain. Activation of Mecp2 in ∼70% of neurons reversed many morphological defects in the motor cortex, including neuronal size and dendritic complexity. Restoration of Mecp2 expression was also accompanied by a significant improvement in respiratory and sensory-motor functions, including breathing pattern, grip strength, balance beam and rotarod performance. Our findings sustain the view that MeCP2 does not play a pivotal role in brain development, but may instead be required to maintain full neurological function once development is complete.

  12. Modeling disease using three dimensional cell culture: multi-lumen and inverted cyst phenotypes.

    PubMed

    Monteleon, Christine L; D'Souza-Schorey, Crislyn

    2012-06-01

    Three-dimensional cell culture provides a unique system to investigate intrinsic mechanisms and micro environmental cues involved in the morphogenesis of epithelial glandular architectures. While this culture system allows insight into normal tissue development, it is also is readily amenable to manipulations that permit cellular modeling of various disease states. Here, we discuss a range of cellular and genetic alterations that result in two distinct cyst phenotypes, the multi-lumen cyst and the inverted cyst, both of which involve defects in cell polarity and lumen formation. Multi-lumen cyst formation results from disturbances in the mechanisms that regulate cell polarity, apical assembly, and the rate of lumen clearance. In the inverted cyst, the apical domain is oriented adjacent to the matrix, markedly affecting the morphogenic cues the matrix provides for cystogenesis. Both of these abnormal glandular phenotypes are highly reminiscent of histological patterns used to classify a number of diseases. A better understanding of the causes of multi-lumen and inverted cysts will provide insights into the origin and progression of epithelial diseases, potentially leading to the development of new therapies.

  13. Abnormal motor phenotype in the SMNΔ7 mouse model of spinal muscular atrophy

    PubMed Central

    Butchbach, Matthew E. R.; Edwards, Jonathan D.; Burghes, Arthur H. M.

    2009-01-01

    Spinal muscular atrophy (SMA) is recessive motor neuron disease that affects motor neurons in the anterior horn of the spinal cord. SMA results from the reduction of SMN (survival motor neuron) protein. Even though SMN is ubiquitously expressed, motor neurons are more sensitive to the reduction in SMN than other cell types. We have previously generated mouse models of SMA with varying degrees of clinical severity. So as to more clearly understand the pathogenesis of motor neuron degeneration in SMA, we have characterized the phenotype of the SMNΔ7 SMA mouse which normally lives for 13.6 ± 0.7 days. These mice are smaller than their non-SMA littermates and begin to lose body mass at 10.4 ± 0.4 days. SMNΔ7 SMA mice exhibit impaired responses to surface righting, negative geotaxis and cliff aversion but not to tactile stimulation. Spontaneous motor activity and grip strength are also significantly impaired in SMNΔ7 SMA mice. In summary, we have demonstrated an impairment of neonatal motor responses in SMNΔ7 SMA mice. This phenotype characterization could be used to assess the effectiveness of potential therapies for SMA. PMID:17561409

  14. UAS Modeling of the Communication Links Study Results

    NASA Technical Reports Server (NTRS)

    Birr, Richard; Murray, Jennifer; Girgis, nancy

    2011-01-01

    There were many links calculated for this and the other scenarios. The rain was analyzed for 99.9% availability with rain rated of none, 20 mm/hr and 90 mm/hr at a height of 5 km out to 25 NM. This was done for each scenario for LOS and for BLOS links for Scenario 5 and 6. Scenario 1 was a LOS-only scenario. Use of two 3 dB Antennas on both ends. The CS2 was unable to maintain a control RF Link during the flight. The largest access gap periods between object top and bottom UA antennae were caused by terrain (ridges and hills). The CS Antenna was changed to High Gain Directional Antenna, all three CS maintained lock on vehicle. There were RF dropouts between the top and bottom UA antennae caused by aircraft obstructions (fuselage, wings, wheel assembles, etc.). Note that for this study antenna locations were placed on top and bottom center of the UA body. Future study should include actual UA antenna locations on the aircraft providing manufactures are willing to provide information. The importance of CS location(s) was demonstrated for primary or backup CS. With a second backup CS placed in a suitable location the UA was able to maintain an overall RF link. The actual location of both backup CSs required the antenna location to be place 150 ft above ground in order to establish a RF link between the UA and CS.

  15. Optimizing human hepatocyte models for metabolic phenotype and function: effects of treatment with dimethyl sulfoxide (DMSO).

    PubMed

    Nikolaou, Nikolaos; Green, Charlotte J; Gunn, Pippa J; Hodson, Leanne; Tomlinson, Jeremy W

    2016-11-01

    Primary human hepatocytes are considered to be the "gold standard" cellular model for studying hepatic fatty acid and glucose metabolism; however, they come with limitations. Although the HepG2 cell line retains many of the primary hepatocyte metabolic functions they have a malignant origin and low rates of triglyceride secretion. The aim of this study was to investigate whether dimethyl sulfoxide supplementation in the media of HepG2 cells would enhance metabolic functionality leading to the development of an improved in vitro cell model that closely recapitulates primary human hepatocyte metabolism. HepG2 cells were cultured in media containing 1% dimethyl sulfoxide for 2, 4, 7, 14, and 21 days. Gene expression, protein levels, intracellular triglyceride, and media concentrations of triglyceride, urea, and 3-hydroxybutyrate concentrations were measured. Dimethyl sulfoxide treatment altered the expression of genes involved in lipid (FAS, ACC1, ACC2, DGAT1, DGAT2, SCD) and glucose (PEPCK, G6Pase) metabolism as well as liver functionality (albumin, alpha-1-antitrypsin, AFP). mRNA changes were paralleled by alterations at the protein level. DMSO treatment decreased intracellular triglyceride content and lactate production and increased triglyceride and 3-hydroxybutyrate concentrations in the media in a time-dependent manner. We have demonstrated that the addition of 1% dimethyl sulfoxide to culture media changes the metabolic phenotype of HepG2 cells toward a more primary human hepatocyte phenotype. This will enhance the currently available in vitro model systems for the study of hepatocyte biology related to pathological processes that contribute to disease and their response to specific therapeutic interventions.

  16. Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity

    SciTech Connect

    Almendro, Vanessa; Cheng, Yu -Kang; Randles, Amanda; Itzkovitz, Shalev; Marusyk, Andriy; Ametller, Elisabet; Gonzalez-Farre, Xavier; Muñoz, Montse; Russnes, Hege  G.; Helland, Åslaug; Rye, Inga  H.; Borresen-Dale, Anne -Lise; Maruyama, Reo; van Oudenaarden, Alexander; Dowsett, Mitchell; Jones, Robin  L.; Reis-Filho, Jorge; Gascon, Pere; Gönen, Mithat; Michor, Franziska; Polyak, Kornelia

    2014-02-01

    Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here, we report the analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre- and post-neoadjuvant chemotherapy. We found that intratumor genetic diversity was tumor-subtype specific, and it did not change during treatment in tumors with partial or no response. However, lower pretreatment genetic diversity was significantly associated with pathologic complete response. In contrast, phenotypic diversity was different between pre- and post-treatment samples. We also observed significant changes in the spatial distribution of cells with distinct genetic and phenotypic features. We used these experimental data to develop a stochastic computational model to infer tumor growth patterns and evolutionary dynamics. Our results highlight the importance of integrated analysis of genotypes and phenotypes of single cells in intact tissues to predict tumor evolution.

  17. Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity

    DOE PAGES

    Almendro, Vanessa; Cheng, Yu -Kang; Randles, Amanda; ...

    2014-02-01

    Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here, we report the analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre- and post-neoadjuvant chemotherapy. We found that intratumor genetic diversity was tumor-subtype specific, and it did not change during treatment in tumors with partial or no response. However, lower pretreatment genetic diversity was significantly associated with pathologic complete response. In contrast, phenotypic diversity was different between pre- and post-treatment samples. We also observed significant changes in the spatialmore » distribution of cells with distinct genetic and phenotypic features. We used these experimental data to develop a stochastic computational model to infer tumor growth patterns and evolutionary dynamics. Our results highlight the importance of integrated analysis of genotypes and phenotypes of single cells in intact tissues to predict tumor evolution.« less

  18. Ovarian angiogenesis. Phenotypic characterization of endothelial cells in a physiological model of blood vessel growth and regression.

    PubMed Central

    Augustin, H. G.; Braun, K.; Telemenakis, I.; Modlich, U.; Kuhn, W.

    1995-01-01

    Angiogenesis occurs during embryogenesis and is a down-regulated process in the healthy adult that is almost exclusively linked to pathological conditions such as tumor growth, wound healing, and inflammation. Physiological angiogenic processes in the adult are restricted to the female reproductive system where they occur cyclically during the ovarian and uterine cycle as well as during pregnancy. By systematically analyzing the phenotypic changes of endothelial cells during bovine corpus luteum (CL) formation and regression, we have established a physiological model of blood vessel growth and regression. Quantitation of vessel density, percentage of vessels with lumen, and ratio of Bandeiraea simplicifolia-I to von Willebrand Factor-positive endothelial cells were established as parameters of angiogenesis. Sprouting endothelial cells invade the growing CL and continue to grow throughout the first third of the ovarian cycle. Thereafter the mature CL is characterized by a dense network of vessels with gradually decreasing vessel density. During luteolysis and for several weeks thereafter (regressing and residual CL) all newly formed vessels regress, which is accompanied by gradual foreshortening and rounding of endothelial cells and subsequent detachment. Based on histochemical detection of nucleosomal fragmentation products physiological blood vessel regression in the cyclic CL does not appear to involve endothelial cell apoptosis. Lectin histochemical analysis revealed a distinct alteration of endothelial cell glycoconjugate expression during ovarian angiogenesis comparable with the distinct pattern of hyperglycosylation of cultured migrating endothelial cells (up-regulation of binding sites for Lycopersicon esculentum lectin, wheat germ agglutinin, neuraminidase-treated peanut agglutinin, and Ricinus communis agglutinin-I on sprouting ECs). Northern blot analysis of glycosyltransferases during the different stages of angiogenesis revealed an up-regulation of beta

  19. A novel animal model linking adiposity to altered circadian rhythms

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Researchers have provided evidence for a link between obesity and altered circadian rhythms (e.g., shift work, disrupted sleep), but the mechanism for this association is still unknown. Adipocytes possess an intrinsic circadian clock, and circadian rhythms in adipocytokines and adipose tissue metab...

  20. Metal Homeostasis Regulators Suppress FRDA Phenotypes in a Drosophila Model of the Disease

    PubMed Central

    Soriano, Sirena; Calap-Quintana, Pablo; Llorens, José Vicente; Al-Ramahi, Ismael; Gutiérrez, Lucía; Martínez-Sebastián, María José; Botas, Juan; Moltó, María Dolores

    2016-01-01

    Friedreich’s ataxia (FRDA), the most commonly inherited ataxia in populations of European origin, is a neurodegenerative disorder caused by a decrease in frataxin levels. One of the hallmarks of the disease is the accumulation of iron in several tissues including the brain, and frataxin has been proposed to play a key role in iron homeostasis. We found that the levels of zinc, copper, manganese and aluminum were also increased in a Drosophila model of FRDA, and that copper and zinc chelation improve their impaired motor performance. By means of a candidate genetic screen, we identified that genes implicated in iron, zinc and copper transport and metal detoxification can restore frataxin deficiency-induced phenotypes. Taken together, these results demonstrate that the metal dysregulation in FRDA includes other metals besides iron, therefore providing a new set of potential therapeutic targets. PMID:27433942

  1. Vitamin B12 ameliorates the phenotype of a mouse model of DiGeorge syndrome.

    PubMed

    Lania, Gabriella; Bresciani, Alberto; Bisbocci, Monica; Francone, Alessandra; Colonna, Vincenza; Altamura, Sergio; Baldini, Antonio

    2016-08-09

    Pathological conditions caused by reduced dosage of a gene, such as gene haploinsufficiency, can potentially be reverted by enhancing the expression of the functional allele. In practice, low specificity of therapeutic agents, or their toxicity reduces their clinical applicability. Here, we have used a high throughput screening (HTS) approach to identify molecules capable of increasing the expression of the gene Tbx1, which is involved in one of the most common gene haploinsufficiency syndromes, the 22q11.2 deletion syndrome. Surprisingly, we found that one of the two compounds identified by the HTS is the vitamin B12. Validation in a mouse model demonstrated that vitamin B12 treatment enhances Tbx1 gene expression and partially rescues the haploinsufficiency phenotype. These results lay the basis for preclinical and clinical studies to establish the effectiveness of this drug in the human syndrome.

  2. Phenotypic and pathologic evaluation of the myd mouse. A candidate model for facioscapulohumeral dystrophy

    SciTech Connect

    Mathews, K.D.; Rapisarda, D.; Bailey, H.L.

    1995-07-01

    Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant disease of unknown pathogenesis which is characterized by weakness of the face and shoulder girdle. It is associated with a sensorineural hearing loss which may be subclinical. FSHD has been mapped to the distalmost portion of 4q35, although the gene has not yet been identified. Distal 4q has homology with a region of mouse chromosome 8 to which a mouse mutant, myodystrophy (myd), has been mapped. Muscle from homozygotes for the myd mutation appears dystrophic, showing degenerating and regenerating fibers, inflammatory infiltrates, central nuclei, and variation in fiber size. Brainstem auditory evoked potentials reveal a sensorineural hearing loss in myd homozygotes. Based on the homologous genetic map locations, and the phenotypic syndrome of dystrophic muscle with sensorineural hearing loss, we suggest that myd represents an animal model for the human disease FSHD. 28 refs., 4 figs.

  3. Transgenic rescue of phenotypic deficits in a mouse model of alternating hemiplegia of childhood.

    PubMed

    Kirshenbaum, Greer S; Dachtler, James; Roder, John C; Clapcote, Steven J

    2016-01-01

    Missense mutations in ATP1A3 encoding Na(+),K(+)-ATPase α3 are the primary cause of alternating hemiplegia of childhood (AHC). Most ATP1A3 mutations in AHC lie within a cluster in or near transmembrane α-helix TM6, including I810N that is also found in the Myshkin mouse model of AHC. These mutations all substantially reduce Na(+),K(+)-ATPase α3 activity. Herein, we show that Myshkin mice carrying a wild-type Atp1a3 transgene that confers a 16 % increase in brain-specific total Na(+),K(+)-ATPase activity show significant phenotypic improvements compared with non-transgenic Myshkin mice. Interventions to increase the activity of wild-type Na(+),K(+)-ATPase α3 in AHC patients should be investigated further.

  4. Application of a two-phenotype color-shift model with heterogeneous growth to a rat hepatocarcinogenesis experiment.

    PubMed

    Groos, Jutta; Kopp-Schneider, Annette

    2010-04-01

    The color-shift model (CSM) was introduced by Kopp-Schneider et al. [1] to describe formation and progression of foci of altered hepatocytes (FAH). It incorporates the field-effect hypothesis which postulates that entire colonies of altered hepatocytes simultaneously alter their phenotype. In the original CSM, FAH grow with deterministic growth rate and change their phenotype after an exponentially distributed waiting time. A modification of the original color-shift model (CSM beta) is presented here in which the growth rate varies from focus to focus according to a beta distribution. The concept of an exponentially distributed waiting time to phenotype change is modified to the concept of a random radius at which phenotype changes and this radius is modelled as beta distributed. The original and the modified CSM are applied to data from an initiation-promotion rat hepatocarcinogenesis experiment with diethylnitrosomorpholine (DEN) and N-nitrosomorpholine (NNM), in which two phenotypes of FAH were observed in hematoxilin/eosin (H&E) stained liver sections. The Cramer-von-Mises Distance is used as a measure for the discrepancy between empirical and theoretical size distributions. Comparisons of model fit show that considerable improvement is obtained for CSM beta compared to the original CSM.

  5. Modeling the evolution of phenotypic plasticity in resource allocation in wing-dimorphic insects.

    PubMed

    King, Elizabeth G; Roff, Derek A

    2010-06-01

    In nature, resource availability varies spatially and temporally both within and across generations, leading to variation in the amount of energy available to individuals. The optimal allocation strategy can change, depending on the amount of resources available to allocate to life-history functions. If so, selection should favor the evolution of allocation strategies that can respond to variation in environmental resource levels. We address this issue by using two quantitative genetic simulation models in a model system for studying trade-offs, wing-dimorphic insects. Wing dimorphic insects typically exhibit a trade-off in the allocation of resources between migratory ability and reproduction. In our models, we focus on allocation as a genetic trait and model the evolution of phenotypic plasticity in this trait in response to spatiotemporal variation in resource availability. We show that the evolved allocation strategy depends on the predictability of resource levels across time. Specifically, selection favors higher investment in flight under poor conditions in predictable environments and lower investment in unpredictable environments.

  6. Phenotypic Screening Identifies Modulators of Amyloid Precursor Protein Processing in Human Stem Cell Models of Alzheimer's Disease.

    PubMed

    Brownjohn, Philip W; Smith, James; Portelius, Erik; Serneels, Lutgarde; Kvartsberg, Hlin; De Strooper, Bart; Blennow, Kaj; Zetterberg, Henrik; Livesey, Frederick J

    2017-03-06

    Human stem cell models have the potential to provide platforms for phenotypic screens to identify candidate treatments and cellular pathways involved in the pathogenesis of neurodegenerative disorders. Amyloid precursor protein (APP) processing and the accumulation of APP-derived amyloid β (Aβ) peptides are key processes in Alzheimer's disease (AD). We designed a phenotypic small-molecule screen to identify modulators of APP processing in trisomy 21/Down syndrome neurons, a complex genetic model of AD. We identified the avermectins, commonly used as anthelmintics, as compounds that increase the relative production of short Aβ peptides at the expense of longer, potentially more toxic peptides. Further studies demonstrated that this effect is not due to an interaction with the core γ-secretase responsible for Aβ production. This study demonstrates the feasibility of phenotypic drug screening in human stem cell models of Alzheimer-type dementia, and points to possibilities for indirectly modulating APP processing, independently of γ-secretase modulation.

  7. Multilevel and Latent Variable Modeling with Composite Links and Exploded Likelihoods

    ERIC Educational Resources Information Center

    Rabe-Hesketh, Sophia; Skrondal, Anders

    2007-01-01

    Composite links and exploded likelihoods are powerful yet simple tools for specifying a wide range of latent variable models. Applications considered include survival or duration models, models for rankings, small area estimation with census information, models for ordinal responses, item response models with guessing, randomized response models,…

  8. Identification of Multiple QTLs Linked to Neuropathology in the Engrailed-1 Heterozygous Mouse Model of Parkinson's Disease.

    PubMed

    Kurowska, Zuzanna; Jewett, Michael; Brattås, Per Ludvik; Jimenez-Ferrer, Itzia; Kenéz, Xuyian; Björklund, Tomas; Nordström, Ulrika; Brundin, Patrik; Swanberg, Maria

    2016-08-23

    Motor symptoms in Parkinson's disease are attributed to degeneration of midbrain dopaminergic neurons (DNs). Heterozygosity for Engrailed-1 (En1), one of the key factors for programming and maintenance of DNs, results in a parkinsonian phenotype featuring progressive degeneration of DNs in substantia nigra pars compacta (SNpc), decreased striatal dopamine levels and swellings of nigro-striatal axons in the SwissOF1-En1+/- mouse strain. In contrast, C57Bl/6-En1+/- mice do not display this neurodegenerative phenotype, suggesting that susceptibility to En1 heterozygosity is genetically regulated. Our goal was to identify quantitative trait loci (QTLs) that regulate the susceptibility to PD-like neurodegenerative changes in response to loss of one En1 allele. We intercrossed SwissOF1-En1+/- and C57Bl/6 mice to obtain F2 mice with mixed genomes and analyzed number of DNs in SNpc and striatal axonal swellings in 120 F2-En1+/- 17 week-old male mice. Linkage analyses revealed 8 QTLs linked to number of DNs (p = 2.4e-09, variance explained = 74%), 7 QTLs linked to load of axonal swellings (p = 1.7e-12, variance explained = 80%) and 8 QTLs linked to size of axonal swellings (p = 7.0e-11, variance explained = 74%). These loci should be of prime interest for studies of susceptibility to Parkinson's disease-like damage in rodent disease models and considered in clinical association studies in PD.

  9. Identification of Multiple QTLs Linked to Neuropathology in the Engrailed-1 Heterozygous Mouse Model of Parkinson’s Disease

    PubMed Central

    Kurowska, Zuzanna; Jewett, Michael; Brattås, Per Ludvik; Jimenez-Ferrer, Itzia; Kenéz, Xuyian; Björklund, Tomas; Nordström, Ulrika; Brundin, Patrik; Swanberg, Maria

    2016-01-01

    Motor symptoms in Parkinson’s disease are attributed to degeneration of midbrain dopaminergic neurons (DNs). Heterozygosity for Engrailed-1 (En1), one of the key factors for programming and maintenance of DNs, results in a parkinsonian phenotype featuring progressive degeneration of DNs in substantia nigra pars compacta (SNpc), decreased striatal dopamine levels and swellings of nigro-striatal axons in the SwissOF1-En1+/− mouse strain. In contrast, C57Bl/6-En1+/− mice do not display this neurodegenerative phenotype, suggesting that susceptibility to En1 heterozygosity is genetically regulated. Our goal was to identify quantitative trait loci (QTLs) that regulate the susceptibility to PD-like neurodegenerative changes in response to loss of one En1 allele. We intercrossed SwissOF1-En1+/− and C57Bl/6 mice to obtain F2 mice with mixed genomes and analyzed number of DNs in SNpc and striatal axonal swellings in 120 F2-En1+/− 17 week-old male mice. Linkage analyses revealed 8 QTLs linked to number of DNs (p = 2.4e-09, variance explained = 74%), 7 QTLs linked to load of axonal swellings (p = 1.7e-12, variance explained = 80%) and 8 QTLs linked to size of axonal swellings (p = 7.0e-11, variance explained = 74%). These loci should be of prime interest for studies of susceptibility to Parkinson’s disease-like damage in rodent disease models and considered in clinical association studies in PD. PMID:27550741

  10. MtDNA meta-analysis reveals both phenotype specificity and allele heterogeneity: a model for differential association

    PubMed Central

    Marom, Shani; Friger, Michael; Mishmar, Dan

    2017-01-01

    Human mtDNA genetic variants have traditionally been considered markers for ancient population migrations. However, during the past three decades, these variants have been associated with altered susceptibility to various phenotypes, thus supporting their importance for human health. Nevertheless, mtDNA disease association has frequently been supported only in certain populations, due either to population stratification or differential epistatic compensations among populations. To partially overcome these obstacles, we performed meta-analysis of the multiple mtDNA association studies conducted until 2016, encompassing 53,975 patients and 63,323 controls. Our findings support the association of mtDNA haplogroups and recurrent variants with specific phenotypes such as Parkinson’s disease, type 2 diabetes, longevity, and breast cancer. Strikingly, our assessment of mtDNA variants’ involvement with multiple phenotypes revealed significant impact for Caucasian haplogroups H, J, and K. Therefore, ancient mtDNA variants could be divided into those that affect specific phenotypes, versus others with a general impact on phenotype combinations. We suggest that the mtDNA could serve as a model for phenotype specificity versus allele heterogeneity. PMID:28230165

  11. Genotypic and phenotypic characterization of P23H line 1 rat model.

    PubMed

    Orhan, Elise; Dalkara, Deniz; Neuillé, Marion; Lechauve, Christophe; Michiels, Christelle; Picaud, Serge; Léveillard, Thierry; Sahel, José-Alain; Naash, Muna I; Lavail, Matthew M; Zeitz, Christina; Audo, Isabelle

    2015-01-01

    Rod-cone dystrophy, also known as retinitis pigmentosa (RP), is the most common inherited degenerative photoreceptor disease, for which no therapy is currently available. The P23H rat is one of the most commonly used autosomal dominant RP models. It has been created by incorporation of a mutated mouse rhodopsin (Rho) transgene in the wild-type (WT) Sprague Dawley rat. Detailed genetic characterization of this transgenic animal has however never been fully reported. Here we filled this knowledge gap on P23H Line 1 rat (P23H-1) and provide additional phenotypic information applying non-invasive and state-of-the-art in vivo techniques that are relevant for preclinical therapeutic evaluations. Transgene sequence was analyzed by Sanger sequencing. Using quantitative PCR, transgene copy number was calculated and its expression measured in retinal tissue. Full field electroretinography (ERG) and spectral domain optical coherence tomography (SD-OCT) were performed at 1-, 2-, 3- and 6-months of age. Sanger sequencing revealed that P23H-1 rat carries the mutated mouse genomic Rho sequence from the promoter to the 3' UTR. Transgene copy numbers were estimated at 9 and 18 copies in the hemizygous and homozygous rats respectively. In 1-month-old hemizygous P23H-1 rats, transgene expression represented 43% of all Rho expressed alleles. ERG showed a progressive rod-cone dysfunction peaking at 6 months-of-age. SD-OCT confirmed a progressive thinning of the photoreceptor cell layer leading to the disappearance of the outer retina by 6 months with additional morphological changes in the inner retinal cell layers in hemizygous P23H-1 rats. These results provide precise genotypic information of the P23H-1 rat with additional phenotypic characterization that will serve basis for therapeutic interventions, especially for those aiming at gene editing.

  12. Genotypic and Phenotypic Characterization of P23H Line 1 Rat Model

    PubMed Central

    Orhan, Elise; Dalkara, Deniz; Neuillé, Marion; Lechauve, Christophe; Michiels, Christelle; Picaud, Serge; Léveillard, Thierry; Sahel, José-Alain; Naash, Muna I.; Lavail, Matthew M.; Zeitz, Christina; Audo, Isabelle

    2015-01-01

    Rod-cone dystrophy, also known as retinitis pigmentosa (RP), is the most common inherited degenerative photoreceptor disease, for which no therapy is currently available. The P23H rat is one of the most commonly used autosomal dominant RP models. It has been created by incorporation of a mutated mouse rhodopsin (Rho) transgene in the wild-type (WT) Sprague Dawley rat. Detailed genetic characterization of this transgenic animal has however never been fully reported. Here we filled this knowledge gap on P23H Line 1 rat (P23H-1) and provide additional phenotypic information applying non-invasive and state-of-the-art in vivo techniques that are relevant for preclinical therapeutic evaluations. Transgene sequence was analyzed by Sanger sequencing. Using quantitative PCR, transgene copy number was calculated and its expression measured in retinal tissue. Full field electroretinography (ERG) and spectral domain optical coherence tomography (SD-OCT) were performed at 1-, 2-, 3- and 6-months of age. Sanger sequencing revealed that P23H-1 rat carries the mutated mouse genomic Rho sequence from the promoter to the 3’ UTR. Transgene copy numbers were estimated at 9 and 18 copies in the hemizygous and homozygous rats respectively. In 1-month-old hemizygous P23H-1 rats, transgene expression represented 43% of all Rho expressed alleles. ERG showed a progressive rod-cone dysfunction peaking at 6 months-of-age. SD-OCT confirmed a progressive thinning of the photoreceptor cell layer leading to the disappearance of the outer retina by 6 months with additional morphological changes in the inner retinal cell layers in hemizygous P23H-1 rats. These results provide precise genotypic information of the P23H-1 rat with additional phenotypic characterization that will serve basis for therapeutic interventions, especially for those aiming at gene editing. PMID:26009893

  13. Mechanisms of developmental regression in autism and the broader phenotype: a neural network modeling approach.

    PubMed

    Thomas, Michael S C; Knowland, Victoria C P; Karmiloff-Smith, Annette

    2011-10-01

    Loss of previously established behaviors in early childhood constitutes a markedly atypical developmental trajectory. It is found almost uniquely in autism and its cause is currently unknown (Baird et al., 2008). We present an artificial neural network model of developmental regression, exploring the hypothesis that regression is caused by overaggressive synaptic pruning and identifying the mechanisms involved. We used a novel population-modeling technique to investigate developmental deficits, in which both neurocomputational parameters and the learning environment were varied across a large number of simulated individuals. Regression was generated by the atypical setting of a single pruning-related parameter. We observed a probabilistic relationship between the atypical pruning parameter and the presence of regression, as well as variability in the onset, severity, behavioral specificity, and recovery from regression. Other neurocomputational parameters that varied across the population modulated the risk that an individual would show regression. We considered a further hypothesis that behavioral regression may index an underlying anomaly characterizing the broader autism phenotype. If this is the case, we show how the model also accounts for several additional findings: shared gene variants between autism and language impairment (Vernes et al., 2008); larger brain size in autism but only in early development (Redcay & Courchesne, 2005); and the possibility of quasi-autism, caused by extreme environmental deprivation (Rutter et al., 1999). We make a novel prediction that the earliest developmental symptoms in the emergence of autism should be sensory and motor rather than social and review empirical data offering preliminary support for this prediction.

  14. Mouse Models for the p53 R72P Polymorphism Mimic Human Phenotypes

    PubMed Central

    Zhu, Feng; Dollé, Martijn E.T.; Berton, Thomas R.; Kuiper, Raoul V.; Capps, Carrie; Espejo, Alexsandra; McArthur, Mark J.; Bedford, Mark T.; van Steeg, Harry; de Vries, Annemieke; Johnson, David G.

    2010-01-01

    The p53 tumor suppressor gene contains a common single nucleotide polymorphism (SNP) that results in either an arginine or proline at position 72 of the p53 protein. This polymorphism affects the apoptotic activity of p53 but the mechanistic basis and physiological relevance of this phenotypic difference remain unclear. Here we describe the development of mouse models for the p53 R72P SNP using two different approaches. In both sets of models the human or humanized p53 proteins are functional as evidenced by the transcriptional induction of p53 target genes in response to DNA damage and the suppression of early lymphomagenesis. Consistent with in vitro studies, mice expressing the 72R variant protein (p53R) have a greater apoptotic response to several stimuli compared to mice expressing the p53P variant. Molecular studies suggest that both transcriptional and non-transcriptional mechanisms may contribute to the differential abilities of the p53 variants to induce apoptosis. Despite a difference in the acute response to ultraviolet (UV) radiation, no difference in the tumorigenic response to chronic UV exposure was observed between the polymorphic mouse models. These findings suggest that under at least some conditions, the modulation of apoptosis by the R72P polymorphism does not impact the process of carcinogenesis. PMID:20587514

  15. Linking mechanistic models of tree physiology with models of forest dynamics: Problems of temporal scale

    SciTech Connect

    King, A.W.; Emanuel, W.R.; O'Neill, R.V.

    1988-01-01

    The individual-based forest gap models are a potential resource in the study of forest growth responses to environmental stress acting on physiological processes. This approach is currently limited by the lack of physiological detail in the gap models and by the temporal scales separating tree physiology and the annual tree growth simulated by the gap models. We describe a general procedure that integrates process-based models of tree physiology with forest gap models. The procedure involves (1) a link between a physiological model and a gap model provided by the simulation of annual wood production (AWP), (2) a factorial execution of a physiological model to generate AWP, (3) a response-surface model describing the relationship between AWP and driving variables appropriate to the annual time scale of a gap model, and (4) a revised gap model that includes a rescaled physiological model. The modified gap model can be used to simulate the impact of environmental stress on forest growth and succession. 18 refs., 2 figs.

  16. Global land-use allocation model linked to an integrated assessment model.

    PubMed

    Hasegawa, Tomoko; Fujimori, Shinichiro; Ito, Akihiko; Takahashi, Kiyoshi; Masui, Toshihiko

    2017-02-15

    We developed a global land-use allocation model that can be linked to integrated assessment models (IAMs) with a coarser spatial resolution. Using the model, we performed a downscaling of the IAMs' regional aggregated land-use projections to obtain a spatial land-use distribution, which could subsequently be used by Earth system models for global environmental assessments of ecosystem services, food security, and climate policies. Here we describe the land-use allocation model, discuss the verification of the downscaling technique, and explain the influences of the downscaling on estimates of land-use carbon emissions. A comparison of the emissions estimated with and without downscaling suggested that the land-use downscaling would help capture the spatial distribution of carbon stock density and regional heterogeneity of carbon emissions caused by cropland and pasture land expansion.

  17. Using Mouse Models to Explore Genotype-Phenotype Relationship in Down Syndrome

    ERIC Educational Resources Information Center

    Salehi, Ahmad; Faizi, Mehrdad; Belichenko, Pavel V.; Mobley, William C.

    2007-01-01

    Down Syndrome (DS) caused by trisomy 21 is characterized by a variety of phenotypes and involves multiple organs. Sequencing of human chromosome 21 (HSA21) and subsequently of its orthologues on mouse chromosome 16 have created an unprecedented opportunity to explore the complex relationship between various DS phenotypes and the extra copy of…

  18. Guidance for the utility of linear models in meta-analysis of genetic association studies of binary phenotypes.

    PubMed

    Cook, James P; Mahajan, Anubha; Morris, Andrew P

    2017-02-01

    Linear mixed models are increasingly used for the analysis of genome-wide association studies (GWAS) of binary phenotypes because they can efficiently and robustly account for population stratification and relatedness through inclusion of random effects for a genetic relationship matrix. However, the utility of linear (mixed) models in the context of meta-analysis of GWAS of binary phenotypes has not been previously explored. In this investigation, we present simulations to compare the performance of linear and logistic regression models under alternative weighting schemes in a fixed-effects meta-analysis framework, considering designs that incorporate variable case-control imbalance, confounding factors and population stratification. Our results demonstrate that linear models can be used for meta-analysis of GWAS of binary phenotypes, without loss of power, even in the presence of extreme case-control imbalance, provided that one of the following schemes is used: (i) effective sample size weighting of Z-scores or (ii) inverse-variance weighting of allelic effect sizes after conversion onto the log-odds scale. Our conclusions thus provide essential recommendations for the development of robust protocols for meta-analysis of binary phenotypes with linear models.

