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Sample records for adaptive mutations implications

  1. Complete-proteome mapping of human influenza A adaptive mutations: implications for human transmissibility of zoonotic strains.

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    Olivo Miotto

    Full Text Available BACKGROUND: There is widespread concern that H5N1 avian influenza A viruses will emerge as a pandemic threat, if they become capable of human-to-human (H2H transmission. Avian strains lack this capability, which suggests that it requires important adaptive mutations. We performed a large-scale comparative analysis of proteins from avian and human strains, to produce a catalogue of mutations associated with H2H transmissibility, and to detect their presence in avian isolates. METHODOLOGY/PRINCIPAL FINDINGS: We constructed a dataset of influenza A protein sequences from 92,343 public database records. Human and avian sequence subsets were compared, using a method based on mutual information, to identify characteristic sites where human isolates present conserved mutations. The resulting catalogue comprises 68 characteristic sites in eight internal proteins. Subtype variability prevented the identification of adaptive mutations in the hemagglutinin and neuraminidase proteins. The high number of sites in the ribonucleoprotein complex suggests interdependence between mutations in multiple proteins. Characteristic sites are often clustered within known functional regions, suggesting their functional roles in cellular processes. By isolating and concatenating characteristic site residues, we defined adaptation signatures, which summarize the adaptive potential of specific isolates. Most adaptive mutations emerged within three decades after the 1918 pandemic, and have remained remarkably stable thereafter. Two lineages with stable internal protein constellations have circulated among humans without reassorting. On the contrary, H5N1 avian and swine viruses reassort frequently, causing both gains and losses of adaptive mutations. CONCLUSIONS: Human host adaptation appears to be complex and systemic, involving nearly all influenza proteins. Adaptation signatures suggest that the ability of H5N1 strains to infect humans is related to the presence of an

  2. Cell culture adaptation mutations in foot-and-mouth disease virus serotype A capsid proteins: implications for receptor interactions

    Science.gov (United States)

    In this study we describe the adaptive changes fixed on the capsid of several foot-and-mouth disease virus serotype A strains during propagation in cell monolayers. Viruses passaged extensively in three cell lines (BHK-21, LFBK and IB-RS-2), consistently gained several positively charged amino acids...

  3. Particle Swarm Optimization with Adaptive Mutation

    Institute of Scientific and Technical Information of China (English)

    LU Zhen-su; HOU Zhi-rong; DU Juan

    2006-01-01

    A new adaptive mutation particle swarm optimizer,which is based on the variance of the population's fitness,is presented in this paper.During the rtmning time,the mutation probability for the current best particle is determined by two factors:the variance of the population's fitness and the current optimal solution.The ability of particle swarm optimization (PSO) algorithm to break away from the local optimum is greatly improved by the mutation.The experimental results show that the new algorithm not only has great advantage of convergence property over genetic algorithm and PSO,but can also avoid the premature convergence problem effectively.

  4. Model Driven Mutation Applied to Adaptative Systems Testing

    CERN Document Server

    Bartel, Alexandre; Munoz, Freddy; Klein, Jacques; Mouelhi, Tejeddine; Traon, Yves Le

    2012-01-01

    Dynamically Adaptive Systems modify their behav- ior and structure in response to changes in their surrounding environment and according to an adaptation logic. Critical sys- tems increasingly incorporate dynamic adaptation capabilities; examples include disaster relief and space exploration systems. In this paper, we focus on mutation testing of the adaptation logic. We propose a fault model for adaptation logics that classifies faults into environmental completeness and adaptation correct- ness. Since there are several adaptation logic languages relying on the same underlying concepts, the fault model is expressed independently from specific adaptation languages. Taking benefit from model-driven engineering technology, we express these common concepts in a metamodel and define the operational semantics of mutation operators at this level. Mutation is applied on model elements and model transformations are used to propagate these changes to a given adaptation policy in the chosen formalism. Preliminary resul...

  5. Capability Analysis of Chaotic Mutation and Its Self-Adaption

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    YANG Li-Jiang; CHEN Tian-Lun

    2002-01-01

    Through studying several kinds of chaotic mappings' distributions of orbital points, we analyze the capabilityof the chaotic mutations based on these mappings. Nunerical experiments support our conclusions very well. Thecapability analysis also led to a self-adaptive mechanism of chaotic mutation. The introducing of the self-adaptivechaotic mutation can improve the performance of genetic algorithm very prominently.

  6. Capability Analysis of Chaotic Mutation and Its Self-Adaption

    Institute of Scientific and Technical Information of China (English)

    YANGLi-Jiang; CHENTian-Lun

    2002-01-01

    Through studying several kinds of chaotic mappings distributions of orbital points,we analyze the capabuility of the chaotic mutations based on these mappings,Numerical experiments support our conclusions very well.The capability analysis also led to a self-adaptive mechanism of chaotic mutation.The introducing of the self-adaptive chaotic mutation can improve the performance of genetic algorithm very prominently.

  7. Shifting gears: Thermodynamics of genetic information storage suggest stress-dependence of mutation rate, which can accelerate adaptation

    CERN Document Server

    Hilbert, Lennart

    2011-01-01

    Background: Acceleration of adaptation dynamics by stress-induced hypermutation has been found experimentally. Evolved evolvability is a prominent explanation. We investigate a more generally applicable explanation by a physical constraint. Methods and Results: A generic thermodynamical analysis of genetic information storage obviates physical constraints on the integrity of genetic information. The capability to employ metabolic resources is found as a major determinant of mutation probability in stored genetic information. Incorporation into a non-recombinant, asexual adaptation toy model predicts cases of markedly accelerated adaptation, driven by a transient increase of mutation rate. No change in the mutation rate as a genetic trait is required. The mutation rate of one and the same genotype varies dependent on stress level. Implications: Stress-dependent mutation rates are physically necessary and challenge a condition-independent genotype to mutation rate mapping. This holds implications for evolutiona...

  8. A new experimental system for study on adaptive mutations

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    A super-repressed mutant of purR (purRS), which encodes arepressor protein controlling expression of purine biosynthetic genes in Salmonella typhimurium, grew very slowly on NCE medium with 10 mg / mL Ade and lactose as sole carbon source (cannot form colonies). However, a phenomenon of late-arising mutations was observed when purRS mutants were spread on NCE+lactose plates and subjected to a prolonged non-lethal selection. The reconstruction experiments of revertants showed that the late-arising "lac+" mutants are not slow growing mutants. Statistical analysis indicated that the distribution of late-arising mutants is Poisson distribution, showing that reversion occurred after plating. The result of co-transductional analysis preliminarily showed that late-arising mutation occurred at selected gene purR or 16 bp PUR box, cis element of structural gene purD. The above results suggest that the phenomenon of late-arising mutation observed by our system is a result of adaptive mutations which are different from random mutations. This is the first time to extend target genes at which adaptive mutations could occur from structural genes involved in carbon metabolism and amino acid biosynthesis to trans regulatory gene coding repressor protein. Our results have provided not only a new proof for generality of adaptive mutations but also a new system for study on adaptive mutations.

  9. Neuroglobin mutation associated with hypoxia adaptation in Tibet chicken

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Globin protein family plays an important role in storing and transporting oxygen.As a newly reported globin,the revealed function of neuroglobin includes binding and storing oxygen as well as facilitating the utilization of oxygen in neuronal cells.In the Dresent study,mutations in exons of chicken Ngb gene were identified with the method of sequencing and created restriction site PCR in Tibet chicken and other four lowland chicken breeds.The mutations of Lys-2224(E4)-Asn and Ser-2279(E4)-Gly were identified in exon 4 of the gene.The Lys-2224(E4)-Asn mutation existed only in Tibet chicken and the mutation frequencies increased with increasing altitude.Analysis of the haplotype and diplotype of the two mutations in Tibet chicken populations of different altitudes showed that the frequencies of TG haplotype and TTGG diplotype also increased with increasing altitude,while the reverse tendency was found on GGAA diplotype.Under the hypoxic simulation incubation,the main haplotype was TG in living embryos and GA in dead embryos.The results showed that the Lys-2224(E4)-Asn mutation may be a specific mutation associated with hypoxia adaptation in Tibet chicken.

  10. A new experimental system for study on adaptive mutations

    Institute of Scientific and Technical Information of China (English)

    Lü; Zhong; (

    2001-01-01

    [1]Luria, S. E., Delbrück, M., Mutation of bacteria from virus sensitivity to virus resistance, Genetics, 1943, 28: 491.[2]Lederberg, J., Lederberg, E. M., Replica plating and indirect selection of bacteria mutants, J. Bacteriol., 1952, 63: 399.[3]Carins, J., Overbaugh, J., Miller, S., The origin of mutants, Nature, 1988, 355: 142.[4]Foster, P. L., Adaptive mutation: the uses of adversity, Annu. Rev. Microbiol., 1993, 47: 467.[5]Hall, B. G., Adaptive mutagenesis: a process that generates almost exclusively beneficient mutations, Genetica, 1998, 102/103: 109.[6]Kasak, L., Horak, R., Kivisaar, M., Promotor-creating mutations in Psuedmonas putida: A model system for the study of mutation in starving bacteria, PNAS, 1997, 94: 3134.[7]Steele, D. F., Jinks-Robertson, An examination of adaptive reversion in Saccharomyces cerevisiae, Genetics, 1992, 132: 9.[8]Davis, R. W., Botstein, Roth, J. R., Advanced Bacterial Genetics--A Manual for Genetic Engineering, New York: Cold Spring Harbor Laboratory Press, 1980, 13.[9]Miller, J. H., Experiments in Molecular Genetics, New York: Cold Spring Harbor Laboratory Press, 1972, 352.[10] Lea, D. E., Coulson, C. A., The distribution of the numbers of mutants in bacterial populations, J. Genetics, 1949, 49: 264.[11] Hughes, K. T., Roth, J. R., Transitory cis complementation: a method for provided transposition function to defective transposons, Genetics, 1988, 119: 9.[12] Sanderson, K. E., Roth J., Linkage map of Salmonella typhimurium, Microbiol. Rev., 1988, 52: 485.[13] He, B., Shiau, A., Choi, K. Y., Genes of the E. coli pur region are negatively controlled by a repressor-operator interaction, J. Bacteriol., 1990, 172: 4555.[14] Liu, B., Huang, Y., Wang, A. Q., Regulation of purine biosynthetic genes expression in Salmonella typhimurium (IV)--Oc mutation site of purG and its function analysis, Science in China, Ser. C, 1997, 40(3): 238.[15] Tang, H., Qin, J. C., Wang, A. Q

  11. Self-Adaptive Differential Evolution Algorithm With Zoning Evolution of Control Parameters and Adaptive Mutation Strategies.

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    Fan, Qinqin; Yan, Xuefeng

    2016-01-01

    The performance of the differential evolution (DE) algorithm is significantly affected by the choice of mutation strategies and control parameters. Maintaining the search capability of various control parameter combinations throughout the entire evolution process is also a key issue. A self-adaptive DE algorithm with zoning evolution of control parameters and adaptive mutation strategies is proposed in this paper. In the proposed algorithm, the mutation strategies are automatically adjusted with population evolution, and the control parameters evolve in their own zoning to self-adapt and discover near optimal values autonomously. The proposed algorithm is compared with five state-of-the-art DE algorithm variants according to a set of benchmark test functions. Furthermore, seven nonparametric statistical tests are implemented to analyze the experimental results. The results indicate that the overall performance of the proposed algorithm is better than those of the five existing improved algorithms.

  12. Human RAG mutations: biochemistry and clinical implications.

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    Notarangelo, Luigi D; Kim, Min-Sung; Walter, Jolan E; Lee, Yu Nee

    2016-04-01

    The recombination-activating gene 1 (RAG1) and RAG2 proteins initiate the V(D)J recombination process, which ultimately enables the generation of T cells and B cells with a diversified repertoire of antigen-specific receptors. Mutations of the RAG genes in humans are associated with a broad spectrum of clinical phenotypes, ranging from severe combined immunodeficiency to autoimmunity. Recently, novel insights into the phenotypic diversity of this disease have been provided by resolving the crystal structure of the RAG complex, by developing novel assays to test recombination activity of the mutant RAG proteins and by characterizing the molecular and cellular basis of immune dysregulation in patients with RAG deficiency.

  13. Hypoxia: adapting to high altitude by mutating EPAS-1, the gene encoding HIF-2α.

    Science.gov (United States)

    van Patot, Martha C Tissot; Gassmann, Max

    2011-01-01

    processes have been implicated in the human response to high altitude exposure including erythropoiesis (Kapitsinou et al. 2010), iron homeostasis (Peyssonnaux et al. 2008), metabolism (Shohet et al. 2007; Tormos et al. 2010; Biswas et al. 2010 ; Rankin et al. 2009) and vascular permeability (Chen et al. 2009; Tanaka et al. 2005), among others. Clearly, mutation of EPAS-1 has the potential to bring far more advantage when adapting to high altitude than solely mutating the Epo gene.

  14. Electron holes appear to trigger cancer-implicated mutations

    Science.gov (United States)

    Miller, John; Villagran, Martha

    Malignant tumors are caused by mutations, which also affect their subsequent growth and evolution. We use a novel approach, computational DNA hole spectroscopy [M.Y. Suarez-Villagran & J.H. Miller, Sci. Rep. 5, 13571 (2015)], to compute spectra of enhanced hole probability based on actual sequence data. A hole is a mobile site of positive charge created when an electron is removed, for example by radiation or contact with a mutagenic agent. Peaks in the hole spectrum depict sites where holes tend to localize and potentially trigger a base pair mismatch during replication. Our studies of reveal a correlation between hole spectrum peaks and spikes in human mutation frequencies. Importantly, we also find that hole peak positions that do not coincide with large variant frequencies often coincide with cancer-implicated mutations and/or (for coding DNA) encoded conserved amino acids. This enables combining hole spectra with variant data to identify critical base pairs and potential cancer `driver' mutations. Such integration of DNA hole and variance spectra could also prove invaluable for pinpointing critical regions, and sites of driver mutations, in the vast non-protein-coding genome. Supported by the State of Texas through the Texas Ctr. for Superconductivity.

  15. An adaptive genetic algorithm with diversity-guided mutation and its global convergence property

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    李枚毅; 蔡自兴; 孙国荣

    2004-01-01

    An adaptive genetic algorithm with diversity-guided mutation, which combines adaptive probabilities of crossover and mutation was proposed. By means of homogeneous finite Markov chains, it is proved that adaptive genetic algorithm with diversity-guided mutation and genetic algorithm with diversity-guided mutation converge to the global optimum if they maintain the best solutions, and the convergence of adaptive genetic algorithms with adaptive probabilities of crossover and mutation was studied. The performances of the above algorithms in optimizing several unimodal and multimodal functions were compared. The results show that for multimodal functions the average convergence generation of the adaptive genetic algorithm with diversity-guided mutation is about 900 less than that of adaptive genetic algorithm with adaptive probabilities and genetic algorithm with diversity-guided mutation, and the adaptive genetic algorithm with diversity-guided mutation does not lead to premature convergence. It is also shown that the better balance between overcoming premature convergence and quickening convergence speed can be gotten.

  16. Adaptive introgression in animals: examples and comparison to new mutation and standing variation as sources of adaptive variation.

    Science.gov (United States)

    Hedrick, Philip W

    2013-09-01

    Adaptive genetic variation has been thought to originate primarily from either new mutation or standing variation. Another potential source of adaptive variation is adaptive variants from other (donor) species that are introgressed into the (recipient) species, termed adaptive introgression. Here, the various attributes of these three potential sources of adaptive variation are compared. For example, the rate of adaptive change is generally thought to be faster from standing variation, slower from mutation and potentially intermediate from adaptive introgression. Additionally, the higher initial frequency of adaptive variation from standing variation and lower initial frequency from mutation might result in a higher probability of fixation of the adaptive variants for standing variation. Adaptive variation from introgression might have higher initial frequency than new adaptive mutations but lower than that from standing variation, again making the impact of adaptive introgression variation potentially intermediate. Adaptive introgressive variants might have multiple changes within a gene and affect multiple loci, an advantage also potentially found for adaptive standing variation but not for new adaptive mutants. The processes that might produce a common variant in two taxa, convergence, trans-species polymorphism from incomplete lineage sorting or from balancing selection and adaptive introgression, are also compared. Finally, potential examples of adaptive introgression in animals, including balancing selection for multiple alleles for major histocompatibility complex (MHC), S and csd genes, pesticide resistance in mice, black colour in wolves and white colour in coyotes, Neanderthal or Denisovan ancestry in humans, mimicry genes in Heliconius butterflies, beak traits in Darwin's finches, yellow skin in chickens and non-native ancestry in an endangered native salamander, are examined.

  17. Chemical process dynamic optimization based on the differential evolution algorithm with an adaptive scheduling mutation strategy

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    Zhu, Jun; Yan, Xuefeng; Zhao, Weixiang

    2013-10-01

    To solve chemical process dynamic optimization problems, a differential evolution algorithm integrated with adaptive scheduling mutation strategy (ASDE) is proposed. According to the evolution feedback information, ASDE, with adaptive control parameters, adopts the round-robin scheduling algorithm to adaptively schedule different mutation strategies. By employing an adaptive mutation strategy and control parameters, the real-time optimal control parameters and mutation strategy are obtained to improve the optimization performance. The performance of ASDE is evaluated using a suite of 14 benchmark functions. The results demonstrate that ASDE performs better than four conventional differential evolution (DE) algorithm variants with different mutation strategies, and that the whole performance of ASDE is equivalent to a self-adaptive DE algorithm variant and better than five conventional DE algorithm variants. Furthermore, ASDE was applied to solve a typical dynamic optimization problem of a chemical process. The obtained results indicate that ASDE is a feasible and competitive optimizer for this kind of problem.

  18. Evidence that adaptation in Drosophila is not limited by mutation at single sites.

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    Talia Karasov

    2010-06-01

    Full Text Available Adaptation in eukaryotes is generally assumed to be mutation-limited because of small effective population sizes. This view is difficult to reconcile, however, with the observation that adaptation to anthropogenic changes, such as the introduction of pesticides, can occur very rapidly. Here we investigate adaptation at a key insecticide resistance locus (Ace in Drosophila melanogaster and show that multiple simple and complex resistance alleles evolved quickly and repeatedly within individual populations. Our results imply that the current effective population size of modern D. melanogaster populations is likely to be substantially larger (> or = 100-fold than commonly believed. This discrepancy arises because estimates of the effective population size are generally derived from levels of standing variation and thus reveal long-term population dynamics dominated by sharp--even if infrequent--bottlenecks. The short-term effective population sizes relevant for strong adaptation, on the other hand, might be much closer to census population sizes. Adaptation in Drosophila may therefore not be limited by waiting for mutations at single sites, and complex adaptive alleles can be generated quickly without fixation of intermediate states. Adaptive events should also commonly involve the simultaneous rise in frequency of independently generated adaptive mutations. These so-called soft sweeps have very distinct effects on the linked neutral polymorphisms compared to the standard hard sweeps in mutation-limited scenarios. Methods for the mapping of adaptive mutations or association mapping of evolutionarily relevant mutations may thus need to be reconsidered.

  19. Adaptive synonymous mutations in an experimentally evolved Pseudomonas fluorescens population

    DEFF Research Database (Denmark)

    Bailey, Susan; Hinz, Aaron; Kassen, Rees

    2014-01-01

    in an experimentally evolved population of Pseudomonas fluorescens. We show experimentally that these mutations increase fitness by an amount comparable to non-synonymous mutations and that the fitness increases stem from increased gene expression. These results provide unequivocal evidence that synonymous mutations...

  20. Induced mutations in yeast cell populations adapting to an unforeseen challenge.

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    Moore, Lindsay S; Wei, Wu; Stolovicki, Elad; Benbenishty, Tamar; Wilkening, Stefan; Steinmetz, Lars M; Braun, Erez; David, Lior

    2014-01-01

    The modern evolutionary synthesis assumes that mutations occur at random, independently of the environment in which they confer an advantage. However, there are indications that cells facing challenging conditions can adapt rapidly, utilizing processes beyond selection of pre-existing genetic variation. Here, we show that a strong regulatory challenge can induce mutations in many independent yeast cells, in the absence of general mutagenesis. Whole genome sequencing of cell lineages reveals a repertoire of independent mutations within a single lineage that arose only after the cells were exposed to the challenging environment, while other cells in the same lineage adapted without any mutation in their genomes. Thus, our experiments uncovered multiple alternative routes for heritable adaptation that were all induced in the same lineage during a short time period. Our results demonstrate the existence of adaptation mechanisms beyond random mutation, suggesting a tight connection between physiological and genetic processes.

  1. Reciprocal sign epistasis between frequently experimentally evolved adaptive mutations causes a rugged fitness landscape.

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    Daniel J Kvitek

    2011-04-01

    Full Text Available The fitness landscape captures the relationship between genotype and evolutionary fitness and is a pervasive metaphor used to describe the possible evolutionary trajectories of adaptation. However, little is known about the actual shape of fitness landscapes, including whether valleys of low fitness create local fitness optima, acting as barriers to adaptive change. Here we provide evidence of a rugged molecular fitness landscape arising during an evolution experiment in an asexual population of Saccharomyces cerevisiae. We identify the mutations that arose during the evolution using whole-genome sequencing and use competitive fitness assays to describe the mutations individually responsible for adaptation. In addition, we find that a fitness valley between two adaptive mutations in the genes MTH1 and HXT6/HXT7 is caused by reciprocal sign epistasis, where the fitness cost of the double mutant prohibits the two mutations from being selected in the same genetic background. The constraint enforced by reciprocal sign epistasis causes the mutations to remain mutually exclusive during the experiment, even though adaptive mutations in these two genes occur several times in independent lineages during the experiment. Our results show that epistasis plays a key role during adaptation and that inter-genic interactions can act as barriers between adaptive solutions. These results also provide a new interpretation on the classic Dobzhansky-Muller model of reproductive isolation and display some surprising parallels with mutations in genes often associated with tumors.