  19. Systems Biology for Smart Crops and Agricultural Innovation: Filling the Gaps between Genotype and Phenotype for Complex Traits Linked with Robust Agricultural Productivity and Sustainability

    PubMed Central

    Pathak, Rajesh Kumar; Gupta, Sanjay Mohan; Gaur, Vikram Singh; Pandey, Dinesh

    2015-01-01

    Abstract In recent years, rapid developments in several omics platforms and next generation sequencing technology have generated a huge amount of biological data about plants. Systems biology aims to develop and use well-organized and efficient algorithms, data structure, visualization, and communication tools for the integration of these biological data with the goal of computational modeling and simulation. It studies crop plant systems by systematically perturbing them, checking the gene, protein, and informational pathway responses; integrating these data; and finally, formulating mathematical models that describe the structure of system and its response to individual perturbations. Consequently, systems biology approaches, such as integrative and predictive ones, hold immense potential in understanding of molecular mechanism of agriculturally important complex traits linked to agricultural productivity. This has led to identification of some key genes and proteins involved in networks of pathways involved in input use efficiency, biotic and abiotic stress resistance, photosynthesis efficiency, root, stem and leaf architecture, and nutrient mobilization. The developments in the above fields have made it possible to design smart crops with superior agronomic traits through genetic manipulation of key candidate genes. PMID:26484978

  20. A model-based framework for the phenotypic characterization of the flowering of Medicago truncatula.

    PubMed

    Moreau, Delphine; Salon, Christophe; Munier-Jolain, Nathalie

    2007-02-01

    To facilitate the phenotypic characterization of Medicago truncatula, our aim was to provide a framework of analysis of flowering in response to environmental factors. The flowering of the line A17 was analysed in different conditions of temperature, duration of vernalization and photoperiod. Flowering was characterized using three descriptors at the axis level: the position of the first reproductive node (1RN), the date of beginning of flowering (DBF) and the florochron (RFa-1) corresponding to the reciprocal of the rate of progression of flowering along each axis. As for vegetative development, it was found that flowering could be analysed as a function of thermal time using a base temperature (Tb) of 5 degrees C. Vernalization displayed a sound impact on the flowering. For all the studied axes, increasing the duration of vernalization lowered the 1RN and hastened the DBF. By contrast, for most of the studied axes, RFa-1 was only slightly affected by vernalization. For the branch B0, RFa-1 was a genotypic constant when thermal time was used. Considering B0 as a reference axis, an ecophysiological model was developed to simulate the impact of environmental factors on the three components of flowering. Concrete practical applications of the model-based framework presented herein are proposed for helping the genetic and genomic studies of M. truncatula.

  1. Conserved pharmacological rescue of hereditary spastic paraplegia-related phenotypes across model organisms

    PubMed Central

    Julien, Carl; Lissouba, Alexandra; Madabattula, Surya; Fardghassemi, Yasmin; Rosenfelt, Cory; Androschuk, Alaura; Strautman, Joel; Wong, Clement; Bysice, Andrew; O'sullivan, Julia; Rouleau, Guy A.; Drapeau, Pierre; Parker, J. Alex; Bolduc, François V.

    2016-01-01

    Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative diseases causing progressive gait dysfunction. Over 50 genes have now been associated with HSP. Despite the recent explosion in genetic knowledge, HSP remains without pharmacological treatment. Loss-of-function mutation of the SPAST gene, also known as SPG4, is the most common cause of HSP in patients. SPAST is conserved across animal species and regulates microtubule dynamics. Recent studies have shown that it also modulates endoplasmic reticulum (ER) stress. Here, utilizing null SPAST homologues in C. elegans, Drosophila and zebrafish, we tested FDA-approved compounds known to modulate ER stress in order to ameliorate locomotor phenotypes associated with HSP. We found that locomotor defects found in all of our spastin models could be partially rescued by phenazine, methylene blue, N-acetyl-cysteine, guanabenz and salubrinal. In addition, we show that established biomarkers of ER stress levels correlated with improved locomotor activity upon treatment across model organisms. Our results provide insights into biomarkers and novel therapeutic avenues for HSP. PMID:26744324

  2. Circumventing furin enhances factor VIII biological activity and ameliorates bleeding phenotypes in hemophilia models

    PubMed Central

    Siner, Joshua I.; Samelson-Jones, Benjamin J.; Crudele, Julie M.; French, Robert A.; Lee, Benjamin J.; Zhou, Shanzhen; Merricks, Elizabeth; Raymer, Robin; Camire, Rodney M.; Arruda, Valder R.

    2016-01-01

    Processing by the proprotein convertase furin is believed to be critical for the biological activity of multiple proteins involved in hemostasis, including coagulation factor VIII (FVIII). This belief prompted the retention of the furin recognition motif (amino acids 1645–1648) in the design of B-domain–deleted FVIII (FVIII-BDD) products in current clinical use and in the drug development pipeline, as well as in experimental FVIII gene therapy strategies. Here, we report that processing by furin is in fact deleterious to FVIII-BDD secretion and procoagulant activity. Inhibition of furin increases the secretion and decreases the intracellular retention of FVIII-BDD protein in mammalian cells. Our new variant (FVIII-ΔF), in which this recognition motif is removed, efficiently circumvents furin. FVIII-ΔF demonstrates increased recombinant protein yields, enhanced clotting activity, and higher circulating FVIII levels after adeno-associated viral vector–based liver gene therapy in a murine model of severe hemophilia A (HA) compared with FVIII-BDD. Moreover, we observed an amelioration of the bleeding phenotype in severe HA dogs with sustained therapeutic FVIII levels after FVIII-ΔF gene therapy at a lower vector dose than previously employed in this model. The immunogenicity of FVIII-ΔF did not differ from that of FVIII-BDD as a protein or a gene therapeutic. Thus, contrary to previous suppositions, FVIII variants that can avoid furin processing are likely to have enhanced translational potential for HA therapy. PMID:27734034

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

    PubMed

    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.

  4. Phenotypic and functional characterization of a mouse model of targeted Pig-a deletion in hematopoietic cells

    PubMed Central

    Visconte, Valeria; Raghavachari, Nalini; Liu, Delong; Keyvanfar, Keyvan; Desierto, Marie J.; Chen, Jichun; Young, Neal S.

    2010-01-01

    Background Somatic mutation in the X-linked phosphatidylinositol glycan class A gene (PIG-A) causes glycosyl phosphatidylinositol anchor deficiency in human patients with paroxysmal nocturnal hemoglobinuria. Design and Methods We produced an animal model of paroxysmal nocturnal hemoglobinuria by conditional Pig-a gene inactivation (Pig-a−/−) in hematopoietic cells; mice carrying two lox sites flanking exon 6 of the Pig-a gene were bred with mice carrying the transgene Cre-recombinase under the human c-fes promoter. We characterized the phenotypic and functional properties of glycosyl phosphatidylinositol-deficient and glycosyl phosphatidylinositol-normal hematopoietic cells from these Pig-a−/− mice using gene expression microarray, flow cytometry, bone marrow transplantation, spectratyping, and immunoblotting. Results In comparison to glycosyl phosphatidylinositol-normal bone marrow cells, glycosyl phosphatidylinositol-deficient bone marrow cells from the same Pig-a−/− animals showed up-regulation of the expression of immune function genes and contained a significantly higher proportion of CD8 T cells. Both characteristics were maintained when glycosyl phosphatidylinositol-deficient cells were transplanted into lethally-irradiated recipients. Glycosyl phosphatidylinositol-deficient T cells were inactive, showed pronounced Vβ5.1/5.2 skewing, had fewer γ-interferon-producing cells after lectin stimulation, and contained fewer CD4+CD25+FoxP3+ regulatory T cells. However, the levels of T-cell receptor signaling proteins from glycosyl phosphatidylinositol-deficient cells were normal relative to glycosyl phosphatidylinositol-normal cells from wild type animals, and cells were capable of inducing target cell apoptosis in vitro. Conclusions Deletion of the Pig-a gene in hematopoietic cells does not cause frank marrow failure but leads to the appearance of clonally-restricted, inactive yet functionally competent CD8 T cells. PMID:19679885

  5. Quantitative Modeling of Entangled Polymer Rheology: Experiments, Tube Models and Slip-Link Simulations

    NASA Astrophysics Data System (ADS)

    Desai, Priyanka Subhash

    Rheology properties are sensitive indicators of molecular structure and dynamics. The relationship between rheology and polymer dynamics is captured in the constitutive model, which, if accurate and robust, would greatly aid molecular design and polymer processing. This dissertation is thus focused on building accurate and quantitative constitutive models that can help predict linear and non-linear viscoelasticity. In this work, we have used a multi-pronged approach based on the tube theory, coarse-grained slip-link simulations, and advanced polymeric synthetic and characterization techniques, to confront some of the outstanding problems in entangled polymer rheology. First, we modified simple tube based constitutive equations in extensional rheology and developed functional forms to test the effect of Kuhn segment alignment on a) tube diameter enlargement and b) monomeric friction reduction between subchains. We, then, used these functional forms to model extensional viscosity data for polystyrene (PS) melts and solutions. We demonstrated that the idea of reduction in segmental friction due to Kuhn alignment is successful in explaining the qualitative difference between melts and solutions in extension as revealed by recent experiments on PS. Second, we compiled literature data and used it to develop a universal tube model parameter set and prescribed their values and uncertainties for 1,4-PBd by comparing linear viscoelastic G' and G" mastercurves for 1,4-PBds of various branching architectures. The high frequency transition region of the mastercurves superposed very well for all the 1,4-PBds irrespective of their molecular weight and architecture, indicating universality in high frequency behavior. Therefore, all three parameters of the tube model were extracted from this high frequency transition region alone. Third, we compared predictions of two versions of the tube model, Hierarchical model and BoB model against linear viscoelastic data of blends of 1,4-PBd

  6. Phenotype consequences of myophosphorylase dysfunction: insights from the McArdle mouse model

    PubMed Central

    Brull, Astrid; de Luna, Noemí; Blanco-Grau, Albert; Lucia, Alejandro; Martin, Miguel Angel; Arenas, Joaquin; Martí, Ramon; Andreu, Antoni L; Pinós, Tomàs

    2015-01-01

    McArdle disease, caused by inherited deficiency of the enzyme muscle glycogen phosphorylase (GP-MM), is arguably the paradigm of exercise intolerance. The recent knock-in (p.R50X/p.R50X) mouse disease model allows an investigation of the phenotypic consequences of muscle glycogen unavailability and the physiopathology of exercise intolerance. We analysed, in 2-month-old mice [wild-type (wt/wt), heterozygous (p.R50X/wt) and p.R50X/p.R50X)], maximal endurance exercise capacity and the molecular consequences of an absence of GP-MM in the main glycogen metabolism regulatory enzymes: glycogen synthase, glycogen branching enzyme and glycogen debranching enzyme, as well as glycogen content in slow-twitch (soleus), intermediate (gastrocnemius) and glycolytic/fast-twitch (extensor digitorum longus; EDL) muscles. Compared with wt/wt, exercise capacity (measured in a treadmill test) was impaired in p.R50X/p.R50X (∼48%) and p.R50X/wt mice (∼18%). p.R50X/p.R50X mice showed an absence of GP-MM in the three muscles. GP-MM was reduced in p.R50X/wt mice, especially in the soleus, suggesting that the function of ‘slow-twitch’ muscles is less dependent on glycogen catabolism. p.R50X/p.R50X mice showed increased glycogen debranching enzyme in the soleus, increased glycogen branching enzyme in the gastrocnemius and EDL, as well as reduced levels of mucle glycogen synthase protein in the three muscles (mean ∼70%), reflecting a protective mechanism for preventing deleterious glycogen accumulation. Additionally, glycogen content was highest in the EDL of p.R50X/p.R50X mice. Amongst other findings, the present study shows that the expression of the main muscle glycogen regulatory enzymes differs depending on the muscle phenotype (slow- vs. fast-twitch) and that even partial GP-MM deficiency affects maximal endurance capacity. Our knock-in model might help to provide insights into the importance of glycogen on muscle function. PMID:25873271

  7. Phenotyping animal models of diabetic neuropathy: a consensus statement of the diabetic neuropathy study group of the EASD (Neurodiab)

    PubMed Central

    Biessels, G.J.; Bril, V.; Calcutt, N.A.; Cameron, N.E.; Cotter, M.A.; Dobrowsky, R.; Feldman, E.L.; Fernyhough, P.; Jakobsen, J.; Malik, R.A.; Mizisin, A.P.; Oates, P.J.; Obrosova, I.G.; Pop-Busui, R.; Russell, J.W.; Sima, A.A.; Stevens, M.J.; Schmidt, R.E.; Tesfaye, S.; Veves, A.; Vinik, A.I.; Wright, D.E.; Yagihashi, S.; Yorek, M.A.; Ziegler, D.; Zochodne, D.W.

    2015-01-01

    NIDDK, JDRF, and the Diabetic Neuropathy Study Group of EASD sponsored a meeting to explore the current status of animal models of diabetic peripheral neuropathy. The goal of the workshop was to develop a set of consensus criteria for the phenotyping of rodent models of diabetic neuropathy. The discussion was divided into five areas: (1) status of commonly used rodent models of diabetes, (2) nerve structure, (3) electrophysiological assessments of nerve function, (4) behavioral assessments of nerve function, and (5) the role of biomarkers in disease phenotyping. Participants discussed the current understanding of each area, gold standards (if applicable) for assessments of function, improvements of existing techniques, and utility of known and exploratory biomarkers. The research opportunities in each area were outlined, providing a possible roadmap for future studies. The meeting concluded with a discussion on the merits and limitations of a unified approach to phenotyping rodent models of diabetic neuropathy and a consensus formed on the definition of the minimum criteria required for establishing the presence of the disease. A neuropathy phenotype in rodents was defined as the presence of statistically different values between diabetic and control animals in 2 of 3 assessments (nocifensive behavior, nerve conduction velocities, or nerve structure). The participants propose that this framework would allow different research groups to compare and share data, with an emphasis on data targeted toward the therapeutic efficacy of drug interventions. PMID:24934510

  8. Phenotyping animal models of diabetic neuropathy: a consensus statement of the diabetic neuropathy study group of the EASD (Neurodiab).

    PubMed

    Biessels, G J; Bril, V; Calcutt, N A; Cameron, N E; Cotter, M A; Dobrowsky, R; Feldman, E L; Fernyhough, P; Jakobsen, J; Malik, R A; Mizisin, A P; Oates, P J; Obrosova, I G; Pop-Busui, R; Russell, J W; Sima, A A; Stevens, M J; Schmidt, R E; Tesfaye, S; Veves, A; Vinik, A I; Wright, D E; Yagihashi, S; Yorek, M A; Ziegler, D; Zochodne, D W

    2014-06-01

    NIDDK, JDRF, and the Diabetic Neuropathy Study Group of EASD sponsored a meeting to explore the current status of animal models of diabetic peripheral neuropathy. The goal of the workshop was to develop a set of consensus criteria for the phenotyping of rodent models of diabetic neuropathy. The discussion was divided into five areas: (1) status of commonly used rodent models of diabetes, (2) nerve structure, (3) electrophysiological assessments of nerve function, (4) behavioral assessments of nerve function, and (5) the role of biomarkers in disease phenotyping. Participants discussed the current understanding of each area, gold standards (if applicable) for assessments of function, improvements of existing techniques, and utility of known and exploratory biomarkers. The research opportunities in each area were outlined, providing a possible roadmap for future studies. The meeting concluded with a discussion on the merits and limitations of a unified approach to phenotyping rodent models of diabetic neuropathy and a consensus formed on the definition of the minimum criteria required for establishing the presence of the disease. A neuropathy phenotype in rodents was defined as the presence of statistically different values between diabetic and control animals in 2 of 3 assessments (nocifensive behavior, nerve conduction velocities, or nerve structure). The participants propose that this framework would allow different research groups to compare and share data, with an emphasis on data targeted toward the therapeutic efficacy of drug interventions.

  9. Generalized Modelling of the Stabilizer Link and Static Simulation Using FEM

    NASA Astrophysics Data System (ADS)

    Cofaru, Nicolae Florin; Roman, Lucian Ion; Oleksik, Valentin; Pascu, Adrian

    2016-12-01

    This paper proposes an organological approach of one of the components of front suspension, namely anti-roll power link. There will be realized a CAD 3D modelling of this power link. 3D modelling is generalized and there were used the powers of Catia V5R20 software. Parameterized approach provides a high flexibility in the design, meaning that dimensional and shape changes of the semi-power link are very easy to perform just by changing some parameters. Several new versions are proposed for the anti-roll power link body. At the end of the work, it is made a static analysis of the semi-power link model used in the suspension of vehicles OPEL ASTRA G, ZAFIRA, MERIVA, and constructive optimization of its body.

  10. Longitudinal analysis of the behavioral phenotype in a novel transgenic rat model of early stages of Alzheimer's disease.

    PubMed

    Galeano, Pablo; Martino Adami, Pamela V; Do Carmo, Sonia; Blanco, Eduardo; Rotondaro, Cecilia; Capani, Francisco; Castaño, Eduardo M; Cuello, A Claudio; Morelli, Laura

    2014-01-01

    Intraneuronal accumulation of amyloid β (iAβ) has been linked to mild cognitive impairment that may precede Alzheimer's disease (AD) onset. This neuropathological trait was recently mimicked in a novel animal model of AD, the hemizygous transgenic McGill-R-Thy1-APP (Tg(+/-)) rat. The characterization of the behavioral phenotypes in this animal model could provide a baseline of efficacy for earlier therapeutic interventions. The aim of the present study was to undertake a longitudinal study of Aβ accumulation and a comprehensive behavioral evaluation of this transgenic rat model. We assessed exploratory activity, anxiety-related behaviors, recognition memory, working memory, spatial learning and reference memory at 3, 6, and 12 months of age. In parallel, we measured Aβ by ELISA, Western blots and semiquantitative immunohistochemistry in hippocampal samples. SDS-soluble Aβ peptide accumulated at low levels (~9 pg/mg) without differences among ages. However, Western blots showed SDS-resistant Aβ oligomers (~30 kDa) at 6 and 12 months, but not at 3 months. When compared to wild-type (WT), male Tg(+/-) rats exhibited a spatial reference memory deficit in the Morris Water Maze (MWM) as early as 3 months of age, which persisted at 6 and 12 months. In addition, Tg(+/-) rats displayed a working memory impairment in the Y-maze and higher anxiety levels in the Open Field (OF) at 6 and 12 months of age, but not at 3 months. Exploratory activity in the OF was similar to that of WT at all-time points. Spatial learning in the MWM and the recognition memory, as assessed by the Novel Object Recognition Test, were unimpaired at any time point. The data from the present study demonstrate that the hemizygous transgenic McGill-R-Thy1-APP rat has a wide array of behavioral and cognitive impairments from young adulthood to middle-age. The low Aβ burden and early emotional and cognitive deficits in this transgenic rat model supports its potential use for drug discovery purposes in

  11. Longitudinal analysis of the behavioral phenotype in a novel transgenic rat model of early stages of Alzheimer's disease

    PubMed Central

    Galeano, Pablo; Martino Adami, Pamela V.; Do Carmo, Sonia; Blanco, Eduardo; Rotondaro, Cecilia; Capani, Francisco; Castaño, Eduardo M.; Cuello, A. Claudio; Morelli, Laura

    2014-01-01

    Intraneuronal accumulation of amyloid β (iAβ) has been linked to mild cognitive impairment that may precede Alzheimer's disease (AD) onset. This neuropathological trait was recently mimicked in a novel animal model of AD, the hemizygous transgenic McGill-R-Thy1-APP (Tg+/−) rat. The characterization of the behavioral phenotypes in this animal model could provide a baseline of efficacy for earlier therapeutic interventions. The aim of the present study was to undertake a longitudinal study of Aβ accumulation and a comprehensive behavioral evaluation of this transgenic rat model. We assessed exploratory activity, anxiety-related behaviors, recognition memory, working memory, spatial learning and reference memory at 3, 6, and 12 months of age. In parallel, we measured Aβ by ELISA, Western blots and semiquantitative immunohistochemistry in hippocampal samples. SDS-soluble Aβ peptide accumulated at low levels (~9 pg/mg) without differences among ages. However, Western blots showed SDS-resistant Aβ oligomers (~30 kDa) at 6 and 12 months, but not at 3 months. When compared to wild-type (WT), male Tg+/− rats exhibited a spatial reference memory deficit in the Morris Water Maze (MWM) as early as 3 months of age, which persisted at 6 and 12 months. In addition, Tg+/− rats displayed a working memory impairment in the Y-maze and higher anxiety levels in the Open Field (OF) at 6 and 12 months of age, but not at 3 months. Exploratory activity in the OF was similar to that of WT at all-time points. Spatial learning in the MWM and the recognition memory, as assessed by the Novel Object Recognition Test, were unimpaired at any time point. The data from the present study demonstrate that the hemizygous transgenic McGill-R-Thy1-APP rat has a wide array of behavioral and cognitive impairments from young adulthood to middle-age. The low Aβ burden and early emotional and cognitive deficits in this transgenic rat model supports its potential use for drug discovery purposes in

  12. Axonal transport defects are a common phenotype in Drosophila models of ALS

    PubMed Central

    Baldwin, Katie R.; Godena, Vinay K.; Hewitt, Victoria L.; Whitworth, Alexander J.

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of motor neurons resulting in a catastrophic loss of motor function. Current therapies are severely limited owing to a poor mechanistic understanding of the pathobiology. Mutations in a large number of genes have now been linked to ALS, including SOD1, TARDBP (TDP-43), FUS and C9orf72. Functional analyses of these genes and their pathogenic mutations have provided great insights into the underlying disease mechanisms. Defective axonal transport is hypothesized to be a key factor in the selective vulnerability of motor nerves due to their extraordinary length and evidence that ALS occurs as a distal axonopathy. Axonal transport is seen as an early pathogenic event that precedes cell loss and clinical symptoms and so represents an upstream mechanism for therapeutic targeting. Studies have begun to describe the impact of a few pathogenic mutations on axonal transport but a broad survey across a range of models and cargos is warranted. Here, we assessed the axonal transport of different cargos in multiple Drosophila models of ALS. We found that axonal transport defects are common across all models tested, although they often showed a differential effect between mitochondria and vesicle cargos. Motor deficits were also common across the models and generally worsened with age, though surprisingly there was not a clear correlation between the severity of axonal transport defects and motor ability. These results further support defects in axonal transport as a common factor in models of ALS that may contribute to the pathogenic process. PMID:27056981

  13. Design-oriented analytic model of phase and frequency modulated optical links

    NASA Astrophysics Data System (ADS)

    Monsurrò, Pietro; Saitto, Antonio; Tommasino, Pasquale; Trifiletti, Alessandro; Vannucci, Antonello; Cimmino, Rosario F.

    2016-07-01

    An analytic design-oriented model of phase and frequency modulated microwave optical links has been developed. The models are suitable for design of broadband high dynamic range optical links for antenna remoting and optical beamforming, where noise and linearity of the subsystems are a concern Digital filter design techniques have been applied to the design of optical filters working as frequency discriminator, that are the bottleneck in terms of linearity for these systems. The models of frequency modulated, phase modulated, and coherent I/Q link have been used to compare performance of the different architectures in terms of linearity and SFDR.

  14. Effects of perinatal, late foetal, and early embryonic insults on the cardiovascular phenotype in experimental animal models and humans.

    PubMed

    Meister, Theo Arthur; Rexhaj, Emrush; Rimoldi, Stefano Flavio; Scherrer, Urs; Sartori, Claudio

    2016-11-01

    Cardiovascular diseases are the main cause of mortality and morbidity in Western countries, but the underlying mechanisms are still poorly understood. Genetic polymorphisms, once thought to represent a major determinant of cardiovascular risk, individually and collectively, only explain a tiny fraction of phenotypic variation and disease risk in humans. It is now clear that non-genetic factors, i.e., factors that modify gene activity without changing the DNA sequence and that are sensitive to the environment can cause important alterations of the cardiovascular phenotype in experimental animal models and humans. Here, we will review recent studies demonstrating that distinct pathological events during the perinatal (transient perinatal hypoxemia), late foetal (preeclampsia), and early embryonic (assisted reproductive technologies) periods induce profound alterations of the cardiovascular phenotype in humans and experimental animals. Moreover, we will provide evidence that epigenetic modifications are contributing importantly to this problem and are conferring the potential for its transmission to subsequent generations.

  15. Altered postnatal maturation of striatal GABAergic interneurons in a phenotypic animal model of dystonia.

    PubMed

    Bode, Christoph; Richter, Franziska; Spröte, Christine; Brigadski, Tanja; Bauer, Anne; Fietz, Simone; Fritschy, Jean-Marc; Richter, Angelika

    2017-01-01

    GABAergic disinhibition has been suggested to play a critical role in the pathophysiology of several basal ganglia disorders, including dystonia, a common movement disorder. Previous studies have shown a deficit of striatal GABAergic interneurons (IN) in the dt(sz) mutant hamster, one of the few phenotypic animal models of dystonia. However, mechanisms underlying this deficit are largely unknown. In the present study, we investigated the migration and maturation of striatal IN during postnatal development (18days of age) and at age of highest severity of dystonia (33days of age) in this hamster model. In line with previous findings, the density of GAD67-positive IN and the level of parvalbumin mRNA, a marker for fast spiking GABAergic IN, were lower in the dt(sz) mutant than in control hamsters. However, an unaltered density of Nkx2.1 labeled cells and Nkx2.1 mRNA level suggested that the migration of GABAergic IN into the striatum was not retarded. Therefore, different factors that indicate maturation of GABAergic IN were determined. While mRNA of the KCC2 cation/chloride transporters and the cytosolic carboanhydrase VII, used as markers for the so called GABA switch, as well as BDNF were unaltered, we found a reduced number of IN expressing the alpha1 subunit of the GABAA-receptor (37.5%) in dt(sz) hamsters at an age of 33days, but not after spontaneous remission of dystonia at an age of 90days. Since IN shift expression from alpha2 to alpha1 subunits during postnatal maturation, this result together with a decreased parvalbumin mRNA expression suggest a delayed maturation of striatal GABAergic IN in this animal model, which might underlie abnormal neuronal activity and striatal plasticity.

  16. TCR/pMHC Interaction: Phenotypic Model for an Unsolved Enigma

    PubMed Central

    Gálvez, Jesús; Gálvez, Juan J.; García-Peñarrubia, Pilar

    2016-01-01

    TCR–pMHC interaction is the keystone of the adaptive immune response. This process exhibits an impressive capacity of speed, sensitivity, and discrimination that allows detecting foreign pMHCs at very low concentration among much more abundant self-pMHC ligands. However, and despite over three decades of intensive research, the mechanisms by which this remarkable discrimination and sensitivity is attained remain controversial. In kinetic proofreading mechanisms (KPR), an increase of specificity occurs by reducing the sensitivity. To overcome this difficulty, more elaborate models including feedback processes or induced rebinding have been incorporated into the KPR scheme. Here a new approach based on the assumption that the proofreading chain behaves differently for foreign- and self-pMHC complexes has been integrated into a phenotypic model in which the complexes responsible for T cell activation stabilize (for foreign peptides) or weaken (for foreign peptides), resulting in a dramatic increase in sensitivity and specificity. Stabilization and destabilization of complexes may be caused by conformational changes, rebinding, or any other process leading to variations in the dissociation rate constants of the complexes transmitting the activation. The numerical solution and the analytical expression for the steady-state response as a function of koff(i) (i = 0, 1, …, N, where C0, C1, …, CN are the complexes in the proofreading chain) are provided. The activation chain speeds up, and larger increases in sensitivity and discrimination are obtained if the rate of activation along the proofreading chain increases for foreign pMHCs and decreases for self-ligands. Experimental implications and comparison with current models are discussed. PMID:27881981

  17. Theory and Practice: An Integrative Model Linking Class and Field

    ERIC Educational Resources Information Center

    Lesser, Joan Granucci; Cooper, Marlene

    2006-01-01

    Social work has evolved over the years taking on the challenges of the times. The profession now espouses a breadth of theoretical approaches and treatment modalities. We have developed a model to help graduate social work students master the skill of integrating theory and social work practice. The Integrative Model has five components: (l) The…

  18. A Tiered Model for Linking Students to the Community

    ERIC Educational Resources Information Center

    Meyer, Laura Landry; Gerard, Jean M.; Sturm, Michael R.; Wooldridge, Deborah G.

    2016-01-01

    A tiered practice model (introductory, pre-internship, and internship) embedded in the curriculum facilitates community engagement and creates relevance for students as they pursue a professional identity in Human Development and Family Studies. The tiered model integrates high-impact teaching practices (HIP) and student engagement pedagogies…

  19. Modeling and control of a hydraulically actuated flexible-prismatic link robot

    SciTech Connect

    Love, L.; Kress, R.; Jansen, J.

    1996-12-01

    Most of the research related to flexible link manipulators to date has focused on single link, fixed length, single plane of vibration test beds. In addition, actuation has been predominantly based upon electromagnetic motors. Ironically, these elements are rarely found in the existing industrial long reach systems. This manuscript describes a new hydraulically actuated, long reach manipulator with a flexible prismatic link at Oak Ridge National Laboratory (ORNL). Focus is directed towards both modeling and control of hydraulic actuators as well as flexible links that have variable natural frequencies.

  20. Pkd1 transgenic mice: adult model of polycystic kidney disease with extrarenal and renal phenotypes

    PubMed Central

    Kurbegovic, Almira; Côté, Olivier; Couillard, Martin; Ward, Christopher J.; Harris, Peter C.; Trudel, Marie

    2010-01-01

    While high levels of Pkd1 expression are detected in tissues of patients with autosomal dominant polycystic kidney disease (ADPKD), it is unclear whether enhanced expression could be a pathogenetic mechanism for this systemic disorder. Three transgenic mouse lines were generated from a Pkd1-BAC modified by introducing a silent tag via homologous recombination to target a sustained wild-type genomic Pkd1 expression within the native tissue and temporal regulation. These mice specifically overexpressed the Pkd1 transgene in extrarenal and renal tissues from ∼2- to 15-fold over Pkd1 endogenous levels in a copy-dependent manner. All transgenic mice reproducibly developed tubular and glomerular cysts leading to renal insufficiency. Interestingly, Pkd1TAG mice also exhibited renal fibrosis and calcium deposits in papilla reminiscent of nephrolithiasis as frequently observed in ADPKD. Similar to human ADPKD, these mice consistently displayed hepatic fibrosis and ∼15% intrahepatic cysts of the bile ducts affecting females preferentially. Moreover, a significant proportion of mice developed cardiac anomalies with severe left-ventricular hypertrophy, marked aortic arch distention and/or valvular stenosis and calcification that had profound functional impact. Of significance, Pkd1TAG mice displayed occasional cerebral lesions with evidence of ruptured and unruptured cerebral aneurysms. This Pkd1TAG mouse model demonstrates that overexpression of wild-type Pkd1 can trigger the typical adult renal and extrarenal phenotypes resembling human ADPKD. PMID:20053665

  1. Genetic determinants of cardiometabolic risk: a proposed model for phenotype association and interaction.

    PubMed

    Blackett, Piers R; Sanghera, Dharambir K

    2013-01-01

    This review provides a translational and unifying summary of metabolic syndrome genetics and highlights evidence that genetic studies are starting to unravel and untangle origins of the complex and challenging cluster of disease phenotypes. The associated genes effectively express in the brain, liver, kidney, arterial endothelium, adipocytes, myocytes, and β cells. Progression of syndrome traits has been associated with ectopic lipid accumulation in the arterial wall, visceral adipocytes, myocytes, and liver. Thus, it follows that the genetics of dyslipidemia, obesity, and nonalcoholic fatty liver disease are central in triggering progression of the syndrome to overt expression of disease traits and have become a key focus of interest for early detection and for designing prevention and treatments. To support the "birds' eye view" approach, we provide a road-map depicting commonality and interrelationships between the traits and their genetic and environmental determinants based on known risk factors, metabolic pathways, pharmacologic targets, treatment responses, gene networks, pleiotropy, and association with circadian rhythm. Although only a small portion of the known heritability is accounted for and there is insufficient support for clinical application of gene-based prediction models, there is direction and encouraging progress in a rapidly moving field that is beginning to show clinical relevance.

  2. Human pulmonary artery endothelial cells in the model of mucopolysaccharidosis VI present a prohypertensive phenotype

    PubMed Central

    Golda, Adam; Jurecka, Agnieszka; Gajda, Karolina; Tylki-Szymańska, Anna; Lalik, Anna

    2015-01-01

    Background Mucopolysaccharidosis type VI (MPS VI) is an autosomal recessive lysosomal disorder caused by a deficient activity of N-acetylgalactosamine-4-sulfatase (ARSB). Pulmonary hypertension (PH) occurs in MPS VI patients and is a marker of bad prognosis. Malfunction of endothelium, which regulates vascular tonus and stimulates angiogenesis, can contribute to the occurrence of PH in MPS VI. Aim The aim of the study was to establish a human MPS VI cellular model of pulmonary artery endothelial cells (HPAECs) and evaluate how it affects factors that may trigger PH such as proliferation, apoptosis, expression of endothelial nitric oxide synthase (eNOS), natriuretic peptide type C (NPPC), and vascular endothelial growth factor A (VEGFA). Results Increasing concentrations of dermatan sulfate (DS) reduce the viability of the cells in both ARSB deficiency and controls, but hardly influence apoptosis. The expression of eNOS in HPAECs is reduced up to two thirds in the presence of DS. NPPC shows a biphasic expression reaction with an increase at 50 μg/mL DS and reduction at 0 and 100 μg/mL DS. The expression of VEGFA decreases with increasing DS concentrations and absence of elastin, and increases with increasing DS in the presence of elastin. Conclusion Our data suggest that MPS VI endothelium presents a prohypertensive phenotype due to the reduction of endothelium's proliferation ability and expression of vasorelaxing factors. PMID:26937388

  3. Metabolic acetate therapy improves phenotype in the tremor rat model of Canavan disease.

    PubMed

    Arun, Peethambaran; Madhavarao, Chikkathur N; Moffett, John R; Hamilton, Kristen; Grunberg, Neil E; Ariyannur, Prasanth S; Gahl, William A; Anikster, Yair; Mog, Steven; Hallows, William C; Denu, John M; Namboodiri, Aryan M A

    2010-06-01

    Genetic mutations that severely diminish the activity of aspartoacylase (ASPA) result in the fatal brain dysmyelinating disorder, Canavan disease. There is no effective treatment. ASPA produces free acetate from the concentrated brain metabolite, N-acetylaspartate (NAA). Because acetyl coenzyme A is a key building block for lipid synthesis, we postulated that the inability to catabolize NAA leads to a brain acetate deficiency during a critical period of CNS development, impairing myelination and possibly other aspects of brain development. We tested the hypothesis that acetate supplementation during postnatal myelination would ameliorate the severe phenotype associated with ASPA deficiency using the tremor rat model of Canavan disease. Glyceryltriacetate (GTA) was administered orally to tremor rats starting 7 days after birth, and was continued in food and water after weaning. Motor function, myelin lipids, and brain vacuolation were analyzed in GTA-treated and untreated tremor rats. Significant improvements were observed in motor performance and myelin galactocerebroside content in tremor rats treated with GTA. Further, brain vacuolation was modestly reduced, and these reductions were positively correlated with improved motor performance. We also examined the expression of the acetyl coenzyme A synthesizing enzyme acetyl coenzyme A synthase 1 and found upregulation of expression in tremor rats, with a return to near normal expression levels in GTA-treated tremor rats. These results confirm the critical role played by NAA-derived acetate in brain myelination and development, and demonstrate the potential usefulness of acetate therapy for the treatment of Canavan disease.

  4. Derivation of free energy expressions for tube models from coarse-grained slip-link models

    NASA Astrophysics Data System (ADS)

    Steenbakkers, Rudi J. A.; Schieber, Jay D.

    2012-07-01

    We present the free energy of a single-chain mean-field model for polymer melt dynamics, which uses a continuous (tube-like) approximation to the discrete entanglements with surrounding chains, but, in contrast to previous tube models, includes fluctuations in the number density of Kuhn steps along the primitive path and in the degree of entanglement. The free energy is obtained from that of the slip-link model with fluctuating entanglement positions [J. D. Schieber and K. Horio, J. Chem. Phys. 132, 074905 (2010)], 10.1063/1.3314727 by taking the continuous limit of (functions of) the discrete Kuhn-step numbers and end-to-end vectors of the strands between entanglements. This coarse-graining from a more-detailed level of description has the advantage that no ad hoc arguments need to be introduced. Moreover, the thermodynamic consistency of the slip-link model [J. D. Schieber, J. Non-Equilib. Thermodyn. 28, 179 (2003)], 10.1515/JNETDY.2003.010 can be preserved. Fluctuations in the positions of entanglements lead to a harmonic bending term in the free energy of the continuous chain, similar to that derived by Read et al. [Macromolecules 41, 6843 (2008)], 10.1021/ma8009855 starting from a modified GLaMM model [R. S. Graham, A. E. Likhtman, T. C. B. McLeish, and S. T. Milner, J. Rheol. 47, 1171 (2003)], 10.1122/1.1595099. If these fluctuations are set to zero, the free energy becomes purely Gaussian and corresponds to the continuous limit of the original slip-link model, with affinely moving entanglements [J. D. Schieber, J. Chem. Phys. 118, 5162 (2003)], 10.1063/1.1553764. The free energy reduces to that of Read et al. under their assumptions of a homogeneous Kuhn-step number density and a constant degree of entanglement. Finally, we show how a transformation of the primitive-path coordinate can be applied to make the degree of entanglement an outcome of the model instead of a variable. In summary, this paper constitutes a first step towards a unified mathematical

  5. Monte Carlo simulation of OLS and linear mixed model inference of phenotypic effects on gene expression

    PubMed Central

    2016-01-01

    Background Self-contained tests estimate and test the association between a phenotype and mean expression level in a gene set defined a priori. Many self-contained gene set analysis methods have been developed but the performance of these methods for phenotypes that are continuous rather than discrete and with multiple nuisance covariates has not been well studied. Here, I use Monte Carlo simulation to evaluate the performance of both novel and previously published (and readily available via R) methods for inferring effects of a continuous predictor on mean expression in the presence of nuisance covariates. The motivating data are a high-profile dataset which was used to show opposing effects of hedonic and eudaimonic well-being (or happiness) on the mean expression level of a set of genes that has been correlated with social adversity (the CTRA gene set). The original analysis of these data used a linear model (GLS) of fixed effects with correlated error to infer effects of Hedonia and Eudaimonia on mean CTRA expression. Methods The standardized effects of Hedonia and Eudaimonia on CTRA gene set expression estimated by GLS were compared to estimates using multivariate (OLS) linear models and generalized estimating equation (GEE) models. The OLS estimates were tested using O’Brien’s OLS test, Anderson’s permutation \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{upgreek} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} }{}${r}_{F}^{2}$\\end{document}rF2-test, two permutation F-tests (including GlobalAncova), and a rotation z-test (Roast). The GEE estimates were tested using a Wald test with robust standard errors. The performance (Type I, II, S, and M errors) of all tests was investigated using a Monte Carlo simulation of data explicitly modeled on the re-analyzed dataset. Results GLS estimates are inconsistent between data

  6. Strengthening the weak link: Built Environment modelling for loss analysis

    NASA Astrophysics Data System (ADS)

    Millinship, I.

    2012-04-01

    Methods to analyse insured losses from a range of natural perils, including pricing by primary insurers and catastrophe modelling by reinsurers, typically lack sufficient exposure information. Understanding the hazard intensity in terms of spatial severity and frequency is only the first step towards quantifying the risk of a catastrophic event. For any given event we need to know: Are any structures affected? What type of buildings are they? How much damaged occurred? How much will the repairs cost? To achieve this, detailed exposure information is required to assess the likely damage and to effectively calculate the resultant loss. Modelling exposures in the Built Environment therefore plays as important a role in understanding re/insurance risk as characterising the physical hazard. Across both primary insurance books and aggregated reinsurance portfolios, the location of a property (a risk) and its monetary value is typically known. Exactly what that risk is in terms of detailed property descriptors including structure type and rebuild cost - and therefore its vulnerability to loss - is often omitted. This data deficiency is a primary source of variations between modelled losses and the actual claims value. Built Environment models are therefore required at a high resolution to describe building attributes that relate vulnerability to property damage. However, national-scale household-level datasets are often not computationally practical in catastrophe models and data must be aggregated. In order to provide more accurate risk analysis, we have developed and applied a methodology for Built Environment modelling for incorporation into a range of re/insurance applications, including operational models for different international regions and different perils and covering residential, commercial and industry exposures. Illustrated examples are presented, including exposure modelling suitable for aggregated reinsurance analysis for the UK and bespoke high resolution

  7. Phenotypic characterization of the Komeda miniature rat Ishikawa, an animal model of dwarfism caused by a mutation in Prkg2.

    PubMed

    Tsuchida, Atsuko; Yokoi, Norihide; Namae, Misako; Fuse, Masanori; Masuyama, Taku; Sasaki, Masashi; Kawazu, Shoji; Komeda, Kajuro

    2008-12-01

    The Komeda miniature rat Ishikawa (KMI) is a spontaneous animal model of dwarfism caused by a mutation in Prkg2, which encodes cGMP-dependent protein kinase type II (cGKII). This strain has been maintained as a segregating inbred strain for the mutated allele mri. In this study, we characterized the phenotype of the KMI strain, particularly growth traits, craniofacial measurements, and organ weights. The homozygous mutant (mri/mri) animals were approximately 70% to 80% of the size of normal, heterozygous (mri/+) animals in regard to body length, weight, and naso-occipital length of the calvarium, and the retroperitoneal fat of mri/mri rats was reduced greatly. In addition, among progeny of the (BNxKMI-mri/mri)F1xKMI-mri/mri backcross, animals with the KMI phenotype (mri/mri) were easily distinguished from those showing the wild-type phenotype (mri/+) by using growth traits such as body length and weight. Genetic analysis revealed that all of the backcrossed progeny exhibiting the KMI phenotype were homozygous for the KMI allele in the 1.2-cM region between D14Rat5 and D14Rat80 on chromosome 14, suggesting strongly that mri acts in a completely recessive manner. The KMI strain is the first and only rat model with a confirmed mutation in Prkg2 and is a valuable model for studying dwarfism and longitudinal growth traits in humans and for functional studies of cGKII.

  8. Linking Time and Space Scales in Distributed Hydrological Modelling - a case study for the VIC model

    NASA Astrophysics Data System (ADS)

    Melsen, Lieke; Teuling, Adriaan; Torfs, Paul; Zappa, Massimiliano; Mizukami, Naoki; Clark, Martyn; Uijlenhoet, Remko

    2015-04-01

    One of the famous paradoxes of the Greek philosopher Zeno of Elea (~450 BC) is the one with the arrow: If one shoots an arrow, and cuts its motion into such small time steps that at every step the arrow is standing still, the arrow is motionless, because a concatenation of non-moving parts does not create motion. Nowadays, this reasoning can be refuted easily, because we know that motion is a change in space over time, which thus by definition depends on both time and space. If one disregards time by cutting it into infinite small steps, motion is also excluded. This example shows that time and space are linked and therefore hard to evaluate separately. As hydrologists we want to understand and predict the motion of water, which means we have to look both in space and in time. In hydrological models we can account for space by using spatially explicit models. With increasing computational power and increased data availability from e.g. satellites, it has become easier to apply models at a higher spatial resolution. Increasing the resolution of hydrological models is also labelled as one of the 'Grand Challenges' in hydrology by Wood et al. (2011) and Bierkens et al. (2014), who call for global modelling at hyperresolution (~1 km and smaller). A literature survey on 242 peer-viewed articles in which the Variable Infiltration Capacity (VIC) model was used, showed that the spatial resolution at which the model is applied has decreased over the past 17 years: From 0.5 to 2 degrees when the model was just developed, to 1/8 and even 1/32 degree nowadays. On the other hand the literature survey showed that the time step at which the model is calibrated and/or validated remained the same over the last 17 years; mainly daily or monthly. Klemeš (1983) stresses the fact that space and time scales are connected, and therefore downscaling the spatial scale would also imply downscaling of the temporal scale. Is it worth the effort of downscaling your model from 1 degree to 1

  9. A novel fibre-ensemble level constitutive model for exogenous cross-linked collagenous tissues

    PubMed Central

    Sacks, Michael S.; Wognum, Silvia

    2016-01-01

    Exogenous cross-linking of soft collagenous tissues is a common method for biomaterial development and medical therapies. To enable improved applications through computational methods, physically realistic constitutive models are required. Yet, despite decades of research, development and clinical use, no such model exists. In this study, we develop the first rigorous full structural model (i.e. explicitly incorporating various features of the collagen fibre architecture) for exogenously cross-linked soft tissues. This was made possible, in-part, with the use of native to cross-linked matched experimental datasets and an extension to the collagenous structural constitutive model so that the uncross-linked collagen fibre responses could be mapped to the cross-linked configuration. This allowed us to separate the effects of cross-linking from kinematic changes induced in the cross-linking process, which in turn allowed the non-fibrous tissue matrix component and the interaction effects to be identified. It was determined that the matrix could be modelled as an isotropic material using a modified Yeoh model. The most novel findings of this study were that: (i) the effective collagen fibre modulus was unaffected by cross-linking and (ii) fibre-ensemble interactions played a large role in stress development, often dominating the total tissue response (depending on the stress component and loading path considered). An important utility of the present model is its ability to separate the effects of exogenous cross-linking on the fibres from changes due to the matrix. Applications of this approach include the utilization in the design of novel chemical treatments to produce specific mechanical responses and the study of fatigue damage in bioprosthetic heart valve biomaterials. PMID:26855761

  10. A novel fibre-ensemble level constitutive model for exogenous cross-linked collagenous tissues.

    PubMed

    Sacks, Michael S; Zhang, Will; Wognum, Silvia

    2016-02-06

    Exogenous cross-linking of soft collagenous tissues is a common method for biomaterial development and medical therapies. To enable improved applications through computational methods, physically realistic constitutive models are required. Yet, despite decades of research, development and clinical use, no such model exists. In this study, we develop the first rigorous full structural model (i.e. explicitly incorporating various features of the collagen fibre architecture) for exogenously cross-linked soft tissues. This was made possible, in-part, with the use of native to cross-linked matched experimental datasets and an extension to the collagenous structural constitutive model so that the uncross-linked collagen fibre responses could be mapped to the cross-linked configuration. This allowed us to separate the effects of cross-linking from kinematic changes induced in the cross-linking process, which in turn allowed the non-fibrous tissue matrix component and the interaction effects to be identified. It was determined that the matrix could be modelled as an isotropic material using a modified Yeoh model. The most novel findings of this study were that: (i) the effective collagen fibre modulus was unaffected by cross-linking and (ii) fibre-ensemble interactions played a large role in stress development, often dominating the total tissue response (depending on the stress component and loading path considered). An important utility of the present model is its ability to separate the effects of exogenous cross-linking on the fibres from changes due to the matrix. Applications of this approach include the utilization in the design of novel chemical treatments to produce specific mechanical responses and the study of fatigue damage in bioprosthetic heart valve biomaterials.

  11. A model integration framework for linking SWAT and MODFLOW

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Hydrological response and transport phenomena are driven by atmospheric, surface and subsurface processes. These complex processes occur at different spatiotemporal scales requiring comprehensive modeling to assess the impact of anthropogenic activity on hydrology and fate and transport of chemical ...

  12. Computational Models for Prediction of Yeast Strain Potential for Winemaking from Phenotypic Profiles

    PubMed Central

    Umek, Lan; Fonseca, Elza; Drumonde-Neves, João; Dequin, Sylvie; Zupan, Blaz; Schuller, Dorit

    2013-01-01

    Saccharomyces cerevisiae strains from diverse natural habitats harbour a vast amount of phenotypic diversity, driven by interactions between yeast and the respective environment. In grape juice fermentations, strains are exposed to a wide array of biotic and abiotic stressors, which may lead to strain selection and generate naturally arising strain diversity. Certain phenotypes are of particular interest for the winemaking industry and could be identified by screening of large number of different strains. The objective of the present work was to use data mining approaches to identify those phenotypic tests that are most useful to predict a strain's potential for winemaking. We have constituted a S. cerevisiae collection comprising 172 strains of worldwide geographical origins or technological applications. Their phenotype was screened by considering 30 physiological traits that are important from an oenological point of view. Growth in the presence of potassium bisulphite, growth at 40°C, and resistance to ethanol were mostly contributing to strain variability, as shown by the principal component analysis. In the hierarchical clustering of phenotypic profiles the strains isolated from the same wines and vineyards were scattered throughout all clusters, whereas commercial winemaking strains tended to co-cluster. Mann-Whitney test revealed significant associations between phenotypic results and strain's technological application or origin. Naïve Bayesian classifier identified 3 of the 30 phenotypic tests of growth in iprodion (0.05 mg/mL), cycloheximide (0.1 µg/mL) and potassium bisulphite (150 mg/mL) that provided most information for the assignment of a strain to the group of commercial strains. The probability of a strain to be assigned to this group was 27% using the entire phenotypic profile and increased to 95%, when only results from the three tests were considered. Results show the usefulness of computational approaches to simplify strain selection

  13. Computational models for prediction of yeast strain potential for winemaking from phenotypic profiles.

    PubMed

    Mendes, Inês; Franco-Duarte, Ricardo; Umek, Lan; Fonseca, Elza; Drumonde-Neves, João; Dequin, Sylvie; Zupan, Blaz; Schuller, Dorit

    2013-01-01

    Saccharomyces cerevisiae strains from diverse natural habitats harbour a vast amount of phenotypic diversity, driven by interactions between yeast and the respective environment. In grape juice fermentations, strains are exposed to a wide array of biotic and abiotic stressors, which may lead to strain selection and generate naturally arising strain diversity. Certain phenotypes are of particular interest for the winemaking industry and could be identified by screening of large number of different strains. The objective of the present work was to use data mining approaches to identify those phenotypic tests that are most useful to predict a strain's potential for winemaking. We have constituted a S. cerevisiae collection comprising 172 strains of worldwide geographical origins or technological applications. Their phenotype was screened by considering 30 physiological traits that are important from an oenological point of view. Growth in the presence of potassium bisulphite, growth at 40 °C, and resistance to ethanol were mostly contributing to strain variability, as shown by the principal component analysis. In the hierarchical clustering of phenotypic profiles the strains isolated from the same wines and vineyards were scattered throughout all clusters, whereas commercial winemaking strains tended to co-cluster. Mann-Whitney test revealed significant associations between phenotypic results and strain's technological application or origin. Naïve Bayesian classifier identified 3 of the 30 phenotypic tests of growth in iprodion (0.05 mg/mL), cycloheximide (0.1 µg/mL) and potassium bisulphite (150 mg/mL) that provided most information for the assignment of a strain to the group of commercial strains. The probability of a strain to be assigned to this group was 27% using the entire phenotypic profile and increased to 95%, when only results from the three tests were considered. Results show the usefulness of computational approaches to simplify strain selection

  14. A simple model linking galaxy and dark matter evolution

    SciTech Connect

    Birrer, Simon; Lilly, Simon; Amara, Adam; Paranjape, Aseem; Refregier, Alexandre E-mail: simon.lilly@phys.ethz.ch

    2014-09-20

    We construct a simple phenomenological model for the evolving galaxy population by incorporating predefined baryonic prescriptions into a dark matter hierarchical merger tree. The model is based on the simple gas-regulator model introduced by Lilly et al., coupled with the empirical quenching rules of Peng et al. The simplest model already does quite well in reproducing, without re-adjusting the input parameters, many observables, including the main sequence sSFR-mass relation, the faint end slope of the galaxy mass function, and the shape of the star forming and passive mass functions. Similar to observations and/or the recent phenomenological model of Behroozi et al., which was based on epoch-dependent abundance-matching, our model also qualitatively reproduces the evolution of the main sequence sSFR(z) and SFRD(z) star formation rate density relations, the M{sub s} – M{sub h} stellar-to-halo mass relation, and the SFR – M{sub h} relation. Quantitatively the evolution of sSFR(z) and SFRD(z) is not steep enough, the M{sub s} – M{sub h} relation is not quite peaked enough, and, surprisingly, the ratio of quenched to star forming galaxies around M* is not quite high enough. We show that these deficiencies can simultaneously be solved by ad hoc allowing galaxies to re-ingest some of the gas previously expelled in winds, provided that this is done in a mass-dependent and epoch-dependent way. These allow the model galaxies to reduce an inherent tendency to saturate their star formation efficiency, which emphasizes how efficient galaxies around M* are in converting baryons into stars and highlights the fact that quenching occurs at the point when galaxies are rapidly approaching the maximum possible efficiency of converting baryons into stars.

  15. Evolution of the rate of biological aging using a phenotype based computational model.

    PubMed

    Kittas, Aristotelis

    2010-10-07

    In this work I introduce a simple model to study how natural selection acts upon aging, which focuses on the viability of each individual. It is able to reproduce the Gompertz law of mortality and can make predictions about the relation between the level of mutation rates (beneficial/deleterious/neutral), age at reproductive maturity and the degree of biological aging. With no mutations, a population with low age at reproductive maturity R stabilizes at higher density values, while with mutations it reaches its maximum density, because even for large pre-reproductive periods each individual evolves to survive to maturity. Species with very short pre-reproductive periods can only tolerate a small number of detrimental mutations. The probabilities of detrimental (P(d)) or beneficial (P(b)) mutations are demonstrated to greatly affect the process. High absolute values produce peaks in the viability of the population over time. Mutations combined with low selection pressure move the system towards weaker phenotypes. For low values in the ratio P(d)/P(b), the speed at which aging occurs is almost independent of R, while higher values favor significantly species with high R. The value of R is critical to whether the population survives or dies out. The aging rate is controlled by P(d) and P(b) and the amount of the viability of each individual is modified, with neutral mutations allowing the system more "room" to evolve. The process of aging in this simple model is revealed to be fairly complex, yielding a rich variety of results.

  16. Digastric Muscle Phenotypes of the Ts65Dn Mouse Model of Down Syndrome

    PubMed Central

    Connor, Nadine P.

    2016-01-01

    Down syndrome is frequently associated with complex difficulties in oromotor development, feeding, and swallowing. However, the muscle phenotypes underlying these deficits are unclear. We tested the hypotheses that the Ts65Dn mouse model of DS has significantly altered myosin heavy chain (MyHC) isoform profiles of the muscles involved in feeding and swallowing, as well as reductions in the speed of these movements during behavioral assays. SDS-PAGE, immunofluorescence, and qRT-PCR were used to assess MyHC isoform expression in pertinent muscles, and functional feeding and swallowing performance were quantified through videofluoroscopy and mastication assays. We found that both the anterior digastric (ADG) and posterior digastric (PDG) muscles in 11-day old and 5–6 week old Ts65Dn groups showed significantly lower MyHC 2b protein levels than in age-matched euploid control groups. In videofluoroscopic and videotape assays used to quantify swallowing and mastication performance, 5–6 week old Ts65Dn and euploid controls showed similar swallow rates, inter-swallow intervals, and mastication rates. In analysis of adults, 10–11 week old Ts65Dn mice revealed significantly less MyHC 2b mRNA expression in the posterior digastric, but not the anterior digastric muscle as compared with euploid controls. Analysis of MyHC 2b protein levels across an adult age range (10–53 weeks of age) revealed lower levels of MyHC 2b protein in the PDG of Ts65Dn than in euploids, but similar levels of MyHC 2b in the ADG. Cumulatively, these results indicate biochemical differences in some, but not all, muscles involved in swallowing and jaw movement in Ts65Dn mice that manifest early in post-natal development, and persist into adulthood. These findings suggest potential utility of this model for future investigations of the mechanisms of oromotor difficulties associated with Down syndrome. PMID:27336944

  17. Cardiac remodeling in the mouse model of Marfan syndrome develops into two distinctive phenotypes.

    PubMed

    Tae, Hyun-Jin; Petrashevskaya, Natalia; Marshall, Shannon; Krawczyk, Melissa; Talan, Mark

    2016-01-15

    Marfan syndrome (MFS) is a systemic disorder of connective tissue caused by mutations in fibrillin-1. Cardiac dysfunction in MFS has not been characterized halting the development of therapies of cardiac complication in MFS. We aimed to study the age-dependent cardiac remodeling in the mouse model of MFS FbnC1039G+/- mouse [Marfan heterozygous (HT) mouse] and its association with valvular regurgitation. Marfan HT mice of 2-4 mo demonstrated a mild hypertrophic cardiac remodeling with predominant decline of diastolic function and increased transforming growth factor-β canonical (p-SMAD2/3) and noncanonical (p-ERK1/2 and p-p38 MAPK) signaling and upregulation of hypertrophic markers natriuretic peptides atrium natriuretic peptide and brain natriuretic peptide. Among older HT mice (6-14 mo), cardiac remodeling was associated with two distinct phenotypes, manifesting either dilated or constricted left ventricular chamber. Dilatation of left ventricular chamber was accompanied by biochemical evidence of greater mechanical stress, including elevated ERK1/2 and p38 MAPK phosphorylation and higher brain natriuretic peptide expression. The aortic valve regurgitation was registered in 20% of the constricted group and 60% of the dilated group, whereas mitral insufficiency was observed in 40% of the constricted group and 100% of the dilated group. Cardiac dysfunction was not associated with the increase of interstitial fibrosis and nonmyocyte proliferation. In the mouse model fibrillin-1, haploinsufficiency results in the early onset of nonfibrotic hypertrophic cardiac remodeling and dysfunction, independently from valvular abnormalities. MFS heart is vulnerable to stress-induced cardiac dilatation in the face of valvular regurgitation, and stress-activated MAPK signals represent a potential target for cardiac management in MFS.

  18. Linking Meteorology, Air Quality Models and Observations to ...

    EPA Pesticide Factsheets

    Epidemiologic studies are critical in establishing the association between exposure to air pollutants and adverse health effects. Results of epidemiologic studies are used by U.S. EPA in developing air quality standards to protect the public from the health effects of air pollutants. A major challenge in environmental epidemiology is adequate exposure characterization. Numerous health studies have used measurements from a few central-site ambient monitors to characterize air pollution exposures. Relying solely on central-site ambient monitors does not account for the spatial-heterogeneity of ambient air pollution patterns, the temporal variability in ambient concentrations, nor the influence of infiltration and indoor sources. Central-site monitoring becomes even more problematic for certain air pollutants that exhibit significant spatial heterogeneity. Statistical interpolation techniques and passive monitoring methods can provide additional spatial resolution in ambient concentration estimates. In addition, spatio-temporal models, which integrate GIS data and other factors, such as meteorology, have also been developed to produce more resolved estimates of ambient concentrations. Models, such as the Community Multi-Scale Air Quality (CMAQ) model, estimate ambient concentrations by combining information on meteorology, source emissions, and chemical-fate and transport. Hybrid modeling approaches, which integrate regional scale models with local scale dispersion

  19. Modeling photosynthesis of discontinuous plant canopies by linking Geometric Optical Radiative Transfer model with biochemical processes

    NASA Astrophysics Data System (ADS)

    Xin, Q.; Gong, P.; Li, W.

    2015-02-01

    Modeling vegetation photosynthesis is essential for understanding carbon exchanges between terrestrial ecosystems and the atmosphere. The radiative transfer process within plant canopies is one of the key drivers that regulate canopy photosynthesis. Most vegetation cover consists of discrete plant crowns, of which the physical observation departs from the underlying assumption of a homogenous and uniform medium in classic radiative transfer theory. Here we advance the Geometric Optical Radiative Transfer (GORT) model to simulate photosynthesis activities for discontinuous plant canopies. We separate radiation absorption into two components that are absorbed by sunlit and shaded leaves, and derive analytical solutions by integrating over the canopy layer. To model leaf-level and canopy-level photosynthesis, leaf light absorption is then linked to the biochemical process of gas diffusion through leaf stomata. The canopy gap probability derived from GORT differs from classic radiative transfer theory, especially when the leaf area index is high, due to leaf clumping effects. Tree characteristics such as tree density, crown shape, and canopy length affect leaf clumping and regulate radiation interception. Modeled gross primary production (GPP) for two deciduous forest stands could explain more than 80% of the variance of flux tower measurements at both near hourly and daily time scales. We also demonstrate that the ambient CO2 concentration influences daytime vegetation photosynthesis, which needs to be considered in state-of-the-art biogeochemical models. The proposed model is complementary to classic radiative transfer theory and shows promise in modeling the radiative transfer process and photosynthetic activities over discontinuous forest canopies.

  20. Characterizing cognitive aging in humans with links to animal models

    PubMed Central

    Alexander, Gene E.; Ryan, Lee; Bowers, Dawn; Foster, Thomas C.; Bizon, Jennifer L.; Geldmacher, David S.; Glisky, Elizabeth L.

    2012-01-01

    With the population of older adults expected to grow rapidly over the next two decades, it has become increasingly important to advance research efforts to elucidate the mechanisms associated with cognitive aging, with the ultimate goal of developing effective interventions and prevention therapies. Although there has been a vast research literature on the use of cognitive tests to evaluate the effects of aging and age-related neurodegenerative disease, the need for a set of standardized measures to characterize the cognitive profiles specific to healthy aging has been widely recognized. Here we present a review of selected methods and approaches that have been applied in human research studies to evaluate the effects of aging on cognition, including executive function, memory, processing speed, language, and visuospatial function. The effects of healthy aging on each of these cognitive domains are discussed with examples from cognitive/experimental and clinical/neuropsychological approaches. Further, we consider those measures that have clear conceptual and methodological links to tasks currently in use for non-human animal studies of aging, as well as those that have the potential for translation to animal aging research. Having a complementary set of measures to assess the cognitive profiles of healthy aging across species provides a unique opportunity to enhance research efforts for cross-sectional, longitudinal, and intervention studies of cognitive aging. Taking a cross-species, translational approach will help to advance cognitive aging research, leading to a greater understanding of associated neurobiological mechanisms with the potential for developing effective interventions and prevention therapies for age-related cognitive decline. PMID:22988439

  1. Links between fluid mechanics and quantum mechanics: a model for information in economics?

    PubMed

    Haven, Emmanuel

    2016-05-28

    This paper tallies the links between fluid mechanics and quantum mechanics, and attempts to show whether those links can aid in beginning to build a formal template which is usable in economics models where time is (a)symmetric and memory is absent or present. An objective of this paper is to contemplate whether those formalisms can allow us to model information in economics in a novel way.

  2. Exploring the complete mutational space of the LDL receptor LA5 domain using molecular dynamics: linking SNPs with disease phenotypes in familial hypercholesterolemia.

    PubMed

    Angarica, Vladimir Espinosa; Orozco, Modesto; Sancho, Javier

    2016-03-15

    Familial hypercholesterolemia (FH), a genetic disorder with a prevalence of 0.2%, represents a high-risk factor to develop cardiovascular and cerebrovascular diseases. The majority and most severe FH cases are associated to mutations in the receptor for low-density lipoproteins receptor (LDL-r), but the molecular basis explaining the connection between mutation and phenotype is often unknown, which hinders early diagnosis and treatment of the disease. We have used atomistic simulations to explore the complete SNP mutational space (227 mutants) of the LA5 repeat, the key domain for interacting with LDL that is coded in the exon concentrating the highest number of mutations. Four clusters of mutants of different stability have been identified. The majority of the 50 FH known mutations (33) appear distributed in the unstable clusters, i.e. loss of conformational stability explains two-third of FH phenotypes. However, one-third of FH phenotypes (17 mutations) do not destabilize the LR5 repeat. Combining our simulations with available structural data from different laboratories, we have defined a consensus-binding site for the interaction of the LA5 repeat with LDL-r partner proteins and have found that most (16) of the 17 stable FH mutations occur at binding site residues. Thus, LA5-associated FH arises from mutations that cause either the loss of stability or a decrease in domain's-binding affinity. Based on this finding, we propose the likely phenotype of each possible SNP in the LA5 repeat and outline a procedure to make a full computational diagnosis for FH.