  2. Reciprocal sign epistasis between frequently experimentally evolved adaptive mutations causes a rugged fitness landscape.

    Directory of Open Access Journals (Sweden)

    Daniel J Kvitek

    2011-04-01

    Full Text Available The fitness landscape captures the relationship between genotype and evolutionary fitness and is a pervasive metaphor used to describe the possible evolutionary trajectories of adaptation. However, little is known about the actual shape of fitness landscapes, including whether valleys of low fitness create local fitness optima, acting as barriers to adaptive change. Here we provide evidence of a rugged molecular fitness landscape arising during an evolution experiment in an asexual population of Saccharomyces cerevisiae. We identify the mutations that arose during the evolution using whole-genome sequencing and use competitive fitness assays to describe the mutations individually responsible for adaptation. In addition, we find that a fitness valley between two adaptive mutations in the genes MTH1 and HXT6/HXT7 is caused by reciprocal sign epistasis, where the fitness cost of the double mutant prohibits the two mutations from being selected in the same genetic background. The constraint enforced by reciprocal sign epistasis causes the mutations to remain mutually exclusive during the experiment, even though adaptive mutations in these two genes occur several times in independent lineages during the experiment. Our results show that epistasis plays a key role during adaptation and that inter-genic interactions can act as barriers between adaptive solutions. These results also provide a new interpretation on the classic Dobzhansky-Muller model of reproductive isolation and display some surprising parallels with mutations in genes often associated with tumors.

  3. Adaptive mutation of Acetobacter pasteurianus SKU1108 enhances acetic acid fermentation ability at high temperature.

    Science.gov (United States)

    Matsutani, Minenosuke; Nishikura, Mitsuteru; Saichana, Natsaran; Hatano, Tomoyuki; Masud-Tippayasak, Uraiwan; Theergool, Gunjana; Yakushi, Toshiharu; Matsushita, Kazunobu

    2013-05-20

    In vitro adaptation is one of the most challenging subjects in biology to understand adaptive evolution. Microbial adaptation to temperature is not only interesting in terms of understanding the adaptation mechanism, but also useful for industrial applications. In this study, we attempted the in vitro adaptation of Acetobacter pasteurianus SKU1108 by repeating its cultivation under high-temperature acetic acid fermentation conditions. As a result, thermo-adapted strains having the higher fermentation ability than the wild-type strain were obtained. Mutations and/or disruptions in several proteins of the adapted strains were detected with NGS sequencing technology. In particular, two different adapted strains had mutations or disruptions in three specific genes in common, suggesting that these genes are essential for thermotolerance or fermentation at higher temperature. In order to clarify their involvement in thermotolerance, two of the three genes were disrupted and their phenotype was examined. The results showed that mutations of the two proteins, MarR and an amino acid transporter, are partly responsible for higher fermentation ability and/or thermotolerance. Thus, it was suggested that these elevated abilities of the adapted strains are acquired by assembling several single gene mutations including the above two mutations.

  4. Advantages of a single-cycle production assay to study cell culture-adaptive mutations of hepatitis C virus

    DEFF Research Database (Denmark)

    Russell, Rodney S; Meunier, Jean-Christophe; Takikawa, Shingo

    2008-01-01

    mutations that were selected during serial passage in Huh-7.5 cells were studied. Recombinant genomes containing all five mutations produced 3-4 logs more infectious virions than did wild type. Neither a coding mutation in NS5A nor a silent mutation in E2 was adaptive, whereas coding mutations in E2, p7...

  5. Sex enhances adaptation by unlinking beneficial from detrimental mutations in experimental yeast populations

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    Gray Jeremy C

    2012-03-01

    Full Text Available Abstract Background The maintenance of sexuality is a classic problem in evolutionary biology because it is a less efficient mode of reproduction compared with asexuality; however, many organisms are sexual. Theoretical work suggests sex facilitates natural selection, and experimental data support this. However, there are fewer experimental studies that have attempted to determine the mechanisms underlying the advantage of sex. Two main classes of hypotheses have been proposed to explain its advantage: detrimental mutation clearance and beneficial mutation accumulation. Here we attempt to experimentally differentiate between these two classes by evolving Saccharomyces cerevisiae populations that differ only in their ability to undergo sex, and also manipulate mutation rate. We cannot manipulate the types of mutation that occur, but instead propagate populations in both stressful and permissive environments and assume that the extent of detrimental mutation clearance and beneficial mutation incorporation differs between them. Results After 300 mitotic generations interspersed with 11 rounds of sex we found there was no change or difference in fitness between sexuals and asexuals propagated in the permissive environment, regardless of mutation rate. Sex conferred a greater extent of adaptation in the stressful environment, and wild-type and elevated mutation rate sexual populations adapted equivalently. However, the asexual populations with an elevated mutation rate appeared more retarded in their extent of adaptation compared to asexual wild-type populations. Conclusions Sex provided no advantage in the permissive environment where beneficial mutations were rare. We could not evaluate if sex functioned to clear detrimental mutations more effectively or not here as no additional fitness load was observed in the mutator populations. However, in the stressful environment, where detrimental mutations were likely of more consequence, and where

  6. Some ethical implications of "adaptive" trials.

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    Petrini, C

    2015-01-01

    Adaptive trials are a new type of sequential trial, as yet not very widespread, in which each step can be modified on the basis of findings from the preceding step. In other words, the data accumulated during the study are used to modify the trial design. The potential of this type of trial is highly promising, especially for the development of therapies for rare diseases. The planning, conduct and management of data from adaptive trials are extremely complex processes and call for highly specialised skills. Without going into the merits of the experimental protocols, the aim of this article is to point out some ethical aspects that call for caution, as well as the need for ethics committees to be aware of the challenges posed by these trials.

  7. Adaptive responses to dasatinib-treated lung squamous cell cancer cells harboring DDR2 mutations.

    Science.gov (United States)

    Bai, Yun; Kim, Jae-Young; Watters, January M; Fang, Bin; Kinose, Fumi; Song, Lanxi; Koomen, John M; Teer, Jamie K; Fisher, Kate; Chen, Yian Ann; Rix, Uwe; Haura, Eric B

    2014-12-15

    DDR2 mutations occur in approximately 4% of lung squamous cell cancer (SCC) where the tyrosine kinase inhibitor dasatinib has emerged as a new therapeutic option. We found that ERK and AKT phosphorylation was weakly inhibited by dasatinib in DDR2-mutant lung SCC cells, suggesting that dasatinib inhibits survival signals distinct from other oncogenic receptor tyrosine kinases (RTK) and/or compensatory signals exist that dampen dasatinib activity. To gain better insight into dasatinib's action in these cells, we assessed altered global tyrosine phosphorylation (pY) after dasatinib exposure using a mass spectrometry-based quantitative phosphoproteomics approach. Overlaying protein-protein interaction relationships upon this dasatinib-regulated pY network revealed decreased phosphorylation of Src family kinases and their targets. Conversely, dasatinib enhanced tyrosine phosphorylation in a panel of RTK and their signaling adaptor complexes, including EGFR, MET/GAB1, and IGF1R/IRS2, implicating a RTK-driven adaptive response associated with dasatinib. To address the significance of this observation, these results were further integrated with results from a small-molecule chemical library screen. We found that dasatinib combined with MET and insulin-like growth factor receptor (IGF1R) inhibitors had a synergistic effect, and ligand stimulation of EGFR and MET rescued DDR2-mutant lung SCC cells from dasatinib-induced loss of cell viability. Importantly, we observed high levels of tyrosine-phosphorylated EGFR and MET in a panel of human lung SCC tissues harboring DDR2 mutations. Our results highlight potential RTK-driven adaptive-resistant mechanisms upon DDR2 targeting, and they suggest new, rationale cotargeting strategies for DDR2-mutant lung SCC.

  8. Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications.

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    Chaitanya R Churi

    Full Text Available Cholangiocarcinoma (CCA is clinically heterogeneous; intra and extrahepatic CCA have diverse clinical presentations. Next generation sequencing (NGS technology may identify the genetic differences between these entities and identify molecular subgroups for targeted therapeutics.We describe successful NGS-based testing of 75 CCA patients along with the prognostic and therapeutic implications of findings. Mutation profiling was performed using either a NGS panel of hotspot regions in 46 cancer-related genes using a 318-chip on Ion PGM Sequencer or b Illumina HiSeq 2000 sequencing platform for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X. Clinical data was abstracted and correlated with clinical outcome. Patients with targetable mutations were referred to appropriate clinical trials.There were significant differences between intrahepatic (n = 55 and extrahepatic CCA (n = 20 in regard to the nature and frequency of the genetic aberrations (GAs. IDH1 and DNA repair gene alterations occurred more frequently in intrahepatic CCA, while ERBB2 GAs occurred in the extrahepatic group. Commonly occurring GAs in intrahepatic CCA were TP53 (35%, KRAS (24%, ARID1A (20%, IDH1 (18%, MCL1 (16% and PBRM1 (11%. Most frequent GAs in extrahepatic CCA (n = 20 were TP53 (45%, KRAS (40%, ERBB2 (25%, SMAD4 (25%, FBXW7 (15% and CDKN2A (15%. In intrahepatic CCA, KRAS, TP53 or MAPK/mTOR GAs were significantly associated with a worse prognosis while FGFR GAs correlated with a relatively indolent disease course. IDH1 GAs did not have any prognostic significance. GAs in the chromatin modulating genes, BAP1 and PBRM1 were associated with bone metastases and worse survival in extrahepatic CCA. Radiologic responses and clinical benefit was noted with EGFR, FGFR, C-met, B-RAF and MEK inhibitors.There are significant genetic differences between intra and extrahepatic CCA. NGS can potentially identify disease subsets with distinct

  9. Experimental evolution, loss-of-function mutations, and "the first rule of adaptive evolution".

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    Behe, Michael J

    2010-12-01

    Adaptive evolution can cause a species to gain, lose, or modify a function; therefore, it is of basic interest to determine whether any of these modes dominates the evolutionary process under particular circumstances. Because mutation occurs at the molecular level, it is necessary to examine the molecular changes produced by the underlying mutation in order to assess whether a given adaptation is best considered as a gain, loss, or modification of function. Although that was once impossible, the advance of molecular biology in the past half century has made it feasible. In this paper, I review molecular changes underlying some adaptations, with a particular emphasis on evolutionary experiments with microbes conducted over the past four decades. I show that by far the most common adaptive changes seen in those examples are due to the loss or modification of a pre-existing molecular function, and I discuss the possible reasons for the prominence of such mutations.

  10. Adapting to Adaptations: Behavioural Strategies that are Robust to Mutations and Other Organisational-Transformations

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    Egbert, Matthew D.; Pérez-Mercader, Juan

    2016-01-01

    Genetic mutations, infection by parasites or symbionts, and other events can transform the way that an organism’s internal state changes in response to a given environment. We use a minimalistic computational model to support an argument that by behaving “interoceptively,” i.e. responding to internal state rather than to the environment, organisms can be robust to these organisational-transformations. We suggest that the robustness of interoceptive behaviour is due, in part, to the asymmetrical relationship between an organism and its environment, where the latter more substantially influences the former than vice versa. This relationship means that interoceptive behaviour can respond to the environment, the internal state and the interaction between the two, while exteroceptive behaviour can only respond to the environment. We discuss the possibilities that (i) interoceptive behaviour may play an important role of facilitating adaptive evolution (especially in the early evolution of primitive life) and (ii) interoceptive mechanisms could prove useful in efforts to create more robust synthetic life-forms. PMID:26743579

  11. Adapting to Adaptations: Behavioural Strategies that are Robust to Mutations and Other Organisational-Transformations.

    Science.gov (United States)

    Egbert, Matthew D; Pérez-Mercader, Juan

    2016-01-08

    Genetic mutations, infection by parasites or symbionts, and other events can transform the way that an organism's internal state changes in response to a given environment. We use a minimalistic computational model to support an argument that by behaving "interoceptively," i.e. responding to internal state rather than to the environment, organisms can be robust to these organisational-transformations. We suggest that the robustness of interoceptive behaviour is due, in part, to the asymmetrical relationship between an organism and its environment, where the latter more substantially influences the former than vice versa. This relationship means that interoceptive behaviour can respond to the environment, the internal state and the interaction between the two, while exteroceptive behaviour can only respond to the environment. We discuss the possibilities that (i) interoceptive behaviour may play an important role of facilitating adaptive evolution (especially in the early evolution of primitive life) and (ii) interoceptive mechanisms could prove useful in efforts to create more robust synthetic life-forms.

  12. Hypoxia adaptation and hemoglobin mutation in Tibetan chick embryo

    Institute of Scientific and Technical Information of China (English)

    GOU Xiao; LI Ning; LIAN Linsheng; YAN Dawei; ZHANG Hao; WU Changxin

    2005-01-01

    Tibetan chick lives at high altitudes between 2600 and 4200 m with a high hatchability and low land breeds survive rarely with a hatchability of 3.0% under hypoxia of simulated 4200 m. Under hypoxia of whole 21 d, the hatchability of Tibetan chick and Recessive White Feather broiler differed with a greatest disparity from day 4 to 11 and also significantly in other stages except from day 1 to 3. Hypoxia in each stage did not reduce significantly survival rate of this stage except hatchability. These two results indicated that the hypoxia in the early stage had an adverse effect on the later stage. All exons encoding chick hemoglobins were sequenced to analyze gene polymorphism. The functional mutation Met-32(B13)-Leu, related with hypoxia, was found in αD globin chain and the mutation frequency increased with increased altitude. In addition, under hypoxic conditions, the population with higher mutation frequency had a higher hatchability. The automated homology model building was carried out using crystal structure coordinates of chick HbD. The results indicated that the substitution Met-32(B13)-Leu provides a more hydrophobic environment which leads to higher stability of heme and oxygen affinity of hemoglobin. The occurrence of the mutation Met-32(B13)-Leu is related to the origin of Tibetan chick.

  13. Evolution and adaptation in Pseudomonas aeruginosa biofilms driven by mismatch repair system-deficient mutators.

    Directory of Open Access Journals (Sweden)

    Adela M Luján

    Full Text Available Pseudomonas aeruginosa is an important opportunistic pathogen causing chronic airway infections, especially in cystic fibrosis (CF patients. The majority of the CF patients acquire P. aeruginosa during early childhood, and most of them develop chronic infections resulting in severe lung disease, which are rarely eradicated despite intensive antibiotic therapy. Current knowledge indicates that three major adaptive strategies, biofilm development, phenotypic diversification, and mutator phenotypes [driven by a defective mismatch repair system (MRS], play important roles in P. aeruginosa chronic infections, but the relationship between these strategies is still poorly understood. We have used the flow-cell biofilm model system to investigate the impact of the mutS associated mutator phenotype on development, dynamics, diversification and adaptation of P. aeruginosa biofilms. Through competition experiments we demonstrate for the first time that P. aeruginosa MRS-deficient mutators had enhanced adaptability over wild-type strains when grown in structured biofilms but not as planktonic cells. This advantage was associated with enhanced micro-colony development and increased rates of phenotypic diversification, evidenced by biofilm architecture features and by a wider range and proportion of morphotypic colony variants, respectively. Additionally, morphotypic variants generated in mutator biofilms showed increased competitiveness, providing further evidence for mutator-driven adaptive evolution in the biofilm mode of growth. This work helps to understand the basis for the specific high proportion and role of mutators in chronic infections, where P. aeruginosa develops in biofilm communities.

  14. Evolution and adaptation in Pseudomonas aeruginosa biofilms driven by mismatch repair system-deficient mutators.

    Science.gov (United States)

    Luján, Adela M; Maciá, María D; Yang, Liang; Molin, Søren; Oliver, Antonio; Smania, Andrea M

    2011-01-01

    Pseudomonas aeruginosa is an important opportunistic pathogen causing chronic airway infections, especially in cystic fibrosis (CF) patients. The majority of the CF patients acquire P. aeruginosa during early childhood, and most of them develop chronic infections resulting in severe lung disease, which are rarely eradicated despite intensive antibiotic therapy. Current knowledge indicates that three major adaptive strategies, biofilm development, phenotypic diversification, and mutator phenotypes [driven by a defective mismatch repair system (MRS)], play important roles in P. aeruginosa chronic infections, but the relationship between these strategies is still poorly understood. We have used the flow-cell biofilm model system to investigate the impact of the mutS associated mutator phenotype on development, dynamics, diversification and adaptation of P. aeruginosa biofilms. Through competition experiments we demonstrate for the first time that P. aeruginosa MRS-deficient mutators had enhanced adaptability over wild-type strains when grown in structured biofilms but not as planktonic cells. This advantage was associated with enhanced micro-colony development and increased rates of phenotypic diversification, evidenced by biofilm architecture features and by a wider range and proportion of morphotypic colony variants, respectively. Additionally, morphotypic variants generated in mutator biofilms showed increased competitiveness, providing further evidence for mutator-driven adaptive evolution in the biofilm mode of growth. This work helps to understand the basis for the specific high proportion and role of mutators in chronic infections, where P. aeruginosa develops in biofilm communities.

  15. Enhancement of the safety of live influenza vaccine by attenuating mutations from cold-adapted hemagglutinin

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Yoon Jae [Graduate Program in Biomaterials Science and Engineering, College of Life Science and Biotechnology, Yonsei University, Seoul (Korea, Republic of); Laboratory of Molecular Medicine, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul (Korea, Republic of); Vaccine Translational Research Center, Yonsei University, Seoul (Korea, Republic of); Jang, Yo Han [Laboratory of Molecular Medicine, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul (Korea, Republic of); Kim, Paul; Lee, Yun Ha; Lee, Young Jae [Laboratory of Molecular Medicine, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul (Korea, Republic of); Vaccine Translational Research Center, Yonsei University, Seoul (Korea, Republic of); Byun, Young Ho; Lee, Kwang-Hee; Kim, Kyusik [Laboratory of Molecular Medicine, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul (Korea, Republic of); Seong, Baik Lin, E-mail: blseong@yonsei.ac.kr [Graduate Program in Biomaterials Science and Engineering, College of Life Science and Biotechnology, Yonsei University, Seoul (Korea, Republic of); Laboratory of Molecular Medicine, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul (Korea, Republic of); Vaccine Translational Research Center, Yonsei University, Seoul (Korea, Republic of)

    2016-04-15

    In our previous study, X-31ca-based H5N1 LAIVs, in particular, became more virulent in mice than the X-31ca MDV, possibly by the introduction of the surface antigens of highly pathogenic H5N1 influenza virus, implying that additional attenuation is needed in this cases to increase the safety level of the vaccine. In this report we suggest an approach to further increase the safety of LAIV through additional cold-adapted mutations in the hemagglutinin. The cold-adaptation of X-31 virus resulted in four amino acid mutations in the HA. We generated a panel of 7:1 reassortant viruses each carrying the hemagglutinins with individual single amino acid mutations. We examined their phenotypes and found a major attenuating mutation, N81K. This attenuation marker conferred additional temperature-sensitive and attenuation phenotype to the LAIV. Our data indicate that the cold-adapted mutation in the HA confers additional attenuation to the LAIV strain, without compromising its productivity and immune response. - Highlights: • Cold-adaptation process induced four amino acid mutations in the HA of X-31 virus. • The four mutations in the HA also contributed to attenuation of the X-31ca virus • N81K mutation was the most significant marker for the attenuation of X-31ca virus. • Introduction of N81K mutation into H3N2 LAIV further attenuated the vaccine. • This approach provides a useful guideline for enhancing the safety of the LAIVs.

  16. Mutational effects and population dynamics during viral adaptation challenge current models.

    Science.gov (United States)

    Miller, Craig R; Joyce, Paul; Wichman, Holly A

    2011-01-01

    Adaptation in haploid organisms has been extensively modeled but little tested. Using a microvirid bacteriophage (ID11), we conducted serial passage adaptations at two bottleneck sizes (10(4) and 10(6)), followed by fitness assays and whole-genome sequencing of 631 individual isolates. Extensive genetic variation was observed including 22 beneficial, several nearly neutral, and several deleterious mutations. In the three large bottleneck lines, up to eight different haplotypes were observed in samples of 23 genomes from the final time point. The small bottleneck lines were less diverse. The small bottleneck lines appeared to operate near the transition between isolated selective sweeps and conditions of complex dynamics (e.g., clonal interference). The large bottleneck lines exhibited extensive interference and less stochasticity, with multiple beneficial mutations establishing on a variety of backgrounds. Several leapfrog events occurred. The distribution of first-step adaptive mutations differed significantly from the distribution of second-steps, and a surprisingly large number of second-step beneficial mutations were observed on a highly fit first-step background. Furthermore, few first-step mutations appeared as second-steps and second-steps had substantially smaller selection coefficients. Collectively, the results indicate that the fitness landscape falls between the extremes of smooth and fully uncorrelated, violating the assumptions of many current mutational landscape models.

  17. Glucose starvation as a selective tool for the study of adaptive mutations in Saccharomyces cerevisiae.

    Science.gov (United States)

    Heidenreich, Erich; Steinboeck, Ferdinand

    2017-01-01

    Mutations not only arise in proliferating cells but also in resting - thus non-replicating - cells. Such stationary-phase mutations may occasionally enable an escape from growth repression and e.g. contribute to cancerogenesis or development of drug resistance. The most widely used condition for the study of such adaptive mutations in the eukaryotic model organism Saccharomyces cerevisiae is the starvation for a single amino acid. To overcome some limitations of this experimental setup we developed a new adaptive mutation assay that allows a screening for mutagenic processes during a more regular cell cycle arrest induced by the lack of a fermentable carbon source. We blocked one essential step of gluconeogenesis by inactivation of the FBP1 gene. This drives the cells into a cell cycle arrest when glucose is not available in the medium although a non-fermentable carbon source is present. As another component of the new mutation assay, we established a custom-designed test allele that contains a microsatellite sequence as a target for mutations. We demonstrated the feasibility and validity of this novel experimental setup by the observation and characterization of adaptive mutants.

  18. Implications of mitochondrial DNA mutations and mitochondrial dysfunction in tumorigenesis

    Institute of Scientific and Technical Information of China (English)

    Jianxin Lu; Lokendra Kumar Sharma; Yidong Bai

    2009-01-01

    Alterations in oxidative phosphorylation resulting from mitochondrial dysfunction have long been hypothesized to be involved in tumorigenesis. Mitochondria have recently been shown to play an important role in regulating both programmed cell death and cell proliferation. Furthermore, mitochondrial DNA (mtDNA) mutations have been found in various cancer cells. However, the role of these mtDNA mutations in tumorigenesis remains largely unknown. This review focuses on basic mitochondrial genetics, mtDNA mutations and consequential mitochondrial dysfunction associated with cancer. The potential molecular mechanisms, mediating the pathogenesis from mtDNA mutations and mitochondrial dysfunction to tumorigenesis are also discussed.

  19. Cooperativity of adaptive and innate immunity: implications for cancer therapy

    Science.gov (United States)

    Marincola, Francesco M.

    2012-01-01

    The dichotomy of immunology into innate and adaptive immunity has created conceptual barriers in appreciating the intrinsic two-way interaction between immune cells. An emerging body of evidence in various models of immune rejection, including cancer, indicates an indispensable regulation of innate effector functions by adaptive immune cells. This bidirectional cooperativity in innate and adaptive immune functions has broad implications for immune responses in general and for regulating the tumor-associated inflammation that overrides the protective antitumor immunity. Mechanistic understanding of this two-way immune cross-talk could provide insights into novel strategies for designing better immunotherapy approaches against cancer and other diseases that normally defy immune control. PMID:21656157

  20. Pyrosequencing for EGFR mutation detection: diagnostic accuracy and clinical implications.

    Science.gov (United States)

    Sahnane, Nora; Gueli, Rossana; Tibiletti, Maria G; Bernasconi, Barbara; Stefanoli, Michele; Franzi, Francesca; Pinotti, Graziella; Capella, Carlo; Furlan, Daniela

    2013-12-01

    EGFR-activating mutations predict responsiveness to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients. Mutation screening is crucial to support therapeutic decisions and is commonly conducted using dideoxy sequencing, although its sensitivity is suboptimal in clinical settings. To evaluate the diagnostic performance of pyrosequencing and dideoxy sequencing, we examined EGFR mutation status in a retrospective cohort of 53 patients with NSCLCs clinically selected for TKI therapy and whose clinical outcome was available. Moreover, pyrosequencing quantitative results were compared with EGFR amplification data. EGFR mutations were investigated by pyrosequencing and by dideoxy sequencing. Detection rates of both methods were determined by titration assays using NCI-H1975 and HCC-827 cell lines. Increased EGFR copy number was assessed by fluorescence in situ hybridization (FISH). Pyrosequencing showed a higher detection rate than dideoxy sequencing. Tumor control rate of cases with mutant and wild-type EGFR was 86% and 29%, respectively. EGFR amplification was significantly associated with EGFR mutation and a positive correlation between high percentages of mutant alleles and clinical response to TKI was observed. We concluded that pyrosequencing is more sensitive than dideoxy sequencing in mutation screening for EGFR mutations. Detection rate of dideoxy sequencing was suboptimal when low frequencies of mutant alleles or low tumor cell contents were observed. Pyrosequencing enables quantification of mutant alleles that correlates well with increased EGFR copy number assessed by FISH. Pyrosequencing should be used in molecular diagnostic of NSCLC to appropriately select patients who are likely to benefit from TKI therapy.

  1. Impact of individual mutations on increased fitness in adaptively evolved strains of Escherichia coli.

    Science.gov (United States)

    Applebee, M Kenyon; Herrgård, Markus J; Palsson, Bernhard Ø

    2008-07-01

    We measured the relative fitness among a set of experimentally evolved Escherichia coli strains differing by a small number of adaptive mutations by directly measuring allelic frequencies in head-to-head competitions using a mass spectrometry-based method. We compared the relative effects of mutations to the same or similar genes acquired in multiple strains when expressed in allele replacement strains. We found that the strongest determinant of fitness among the evolved strains was the impact of beneficial mutations to the RNA polymerase beta and beta' subunit genes. We also identified several examples of epistatic interactions between rpoB/C and glpK mutations and identified two other mutations that are beneficial only in the presence of previously acquired mutations but that have little or no adaptive benefit to the wild-type strain. Allele frequency estimation is shown to be a highly sensitive method for measuring selection rates during competitions between strains differing by as little as a single-nucleotide polymorphism and may be of great use for investigating epistatic interactions.

  2. The sequence spectrum of frameshift reversions obtained with a novel adaptive mutation assay in Saccharomyces cerevisiae

    Directory of Open Access Journals (Sweden)

    Erich Heidenreich

    2016-12-01

    Full Text Available Research on the mechanisms of adaptive mutagenesis in resting, i.e. non-replicating cells relies on appropriate mutation assays. Here we provide a novel procedure for the detection of frameshift-reverting mutations in yeast. Proliferation of non-reverted cells in this assay is suppressed by the lack of a fermentable carbon source. The test allele was constructed in a way that the reversions mimic microsatellite instability, a condition often found in cancer cells. We show the cell numbers during these starvation conditions and provide a DNA sequence spectrum of a representative set of revertants. The data in this article support the publication "Glucose starvation as a selective tool for the study of adaptive mutations in Saccharomyces cerevisiae" (Heidenreich and Steinboeck, 2016 [1].

  3. Potential clinical implications of BRAF mutations in histiocytic proliferations

    Science.gov (United States)

    Bubolz, Anna-Maria; Weissinger, Stephanie E.; Stenzinger, Albrecht; Arndt, Annette; Steinestel, Konrad; Brüderlein, Silke; Cario, Holger; Lubatschofski, Anneli; Welke, Claudia; Anagnostopoulos, Ioannis; Barth, Thomas F. E.; Beer, Ambros J.; Möller, Peter; Gottstein, Martin

    2014-01-01

    For a growing number of tumors the BRAF V600E mutation carries therapeutic relevance. In histiocytic proliferations the distribution of BRAF mutations and their relevance has not been clarified. Here we present a retrospective genotyping study and a prospective observational study of a patient treated with a BRAF inhibitor. Genotyping of 69 histiocytic lesions revealed that 23/48 Langerhans cell lesions were BRAF-V600E-mutant whereas all non-Langerhans cell lesions (including dendritic cell sarcoma, juvenile xanthogranuloma, Rosai-Dorfman disease, and granular cell tumor) were wild-type. A metareview of 29 publications showed an overall mutation frequency of 48.5%; and with N=653 samples, this frequency is well defined. The BRAF mutation status cannot be predicted based on clinical parameters and outcome analysis showed no difference. Genotyping identified a 45 year-old woman with an aggressive and treatment-refractory, ultrastructurally confirmed systemic BRAF-mutant LCH. Prior treatments included glucocorticoid/vinblastine and cladribine-monotherapy. Treatment with vemurafenib over 3 months resulted in a dramatic metabolic response by FDG-PET and stable radiographic disease; the patient experienced progression after 6 months. In conclusion, BRAF mutations in histiocytic proliferations are restricted to lesions of the Langerhans-cell type. While for most LCH-patients efficient therapies are available, patients with BRAF mutations may benefit from the BRAF inhibitor vemurafenib. PMID:24938183

  4. BRCA mutation genetic testing implications in the United States.

    Science.gov (United States)

    Bayraktar, Soley; Arun, Banu

    2017-02-01

    BRCA mutation carriers have a very high risk of breast and ovarian cancer by age 70, in the ranges 47%-66% and 40%-57%, respectively. Additionally, women with BRCA mutation-associated breast cancer also have an elevated risk of other or secondary malignancies. Fortunately, the breast and ovarian cancer outcome for BRCA1/2 mutation carriers is at least as good as for non-carriers with chemoprevention, prophylactic surgeries and appropriate use of therapies. Therefore, identification of those who might have a mutation is important so that genetic counseling, testing, screening and prevention strategies can be applied in a timely manner. This article reviews the impact of genetic testing in general, timing of genetic testing after diagnosis and prior knowledge of mutation status in BRCA carriers with newly diagnosed breast cancer. Additionally, risk-reducing surgeries including the prophylactic contralateral mastectomy, and bilateral salpingo-oophorectomy and the sensitivity of BRCA-defective breast cancer cell lines to differential chemotherapeutic agents will be discussed.

  5. Fisher's model and the genomics of adaptation: restricted pleiotropy, heterogenous mutation, and parallel evolution.

    Science.gov (United States)

    Chevin, Luis-Miguel; Martin, Guillaume; Lenormand, Thomas

    2010-11-01

    Genetic theories of adaptation generally overlook the genes in which beneficial substitutions occur, and the likely variation in their mutational effects. We investigate the consequences of heterogeneous mutational effects among loci on the genetics of adaptation. We use a generalization of Fisher's geometrical model, which assumes multivariate Gaussian stabilizing selection on multiple characters. In our model, mutation has a distinct variance-covariance matrix of phenotypic effects for each locus. Consequently, the distribution of selection coefficients s varies across loci. We assume each locus can only affect a limited number of independent linear combinations of phenotypic traits (restricted pleiotropy), which differ among loci, an effect we term "orientation heterogeneity." Restricted pleiotropy can sharply reduce the overall proportion of beneficial mutations. Orientation heterogeneity has little impact on the shape of the genomic distribution, but can substantially increase the probability of parallel evolution (the repeated fixation of beneficial mutations at the same gene in independent populations), which is highest with low pleiotropy. We also consider variation in the degree of pleiotropy and in the mean s across loci. The latter impacts the genomic distribution of s, but has a much milder effect on parallel evolution. We discuss these results in the light of evolution experiments. © 2010 The Author(s). Evolution© 2010 The Society for the Study of Evolution.

  6. Novel Genetic Diversity Through Somatic Mutations: Fuel for Adaptation of Reef Corals?

    Directory of Open Access Journals (Sweden)

    Emily J. Howells

    2011-08-01

    Full Text Available Adaptation of reef corals to climate change is an issue of much debate, and often viewed as too slow a process to be of relevance over decadal time scales. This notion is based on the long sexual generation times typical for some coral species. However, the importance of somatic mutations during asexual reproduction and growth on evolution and adaptation (i.e., cell lineage selection is rarely considered. Here we review the existing literature on cell lineage selection and show that the scope for somatic mutations to arise in the coral animal and associated Symbiodinium is large. For example, we estimate that ~100 million somatic mutations can arise within a branching Acropora coral colony of average size. Similarly, the large population sizes and rapid turn-over times of in hospite Symbiodinium likely result in considerable numbers of somatic mutations. While the fate of new mutations depends on many factors, including ploidy level and force and direction of selection, we argue that they likely play a key role in the evolution of reef corals.

  7. Mutational analysis of the PRYSPRY domain of pyrin and implications for familial mediterranean fever (FMF).

    Science.gov (United States)

    Goulielmos, G N; Fragouli, E; Aksentijevich, I; Sidiropoulos, P; Boumpas, D T; Eliopoulos, E

    2006-07-14

    Familial Mediterranean fever (FMF) is an autosomal, recessively inherited disease, characterized by recurrent fever and serositis that affects mainly patients of the Mediterranean basin. The gene responsible for FMF, named MEFV, was cloned and several missense mutations were found to be responsible for the disease. Based on a recent molecular analysis of MEFV gene mutations in 43 patients from Crete aiming to correlate specific genotypes and clinical manifestations of FMF, we were prompted to construct a three-dimensional model (3-D model) of the PRYSPRY domain of pyrin. The majority of the known MEFV mutations located on this domain have been classified, according to disease severity, and localized on this 3-D model. The functional consequences of these mutations and their implications on disease severity are discussed. Moreover, we report a putative novel missense mutation, S702C, which we identified in exon 10 of the MEFV gene and localized on the constructed 3-D model.

  8. Evolution and Adaptation in Pseudomonas aeruginosa Biofilms Driven by Mismatch Repair System-Deficient Mutators

    DEFF Research Database (Denmark)

    Luján, Adela M.; Maciá, María D.; Yang, Liang

    2011-01-01

    Pseudomonas aeruginosa is an important opportunistic pathogen causing chronic airway infections, especially in cystic fibrosis (CF) patients. The majority of the CF patients acquire P. aeruginosa during early childhood, and most of them develop chronic infections resulting in severe lung disease......, which are rarely eradicated despite intensive antibiotic therapy. Current knowledge indicates that three major adaptive strategies, biofilm development, phenotypic diversification, and mutator phenotypes [driven by a defective mismatch repair system (MRS)], play important roles in P. aeruginosa chronic...... infections, but the relationship between these strategies is still poorly understood. We have used the flow-cell biofilm model system to investigate the impact of the mutS associated mutator phenotype on development, dynamics, diversification and adaptation of P. aeruginosa biofilms. Through competition...

  9. Agammaglobulinemia: causative mutations and their implications for novel therapies.

    Science.gov (United States)

    Berglöf, Anna; Turunen, Janne J; Gissberg, Olof; Bestas, Burcu; Blomberg, K Emelie M; Smith, C I Edvard

    2013-12-01

    Agammaglobulinemias are primary (inherited) immunodeficiencies characterized by the lack of functional B-cells and antibodies, and are caused by mutations in genes encoding components of the pre-B-cell or B-cell receptor, or their signaling pathways. The known genetic defects do not account for all agammaglobulinemic patients, suggesting that novel mutations underlying the disease remain to be found. While efficient, the current life-maintaining therapy with immunoglobulins and antibiotics is non-curative, prompting research into alternative treatment strategies that aim at rescuing the expression of the affected protein, thus giving rise to functional B-cells. These include gene therapy, which could be used to correct the defective gene or replace it with a functional copy. For a number of genetic defects, another alternative is to modulate the splicing of the affected transcripts. While these technologies are not yet ready for clinical trials in agammaglobulinemia, advances in genomic targeting are likely to make this option viable in the near future.

  10. Differential Evolution with Adaptive Mutation and Parameter Control Using Lévy Probability Distribution

    Institute of Scientific and Technical Information of China (English)

    Ren-Jie He; Zhen-Yu Yang

    2012-01-01

    Differential evolution (DE) has become a very popular and effective global optimization algorithm in the area of evolutionary computation.In spite of many advantages such as conceptual simplicity,high efficiency and ease of use,DE has two main components,i.e.,mutation scheme and parameter control,which significantly influence its performance.In this paper we intend to improve the performance of DE by using carefully considered strategies for both of the two components.We first design an adaptive mutation scheme,which adaptively makes use of the bias of superior individuals when generating new solutions.Although introducing such a bias is not a new idea,existing methods often use heuristic rules to control the bias.They can hardly maintain the appropriate balance between exploration and exploitation during the search process,because the preferred bias is often problem and evolution-stage dependent.Instead of using any fixed rule,a novel strategy is adopted in the new adaptive mutation scheme to adjust the bias dynamically based on the identified local fitness landscape captured by the current population.As for the other component,i.e.,parameter control,we propose a mechanism by using the Lévy probability distribution to adaptively control the scale factor F of DE.For every mutation in each generation,an Fi is produced from one of four different Lévy distributions according to their historical performance.With the adaptive mutation scheme and parameter control using Lévy distribution as the main components,we present a new DE variant called Lévy DE (LDE).Experimental studies were carried out on a broad range of benchmark functions in global numerical optimization.The results show that LDE is very competitive,and both of the two main components have contributed to its overall performance.The scalability of LDE is also discussed by conducting experiments on some selected benchmark functions with dimensions from 30 to 200.

  11. Global Rebalancing of Cellular Resources by Pleiotropic Point Mutations Illustrates a Multi-scale Mechanism of Adaptive Evolution

    DEFF Research Database (Denmark)

    Utrilla, José; O'Brien, Edward J.; Chen, Ke

    2016-01-01

    Pleiotropic regulatory mutations affect diverse cellular processes, posing a challenge to our understanding of genotype-phenotype relationships across multiple biological scales. Adaptive laboratory evolution (ALE) allows for such mutations to be found and characterized in the context of clear se......, they share a common adaptive mechanism. In turn, these findings highlight the resource allocation trade-offs organisms face and suggest how the structure of the regulatory network enhances evolvability.......Pleiotropic regulatory mutations affect diverse cellular processes, posing a challenge to our understanding of genotype-phenotype relationships across multiple biological scales. Adaptive laboratory evolution (ALE) allows for such mutations to be found and characterized in the context of clear...... to stress and environmental fluctuations. We detail structural changes in the RNAP that rewire the transcriptional machinery to rebalance proteome and energy allocation toward growth and away from several hedging and stress functions. We find that while these mutations occur in diverse locations in the RNAP...

  12. Functional Characterization of Adaptive Mutations during the West African Ebola Virus Outbreak.

    Science.gov (United States)

    Dietzel, Erik; Schudt, Gordian; Krähling, Verena; Matrosovich, Mikhail; Becker, Stephan

    2017-01-15

    The Ebola virus (EBOV) outbreak in West Africa started in December 2013, claimed more than 11,000 lives, threatened to destabilize a whole region, and showed how easily health crises can turn into humanitarian disasters. EBOV genomic sequences of the West African outbreak revealed nonsynonymous mutations, which induced considerable public attention, but their role in virus spread and disease remains obscure. In this study, we investigated the functional significance of three nonsynonymous mutations that emerged early during the West African EBOV outbreak. Almost 90% of more than 1,000 EBOV genomes sequenced during the outbreak carried the signature of three mutations: a D759G substitution in the active center of the L polymerase, an A82V substitution in the receptor binding domain of surface glycoprotein GP, and an R111C substitution in the self-assembly domain of RNA-encapsidating nucleoprotein NP. Using a newly developed virus-like particle system and reverse genetics, we found that the mutations have an impact on the functions of the respective viral proteins and on the growth of recombinant EBOVs. The mutation in L increased viral transcription and replication, whereas the mutation in NP decreased viral transcription and replication. The mutation in the receptor binding domain of the glycoprotein GP improved the efficiency of GP-mediated viral entry into target cells. Recombinant EBOVs with combinations of the three mutations showed a growth advantage over the prototype isolate Makona C7 lacking the mutations. This study showed that virus variants with improved fitness emerged early during the West African EBOV outbreak. The dimension of the Ebola virus outbreak in West Africa was unprecedented. Amino acid substitutions in the viral L polymerase, surface glycoprotein GP, and nucleocapsid protein NP emerged, were fixed early in the outbreak, and were found in almost 90% of the sequences. Here we showed that these mutations affected the functional activity of

  13. Rapid adaptation of some phytoplankton species to osmium as a result of spontaneous mutations.

    Science.gov (United States)

    Marvá, Fernando; García-Balboa, Camino; Baselga-Cervera, Beatriz; Costas, Eduardo

    2014-03-01

    To understand the vulnerability of individual species to anthropogenic contamination, it is important to evaluate the different abilities of phytoplankton to respond to environmental changes induced by pollution. The ability of a species to adapt, rather than its initial tolerance, is the basis for survival under rapidly increasing levels of anthropogenic contamination. High doses of osmium (Os) cause massive destruction of diverse phytoplankton groups. In this study, we found that the coastal chlorophyte Tetraselmis suecica and the continental chlorophyte Dictyosphaerium chlorelloides were able to adapt to a lethal dose of Os. In these species, Os-resistant cells arose as a result of rare spontaneous mutations (at rates of approximately 10(-6) mutants per cell division) that occurred before exposure to Os. The mutants remained in the microalgal populations by means of mutation-selection balance. The huge size of phytoplankton populations ensures that there are always enough Os-resistant mutants to guarantee the survival of the population under Os pollution. In contrast, we observed that neither a haptophyte species from open ocean regions nor a cyanobacterium from continental freshwater were able to adapt to the lethal Os dose. Adaptation of phytoplankton to Os contamination is relevant because industrial activities are leading to a rapid increase in Os pollution worldwide.

  14. Tourism and climate change: socioeconomic implications, mitigation and adaptation measures

    Directory of Open Access Journals (Sweden)

    Utsab Bhattarai

    2015-06-01

    Full Text Available The relationship between tourism and changing climate has been discussed and studied for a relatively long time in tourism research. Over the past 15 years, more focused studies have begun to appear, and especially recently, the issue of adaptation and mitigation has been emphasized as an urgent research need in tourism and climate change studies. This paper is based on the review of selected articles which discuss the several forms of tourism and climate change and provide recommendations for mitigation and adaptation measures. This review paper assesses the impacts of climate change on the popular forms of tourism such as; mountain tourism, wildlife tourism, adventure tourism, sun/sand tourism; last chance tourism, and describes the extent of tourism vulnerabilities and their implications. The paper concludes that the appropriate adaptation and mitigation measures have to be followed to minimize the risk of climate change while trying to save all forms of tourism. The initiative of this article is to present an overview of the existing literature on the relationship between tourism and climate change in order to establish the current state of corporate and institutional responses within the tourism industry and to set out an agenda for future research. The currency of the review is evident given the recent surge in popular discussion on climate change and its effects on tourism, and the appearance of a broad and disparate array of studies on this topic. DOI: http://dx.doi.org/10.3126/ije.v4i2.12664 International Journal of Environment Vol.4(2 2015: 355-373

  15. Extended adaptive mutation operator for training an explosive hazard detection prescreener in forward looking infrared imagery

    Science.gov (United States)

    Singh, Ravinder; Price, Stanton R.; Anderson, Derek T.