  3. Exploring the complete mutational space of the LDL receptor LA5 domain using molecular dynamics: linking SNPs with disease phenotypes in familial hypercholesterolemia

    PubMed Central

    Angarica, Vladimir Espinosa; Orozco, Modesto; Sancho, Javier

    2016-01-01

    Familial hypercholesterolemia (FH), a genetic disorder with a prevalence of 0.2%, represents a high-risk factor to develop cardiovascular and cerebrovascular diseases. The majority and most severe FH cases are associated to mutations in the receptor for low-density lipoproteins receptor (LDL-r), but the molecular basis explaining the connection between mutation and phenotype is often unknown, which hinders early diagnosis and treatment of the disease. We have used atomistic simulations to explore the complete SNP mutational space (227 mutants) of the LA5 repeat, the key domain for interacting with LDL that is coded in the exon concentrating the highest number of mutations. Four clusters of mutants of different stability have been identified. The majority of the 50 FH known mutations (33) appear distributed in the unstable clusters, i.e. loss of conformational stability explains two-third of FH phenotypes. However, one-third of FH phenotypes (17 mutations) do not destabilize the LR5 repeat. Combining our simulations with available structural data from different laboratories, we have defined a consensus-binding site for the interaction of the LA5 repeat with LDL-r partner proteins and have found that most (16) of the 17 stable FH mutations occur at binding site residues. Thus, LA5-associated FH arises from mutations that cause either the loss of stability or a decrease in domain's-binding affinity. Based on this finding, we propose the likely phenotype of each possible SNP in the LA5 repeat and outline a procedure to make a full computational diagnosis for FH. PMID:26755827

  4. Conceptual Processes for Linking Eutrophication and Network Models

    DTIC Science & Technology

    2006-08-01

    for improvements. Submerged Aquatic Vegetation (SAV). SAV biomass values from ICM (identified as SAV in Table 3) are two to three times lower...Dorothy H. Tillman, Dr. Carl F. Cerco, and Mr. Mark R. Noel of the Water Quality and Contaminant Modeling Branch, Enviromental Laboratory (EL

  5. Linking Models: Reasoning from Patterns to Tables and Equations

    ERIC Educational Resources Information Center

    Switzer, J. Matt

    2013-01-01

    Patterns are commonly used in middle years mathematics classrooms to teach students about functions and modelling with tables, graphs, and equations. Grade 6 students are expected to, "continue and create sequences involving whole numbers, fractions and decimals," and "describe the rule used to create the sequence." (Australian…

  6. Shuttle Communications and Tracking Systems Modeling and TDRSS Link Simulations Studies

    NASA Technical Reports Server (NTRS)

    Chie, C. M.; Dessouky, K.; Lindsey, W. C.; Tsang, C. S.; Su, Y. T.

    1985-01-01

    An analytical simulation package (LinCsim) which allows the analytical verification of data transmission performance through TDRSS satellites was modified. The work involved the modeling of the user transponder, TDRS, TDRS ground terminal, and link dynamics for forward and return links based on the TDRSS performance specifications (4) and the critical design reviews. The scope of this effort has recently been expanded to include the effects of radio frequency interference (RFI) on the bit error rate (BER) performance of the S-band return links. The RFI environment and the modified TDRSS satellite and ground station hardware are being modeled in accordance with their description in the applicable documents.

  7. Modeling water quality, temperature, and flow in Link River, south-central Oregon

    USGS Publications Warehouse

    Sullivan, Annett B.; Rounds, Stewart A.

    2016-09-09

    The 2.1-km (1.3-mi) Link River connects Upper Klamath Lake to the Klamath River in south-central Oregon. A CE-QUAL-W2 flow and water-quality model of Link River was developed to provide a connection between an existing model of the upper Klamath River and any existing or future models of Upper Klamath Lake. Water-quality sampling at six locations in Link River was done during 2013–15 to support model development and to provide a better understanding of instream biogeochemical processes. The short reach and high velocities in Link River resulted in fast travel times and limited water-quality transformations, except for dissolved oxygen. Reaeration through the reach, especially at the falls in Link River, was particularly important in moderating dissolved oxygen concentrations that at times entered the reach at Link River Dam with marked supersaturation or subsaturation. This reaeration resulted in concentrations closer to saturation downstream at the mouth of Link River.

  8. Pioglitazone halts axonal degeneration in a mouse model of X-linked adrenoleukodystrophy

    PubMed Central

    Morató, Laia; Galino, Jorge; Ruiz, Montserrat; Calingasan, Noel Ylagan; Starkov, Anatoly A.; Dumont, Magali; Naudí, Alba; Martínez, Juan José; Aubourg, Patrick; Portero-Otín, Manuel; Pamplona, Reinald; Galea, Elena; Beal, M. Flint; Ferrer, Isidre; Fourcade, Stéphane

    2013-01-01

    X-linked adrenoleukodystrophy is a neurometabolic disorder caused by inactivation of the peroxisomal ABCD1 transporter of very long-chain fatty acids. In mice, ABCD1 loss causes late onset axonal degeneration in the spinal cord in association with locomotor disability resembling the most common phenotype in patients, adrenomyeloneuropathy. Increasing evidence indicates that oxidative stress and bioenergetic failure play major roles in the pathogenesis of X-linked adrenoleukodystrophy. In this study, we aimed to evaluate whether mitochondrial biogenesis is affected in X-linked adrenoleukodystrophy. We demonstrated that Abcd1 null mice show reduced mitochondrial DNA concomitant with downregulation of mitochondrial biogenesis pathway driven by PGC-1α/PPARγ and reduced expression of mitochondrial proteins cytochrome c, NDUFB8 and VDAC. Moreover, we show that the oral administration of pioglitazone, an agonist of PPARγ, restored mitochondrial content and expression of master regulators of biogenesis, neutralized oxidative damage to proteins and DNA, and reversed bioenergetic failure in terms of ATP levels, NAD+/NADH ratios, pyruvate kinase and glutathione reductase activities. Most importantly, the treatment halted locomotor disability and axonal damage in X-linked adrenoleukodystrophy mice. These results lend support to the use of pioglitazone in clinical trials with patients with adrenomyeloneuropathy and reveal novel molecular mechanisms of action of pioglitazone in neurodegeneration. Future studies should address the effects of this anti-diabetic drug on other axonopathies in which oxidative stress and mitochondrial dysfunction are contributing factors. PMID:23794606

  9. Linking agent-based models and stochastic models of financial markets.

    PubMed

    Feng, Ling; Li, Baowen; Podobnik, Boris; Preis, Tobias; Stanley, H Eugene

    2012-05-29

    It is well-known that financial asset returns exhibit fat-tailed distributions and long-term memory. These empirical features are the main objectives of modeling efforts using (i) stochastic processes to quantitatively reproduce these features and (ii) agent-based simulations to understand the underlying microscopic interactions. After reviewing selected empirical and theoretical evidence documenting the behavior of traders, we construct an agent-based model to quantitatively demonstrate that "fat" tails in return distributions arise when traders share similar technical trading strategies and decisions. Extending our behavioral model to a stochastic model, we derive and explain a set of quantitative scaling relations of long-term memory from the empirical behavior of individual market participants. Our analysis provides a behavioral interpretation of the long-term memory of absolute and squared price returns: They are directly linked to the way investors evaluate their investments by applying technical strategies at different investment horizons, and this quantitative relationship is in agreement with empirical findings. Our approach provides a possible behavioral explanation for stochastic models for financial systems in general and provides a method to parameterize such models from market data rather than from statistical fitting.

  10. Linking agent-based models and stochastic models of financial markets

    PubMed Central

    Feng, Ling; Li, Baowen; Podobnik, Boris; Preis, Tobias; Stanley, H. Eugene

    2012-01-01

    It is well-known that financial asset returns exhibit fat-tailed distributions and long-term memory. These empirical features are the main objectives of modeling efforts using (i) stochastic processes to quantitatively reproduce these features and (ii) agent-based simulations to understand the underlying microscopic interactions. After reviewing selected empirical and theoretical evidence documenting the behavior of traders, we construct an agent-based model to quantitatively demonstrate that “fat” tails in return distributions arise when traders share similar technical trading strategies and decisions. Extending our behavioral model to a stochastic model, we derive and explain a set of quantitative scaling relations of long-term memory from the empirical behavior of individual market participants. Our analysis provides a behavioral interpretation of the long-term memory of absolute and squared price returns: They are directly linked to the way investors evaluate their investments by applying technical strategies at different investment horizons, and this quantitative relationship is in agreement with empirical findings. Our approach provides a possible behavioral explanation for stochastic models for financial systems in general and provides a method to parameterize such models from market data rather than from statistical fitting. PMID:22586086

  11. Phenotypic heterogeneity in a SOD1 G93D Italian ALS family: an example of human model to study a complex disease.

    PubMed

    Penco, Silvana; Lunetta, Christian; Mosca, Lorena; Maestri, Eleonora; Avemaria, Francesca; Tarlarini, Claudia; Patrosso, Maria Cristina; Marocchi, Alessandro; Corbo, Massimo

    2011-05-01

    We report different clinical expression in seven members of a large family with amyotrophic lateral sclerosis (ALS) and the G93D mutation in exon 4 of the Cu/Zn superoxide dismutase (SOD1) gene. The ALS clinical course in the proband showed an unusually fast progression of the disease compared to the paucisymptomatic presentation associated to this mutation in the two previously Italian families described. The remaining mutation carriers did not show the aggressive clinical course displayed by the proband. We selected few genes known to be ALS modifiers searching for genetic variants that could explain the wide phenotypic diversity within the family. Exclusion of causative genes such as TDP43, FUS, PGRN and VAPB was performed too. We believe that this kind of family with contrasting phenotypes of ALS may be considered an excellent human model to study the relationship between a wider genetic profile, including modifier genes, and the clinical expression of the disease. Therefore, the novelty of our approach is also represented by the study of a single family to reproduce a composite structure in which search for possible modifier genes/genetic variants linked to SOD1 mutated.

  12. Using a Genetic mixture model to study Phenotypic traits: Differential fecundity among Yukon river Chinook Salmon

    USGS Publications Warehouse

    Bromaghin, J.F.; Evenson, D.F.; McLain, T.H.; Flannery, B.G.

    2011-01-01

    Fecundity is a vital population characteristic that is directly linked to the productivity of fish populations. Historic data from Yukon River (Alaska) Chinook salmon Oncorhynchus tshawytscha suggest that length-adjusted fecundity differs among populations within the drainage and either is temporally variable or has declined. Yukon River Chinook salmon have been harvested in large-mesh gill-net fisheries for decades, and a decline in fecundity was considered a potential evolutionary response to size-selective exploitation. The implications for fishery conservation and management led us to further investigate the fecundity of Yukon River Chinook salmon populations. Matched observations of fecundity, length, and genotype were collected from a sample of adult females captured from the multipopulation spawning migration near the mouth of the Yukon River in 2008. These data were modeled by using a new mixture model, which was developed by extending the conditional maximum likelihood mixture model that is commonly used to estimate the composition of multipopulation mixtures based on genetic data. The new model facilitates maximum likelihood estimation of stock-specific fecundity parameters without first using individual assignment to a putative population of origin, thus avoiding potential biases caused by assignment error.The hypothesis that fecundity of Chinook salmon has declined was not supported; this result implies that fecundity exhibits high interannual variability. However, length-adjusted fecundity estimates decreased as migratory distance increased, and fecundity was more strongly dependent on fish size for populations spawning in the middle and upper portions of the drainage. These findings provide insights into potential constraints on reproductive investment imposed by long migrations and warrant consideration in fisheries management and conservation. The new mixture model extends the utility of genetic markers to new applications and can be easily adapted

  13. An integrative model linking feedback environment and organizational citizenship behavior.

    PubMed

    Peng, Jei-Chen; Chiu, Su-Fen

    2010-01-01

    Past empirical evidence has suggested that a positive supervisor feedback environment may enhance employees' organizational citizenship behavior (OCB). In this study, we aim to extend previous research by proposing and testing an integrative model that examines the mediating processes underlying the relationship between supervisor feedback environment and employee OCB. Data were collected from 259 subordinate-supervisor dyads across a variety of organizations in Taiwan. We used structural equation modeling to test our hypotheses. The results demonstrated that supervisor feedback environment influenced employees' OCB indirectly through (1) both positive affective-cognition and positive attitude (i.e., person-organization fit and organizational commitment), and (2) both negative affective-cognition and negative attitude (i.e., role stressors and job burnout). Theoretical and practical implications are discussed.

  14. Phenotypic transition of microglia into astrocyte-like cells associated with disease onset in a model of inherited ALS

    PubMed Central

    Trias, Emiliano; Díaz-Amarilla, Pablo; Olivera-Bravo, Silvia; Isasi, Eugenia; Drechsel, Derek A.; Lopez, Nathan; Bradford, C. Samuel; Ireton, Kyle E.; Beckman, Joseph S.; Barbeito, Luis

    2013-01-01

    Microglia and reactive astrocytes accumulate in the spinal cord of rats expressing the Amyotrophic lateral sclerosis (ALS)-linked SOD1 G93A mutation. We previously reported that the rapid progression of paralysis in ALS rats is associated with the appearance of proliferative astrocyte-like cells that surround motor neurons. These cells, designated as Aberrant Astrocytes (AbA cells) because of their atypical astrocytic phenotype, exhibit high toxicity to motor neurons. However, the cellular origin of AbA cells remains unknown. Because AbA cells are labeled with the proliferation marker Ki67, we analyzed the phenotypic makers of proliferating glial cells that surround motor neurons by immunohistochemistry. The number of Ki67 +AbA cells sharply increased in symptomatic rats, displaying large cell bodies with processes embracing motor neurons. Most were co-labeled with astrocytic marker GFAP concurrently with the microglial markers Iba1 and CD163. Cultures of spinal cord prepared from symptomatic SOD1 G93A rats yielded large numbers of microglia expressing Iba1, CD11b, and CD68. Cells sorted for CD11b expression by flow cytometry transformed into AbA cells within two weeks. During these two weeks, the expression of microglial markers largely disappeared, while GFAP and S100β expression increased. The phenotypic transition to AbA cells was stimulated by forskolin. These findings provide evidence for a subpopulation of proliferating microglial cells in SOD1 G93A rats that undergo a phenotypic transition into AbA cells after onset of paralysis that may promote the fulminant disease progression. These cells could be a therapeutic target for slowing paralysis progression in ALS. PMID:24399933

  15. Cross Linking and Degradation Mechanisms in Model Sealant Candidates

    NASA Technical Reports Server (NTRS)

    Paciorek, K. L.; Kaufman, J.; Ito, T. I.; Nakahara, J. H.; Kratzer, R. H.

    1977-01-01

    Model compounds were investigated as to which type of heterocyclic ring is the most advantageous for curing sealants based on perfluoroalkylether chains. The relative thermal, thermal oxidative, hydrolytic, and fuel stability of potential crosslinks were determined. Specifically substituted materials were synthesized and evaluation of their stabilities in air, inert atmosphere, water, and Jet-A fuel at 235 and 325 C was made. Three heterocyclic ring systems were considered, namely, triazine, 1,2,4- and 1,3,4-oxadiazoles.

  16. Microbial Life in Soil - Linking Biophysical Models with Observations

    NASA Astrophysics Data System (ADS)

    Or, D.; Tecon, R.; Ebrahimi, A.; Kleyer, H.; Ilie, O.; Wang, G.

    2014-12-01

    Microbial life in soil occurs within fragmented aquatic habitats in complex pore spaces where motility is restricted to short hydration windows (e.g., following rainfall). The limited range of self-dispersion and physical confinement promote spatial association among trophically interdepended microbial species. Competition and preferences for different nutrient resources and byproducts and their diffusion require high level of spatial organization to sustain the functioning of multispecies communities. We report mechanistic modeling studies of competing multispecies microbial communities grown on hydrated surfaces and within artificial soil aggregates (represented by 3-D pore network). Results show how trophic dependencies and cell-level interactions within patchy diffusion fields promote spatial self-organization of motile microbial cells. The spontaneously forming patterns of segregated, yet coexisting species were robust to spatial heterogeneities and to temporal perturbations (hydration dynamics), and respond primarily to the type of trophic dependencies. Such spatially self-organized consortia may reflect ecological templates that optimize substrate utilization and could form the basic architecture for more permanent surface-attached microbial colonies. Hydration dynamics affect structure and spatial arrangement of aerobic and anaerobic microbial communities and their biogeochemical functions. Experiments with well-characterized artificial soil microbial assemblies grown on porous surfaces provide access to community dynamics during wetting and drying cycles detected through genetic fingerprinting. Experiments for visual observations of spatial associations of tagged bacterial species with known trophic dependencies on model porous surfaces are underway. Biophysical modeling provide a means for predicting hydration-mediated critical separation distances for activation of spatial self-organization. The study provides new modeling and observational tools that

  17. Microbial Life in Soil - Linking Biophysical Models with Observations

    NASA Astrophysics Data System (ADS)

    Or, Dani; Tecon, Robin; Ebrahimi, Ali; Kleyer, Hannah; Ilie, Olga; Wang, Gang

    2015-04-01

    Microbial life in soil occurs within fragmented aquatic habitats formed in complex pore spaces where motility is restricted to short hydration windows (e.g., following rainfall). The limited range of self-dispersion and physical confinement promote spatial association among trophically interdepended microbial species. Competition and preferences for different nutrient resources and byproducts and their diffusion require high level of spatial organization to sustain the functioning of multispecies communities. We report mechanistic modeling studies of competing multispecies microbial communities grown on hydrated surfaces and within artificial soil aggregates (represented by 3-D pore network). Results show how trophic dependencies and cell-level interactions within patchy diffusion fields promote spatial self-organization of motile microbial cells. The spontaneously forming patterns of segregated, yet coexisting species were robust to spatial heterogeneities and to temporal perturbations (hydration dynamics), and respond primarily to the type of trophic dependencies. Such spatially self-organized consortia may reflect ecological templates that optimize substrate utilization and could form the basic architecture for more permanent surface-attached microbial colonies. Hydration dynamics affect structure and spatial arrangement of aerobic and anaerobic microbial communities and their biogeochemical functions. Experiments with well-characterized artificial soil microbial assemblies grown on porous surfaces provide access to community dynamics during wetting and drying cycles detected through genetic fingerprinting. Experiments for visual observations of spatial associations of tagged bacterial species with known trophic dependencies on model porous surfaces are underway. Biophysical modeling provide a means for predicting hydration-mediated critical separation distances for activation of spatial self-organization. The study provides new modeling and observational tools

  18. Modeling Prairie Pothole Lakes: Linking Satellite Observation and Calibration (Invited)

    NASA Astrophysics Data System (ADS)

    Schwartz, F. W.; Liu, G.; Zhang, B.; Yu, Z.

    2009-12-01

    This paper examines the response of a complex lake wetland system to variations in climate. The focus is on the lakes and wetlands of the Missouri Coteau, which is part of the larger Prairie Pothole Region of the Central Plains of North America. Information on lake size was enumerated from satellite images, and yielded power law relationships for different hydrological conditions. More traditional lake-stage data were made available to us from the USGS Cottonwood Lake Study Site in North Dakota. A Probabilistic Hydrologic Model (PHM) was developed to simulate lake complexes comprised of tens-of-thousands or more individual closed-basin lakes and wetlands. What is new about this model is a calibration scheme that utilizes remotely-sensed data on lake area as well as stage data for individual lakes. Some ¼ million individual data points are used within a Genetic Algorithm to calibrate the model by comparing the simulated results with observed lake area-frequency power law relationships derived from Landsat images and water depths from seven individual lakes and wetlands. The simulated lake behaviors show good agreement with the observations under average, dry, and wet climatic conditions. The calibrated model is used to examine the impact of climate variability on a large lake complex in ND, in particular, the “Dust Bowl Drought” 1930s. This most famous drought of the 20th Century devastated the agricultural economy of the Great Plains with health and social impacts lingering for years afterwards. Interestingly, the drought of 1930s is unremarkable in relation to others of greater intensity and frequency before AD 1200 in the Great Plains. Major droughts and deluges have the ability to create marked variability of the power law function (e.g. up to one and a half orders of magnitude variability from the extreme Dust Bowl Drought to the extreme 1993-2001 deluge). This new probabilistic modeling approach provides a novel tool to examine the response of the

  19. LINKING THE CMAQ AND HYSPLIT MODELING SYSTEM INTERFACE PROGRAM AND EXAMPLE APPLICATION

    EPA Science Inventory

    A new software tool has been developed to link the Eulerian-based Community Multiscale Air Quality (CMAQ) modeling system with the Lagrangian-based HYSPLIT (HYbrid Single-Particle Lagrangian Integrated Trajectory) model. Both models require many of the same hourly meteorological...

  20. A Dual-Process Model of the Alcohol-Behavior Link for Social Drinking

    ERIC Educational Resources Information Center

    Moss, Antony C.; Albery, Ian P.

    2009-01-01

    A dual-process model of the alcohol-behavior link is presented, synthesizing 2 of the major social-cognitive approaches: expectancy and myopia theories. Substantial evidence has accrued to support both of these models, and recent neurocognitive models of the effects of alcohol on thought and behavior have provided evidence to support both as well.…

  1. Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy.

    PubMed

    Wang, Zhi-Bo; Zhang, Xiaoqing; Li, Xue-Jun

    2013-03-01

    Establishing human cell models of spinal muscular atrophy (SMA) to mimic motor neuron-specific phenotypes holds the key to understanding the pathogenesis of this devastating disease. Here, we developed a closely representative cell model of SMA by knocking down the disease-determining gene, survival motor neuron (SMN), in human embryonic stem cells (hESCs). Our study with this cell model demonstrated that knocking down of SMN does not interfere with neural induction or the initial specification of spinal motor neurons. Notably, the axonal outgrowth of spinal motor neurons was significantly impaired and these disease-mimicking neurons subsequently degenerated. Furthermore, these disease phenotypes were caused by SMN-full length (SMN-FL) but not SMN-Δ7 (lacking exon 7) knockdown, and were specific to spinal motor neurons. Restoring the expression of SMN-FL completely ameliorated all of the disease phenotypes, including specific axonal defects and motor neuron loss. Finally, knockdown of SMN-FL led to excessive mitochondrial oxidative stress in human motor neuron progenitors. The involvement of oxidative stress in the degeneration of spinal motor neurons in the SMA cell model was further confirmed by the administration of N-acetylcysteine, a potent antioxidant, which prevented disease-related apoptosis and subsequent motor neuron death. Thus, we report here the successful establishment of an hESC-based SMA model, which exhibits disease gene isoform specificity, cell type specificity, and phenotype reversibility. Our model provides a unique paradigm for studying how motor neurons specifically degenerate and highlights the potential importance of antioxidants for the treatment of SMA.

  2. Mouse models for xeroderma pigmentosum group A and group C show divergent cancer phenotypes.

    PubMed

    Melis, Joost P M; Wijnhoven, Susan W P; Beems, Rudolf B; Roodbergen, Marianne; van den Berg, Jolanda; Moon, Hojin; Friedberg, Errol; van der Horst, Gijsbertus T J; Hoeijmakers, Jan H J; Vijg, Jan; van Steeg, Harry

    2008-03-01

    The accumulation of DNA damage is a slow but hazardous phenomenon that may lead to cell death, accelerated aging, and cancer. One of the most versatile defense mechanisms against the accumulation of DNA damage is nucleotide excision repair, in which, among others, the Xeroderma pigmentosum group C (XPC) and group A (XPA) proteins are involved. To elucidate differences in the functions of these two proteins, comprehensive survival studies with Xpa(-/-), Xpc(-/-) and wild-type control female mice in a pure C57BL/6J background were done. The median survival of Xpc(-/-) mice showed a significant decrease, whereas the median survival of Xpa(-/-) mice did not. Strikingly, Xpa(-/-) and Xpc(-/-) mice also showed a phenotypical difference in terms of tumor spectrum. Xpc(-/-) mice displayed a significant increase in lung tumors and a trend toward increased liver tumors compared with Xpa-deficient or wild-type mice. Xpa(-/-) mice showed a significant elevation in liver tumors. Additionally, Xpc-deficient mice exhibited a strong increase in mutant frequency in lung compared with Xpa(-/-) mice, whereas in both models mutant frequency is increased in liver. Our in vitro data displayed an elevated sensitivity to oxygen in Xpc(-/-) in mouse embryonic fibroblasts (MEF) when compared with Xpa(-/-) and wild-type fibroblasts. We believe that XPC plays a role in the removal of oxidative DNA damage and that, therefore, Xpc(-/-) mice display a significant increase in lung tumors and a significant elevation in mutant frequency in lung, and Xpc-deficient MEFs show greater sensitivity to oxygen when compared with Xpa(-/-) and wild-type mice.

  3. Phenotype-genotype correlations in mouse models of amelogenesis imperfecta caused by Amelx and Enam mutations.

    PubMed

    Coxon, Thomas Liam; Brook, Alan Henry; Barron, Martin John; Smith, Richard Nigel

    2012-01-01

    Mutations in human and in mouse orthologous genes Amelx and Enam result in a diverse range of enamel defects. In this study we aimed to investigate the phenotype-genotype correlation between the mutants and the wild-type controls in mouse models of amelogenesis imperfecta using novel measurement approaches. Ten hemi-mandibles and incisors were dissected from each group of Amelx(WT), Amelx(X/Y64H), Amelx(Y/Y64H), Amelx(Y64H/Y64H), and Enam(WT), Enam(Rgsc395) heterozygous and Enam(Rgsc395) homozygous mice. Their macro-morphology, colour and micro-topography were assessed using bespoke 2D and 3D image analysis systems and customized colour and whiteness algorithms. The novel methods identified significant differences (p ≤ 0.05) between the Amelx groups for mandible and incisor size and enamel colour and between the Enam groups for incisor size and enamel colour. The Amelx(WT) mice had the largest mandibles and incisors, followed in descending order of size by the Amelx(X/Y64H), Amelx(Y/Y64H) and Amelx(Y64H/Y64H) mice. Within the Enam groups the Enam(WT) incisors were largest and the Enam(Rgsc395) heterozygous mice were smallest. The effect on tooth morphology was also reflected by the severity of the enamel defects in the colour and whiteness assessment. Amelogenin affected mandible morphology and incisor enamel formation, while enamelin only affected incisors, supporting the multifunctional role of amelogenin. The enamelin mutation was associated with earlier forming enamel defects. The study supported the critical involvement of amelogenin and enamelin in enamel mineralization.

  4. Phenotypic plasticity of composite beef cattle performance using reaction norms model with unknown covariate.

    PubMed

    Santana, M L; Eler, J P; Cardoso, F F; Albuquerque, L G; Ferraz, J B S

    2013-02-01

    The objective of the present study was to determine the presence of genotype by environment interaction (G × E) and to characterize the phenotypic plasticity of birth weight (BW), weaning weight (WW), postweaning weight gain (PWG) and yearling scrotal circumference (SC) in composite beef cattle using the reaction norms model with unknown covariate. The animals were born between 1995 and 2008 on 33 farms located throughout all Brazilian biomes between latitude -7° and -31°, longitude -40° and -63°. The contemporary group was chosen as the environmental descriptor, that is, the environmental covariate of the reaction norms. In general, higher estimates of direct heritability were observed in extreme favorable environments. The mean of direct heritability across the environmental gradient ranged from 0.05 to 0.51, 0.09 to 0.43, 0.01 to 0.43 and from 0.12 to 0.26 for BW, WW, PWG and SC, respectively. The variation in direct heritability observed indicates a different response to selection according to the environment in which the animals of the population are evaluated. The correlation between the level and slope of the reaction norm for BW and PWG was high, indicating that animals with higher average breeding values responded better to improvement in environmental conditions, a fact characterizing a scale of G × E. Low correlation between the intercept and slope was obtained for WW and SC, implying re-ranking of animals in different environments. Genetic variation exists in the sensitivity of animals to the environment, a fact that permits the selection of more plastic or robust genotypes in the population studied. Thus, the G × E is an important factor that should be considered in the genetic evaluation of the present population of composite beef cattle.

  5. Linking seasonal climate forecasts with crop models in Iberian Peninsula

    NASA Astrophysics Data System (ADS)

    Capa, Mirian; Ines, Amor; Baethgen, Walter; Rodriguez-Fonseca, Belen; Han, Eunjin; Ruiz-Ramos, Margarita

    2015-04-01

    Translating seasonal climate forecasts into agricultural production forecasts could help to establish early warning systems and to design crop management adaptation strategies that take advantage of favorable conditions or reduce the effect of adverse conditions. In this study, we use seasonal rainfall forecasts and crop models to improve predictability of wheat yield in the Iberian Peninsula (IP). Additionally, we estimate economic margins and production risks associated with extreme scenarios of seasonal rainfall forecast. This study evaluates two methods for disaggregating seasonal climate forecasts into daily weather data: 1) a stochastic weather generator (CondWG), and 2) a forecast tercile resampler (FResampler). Both methods were used to generate 100 (with FResampler) and 110 (with CondWG) weather series/sequences for three scenarios of seasonal rainfall forecasts. Simulated wheat yield is computed with the crop model CERES-wheat (Ritchie and Otter, 1985), which is included in Decision Support System for Agrotechnology Transfer (DSSAT v.4.5, Hoogenboom et al., 2010). Simulations were run at two locations in northeastern Spain where the crop model was calibrated and validated with independent field data. Once simulated yields were obtained, an assessment of farmer's gross margin for different seasonal climate forecasts was accomplished to estimate production risks under different climate scenarios. This methodology allows farmers to assess the benefits and risks of a seasonal weather forecast in IP prior to the crop growing season. The results of this study may have important implications on both, public (agricultural planning) and private (decision support to farmers, insurance companies) sectors. Acknowledgements Research by M. Capa-Morocho has been partly supported by a PICATA predoctoral fellowship of the Moncloa Campus of International Excellence (UCM-UPM) and MULCLIVAR project (CGL2012-38923-C02-02) References Hoogenboom, G. et al., 2010. The Decision

  6. Model analysis of the link between interest rates and crashes

    NASA Astrophysics Data System (ADS)

    Broga, Kristijonas M.; Viegas, Eduardo; Jensen, Henrik Jeldtoft

    2016-09-01

    We analyse the effect of distinct levels of interest rates on the stability of the financial network under our modelling framework. We demonstrate that banking failures are likely to emerge early on under sustained high interest rates, and at much later stage-with higher probability-under a sustained low interest rate scenario. Moreover, we demonstrate that those bank failures are of a different nature: high interest rates tend to result in significantly more bankruptcies associated to credit losses whereas lack of liquidity tends to be the primary cause of failures under lower rates.

  7. Atempts to link Quanta & Atoms before the Bohr Atom model

    NASA Astrophysics Data System (ADS)

    Venkatesan, A.; Lieber, M.

    2005-03-01

    Attempts to quantize atomic phenomena before Bohr are hardly ever mentioned in elementary textbooks.This presentation will elucidate the contributions of A.Haas around 1910. Haas tried to quantize the Thomson atom model as an optical resonator made of positive and negative charges. The inherent ambiguity of charge distribution in the model made him choose a positive spherical distribution around which the electrons were distributed.He obtained expressions for the Rydberg constant and what is known today as the Bohr radius by balancing centrifugal energy with Coulomb energy and quantizing it with Planck's relation E=hν. We point out that Haas would have arrived at better estimates of these constants had he used the virial theorem apart from the fact that the fundamental constants were not well known. The crux of Haas's physical picture was to derive Planck's constant h from charge quantum e , mass of electron m and atomic radius. Haas faced severe criticism for applying thermodynamic concepts like Planck distribution to microscopic phenomena. We will try to give a flavor for how quantum phenomena were viewed at that time. It is of interest to note that the driving force behind Haas's work was to present a paper that would secure him a position as a Privatdozent in History of Physics. We end with comments by Bohr and Sommerfeld on Haas's work and with some brief biographical remarks.

  8. Reciprocal Effects on Neurocognitive and Metabolic Phenotypes in Mouse Models of 16p11.2 Deletion and Duplication Syndromes

    PubMed Central

    Arbogast, Thomas; Ouagazzal, Abdel-Mouttalib; Chevalier, Claire; Kopanitsa, Maksym; Afinowi, Nurudeen; Migliavacca, Eugenia; Cowling, Belinda S.; Birling, Marie-Christine; Champy, Marie-France; Reymond, Alexandre; Herault, Yann

    2016-01-01

    The 16p11.2 600 kb BP4-BP5 deletion and duplication syndromes have been associated with developmental delay; autism spectrum disorders; and reciprocal effects on the body mass index, head circumference and brain volumes. Here, we explored these relationships using novel engineered mouse models carrying a deletion (Del/+) or a duplication (Dup/+) of the Sult1a1-Spn region homologous to the human 16p11.2 BP4-BP5 locus. On a C57BL/6N inbred genetic background, Del/+ mice exhibited reduced weight and impaired adipogenesis, hyperactivity, repetitive behaviors, and recognition memory deficits. In contrast, Dup/+ mice showed largely opposite phenotypes. On a F1 C57BL/6N × C3B hybrid genetic background, we also observed alterations in social interaction in the Del/+ and the Dup/+ animals, with other robust phenotypes affecting recognition memory and weight. To explore the dosage effect of the 16p11.2 genes on metabolism, Del/+ and Dup/+ models were challenged with high fat and high sugar diet, which revealed opposite energy imbalance. Transcriptomic analysis revealed that the majority of the genes located in the Sult1a1-Spn region were sensitive to dosage with a major effect on several pathways associated with neurocognitive and metabolic phenotypes. Whereas the behavioral consequence of the 16p11 region genetic dosage was similar in mice and humans with activity and memory alterations, the metabolic defects were opposite: adult Del/+ mice are lean in comparison to the human obese phenotype and the Dup/+ mice are overweight in comparison to the human underweight phenotype. Together, these data indicate that the dosage imbalance at the 16p11.2 locus perturbs the expression of modifiers outside the CNV that can modulate the penetrance, expressivity and direction of effects in both humans and mice. PMID:26872257

  9. High-Throughput Phenotyping of Sorghum Plant Height Using an Unmanned Aerial Vehicle and Its Application to Genomic Prediction Modeling

    PubMed Central

    Watanabe, Kakeru; Guo, Wei; Arai, Keigo; Takanashi, Hideki; Kajiya-Kanegae, Hiromi; Kobayashi, Masaaki; Yano, Kentaro; Tokunaga, Tsuyoshi; Fujiwara, Toru; Tsutsumi, Nobuhiro; Iwata, Hiroyoshi

    2017-01-01

    Genomics-assisted breeding methods have been rapidly developed with novel technologies such as next-generation sequencing, genomic selection and genome-wide association study. However, phenotyping is still time consuming and is a serious bottleneck in genomics-assisted breeding. In this study, we established a high-throughput phenotyping system for sorghum plant height and its response to nitrogen availability; this system relies on the use of unmanned aerial vehicle (UAV) remote sensing with either an RGB or near-infrared, green and blue (NIR-GB) camera. We evaluated the potential of remote sensing to provide phenotype training data in a genomic prediction model. UAV remote sensing with the NIR-GB camera and the 50th percentile of digital surface model, which is an indicator of height, performed well. The correlation coefficient between plant height measured by UAV remote sensing (PHUAV) and plant height measured with a ruler (PHR) was 0.523. Because PHUAV was overestimated (probably because of the presence of taller plants on adjacent plots), the correlation coefficient between PHUAV and PHR was increased to 0.678 by using one of the two replications (that with the lower PHUAV value). Genomic prediction modeling performed well under the low-fertilization condition, probably because PHUAV overestimation was smaller under this condition due to a lower plant height. The predicted values of PHUAV and PHR were highly correlated with each other (r = 0.842). This result suggests that the genomic prediction models generated with PHUAV were almost identical and that the performance of UAV remote sensing was similar to that of traditional measurements in genomic prediction modeling. UAV remote sensing has a high potential to increase the throughput of phenotyping and decrease its cost. UAV remote sensing will be an important and indispensable tool for high-throughput genomics-assisted plant breeding.