    2015-05-01

    A big challenge with forward looking (FL), versus downward looking, sensors mounted on a ground vehicle for explosive hazard detection (EHD) is they "see everything", on and off road. Even if a technology such as road detection is used, we still have to find and subsequently discriminate targets versus clutter on the road and often road side. When designing an automatic detection system for FL-EHD, we typically make use of a prescreener to identify regions of interest (ROI) instead of searching for targets in an inefficient brute force fashion by extracting complicated features and running expensive classifiers at every possible translation, rotation and scale. In this article, we explore the role of genetic algorithms (GAs), specifically with respect to a new adaptive mutation operator, for learning the parameters of a FL-EHD prescreener in FL infrared (FLIR) imagery. The proposed extended adaptive mutation (eAM) algorithm is driven by fitness similarities in the chromosome population. Currently, our prescreener consists of many free parameters that are empirically chosen by a researcher. The parameters are learned herein using the proposed optimization technique and the performance of the system is measured using receiver operating characteristic (ROC) curves on data obtained from a U.S. Army test site that includes a variety of target types buried at varying depths and from different times of day. The proposed technique is also applied to numerous synthetic fitness landscapes to further assess the effectiveness of the eAM algorithm. Results show that the new adaptive mutation technique converges faster to a better solution than a GA with fixed mutation.

  16. Genetic mutations in early-onset Parkinson's disease Mexican patients: molecular testing implications.

    Science.gov (United States)

    Monroy-Jaramillo, Nancy; Guerrero-Camacho, Jorge Luis; Rodríguez-Violante, Mayela; Boll-Woehrlen, Marie-Catherine; Yescas-Gómez, Petra; Alonso-Vilatela, María Elisa; López-López, Marisol

    2014-04-01

    Mutations in PARK2, PINK1, and DJ-1 have been associated with autosomal recessive early-onset Parkinson's disease. Here, we report the prevalence of sequence and structural mutations in these three main recessive genes in Mexican Mestizo patients. The complete sequences of these three genes were analyzed by homo/heteroduplex DNA formation and direct sequencing; exon dosage was determined by multiplex ligation-dependent probe amplification and real-time PCR in 127 patients belonging to 122 families and 120 healthy Mexican Mestizo controls. All individuals had been previously screened for the three most common LRRK2 mutations. The presence of two mutations in compound heterozygous or homozygous genotypes was found in 16 unrelated patients, 10 had mutations in PARK2, six in PINK1, and none in DJ-1. Two PARK2-PINK1 and one PARK2-LRRK2 digenic cases were observed. Novel mutations were identified in PARK2 and PINK1 genes, including PINK1 duplication for the first time. Exon dosage deletions were the most frequent mutations in PARK2 (mainly in exons 9 and 12), followed by those in PINK1. The high prevalence of heterozygous mutations in PARK2 (12.3%) and the novel heterozygous and homozygous point mutations in PINK1 observed in familial and sporadic cases from various states of Mexico support the concept that single heterozygous mutations in recessive Parkinson's disease genes play a pathogenic role. These data have important implications for genetic counseling of Mexican Mestizo patients with early-onset Parkinson's disease. The presence of digenic inheritance underscores the importance of studying several genes in this disease. A step-ordered strategy for molecular diagnosis is proposed.

  17. Multifunctional adaptive NS1 mutations are selected upon human influenza virus evolution in the mouse.

    Directory of Open Access Journals (Sweden)

    Nicole E Forbes

    Full Text Available The role of the NS1 protein in modulating influenza A virulence and host range was assessed by adapting A/Hong Kong/1/1968 (H3N2 (HK-wt to increased virulence in the mouse. Sequencing the NS genome segment of mouse-adapted variants revealed 11 mutations in the NS1 gene and 4 in the overlapping NEP gene. Using the HK-wt virus and reverse genetics to incorporate mutant NS gene segments, we demonstrated that all NS1 mutations were adaptive and enhanced virus replication (up to 100 fold in mouse cells and/or lungs. All but one NS1 mutant was associated with increased virulence measured by survival and weight loss in the mouse. Ten of twelve NS1 mutants significantly enhanced IFN-β antagonism to reduce the level of IFN β production relative to HK-wt in infected mouse lungs at 1 day post infection, where 9 mutants induced viral yields in the lung that were equivalent to or significantly greater than HK-wt (up to 16 fold increase. Eight of 12 NS1 mutants had reduced or lost the ability to bind the 30 kDa cleavage and polyadenylation specificity factor (CPSF30 thus demonstrating a lack of correlation with reduced IFN β production. Mutant NS1 genes resulted in increased viral mRNA transcription (10 of 12 mutants, and protein production (6 of 12 mutants in mouse cells. Increased transcription activity was demonstrated in the influenza mini-genome assay for 7 of 11 NS1 mutants. Although we have shown gain-of-function properties for all mutant NS genes, the contribution of the NEP mutations to phenotypic changes remains to be assessed. This study demonstrates that NS1 is a multifunctional virulence factor subject to adaptive evolution.

  18. An adaptive differential evolution algorithm with novel mutation and crossover strategies for global numerical optimization.

    Science.gov (United States)

    Islam, Sk Minhazul; Das, Swagatam; Ghosh, Saurav; Roy, Subhrajit; Suganthan, Ponnuthurai Nagaratnam

    2012-04-01

    Differential evolution (DE) is one of the most powerful stochastic real parameter optimizers of current interest. In this paper, we propose a new mutation strategy, a fitness-induced parent selection scheme for the binomial crossover of DE, and a simple but effective scheme of adapting two of its most important control parameters with an objective of achieving improved performance. The new mutation operator, which we call DE/current-to-gr_best/1, is a variant of the classical DE/current-to-best/1 scheme. It uses the best of a group (whose size is q% of the population size) of randomly selected solutions from current generation to perturb the parent (target) vector, unlike DE/current-to-best/1 that always picks the best vector of the entire population to perturb the target vector. In our modified framework of recombination, a biased parent selection scheme has been incorporated by letting each mutant undergo the usual binomial crossover with one of the p top-ranked individuals from the current population and not with the target vector with the same index as used in all variants of DE. A DE variant obtained by integrating the proposed mutation, crossover, and parameter adaptation strategies with the classical DE framework (developed in 1995) is compared with two classical and four state-of-the-art adaptive DE variants over 25 standard numerical benchmarks taken from the IEEE Congress on Evolutionary Computation 2005 competition and special session on real parameter optimization. Our comparative study indicates that the proposed schemes improve the performance of DE by a large magnitude such that it becomes capable of enjoying statistical superiority over the state-of-the-art DE variants for a wide variety of test problems. Finally, we experimentally demonstrate that, if one or more of our proposed strategies are integrated with existing powerful DE variants such as jDE and JADE, their performances can also be enhanced.

  19. Novel Polymerase Gene Mutations for Human Adaptation in Clinical Isolates of Avian H5N1 Influenza Viruses.

    Science.gov (United States)

    Arai, Yasuha; Kawashita, Norihito; Daidoji, Tomo; Ibrahim, Madiha S; El-Gendy, Emad M; Takagi, Tatsuya; Takahashi, Kazuo; Suzuki, Yasuo; Ikuta, Kazuyoshi; Nakaya, Takaaki; Shioda, Tatsuo; Watanabe, Yohei

    2016-04-01

    A major determinant in the change of the avian influenza virus host range to humans is the E627K substitution in the PB2 polymerase protein. However, the polymerase activity of avian influenza viruses with a single PB2-E627K mutation is still lower than that of seasonal human influenza viruses, implying that avian viruses require polymerase mutations in addition to PB2-627K for human adaptation. Here, we used a database search of H5N1 clade 2.2.1 virus sequences with the PB2-627K mutation to identify other polymerase adaptation mutations that have been selected in infected patients. Several of the mutations identified acted cooperatively with PB2-627K to increase viral growth in human airway epithelial cells and mouse lungs. These mutations were in multiple domains of the polymerase complex other than the PB2-627 domain, highlighting a complicated avian-to-human adaptation pathway of avian influenza viruses. Thus, H5N1 viruses could rapidly acquire multiple polymerase mutations that function cooperatively with PB2-627K in infected patients for optimal human adaptation.

  20. Role of epistasis on the fixation probability of a non-mutator in an adapted asexual population.

    Science.gov (United States)

    James, Ananthu

    2016-10-21

    The mutation rate of a well adapted population is prone to reduction so as to have a lower mutational load. We aim to understand the role of epistatic interactions between the fitness affecting mutations in this process. Using a multitype branching process, the fixation probability of a single non-mutator emerging in a large asexual mutator population is analytically calculated here. The mutator population undergoes deleterious mutations at constant, but at a much higher rate than that of the non-mutator. We find that antagonistic epistasis lowers the chances of mutation rate reduction, while synergistic epistasis enhances it. Below a critical value of epistasis, the fixation probability behaves non-monotonically with variation in the mutation rate of the background population. Moreover, the variation of this critical value of the epistasis parameter with the strength of the mutator is discussed in the appendix. For synergistic epistasis, when selection is varied, the fixation probability reduces overall, with damped oscillations. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Evolution of Escherichia coli to 42 °C and Subsequent Genetic Engineering Reveals Adaptive Mechanisms and Novel Mutations

    DEFF Research Database (Denmark)

    Sandberg, Troy E.; Pedersen, Margit; LaCroix, Ryan A.

    2014-01-01

    Adaptive laboratory evolution (ALE) has emerged as a valuable method by which to investigate microbial adaptation to a desired environment. Here, we performed ALE to 42 °C of ten parallel populations of Escherichia coli K-12 MG1655 grown in glucose minimal media. Tightly controlled experimental...... conditions allowed selection based on exponential-phase growth rate, yielding strains that uniformly converged toward a similar phenotype along distinct genetic paths. Adapted strains possessed as few as 6 and as many as 55 mutations, and of the 144 genes that mutated in total, 14 arose independently across...... reaffirmed the impact of the key mutations on the growth rate at 42 °C. Interestingly, most of the identified key gene targets differed significantly from those found in similar temperature adaptation studies, highlighting the sensitivity of genetic evolution to experimental conditions and ancestral genotype...

  2. Rural Households’ Adaptation to Climate Change and its Implications for Policy Designs in Lijiang, China

    DEFF Research Database (Denmark)

    Zheng, Yuan

    . The thesis, carried out in three mountain villages in southwest China, seeks to advance the understanding of local adaptation process and its implications for vulnerability and policy designs. In particular, the research contributes to quantitative assessment of current and forward-looking adaptation...... and perceived adaptive capacity, when it comes to explaining adaptation intention; 3) the significance of households’ assets and access to them as well as livelihood features as key constituents of capacity to cope and adapt; 4) the heterogeneity of adaptations and vulnerability profiles across individual...

  3. Adaptive mutations in the JC virus protein capsid are associated with progressive multifocal leukoencephalopathy (PML.

    Directory of Open Access Journals (Sweden)

    Shamil R Sunyaev

    2009-02-01

    Full Text Available PML is a progressive and mostly fatal demyelinating disease caused by JC virus infection and destruction of infected oligodendrocytes in multiple brain foci of susceptible individuals. While JC virus is highly prevalent in the human population, PML is a rare disease that exclusively afflicts only a small percentage of immunocompromised individuals including those affected by HIV (AIDS or immunosuppressive drugs. Viral- and/or host-specific factors, and not simply immune status, must be at play to account for the very large discrepancy between viral prevalence and low disease incidence. Here, we show that several amino acids on the surface of the JC virus capsid protein VP1 display accelerated evolution in viral sequences isolated from PML patients but not in sequences isolated from healthy subjects. We provide strong evidence that at least some of these mutations are involved in binding of sialic acid, a known receptor for the JC virus. Using statistical methods of molecular evolution, we performed a comprehensive analysis of JC virus VP1 sequences isolated from 55 PML patients and 253 sequences isolated from the urine of healthy individuals and found that a subset of amino acids found exclusively among PML VP1 sequences is acquired via adaptive evolution. By modeling of the 3-D structure of the JC virus capsid, we showed that these residues are located within the sialic acid binding site, a JC virus receptor for cell infection. Finally, we go on to demonstrate the involvement of some of these sites in receptor binding by demonstrating a profound reduction in hemagglutination properties of viral-like particles made of the VP1 protein carrying these mutations. Collectively, these results suggest that a more virulent PML causing phenotype of JC virus is acquired via adaptive evolution that changes viral specificity for its cellular receptor(s.

  4. Enhanced Differential Evolution Based on Adaptive Mutation and Wrapper Local Search Strategies for Global Optimization Problems

    Directory of Open Access Journals (Sweden)

    Chun-Liang Lu

    2014-12-01

    Full Text Available Differential evolution (DE is a simple, powerful optimization algorithm, which has been widely used in many areas. However, the choices of the best mutation and search strategies are difficult for the specific issues. To alleviate these drawbacks and enhance the performance of DE, in this paper, the hybrid framework based on the adaptive mutation and Wrapper Local Search (WLS schemes, is proposed to improve searching ability to efficiently guide the evolution of the population toward the global optimum. Furthermore, the effective particle encoding representation named Particle Segment Operation-Machine Assignment (PSOMA that we previously published is applied to always produce feasible candidate solutions for solving the Flexible Job-shop Scheduling Problem (FJSP. Experiments were conducted on comprehensive set of complex benchmarks including the unimodal, multimodal and hybrid composition function, to validate performance of the proposed method and to compare with other state-of-the art DE variants such as jDE, JADE, MDE_pBX etc. Meanwhile, the hybrid DE model incorporating PSOMA is used to solve different representative instances based on practical data for multi-objective FJSP verifications. Simulation results indicate that the proposed method performs better for the majority of the single-objective scalable benchmark functions in terms of the solution accuracy and convergence rate. In addition, the wide range of Pareto-optimal solutions and more Gantt chart decision-makings can be provided for the multi-objective FJSP combinatorial optimizations.

  5. A noncoding, regulatory mutation implicates HCFC1 in nonsyndromic intellectual disability.

    Science.gov (United States)

    Huang, Lingli; Jolly, Lachlan A; Willis-Owen, Saffron; Gardner, Alison; Kumar, Raman; Douglas, Evelyn; Shoubridge, Cheryl; Wieczorek, Dagmar; Tzschach, Andreas; Cohen, Monika; Hackett, Anna; Field, Michael; Froyen, Guy; Hu, Hao; Haas, Stefan A; Ropers, Hans-Hilger; Kalscheuer, Vera M; Corbett, Mark A; Gecz, Jozef

    2012-10-01

    The discovery of mutations causing human disease has so far been biased toward protein-coding regions. Having excluded all annotated coding regions, we performed targeted massively parallel resequencing of the nonrepetitive genomic linkage interval at Xq28 of family MRX3. We identified in the binding site of transcription factor YY1 a regulatory mutation that leads to overexpression of the chromatin-associated transcriptional regulator HCFC1. When tested on embryonic murine neural stem cells and embryonic hippocampal neurons, HCFC1 overexpression led to a significant increase of the production of astrocytes and a considerable reduction in neurite growth. Two other nonsynonymous, potentially deleterious changes have been identified by X-exome sequencing in individuals with intellectual disability, implicating HCFC1 in normal brain function.

  6. Studies of adaptive response and mutation induction in MCF-10A cells following exposure to chronic or acute ionizing radiation.

    Science.gov (United States)

    Manesh, Sara Shakeri; Sangsuwan, Traimate; Wojcik, Andrzej; Haghdoost, Siamak

    2015-10-01

    A phenomenon in which exposure to a low adapting dose of radiation makes cells more resistant to the effects of a subsequent high dose exposure is termed radio-adaptive response. Adaptive response could hypothetically reduce the risk of late adverse effects of chronic or acute radiation exposures in humans. Understanding the underlying mechanisms of such responses is of relevance for radiation protection as well as for the clinical applications of radiation in medicine. However, due to the variability of responses depending on the model system and radiation condition, there is a need to further study under what conditions adaptive response can be induced. In this study, we analyzed if there is a dose rate dependence for the adapting dose, assuming that the adapting dose induces DNA response/repair pathways that are dose rate dependent. MCF-10A cells were exposed to a 50mGy adapting dose administered acutely (0.40Gy/min) or chronically (1.4mGy/h or 4.1mGy/h) and then irradiated by high acute challenging doses. The endpoints of study include clonogenic cell survival and mutation frequency at X-linked hprt locus. In another series of experiment, cells were exposed to 100mGy and 1Gy at different dose rates (acutely and chronically) and then the mutation frequencies were studied. Adaptive response was absent at the level of clonogenic survival. The mutation frequencies were significantly decreased in the cells pre-exposed to 50mGy at 1.4mGy/h followed by 1Gy acute exposure as challenging dose. Importantly, at single dose exposures (1 Gy or 100mGy), no differences at the level of mutation were found comparing different dose rates. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Local adaptation in brown trout early life-history traits: implications for climate change adaptability

    DEFF Research Database (Denmark)

    Jensen, L.F.; Hansen, Michael Møller; Pertoldi, C.

    2008-01-01

    to adapt. Temperature-related adaptability in traits related to phenology and early life history are expected to be particularly important in salmonid fishes. We focused on the latter and investigated whether four populations of brown trout (Salmo trutta) are locally adapted in early life-history traits...... and heritable variation in phenotypic plasticity suggest that although increasing temperatures are likely to affect some populations negatively, they may have the potential to adapt to changing temperature regimes.  ...

  8. Single string based global optimizer for geometry optimization in strongly coupled finite clusters: An adaptive mutation-driven strategy.

    Science.gov (United States)

    Sarkar, Kanchan; Bhattacharyya, S P

    2013-08-21

    We propose and implement a simple adaptive heuristic to optimize the geometries of clusters of point charges or ions with the ability to find the global minimum energy configurations. The approach uses random mutations of a single string encoding the geometry and accepts moves that decrease the energy. Mutation probability and mutation intensity are allowed to evolve adaptively on the basis of continuous evaluation of past explorations. The resulting algorithm has been called Completely Adaptive Random Mutation Hill Climbing method. We have implemented this method to search through the complex potential energy landscapes of parabolically confined 3D classical Coulomb clusters of hundreds or thousands of charges--usually found in high frequency discharge plasmas. The energy per particle (EN∕N) and its first and second differences, structural features, distribution of the oscillation frequencies of normal modes, etc., are analyzed as functions of confinement strength and the number of charges in the system. Certain magic numbers are identified. In order to test the feasibility of the algorithm in cluster geometry optimization on more complex energy landscapes, we have applied the algorithm for optimizing the geometries of MgO clusters, described by Coulomb-Born-Mayer potential and finding global minimum of some Lennard-Jones clusters. The convergence behavior of the algorithm compares favorably with those of other existing global optimizers.

  9. Global Rebalancing of Cellular Resources by Pleiotropic Point Mutations Illustrates a Multi-scale Mechanism of Adaptive Evolution.

    Science.gov (United States)

    Utrilla, Jose; O'Brien, Edward J; Chen, Ke; McCloskey, Douglas; Cheung, Jacky; Wang, Harris; Armenta-Medina, Dagoberto; Feist, Adam M; Palsson, Bernhard O

    2016-04-27

    Pleiotropic regulatory mutations affect diverse cellular processes, posing a challenge to our understanding of genotype-phenotype relationships across multiple biological scales. Adaptive laboratory evolution (ALE) allows for such mutations to be found and characterized in the context of clear selection pressures. Here, several ALE-selected single-mutation variants in RNA polymerase (RNAP) of Escherichia coli are detailed using an integrated multi-scale experimental and computational approach. While these mutations increase cellular growth rates in steady environments, they reduce tolerance to stress and environmental fluctuations. We detail structural changes in the RNAP that rewire the transcriptional machinery to rebalance proteome and energy allocation toward growth and away from several hedging and stress functions. We find that while these mutations occur in diverse locations in the RNAP, they share a common adaptive mechanism. In turn, these findings highlight the resource allocation trade-offs organisms face and suggest how the structure of the regulatory network enhances evolvability. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Mutation-Driven Divergence and Convergence Indicate Adaptive Evolution of the Intracellular Human-Restricted Pathogen, Bartonella bacilliformis.

    Directory of Open Access Journals (Sweden)

    Sandip Paul

    2016-05-01

    Full Text Available Among all species of Bartonella, human-restricted Bartonella bacilliformis is the most virulent but harbors one of the most reduced genomes. Carrión's disease, the infection caused by B. bacilliformis, has been afflicting poor rural populations for centuries in the high-altitude valleys of the South American Andes, where the pathogen's distribution is probably restricted by its sand fly vector's range. Importantly, Carrión's disease satisfies the criteria set by the World Health Organization for a disease amenable to elimination. However, to date, there are no genome-level studies to identify potential footprints of B. bacilliformis (pathoadaptation. Our comparative genomic approach demonstrates that the evolution of this intracellular pathogen is shaped predominantly via mutation. Analysis of strains having publicly-available genomes shows high mutational divergence of core genes leading to multiple sub-species. We infer that the sub-speciation event might have happened recently where a possible adaptive divergence was accelerated by intermediate emergence of a mutator phenotype. Also, within a sub-species the pathogen shows inter-clonal adaptive evolution evidenced by non-neutral accumulation of convergent amino acid mutations. A total of 67 non-recombinant core genes (over-representing functional categories like DNA repair, glucose metabolic process, ATP-binding and ligase were identified as candidates evolving via adaptive mutational convergence. Such convergence, both at the level of genes and their encoded functions, indicates evolution of B. bacilliformis clones along common adaptive routes, while there was little diversity within a single clone.

  11. Mutations in presenilin 2 and its implications in Alzheimer’s disease and other dementia-associated disorders

    Directory of Open Access Journals (Sweden)

    Cai Y

    2015-07-01

    Full Text Available Yan Cai,1 Seong Soo A An,1 SangYun Kim2 1Department of Bionano Technology, Gachon Medical Research Institute, Gachon University, 2Department of Neurology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, South Korea Abstract: Alzheimer’s disease (AD is the most common form of dementia. Mutations in the genes encoding presenilin 1 (PSEN1, presenilin 2 (PSEN2, and amyloid precursor protein have been identified as the main genetic causes of familial AD. To date, more than 200 mutations have been described worldwide in PSEN1, which is highly homologous with PSEN2, while mutations in PSEN2 have been rarely reported. We performed a systematic review of studies describing the mutations identified in PSEN2. Most PSEN2 mutations were detected in European and in African populations. Only two were found in Korean populations. Interestingly, PSEN2 mutations appeared not only in AD patients but also in patients with other disorders, including frontotemporal dementia, dementia with Lewy bodies, breast cancer, dilated cardiomyopathy, and Parkinson’s disease with dementia. Here, we have summarized the PSEN2 mutations and the potential implications of these mutations in dementia-associated disorders. Keywords: mutations in presenilin 2, Alzheimer’s disease

  12. Epistatic roles of E2 glycoprotein mutations in adaption of chikungunya virus to Aedes albopictus and Ae. aegypti mosquitoes.

    Directory of Open Access Journals (Sweden)

    Konstantin A Tsetsarkin

    Full Text Available Between 2005 and 2007 Chikungunya virus (CHIKV caused its largest outbreak/epidemic in documented history. An unusual feature of this epidemic is the involvement of Ae. albopictus as a principal vector. Previously we have demonstrated that a single mutation E1-A226V significantly changed the ability of the virus to infect and be transmitted by this vector when expressed in the background of well characterized CHIKV strains LR2006 OPY1 and 37997. However, in the current study we demonstrate that introduction of the E1-A226V mutation into the background of an infectious clone derived from the Ag41855 strain (isolated in Uganda in 1982 does not significantly increase infectivity for Ae. albopictus. In order to elucidate the genetic determinants that affect CHIKV sensitivity to the E1-A226V mutation in Ae. albopictus, the genomes of the LR2006 OPY1 and Ag41855 strains were used for construction of chimeric viruses and viruses with a specific combination of point mutations at selected positions. Based upon the midgut infection rates of the derived viruses in Ae. albopictus and Ae. aegypti mosquitoes, a critical role of the mutations at positions E2-60 and E2-211 on vector infection was revealed. The E2-G60D mutation was an important determinant of CHIKV infectivity for both Ae. albopictus and Ae. aegypti, but only moderately modulated the effect of the E1-A226V mutation in Ae. albopictus. However, the effect of the E2-I211T mutation with respect to mosquito infections was much more specific, strongly modifying the effect of the E1-A226V mutation in Ae. albopictus. In contrast, CHIKV infectivity for Ae. aegypti was not influenced by the E2-1211T mutation. The occurrence of the E2-60G and E2-211I residues among CHIKV isolates was analyzed, revealing a high prevalence of E2-211I among strains belonging to the Eastern/Central/South African (ECSA clade. This suggests that the E2-211I might be important for adaptation of CHIKV to some particular conditions

  13. Epistatic roles of E2 glycoprotein mutations in adaption of chikungunya virus to Aedes albopictus and Ae. aegypti mosquitoes.

    Science.gov (United States)

    Tsetsarkin, Konstantin A; McGee, Charles E; Volk, Sara M; Vanlandingham, Dana L; Weaver, Scott C; Higgs, Stephen

    2009-08-31

    Between 2005 and 2007 Chikungunya virus (CHIKV) caused its largest outbreak/epidemic in documented history. An unusual feature of this epidemic is the involvement of Ae. albopictus as a principal vector. Previously we have demonstrated that a single mutation E1-A226V significantly changed the ability of the virus to infect and be transmitted by this vector when expressed in the background of well characterized CHIKV strains LR2006 OPY1 and 37997. However, in the current study we demonstrate that introduction of the E1-A226V mutation into the background of an infectious clone derived from the Ag41855 strain (isolated in Uganda in 1982) does not significantly increase infectivity for Ae. albopictus. In order to elucidate the genetic determinants that affect CHIKV sensitivity to the E1-A226V mutation in Ae. albopictus, the genomes of the LR2006 OPY1 and Ag41855 strains were used for construction of chimeric viruses and viruses with a specific combination of point mutations at selected positions. Based upon the midgut infection rates of the derived viruses in Ae. albopictus and Ae. aegypti mosquitoes, a critical role of the mutations at positions E2-60 and E2-211 on vector infection was revealed. The E2-G60D mutation was an important determinant of CHIKV infectivity for both Ae. albopictus and Ae. aegypti, but only moderately modulated the effect of the E1-A226V mutation in Ae. albopictus. However, the effect of the E2-I211T mutation with respect to mosquito infections was much more specific, strongly modifying the effect of the E1-A226V mutation in Ae. albopictus. In contrast, CHIKV infectivity for Ae. aegypti was not influenced by the E2-1211T mutation. The occurrence of the E2-60G and E2-211I residues among CHIKV isolates was analyzed, revealing a high prevalence of E2-211I among strains belonging to the Eastern/Central/South African (ECSA) clade. This suggests that the E2-211I might be important for adaptation of CHIKV to some particular conditions prevalent in

  14. Implications of physical symmetries in adaptive image classifiers

    DEFF Research Database (Denmark)

    Sams, Thomas; Hansen, Jonas Lundbek

    2000-01-01

    It is demonstrated that rotational invariance and reflection symmetry of image classifiers lead to a reduction in the number of free parameters in the classifier. When used in adaptive detectors, e.g. neural networks, this may be used to decrease the number of training samples necessary to learn ...... a given classification task, or to improve generalization of the neural network. Notably, the symmetrization of the detector does not compromise the ability to distinguish objects that break the symmetry. (C) 2000 Elsevier Science Ltd. All rights reserved....

  15. Frequent heterogeneous missense mutations of GGAP2 in prostate cancer: implications for tumor biology, clonality and mutation analysis.

    Directory of Open Access Journals (Sweden)

    Yi Cai

    Full Text Available Prostate cancer is the most common visceral malignancy in Western men and a major cause of cancer deaths. Increased activation of the AKT and NFkB pathways have been identified as critical steps in prostate cancer initiation and progression. GGAP2 (GTP-binding and GTPase activating protein 2 is a multidomain protein that contains an N-terminal Ras homology domain (GTPase, followed by a PH domain, a C-terminal GAP domain and an ankyrin repeat domain. GGAP2 can directly activate signaling via both the AKT and NFkB pathways and acts as a node of crosstalk between these pathways. Increased GGAP2 expression is present in three quarters of prostate cancers. Mutations of GGAP2 have been reported in cell lines from other malignancies. We therefore analyzed 84 prostate cancer tissues and 43 benign prostate tissues for somatic mutations in GGAP2 by direct sequencing of individual clones derived from the GAP and GTPase domains of normal and tumor tissue. Overall, half of cancers contained mutant GAP domain clones and in 20% of cancers, 30% or more of clones were mutant in the GAP domain. Surprisingly, the mutations were heterogeneous and nonclonal, with multiple different mutations being present in many tumors. Similar findings were observed in the analysis of the GTPase domain. Mutant GGAP2 proteins had significantly higher transcriptional activity using AP-1 responsive reporter constructs when compared to wild-type protein. Furthermore, the presence of these mutations was associated with aggressive clinical behavior. The presence of high frequency nonclonal mutations of a single gene is novel and represents a new mode of genetic alteration that can promote tumor progression. Analysis of mutations in cancer has been used to predict outcome and guide therapeutic target identification but such analysis has focused on clonal mutations. Our studies indicate that in some cases high frequency nonclonal mutations may need to be assessed as well.

  16. Frequent heterogeneous missense mutations of GGAP2 in prostate cancer: implications for tumor biology, clonality and mutation analysis.

    Science.gov (United States)

    Cai, Yi; Wang, Jianghua; Ren, Chengxi; Ittmann, Michael

    2012-01-01

    Prostate cancer is the most common visceral malignancy in Western men and a major cause of cancer deaths. Increased activation of the AKT and NFkB pathways have been identified as critical steps in prostate cancer initiation and progression. GGAP2 (GTP-binding and GTPase activating protein 2) is a multidomain protein that contains an N-terminal Ras homology domain (GTPase), followed by a PH domain, a C-terminal GAP domain and an ankyrin repeat domain. GGAP2 can directly activate signaling via both the AKT and NFkB pathways and acts as a node of crosstalk between these pathways. Increased GGAP2 expression is present in three quarters of prostate cancers. Mutations of GGAP2 have been reported in cell lines from other malignancies. We therefore analyzed 84 prostate cancer tissues and 43 benign prostate tissues for somatic mutations in GGAP2 by direct sequencing of individual clones derived from the GAP and GTPase domains of normal and tumor tissue. Overall, half of cancers contained mutant GAP domain clones and in 20% of cancers, 30% or more of clones were mutant in the GAP domain. Surprisingly, the mutations were heterogeneous and nonclonal, with multiple different mutations being present in many tumors. Similar findings were observed in the analysis of the GTPase domain. Mutant GGAP2 proteins had significantly higher transcriptional activity using AP-1 responsive reporter constructs when compared to wild-type protein. Furthermore, the presence of these mutations was associated with aggressive clinical behavior. The presence of high frequency nonclonal mutations of a single gene is novel and represents a new mode of genetic alteration that can promote tumor progression. Analysis of mutations in cancer has been used to predict outcome and guide therapeutic target identification but such analysis has focused on clonal mutations. Our studies indicate that in some cases high frequency nonclonal mutations may need to be assessed as well.

  17. Genetic mapping of ada and adc mutations affecting the adaptive response of Escherichia coli to alkylating agents.

    Science.gov (United States)

    Sedgwick, B

    1982-05-01

    The adaptive response to alkylating agents is an inducible repair system which protects Escherichia coli against the mutagenicity and toxicity of these agents. Four mutations, ada-3, ada-5, ada-6, and adc-1, which confer differing phenotypes as regards this response, were shown to be cotransducible with gyrA, and were located at 47 min on the E. coli genetic map. A mutation already shown on the map at 47 min as tag (B. J. Bachmann and K. B. Low, Microbiol. Rev. 44:1--56, 1980; Karran et al., J. Mol. Biol. 140:101--127, 1980) is now known to be an ada mutation (G. Evensen and E. Seeberg, personal communication).

  18. Implementation of Adaptive Multiple Bit Mutation Genetic Algorithm%自适应多位变异遗传算法的实现

    Institute of Scientific and Technical Information of China (English)

    王基一; 吴燕仙

    2003-01-01

    Genetic algorithm is a widely used optimization method. Crossover and mutation are two Basicl operatorsof the genetic algorithm. On the basis of analyzing the principles of simple genetic algorithm and discussing its exist-ing problems of crossover point and mutation bit, this paper presents a way of the adaptive multiple bit mutation ge-netic algorithm , which not only can keep the population diversity but also has quicker convergence speed. The resultsof the multi-modal function optimization show that the adaptive multiple bit mutation genetic algorithm is practicaland efficient.

  19. Human APOBEC3 induced mutation of human immunodeficiency virus type-1 contributes to adaptation and evolution in natural infection.

    Directory of Open Access Journals (Sweden)

    Eun-Young Kim

    2014-07-01

    Full Text Available Human APOBEC3 proteins are cytidine deaminases that contribute broadly to innate immunity through the control of exogenous retrovirus replication and endogenous retroelement retrotransposition. As an intrinsic antiretroviral defense mechanism, APOBEC3 proteins induce extensive guanosine-to-adenosine (G-to-A mutagenesis and inhibit synthesis of nascent human immunodeficiency virus-type 1 (HIV-1 cDNA. Human APOBEC3 proteins have additionally been proposed to induce infrequent, potentially non-lethal G-to-A mutations that make subtle contributions to sequence diversification of the viral genome and adaptation though acquisition of beneficial mutations. Using single-cycle HIV-1 infections in culture and highly parallel DNA sequencing, we defined trinucleotide contexts of the edited sites for APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H. We then compared these APOBEC3 editing contexts with the patterns of G-to-A mutations in HIV-1 DNA in cells obtained sequentially from ten patients with primary HIV-1 infection. Viral substitutions were highest in the preferred trinucleotide contexts of the edited sites for the APOBEC3 deaminases. Consistent with the effects of immune selection, amino acid changes accumulated at the APOBEC3 editing contexts located within human leukocyte antigen (HLA-appropriate epitopes that are known or predicted to enable peptide binding. Thus, APOBEC3 activity may induce mutations that influence the genetic diversity and adaptation of the HIV-1 population in natural infection.

  20. Mast cells in allergy and autoimmunity: implications for adaptive immunity.

    Science.gov (United States)

    Gregory, Gregory D; Brown, Melissa A

    2006-01-01

    As in the fashion industry, trends in a particular area of scientific investigation often are fleeting but then return with renewed and enthusiastic interest. Studies of mast cell biology are good examples of this. Although dogma once relegated mast cells almost exclusively to roles in pathological inflammation associated with allergic disease, these cells are emerging as important players in a number of other physiological processes. Consequently, they are quickly becoming the newest "trendy" cell, both within and outside the field of immunology. As sources of a large array of pro- and anti-inflammatory mediators, mast cells also express cell surface molecules with defined functions in lymphocyte activation and trafficking. Here, we provide an overview of the traditional and newly appreciated contributions of mast cells to both innate and adaptive immune responses.

  1. Proposing an adaptive mutation to improve XCSF performance to classify ADHD and BMD patients

    Science.gov (United States)

    Sadatnezhad, Khadijeh; Boostani, Reza; Ghanizadeh, Ahmad

    2010-12-01

    There is extensive overlap of clinical symptoms observed among children with bipolar mood disorder (BMD) and those with attention deficit hyperactivity disorder (ADHD). Thus, diagnosis according to clinical symptoms cannot be very accurate. It is therefore desirable to develop quantitative criteria for automatic discrimination between these disorders. This study is aimed at designing an efficient decision maker to accurately classify ADHD and BMD patients by analyzing their electroencephalogram (EEG) signals. In this study, 22 channels of EEGs have been recorded from 21 subjects with ADHD and 22 individuals with BMD. Several informative features, such as fractal dimension, band power and autoregressive coefficients, were extracted from the recorded signals. Considering the multimodal overlapping distribution of the obtained features, linear discriminant analysis (LDA) was used to reduce the input dimension in a more separable space to make it more appropriate for the proposed classifier. A piecewise linear classifier based on the extended classifier system for function approximation (XCSF) was modified by developing an adaptive mutation rate, which was proportional to the genotypic content of best individuals and their fitness in each generation. The proposed operator controlled the trade-off between exploration and exploitation while maintaining the diversity in the classifier's population to avoid premature convergence. To assess the effectiveness of the proposed scheme, the extracted features were applied to support vector machine, LDA, nearest neighbor and XCSF classifiers. To evaluate the method, a noisy environment was simulated with different noise amplitudes. It is shown that the results of the proposed technique are more robust as compared to conventional classifiers. Statistical tests demonstrate that the proposed classifier is a promising method for discriminating between ADHD and BMD patients.

  2. Public Sector Reform and Governance for Adaptation: Implications of New Public Management for Adaptive Capacity in Mexico and Norway

    Science.gov (United States)

    Eakin, Hallie; Eriksen, Siri; Eikeland, Per-Ove; Øyen, Cecilie

    2011-03-01

    Although many governments are assuming the responsibility of initiating adaptation policy in relation to climate change, the compatibility of "governance-for-adaptation" with the current paradigms of public administration has generally been overlooked. Over the last several decades, countries around the globe have embraced variants of the philosophy of administration broadly called "New Public Management" (NPM) in an effort to improve administrative efficiencies and the provision of public services. Using evidence from a case study of reforms in the building sector in Norway, and a case study of water and flood risk management in central Mexico, we analyze the implications of the adoption of the tenets of NPM for adaptive capacity. Our cases illustrate that some of the key attributes associated with governance for adaptation—namely, technical and financial capacities; institutional memory, learning and knowledge; and participation and accountability—have been eroded by NPM reforms. Despite improvements in specific operational tasks of the public sector in each case, we show that the success of NPM reforms presumes the existence of core elements of governance that have often been found lacking, including solid institutional frameworks and accountability. Our analysis illustrates the importance of considering both longer-term adaptive capacities and short-term efficiency goals in public sector administration reform.

  3. Adapting to a changing world: Implications for water management.

    Science.gov (United States)

    Loucks, Daniel

    2010-05-01

    Everyone is aware that the world is changing, and that many of these changes will impact our water resource supplies and how they are used and managed. It's always a challenge to try to predict the future, especially the very uncertain distant future. But one thing is certain, the future environment our descendants will experience will differ from the economic, social, technological and natural conditions we experience today. Some aspects of the changes that are happening may not be under human control, but many are. And to the extent they are, we can influence that future. In this paper I attempt to speculate about a future some 40 to 50 years from now, and how water will need to be managed then. My goal is to motivate some thinking and discussion about how we as water managers can influence and prepare ourselves (or our successors) for that future. It will require collaboration among multiple disciplines to determine how best we as a profession can help society adapt to these changes, and this in turn will require all of us to learn how to work together more effectively than we do now. This theme fits in with the current interest in sustainability, for no matter how it is defined, sustainability makes us think about the long-term future. How do we develop and manage our natural and cultural resources in ways that benefit both us and future generations of people living on this earth? What will their needs and goals be? We don't know and that is the major challenge in deciding what decisions we might make today on their behalf. Here I attempt to identify the challenges and issues water managers could be addressing some 40 to 50 years from now, and what we in each of our disciplines, and together, can begin to do now to address them.

  4. Gaucher disease: Pseudoreversion of a disease mutation`s effects--implications for structure/function and genotype/phenotype correlations

    Energy Technology Data Exchange (ETDEWEB)

    Ponce, E.; Mear, J; Grabowski, G.A. [Children`s Hospital Research Foundation, Cincinnati, OH (United States)

    1994-09-01

    Numerous mutations ({approximately}45) of the acid {beta}-glucosidase gene have been identified in patients with Gaucher disease. Many of these have been characterized by partial sequencing of cDNAs derived by RT-PCR or PCR of genomic DNA. In addition, genotype/phenotype correlations have been based on screening for known mutations. Thus, only a part of the gene is characterized in any population of affected patients. Several Gaucher disease alleles contain multiple, authentic point mutations that raises concern about conclusions based on only partial genetic characterization. Several wild-type cDNAs for acid {beta}-glucosidase have been sequenced. One contained a cloning artifact encoding R495H. We expressed this cDNA and showed that the R495H enzyme had normal kinetic and stability properties. A disease-associated allele encoding R496H has been found by several groups. The close association and similarities of these two substitutions led us to question the disease casuality of the R496H allele. To evaluate this, we created and/or expressed cDNAs encoding R495, R496 (wild-type), (R495H, R496), (R495, R496H) and (R495H, R496H). The (wild-type) and (R495H, R496) enzymes had indistinguishable properties whereas the (R495, R496H) enzyme was essentially inactive. The introduction of both mutations (R495H, R496H) produced an enzyme whose activity was 25 to 50% of the wild-type. These results indicate that a pseudoreversion to a functional enzyme can occur by introducing a functionally neutral mutation together with a severe mutation. These results have major implications to structure/function and genotype/phenotype correlations in this disease.

  5. Efficient Culture Adaptation of Hepatitis C Virus Recombinants with Genotype-Specific Core-NS2 by Using Previously Identified Mutations

    DEFF Research Database (Denmark)

    Scheel, Troels Kasper Høyer; Gottwein, Judith M; Carlsen, Thomas H R

    2011-01-01

    ) but not to ED43 (4a). The mutations permitting robust virus production in Huh7.5 cells had no apparent effect on viral replication but allowed efficient assembly of intracellular infectious HCV for adapted novel or previously developed recombinants. In conclusion, previously identified mutations permitted...

  6. Understanding Climate Adaptation on Public Lands in the Upper Midwest: Implications for Monitoring and Tracking Progress.

    Science.gov (United States)

    Anhalt-Depies, Christine M; Knoot, Tricia Gorby; Rissman, Adena R; Sharp, Anthony K; Martin, Karl J

    2016-05-01

    There are limited examples of efforts to systematically monitor and track climate change adaptation progress in the context of natural resource management, despite substantial investments in adaptation initiatives. To better understand the status of adaptation within state natural resource agencies, we utilized and problematized a rational decision-making framework to characterize adaptation at the level of public land managers in the Upper Midwest. We conducted in-depth interviews with 29 biologists and foresters to provide an understanding of managers' experiences with, and perceptions of, climate change impacts, efforts towards planning for climate change, and a full range of actions implemented to address climate change. While the majority of managers identified climate change impacts affecting their region, they expressed significant uncertainty in interpreting those signals. Just under half of managers indicated planning efforts are underway, although most planning is remote from local management. Actions already implemented include both forward-looking measures and those aimed at coping with current impacts. In addition, cross-scale dynamics emerged as an important theme related to the overall adaptation process. The results hold implications for tracking future progress on climate change adaptation. Common definitions or measures of adaptation (e.g., presence of planning documents) may need to be reassessed for applicability at the level of public land managers.

  7. Understanding Climate Adaptation on Public Lands in the Upper Midwest: Implications for Monitoring and Tracking Progress

    Science.gov (United States)

    Anhalt-Depies, Christine M.; Knoot, Tricia Gorby; Rissman, Adena R.; Sharp, Anthony K.; Martin, Karl J.

    2016-05-01

    There are limited examples of efforts to systematically monitor and track climate change adaptation progress in the context of natural resource management, despite substantial investments in adaptation initiatives. To better understand the status of adaptation within state natural resource agencies, we utilized and problematized a rational decision-making framework to characterize adaptation at the level of public land managers in the Upper Midwest. We conducted in-depth interviews with 29 biologists and foresters to provide an understanding of managers' experiences with, and perceptions of, climate change impacts, efforts towards planning for climate change, and a full range of actions implemented to address climate change. While the majority of managers identified climate change impacts affecting their region, they expressed significant uncertainty in interpreting those signals. Just under half of managers indicated planning efforts are underway, although most planning is remote from local management. Actions already implemented include both forward-looking measures and those aimed at coping with current impacts. In addition, cross-scale dynamics emerged as an important theme related to the overall adaptation process. The results hold implications for tracking future progress on climate change adaptation. Common definitions or measures of adaptation (e.g., presence of planning documents) may need to be reassessed for applicability at the level of public land managers.

  8. Adaptive mutations in sugar metabolism restore growth on glucose in a pyruvate decarboxylase negative yeast strain

    DEFF Research Database (Denmark)

    Zhang, Yiming; Liu, Guodong; Engqvist, Martin K. M.