  10. High-Throughput Phenotyping of Sorghum Plant Height Using an Unmanned Aerial Vehicle and Its Application to Genomic Prediction Modeling.

    PubMed

    Watanabe, Kakeru; Guo, Wei; Arai, Keigo; Takanashi, Hideki; Kajiya-Kanegae, Hiromi; Kobayashi, Masaaki; Yano, Kentaro; Tokunaga, Tsuyoshi; Fujiwara, Toru; Tsutsumi, Nobuhiro; Iwata, Hiroyoshi

    2017-01-01

    Genomics-assisted breeding methods have been rapidly developed with novel technologies such as next-generation sequencing, genomic selection and genome-wide association study. However, phenotyping is still time consuming and is a serious bottleneck in genomics-assisted breeding. In this study, we established a high-throughput phenotyping system for sorghum plant height and its response to nitrogen availability; this system relies on the use of unmanned aerial vehicle (UAV) remote sensing with either an RGB or near-infrared, green and blue (NIR-GB) camera. We evaluated the potential of remote sensing to provide phenotype training data in a genomic prediction model. UAV remote sensing with the NIR-GB camera and the 50th percentile of digital surface model, which is an indicator of height, performed well. The correlation coefficient between plant height measured by UAV remote sensing (PHUAV) and plant height measured with a ruler (PHR) was 0.523. Because PHUAV was overestimated (probably because of the presence of taller plants on adjacent plots), the correlation coefficient between PHUAV and PHR was increased to 0.678 by using one of the two replications (that with the lower PHUAV value). Genomic prediction modeling performed well under the low-fertilization condition, probably because PHUAV overestimation was smaller under this condition due to a lower plant height. The predicted values of PHUAV and PHR were highly correlated with each other (r = 0.842). This result suggests that the genomic prediction models generated with PHUAV were almost identical and that the performance of UAV remote sensing was similar to that of traditional measurements in genomic prediction modeling. UAV remote sensing has a high potential to increase the throughput of phenotyping and decrease its cost. UAV remote sensing will be an important and indispensable tool for high-throughput genomics-assisted plant breeding.

  11. Horizontal gene transfer in eukaryotes: The weak-link model

    PubMed Central

    Huang, Jinling

    2013-01-01

    The significance of horizontal gene transfer (HGT) in eukaryotic evolution remains controversial. Although many eukaryotic genes are of bacterial origin, they are often interpreted as being derived from mitochondria or plastids. Because of their fixed gene pool and gene loss, however, mitochondria and plastids alone cannot adequately explain the presence of all, or even the majority, of bacterial genes in eukaryotes. Available data indicate that no insurmountable barrier to HGT exists, even in complex multicellular eukaryotes. In addition, the discovery of both recent and ancient HGT events in all major eukaryotic groups suggests that HGT has been a regular occurrence throughout the history of eukaryotic evolution. A model of HGT is proposed that suggests both unicellular and early developmental stages as likely entry points for foreign genes into multicellular eukaryotes. PMID:24037739

  12. Horizontal gene transfer in eukaryotes: the weak-link model.

    PubMed

    Huang, Jinling

    2013-10-01

    The significance of horizontal gene transfer (HGT) in eukaryotic evolution remains controversial. Although many eukaryotic genes are of bacterial origin, they are often interpreted as being derived from mitochondria or plastids. Because of their fixed gene pool and gene loss, however, mitochondria and plastids alone cannot adequately explain the presence of all, or even the majority, of bacterial genes in eukaryotes. Available data indicate that no insurmountable barrier to HGT exists, even in complex multicellular eukaryotes. In addition, the discovery of both recent and ancient HGT events in all major eukaryotic groups suggests that HGT has been a regular occurrence throughout the history of eukaryotic evolution. A model of HGT is proposed that suggests both unicellular and early developmental stages as likely entry points for foreign genes into multicellular eukaryotes.

  13. Plausibility of inferred ancestral phenotypes and the evaluation of alternative models of limb evolution in scincid lizards.

    PubMed

    Skinner, Adam; Lee, Michael S Y

    2010-06-23

    Phylogenetic approaches to inferring ancestral character states are becoming increasingly sophisticated; however, the potential remains for available methods to yield strongly supported but inaccurate ancestral state estimates. The consistency of ancestral states inferred for two or more characters affords a useful criterion for evaluating ancestral trait reconstructions. Ancestral state estimates for multiple characters that entail plausible phenotypes when considered together may reasonably be assumed to be reliable. However, the accuracy of inferred ancestral states for one or more characters may be questionable where combined reconstructions imply implausible phenotypes for a proportion of internal nodes. This criterion for assessing reconstructed ancestral states is applied here in evaluating inferences of ancestral limb morphology in the scincid lizard clade Lerista. Ancestral numbers of digits for the manus and pes inferred assuming the models that best fit the data entail ancestral digit configurations for many nodes that differ fundamentally from configurations observed among known species. However, when an alternative model is assumed for the pes, inferred ancestral digit configurations are invariably represented among observed phenotypes. This indicates that a suboptimal model for the pes (and not the model providing the best fit to the data) yields accurate ancestral state estimates.

  14. Linking Air Quality and Watershed Models for Environmental Assessments: Analysis of the Effects of Model-Specific Precipitation Estimates on Calculated Water Flux

    EPA Science Inventory

    Directly linking air quality and watershed models could provide an effective method for estimating spatially-explicit inputs of atmospheric contaminants to watershed biogeochemical models. However, to adequately link air and watershed models for wet deposition estimates, each mod...

  15. Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease.

    PubMed

    Vinchi, Francesca; Costa da Silva, Milene; Ingoglia, Giada; Petrillo, Sara; Brinkman, Nathan; Zuercher, Adrian; Cerwenka, Adelheid; Tolosano, Emanuela; Muckenthaler, Martina U

    2016-01-28

    Hemolytic diseases, such as sickle cell anemia and thalassemia, are characterized by enhanced release of hemoglobin and heme into the circulation, heme-iron loading of reticulo-endothelial system macrophages, and chronic inflammation. Here we show that in addition to activating the vascular endothelium, hemoglobin and heme excess alters the macrophage phenotype in sickle cell disease. We demonstrate that exposure of cultured macrophages to hemolytic aged red blood cells, heme, or iron causes their functional phenotypic change toward a proinflammatory state. In addition, hemolysis and macrophage heme/iron accumulation in a mouse model of sickle disease trigger similar proinflammatory phenotypic alterations in hepatic macrophages. On the mechanistic level, this critically depends on reactive oxygen species production and activation of the Toll-like receptor 4 signaling pathway. We further demonstrate that the heme scavenger hemopexin protects reticulo-endothelial macrophages from heme overload in heme-loaded Hx-null mice and reduces production of cytokines and reactive oxygen species. Importantly, in sickle mice, the administration of human exogenous hemopexin attenuates the inflammatory phenotype of macrophages. Taken together, our data suggest that therapeutic administration of hemopexin is beneficial to counteract heme-driven macrophage-mediated inflammation and its pathophysiologic consequences in sickle cell disease.

  16. Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease

    PubMed Central

    Vinchi, Francesca; Costa da Silva, Milene; Ingoglia, Giada; Petrillo, Sara; Brinkman, Nathan; Zuercher, Adrian; Cerwenka, Adelheid; Tolosano, Emanuela

    2016-01-01

    Hemolytic diseases, such as sickle cell anemia and thalassemia, are characterized by enhanced release of hemoglobin and heme into the circulation, heme-iron loading of reticulo-endothelial system macrophages, and chronic inflammation. Here we show that in addition to activating the vascular endothelium, hemoglobin and heme excess alters the macrophage phenotype in sickle cell disease. We demonstrate that exposure of cultured macrophages to hemolytic aged red blood cells, heme, or iron causes their functional phenotypic change toward a proinflammatory state. In addition, hemolysis and macrophage heme/iron accumulation in a mouse model of sickle disease trigger similar proinflammatory phenotypic alterations in hepatic macrophages. On the mechanistic level, this critically depends on reactive oxygen species production and activation of the Toll-like receptor 4 signaling pathway. We further demonstrate that the heme scavenger hemopexin protects reticulo-endothelial macrophages from heme overload in heme-loaded Hx-null mice and reduces production of cytokines and reactive oxygen species. Importantly, in sickle mice, the administration of human exogenous hemopexin attenuates the inflammatory phenotype of macrophages. Taken together, our data suggest that therapeutic administration of hemopexin is beneficial to counteract heme-driven macrophage-mediated inflammation and its pathophysiologic consequences in sickle cell disease. PMID:26675351

  17. Modeling and Executing Electronic Health Records Driven Phenotyping Algorithms using the NQF Quality Data Model and JBoss® Drools Engine

    PubMed Central

    Li, Dingcheng; Endle, Cory M; Murthy, Sahana; Stancl, Craig; Suesse, Dale; Sottara, Davide; Huff, Stanley M.; Chute, Christopher G.; Pathak, Jyotishman

    2012-01-01

    With increasing adoption of electronic health records (EHRs), the need for formal representations for EHR-driven phenotyping algorithms has been recognized for some time. The recently proposed Quality Data Model from the National Quality Forum (NQF) provides an information model and a grammar that is intended to represent data collected during routine clinical care in EHRs as well as the basic logic required to represent the algorithmic criteria for phenotype definitions. The QDM is further aligned with Meaningful Use standards to ensure that the clinical data and algorithmic criteria are represented in a consistent, unambiguous and reproducible manner. However, phenotype definitions represented in QDM, while structured, cannot be executed readily on existing EHRs. Rather, human interpretation, and subsequent implementation is a required step for this process. To address this need, the current study investigates open-source JBoss® Drools rules engine for automatic translation of QDM criteria into rules for execution over EHR data. In particular, using Apache Foundation’s Unstructured Information Management Architecture (UIMA) platform, we developed a translator tool for converting QDM defined phenotyping algorithm criteria into executable Drools rules scripts, and demonstrated their execution on real patient data from Mayo Clinic to identify cases for Coronary Artery Disease and Diabetes. To the best of our knowledge, this is the first study illustrating a framework and an approach for executing phenotyping criteria modeled in QDM using the Drools business rules management system. PMID:23304325

  18. Modeling and executing electronic health records driven phenotyping algorithms using the NQF Quality Data Model and JBoss® Drools Engine.

    PubMed

    Li, Dingcheng; Endle, Cory M; Murthy, Sahana; Stancl, Craig; Suesse, Dale; Sottara, Davide; Huff, Stanley M; Chute, Christopher G; Pathak, Jyotishman

    2012-01-01

    With increasing adoption of electronic health records (EHRs), the need for formal representations for EHR-driven phenotyping algorithms has been recognized for some time. The recently proposed Quality Data Model from the National Quality Forum (NQF) provides an information model and a grammar that is intended to represent data collected during routine clinical care in EHRs as well as the basic logic required to represent the algorithmic criteria for phenotype definitions. The QDM is further aligned with Meaningful Use standards to ensure that the clinical data and algorithmic criteria are represented in a consistent, unambiguous and reproducible manner. However, phenotype definitions represented in QDM, while structured, cannot be executed readily on existing EHRs. Rather, human interpretation, and subsequent implementation is a required step for this process. To address this need, the current study investigates open-source JBoss® Drools rules engine for automatic translation of QDM criteria into rules for execution over EHR data. In particular, using Apache Foundation's Unstructured Information Management Architecture (UIMA) platform, we developed a translator tool for converting QDM defined phenotyping algorithm criteria into executable Drools rules scripts, and demonstrated their execution on real patient data from Mayo Clinic to identify cases for Coronary Artery Disease and Diabetes. To the best of our knowledge, this is the first study illustrating a framework and an approach for executing phenotyping criteria modeled in QDM using the Drools business rules management system.

  19. Modelling soil nitrogen: the MAGIC model with nitrogen retention linked to carbon turnover using decomposer dynamics.

    PubMed

    Oulehle, F; Cosby, B J; Wright, R F; Hruška, J; Kopáček, J; Krám, P; Evans, C D; Moldan, F

    2012-06-01

    We present a new formulation of the acidification model MAGIC that uses decomposer dynamics to link nitrogen (N) cycling to carbon (C) turnover in soils. The new model is evaluated by application to 15-30 years of water chemistry data at three coniferous-forested sites in the Czech Republic where deposition of sulphur (S) and N have decreased by >80% and 40%, respectively. Sulphate concentrations in waters have declined commensurately with S deposition, but nitrate concentrations have shown much larger decreases relative to N deposition. This behaviour is inconsistent with most conceptual models of N saturation, and with earlier versions of MAGIC which assume N retention to be a first-order function of N deposition and/or controlled by the soil C/N ratio. In comparison with earlier versions, the new formulation more correctly simulates observed short-term changes in nitrate leaching, as well as long-term retention of N in soils. The model suggests that, despite recent deposition reductions and recovery, progressive N saturation will lead to increased future nitrate leaching, ecosystem eutrophication and re-acidification.

  20. A Novel Letrozole Model Recapitulates Both the Reproductive and Metabolic Phenotypes of Polycystic Ovary Syndrome in Female Mice.

    PubMed

    Kauffman, Alexander S; Thackray, Varykina G; Ryan, Genevieve E; Tolson, Kristen P; Glidewell-Kenney, Christine A; Semaan, Sheila J; Poling, Matthew C; Iwata, Nahoko; Breen, Kellie M; Duleba, Antoni J; Stener-Victorin, Elisabet; Shimasaki, Shunichi; Webster, Nicholas J; Mellon, Pamela L

    2015-09-01

    Polycystic ovary syndrome (PCOS) pathophysiology is poorly understood, due partly to lack of PCOS animal models fully recapitulating this complex disorder. Recently, a PCOS rat model using letrozole (LET), a nonsteroidal aromatase inhibitor, mimicked multiple PCOS phenotypes, including metabolic features absent in other models. Given the advantages of using genetic and transgenic mouse models, we investigated whether LET produces a similar PCOS phenotype in mice. Pubertal female C57BL/6N mice were treated for 5 wk with LET, which resulted in increased serum testosterone and normal diestrus levels of estradiol, similar to the hyperandrogenemia and follicular phase estrogen levels of PCOS women. As in PCOS, ovaries from LET mice were larger, polycystic, and lacked corpora lutea versus controls. Most LET females were acyclic, and all were infertile. LET females displayed elevated serum LH levels and higher Lhb mRNA in the pituitary. In contrast, serum FSH and Fshb were significantly reduced in LET females, demonstrating differential effects on gonadotropins, as in PCOS. Within the ovary, LET females had higher Cyp17, Cyp19, and Fsh receptor mRNA expression. In the hypothalamus, LET females had higher kisspeptin receptor mRNA expression but lower progesterone receptor mRNA levels. LET females also gained more weight than controls, had increased abdominal adiposity and adipocyte size, elevated adipose inflammatory mRNA levels, and impaired glucose tolerance, mirroring the metabolic phenotype in PCOS women. This is the first report of a LET paradigm in mice that recapitulates both reproductive and metabolic PCOS phenotypes and will be useful to genetically probe the PCOS condition.

  1. A Novel Letrozole Model Recapitulates Both the Reproductive and Metabolic Phenotypes of Polycystic Ovary Syndrome in Female Mice1

    PubMed Central

    Kauffman, Alexander S.; Thackray, Varykina G.; Ryan, Genevieve E.; Tolson, Kristen P.; Glidewell-Kenney, Christine A.; Semaan, Sheila J.; Poling, Matthew C.; Iwata, Nahoko; Breen, Kellie M.; Duleba, Antoni J.; Stener-Victorin, Elisabet; Shimasaki, Shunichi; Webster, Nicholas J.; Mellon, Pamela L.

    2015-01-01

    Polycystic ovary syndrome (PCOS) pathophysiology is poorly understood, due partly to lack of PCOS animal models fully recapitulating this complex disorder. Recently, a PCOS rat model using letrozole (LET), a nonsteroidal aromatase inhibitor, mimicked multiple PCOS phenotypes, including metabolic features absent in other models. Given the advantages of using genetic and transgenic mouse models, we investigated whether LET produces a similar PCOS phenotype in mice. Pubertal female C57BL/6N mice were treated for 5 wk with LET, which resulted in increased serum testosterone and normal diestrus levels of estradiol, similar to the hyperandrogenemia and follicular phase estrogen levels of PCOS women. As in PCOS, ovaries from LET mice were larger, polycystic, and lacked corpora lutea versus controls. Most LET females were acyclic, and all were infertile. LET females displayed elevated serum LH levels and higher Lhb mRNA in the pituitary. In contrast, serum FSH and Fshb were significantly reduced in LET females, demonstrating differential effects on gonadotropins, as in PCOS. Within the ovary, LET females had higher Cyp17, Cyp19, and Fsh receptor mRNA expression. In the hypothalamus, LET females had higher kisspeptin receptor mRNA expression but lower progesterone receptor mRNA levels. LET females also gained more weight than controls, had increased abdominal adiposity and adipocyte size, elevated adipose inflammatory mRNA levels, and impaired glucose tolerance, mirroring the metabolic phenotype in PCOS women. This is the first report of a LET paradigm in mice that recapitulates both reproductive and metabolic PCOS phenotypes and will be useful to genetically probe the PCOS condition. PMID:26203175

  2. Linking individual phenotype to density-dependent population growth: the influence of body size on the population dynamics of malaria vectors.

    PubMed

    Russell, Tanya L; Lwetoijera, Dickson W; Knols, Bart G J; Takken, Willem; Killeen, Gerry F; Ferguson, Heather M

    2011-10-22

    Understanding the endogenous factors that drive the population dynamics of malaria mosquitoes will facilitate more accurate predictions about vector control effectiveness and our ability to destabilize the growth of either low- or high-density insect populations. We assessed whether variation in phenotypic traits predict the dynamics of Anopheles gambiae sensu lato mosquitoes, the most important vectors of human malaria. Anopheles gambiae dynamics were monitored over a six-month period of seasonal growth and decline. The population exhibited density-dependent feedback, with the carrying capacity being modified by rainfall (97% wAIC(c) support). The individual phenotypic expression of the maternal (p = 0.0001) and current (p = 0.040) body size positively influenced population growth. Our field-based evidence uniquely demonstrates that individual fitness can have population-level impacts and, furthermore, can mitigate the impact of exogenous drivers (e.g. rainfall) in species whose reproduction depends upon it. Once frontline interventions have suppressed mosquito densities, attempts to eliminate malaria with supplementary vector control tools may be attenuated by increased population growth and individual fitness.

  3. Linking individual phenotype to density-dependent population growth: the influence of body size on the population dynamics of malaria vectors

    PubMed Central

    Russell, Tanya L.; Lwetoijera, Dickson W.; Knols, Bart G. J.; Takken, Willem; Killeen, Gerry F.; Ferguson, Heather M.

    2011-01-01

    Understanding the endogenous factors that drive the population dynamics of malaria mosquitoes will facilitate more accurate predictions about vector control effectiveness and our ability to destabilize the growth of either low- or high-density insect populations. We assessed whether variation in phenotypic traits predict the dynamics of Anopheles gambiae sensu lato mosquitoes, the most important vectors of human malaria. Anopheles gambiae dynamics were monitored over a six-month period of seasonal growth and decline. The population exhibited density-dependent feedback, with the carrying capacity being modified by rainfall (97% wAICc support). The individual phenotypic expression of the maternal (p = 0.0001) and current (p = 0.040) body size positively influenced population growth. Our field-based evidence uniquely demonstrates that individual fitness can have population-level impacts and, furthermore, can mitigate the impact of exogenous drivers (e.g. rainfall) in species whose reproduction depends upon it. Once frontline interventions have suppressed mosquito densities, attempts to eliminate malaria with supplementary vector control tools may be attenuated by increased population growth and individual fitness. PMID:21389034

  4. A methodology for linking 2D overland flow models with the sewer network model SWMM 5.1 based on dynamic link libraries.

    PubMed

    Leandro, Jorge; Martins, Ricardo

    2016-01-01

    Pluvial flooding in urban areas is characterized by a gradually varying inundation process caused by surcharge of the sewer manholes. Therefore urban flood models need to simulate the interaction between the sewer network and the overland flow in order to accurately predict the flood inundation extents. In this work we present a methodology for linking 2D overland flow models with the storm sewer model SWMM 5. SWMM 5 is a well-known free open-source code originally developed in 1971. The latest major release saw its structure re-written in C ++ allowing it to be compiled as a command line executable or through a series of calls made to function inside a dynamic link library (DLL). The methodology developed herein is written inside the same DLL in C + +, and is able to simulate the bi-directional interaction between both models during simulation. Validation is done in a real case study with an existing urban flood coupled model. The novelty herein is that the new methodology can be added to SWMM without the need for editing SWMM's original code. Furthermore, it is directly applicable to other coupled overland flow models aiming to use SWMM 5 as the sewer network model.

  5. Investigating Phenotypic Heterogeneity in Children with Autism Spectrum Disorder: A Factor Mixture Modeling Approach

    ERIC Educational Resources Information Center

    Georgiades, Stelios; Szatmari, Peter; Boyle, Michael; Hanna, Steven; Duku, Eric; Zwaigenbaum, Lonnie; Bryson, Susan; Fombonne, Eric; Volden, Joanne; Mirenda, Pat; Smith, Isabel; Roberts, Wendy; Vaillancourt, Tracy; Waddell, Charlotte; Bennett, Teresa; Thompson, Ann

    2013-01-01

    Background: Autism spectrum disorder (ASD) is characterized by notable phenotypic heterogeneity, which is often viewed as an obstacle to the study of its etiology, diagnosis, treatment, and prognosis. On the basis of empirical evidence, instead of three binary categories, the upcoming edition of the DSM 5 will use two dimensions--social…

  6. Transcriptome Sequencing of Two Phenotypic Mosaic Eucalyptus Trees Reveals Large Scale Transcriptome Re-Modelling

    PubMed Central

    Padovan, Amanda; Patel, Hardip R.; Chuah, Aaron; Huttley, Gavin A.; Krause, Sandra T.; Degenhardt, Jörg; Foley, William J.; Külheim, Carsten

    2015-01-01

    Phenotypic mosaic trees offer an ideal system for studying differential gene expression. We have investigated two mosaic eucalypt trees from two closely related species (Eucalyptus melliodora and E. sideroxylon), which each support two types of leaves: one part of the canopy is resistant to insect herbivory and the remaining leaves are susceptible. Driving this ecological distinction are differences in plant secondary metabolites. We used these phenotypic mosaics to investigate genome wide patterns of foliar gene expression with the aim of identifying patterns of differential gene expression and the somatic mutation(s) that lead to this phenotypic mosaicism. We sequenced the mRNA pool from leaves of the resistant and susceptible ecotypes from both mosaic eucalypts using the Illumina HiSeq 2000 platform. We found large differences in pathway regulation and gene expression between the ecotypes of each mosaic. The expression of the genes in the MVA and MEP pathways is reflected by variation in leaf chemistry, however this is not the case for the terpene synthases. Apart from the terpene biosynthetic pathway, there are several other metabolic pathways that are differentially regulated between the two ecotypes, suggesting there is much more phenotypic diversity than has been described. Despite the close relationship between the two species, they show large differences in the global patterns of gene and pathway regulation. PMID:25978451

  7. Phenotypic Consequences of Copy Number Variation: Insights from Smith-Magenis and Potocki-Lupski Syndrome Mouse Models

    PubMed Central

    Chrast, Jacqueline; Gu, Wenli; Gheldof, Nele; Pradervand, Sylvain; Schütz, Frédéric; Young, Juan I.; Lupski, James R.; Reymond, Alexandre; Walz, Katherina

    2010-01-01

    A large fraction of genome variation between individuals is comprised of submicroscopic copy number variation of genomic DNA segments. We assessed the relative contribution of structural changes and gene dosage alterations on phenotypic outcomes with mouse models of Smith-Magenis and Potocki-Lupski syndromes. We phenotyped mice with 1n (Deletion/+), 2n (+/+), 3n (Duplication/+), and balanced 2n compound heterozygous (Deletion/Duplication) copies of the same region. Parallel to the observations made in humans, such variation in gene copy number was sufficient to generate phenotypic consequences: in a number of cases diametrically opposing phenotypes were associated with gain versus loss of gene content. Surprisingly, some neurobehavioral traits were not rescued by restoration of the normal gene copy number. Transcriptome profiling showed that a highly significant propensity of transcriptional changes map to the engineered interval in the five assessed tissues. A statistically significant overrepresentation of the genes mapping to the entire length of the engineered chromosome was also found in the top-ranked differentially expressed genes in the mice containing rearranged chromosomes, regardless of the nature of the rearrangement, an observation robust across different cell lineages of the central nervous system. Our data indicate that a structural change at a given position of the human genome may affect not only locus and adjacent gene expression but also “genome regulation.” Furthermore, structural change can cause the same perturbation in particular pathways regardless of gene dosage. Thus, the presence of a genomic structural change, as well as gene dosage imbalance, contributes to the ultimate phenotype. PMID:21124890

  8. Phenotypic consequences of copy number variation: insights from Smith-Magenis and Potocki-Lupski syndrome mouse models.

    PubMed

    Ricard, Guénola; Molina, Jessica; Chrast, Jacqueline; Gu, Wenli; Gheldof, Nele; Pradervand, Sylvain; Schütz, Frédéric; Young, Juan I; Lupski, James R; Reymond, Alexandre; Walz, Katherina

    2010-11-23

    A large fraction of genome variation between individuals is comprised of submicroscopic copy number variation of genomic DNA segments. We assessed the relative contribution of structural changes and gene dosage alterations on phenotypic outcomes with mouse models of Smith-Magenis and Potocki-Lupski syndromes. We phenotyped mice with 1n (Deletion/+), 2n (+/+), 3n (Duplication/+), and balanced 2n compound heterozygous (Deletion/Duplication) copies of the same region. Parallel to the observations made in humans, such variation in gene copy number was sufficient to generate phenotypic consequences: in a number of cases diametrically opposing phenotypes were associated with gain versus loss of gene content. Surprisingly, some neurobehavioral traits were not rescued by restoration of the normal gene copy number. Transcriptome profiling showed that a highly significant propensity of transcriptional changes map to the engineered interval in the five assessed tissues. A statistically significant overrepresentation of the genes mapping to the entire length of the engineered chromosome was also found in the top-ranked differentially expressed genes in the mice containing rearranged chromosomes, regardless of the nature of the rearrangement, an observation robust across different cell lineages of the central nervous system. Our data indicate that a structural change at a given position of the human genome may affect not only locus and adjacent gene expression but also "genome regulation." Furthermore, structural change can cause the same perturbation in particular pathways regardless of gene dosage. Thus, the presence of a genomic structural change, as well as gene dosage imbalance, contributes to the ultimate phenotype.

  9. BMP antagonists enhance myogenic differentiation and ameliorate the dystrophic phenotype in a DMD mouse model.

    PubMed

    Shi, SongTing; Hoogaars, Willem M H; de Gorter, David J J; van Heiningen, Sandra H; Lin, Herbert Y; Hong, Charles C; Kemaladewi, Dwi U; Aartsma-Rus, Annemieke; ten Dijke, Peter; 't Hoen, Peter A C

    2011-02-01

    Duchenne Muscular Dystrophy (DMD) is an X-linked lethal muscle wasting disease characterized by muscle fiber degeneration and necrosis. The progressive pathology of DMD can be explained by an insufficient regenerative response resulting in fibrosis and adipose tissue formation. BMPs are known to inhibit myogenic differentiation and in a previous study we found an increased expression of a BMP family member BMP4 in DMD myoblasts. The aim of the current study was therefore to investigate whether inhibition of BMP signaling could be beneficial for myoblast differentiation and muscle regeneration processes in a DMD context. All tested BMP inhibitors, Noggin, dorsomorphin and LDN-193189, were able to accelerate and enhance myogenic differentiation. However, dorsomorphin repressed both BMP and TGFβ signaling and was found to be toxic to primary myoblast cell cultures. In contrast, Noggin was found to be a potent and selective BMP inhibitor and was therefore tested in vivo in a DMD mouse model. Local adenoviral-mediated overexpression of Noggin in muscle resulted in an increased expression of the myogenic regulatory genes Myog and Myod1 and improved muscle histology. In conclusion, our results suggest that repression of BMP signaling may constitute an attractive adjunctive therapy for DMD patients.

  10. Computer modeling and analysis of thermal link performance for an optical refrigerator

    NASA Astrophysics Data System (ADS)

    Byram, Kevin; Mar, David; Parker, John; Von der Porten, Steven; Hankinson, John; Lee, Chris; Mayeda, Kai; Haskell, Richard C.; Yang, Qimin; Greenfield, Scott R.; Epstein, Richard I.

    2008-02-01

    We have used the thermal modeling tool in COMSOL Multiphysics to investigate factors that affect the thermal performance of the optical refrigerator. Assuming an ideal cooling element and a non-absorptive dielectric trapping mirror, the three dominant heating factors are blackbody radiation from the surrounding environment, conductive heat transfer through mechanical supports, and the absorption of fluoresced photons transmitted through the thermal link. Laboratory experimentation coupled with computer modeling using Code V optical software have resulted in link designs capable of reducing the transmission to 0.04% of the fluoresced photons emitted toward the thermal link. The ideal thermal link will have minimal surface area, provide complete optical isolation for the load, and possess high thermal conductivity. Modeling results imply that a 1cm 3 load can be chilled to 102 K with currently available cooling efficiencies using a 100 W pump laser on a YB:ZBLANP system, and using an ideal link that has minimal surface area and no optical transmission. We review the simulated steady-state cooling temperatures reached by the heat load for several link designs and system configurations as a comparative measure of how well particular configurations perform.

  11. A Simple Forecasting Model Linking Macroeconomic Policy to Industrial Employment Demand.

    ERIC Educational Resources Information Center

    Malley, James R.; Hady, Thomas F.

    A study detailed further a model linking monetary and fiscal policy to industrial employment in metropolitan and nonmetropolitan areas of four United States regions. The model was used to simulate the impacts on area and regional employment of three events in the economy: changing real gross national product (GNP) via monetary policy, holding the…

  12. An Extension of Least Squares Estimation of IRT Linking Coefficients for the Graded Response Model

    ERIC Educational Resources Information Center

    Kim, Seonghoon

    2010-01-01

    The three types (generalized, unweighted, and weighted) of least squares methods, proposed by Ogasawara, for estimating item response theory (IRT) linking coefficients under dichotomous models are extended to the graded response model. A simulation study was conducted to confirm the accuracy of the extended formulas, and a real data study was…

  13. A responsive human triple-culture model of the air-blood barrier: incorporation of different macrophage phenotypes.

    PubMed

    Kasper, Jennifer Y; Hermanns, Maria I; Unger, Ronald E; Kirkpatrick, C James

    2015-06-15

    Current pulmonary research underlines the relevance of the alveolar macrophage (AM) integrated in multicellular co-culture-systems of the respiratory tract to unravel, for example, the mechanisms of tissue regeneration. AMs demonstrate a specific functionality, as they inhabit a unique microenvironment with high oxygen levels and exposure to external hazards. Healthy AMs display an anti-inflammatory phenotype, prevent hypersensitivity to normally innocuous contaminants and maintain tissue homeostasis in the alveolus. To mirror the actual physiological function of the AM, we developed three different polarized [classically activated (M1) and alternatively activated (M2wh , wound-healing; M2reg , regulatory)] macrophage models using a mixture of differentiation mediators, as described in the current literature. To test their immunological impact, these distinct macrophage phenotypes were seeded on to the epithelial layer of an established in vitro air-blood barrier co-culture, consisting of alveolar epithelial cells A549 or H441 and microvascular endothelial cells ISO-HAS-1 on the opposite side of a Transwell filter-membrane. IL-8 and sICAM release were measured as functionality parameters after LPS challenge. The M1 model itself already provoked a severe inflammatory-like response of the air-blood barrier co-culture, thus demonstrating its potential as a useful in vitro model for inflammatory lung diseases. The two M2 models represent a 'non-inflammatory' phenotype but still showed the ability to trigger inflammation following LPS challenge. Hence, the latter could be used to establish a quiescent, physiological in vitro air-blood model. Thus, the more complex differentiation protocol developed in the present study provides a responsive in vitro triple-culture model of the air-blood-barrier that mimics AM features as they occur in vivo. © 2015 The Authors Journal of Tissue Engineering and Regenerative Medicine Published by John Wiley & Sons, Ltd.