    2015-01-01

    DNA sequencing. Among these genetic changes, 4 genes were found to carry point mutations in at least two of the evolved strains: MTH1 encoding a negative regulator of the glucose-sensing signal transduction pathway, HXT2 encoding a hexose transporter, CIT1 encoding a mitochondrial citrate synthase...... further increased the maximum specific growth rate to 0.069 h-1. Conclusions: In this study, possible evolving mechanisms of Pdc negative strains on glucose were investigated by genome sequencing and reverse engineering. The non-synonymous mutations in MTH1 alleviated the glucose repression by repressing...... expression of several hexose transporter genes. The non-synonymous mutations in HXT2 and CIT1 may function in the presence of mutated MTH1 alleles and could be related to an altered central carbon metabolism in order to ensure production of cytosolic acetyl-CoA in the Pdc negative strain....

  9. Clinical implications of TP53 mutations in myelodysplastic syndromes treated with hypomethylating agents.

    Science.gov (United States)

    Takahashi, Koichi; Patel, Keyur; Bueso-Ramos, Carlos; Zhang, Jianhua; Gumbs, Curtis; Jabbour, Elias; Kadia, Tapan; Andreff, Michael; Konopleva, Marina; DiNardo, Courtney; Daver, Naval; Cortes, Jorge; Estrov, Zeev; Futreal, Andrew; Kantarjian, Hagop; Garcia-Manero, Guillermo

    2016-03-22

    We screened TP53 mutations in 168 MDS patients who were treated with HMA and evaluated predictive and prognostic value of TP53 mutations. Overall response to HMA was not different based on TP53 mutation status (45% vs. 32% in TP53-mutated and wild type [WT], respectively, P = 0.13). However, response duration was significantly shorter in TP53-mutated patients compared to WT patients (5.7 months vs. 28.5 months, P = 0.003). Longitudinal analysis of TP53 mutations after HMA showed that TP53 mutations almost always persisted at times of disease progression. TP53-mutated patients showed significantly worse overall survival (OS) compared to WT patients (9.4 months vs. 20.7 months, P TP53 mutations distinguished prognosis in the subgroup of patients with complex karyotype and Revised International Prognostic Scoring System (IPSS-R) defined very high-risk disease. Multivariate analysis showed that TP53 mutation status is significantly prognostic for OS after adjusting prognostic effect from other factors. The current study provides evidence that TP53 mutations are independently prognostic in MDS patients treated with HMA. While TP53-mutated MDS patients initially respond well to HMA, their duration of response is significantly shorter than WT patients. Novel strategies to improve duration of response in TP53-mutated MDS are urgently needed.

  10. A novel radiation-induced p53 mutation is not implicated in radiation resistance via a dominant-negative effect.

    Directory of Open Access Journals (Sweden)

    Yunguang Sun

    Full Text Available Understanding the mutations that confer radiation resistance is crucial to developing mechanisms to subvert this resistance. Here we describe the creation of a radiation resistant cell line and characterization of a novel p53 mutation. Treatment with 20 Gy radiation was used to induce mutations in the H460 lung cancer cell line; radiation resistance was confirmed by clonogenic assay. Limited sequencing was performed on the resistant cells created and compared to the parent cell line, leading to the identification of a novel mutation (del at the end of the DNA binding domain of p53. Levels of p53, phospho-p53, p21, total caspase 3 and cleaved caspase 3 in radiation resistant cells and the radiation susceptible (parent line were compared, all of which were found to be similar. These patterns held true after analysis of p53 overexpression in H460 cells; however, H1299 cells transfected with mutant p53 did not express p21, whereas those given WT p53 produced a significant amount, as expected. A luciferase assay demonstrated the inability of mutant p53 to bind its consensus elements. An MTS assay using H460 and H1299 cells transfected with WT or mutant p53 showed that the novel mutation did not improve cell survival. In summary, functional characterization of a radiation-induced p53 mutation in the H460 lung cancer cell line does not implicate it in the development of radiation resistance.

  11. Short-term differential adaptation to anaerobic stress via genomic mutations by Escherichia coli strains K-12 and B lacking alcohol dehydrogenase.

    Science.gov (United States)

    Kim, Hyun Ju; Jeong, Haeyoung; Hwang, Seungwoo; Lee, Moo-Seung; Lee, Yong-Jik; Lee, Dong-Woo; Lee, Sang Jun

    2014-01-01

    Microbial adaptations often occur via genomic mutations under adverse environmental conditions. This study used Escherichia coli ΔadhE cells as a model system to investigate adaptation to anaerobic conditions, which we then compared with the adaptive mechanisms of two closely related E. coli strains, K-12 and B. In contrast to K-12 ΔadhE cells, the E. coli B ΔadhE cells exhibited significantly delayed adaptive growth under anaerobic conditions. Adaptation by the K-12 and B strains mainly employed anaerobic lactate fermentation to restore cellular growth. Several mutations were identified in the pta or pflB genes of adapted K-12 cells, but mostly in the pta gene of the B strains. However, the types of mutation in the adapted K-12 and B strains were similar. Cellular viability was affected directly by severe redox imbalance in B ΔadhE cells, which also impaired their ability to adapt to anaerobic conditions. This study demonstrates that closely related microorganisms may undergo different adaptations under the same set of adverse conditions, which might be associated with the specific metabolic characteristics of each strain. This study provides new insights into short-term microbial adaptation to stressful conditions, which may reflect dynamic microbial population changes in nature.

  12. Short-term differential adaptation to anaerobic stress via genomic mutations by Escherichia coli strains K-12 and B lacking alcohol dehydrogenase

    Directory of Open Access Journals (Sweden)

    Hyun Ju eKim

    2014-09-01

    Full Text Available Microbial adaptations often occur via genomic mutations under adverse environmental conditions. This study used Escherichia coli adhE cells as a model system to investigate adaptation to anaerobic conditions, which we then compared with the adaptive mechanisms of two closely related E. coli strains, K-12 and B. In contrast to K-12 adhE cells, the E. coli B adhE cells exhibited significantly delayed adaptive growth under anaerobic conditions. Adaptation by the K-12 and B strains mainly employed anaerobic lactate fermentation to restore cellular growth. Several mutations were identified in the pta or pflB genes of adapted K-12 cells, but mostly in the pta gene of the B strains. However, the types of mutation in the adapted K-12 and B strains were similar. Cellular viability was affected directly by severe redox imbalance in B adhE cells, which also impaired their ability to adapt to anaerobic conditions.This study demonstrates that closely related microorganisms may undergo different adaptations under the same set of adverse conditions, which might be associated with the specific metabolic characteristics of each strain. This study provides new insights into short-term microbial adaptation to stressful conditions, which may reflect dynamic microbial population changes in nature.

  13. Effect of mutators on adaptability in time-varying fitness landscapes

    Science.gov (United States)

    Gorodetsky, Pavel; Tannenbaum, Emmanuel

    2008-04-01

    This Brief Report studies the quasispecies dynamics of a population capable of genetic repair evolving on a time-dependent fitness landscape. We develop a model that considers an asexual population of single-stranded, conservatively replicating genomes, whose only source of genetic variation is due to copying errors during replication. We consider a time-dependent, single-fitness-peak landscape where the master sequence changes by a single point mutation at every time τ . We are able to analytically solve for the evolutionary dynamics of the population in the point-mutation limit. In particular, our model provides an analytical expression for the fraction of mutators in the dynamic fitness landscape that agrees well with results from stochastic simulations.

  14. The emerging role of SMPD1 mutations in Parkinson's disease: Implications for future studies.

    Science.gov (United States)

    Gan-Or, Ziv; Orr-Urtreger, Avi; Alcalay, Roy N; Bressman, Susan; Giladi, Nir; Rouleau, Guy A

    2015-10-01

    Recently, an additional study confirmed the association between SMPD1 mutations and Parkinson's disease (PD). While the first study on SMPD1 and PD suggested that only one SMPD1 mutations is responsible for the association to PD, the recent study argued that all SMPD1 mutations may be associated with an increased risk for PD. Since SMPD1 mutations are being routinely screened in some populations with high carrier frequencies, and since it will be further screened in additional PD populations, it is important to better define the association between SMPD1 and PD. We reanalyzed the data from the recent and previous papers, and we show that the association between SMPD1 and PD is indeed not driven by only one mutation, but it is also not driven by all SMPD1 mutations. In the Ashkenazi-Jewish population, the p.fs330P (OR = 3.03, p = 0.0026) and p.L302P (OR = 9.62, p < 0.0001) are associated with PD, and the p.R496L mutation is not (OR = 0.84, p = 0.71), and similar observation was noted in the Chinese population. Thus, we conclude that similar to the GBA gene where different mutations have differential effects, SMPD1 mutations also have a differential effects on the risk for PD. Future studies should therefore examine the association by mutation and not by accumulative risk of all mutations.

  15. Bounding The Rate of Adaptation In A Large Asexually Reproducing Population With Fast Mutation Rates

    CERN Document Server

    Kelly, Michael

    2011-01-01

    We consider a model of asexually reproducing individuals. The birth and death rates of the individuals are affected by a fitness parameter. The rate of mutations that cause the fitnesses to change is proportional to the population size, $N$. The mutations may be either beneficial or deleterious. In a paper by Yu, Etheridge and Cuthbertson (2009) it was shown that the average rate at which the mean fitness increases in this model is bounded below by $\\log^{1-\\delta} N$ for any $\\delta > 0$. We achieve an upper bound on the average rate at which the mean fitness increases of $O(\\log N/\\log \\log N)$.

  16. Diminishing-returns epistasis among random beneficial mutations in a multicellular fungus

    NARCIS (Netherlands)

    Schoustra, Sijmen; Hwang, Sungmin; Krug, Joachim; Visser, de Arjan

    2016-01-01

    Adaptive evolution ultimately is fuelled by mutations generating novel genetic variation. Non-additivity of fitness effects of mutations (called epistasis) may affect the dynamics and repeatability of adaptation. However, understanding the importance and implications of epistasis is hampered by

  17. Growth parameter components of adaptive specificity during experimental evolution of the UVR-inducible mutator Pseudomonas cichorii 302959.

    Directory of Open Access Journals (Sweden)

    Michael R Weigand

    Full Text Available BACKGROUND: Mutagenic DNA repair (MDR transiently increases mutation rate through the activation of low-fidelity repair polymerases in response to specific, DNA-damaging environmental stress conditions such as ultraviolet radiation (UVR exposure. These repair polymerases also confer UVR tolerance, intimately linking mutability and survival in bacteria that colone habitats subject to regular UVR exposure. METHODOLOGY/PRINCIPAL FINDINGS: Here, we investigate adaptive specificity in experimental lineages of the highly UVR-mutable epiphytic plant pathogen Pseudomonas cichorii 302959. Relative fitness measurements of isolates and population samples from replicate lineages indicated that adaptive improvements emerged early in all lineages of our evolution experiment and specific increases in relative fitness correlated with distinct improvements in doubling and lag times. Adaptive improvements gained under UVR and non-UVR conditions were acquired preferentially, and differentially contributed to relative fitness under varied growth conditions. CONCLUSIONS: These results support our earlier observations that MDR activation may contribute to gains in relative fitness without impeding normal patterns of adaptive specificity in P. cichorii 302959.

  18. DNA mutations mediate microevolution between host-adapted forms of the pathogenic fungus Cryptococcus neoformans.

    Directory of Open Access Journals (Sweden)

    Denise A Magditch

    Full Text Available The disease cryptococcosis, caused by the fungus Cryptococcus neoformans, is acquired directly from environmental exposure rather than transmitted person-to-person. One explanation for the pathogenicity of this species is that interactions with environmental predators select for virulence. However, co-incubation of C. neoformans with amoeba can cause a "switch" from the normal yeast morphology to a pseudohyphal form, enabling fungi to survive exposure to amoeba, yet conversely reducing virulence in mammalian models of cryptococcosis. Like other human pathogenic fungi, C. neoformans is capable of microevolutionary changes that influence the biology of the organism and outcome of the host-pathogen interaction. A yeast-pseudohyphal phenotypic switch also happens under in vitro conditions. Here, we demonstrate that this morphological switch, rather than being under epigenetic control, is controlled by DNA mutation since all pseudohyphal strains bear mutations within genes encoding components of the RAM pathway. High rates of isolation of pseudohyphal strains can be explained by the physical size of RAM pathway genes and a hypermutator phenotype of the strain used in phenotypic switching studies. Reversion to wild type yeast morphology in vitro or within a mammalian host can occur through different mechanisms, with one being counter-acting mutations. Infection of mice with RAM mutants reveals several outcomes: clearance of the infection, asymptomatic maintenance of the strains, or reversion to wild type forms and progression of disease. These findings demonstrate a key role of mutation events in microevolution to modulate the ability of a fungal pathogen to cause disease.

  19. Mutation at the circadian clock gene EARLY MATURITY 8 adapts domesticated barley (Hordeum vulgare) to short growing seasons.

    Science.gov (United States)

    Faure, Sebastien; Turner, Adrian S; Gruszka, Damian; Christodoulou, Vangelis; Davis, Seth J; von Korff, Maria; Laurie, David A

    2012-05-22

    The circadian clock is an autonomous oscillator that produces endogenous biological rhythms with a period of about 24 h. This clock allows organisms to coordinate their metabolism and development with predicted daily and seasonal changes of the environment. In plants, circadian rhythms contribute to both evolutionary fitness and agricultural productivity. Nevertheless, we show that commercial barley varieties bred for short growing seasons by use of early maturity 8 (eam8) mutations, also termed mat-a, are severely compromised in clock gene expression and clock outputs. We identified EAM8 as a barley ortholog of the Arabidopsis thaliana circadian clock regulator EARLY FLOWERING3 (ELF3) and demonstrate that eam8 accelerates the transition from vegetative to reproductive growth and inflorescence development. We propose that eam8 was selected as barley cultivation moved to high-latitude short-season environments in Europe because it allowed rapid flowering in genetic backgrounds that contained a previously selected late-flowering mutation of the photoperiod response gene Ppd-H1. We show that eam8 mutants have increased expression of the floral activator HvFT1, which is independent of allelic variation at Ppd-H1. The selection of independent eam8 mutations shows that this strategy facilitates short growth-season adaptation and expansion of the geographic range of barley, despite the pronounced clock defect.

  20. [A Brillouin Scattering Spectrum Feature Extraction Based on Flies Optimization Algorithm with Adaptive Mutation and Generalized Regression Neural Network].

    Science.gov (United States)

    Zhang, Yan-jun; Liu, Wen-zhe; Fu, Xing-hu; Bi, Wei-hong

    2015-10-01

    According to the high precision extracting characteristics of scattering spectrum in Brillouin optical time domain reflection optical fiber sensing system, this paper proposes a new algorithm based on flies optimization algorithm with adaptive mutation and generalized regression neural network. The method takes advantages of the generalized regression neural network which has the ability of the approximation ability, learning speed and generalization of the model. Moreover, by using the strong search ability of flies optimization algorithm with adaptive mutation, it can enhance the learning ability of the neural network. Thus the fitting degree of Brillouin scattering spectrum and the extraction accuracy of frequency shift is improved. Model of actual Brillouin spectrum are constructed by Gaussian white noise on theoretical spectrum, whose center frequency is 11.213 GHz and the linewidths are 40-50, 30-60 and 20-70 MHz, respectively. Comparing the algorithm with the Levenberg-Marquardt fitting method based on finite element analysis, hybrid algorithm particle swarm optimization, Levenberg-Marquardt and the least square method, the maximum frequency shift error of the new algorithm is 0.4 MHz, the fitting degree is 0.991 2 and the root mean square error is 0.024 1. The simulation results show that the proposed algorithm has good fitting degree and minimum absolute error. Therefore, the algorithm can be used on distributed optical fiber sensing system based on Brillouin optical time domain reflection, which can improve the fitting of Brillouin scattering spectrum and the precision of frequency shift extraction effectively.

  1. Pandemic influenza A viruses escape from restriction by human MxA through adaptive mutations in the nucleoprotein.

    Directory of Open Access Journals (Sweden)

    Benjamin Mänz

    2013-03-01

    Full Text Available The interferon-induced dynamin-like MxA GTPase restricts the replication of influenza A viruses. We identified adaptive mutations in the nucleoprotein (NP of pandemic strains A/Brevig Mission/1/1918 (1918 and A/Hamburg/4/2009 (pH1N1 that confer MxA resistance. These resistance-associated amino acids in NP differ between the two strains but form a similar discrete surface-exposed cluster in the body domain of NP, indicating that MxA resistance evolved independently. The 1918 cluster was conserved in all descendent strains of seasonal influenza viruses. Introduction of this cluster into the NP of the MxA-sensitive influenza virus A/Thailand/1(KAN-1/04 (H5N1 resulted in a gain of MxA resistance coupled with a decrease in viral replication fitness. Conversely, introduction of MxA-sensitive amino acids into pH1N1 NP enhanced viral growth in Mx-negative cells. We conclude that human MxA represents a barrier against zoonotic introduction of avian influenza viruses and that adaptive mutations in the viral NP should be carefully monitored.

  2. The implications of the Sequestosome 1 mutation P392L in patients with Paget's disease in a United States cohort

    Science.gov (United States)

    Seton, Margaret; Hansen, Marc; Solomon, Daniel H.

    2016-01-01

    Background Paget's disease of bone (PDB) is associated with a germline mutation in Sequestosome1 /p62 (SQSTM1) found in ≤ 16% of sporadic cases worldwide, and in 19-46% of those studied with familial PDB. The P392L is the most prevalent mutation identified to date. This mutation by itself does not confer PDB or define the phenotype of PDB in a given person. Environmental determinants remain elusive, although increasing age of the individual, other gene polymorphisms in the context of SQSTM1 mutations, and measles virus have been implicated. Measles exposure has been unexamined in this context. Objectives The goal of this study is to compare the background history and phenotype of patients with PDB carrying the SQSTM1 P392L mutation to those patients without. Focusing on age, ancestry, P329L mutation, family history, measles exposure, distribution of PDB and age of onset, we examined outcomes at 10 years. We postulated that aging may play a role in defining phenotype, and that this may become more visible in a well characterized cohort. Methods This is an observational study focused on a cohort of patients with PDB drawn from the New England Registry in whom environmental and family history has been catalogued, linked to radiographic data. Of the 217 persons who were enrolled in the Registry, 42 (19%) responded to a letter inviting them to participate in testing for the presence of the measles antibody, and in genetic testing for the P392L mutation. Results The mean age of the cohort in 2001 was 70 years (range 55-79); 27 were men (64%). The measles antibody was found in all cases tested. Nine patients had the P392L mutation (21%), 2 with familial PDB. In these persons, early diagnosis of disease and spinal stenosis marked the male phenotype only. European ancestry was noted in the minority of those with P392L mutation. Most deaths recorded occurred in the 9th decade of life or later. Conclusions Spinal stenosis emerges as a prominent phenotype in SQSTM1 P392L

  3. Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt.

    Science.gov (United States)

    Pelleau, Stéphane; Moss, Eli L; Dhingra, Satish K; Volney, Béatrice; Casteras, Jessica; Gabryszewski, Stanislaw J; Volkman, Sarah K; Wirth, Dyann F; Legrand, Eric; Fidock, David A; Neafsey, Daniel E; Musset, Lise

    2015-09-15

    In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations can attain 100% prevalence, thereby precluding the return of WT parasites after the complete removal of drug pressure. In French Guiana, despite the fixation of the K76T allele, the prevalence of CQR isolates progressively dropped from >90% to <30% during 17 y after CQ withdrawal in 1995. Using a genome-wide association study with CQ-sensitive (CQS) and CQR isolates, we have identified a single mutation in pfcrt encoding a C350R substitution that is associated with the restoration of CQ susceptibility. Genome editing of the CQR reference strain 7G8 to incorporate PfCRT C350R caused a complete loss of CQR. A retrospective molecular survey on 580 isolates collected from 1997 to 2012 identified all C350R mutant parasites as being CQS. This mutation emerged in 2002 and rapidly spread throughout the P. falciparum population. The C350R allele is also associated with a significant decrease in piperaquine susceptibility in vitro, suggesting that piperaquine pressure in addition to potential fitness costs associated with the 7G8-type CQR pfcrt allele may have selected for this mutation. These findings have important implications for understanding the evolutionary dynamics of antimalarial drug resistance.

  4. Gene Expression Noise Facilitates Adaptation and Drug Resistance Independently of Mutation

    CERN Document Server

    Charlebois, Daniel A; Kaern, Mads

    2011-01-01

    We show that the effect of stress on the reproductive fitness of noisy cell populations can be modelled as first-passage time problem, and demonstrate that even relatively short-lived fluctuations in gene expression can ensure long-term survival of a drug-resistant population. We examine how this effect contributes to the development of drug-resistant cancer cells, and demonstrate that permanent immunity can arise independently of mutations.

  5. Non-homologous end joining dependency of {gamma}-irradiation-induced adaptive frameshift mutation formation in cell cycle-arrested yeast cells

    Energy Technology Data Exchange (ETDEWEB)

    Heidenreich, Erich [Institute of Cancer Research, Division of Molecular Genetics, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna (Austria)]. E-mail: erich.heidenreich@meduniwien.ac.at; Eisler, Herfried [Institute of Cancer Research, Division of Molecular Genetics, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna (Austria)

    2004-11-22

    There is a strong selective pressure favoring adaptive mutations which relieve proliferation-limiting adverse living conditions. Due to their importance for evolution and pathogenesis, we are interested in the mechanisms responsible for the formation of such adaptive, gain-of-fitness mutations in stationary-phase cells. During previous studies on the occurrence of spontaneous reversions of an auxotrophy-causing frameshift allele in the yeast Saccharomyces cerevisiae, we noticed that about 50% of the adaptive reversions depended on a functional non-homologous end joining (NHEJ) pathway of DNA double-strand break (DSB) repair. Here, we show that the occasional NHEJ component Pol4, which is the yeast ortholog of mammalian DNA polymerase lambda, is not required for adaptive mutagenesis. An artificially imposed excess of DSBs by {gamma}-irradiation resulted in a dramatic increase in the incidence of adaptive, cell cycle arrest-releasing frameshift reversions. By the use of DNA ligase IV-deficient strains we detected that the majority of the {gamma}-induced adaptive mutations were also dependent on a functional NHEJ pathway. This suggests that the same mutagenic NHEJ mechanism acts on spontaneously arising as well as on ionizing radiation-induced DSBs. Inaccuracy of the NHEJ repair pathway may extensively contribute to the incidence of frameshift mutations in resting (non-dividing) eukaryotic cells, and thus act as a driving force in tumor development.