  14. The molecular genetics and neurobiology of developmental dyslexia as model of a complex phenotype.

    PubMed

    Kere, Juha

    2014-09-19

    Among complex disorders, those concerning neuropsychiatric phenotypes involve particular challenges compared to disorders with more easily distinguished clinical signs and measures. One such common and unusually challenging phenotype to disentangle genetically is developmental dyslexia (DD), or reading disability, defined as the inability to learn to read and write for an otherwise normally intelligent child with normal senses and educational opportunity. There is presently ample evidence for the strongly biological etiology for DD, and a dozen susceptibility genes have been suggested. Many of these genes point to common but previously unsuspected biological mechanisms, such as neuronal migration and cilia functions. I discuss here the state-of-the-art in genomic and neurobiological aspects of DD research, starting with short general background to its history.

  15. Innovations in phenotyping of mouse models in the German Mouse Clinic.

    PubMed

    Fuchs, Helmut; Gailus-Durner, Valérie; Neschen, Susanne; Adler, Thure; Afonso, Luciana Caminha; Aguilar-Pimentel, Juan Antonio; Becker, Lore; Bohla, Alexander; Calzada-Wack, Julia; Cohrs, Christian; Dewert, Anna; Fridrich, Barbara; Garrett, Lillian; Glasl, Lisa; Götz, Alexander; Hans, Wolfgang; Hölter, Sabine M; Horsch, Marion; Hurt, Anja; Janas, Eva; Janik, Dirk; Kahle, Melanie; Kistler, Martin; Klein-Rodewald, Tanja; Lengger, Christoph; Ludwig, Tonia; Maier, Holger; Marschall, Susan; Micklich, Kateryna; Möller, Gabriele; Naton, Beatrix; Prehn, Cornelia; Puk, Oliver; Rácz, Ildikó; Räss, Michael; Rathkolb, Birgit; Rozman, Jan; Scheerer, Markus; Schiller, Evelyn; Schrewe, Anja; Steinkamp, Ralph; Stöger, Claudia; Sun, Minxuan; Szymczak, Wilfried; Treise, Irina; Vargas Panesso, Ingrid Liliana; Vernaleken, Alexandra M; Willershäuser, Monja; Wolff-Muscate, Annemarie; Zeh, Ramona; Adamski, Jerzy; Beckers, Johannes; Bekeredjian, Raffi; Busch, Dirk H; Eickelberg, Oliver; Favor, Jack; Graw, Jochen; Höfler, Heinz; Höschen, Christoph; Katus, Hugo; Klingenspor, Martin; Klopstock, Thomas; Neff, Frauke; Ollert, Markus; Schulz, Holger; Stöger, Tobias; Wolf, Eckhard; Wurst, Wolfgang; Yildirim, Ali Önder; Zimmer, Andreas; Hrabě de Angelis, Martin

    2012-10-01

    Under the label of the German Mouse Clinic (GMC), a concept has been developed and implemented that allows the better understanding of human diseases on the pathophysiological and molecular level. This includes better understanding of the crosstalk between different organs, pleiotropy of genes, and the systemic impact of envirotypes and drugs. In the GMC, experts from various fields of mouse genetics and physiology, in close collaboration with clinicians, work side by side under one roof. The GMC is an open-access platform for the scientific community by providing phenotypic analysis in bilateral collaborations ("bottom-up projects") and as a partner and driver in international large-scale biology projects ("top-down projects"). Furthermore, technology development is a major topic in the GMC. Innovative techniques for primary and secondary screens are developed and implemented into the phenotyping pipelines (e.g., detection of volatile organic compounds, VOCs).

  16. Modeling Phenotypic Metabolic Adaptations of Mycobacterium tuberculosis H37Rv under Hypoxia

    DTIC Science & Technology

    2012-09-13

    tubercu- losis granulomas in guinea pig, rabbit, and nonhuman primate PLOS Computational Biology | www.ploscompbiol.org 1 September 2012 | Volume 8...Phenotypic metabolic changes of M. tuberculosis H37Rv under hypoxia The persistence of M. tuberculosis in human granulomas is partly due to its...Carrillo J, Allen SS, et al. (2008) Tuberculous granulomas are hypoxic in guinea pigs, rabbits, and nonhuman primates. Infect Immun 76: 2333–2340. 23

  17. Plasticity, stability, and yield: the origins of Anthony David Bradshaw's model of adaptive phenotypic plasticity.

    PubMed

    Peirson, B R Erick

    2015-04-01

    Plant ecologist Anthony David Bradshaw's account of the evolution of adaptive phenotypic plasticity remains central to contemporary research aimed at understanding how organisms persist in heterogeneous environments. Bradshaw suggested that changes in particular traits in response to specific environmental factors could be under direct genetic control, and that natural selection could therefore act directly to shape those responses: plasticity was not "noise" obscuring a genetic signal, but could be specific and refined just as any other adaptive phenotypic trait. In this paper, I document the contexts and development of Bradshaw's investigation of phenotypic plasticity in plants, including a series of unreported experiments in the late 1950s and early 1960s. Contrary to the mythology that later emerged around Bradshaw's ideas, Bradshaw was engaged in a serious and sustained empirical research program concerning plasticity in the 1950s and 1960s that went far beyond a single review paper. Moreover, that work was not isolated, but was surrounded by an already rich theoretical discourse and a substantial body of empirical research concerning the evolution of developmental plasticity and stability. Bradshaw recast the problem of how to understand (and control) plasticity and stability within an epistemic framework focused on genetic differences and natural selection.

  18. Simple and robust determination of the activity signature of key carbohydrate metabolism enzymes for physiological phenotyping in model and crop plants.

    PubMed

    Jammer, Alexandra; Gasperl, Anna; Luschin-Ebengreuth, Nora; Heyneke, Elmien; Chu, Hyosub; Cantero-Navarro, Elena; Großkinsky, Dominik K; Albacete, Alfonso A; Stabentheiner, Edith; Franzaring, Jürgen; Fangmeier, Andreas; van der Graaff, Eric; Roitsch, Thomas

    2015-09-01

    The analysis of physiological parameters is important to understand the link between plant phenotypes and their genetic bases, and therefore is needed as an important element in the analysis of model and crop plants. The activities of enzymes involved in primary carbohydrate metabolism have been shown to be strongly associated with growth performance, crop yield, and quality, as well as stress responses. A simple, fast, and cost-effective method to determine activities for 13 key enzymes involved in carbohydrate metabolism has been established, mainly based on coupled spectrophotometric kinetic assays. The comparison of extraction buffers and requirement for dialysis of crude protein extracts resulted in a universal protein extraction protocol, suitable for the preparation of protein extracts from different organs of various species. Individual published kinetic activity assays were optimized and adapted for a semi-high-throughput 96-well assay format. These assays proved to be robust and are thus suitable for physiological phenotyping, enabling the characterization and diagnosis of the physiological state. The potential of the determination of distinct enzyme activity signatures as part of a physiological fingerprint was shown for various organs and tissues from three monocot and five dicot model and crop species, including two case studies with external stimuli. Differential and specific enzyme activity signatures are apparent during inflorescence development and upon in vitro cold treatment of young inflorescences in the monocot ryegrass, related to conditions for doubled haploid formation. Likewise, treatment of dicot spring oilseed rape with elevated CO2 concentration resulted in distinct patterns of enzyme activity responses in leaves.

  19. Selection and mutation in X-linked recessive diseases epidemiological model.

    PubMed

    Verrilli, Francesca; Kebriaei, Hamed; Glielmo, Luigi; Corless, Martin; Del Vecchio, Carmen

    2015-01-01

    To describe the epidemiology of X-linked recessive diseases we developed a discrete time, structured, non linear mathematical model. The model allows for de novo mutations (i.e. affected sibling born to unaffected parents) and selection (i.e., distinct fitness rates depending on individual's health conditions). Applying Lyapunov direct method we found the domain of attraction of model's equilibrium point and studied the convergence properties of the degenerate equilibrium where only affected individuals survive.

  20. Surface Topography and Mechanical Strain Promote Keratocyte Phenotype and Extracellular Matrix Formation in a Biomimetic 3D Corneal Model.

    PubMed

    Zhang, Wei; Chen, Jialin; Backman, Ludvig J; Malm, Adam D; Danielson, Patrik

    2017-03-01

    The optimal functionality of the native corneal stroma is mainly dependent on the well-ordered arrangement of extracellular matrix (ECM) and the pressurized structure. In order to develop an in vitro corneal model, it is crucial to mimic the in vivo microenvironment of the cornea. In this study, the influence of surface topography and mechanical strain on keratocyte phenotype and ECM formation within a biomimetic 3D corneal model is studied. By modifying the surface topography of materials, it is found that patterned silk fibroin film with 600 grooves mm(-1) optimally supports cell alignment and ECM arrangement. Furthermore, treatment with 3% dome-shaped mechanical strain, which resembles the shape and mechanics of native cornea, significantly enhances the expression of keratocyte markers as compared to flat-shaped strain. Accordingly, a biomimetic 3D corneal model, in the form of a collagen-modified, silk fibroin-patterned construct subjected to 3% dome-shaped strain, is created. Compared to traditional 2D cultures, it supports a significantly higher expression of keratocyte and ECM markers, and in conclusion better maintains keratocyte phenotype, alignment, and fusiform cell shape. Therefore, the novel biomimetic 3D corneal model developed in this study serves as a useful in vitro 3D culture model to improve current 2D cultures for corneal studies.

  1. Discovering link communities in complex networks by an integer programming model and a genetic algorithm.

    PubMed

    Li, Zhenping; Zhang, Xiang-Sun; Wang, Rui-Sheng; Liu, Hongwei; Zhang, Shihua

    2013-01-01

    Identification of communities in complex networks is an important topic and issue in many fields such as sociology, biology, and computer science. Communities are often defined as groups of related nodes or links that correspond to functional subunits in the corresponding complex systems. While most conventional approaches have focused on discovering communities of nodes, some recent studies start partitioning links to find overlapping communities straightforwardly. In this paper, we propose a new quantity function for link community identification in complex networks. Based on this quantity function we formulate the link community partition problem into an integer programming model which allows us to partition a complex network into overlapping communities. We further propose a genetic algorithm for link community detection which can partition a network into overlapping communities without knowing the number of communities. We test our model and algorithm on both artificial networks and real-world networks. The results demonstrate that the model and algorithm are efficient in detecting overlapping community structure in complex networks.

  2. Tension monitoring during epithelial-to-mesenchymal transition links the switch of phenotype to expression of moesin and cadherins in NMuMG cells.

    PubMed

    Schneider, David; Baronsky, Thilo; Pietuch, Anna; Rother, Jan; Oelkers, Marieelen; Fichtner, Dagmar; Wedlich, Doris; Janshoff, Andreas

    2013-01-01

    Structural alterations during epithelial-to-mesenchymal transition (EMT) pose a substantial challenge to the mechanical response of cells and are supposed to be key parameters for an increased malignancy during metastasis. Herein, we report that during EMT, apical tension of the epithelial cell line NMuMG is controlled by cell-cell contacts and the architecture of the underlying actin structures reflecting the mechanistic interplay between cellular structure and mechanics. Using force spectroscopy we find that tension in NMuMG cells slightly increases 24 h after EMT induction, whereas upon reaching the final mesenchymal-like state characterized by a complete loss of intercellular junctions and a concerted down-regulation of the adherens junction protein E-cadherin, the overall tension becomes similar to that of solitary adherent cells and fibroblasts. Interestingly, the contribution of the actin cytoskeleton on apical tension increases significantly upon EMT induction, most likely due to the formation of stable and highly contractile stress fibers which dominate the elastic properties of the cells after the transition. The structural alterations lead to the formation of single, highly motile cells rendering apical tension a good indicator for the cellular state during phenotype switching. In summary, our study paves the way towards a more profound understanding of cellular mechanics governing fundamental morphological programs such as the EMT.

  3. Tension Monitoring during Epithelial-to-Mesenchymal Transition Links the Switch of Phenotype to Expression of Moesin and Cadherins in NMuMG Cells

    PubMed Central

    Schneider, David; Baronsky, Thilo; Pietuch, Anna; Rother, Jan; Oelkers, Marieelen; Fichtner, Dagmar; Wedlich, Doris; Janshoff, Andreas

    2013-01-01

    Structural alterations during epithelial-to-mesenchymal transition (EMT) pose a substantial challenge to the mechanical response of cells and are supposed to be key parameters for an increased malignancy during metastasis. Herein, we report that during EMT, apical tension of the epithelial cell line NMuMG is controlled by cell-cell contacts and the architecture of the underlying actin structures reflecting the mechanistic interplay between cellular structure and mechanics. Using force spectroscopy we find that tension in NMuMG cells slightly increases 24 h after EMT induction, whereas upon reaching the final mesenchymal-like state characterized by a complete loss of intercellular junctions and a concerted down-regulation of the adherens junction protein E-cadherin, the overall tension becomes similar to that of solitary adherent cells and fibroblasts. Interestingly, the contribution of the actin cytoskeleton on apical tension increases significantly upon EMT induction, most likely due to the formation of stable and highly contractile stress fibers which dominate the elastic properties of the cells after the transition. The structural alterations lead to the formation of single, highly motile cells rendering apical tension a good indicator for the cellular state during phenotype switching. In summary, our study paves the way towards a more profound understanding of cellular mechanics governing fundamental morphological programs such as the EMT. PMID:24339870

  4. Metabolomic analysis of the selection response of Drosophila melanogaster to environmental stress: are there links to gene expression and phenotypic traits?

    NASA Astrophysics Data System (ADS)

    Malmendal, Anders; Sørensen, Jesper Givskov; Overgaard, Johannes; Holmstrup, Martin; Nielsen, Niels Chr.; Loeschcke, Volker

    2013-05-01

    We investigated the global metabolite response to artificial selection for tolerance to stressful conditions such as cold, heat, starvation, and desiccation, and for longevity in Drosophila melanogaster. Our findings were compared to data from other levels of biological organization, including gene expression, physiological traits, and organismal stress tolerance phenotype. Overall, we found that selection for environmental stress tolerance changes the metabolomic 1H NMR fingerprint largely in a similar manner independent of the trait selected for, indicating that experimental evolution led to a general stress selection response at the metabolomic level. Integrative analyses across data sets showed little similarity when general correlations between selection effects at the level of the metabolome and gene expression were compared. This is likely due to the fact that the changes caused by these selection regimes were rather mild and/or that the dominating determinants for gene expression and metabolite levels were different. However, expression of a number of genes was correlated with the metabolite data. Many of the identified genes were general stress response genes that are down-regulated in response to selection for some of the stresses in this study. Overall, the results illustrate that selection markedly alters the metabolite profile and that the coupling between different levels of biological organization indeed is present though not very strong for stress selection at this level. The results highlight the extreme complexity of environmental stress adaptation and the difficulty of extrapolating and interpreting responses across levels of biological organization.

  5. Genome-wide association mapping in a wild avian population identifies a link between genetic and phenotypic variation in a life-history trait.

    PubMed

    Husby, Arild; Kawakami, Takeshi; Rönnegård, Lars; Smeds, Linnéa; Ellegren, Hans; Qvarnström, Anna

    2015-05-07

    Understanding the genetic basis of traits involved in adaptation is a major challenge in evolutionary biology but remains poorly understood. Here, we use genome-wide association mapping using a custom 50 k single nucleotide polymorphism (SNP) array in a natural population of collared flycatchers to examine the genetic basis of clutch size, an important life-history trait in many animal species. We found evidence for an association on chromosome 18 where one SNP significant at the genome-wide level explained 3.9% of the phenotypic variance. We also detected two suggestive quantitative trait loci (QTLs) on chromosomes 9 and 26. Fitness differences among genotypes were generally weak and not significant, although there was some indication of a sex-by-genotype interaction for lifetime reproductive success at the suggestive QTL on chromosome 26. This implies that sexual antagonism may play a role in maintaining genetic variation at this QTL. Our findings provide candidate regions for a classic avian life-history trait that will be useful for future studies examining the molecular and cellular function of, as well as evolutionary mechanisms operating at, these loci.

  6. Mutations in BCAP31 Cause a Severe X-Linked Phenotype with Deafness, Dystonia, and Central Hypomyelination and Disorganize the Golgi Apparatus

    PubMed Central

    Cacciagli, Pierre; Sutera-Sardo, Julie; Borges-Correia, Ana; Roux, Jean-Christophe; Dorboz, Imen; Desvignes, Jean-Pierre; Badens, Catherine; Delepine, Marc; Lathrop, Mark; Cau, Pierre; Lévy, Nicolas; Girard, Nadine; Sarda, Pierre; Boespflug-Tanguy, Odile; Villard, Laurent

    2013-01-01

    BAP31 is one of the most abundant endoplasmic reticulum (ER) membrane proteins. It is a chaperone protein involved in several pathways, including ER-associated degradation, export of ER proteins to the Golgi apparatus, and programmed cell death. BAP31 is encoded by BCAP31, located in human Xq28 and highly expressed in neurons. We identified loss-of-function mutations in BCAP31 in seven individuals from three families. These persons suffered from motor and intellectual disabilities, dystonia, sensorineural deafness, and white-matter changes, which together define an X-linked syndrome. In the primary fibroblasts of affected individuals, we found that BCAP31 deficiency altered ER morphology and caused a disorganization of the Golgi apparatus in a significant proportion of cells. Contrary to what has been described with transient-RNA-interference experiments, we demonstrate that constitutive BCAP31 deficiency does not activate the unfolded protein response or cell-death effectors. Rather, our data demonstrate that the lack of BAP31 disturbs ER metabolism and impacts the Golgi apparatus, highlighting an important role for BAP31 in ER-to-Golgi crosstalk. These findings provide a molecular basis for a Mendelian syndrome and link intracellular protein trafficking to severe congenital brain dysfunction and deafness. PMID:24011989

  7. Mutations in BCAP31 cause a severe X-linked phenotype with deafness, dystonia, and central hypomyelination and disorganize the Golgi apparatus.

    PubMed

    Cacciagli, Pierre; Sutera-Sardo, Julie; Borges-Correia, Ana; Roux, Jean-Christophe; Dorboz, Imen; Desvignes, Jean-Pierre; Badens, Catherine; Delepine, Marc; Lathrop, Mark; Cau, Pierre; Lévy, Nicolas; Girard, Nadine; Sarda, Pierre; Boespflug-Tanguy, Odile; Villard, Laurent

    2013-09-05

    BAP31 is one of the most abundant endoplasmic reticulum (ER) membrane proteins. It is a chaperone protein involved in several pathways, including ER-associated degradation, export of ER proteins to the Golgi apparatus, and programmed cell death. BAP31 is encoded by BCAP31, located in human Xq28 and highly expressed in neurons. We identified loss-of-function mutations in BCAP31 in seven individuals from three families. These persons suffered from motor and intellectual disabilities, dystonia, sensorineural deafness, and white-matter changes, which together define an X-linked syndrome. In the primary fibroblasts of affected individuals, we found that BCAP31 deficiency altered ER morphology and caused a disorganization of the Golgi apparatus in a significant proportion of cells. Contrary to what has been described with transient-RNA-interference experiments, we demonstrate that constitutive BCAP31 deficiency does not activate the unfolded protein response or cell-death effectors. Rather, our data demonstrate that the lack of BAP31 disturbs ER metabolism and impacts the Golgi apparatus, highlighting an important role for BAP31 in ER-to-Golgi crosstalk. These findings provide a molecular basis for a Mendelian syndrome and link intracellular protein trafficking to severe congenital brain dysfunction and deafness.

  8. Platelet dysfunction and a high bone mass phenotype in a murine model of platelet-type von Willebrand disease.

    PubMed

    Suva, Larry J; Hartman, Eric; Dilley, Joshua D; Russell, Susan; Akel, Nisreen S; Skinner, Robert A; Hogue, William R; Budde, Ulrich; Varughese, Kottayil I; Kanaji, Taisuke; Ware, Jerry

    2008-02-01

    The platelet glycoprotein Ib-IX receptor binds surface-bound von Willebrand factor and supports platelet adhesion to damaged vascular surfaces. A limited number of mutations within the glycoprotein Ib-IX complex have been described that permit a structurally altered receptor to interact with soluble von Willebrand factor, and this is the molecular basis of platelet-type von Willebrand disease. We have developed and characterized a mouse model of platelet-type von Willebrand disease (G233V) and have confirmed a platelet phenotype mimicking the human disorder. The mice have a dramatic increase in splenic megakaryocytes and splenomegaly. Recent studies have demonstrated that hematopoetic cells can influence the differentiation of osteogenic cells. Thus, we examined the skeletal phenotype of mice expressing the G233V variant complex. At 6 months of age, G233V mice exhibit a high bone mass phenotype with an approximate doubling of trabecular bone volume in both the tibia and femur. Serum measures of bone resorption were significantly decreased in G233V animals. With decreased bone resorption, cortical thickness was increased, medullary area decreased, and consequently, the mechanical strength of the femur was significantly increased. Using ex vivo bone marrow cultures, osteoclast-specific staining in the G233V mutant marrow was diminished, whereas osteoblastogenesis was unaffected. These studies provide new insights into the relationship between the regulation of megakaryocytopoiesis and bone mass.

  9. Oxidative stress is increased in C. elegans models of Huntington's disease but does not contribute to polyglutamine toxicity phenotypes.

    PubMed

    Machiela, Emily; Dues, Dylan J; Senchuk, Megan M; Van Raamsdonk, Jeremy M

    2016-12-01

    Huntington's disease (HD) is an adult onset neurodegenerative disorder for which there is currently no cure. While HD patients and animal models of the disease exhibit increased oxidative damage, it is currently uncertain to what extent oxidative stress contributes to disease pathogenesis. In this work, we use a genetic approach to define the role of oxidative stress in HD. We find that a C. elegans model of HD expressing a disease-length polyglutamine tract in the body wall muscle is hypersensitive to oxidative stress and shows an upregulation of antioxidant defense genes, indicating that the HD worm model has increased levels of oxidative stress. To determine whether this increase in oxidative stress contributes to the development of polyglutamine-toxicity phenotypes in this HD model, we examined the effect of deleting individual superoxide dismutase (sod) genes in the HD worm model. As predicted, we found that deletion of sod genes in the HD worm model resulted in a clear increase in sensitivity to oxidative stress. However, we found that increasing oxidative stress in the HD worm model did not exacerbate deficits caused by polyglutamine toxicity. We confirmed these observations in two worm models expressing disease-length polyglutamine tracts in neurons. Furthermore, we found that treatment with antioxidants failed to rescue movement deficits or decrease aggregation in HD worm models. Combined, this suggests that the increase in oxidative stress in worm models of HD does not contribute to the phenotypic deficits observed in these worms, and provides a possible explanation for the failure of antioxidants in HD clinical trials.

  10. Functional Characterization of IPSC-Derived Brain Cells as a Model for X-Linked Adrenoleukodystrophy.

    PubMed

    Baarine, Mauhamad; Khan, Mushfiquddin; Singh, Avtar; Singh, Inderjit

    2015-01-01

    X-ALD is an inherited neurodegenerative disorder where mutations in the ABCD1 gene result in clinically diverse phenotypes: the fatal disorder of cerebral childhood ALD (cALD) or a milder disorder of adrenomyeloneuropathy (AMN). The various models used to study the pathobiology of X-ALD disease lack the appropriate presentation for different phenotypes of cALD vs AMN. This study demonstrates that induced pluripotent stem cells (IPSC) derived brain cells astrocytes (Ast), neurons and oligodendrocytes (OLs) express morphological and functional activities of the respective brain cell types. The excessive accumulation of saturated VLCFA, a "hallmark" of X-ALD, was observed in both AMN OLs and cALD OLs with higher levels observed in cALD OLs than AMN OLs. The levels of ELOVL1 (ELOVL Fatty Acid Elongase 1) mRNA parallel the VLCFA load in AMN and cALD OLs. Furthermore, cALD Ast expressed higher levels of proinflammatory cytokines than AMN Ast and control Ast with or without stimulation with lipopolysaccharide. These results document that IPSC-derived Ast and OLs from cALD and AMN fibroblasts mimic the respective biochemical disease phenotypes and thus provide an ideal platform to investigate the mechanism of VLCFA load in cALD OLs and VLCFA-induced inflammatory disease mechanisms of cALD Ast and thus for testing of new therapeutics for AMN and cALD disease of X-ALD.

  11. Behavioral phenotypic properties of a natural occurring rat model of congenital stationary night blindness with Cacna1f mutation.

    PubMed

    An, Jing; Wang, Li; Guo, Qun; Li, Li; Xia, Feng; Zhang, Zuoming

    2012-09-01

    Cacna1f gene mutation could lead to incomplete congenital stationary night blindness (iCSNB) disease. The CSNB-like phenotype rat is a spontaneous rat model caused by Cacna1f gene mutation. The present study explored the phenotypic properties of behavior performance in CSNB rats further. The vision-related behaviors of CSNB rats were assessed with a Morris water maze (MWM), passive avoidance tests, and open-field test. Motor ability was evaluated with a rotarod test and a wire hang test, and mechanical pain and thermalgia were used to evaluate sensory system function. Electroretinograms (ERGs) were recorded to evaluate the function of the retina. The vision-related results showed that longer latencies of escape and reduced probe trial in MWM for CSNB rats. There were more errors in avoidance test; CSNB rats were more active in the open field and presented a different pattern of exploration. The locomotor-related behaviors showed shorter falling latencies in the rotarod test and shorter gripping time in CSNB rats. And mechanical thresholds of pain increased in CSNB rats. The ERGs indicated that both the amplitude and latency of rod and cone systems were impaired in the CSNB rats. In summary, Cacna1f gene mutation changed the performance of various behaviors in the CSNB rat aside from vision-related phenotype. Cacna1f gene might play a role in a wide range of responses in the organism. These results confirm the importance of a comprehensive profile for understanding the behavior phenotype of Cacna1f gene mutation in CSNB rat.

  12. Genotype-phenotype modeling considering intermediate level of biological variation: a case study involving sensory traits, metabolites and QTLs in ripe tomatoes.

    PubMed

    Wang, Huange; Paulo, Joao; Kruijer, Willem; Boer, Martin; Jansen, Hans; Tikunov, Yury; Usadel, Björn; van Heusden, Sjaak; Bovy, Arnaud; van Eeuwijk, Fred

    2015-11-01

    Modeling genotype-phenotype relationships is a central objective in plant genetics and breeding. Commonly, variations in phenotypic traits are modeled directly in relation to variations at the DNA level, regardless of intermediate levels of biological variation. Here we present an integrative method for the simultaneous modeling of a set of multilevel phenotypic responses to variations at the DNA level. More specifically, for ripe tomato fruits, we use Gaussian graphical models and causal inference techniques to learn the dependencies of 24 sensory traits on 29 metabolites and the dependencies of those sensory and metabolic traits on 21 QTLs. The inferred dependency network which, though not essentially representing biological pathways, suggests how the effects of allele substitutions propagate through multilevel phenotypes. Such simultaneous study of the underlying genetic architecture and multifactorial interactions is expected to enhance the prediction and manipulation of complex traits.

  13. The calcineurin inhibitor Sarah (Nebula) exacerbates Aβ42 phenotypes in a Drosophila model of Alzheimer's disease.

    PubMed

    Lee, Soojin; Bang, Se Min; Hong, Yoon Ki; Lee, Jang Ho; Jeong, Haemin; Park, Seung Hwan; Liu, Quan Feng; Lee, Im-Soon; Cho, Kyoung Sang

    2016-03-01

    Expression of the Down syndrome critical region 1 (DSCR1) protein, an inhibitor of the Ca(2+)-dependent phosphatase calcineurin, is elevated in the brains of individuals with Down syndrome (DS) or Alzheimer's disease (AD). Although increased levels of DSCR1 were often observed to be deleterious to neuronal health, its beneficial effects against AD neuropathology have also been reported, and the roles of DSCR1 on the pathogenesis of AD remain controversial. Here, we investigated the role of sarah (sra; also known as nebula), a Drosophila DSCR1 ortholog, in amyloid-β42 (Aβ42)-induced neurological phenotypes in Drosophila. We detected sra expression in the mushroom bodies of the fly brain, which are a center for learning and memory in flies. Moreover, similar to humans with AD, Aβ42-expressing flies showed increased Sra levels in the brain, demonstrating that the expression pattern of DSCR1 with regard to AD pathogenesis is conserved in Drosophila. Interestingly, overexpression of sra using the UAS-GAL4 system exacerbated the rough-eye phenotype, decreased survival rates and increased neuronal cell death in Aβ42-expressing flies, without modulating Aβ42 expression. Moreover, neuronal overexpression of sra in combination with Aβ42 dramatically reduced both locomotor activity and the adult lifespan of flies, whereas flies with overexpression of sra alone showed normal climbing ability, albeit with a slightly reduced lifespan. Similarly, treatment with chemical inhibitors of calcineurin, such as FK506 and cyclosporin A, or knockdown of calcineurin expression by RNA interference (RNAi), exacerbated the Aβ42-induced rough-eye phenotype. Furthermore, sra-overexpressing flies displayed significantly decreased mitochondrial DNA and ATP levels, as well as increased susceptibility to oxidative stress compared to that of control flies. Taken together, our results demonstrating that sra overexpression augments Aβ42 cytotoxicity in Drosophila suggest that DSCR1

  14. The calcineurin inhibitor Sarah (Nebula) exacerbates Aβ42 phenotypes in a Drosophila model of Alzheimer's disease

    PubMed Central

    Lee, Soojin; Bang, Se Min; Hong, Yoon Ki; Lee, Jang Ho; Jeong, Haemin; Park, Seung Hwan; Liu, Quan Feng; Lee, Im-Soon; Cho, Kyoung Sang

    2016-01-01

    ABSTRACT Expression of the Down syndrome critical region 1 (DSCR1) protein, an inhibitor of the Ca2+-dependent phosphatase calcineurin, is elevated in the brains of individuals with Down syndrome (DS) or Alzheimer's disease (AD). Although increased levels of DSCR1 were often observed to be deleterious to neuronal health, its beneficial effects against AD neuropathology have also been reported, and the roles of DSCR1 on the pathogenesis of AD remain controversial. Here, we investigated the role of sarah (sra; also known as nebula), a Drosophila DSCR1 ortholog, in amyloid-β42 (Aβ42)-induced neurological phenotypes in Drosophila. We detected sra expression in the mushroom bodies of the fly brain, which are a center for learning and memory in flies. Moreover, similar to humans with AD, Aβ42-expressing flies showed increased Sra levels in the brain, demonstrating that the expression pattern of DSCR1 with regard to AD pathogenesis is conserved in Drosophila. Interestingly, overexpression of sra using the UAS-GAL4 system exacerbated the rough-eye phenotype, decreased survival rates and increased neuronal cell death in Aβ42-expressing flies, without modulating Aβ42 expression. Moreover, neuronal overexpression of sra in combination with Aβ42 dramatically reduced both locomotor activity and the adult lifespan of flies, whereas flies with overexpression of sra alone showed normal climbing ability, albeit with a slightly reduced lifespan. Similarly, treatment with chemical inhibitors of calcineurin, such as FK506 and cyclosporin A, or knockdown of calcineurin expression by RNA interference (RNAi), exacerbated the Aβ42-induced rough-eye phenotype. Furthermore, sra-overexpressing flies displayed significantly decreased mitochondrial DNA and ATP levels, as well as increased susceptibility to oxidative stress compared to that of control flies. Taken together, our results demonstrating that sra overexpression augments Aβ42 cytotoxicity in Drosophila suggest that DSCR1

  15. How plastic can phenotypic plasticity be? The branching coral Stylophora pistillata as a model system.

    PubMed

    Shaish, Lee; Abelson, Avigdor; Rinkevich, Baruch

    2007-07-25

    Phenotypic plasticity enables multicellular organisms to adjust morphologies and various life history traits to variable environmental challenges. Here, we elucidate fixed and plastic architectural rules for colony astogeny in multiple types of colonial ramets, propagated by cutting from genets of the branching coral Stylophora pistillata from Eilat, the Red Sea. We examined 16 morphometric parameters on 136 one-year old S. pistillata colonies (of seven genotypes), originating from small fragments belonging, each, to one of three single-branch types (single tips, start-up, and advanced bifurcating tips) or to structural preparative manipulations (representing a single or two growth axes). Experiments were guided by the rationale that in colonial forms, complexity of evolving phenotypic plasticity can be associated with a degree of structural modularity, where shapes are approached by erecting iterative growth patterns at different levels of coral-colony organization. Analyses revealed plastic morphometric characters at branch level, and predetermined morphometric traits at colony level (only single trait exhibited plasticity under extreme manipulation state). Therefore, under the experimental manipulations of this study, phenotypic plasticity in S. pistillata appears to be related to branch level of organization, whereas colony traits are controlled by predetermined genetic architectural rules. Each level of organization undergoes its own mode of astogeny. However, depending on the original ramet structure, the spherical 3-D colonial architecture in this species is orchestrated and assembled by both developmental trajectories at the branch level, and traits at the colony level of organization. In nature, branching colonial forms are often subjected to harsh environmental conditions that cause fragmentation of colony into ramets of different sizes and structures. Developmental traits that are plastic, responding to fragment structure and are not predetermine in

  16. Summary goodness-of-fit statistics for binary generalized linear models with noncanonical link functions.

    PubMed

    Canary, Jana D; Blizzard, Leigh; Barry, Ronald P; Hosmer, David W; Quinn, Stephen J

    2016-05-01

    Generalized linear models (GLM) with a canonical logit link function are the primary modeling technique used to relate a binary outcome to predictor variables. However, noncanonical links can offer more flexibility, producing convenient analytical quantities (e.g., probit GLMs in toxicology) and desired measures of effect (e.g., relative risk from log GLMs). Many summary goodness-of-fit (GOF) statistics exist for logistic GLM. Their properties make the development of GOF statistics relatively straightforward, but it can be more difficult under noncanonical links. Although GOF tests for logistic GLM with continuous covariates (GLMCC) have been applied to GLMCCs with log links, we know of no GOF tests in the literature specifically developed for GLMCCs that can be applied regardless of link function chosen. We generalize the Tsiatis GOF statistic originally developed for logistic GLMCCs, (TG), so that it can be applied under any link function. Further, we show that the algebraically related Hosmer-Lemeshow (HL) and Pigeon-Heyse (J(2) ) statistics can be applied directly. In a simulation study, TG, HL, and J(2) were used to evaluate the fit of probit, log-log, complementary log-log, and log models, all calculated with a common grouping method. The TG statistic consistently maintained Type I error rates, while those of HL and J(2) were often lower than expected if terms with little influence were included. Generally, the statistics had similar power to detect an incorrect model. An exception occurred when a log GLMCC was incorrectly fit to data generated from a logistic GLMCC. In this case, TG had more power than HL or J(2) .

  17. An efficient strategy for gene targeting and phenotypic assessment in the Plasmodium yoelii rodent malaria model.

    PubMed

    Mikolajczak, Sebastian A; Aly, Ahmed S I; Dumpit, Ronald F; Vaughan, Ashley M; Kappe, Stefan H I

    2008-04-01

    In this report, we describe a cloning procedure for gene replacement by double homologous recombination in Plasmodium yoelii, which requires only one digestion and ligation step. This significantly shortens the time required to complete the production of the targeting vector. Furthermore, for more efficient phenotypic evaluation of the gene knockout parasites, we have also introduced a fluorescent protein cassette into the targeting vector. This allows for a more rapid assessment of parasite growth in all of its developmental stages. In addition, the introduction of the fluorescent marker via the replacement strategy confers the stable integration of the marker.

  18. Once a Batesian mimic, not always a Batesian mimic: mimic reverts back to ancestral phenotype when the model is absent.

    PubMed

    Prudic, Kathleen L; Oliver, Jeffrey C

    2008-05-22

    Batesian mimics gain protection from predation through the evolution of physical similarities to a model species that possesses anti-predator defences. This protection should not be effective in the absence of the model since the predator does not identify the mimic as potentially dangerous and both the model and the mimic are highly conspicuous. Thus, Batesian mimics should probably encounter strong predation pressure outside the geographical range of the model species. There are several documented examples of Batesian mimics occurring in locations without their models, but the evolutionary responses remain largely unidentified. A mimetic species has four alternative evolutionary responses to the loss of model presence. If predation is weak, it could maintain its mimetic signal. If predation is intense, it is widely presumed the mimic will go extinct. However, the mimic could also evolve a new colour pattern to mimic another model species or it could revert back to its ancestral, less conspicuous phenotype. We used molecular phylogenetic approaches to reconstruct and test the evolution of mimicry in the North American admiral butterflies (Limenitis: Nymphalidae). We confirmed that the more cryptic white-banded form is the ancestral phenotype of North American admiral butterflies. However, one species, Limenitis arthemis, evolved the black pipevine swallowtail mimetic form but later reverted to the white-banded more cryptic ancestral form. This character reversion is strongly correlated with the geographical absence of the model species and its host plant, but not the host plant distribution of L. arthemis. Our results support the prediction that a Batesian mimic does not persist in locations without its model, but it does not go extinct either. The mimic can revert back to its ancestral, less conspicuous form and persist.

  19. The parental phenotype of diabetes, but not of essential hypertension, is linked to the development of metabolic syndrome in Mexican individuals.

    PubMed

    Rodríguez-Morán, M; Guerrero-Romero, F

    2001-01-01

    Studies on the role of parental history on the risk of developing metabolic syndrome (MS) show inconsistent data that may depend on misclassification of the parental history. Confirming carefully the parental phenotype (PF) of type 2 diabetes mellitus (DM) and essential hypertension (EH) of participants' parents, we determined the relationship between PF of either DM or EH and the risk of developing MS in Mexican individuals. A case-control study of 210 subjects randomly recruited from Durango, Mexico was carried out. Subjects with MS (cases) were compared with a control group of subjects without MS matched by age and gender. MS was defined by the presence of two or more of the following: fasting glucose > or =7.0 mmol/l; blood pressure > or =160/90 mmHg; fasting triglycerides > or =1.7 mmol/l and/or HDL-cholesterol <1.0 mmol/l; and obesity (body mass index > or =30 kg/m2 and/or waist-to-hip ratio > or =0.85). The PF of DM and EH was confirmed by direct clinical examination and/or review of certificates of death of each of the participants' parents. Incomplete or unclear data about PH were exclusion criteria. Multivariate analysis showed that PF of DM without EH (odds ratio (OR) 2.6; 95% CI, 1.3-7.8, p=0.044) and PF of both DM and EH (OR, 3.1; 95% CI, 1.5-9.1, p=0.0001), but not the PF of EH without DM are independent predictors for developing MS in Mexican individuals. In the offspring generation of Mexican subjects, the PF of DM seems to increase the risk of developing MS, whereas PF of EH does not.

  20. Linking of mPGES-1 and iNOS activates stem-like phenotype in EGFR-driven epithelial tumor cells.

    PubMed

    Terzuoli, Erika; Finetti, Federica; Costanza, Filomena; Giachetti, Antonio; Ziche, Marina; Donnini, Sandra

    2017-03-01

    Inflammatory prostaglandin E-2 (PGE-2) favors cancer progression in epithelial tumors characterized by persistent oncogene input. However, its effects on tumor cell stemness are poorly understood at molecular level. Here we describe two epithelial tumor cells A431 and A459, originating from human lung and skin tumors, in which epithelial growth factor (EGF) induces sequential up-regulation of mPGES-1 and iNOS enzymes, producing an inflammatory intracellular milieu. We demonstrated that concerted action of EGF, mPGES-1 and iNOS causes sharp changes in cell phenotype demonstrated by acquisition of stem-cell features and activation of the epithelial-mesenchymal transition (EMT). When primed with EGF, epithelial tumor cells transfected with mPGES-1 or iNOS to ensure steady enzyme levels display major stem-like and EMT markers, such as reduction in E-cadherin with a concomitant rise in vimentin, ALDH-1, CD133 and ALDH activity. Tumorsphere studies with these cells show increased sphere number and size, enhanced migratory and clonogenic capacity and sharp changes in EMT markers, indicating activation of this process. The concerted action of the enzymes forms a well-orchestrated cascade where expression of iNOS depends on overexpression of mPGES-1. Indeed, we show that through its downstream effectors (PGE-2, PKA, PI3K/Akt), mPGES-1 recruits non-canonical transcription factors, thus facilitating iNOS production. In conclusion, we propose that the initial event leading to tumor stem-cell activation may be a leveraged intrinsic mechanism in which all players are either inherent constituents (EGF) or highly inducible proteins (mPGES-1, iNOS) of tumor cells. We suggest that incipient tumor aggressiveness may be moderated by reducing pivotal input of mPGES-1.

  1. Exploring Alternative Characteristic Curve Approaches to Linking Parameter Estimates from the Generalized Partial Credit Model.

    ERIC Educational Resources Information Center

    Roberts, James S.; Bao, Han; Huang, Chun-Wei; Gagne, Phill

    Characteristic curve approaches for linking parameters from the generalized partial credit model were examined for cases in which common (anchor) items are calibrated separately in two groups. Three of these approaches are simple extensions of the test characteristic curve (TCC), item characteristic curve (ICC), and operating characteristic curve…

  2. What Works Clearinghouse Quick Review: "A Model for Success: CART's Linked Learning Program Increases College Enrollment"

    ERIC Educational Resources Information Center

    What Works Clearinghouse, 2012

    2012-01-01

    The study, "A Model for Success: CART's Linked Learning Program Increases College Enrollment" examined whether students who enrolled in courses at a high school that combined academics and technical education had higher college enrollment rates than students who did not. The research described in this report does not meet What Works…

  3. The Chain-Link Fence Model: A Framework for Creating Security Procedures

    ERIC Educational Resources Information Center

    Houghton, Robert F.

    2013-01-01

    A long standing problem in information technology security is how to help reduce the security footprint. Many specific proposals exist to address specific problems in information technology security. Most information technology solutions need to be repeatable throughout the course of an information systems lifecycle. The Chain-Link Fence Model is…

  4. Multiscale Modeling for Linking Growth, Microstructure, and Properties of Inorganic Microporous Films

    NASA Technical Reports Server (NTRS)

    Vlachos, Dion G.

    2002-01-01

    The focus of this presentation is on multiscale modeling in order to link processing, microstructure, and properties of materials. Overview of problems we study includes: Growth mechanisms in chemical and physical vapor epitaxy; thin films of zeolites for separation and sensing; thin Pd films for hydrogen separation and pattern formation by self-regulation routes.

  5. The Gender-Linked Language Effect: An Empirical Test of a General Process Model

    ERIC Educational Resources Information Center

    Mulac, Anthony; Giles, Howard; Bradac, James J.; Palomares, Nicholas A.

    2013-01-01

    The gender-linked language effect (GLLE) is a phenomenon in which transcripts of female communicators are rated higher on Socio-Intellectual Status and Aesthetic Quality and male communicators are rated higher on Dynamism. This study proposed and tested a new general process model explanation for the GLLE, a central mediating element of which…

  6. Adaptive evolution of molecular phenotypes

    NASA Astrophysics Data System (ADS)

    Held, Torsten; Nourmohammad, Armita; Lässig, Michael

    2014-09-01

    Molecular phenotypes link genomic information with organismic functions, fitness, and evolution. Quantitative traits are complex phenotypes that depend on multiple genomic loci. In this paper, we study the adaptive evolution of a quantitative trait under time-dependent selection, which arises from environmental changes or through fitness interactions with other co-evolving phenotypes. We analyze a model of trait evolution under mutations and genetic drift in a single-peak fitness seascape. The fitness peak performs a constrained random walk in the trait amplitude, which determines the time-dependent trait optimum in a given population. We derive analytical expressions for the distribution of the time-dependent trait divergence between populations and of the trait diversity within populations. Based on this solution, we develop a method to infer adaptive evolution of quantitative traits. Specifically, we show that the ratio of the average trait divergence and the diversity is a universal function of evolutionary time, which predicts the stabilizing strength and the driving rate of the fitness seascape. From an information-theoretic point of view, this function measures the macro-evolutionary entropy in a population ensemble, which determines the predictability of the evolutionary process. Our solution also quantifies two key characteristics of adapting populations: the cumulative fitness flux, which measures the total amount of adaptation, and the adaptive load, which is the fitness cost due to a population's lag behind the fitness peak.

  7. Evaluation of spontaneous propulsive movement as a screening tool to detect rescue of Parkinsonism phenotypes in zebrafish models.

    PubMed

    Farrell, Thomas C; Cario, Clinton L; Milanese, Chiara; Vogt, Andreas; Jeong, Jong-Hyeon; Burton, Edward A

    2011-10-01

    Zebrafish models of human neuropsychiatric diseases offer opportunities to identify novel therapeutic targets and treatments through phenotype-based genetic or chemical modifier screens. In order to develop an assay to detect rescue of zebrafish models of Parkinsonism, we characterized spontaneous zebrafish larval motor behavior from 3 to 9 days post fertilization in a microtiter plate format suitable for screening, and clarified the role of dopaminergic signaling in its regulation. The proportion of time that larvae spent moving increased progressively between 3 and 9 dpf, whereas their active velocity decreased between 5 and 6 dpf as sporadic burst movements gave way to a more mature beat-and-glide pattern. Spontaneous movement varied between larvae and during the course of recordings as a result of intrinsic larval factors including genetic background. Variability decreased with age, such that small differences between groups of larvae exposed to different experimental conditions could be detected robustly by 6 to 7 dpf. Suppression of endogenous dopaminergic signaling by exposure to MPP(+), haloperidol or chlorpromazine reduced mean velocity by decreasing the frequency with which spontaneous movements were initiated, but did not alter active velocity. The variability of mean velocity assays could be reduced by analyzing groups of larvae for each data point, yielding acceptable screening window coefficients; the sample size required in each group was determined by the magnitude of the motor phenotype in different models. For chlorpromazine exposure, samples of four larvae allowed robust separation of treated and untreated data points (Z=0.42), whereas the milder impairment provoked by MPP(+) necessitated groups of eight larvae in order to provide a useful discovery assay (Z=0.13). Quantification of spontaneous larval movement offers a simple method to determine functional integrity of motor systems, and may be a useful tool to isolate novel molecular modulators

  8. Memantine normalizes several phenotypic features in the Ts65Dn mouse model of Down syndrome.

    PubMed

    Rueda, Noemí; Llorens-Martín, María; Flórez, Jesús; Valdizán, Elsa; Banerjee, Pradeep; Trejo, Jose Luis; Martínez-Cué, Carmen

    2010-01-01

    Ts65Dn (TS) mice exhibit several phenotypic characteristics of human Down syndrome, including an increased brain expression of amyloid-beta protein precursor (AbetaPP) and cognitive disturbances. Aberrant N-methyl-D-aspartate (NMDA) receptor signaling has been suspected in TS mice, due to an impaired generation of hippocampal long-term potentiation (LTP). Memantine, an uncompetitive NMDA receptor antagonist approved for the treatment of moderate to severe Alzheimer's disease, is known to normalize LTP and improve cognition in transgenic mice with high brain levels of AbetaPP and amyloid-beta protein. It has recently been demonstrated that acute injections of memantine rescue performance deficits of TS mice on a fear conditioning test. Here we show that oral treatment of aged TS mice with a clinically relevant dose of memantine (30 mg/kg/day for 9 weeks) improved spatial learning in the water maze task and slightly reduced brain AbetaPP levels. We also found that TS mice exhibited a significantly reduced granule cell count and vesicular glutamate transporter-1 (VGLUT1) labeling compared to disomic control mice. After memantine treatment, the levels of hippocampal VGLUT1 were significantly increased, reaching the levels observed in vehicle treated-control animals. Memantine did not significantly affect granule cell density. These data indicate that memantine may normalize several phenotypic abnormalities in TS mice, many of which--such as impaired cognition--are also associated with Down syndrome and Alzheimer's disease.

  9. Deletion of TMPRSS6 attenuates the phenotype in a mouse model of β-thalassemia

    PubMed Central

    Nai, Antonella; Pagani, Alessia; Mandelli, Giacomo; Lidonnici, Maria Rosa; Silvestri, Laura; Ferrari, Giuliana

    2012-01-01

    Inappropriately low expression of the key iron regulator hepcidin (HAMP) causes iron overload in untransfused patients affected by β-thalassemia intermedia and Hamp modulation provides improvement of the thalassemic phenotype of the Hbbth3/+ mouse. HAMP expression is activated by iron through the bone morphogenetic protein (BMP)–son of mothers against decapentaplegic signaling pathway and inhibited by ineffective erythropoiesis through an unknown “erythroid regulator.” The BMP pathway is inactivated by the serine protease TMPRSS6 that cleaves the BMP coreceptor hemojuvelin. Here, we show that homozygous loss of Tmprss6 in Hbbth3/+ mice improves anemia and reduces ineffective erythropoiesis, splenomegaly, and iron loading. All these effects are mediated by Hamp up-regulation, which inhibits iron absorption and recycling. Because Hbbth3/+ mice lacking Tmprss6 show residual ineffective erythropoiesis, our results indicate that Tmprss6 is essential for Hamp inhibition by the erythroid regulator. We also obtained partial correction of the phenotype in Tmprss6 haploinsufficient Hbbth3/+ male but not female mice and showed that the observed sex difference reflects an unequal balance between iron and erythropoiesis-mediated Hamp regulation. Our study indicates that preventing iron overload improves β-thalassemia and strengthens the essential role of Tmprss6 for Hamp suppression, providing a proof of concept that Tmprss6 manipulation can offer a novel therapeutic option in this condition. PMID:22490684

  10. How the cerebral serotonin homeostasis predicts environmental changes: a model to explain seasonal changes of brain 5-HTT as intermediate phenotype of the 5-HTTLPR.

    PubMed

    Kalbitzer, Jan; Kalbitzer, Urs; Knudsen, Gitte Moos; Cumming, Paul; Heinz, Andreas

    2013-12-01

    Molecular imaging studies with positron emission tomography have revealed that the availability of serotonin transporter (5-HTT) in the human brain fluctuates over the course of the year. This effect is most pronounced in carriers of the short allele of the 5-HTT promoter region (5-HTTLPR), which has in several previous studies been linked to an increased risk to develop mood disorders. We argue that long-lasting fluctuations in the cerebral serotonin transmission, which is regulated via the 5-HTT, are responsible for mediating responses to environmental changes based on an assessment of the expected "safety" of the environment; this response is obtained in part through serotonergic modulation of the hypothalamic-pituitary-adrenal (HPA) axis. We posit that the intermediate phenotype of the s-allele may properly be understood as mediating a trade-off, wherein increased responsiveness of cerebral serotonin transmission to seasonal and other forms of environmental change imparts greater behavioral flexibility, at the expense of increased vulnerability to stress. This model may explain the somewhat higher prevalence of the s-allele in some human populations dwelling at geographic latitudes with pronounced seasonal climatic changes, while this hypothesis does not rule out that genetic drift plays an additional or even exclusive role. We argue that s-allele manifests as an intermediate phenotype in terms of an increased responsiveness of the 5-HTT expression to number of daylight hours, which may serve as a stable surrogate marker of other environmental factors, such as availability of food and safety of the environment in populations that live closer to the geographic poles.

  11. Model of Host-Pathogen Interaction Dynamics Links In Vivo Optical Imaging and Immune Responses

    PubMed Central

    Ale, Angelique; Crepin, Valerie F.; Collins, James W.; Constantinou, Nicholas; Habibzay, Maryam; Babtie, Ann C.

    2016-01-01

    ABSTRACT Tracking disease progression in vivo is essential for the development of treatments against bacterial infection. Optical imaging has become a central tool for in vivo tracking of bacterial population development and therapeutic response. For a precise understanding of in vivo imaging results in terms of disease mechanisms derived from detailed postmortem observations, however, a link between the two is needed. Here, we develop a model that provides that link for the investigation of Citrobacter rodentium infection, a mouse model for enteropathogenic Escherichia coli (EPEC). We connect in vivo disease progression of C57BL/6 mice infected with bioluminescent bacteria, imaged using optical tomography and X-ray computed tomography, to postmortem measurements of colonic immune cell infiltration. We use the model to explore changes to both the host immune response and the bacteria and to evaluate the response to antibiotic treatment. The developed model serves as a novel tool for the identification and development of new therapeutic interventions. PMID:27821583

  12. Towards causally cohesive genotype–phenotype modelling for characterization of the soft-tissue mechanics of the heart in normal and pathological geometries

    PubMed Central

    Nordbø, Øyvind; Gjuvsland, Arne B.; Nermoen, Anders; Land, Sander; Niederer, Steven; Lamata, Pablo; Lee, Jack; Smith, Nicolas P.; Omholt, Stig W.; Vik, Jon Olav

    2015-01-01

    A scientific understanding of individual variation is key to personalized medicine, integrating genotypic and phenotypic information via computational physiology. Genetic effects are often context-dependent, differing between genetic backgrounds or physiological states such as disease. Here, we analyse in silico genotype–phenotype maps (GP map) for a soft-tissue mechanics model of the passive inflation phase of the heartbeat, contrasting the effects of microstructural and other low-level parameters assumed to be genetically influenced, under normal, concentrically hypertrophic and eccentrically hypertrophic geometries. For a large number of parameter scenarios, representing mock genetic variation in low-level parameters, we computed phenotypes describing the deformation of the heart during inflation. The GP map was characterized by variance decompositions for each phenotype with respect to each parameter. As hypothesized, the concentric geometry allowed more low-level parameters to contribute to variation in shape phenotypes. In addition, the relative importance of overall stiffness and fibre stiffness differed between geometries. Otherwise, the GP map was largely similar for the different heart geometries, with little genetic interaction between the parameters included in this study. We argue that personalized medicine can benefit from a combination of causally cohesive genotype–phenotype modelling, and strategic phenotyping that captures effect modifiers not explicitly included in the mechanistic model. PMID:25833237

  13. Linking Parameters Estimated with the Generalized Graded Unfolding Model: A Comparison of the Accuracy of Characteristic Curve Methods

    ERIC Educational Resources Information Center

    Anderson Koenig, Judith; Roberts, James S.

    2007-01-01

    Methods for linking item response theory (IRT) parameters are developed for attitude questionnaire responses calibrated with the generalized graded unfolding model (GGUM). One class of IRT linking methods derives the linking coefficients by comparing characteristic curves, and three of these methods---test characteristic curve (TCC), item…

  14. High-throughput phenotyping (HTP) identifies seedling root traits linked to variation in seed yield and nutrient capture in field-grown oilseed rape (Brassica napus L.)

    PubMed Central

    Thomas, C. L.; Graham, N. S.; Hayden, R.; Meacham, M. C.; Neugebauer, K.; Nightingale, M.; Dupuy, L. X.; Hammond, J. P.; White, P. J.; Broadley, M. R.

    2016-01-01

    Background and Aims Root traits can be selected for crop improvement. Techniques such as soil excavations can be used to screen root traits in the field, but are limited to genotypes that are well-adapted to field conditions. The aim of this study was to compare a low-cost, high-throughput root phenotyping (HTP) technique in a controlled environment with field performance, using oilseed rape (OSR; Brassica napus) varieties. Methods Primary root length (PRL), lateral root length and lateral root density (LRD) were measured on 14-d-old seedlings of elite OSR varieties (n = 32) using a ‘pouch and wick’ HTP system (∼40 replicates). Six field experiments were conducted using the same varieties at two UK sites each year for 3 years. Plants were excavated at the 6- to 8-leaf stage for general vigour assessments of roots and shoots in all six experiments, and final seed yield was determined. Leaves were sampled for mineral composition from one of the field experiments. Key Results Seedling PRL in the HTP system correlated with seed yield in four out of six (r = 0·50, 0·50, 0·33, 0·49; P < 0·05) and with emergence in three out of five (r = 0·59, 0·22, 0·49; P < 0·05) field experiments. Seedling LRD correlated positively with leaf concentrations of some minerals, e.g. calcium (r = 0·46; P < 0·01) and zinc (r = 0·58; P < 0·001), but did not correlate with emergence, general early vigour or yield in the field. Conclusions Associations between PRL and field performance are generally related to early vigour. These root traits might therefore be of limited additional selection value, given that vigour can be measured easily on shoots/canopies. In contrast, LRD cannot be assessed easily in the field and, if LRD can improve nutrient uptake, then it may be possible to use HTP systems to screen this trait in both elite and more genetically diverse, non-field-adapted OSR. PMID:27052342

  15. Dynamical modeling of serial manipulators with flexible links and joints using the method of kinematic influence

    NASA Technical Reports Server (NTRS)

    Graves, Philip L.

    1989-01-01

    A method of formulating the dynamical equations of a flexible, serial manipulator is presented, using the Method of Kinematic Influence. The resulting equations account for rigid body motion, structural motion due to link and joint flexibilities, and the coupling between these two motions. Nonlinear inertial loads are included in the equations. A finite order mode summation method is used to model flexibilities. The structural data may be obtained from experimental, finite element, or analytical methods. Nonlinear flexibilities may be included in the model.

  16. High Bandwidth Communications Links Between Heterogeneous Autonomous Vehicles Using Sensor Network Modeling and Extremum Control Approaches

    DTIC Science & Technology

    2008-12-01

    two- fold. First, a communication propagation model was developed to predict the signal-to-noise ( SNR ) ratio of the communication link, which is used...as a reference SNR signal for the UAVs. Second, the communication model was then integrated into a feedback control loop to formulate a new real-time...loitering path using SNR as the cost function. 15. NUMBER OF PAGES 75 14. SUBJECT TERMS Unmanned Aerial Vehicle, UAV, Extremum Seeking

  17. The GhTT2_A07 gene is linked to the brown colour and natural flame retardancy phenotypes of Lc1 cotton (Gossypium hirsutum L.) fibres

    PubMed Central

    Hinchliffe, Doug J.; Condon, Brian D.; Thyssen, Gregory; Naoumkina, Marina; Madison, Crista A.; Reynolds, Michael; Delhom, Christopher D.; Fang, David D.; Li, Ping; McCarty, Jack

    2016-01-01

    Some naturally coloured brown cotton fibres from accessions of Gossypium hirsutum L. can be used to make textiles with enhanced flame retardancy (FR). Several independent brown fibre loci have been identified and mapped to chromosomes, but the underlying genes have not yet been identified, and the mechanism of lint fibre FR is not yet fully understood. In this study, we show that both the brown colour and enhanced FR of the Lc1 lint colour locus are linked to a 1.4Mb inversion on chromosome A07 that is immediately upstream of a gene with similarity to Arabidopsis TRANSPARENT TESTA 2 (TT2). As a result of the alternative upstream sequence, the transcription factor GhTT2_A07 is highly up-regulated in developing fibres. In turn, genes in the phenylpropanoid metabolic pathway are activated, leading to biosynthesis of proanthocyanidins and accumulation of inorganic elements. We show that enhanced FR and anthocyanin precursors appear in developing brown fibres well before the brown colour is detectible, demonstrating for the first time that the polymerized proanthocyanidins that constitute the brown colour are not the source of enhanced FR. Identifying the particular colourless metabolite that provides Lc1 cotton with enhanced FR could help minimize the use of synthetic chemical flame retardant additives in textiles. PMID:27567364

  18. A prosthesis-specific multi-link segment model of lower-limb amputee sprinting.

    PubMed

    Rigney, Stacey M; Simmons, Anne; Kark, Lauren

    2016-10-03

    Lower-limb amputees commonly utilize non-articulating energy storage and return (ESAR) prostheses for high impact activities such as sprinting. Despite these prostheses lacking an articulating ankle joint, amputee gait analysis conventionally features a two-link segment model of the prosthetic foot. This paper investigated the effects of the selected link segment model׳s marker-set and geometry on a unilateral amputee sprinter׳s calculated lower-limb kinematics, kinetics and energetics. A total of five lower-limb models of the Ottobock(®) 1E90 Sprinter were developed, including two conventional shank-foot models that each used a different version of the Plug-in-Gait (PiG) marker-set to test the effect of prosthesis ankle marker location. Two Hybrid prosthesis-specific models were then developed, also using the PiG marker-sets, with the anatomical shank and foot replaced by prosthesis-specific geometry separated into two segments. Finally, a Multi-link segment (MLS) model was developed, consisting of six segments for the prosthesis as defined by a custom marker-set. All full-body musculoskeletal models were tested using four trials of experimental marker trajectories within OpenSim 3.2 (Stanford, California, USA) to find the affected and unaffected hip, knee and ankle kinematics, kinetics and energetics. The geometry of the selected lower-limb prosthesis model was found to significantly affect all variables on the affected leg (p < 0.05), and the marker-set also significantly affected all variables on the affected leg, and none of the unaffected leg variables. The results indicate that the omission of prosthesis-specific spatial, inertial and elastic properties from full-body models significantly affects the calculated amputee gait characteristics, and we therefore recommend the implementation of a MLS model.

  19. Plant phenomics and the need for physiological phenotyping across scales to narrow the genotype-to-phenotype knowledge gap.

    PubMed

    Großkinsky, Dominik K; Svensgaard, Jesper; Christensen, Svend; Roitsch, Thomas

    2015-09-01

    Plants are affected by complex genome×environment×management interactions which determine phenotypic plasticity as a result of the variability of genetic components. Whereas great advances have been made in the cost-efficient and high-throughput analyses of genetic information and non-invasive phenotyping, the large-scale analyses of the underlying physiological mechanisms lag behind. The external phenotype is determined by the sum of the complex interactions of metabolic pathways and intracellular regulatory networks that is reflected in an internal, physiological, and biochemical phenotype. These various scales of dynamic physiological responses need to be considered, and genotyping and external phenotyping should be linked to the physiology at the cellular and tissue level. A high-dimensional physiological phenotyping across scales is needed that integrates the precise characterization of the internal phenotype into high-throughput phenotyping of whole plants and canopies. By this means, complex traits can be broken down into individual components of physiological traits. Since the higher resolution of physiological phenotyping by 'wet chemistry' is inherently limited in throughput, high-throughput non-invasive phenotyping needs to be validated and verified across scales to be used as proxy for the underlying processes. Armed with this interdisciplinary and multidimensional phenomics approach, plant physiology, non-invasive phenotyping, and functional genomics will complement each other, ultimately enabling the in silico assessment of responses under defined environments with advanced crop models. This will allow generation of robust physiological predictors also for complex traits to bridge the knowledge gap between genotype and phenotype for applications in breeding, precision farming, and basic research.

  20. Analytical model and figures of merit for filtered Microwave Photonic Links.

    PubMed

    Gasulla, Ivana; Capmany, José

    2011-09-26

    The concept of filtered Microwave Photonic Links is proposed in order to provide the most general and versatile description of complex analog photonic systems. We develop a field propagation model where a global optical filter, characterized by its optical transfer function, embraces all the intermediate optical components in a linear link. We assume a non-monochromatic light source characterized by an arbitrary spectral distribution which has a finite linewidth spectrum and consider both intensity modulation and phase modulation with balanced and single detection. Expressions leading to the computation of the main figures of merit concerning the link gain, noise and intermodulation distortion are provided which, to our knowledge, are not available in the literature. The usefulness of this derivation resides in the capability to directly provide performance criteria results for complex links just by substituting in the overall closed-form formulas the numerical or measured optical transfer function characterizing the link. This theory is presented thus as a potential tool for a wide range of relevant microwave photonic application cases which is extendable to multiport radio over fiber systems.

  1. Dynamic modelling and link mechanism design of four-legged mobile robot

    NASA Astrophysics Data System (ADS)

    Park, Sung-Ho

    In order to apply the advanced biological phenomena to the leg design of mobile robots, the structural and locomotive characteristics of several selected animals and insects are studied, and the four-legged mobile robot which can cover all existing leg arrangements and locomotion patterns is modeled by a rigid multibody system consisting of links and joints. The model is simulated to prove that the given structure or locomotive conditions satisfy the requirement of minimum energy expenditure. According to the first simulation, there exist ideal forward and backward stroke distances for each pair leg. Therefore, the walking volume and link lengths of existing legged mobile robots should be modified. Also, for other structural and locomotive characteristics which have been used by living creatures, the model is simulated to determine whether or not the actual or possible biological phenomena can be applied to the leg mechanism design of mobile robot.

  2. Assessment of sea ice-atmosphere links in CMIP5 models

    NASA Astrophysics Data System (ADS)

    Boland, Emma J. D.; Bracegirdle, Thomas J.; Shuckburgh, Emily F.

    2016-09-01

    The Arctic is currently undergoing drastic changes in climate, largely thought to be due to so-called `Arctic amplification', whereby local feedbacks enhance global warming. Recently, a number of observational and modelling studies have questioned what the implications of this change in Arctic sea ice extent might be for weather in Northern Hemisphere midlatitudes, and in particular whether recent extremely cold winters such as 2009/10 might be consistent with an influence from observed Arctic sea ice decline. However, the proposed mechanisms for these links have not been consistently demonstrated. In a uniquely comprehensive cross-season and cross-model study, we show that the CMIP5 models provide no support for a relationship between declining Arctic sea ice and a negative NAM, or between declining Barents-Kara sea ice and cold European temperatures. The lack of evidence for the proposed links is consistent with studies that report a low signal-to-noise ratio in these relationships. These results imply that, whilst links may exist between declining sea ice and extreme cold weather events in the Northern Hemisphere, the CMIP5 model experiments do not show this to be a leading order effect in the long-term. We argue that this is likely due to a combination of the limitations of the CMIP5 models and an indication of other important long-term influences on Northern Hemisphere climate.