  6. Prognostic implication of N-RAS gene mutations in Egyptian adult acute myeloid leukemia.

    Science.gov (United States)

    Elghannam, Doaa M; Abousamra, Nashwa Khayrat; Shahin, Doaa A; Goda, Enas F; Azzam, Hanan; Azmy, Emad; El-Din, Manal Salah; El-Refaei, Mohamed F

    2009-01-01

    The pathogenesis of acute myeloid leukemia (AML) involves the cooperation of mutations promoting proliferation/survival and those impairing differentiation. Point mutations of the N-RAS gene are the most frequent somatic mutations causing aberrant signal-transduction in acute myeloid leukemia (AML). The aim of the present work is to study the frequency and prognostic significance of N-RAS gene mutations (N-RASmut) in de novo Egyptian adult AML. Bone marrow specimens from 150 patients with de novo acute myeloid leukemia and controls were analyzed by genomic PCR-SSCP at codons 12, 13 (exon 1), and 61 (exon 2) for N-RAS mutations. In 12.7% (19/150) AML cases, N-RAS gene mutations were found and were observed more frequently in the FAB subtype M4eo (P = 0.028) and with codon 12, 13 (14 of 19; 73.7%). Patients with N-RAS mutation had a significant lower peripheral and marrow blasts (P = 0.004, P = 0.03) and clinical outcome did not improve more than in patients without mutation. In patients with N-RAS gene mutation vs. those without, complete remission rate was (63.2% vs. 56.5%; P = 0.46), resistant disease (15.8% vs. 23.6%; P = 0.51), three years overall survival (44% vs 42%; P= 0.85) and disease free survival (42.1% vs. 38.9%, P = 0.74). Multivariate analysis showed that age was the strongest unfavorable factor for overall survival (relative risk [RR], 1.9; P = 0.002), followed by cytogenetics (P = 0.004). FAB types, N-RAS mutation and leukocytosis were the least important. In conclusion, the frequency and spectrum of N-RAS gene mutation differ between biologically distinct subtypes of AML but do not significantly influence prognosis and clinical outcome in patients with AML.

  7. TET2 mutations in cytogenetically normal acute myeloid leukemia: clinical implications and evolutionary patterns.

    Science.gov (United States)

    Damm, Frederik; Markus, Birgit; Thol, Felicitas; Morgan, Michael; Göhring, Gudrun; Schlegelberger, Brigitte; Krauter, Jürgen; Heuser, Michael; Bernard, Olivier A; Ganser, Arnold

    2014-10-01

    Mutations of the Ten-Eleven-Translocation 2 (TET2) gene have been identified in patients with various myeloid neoplasms, but the clinical relevance of these mutations and their timing during disease development in cytogenetically normal acute myeloid leukemia (CN-AML) remain unclear. The total coding region of TET2 was analyzed by direct sequencing in 215 CN-AML patients younger than 60 years from multicenter treatment trials AML-SHG 0199 (ClinicalTrials Identifier NCT00209833) and 0295. Associations were analyzed in the context of other molecular markers, such as CEBPA, DNMT3A, NMP1, FLT3, IDH1/2, RAS, and WT1. To investigate the order of appearance of TET2 and concomitant mutations, targeted deep resequencing was performed in six patients. At least one sequence variation with impact on TET2 protein sequence was found in 13 of the 215 CN-AML patients (6%). Patients with TET2 mutations tended to be older (P = 0.078) and had higher platelet counts (P = 0.041). TET2-mutated patients were more likely to have concomitant NPM1 (11 of 13; P = 0.047) and DNMT3A (10 of 13; P = 0.001) mutations but were mutually exclusive to partial tandem duplication of the MLL gene (MLL-PTD) and IDH1/2 mutations. TET2 mutations were identified as subclones in four of the six investigated patients by deep sequencing. Progenitor-derived colony assays suggest a stepwise acquisition of mutations during disease development, TET2 mutation being later than NPM1 and DNMT3A. The TET2 mutation status did not influence overall or relapse-free survival.

  8. Mouse models of NPM1-mutated acute myeloid leukemia: biological and clinical implications.

    Science.gov (United States)

    Sportoletti, P; Varasano, E; Rossi, R; Mupo, A; Tiacci, E; Vassiliou, G; Martelli, M P; Falini, B

    2015-02-01

    Acute myeloid leukemia (AML) carrying nucleophosmin (NPM1) mutations displays distinct biological and clinical features that led to its inclusion as a provisional disease entity in the 2008 World Health Organization (WHO) classification of myeloid neoplasms. Studies of the molecular mechanisms underlying the pathogenesis of NPM1-mutated AML have benefited greatly from several mouse models of this leukemia developed over the past few years. Immunocompromised mice xenografted with NPM1-mutated AML served as the first valuable tool for defining the biology of the disease in vivo. Subsequently, genetically engineered mouse models of the NPM1 mutation, including transgenic and knock-in alleles, allowed the generation of mice with a constant genotype and a reproducible phenotype. These models have been critical for investigating the nature of the molecular effects of these mutations, defining the function of leukemic stem cells in NPM1-mutated AML, identifying chemoresistant preleukemic hemopoietic stem cells and unraveling the key molecular events that cooperate with NPM1 mutations to induce AML in vivo. Moreover, they can serve as a platform for the discovery and validation of new antileukemic drugs in vivo. Advances derived from the analysis of these mouse models promise to greatly accelerate the development of new molecularly targeted therapies for patients with NPM1-mutated AML.

  9. Host-selected mutations converging on a global regulator drive an adaptive leap towards symbiosis in bacteria

    Science.gov (United States)

    Sabrina Pankey, M; Foxall, Randi L; Ster, Ian M; Perry, Lauren A; Schuster, Brian M; Donner, Rachel A; Coyle, Matthew; Cooper, Vaughn S; Whistler, Cheryl A

    2017-01-01

    Host immune and physical barriers protect against pathogens but also impede the establishment of essential symbiotic partnerships. To reveal mechanisms by which beneficial organisms adapt to circumvent host defenses, we experimentally evolved ecologically distinct bioluminescent Vibrio fischeri by colonization and growth within the light organs of the squid Euprymna scolopes. Serial squid passaging of bacteria produced eight distinct mutations in the binK sensor kinase gene, which conferred an exceptional selective advantage that could be demonstrated through both empirical and theoretical analysis. Squid-adaptive binK alleles promoted colonization and immune evasion that were mediated by cell-associated matrices including symbiotic polysaccharide (Syp) and cellulose. binK variation also altered quorum sensing, raising the threshold for luminescence induction. Preexisting coordinated regulation of symbiosis traits by BinK presented an efficient solution where altered BinK function was the key to unlock multiple colonization barriers. These results identify a genetic basis for microbial adaptability and underscore the importance of hosts as selective agents that shape emergent symbiont populations. DOI: http://dx.doi.org/10.7554/eLife.24414.001 PMID:28447935

  10. Large family with both parents affected by distinct BRCA1 mutations: implications for genetic testing

    Directory of Open Access Journals (Sweden)

    Sokolenko Anna P

    2009-01-01

    Full Text Available Abstract Although the probability of both parents being affected by BRCA1 mutations is not negligible, such families have not been systematically described in the literature. Here we present a large breast-ovarian cancer family, where 3 sisters and 1 half-sister inherited maternal BRCA1 5382insC mutation while the remaining 2 sisters carried paternal BRCA1 1629delC allele. No BRCA1 homozygous mutations has been detected, that is consistent with the data on lethality of BRCA1 knockout mice. This report exemplifies that the identification of a single cancer-predisposing mutation within the index patient may not be sufficient in some circumstances. Ideally, all family members affected by breast or ovarian tumor disease have to be subjected to the DNA testing, and failure to detect the mutation in any of them calls for the search of the second cancer-associated allele.

  11. Large family with both parents affected by distinct BRCA1 mutations: implications for genetic testing

    Science.gov (United States)

    Sokolenko, Anna P; Voskresenskiy, Dmitry A; Iyevleva, Aglaya G; Bit-Sava, Elena M; Gutkina, Nadezhda I; Anisimenko, Maxim S; Yu Sherina, Nathalia; Mitiushkina, Nathalia V; Ulibina, Yulia M; Yatsuk, Olga S; Zaitseva, Olga A; Suspitsin, Evgeny N; Togo, Alexandr V; Pospelov, Valery A; Kovalenko, Sergey P; Semiglazov, Vladimir F; Imyanitov, Evgeny N

    2009-01-01

    Although the probability of both parents being affected by BRCA1 mutations is not negligible, such families have not been systematically described in the literature. Here we present a large breast-ovarian cancer family, where 3 sisters and 1 half-sister inherited maternal BRCA1 5382insC mutation while the remaining 2 sisters carried paternal BRCA1 1629delC allele. No BRCA1 homozygous mutations has been detected, that is consistent with the data on lethality of BRCA1 knockout mice. This report exemplifies that the identification of a single cancer-predisposing mutation within the index patient may not be sufficient in some circumstances. Ideally, all family members affected by breast or ovarian tumor disease have to be subjected to the DNA testing, and failure to detect the mutation in any of them calls for the search of the second cancer-associated allele. PMID:19338681

  12. Addressing potential local adaptation in species distribution models: implications for conservation under climate change

    Science.gov (United States)

    Hällfors, Maria Helena; Liao, Jishan; Dzurisin, Jason D. K.; Grundel, Ralph; Hyvärinen, Marko; Towle, Kevin; Wu, Grace C.; Hellmann, Jessica J.

    2016-01-01

    Species distribution models (SDMs) have been criticized for involving assumptions that ignore or categorize many ecologically relevant factors such as dispersal ability and biotic interactions. Another potential source of model error is the assumption that species are ecologically uniform in their climatic tolerances across their range. Typically, SDMs to treat a species as a single entity, although populations of many species differ due to local adaptation or other genetic differentiation. Not taking local adaptation into account, may lead to incorrect range prediction and therefore misplaced conservation efforts. A constraint is that we often do not know the degree to which populations are locally adapted, however. Lacking experimental evidence, we still can evaluate niche differentiation within a species' range to promote better conservation decisions. We explore possible conservation implications of making type I or type II errors in this context. For each of two species, we construct three separate MaxEnt models, one considering the species as a single population and two of disjunct populations. PCA analyses and response curves indicate different climate characteristics in the current environments of the populations. Model projections into future climates indicate minimal overlap between areas predicted to be climatically suitable by the whole species versus population-based models. We present a workflow for addressing uncertainty surrounding local adaptation in SDM application and illustrate the value of conducting population-based models to compare with whole-species models. These comparisons might result in more cautious management actions when alternative range outcomes are considered.

  13. Addressing potential local adaptation in species distribution models: implications for conservation under climate change.

    Science.gov (United States)

    Hällfors, Maria Helena; Liao, Jishan; Dzurisin, Jason; Grundel, Ralph; Hyvärinen, Marko; Towle, Kevin; Wu, Grace C; Hellmann, Jessica J

    2016-06-01

    Species distribution models (SDMs) have been criticized for involving assumptions that ignore or categorize many ecologically relevant factors such as dispersal ability and biotic interactions. Another potential source of model error is the assumption that species are ecologically uniform in their climatic tolerances across their range. Typically, SDMs treat a species as a single entity, although populations of many species differ due to local adaptation or other genetic differentiation. Not taking local adaptation into account may lead to incorrect range prediction and therefore misplaced conservation efforts. A constraint is that we often do not know the degree to which populations are locally adapted. Lacking experimental evidence, we still can evaluate niche differentiation within a species' range to promote better conservation decisions. We explore possible conservation implications of making type I or type II errors in this context. For each of two species, we construct three separate Max-Ent models, one considering the species as a single population and two of disjunct populations. Principal component analyses and response curves indicate different climate characteristics in the current environments of the populations. Model projections into future climates indicate minimal overlap between areas predicted to be climatically suitable by the whole species vs. population-based models. We present a workflow for addressing uncertainty surrounding local adaptation in SDM application and illustrate the value of conducting population-based models to compare with whole-species models. These comparisons might result in more cautious management actions when alternative range outcomes are considered.

  14. X-ray diffraction from flight muscle with a headless myosin mutation: implications for interpreting reflection patterns

    Science.gov (United States)

    Iwamoto, Hiroyuki; Trombitás, Károly; Yagi, Naoto; Suggs, Jennifer A.; Bernstein, Sanford I.

    2014-01-01

    Fruit fly (Drosophila melanogaster) is one of the most useful animal models to study the causes and effects of hereditary diseases because of its rich genetic resources. It is especially suitable for studying myopathies caused by myosin mutations, because specific mutations can be induced to the flight muscle-specific myosin isoform, while leaving other isoforms intact. Here we describe an X-ray-diffraction-based method to evaluate the structural effects of mutations in contractile proteins in Drosophila indirect flight muscle. Specifically, we describe the effect of the headless myosin mutation, Mhc10-Y97, in which the motor domain of the myosin head is deleted, on the X-ray diffraction pattern. The loss of general integrity of the filament lattice is evident from the pattern. A striking observation, however, is the prominent meridional reflection at d = 14.5 nm, a hallmark for the regularity of the myosin-containing thick filament. This reflection has long been considered to arise mainly from the myosin head, but taking the 6th actin layer line reflection as an internal control, the 14.5-nm reflection is even stronger than that of wild-type muscle. We confirmed these results via electron microscopy, wherein image analysis revealed structures with a similar periodicity. These observations have major implications on the interpretation of myosin-based reflections. PMID:25400584

  15. Breast cancer risk and clinical implications for germline PTEN mutation carriers.

    Science.gov (United States)

    Ngeow, Joanne; Sesock, Kaitlin; Eng, Charis

    2017-08-01

    PTEN Hamartoma Tumor syndrome (PHTS) encompasses a clinical spectrum of heritable disorders including Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome, and Proteus and Proteus-like syndrome that are associated with germline mutations in the PTEN tumor suppressor gene. Breast cancer risk estimates (67-85 %) for women with germline PTEN mutations are similar to those quoted for patients with germline mutations in the BRCA1/2 genes. With PTEN on several germline gene testing panels, finding PTEN mutations and variants have increased exponentially. PHTS can be differentiated from other hereditary cancer syndromes including Hereditary Breast Ovarian Cancer syndrome, Lynch syndrome, and hamartomatous polyposis syndromes based on personal as well as family history. However, many of the benign features of CS are common in the general population, making the diagnosis of CS challenging. Breast cancer patients with an identified germline PTEN mutation are at increased risk of endometrial, thyroid, renal, and colorectal cancers as well as a second breast cancer. Increased screening for the various component cancers as well as predictive testing in first-degree relatives is recommended. Prophylactic mastectomy may be considered especially if breast tissue is dense or if repeated breast biopsies have been necessary. Management of women with breast cancer suspected of CS who test negative for germline PTEN mutations should be managed as per a mutation carrier if she meets CS diagnostic criteria, and should be offered enrollment in research to identify other predisposition genes.

  16. Constitutive RB1 mutation in a child conceived by in vitro fertilization: implications for genetic counseling

    Directory of Open Access Journals (Sweden)

    Lucena Evandro

    2009-07-01

    Full Text Available Abstract Background The purpose of this study was to identify mutations associated with bilateral retinoblastoma in a quadruplet conceived by in vitro fertilization, and to trace the parental origin of mutations in the four quadruplets and their father. Methods Mutational screening was carried out by sequencing. Genotyping was carried out for determining quadruplet zygosity. Results The proband was a carrier of a novel RB1 constitutive mutation (g.2056C>G which was not detected in her father or her unaffected sisters, and of two other mutations (g.39606 C>T and g.174351T>A also present in two monozygotic sisters. The novel mutation probably occurred de novo while the others were of likely maternal origin. The novel mutation, affecting the Kozak consensus at the 5'UTR of RB1 and g.174351T>A were likely associated to retinoblastoma in the proband. Conclusion Molecular diagnosis of retinoblastoma requires genotypic data of the family for determining hereditary transmission. In the case of children generated by IVF with oocytes from an anonymous donor which had been stored in a cell repository, this might not be successfully accomplished, making precise diagnosis impracticable for genetic counseling.

  17. Replication and adaptive mutations of low pathogenic avian influenza viruses in tracheal organ cultures of different avian species.

    Directory of Open Access Journals (Sweden)

    Henning Petersen

    Full Text Available Transmission of avian influenza viruses (AIV between different avian species may require genome mutations that allow efficient virus replication in a new species and could increase virulence. To study the role of domestic poultry in the evolution of AIV we compared replication of low pathogenic (LP AIV of subtypes H9N2, H7N7 and H6N8 in tracheal organ cultures (TOC and primary embryo fibroblast cultures of chicken, turkey, Pekin duck and homing pigeon. Virus strain-dependent and avian species-related differences between LPAIV were observed in growth kinetics and induction of ciliostasis in TOC. In particular, our data demonstrate high susceptibility to LPAIV of turkey TOC contrasted with low susceptibility of homing pigeon TOC. Serial virus passages in the cells of heterologous host species resulted in adaptive mutations in the AIV genome, especially in the receptor-binding site and protease cleavage site of the hemagglutinin. Our data highlight differences in susceptibility of different birds to AIV viruses and emphasizes potential role of poultry in the emergence of new virus variants.

  18. No Incidence of BRAF Mutations in Salivary Gland Carcinomas—Implications for Anti-EGFR Therapies

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    Regine Dahse

    2009-01-01

    These findings imply that SGC rarely acquires mutations that result in a constitutive activation of the signaling cascade downstream of EGFR and this pleads in favor of further therapeutic trials with EGFR-targeting monoclonal antibodies.

  19. Microevolutionary, macroevolutionary, ecological and taxonomical implications of punctuational theories of adaptive evolution.

    Science.gov (United States)

    Flegr, Jaroslav

    2013-01-16

    Punctuational theories of evolution suggest that adaptive evolution proceeds mostly, or even entirely, in the distinct periods of existence of a particular species. The mechanisms of this punctuated nature of evolution suggested by the various theories differ. Therefore the predictions of particular theories concerning various evolutionary phenomena also differ.Punctuational theories can be subdivided into five classes, which differ in their mechanism and their evolutionary and ecological implications. For example, the transilience model of Templeton (class III), genetic revolution model of Mayr (class IV) or the frozen plasticity theory of Flegr (class V), suggests that adaptive evolution in sexual species is operative shortly after the emergence of a species by peripatric speciation--while it is evolutionary plastic. To a major degree, i.e. throughout 98-99% of their existence, sexual species are evolutionarily frozen (class III) or elastic (class IV and V) on a microevolutionary time scale and evolutionarily frozen on a macroevolutionary time scale and can only wait for extinction, or the highly improbable return of a population segment to the plastic state due to peripatric speciation.The punctuational theories have many evolutionary and ecological implications. Most of these predictions could be tested empirically, and should be analyzed in greater depth theoretically. The punctuational theories offer many new predictions that need to be tested, but also provide explanations for a much broader spectrum of known biological phenomena than classical gradualistic evolutionary theories.

  20. Hyperactive Arg39Lys mutated mnemiopsin: implication of positively charged residue in chromophore binding cavity.

    Science.gov (United States)

    Mahdavi, Atiyeh; Sajedi, Reza H; Hosseinkhani, Saman; Taghdir, Majid

    2015-04-01

    Mnemiopsin, a Ca(2+)-regulated photoprotein isolated from Mnemiopsis leidyi, belongs to the family of ctenophore photoproteins. These proteins emit blue light from a chromophore, which is tightly but non-covalently bound in their central hydrophobic core that contains 21 conserved residues. In an effort to investigate the role of Arg39 (the sole charged residue in coelenterazine binding cavity of ctenophore photoproteins) in bioluminescence properties of these photoproteins, three mutated forms of mnemiopsin 1 (R39E, R39K and R39M) were constructed and characterized. The results indicate that while the luminescence activity of R39K mutated mnemiopsin has increased about nine fold compared to the wild type, R39M and R39E mutated mnemiopsins have entirely lost their activities. The most distinguished properties of R39K mutated photoprotein are its high activity, slow rate of luminescence decay and broad pH profile compared to the wild type. The complete loss of bioluminescence activity in mutated photoproteins with negatively charged and aliphatic residues (R39E and R39M, respectively) shows that the presence of a positively charged residue at this position is necessary. The results of spectroscopic studies, including CD, intrinsic and extrinsic fluorescence measurements and acrylamide quenching studies show that, while the substitutions lead to structural rigidity in R39E and R39M mutated mnemiopsins, structural flexibility is obvious in R39K mutated mnemiopsin. The presence of a more localized positive charge on ε-amino group of Lys compared to guanidinium group of Arg residue in close proximity to the choromophre might affect its fixation in the binding cavity and result in increased bioluminescence activity in this mutated photoprotein. It appears that the polarity and flexibility of positively charged residue at this position finely tunes the luminescence properties of ctenophore photoproteins.

  1. Identification of adaptive mutations in the influenza A virus non-structural 1 gene that increase cytoplasmic localization and differentially regulate host gene expression.