  3. Sustained phenotypic reversion of junctional epidermolysis bullosa dog keratinocytes: Establishment of an immunocompetent animal model for cutaneous gene therapy

    SciTech Connect

    Spirito, Flavia; Capt, Annabelle; Rio, Marcela Del; Larcher, Fernando; Guaguere, Eric; Danos, Olivier; Meneguzzi, Guerrino . E-mail: meneguzz@unice.fr

    2006-01-20

    Gene transfer represents the unique therapeutic issue for a number of inherited skin disorders including junctional epidermolysis bullosa (JEB), an untreatable genodermatose caused by mutations in the adhesion ligand laminin 5 ({alpha}3{beta}3{gamma}2) that is secreted in the extracellular matrix by the epidermal basal keratinocytes. Because gene therapy protocols require validation in animal models, we have phenotypically reverted by oncoretroviral transfer of the curative gene the keratinocytes isolated from dogs with a spontaneous form of JEB associated with a genetic mutation in the {alpha}3 chain of laminin 5. We show that the transduced dog JEB keratinocytes: (1) display a sustained secretion of laminin 5 in the extracellular matrix; (2) recover the adhesion, proliferation, and clonogenic capacity of wild-type keratinocytes; (3) generate fully differentiated stratified epithelia that after grafting on immunocompromised mice produce phenotypically normal skin and sustain permanent expression of the transgene. We validate an animal model that appears particularly suitable to demonstrate feasibility, efficacy, and safety of genetic therapeutic strategies for cutaneous disorders before undertaking human clinical trials.

  4. Simultaneous Modeling of Disease Status and Clinical Phenotypes To Increase Power in Genome-Wide Association Studies.

    PubMed

    Bilow, Michael; Crespo, Fernando; Pan, Zhicheng; Eskin, Eleazar; Eyheramendy, Susana

    2017-03-01

    Genome-wide association studies have identified thousands of variants implicated in dozens of complex diseases. Most studies collect individuals with and without disease and search for variants with different frequencies between the groups. For many of these studies, additional disease traits are also collected. Jointly modeling clinical phenotype and disease status is a promising way to increase power to detect true associations between genetics and disease. In particular, this approach increases the potential for discovering genetic variants that are associated with both a clinical phenotype and a disease. Standard multivariate techniques fail to effectively solve this problem, because their case-control status is discrete and not continuous. Standard approaches to estimate model parameters are biased due to the ascertainment in case-control studies. We present a novel method that resolves both of these issues for simultaneous association testing of genetic variants that have both case status and a clinical covariate. We demonstrate the utility of our method using both simulated data and the Northern Finland Birth Cohort data.

  5. A linked hydrodynamic and water quality model for the Salton Sea

    USGS Publications Warehouse

    Chung, E.G.; Schladow, S.G.; Perez-Losada, J.; Robertson, D.M.

    2008-01-01

    A linked hydrodynamic and water quality model was developed and applied to the Salton Sea. The hydrodynamic component is based on the one-dimensional numerical model, DLM. The water quality model is based on a new conceptual model for nutrient cycling in the Sea, and simulates temperature, total suspended sediment concentration, nutrient concentrations, including PO4-3, NO3-1 and NH4+1, DO concentration and chlorophyll a concentration as functions of depth and time. Existing water temperature data from 1997 were used to verify that the model could accurately represent the onset and breakup of thermal stratification. 1999 is the only year with a near-complete dataset for water quality variables for the Salton Sea. The linked hydrodynamic and water quality model was run for 1999, and by adjustment of rate coefficients and other water quality parameters, a good match with the data was obtained. In this article, the model is fully described and the model results for reductions in external phosphorus load on chlorophyll a distribution are presented. ?? 2008 Springer Science+Business Media B.V.

  6. Phenotypic characterization of glioblastoma identified through shape descriptors

    NASA Astrophysics Data System (ADS)

    Chaddad, Ahmad; Desrosiers, Christian; Toews, Matthew

    2016-03-01

    This paper proposes quantitatively describing the shape of glioblastoma (GBM) tissue phenotypes as a set of shape features derived from segmentations, for the purposes of discriminating between GBM phenotypes and monitoring tumor progression. GBM patients were identified from the Cancer Genome Atlas, and quantitative MR imaging data were obtained from the Cancer Imaging Archive. Three GBM tissue phenotypes are considered including necrosis, active tumor and edema/invasion. Volumetric tissue segmentations are obtained from registered T1˗weighted (T1˗WI) postcontrast and fluid-attenuated inversion recovery (FLAIR) MRI modalities. Shape features are computed from respective tissue phenotype segmentations, and a Kruskal-Wallis test was employed to select features capable of classification with a significance level of p < 0.05. Several classifier models are employed to distinguish phenotypes, where a leave-one-out cross-validation was performed. Eight features were found statistically significant for classifying GBM phenotypes with p <0.05, orientation is uninformative. Quantitative evaluations show the SVM results in the highest classification accuracy of 87.50%, sensitivity of 94.59% and specificity of 92.77%. In summary, the shape descriptors proposed in this work show high performance in predicting GBM tissue phenotypes. They are thus closely linked to morphological characteristics of GBM phenotypes and could potentially be used in a computer assisted labeling system.

  7. Link functions in multi-locus genetic models: implications for testing, prediction, and interpretation.

    PubMed

    Clayton, David

    2012-05-01

    "Complex" diseases are, by definition, influenced by multiple causes, both genetic and environmental, and statistical work on the joint action of multiple risk factors has, for more than 40 years, been dominated by the generalized linear model (GLM). In genetics, models for dichotomous traits have traditionally been approached via the model of an underlying, normally distributed, liability. This corresponds to the GLM with binomial errors and a probit link function. Elsewhere in epidemiology, however, the logistic regression model, a GLM with logit link function, has been the tool of choice, largely because of its convenient properties in case-control studies. The choice of link function has usually been dictated by mathematical convenience, but it has some important implications in (a) the choice of association test statistic in the presence of existing strong risk factors, (b) the ability to predict disease from genotype given its heritability, and (c) the definition, and interpretation of epistasis (or epistacy). These issues are reviewed, and a new association test proposed.

  8. Equilibrium and kinetic modeling of adsorption of reactive dye on cross-linked chitosan beads.

    PubMed

    Chiou, Ming Shen; Li, Hsing Ya

    2002-07-22

    The adsorption of reactive dye (Reactive Red 189) from aqueous solutions on cross-linked chitosan beads was studied in a batch system. The equilibrium isotherms at different particle sizes (2.3-2.5, 2.5-2.7 and 3.5-3.8mm) and the kinetics of adsorption with respect to the initial dye concentration (4320, 5760 and 7286 g/m(3)), temperature (30, 40 and 50 degrees C), pH (1.0, 3.0, 6.0 and 9.0), and cross-linking ratio (cross-linking agent/chitosan weight ratio: 0.2, 0.5, 0.7 and 1.0) were investigated. Langmuir and Freundlich adsorption models were applied to describe the experimental isotherms and isotherm constants. Equilibrium data fitted very well to the Langmuir model in the entire saturation concentration range (0-1800 g/m(3)). The maximum monolayer adsorption capacities obtained from the Langmuir model are very large, which are 1936, 1686 and 1642 g/kg for small, mediumand large particle sizes, respectively, at pH 3.0, 30 degrees C, and the cross-linking ratio of 0.2. The pseudo first- and second-order kinetic models were used to describe the kinetic data, and the rate constants were evaluated. The experimental data fitted well to the second-order kinetic model, which indicates that the chemical sorption is the rate-limiting step, instead of mass transfer. The initial dye concentration and the solution pH both significantly affect the adsorption capacity, but the temperature and the cross-linking ratio are relatively minor factors. An increase in initial dye concentration results in the increase of adsorption capacity, which also increases with decreasing pH. The activation energy is 43.0 kJ/mol for the adsorption of the dye on the cross-linked chitosan beads at pH 3.0 and initial dye concentration 3768 g/m(3).

  9. Framework for Smart Electronic Health Record-Linked Predictive Models to Optimize Care for Complex Digestive Diseases

    DTIC Science & Technology

    2012-06-01

    Regueiro MD, Krasinskas AM, Saul M, Sapienza D, Binion DG, Hartman D. Mucosal IgG4 Cell Infiltration in Ulcerative Colitis (UC) is Linked to Disease ...Record-Linked Predictive Models to Optimize Care for Complex Digestive Diseases PRINCIPAL INVESTIGATOR: Michael A. Dunn, MD CONTRACTING...Framework for Smart Electronic Health Record-Linked Predictive Models to Optimize Care for Complex Digestive Diseases 5b. GRANT NUMBER W81XWH11-2

  10. Phenotypic diversity and selection maintain Leishmania amazonensis infectivity in BALB/c mouse model

    PubMed Central

    Espiau, Benoît; Vilhena, Virginia; Cuvillier, Armelle; Barral, Aldina; Merlin, Gilles

    2017-01-01

    Leishmania are protozoan parasites that show remarkable diversity, as revealed by the various clinical forms of leishmaniasis, which can range from mild skin lesions to severe metastatic cutaneous/mucosal lesions. The exact nature and extent of Leishmania phenotypic diversity in establishing infection is not fully understood. In order to try to understand some aspects of this diversity, we subcutaneously infected BALB/c mice with first and second generation subclones of a L. amazonensis strain isolated from a patient (BA125) and examined in vivo lesion growth rate and antimony susceptibility. In vivo fast-, medium- and slow-growing subclones were obtained; moreover, fast-growing subclones could generate slow-growing subclones and inversely, revealing the continuous generation of diversity after passage into mice. No antimony-resistant subclone appeared, probably a rare occurrence. By tagging subclone cells with a L. amazonensis genomic cosmid library, we found that only a very small number of founding cells could produce lesions. Leishmania clones transfected with in vivo selected individual cosmids were also diverse in terms of lesion growth rate, revealing the cosmid-independent intrinsic characteristics of each clone. Our results suggest that only a few of the infecting parasites are able to grow and produce lesions; later, within the cell mixture of each lesion, there coexist several parasite populations with different potentialities to grow lesions during the next infection round. This may reflect a sort of programmed heterogeneity of individual parasites, favoring the survival of some individuals in various environmental conditions. PMID:28076468

  11. An Imaging Workflow for Characterizing Phenotypical Change in Large Histological Mouse Model Datasets

    PubMed Central

    Mosaliganti, Kishore; Pan, Tony; Ridgway, Randall; Sharp, Richard; Cooper, Lee; Gulacy, Alex; Sharma, Ashish; Irfanoglu, Okan; Machiraju, Raghu; Kurc, Tahsin; de Bruin, Alain; Wenzel, Pamela; Leone, Gustavo; Saltz, Joel; Huang, Kun

    2008-01-01

    Motivation This paper presents a workflow designed to quantitatively characterize the 3-D structural attributes of macroscopic tissue specimens acquired at a micron level resolution using light microscopy. The specific application is a study of the morphological change in a mouse placenta induced by knocking out the retinoblastoma gene. Result This workflow includes four major components: (i) Serial-section image acquisition, (ii) image preprocessing, (iii) image analysis involving 2-D pair-wise registration, 2-D segmentation and 3-D reconstruction, and (iv) visualization and quantification of phenotyping parameters. Several new algorithms have been developed within each workflow component. The results confirm the hypotheses that (i) the volume of labyrinth tissue decreases in mutant mice with the retinoblastoma (Rb) gene knockout and (ii) there is more interdigitation at the surface between the labyrinth and spongiotrophoblast tissues in mutant placenta. Additional confidence stem from agreement in the 3-D visualization and the quantitative results generated. Availability The source code is available upon request. PMID:18502696

  12. Role of weakest links and system-size scaling in multiscale modeling of stochastic plasticity

    NASA Astrophysics Data System (ADS)

    Ispánovity, Péter Dusán; Tüzes, Dániel; Szabó, Péter; Zaiser, Michael; Groma, István

    2017-02-01

    Plastic deformation of crystalline and amorphous matter often involves intermittent local strain burst events. To understand the physical background of the phenomenon a minimal stochastic mesoscopic model was introduced, where details of the microstructure evolution are statistically represented in terms of a fluctuating local yield threshold. In the present paper we propose a method for determining the corresponding yield stress distribution for the case of crystal plasticity from lower scale discrete dislocation dynamics simulations which we combine with weakest link arguments. The success of scale linking is demonstrated by comparing stress-strain curves obtained from the resulting mesoscopic and the underlying discrete dislocation models in the microplastic regime. As shown by various scaling relations they are statistically equivalent and behave identically in the thermodynamic limit. The proposed technique is expected to be applicable to different microstructures and also to amorphous materials.

  13. Space Station communications and tracking systems modeling and RF link simulation

    NASA Technical Reports Server (NTRS)

    Tsang, Chit-Sang; Chie, Chak M.; Lindsey, William C.

    1986-01-01

    In this final report, the effort spent on Space Station Communications and Tracking System Modeling and RF Link Simulation is described in detail. The effort is mainly divided into three parts: frequency division multiple access (FDMA) system simulation modeling and software implementation; a study on design and evaluation of a functional computerized RF link simulation/analysis system for Space Station; and a study on design and evaluation of simulation system architecture. This report documents the results of these studies. In addition, a separate User's Manual on Space Communications Simulation System (SCSS) (Version 1) documents the software developed for the Space Station FDMA communications system simulation. The final report, SCSS user's manual, and the software located in the NASA JSC system analysis division's VAX 750 computer together serve as the deliverables from LinCom for this project effort.

  14. Simulink models for performance analysis of high speed DQPSK modulated optical link

    NASA Astrophysics Data System (ADS)

    Sharan, Lucky; Rupanshi, Chaubey, V. K.

    2016-03-01

    This paper attempts to present the design approach for development of simulation models to study and analyze the transmission of 10 Gbps DQPSK signal over a single channel Peer to Peer link using Matlab Simulink. The simulation model considers the different optical components used in link design with their behavior represented initially by theoretical interpretation, including the transmitter topology, Mach Zehnder Modulator(MZM) module and, the propagation model for optical fibers etc. thus allowing scope for direct realization in experimental configurations. It provides the flexibility to incorporate the various photonic components as either user-defined or fixed and, can also be enhanced or removed from the model as per the design requirements. We describe the detailed operation and need of every component model and its representation in Simulink blocksets. Moreover the developed model can be extended in future to support Dense Wavelength Division Multiplexing (DWDM) system, thereby allowing high speed transmission with N × 40 Gbps systems. The various compensation techniques and their influence on system performance can be easily investigated by using such models.

  15. Constructing a Conceptual Model Linking Drivers and Ecosystem Services in Piedmont Streams

    DTIC Science & Technology

    2011-04-01

    CONSTRUCTING A CONCEPTUAL MODEL LINKING DRIVERS AND ECOSYSTEM SERVICES IN PIEDMONT STREAMS S . Kyle McKay1, Bruce A. Pruitt1, Christopher J...5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR( S ) 5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER 7...PERFORMING ORGANIZATION NAME( S ) AND ADDRESS(ES) U.S. Army Engineer Research and Development Center,Athens,GA,30606 8. PERFORMING ORGANIZATION REPORT NUMBER

  16. Large-Scale Phenotype-Based Antiepileptic Drug Screening in a Zebrafish Model of Dravet Syndrome1,2,3

    PubMed Central

    Dinday, Matthew T.

    2015-01-01

    Abstract Mutations in a voltage-gated sodium channel (SCN1A) result in Dravet Syndrome (DS), a catastrophic childhood epilepsy. Zebrafish with a mutation in scn1Lab recapitulate salient phenotypes associated with DS, including seizures, early fatality, and resistance to antiepileptic drugs. To discover new drug candidates for the treatment of DS, we screened a chemical library of ∼1000 compounds and identified 4 compounds that rescued the behavioral seizure component, including 1 compound (dimethadione) that suppressed associated electrographic seizure activity. Fenfluramine, but not huperzine A, also showed antiepileptic activity in our zebrafish assays. The effectiveness of compounds that block neuronal calcium current (dimethadione) or enhance serotonin signaling (fenfluramine) in our zebrafish model suggests that these may be important therapeutic targets in patients with DS. Over 150 compounds resulting in fatality were also identified. We conclude that the combination of behavioral and electrophysiological assays provide a convenient, sensitive, and rapid basis for phenotype-based drug screening in zebrafish mimicking a genetic form of epilepsy. PMID:26465006

  17. Sirenomelia Phenotype in Bmp7;Shh Compound Mutants: A Novel Experimental Model for Studies of Caudal Body Malformations

    PubMed Central

    Garrido-Allepuz, Carlos; González-Lamuño, Domingo; Ros, Maria A.

    2012-01-01

    Sirenomelia is a severe congenital malformation of the lower body characterized by the fusion of the legs into a single lower limb. This striking external phenotype consistently associates severe visceral abnormalities, most commonly of the kidneys, intestine, and genitalia that generally make the condition lethal. Although the causes of sirenomelia remain unknown, clinical studies have yielded two major hypotheses: i) a primary defect in the generation of caudal mesoderm, ii) a primary vascular defect that leaves the caudal part of the embryo hypoperfused. Interestingly, Sirenomelia has been shown to have a genetic basis in mice, and although it has been considered a sporadic condition in humans, recently some possible familial cases have been reported. Here, we report that the removal of one or both functional alleles of Shh from the Bmp7-null background leads to a sirenomelia phenotype that faithfully replicates the constellation of external and internal malformations, typical of the human condition. These mutants represent an invaluable model in which we have analyzed the pathogenesis of sirenomelia. We show that the signaling defect predominantly impacts the morphogenesis of the hindgut and the development of the caudal end of the dorsal aortas. The deficient formation of ventral midline structures, including the interlimb mesoderm caudal to the umbilicus, leads to the approximation and merging of the hindlimb fields. Our study provides new insights for the understanding of the mechanisms resulting in caudal body malformations, including sirenomelia. PMID:23028704

  18. M-cadherin, a candidate gene for type 2 diabetes and related phenotypes in a KK/Ta mouse model.

    PubMed

    Shiina, K; Gohda, T; Murakoshi, M; Yamada, K; Aoki, T; Yamazaki, T; Tanimoto, M; Tomino, Y

    2007-03-01

    The KK/Ta strain serves as a suitable polygenic mouse model for type 2 diabetes associated with fasting hyperglycaemia, glucose intolerance, hyperinsulinaemia, mild obesity and dyslipidaemia. Recently, we reported the susceptibility loci contributing to type 2 diabetes and related phenotypes in KK/Ta mice. In the present study, to identify susceptibility genes for type 2 diabetes and related disorders, GeneChip Expression Analysis was employed to survey the gene expression profile in the liver of KK/Ta and BALB/c mice. M-cadherin, a calciumdependent intercellular adhesion molecule, showed increased expression in the liver of KK/Ta mice, and sequence analysis revealed three missense mutations. The relationship between these polymorphisms and various phenotypes in 208 KK/Ta x (BALB/c x KK/Ta) F1 backcross mice was analysed. Statistical analysis revealed that M-cadherin exhibits linkage to levels of triglyceride and insulin in sera, glucose tolerance and body weight. Although it has been postulated that M-cadherin may be important for the regulation of morphogenesis of skeletal muscle cells, these results suggest that M-cadherin may influence hypertriglyceridaemia, glucose intolerance, hyperinsulinaemia and obesity in KK/Ta mice.

  19. Growth Curve Models for the Analysis of Phenotype Arrays for a Systems Biology Overview of Yersinia pestis

    SciTech Connect

    Fodor, I K; Holtz-Morris, A E; McCutchen-Maloney, S L

    2005-09-08

    The Phenotype MicroArray technology of Biolog, Inc. (Hayward, CA) measures the respiration of cells as a function of time in thousands of microwells simultaneously, and thus provides a high-throughput means of studying cellular phenotypes. The microwells contain compounds involved in a number of biochemical pathways, as well as chemicals that test the sensitivity of cells against antibiotics and stress. While the PM experimental workflow is completely automated, statistical methods to analyze and interpret the data are lagging behind. To take full advantage of the technology, it is essential to develop efficient analytical methods to quantify the information in the complex datasets resulting from PM experiments. We propose the use of statistical growth-curve models to rigorously quantify observed differences in PM experiments, in the context of the growth and metabolism of Yersinia pestis cells grown under different physiological conditions. The information from PM experiments complement genomic and proteomic results and can be used to identify gene function and in drug development. Successful coupling of phenomics results with genomics and proteomics will lead to an unprecedented ability to characterize bacterial function at a systems biology level.

  20. Right ventricular nitric oxide signaling in an ovine model of congenital heart disease: a preserved fetal phenotype.

    PubMed

    Kameny, Rebecca Johnson; He, Youping; Morris, Catherine; Sun, Christine; Johengen, Michael; Gong, Wenhui; Raff, Gary W; Datar, Sanjeev A; Oishi, Peter E; Fineman, Jeffrey R

    2015-07-01

    We recently reported superior right ventricle (RV) performance in response to acute afterload challenge in lambs with a model of congenital heart disease with chronic left-to-right cardiac shunts. Compared with control animals, shunt lambs demonstrated increased contractility because of an enhanced Anrep effect (the slow increase in contractility following myocyte stretch). This advantageous physiological response may reflect preservation of a fetal phenotype, since the RV of shunt lambs remains exposed to increased pressure postnatally. Nitric oxide (NO) production by NO synthase (NOS) is activated by myocyte stretch and is a necessary intermediary of the Anrep response. The purpose of this study was to test the hypothesis that NO signaling is increased in the RV of fetal lambs compared with controls and shunt lambs have persistence of this fetal pattern. An 8-mm graft was placed between the pulmonary artery and aorta in fetal lambs (shunt). NOS isoform expression, activity, and association with activating cofactors were determined in fetal tissue obtained during late-gestation and in 4-wk-old juvenile shunt and control lambs. We demonstrated increased RNA and protein expression of NOS isoforms and increased total NOS activity in the RV of both shunt and fetal lambs compared with control. We also found increased NOS activation and association with cofactors in shunt and fetal RV compared with control. These data demonstrate preserved fetal NOS phenotype and NO signaling in shunt RV, which may partially explain the mechanism underlying the adaptive response to increased afterload seen in the RV of shunt lambs.

  1. A Mouse Model of X-linked Intellectual Disability Associated with Impaired Removal of Histone Methylation.

    PubMed

    Iwase, Shigeki; Brookes, Emily; Agarwal, Saurabh; Badeaux, Aimee I; Ito, Hikaru; Vallianatos, Christina N; Tomassy, Giulio Srubek; Kasza, Tomas; Lin, Grace; Thompson, Andrew; Gu, Lei; Kwan, Kenneth Y; Chen, Chinfei; Sartor, Maureen A; Egan, Brian; Xu, Jun; Shi, Yang

    2016-02-09

    Mutations in a number of chromatin modifiers are associated with human neurological disorders. KDM5C, a histone H3 lysine 4 di- and tri-methyl (H3K4me2/3)-specific demethylase, is frequently mutated in X-linked intellectual disability (XLID) patients. Here, we report that disruption of the mouse Kdm5c gene recapitulates adaptive and cognitive abnormalities observed in XLID, including impaired social behavior, memory deficits, and aggression. Kdm5c-knockout brains exhibit abnormal dendritic arborization, spine anomalies, and altered transcriptomes. In neurons, Kdm5c is recruited to promoters that harbor CpG islands decorated with high levels of H3K4me3, where it fine-tunes H3K4me3 levels. Kdm5c predominantly represses these genes, which include members of key pathways that regulate the development and function of neuronal circuitries. In summary, our mouse behavioral data strongly suggest that KDM5C mutations are causal to XLID. Furthermore, our findings suggest that loss of KDM5C function may impact gene expression in multiple regulatory pathways relevant to the clinical phenotypes.

  2. A mouse model of X-linked intellectual disability associated with impaired removal of histone methylation

    PubMed Central

    Iwase, Shigeki; Brookes, Emily; Agarwal, Saurabh; Badeaux, Aimee I; Ito, Hikaru; Vallianatos, Christina N; Tomassy, Giulio Srubek; Kasza, Tomas; Lin, Grace; Thompson, Andrew; Gu, Lei; Kwan, Kenneth Y.; Chen, Chinfei; Sartor, Maureen A.; Egan, Brian; Xu, Jun; Shi, Yang

    2015-01-01

    Mutations in a number of chromatin modifiers are associated with human neurological disorders. KDM5C, a histone H3 lysine 4 di- and tri-methyl (H3K4me2/3)-specific demethylase, is frequently mutated in X-linked intellectual disability (XLID) patients. Here, we report that disruption of the mouse Kdm5c gene recapitulates adaptive and cognitive abnormalities observed in XLID, including impaired social behavior and memory, and aggression. Kdm5c-knockout brains exhibit impaired dendritic arborization, spine abnormalities, and altered transcriptomes. In neurons, Kdm5c is recruited to promoters that harbor CpG islands decorated with high levels of H3K4me3, where it fine-tunes H3K4me3 levels. Kdm5c predominantly represses these genes, which include members of key pathways that regulate the development and function of neuronal circuitries. In summary, our mouse behavioral data strongly suggests that KDM5C mutations are causal to XLID. Furthermore, our findings suggest that loss of KDM5C function may impact gene expression in multiple regulatory pathways relevant to the clinical phenotypes. PMID:26804915

  3. Severity of infantile nystagmus syndrome-like ocular motor phenotype is linked to the extent of the underlying optic nerve projection defect in zebrafish belladonna mutant.

    PubMed

    Huber-Reggi, Sabina P; Chen, Chien-Cheng; Grimm, Lea; Straumann, Dominik; Neuhauss, Stephan C F; Huang, Melody Ying-Yu

    2012-12-12

    Infantile nystagmus syndrome (INS), formerly known as congenital nystagmus, is an ocular motor disorder in humans characterized by spontaneous eye oscillations (SOs) and, in several cases, reversed optokinetic response (OKR). Its etiology and pathomechanism is largely unknown, but misrouting of the optic nerve has been observed in some patients. Likewise, optic nerve misrouting, a reversed OKR and SOs with INS-like waveforms are observed in zebrafish belladonna (bel) mutants. We aimed to investigate whether and how misrouting of the optic nerve correlates with the ocular motor behaviors in bel larvae. OKR and SOs were quantified and subsequently the optic nerve fibers were stained with fluorescent lipophilic dyes. Eye velocity during OKR was reduced in larvae with few misprojecting optic nerve fibers and reversed in larvae with a substantial fraction of misprojecting fibers. All larvae with reversed OKR also displayed SOs. A stronger reversed OKR correlated with more frequent SOs. Since we did not find a correlation between additional retinal defects and ocular motor behavior, we suggest that axon misrouting is in fact origin of INS in the zebrafish animal model. Depending on the ratio between misprojecting ipsilateral and correctly projecting contralateral fibers, the negative feedback loop normally regulating OKR can turn into a positive loop, resulting in an increase in retinal slip. Our data not only give new insights into the etiology of INS but may also be of interest for studies on how the brain deals with and adapts to conflicting inputs.

  4. NEW GHOST-NODE METHOD FOR LINKING DIFFERENT MODELS WITH VARIED GRID REFINEMENT

    SciTech Connect

    S.C. James; J.E. Dickinson; S.W. Mehl; M.C. Hill; S.A. Leake; G.A. zyvoloski; A. Eddebbarh

    2006-02-15

    A flexible, robust method for linking grids of locally refined models constructed with different numerical methods is needed to address a variety of hydrologic problems. This work outlines and tests a new ghost-node model-linking method for a refined ''child'' model that is contained within a larger and coarser ''parent'' model that is based on the iterative method of Mehl and Hill (2002, 2004). The method is applicable to steady-state solutions for ground-water flow. Tests are presented for a homogeneous two-dimensional system that has either matching grids (parent cells border an integer number of child cells; Figure 2a) or non-matching grids (parent cells border a non-integer number of child cells; Figure 2b). The coupled grids are simulated using the finite-difference and finite-element models MODFLOW and FEHM, respectively. The simulations require no alteration of the MODFLOW or FEHM models and are executed using a batch file on Windows operating systems. Results indicate that when the grids are matched spatially so that nodes and child cell boundaries are aligned, the new coupling technique has error nearly equal to that when coupling two MODFLOW models (Mehl and Hill, 2002). When the grids are non-matching, model accuracy is slightly increased over matching-grid cases. Overall, results indicate that the ghost-node technique is a viable means to accurately couple distinct models because the overall error is less than if only the regional model was used to simulate flow in the child model's domain.

  5. New Ghost-node method for linking different models with varied grid refinement.

    SciTech Connect

    Mehl, Steffen W.; Hill, Mary Catherine.; James, Scott Carlton; Leake, Stanley A.; Zyvoloski, George A.; Dickinson, Jesse E.; Eddebbarh, Al A.

    2006-01-01

    A flexible, robust method for linking grids of locally refined models constructed with different numerical methods is needed to address a variety of hydrologic problems. This work outlines and tests a new ghost-node model-linking method for a refined 'child' model that is contained within a larger and coarser 'parent' model that is based on the iterative method of Mehl and Hill (2002, 2004). The method is applicable to steady-state solutions for ground-water flow. Tests are presented for a homogeneous two-dimensional system that has either matching grids (parent cells border an integer number of child cells; Figure 2a) or non-matching grids (parent cells border a non-integer number of child cells; Figure 2b). The coupled grids are simulated using the finite-difference and finite-element models MODFLOW and FEHM, respectively. The simulations require no alteration of the MODFLOW or FEHM models and are executed using a batch file on Windows operating systems. Results indicate that when the grids are matched spatially so that nodes and child cell boundaries are aligned, the new coupling technique has error nearly equal to that when coupling two MODFLOW models (Mehl and Hill, 2002). When the grids are non-matching, model accuracy is slightly increased over matching-grid cases. Overall, results indicate that the ghost-node technique is a viable means to accurately couple distinct models because the overall error is less than if only the regional model was used to simulate flow in the child model's domain.

  6. New ghost-node method for linking different models with varied grid refinement

    USGS Publications Warehouse

    James, S.C.; Dickinson, J.E.; Mehl, S.W.; Hill, M.C.; Leake, S.A.; Zyvoloski, G.A.; Eddebbarh, A.-A.

    2006-01-01

    A flexible, robust method for linking grids of locally refined ground-water flow models constructed with different numerical methods is needed to address a variety of hydrologic problems. This work outlines and tests a new ghost-node model-linking method for a refined "child" model that is contained within a larger and coarser "parent" model that is based on the iterative method of Steffen W. Mehl and Mary C. Hill (2002, Advances in Water Res., 25, p. 497-511; 2004, Advances in Water Res., 27, p. 899-912). The method is applicable to steady-state solutions for ground-water flow. Tests are presented for a homogeneous two-dimensional system that has matching grids (parent cells border an integer number of child cells) or nonmatching grids. The coupled grids are simulated by using the finite-difference and finite-element models MODFLOW and FEHM, respectively. The simulations require no alteration of the MODFLOW or FEHM models and are executed using a batch file on Windows operating systems. Results indicate that when the grids are matched spatially so that nodes and child-cell boundaries are aligned, the new coupling technique has error nearly equal to that when coupling two MODFLOW models. When the grids are nonmatching, model accuracy is slightly increased compared to that for matching-grid cases. Overall, results indicate that the ghost-node technique is a viable means to couple distinct models because the overall head and flow errors relative to the analytical solution are less than if only the regional coarse-grid model was used to simulate flow in the child model's domain.

  7. Modelling the multidimensional niche by linking functional traits to competitive performance

    PubMed Central

    Maynard, Daniel S.; Leonard, Kenneth E.; Drake, John M.; Hall, David W.; Crowther, Thomas W.; Bradford, Mark A.

    2015-01-01

    Linking competitive outcomes to environmental conditions is necessary for understanding species' distributions and responses to environmental change. Despite this importance, generalizable approaches for predicting competitive outcomes across abiotic gradients are lacking, driven largely by the highly complex and context-dependent nature of biotic interactions. Here, we present and empirically test a novel niche model that uses functional traits to model the niche space of organisms and predict competitive outcomes of co-occurring populations across multiple resource gradients. The model makes no assumptions about the underlying mode of competition and instead applies to those settings where relative competitive ability across environments correlates with a quantifiable performance metric. To test the model, a series of controlled microcosm experiments were conducted using genetically related strains of a widespread microbe. The model identified trait microevolution and performance differences among strains, with the predicted competitive ability of each organism mapped across a two-dimensional carbon and nitrogen resource space. Areas of coexistence and competitive dominance between strains were identified, and the predicted competitive outcomes were validated in approximately 95% of the pairings. By linking trait variation to competitive ability, our work demonstrates a generalizable approach for predicting and modelling competitive outcomes across changing environmental contexts. PMID:26136444

  8. Link between statistical equilibrium fidelity and forecasting skill for complex systems with model error.

    PubMed