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    Nicole Forbes

    Full Text Available The NS1 protein of influenza A virus (IAV is a multifunctional virulence factor. We have previously characterized gain-of-function mutations in the NS1 protein arising from the experimental adaptation of the human isolate A/Hong Kong/1/1968(H3N2 (HK to the mouse. The majority of these mouse adapted NS1 mutations were demonstrated to increase virulence, viral fitness, and interferon antagonism, but differ in binding to the post-transcriptional processing factor cleavage and polyadenylation specificity factor 30 (CPSF30. Because nuclear trafficking is a major genetic determinant of influenza virus host adaptation, we assessed subcellular localization and host gene expression of NS1 adaptive mutations. Recombinant HK viruses with adaptive mutations in the NS1 gene were assessed for NS1 protein subcellular localization in mouse and human cells using confocal microscopy and cellular fractionation. In human cells the HK wild-type (HK-wt virus NS1 protein partitioned equivalently between the cytoplasm and nucleus but was defective in cytoplasmic localization in mouse cells. Several adaptive mutations increased the proportion of NS1 in the cytoplasm of mouse cells with the greatest effects for mutations M106I and D125G. The host gene expression profile of the adaptive mutants was determined by microarray analysis of infected mouse cells to show either high or low extents of host-gene regulation (HGR or LGR phenotypes. While host genes were predominantly down regulated for the HGR group of mutants (D2N, V23A, F103L, M106I+L98S, L98S, M106V, and M106V+M124I, the LGR phenotype mutants (D125G, M106I, V180A, V226I, and R227K were characterized by a predominant up regulation of host genes. CPSF30 binding affinity of NS1 mutants did not predict effects on host gene expression. To our knowledge this is the first report of roles of adaptive NS1 mutations that impact intracellular localization and regulation of host gene expression.

  2. Identification of Adaptive Mutations in the Influenza A Virus Non-Structural 1 Gene That Increase Cytoplasmic Localization and Differentially Regulate Host Gene Expression

    Science.gov (United States)

    Forbes, Nicole; Selman, Mohammed; Pelchat, Martin; Jia, Jian Jun; Stintzi, Alain; Brown, Earl G.

    2013-01-01

    The NS1 protein of influenza A virus (IAV) is a multifunctional virulence factor. We have previously characterized gain-of-function mutations in the NS1 protein arising from the experimental adaptation of the human isolate A/Hong Kong/1/1968(H3N2) (HK) to the mouse. The majority of these mouse adapted NS1 mutations were demonstrated to increase virulence, viral fitness, and interferon antagonism, but differ in binding to the post-transcriptional processing factor cleavage and polyadenylation specificity factor 30 (CPSF30). Because nuclear trafficking is a major genetic determinant of influenza virus host adaptation, we assessed subcellular localization and host gene expression of NS1 adaptive mutations. Recombinant HK viruses with adaptive mutations in the NS1 gene were assessed for NS1 protein subcellular localization in mouse and human cells using confocal microscopy and cellular fractionation. In human cells the HK wild-type (HK-wt) virus NS1 protein partitioned equivalently between the cytoplasm and nucleus but was defective in cytoplasmic localization in mouse cells. Several adaptive mutations increased the proportion of NS1 in the cytoplasm of mouse cells with the greatest effects for mutations M106I and D125G. The host gene expression profile of the adaptive mutants was determined by microarray analysis of infected mouse cells to show either high or low extents of host-gene regulation (HGR or LGR) phenotypes. While host genes were predominantly down regulated for the HGR group of mutants (D2N, V23A, F103L, M106I+L98S, L98S, M106V, and M106V+M124I), the LGR phenotype mutants (D125G, M106I, V180A, V226I, and R227K) were characterized by a predominant up regulation of host genes. CPSF30 binding affinity of NS1 mutants did not predict effects on host gene expression. To our knowledge this is the first report of roles of adaptive NS1 mutations that impact intracellular localization and regulation of host gene expression. PMID:24391972

  3. Molecular dynamics of mesophilic-like mutants of a cold-adapted enzyme: insights into distal effects induced by the mutations.

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    Elena Papaleo

    Full Text Available Networks and clusters of intramolecular interactions, as well as their "communication" across the three-dimensional architecture have a prominent role in determining protein stability and function. Special attention has been dedicated to their role in thermal adaptation. In the present contribution, seven previously experimentally characterized mutants of a cold-adapted α-amylase, featuring mesophilic-like behavior, have been investigated by multiple molecular dynamics simulations, essential dynamics and analyses of correlated motions and electrostatic interactions. Our data elucidate the molecular mechanisms underlying the ability of single and multiple mutations to globally modulate dynamic properties of the cold-adapted α-amylase, including both local and complex unpredictable distal effects. Our investigation also shows, in agreement with the experimental data, that the conversion of the cold-adapted enzyme in a warm-adapted variant cannot be completely achieved by the introduction of few mutations, also providing the rationale behind these effects. Moreover, pivotal residues, which are likely to mediate the effects induced by the mutations, have been identified from our analyses, as well as a group of suitable candidates for protein engineering. In fact, a subset of residues here identified (as an isoleucine, or networks of mesophilic-like salt bridges in the proximity of the catalytic site should be considered, in experimental studies, to get a more efficient modification of the features of the cold-adapted enzyme.

  4. Proliferation and survival molecules implicated in the inhibition of BRAF pathway in thyroid cancer cells harbouring different genetic mutations

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    Seca Hugo

    2009-10-01

    Full Text Available Abstract Background Thyroid carcinomas show a high prevalence of mutations in the oncogene BRAF which are inversely associated with RAS or RET/PTC oncogenic activation. The possibility of using inhibitors on the BRAF pathway as became an interesting therapeutic approach. In thyroid cancer cells the target molecules, implicated on the cellular effects, mediated by inhibition of BRAF are not well established. In order to fill this lack of knowledge we studied the proliferation and survival pathways and associated molecules induced by BRAF inhibition in thyroid carcinoma cell lines harbouring distinct genetic backgrounds. Methods Suppression of BRAF pathway in thyroid cancer cell lines (8505C, TPC1 and C643 was achieved using RNA interference (RNAi for BRAF and the kinase inhibitor, sorafenib. Proliferation analysis was performed by BrdU incorporation and apoptosis was accessed by TUNEL assay. Levels of protein expression were analysed by western-blot. Results Both BRAF RNAi and sorafenib inhibited proliferation in all the cell lines independently of the genetic background, mostly in cells with BRAFV600E mutation. In BRAFV600E mutated cells inhibition of BRAF pathway lead to a decrease in ERK1/2 phosphorylation and cyclin D1 levels and an increase in p27Kip1. Specific inhibition of BRAF by RNAi in cells with BRAFV600E mutation had no effect on apoptosis. In the case of sorafenib treatment, cells harbouring BRAFV600E mutation showed increase levels of apoptosis due to a balance of the anti-apoptotic proteins Mcl-1 and Bcl-2. Conclusion Our results in thyroid cancer cells, namely those harbouring BRAFV600Emutation showed that BRAF signalling pathway provides important proliferation signals. We have shown that in thyroid cancer cells sorafenib induces apoptosis by affecting Mcl-1 and Bcl-2 in BRAFV600E mutated cells which was independent of BRAF. These results suggest that sorafenib may prove useful in the treatment of thyroid carcinomas, particularly

  5. Time-Resolved Tracking of Mutations Reveals Diverse Allele Dynamics during Escherichia coli Antimicrobial Adaptive Evolution to Single Drugs and Drug Pairs

    DEFF Research Database (Denmark)

    Hickman, Rachel A.; Munck, Christian; Sommer, Morten Otto Alexander

    2017-01-01

    at several time-points during adaptive evolution experiments involving five different antibiotic conditions. We monitor the mutational spectra in lineages evolved to be resistant to single antibiotics [amikacin (AMK), chloramphenicol (CHL), and ciprofloxacin (CIP)], as well as antibiotic combinations (AMK...

  6. A novel homozygous truncating GNAT1 mutation implicated in retinal degeneration.

    LENUS (Irish Health Repository)

    Carrigan, Matthew

    2016-04-01

    The GNAT1 gene encodes the α subunit of the rod transducin protein, a key element in the rod phototransduction cascade. Variants in GNAT1 have been implicated in stationary night-blindness in the past, but unlike other proteins in the same pathway, it has not previously been implicated in retinitis pigmentosa.

  7. The implication of dihydrofolate reductase and dihydropteroate synthetase gene mutations in modification of Plasmodium falciparum characteristics

    DEFF Research Database (Denmark)

    A-Elbasit, Ishraga E; Alifrangis, Michael; Khalil, Insaf F

    2007-01-01

    the effects of dhfr/dhps mutations on parasite characteristics other than SP resistance. METHOD: Parasite infections obtained from 153 Sudanese patients with uncomplicated falciparum malaria treated with SP or SP + chloroquine, were successfully genotyped at nine codons in the dhfr/dhps genes by PCR......BACKGROUND: The Plasmodium falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) are enzymes of central importance in parasite metabolism. The dhfr and dhps gene mutations are known to be associated with sulphadoxine/pyrimethamine (SP) resistance. OBJECTIVE: To investigate...

  8. Melanoma-Derived BRAFV600E Mutation in Peritumoral Stromal Cells: Implications for in Vivo Cell Fusion

    Directory of Open Access Journals (Sweden)

    Zsuzsanna Kurgyis

    2016-06-01

    Full Text Available Melanoma often recurs in patients after the removal of the primary tumor, suggesting the presence of recurrent tumor-initiating cells that are undetectable using standard diagnostic methods. As cell fusion has been implicated to facilitate the alteration of a cell’s phenotype, we hypothesized that cells in the peritumoral stroma having a stromal phenotype that initiate recurrent tumors might originate from the fusion of tumor and stromal cells. Here, we show that in patients with BRAFV600E melanoma, melanoma antigen recognized by T-cells (MART1-negative peritumoral stromal cells express BRAFV600E protein. To confirm the presence of the oncogene at the genetic level, peritumoral stromal cells were microdissected and screened for the presence of BRAFV600E with a mutation-specific polymerase chain reaction. Interestingly, cells carrying the BRAFV600E mutation were not only found among cells surrounding the primary tumor but were also present in the stroma of melanoma metastases as well as in a histologically tumor-free re-excision sample from a patient who subsequently developed a local recurrence. We did not detect any BRAFV600E mutation or protein in the peritumoral stroma of BRAFWT melanoma. Therefore, our results suggest that peritumoral stromal cells contain melanoma-derived oncogenic information, potentially as a result of cell fusion. These hybrid cells display the phenotype of stromal cells and are therefore undetectable using routine histological assessments. Our results highlight the importance of genetic analyses and the application of mutation-specific antibodies in the identification of potentially recurrent-tumor-initiating cells, which may help better predict patient survival and disease outcome.

  9. Melanoma-Derived BRAF(V600E) Mutation in Peritumoral Stromal Cells: Implications for in Vivo Cell Fusion.

    Science.gov (United States)

    Kurgyis, Zsuzsanna; Kemény, Lajos V; Buknicz, Tünde; Groma, Gergely; Oláh, Judit; Jakab, Ádám; Polyánka, Hilda; Zänker, Kurt; Dittmar, Thomas; Kemény, Lajos; Németh, István B

    2016-06-21

    Melanoma often recurs in patients after the removal of the primary tumor, suggesting the presence of recurrent tumor-initiating cells that are undetectable using standard diagnostic methods. As cell fusion has been implicated to facilitate the alteration of a cell's phenotype, we hypothesized that cells in the peritumoral stroma having a stromal phenotype that initiate recurrent tumors might originate from the fusion of tumor and stromal cells. Here, we show that in patients with BRAF(V600E) melanoma, melanoma antigen recognized by T-cells (MART1)-negative peritumoral stromal cells express BRAF(V600E) protein. To confirm the presence of the oncogene at the genetic level, peritumoral stromal cells were microdissected and screened for the presence of BRAF(V600E) with a mutation-specific polymerase chain reaction. Interestingly, cells carrying the BRAF(V600E) mutation were not only found among cells surrounding the primary tumor but were also present in the stroma of melanoma metastases as well as in a histologically tumor-free re-excision sample from a patient who subsequently developed a local recurrence. We did not detect any BRAF(V600E) mutation or protein in the peritumoral stroma of BRAF(WT) melanoma. Therefore, our results suggest that peritumoral stromal cells contain melanoma-derived oncogenic information, potentially as a result of cell fusion. These hybrid cells display the phenotype of stromal cells and are therefore undetectable using routine histological assessments. Our results highlight the importance of genetic analyses and the application of mutation-specific antibodies in the identification of potentially recurrent-tumor-initiating cells, which may help better predict patient survival and disease outcome.

  10. Mutation in PHC1 implicates chromatin remodeling in primary microcephaly pathogenesis.

    Science.gov (United States)

    Awad, Salma; Al-Dosari, Mohammed S; Al-Yacoub, Nadya; Colak, Dilek; Salih, Mustafa A; Alkuraya, Fowzan S; Poizat, Coralie

    2013-06-01

    Primary microcephaly (PM) is a developmental disorder of early neuroprogenitors that results in reduction of the brain mass, particularly the cortex. To gain fresh insight into the pathogenesis of PM, we describe a consanguineous family with a novel genetic variant responsible for the disease. We performed autozygosity mapping followed by exome sequencing to detect the causal genetic variant. Several functional assays in cells expressing the wild-type or mutant gene were performed to understand the pathogenesis of the identified mutation. We identify a novel mutation in PHC1, a human orthologue of the Drosophila polyhomeotic member of polycomb group (PcG), which significantly decreases PHC1 protein expression, increases Geminin protein level and markedly abolishes the capacity to ubiquitinate histone H2A in patient cells. PHC1 depletion in control cells similarly enhances Geminin expression and decreases histone H2A ubiquitination. The ubiquitination defect and accumulation of Geminin with consequent defect in cell cycle are rescued by over-expression of PHC1 in patient cells. Although patients with the PHC1 mutation exhibit PM with no overt progression of the disease, patient cells also show aberrant DNA damage repair, which is rescued by PHC1 overexpression. These findings reveal several cellular defects in cells carrying the PHC1 mutation and highlight the role of chromatin remodeling in the pathogenesis of PM.

  11. Mutational properties of amino acid residues: implications for evolvability of phosphorylatable residues

    DEFF Research Database (Denmark)

    Creixell, Pau; Schoof, Erwin M.; Tan, Chris Soon Heng

    2012-01-01

    As François Jacob pointed out over 30 years ago, evolution is a tinkering process, and, as such, relies on the genetic diversity produced by mutation subsequently shaped by Darwinian selection. However, there is one implicit assumption that is made when studying this tinkering process; it is typi...

  12. Clinical applications and implications of common and founder mutations in Indian subpopulations.

    Science.gov (United States)

    Ankala, Arunkanth; Tamhankar, Parag M; Valencia, C Alexander; Rayam, Krishna K; Kumar, Manisha M; Hegde, Madhuri R

    2015-01-01

    South Asian Indians represent a sixth of the world's population and are a racially, geographically, and genetically diverse people. Their unique anthropological structure, prevailing caste system, and ancient religious practices have all impacted the genetic composition of most of the current-day Indian population. With the evolving socio-religious and economic activities of the subsects and castes, endogamous and consanguineous marriages became a commonplace. Consequently, the frequency of founder mutations and the burden of heritable genetic disorders rose significantly. Specifically, the incidence of certain autosomal-recessive disorders is relatively high in select Indian subpopulations and communities that share common recent ancestry. Although today clinical genetics and molecular diagnostic services are making inroads in India, the high costs associated with the technology and the tests often keep patients from an exact molecular diagnosis, making more customized and tailored tests, such as those interrogating the most common and founder mutations or those that cater to select sects within the population, highly attractive. These tests offer a quick first-hand affordable diagnostic and carrier screening tool. Here, we provide a comprehensive catalog of known common mutations and founder mutations in the Indian population and discuss them from a molecular, clinical, and historical perspective.

  13. Microevolutionary, macroevolutionary, ecological and taxonomical implications of punctuational theories of adaptive evolution

    Directory of Open Access Journals (Sweden)

    Flegr Jaroslav

    2013-01-01

    Full Text Available Abstract Punctuational theories of evolution suggest that adaptive evolution proceeds mostly, or even entirely, in the distinct periods of existence of a particular species. The mechanisms of this punctuated nature of evolution suggested by the various theories differ. Therefore the predictions of particular theories concerning various evolutionary phenomena also differ. Punctuational theories can be subdivided into five classes, which differ in their mechanism and their evolutionary and ecological implications. For example, the transilience model of Templeton (class III, genetic revolution model of Mayr (class IV or the frozen plasticity theory of Flegr (class V, suggests that adaptive evolution in sexual species is operative shortly after the emergence of a species by peripatric speciation – while it is evolutionary plastic. To a major degree, i.e. throughout 98-99% of their existence, sexual species are evolutionarily frozen (class III or elastic (class IV and V on a microevolutionary time scale and evolutionarily frozen on a macroevolutionary time scale and can only wait for extinction, or the highly improbable return of a population segment to the plastic state due to peripatric speciation. The punctuational theories have many evolutionary and ecological implications. Most of these predictions could be tested empirically, and should be analyzed in greater depth theoretically. The punctuational theories offer many new predictions that need to be tested, but also provide explanations for a much broader spectrum of known biological phenomena than classical gradualistic evolutionary theories. Reviewers This article was reviewed by Claus Wilke, Pierre Pantarotti and David Penny (nominated by Anthony Poole.

  14. Fanconi anaemia, BRCA2 mutations and childhood cancer: a developmental perspective from clinical and epidemiological observations with implications for genetic counselling.

    Science.gov (United States)

    Meyer, Stefan; Tischkowitz, Marc; Chandler, Kate; Gillespie, Alan; Birch, Jillian M; Evans, D Gareth

    2014-02-01

    Fanconi anaemia (FA) is an inherited condition characterised by congenital and developmental abnormalities and a strong cancer predisposition. In around 3-5% of cases FA is caused by biallelic mutations in the BRCA2 gene. Individuals heterozygous for BRCA2 mutations have an increased risk of inherited breast and ovarian cancer. We reviewed the mutation spectrum in BRCA2-associated FA, and the spectrum and frequency of BRCA2 mutations in distinct populations. The rarity of FA due to biallelic BRCA2 mutations supports a fundamental role of BRCA2 for prevention of malignant transformation during development. The spectrum of malignancies seen associated with FA support the concept of a tissue selectivity of BRCA2 mutations for development of FA-associated cancers. This specificity is illustrated by the distinct FA-associated BRCA2 mutations that appear to predispose to specific brain or haematological malignancies. For some populations, the number of FA-patients with biallelic BRCA2 disruption is smaller than that expected from the carrier frequency, and this implies that some pregnancies with biallelic BRCA2 mutations do not go to term. The apparent discrepancy between expected and observed incidence of BRCA2 mutation-associated FA in high-frequency carrier populations has important implications for the genetic counselling of couples with recurrent miscarriages from high-risk populations.

  15. Genetic adaptation of Pseudomonas aeruginosa during chronic lung infection of patients with cystic fibrosis: strong and weak mutators with heterogeneous genetic backgrounds emerge in mucA and/or lasR mutants

    DEFF Research Database (Denmark)

    Ciofu, Oana; Mandsberg, Lotte F.; Bjarnsholt, Thomas

    2010-01-01

    During the chronic lung infection of patients with cystic fibrosis (CF), Pseudomonas aeruginosa can survive for long periods due to adaptive evolution mediated by genetic variation. Hypermutability is considered to play an important role in this adaptive evolution and it has been demonstrated tha...... evolutionary pathways concordant with adaptive radiation were observed in different clonal lineages of P. aeruginosa from CF patients.......During the chronic lung infection of patients with cystic fibrosis (CF), Pseudomonas aeruginosa can survive for long periods due to adaptive evolution mediated by genetic variation. Hypermutability is considered to play an important role in this adaptive evolution and it has been demonstrated...... that mutator populations are amplified in the CF lung by hitchhiking with adaptive mutations. Two of the genes that are frequently mutated in isolates from chronic infection are mucA and lasR. Loss-of-function mutations in these genes determine the phenotypic switch to mucoidy and loss of quorum sensing, which...

  16. Cancer-Specific Telomerase Reverse Transcriptase (TERT Promoter Mutations: Biological and Clinical Implications

    Directory of Open Access Journals (Sweden)

    Tiantian Liu

    2016-07-01

    Full Text Available The accumulated evidence has pointed to a key role of telomerase in carcinogenesis. As a RNA-dependent DNA polymerase, telomerase synthesizes telomeric DNA at the end of linear chromosomes, and attenuates or prevents telomere erosion associated with cell divisions. By lengthening telomeres, telomerase extends cellular life-span or even induces immortalization. Consistent with its functional activity, telomerase is silent in most human normal somatic cells while active only in germ-line, stem and other highly proliferative cells. In contrast, telomerase activation widely occurs in human cancer and the enzymatic activity is detectable in up to 90% of malignancies. Recently, hotspot point mutations in the regulatory region of the telomerase reverse transcriptase (TERT gene, encoding the core catalytic component of telomerase, was identified as a novel mechanism to activate telomerase in cancer. This review discusses the cancer-specific TERT promoter mutations and potential biological and clinical significances.

  17. Overview of hepatitis B virus mutations and their implications in the management of infection.

    Science.gov (United States)

    Caligiuri, Patrizia; Cerruti, Rita; Icardi, Giancarlo; Bruzzone, Bianca

    2016-01-07

    Hepatitis B virus (HBV) affects approximately two billion people worldwide and more than 240 million people in the world are currently chronic carrier that could develop serious complications in the future, like liver cirrhosis and hepatocellular carcinoma. Although an extended HBV immunization program is being carried out since the early '80s, representing effective preventive measure, leading to a dramatic reduction of HBV hepatitis incidence, globally HBV infection still represents a major public health problem. The HBV virus is a DNA virus belongs to the Hepadnaviridae family. The HBV-DNA is a circular, partial double strand genome. All coding information is on the minus DNA strand and it is organized into four open reading frames. Despite hepatitis B virus is a DNA virus, it has a high mutation rate due to its replicative strategy, that leads to the production of many non-identical variants at each cycle of replication. In fact, it contains a polymerase without the proofreading activity, and uses an RNA intermediate (pgRNA) during its replication, so error frequencies are comparable to those seen in retroviruses and other RNA viruses rather than in more stable DNA viruses. Due to the low fidelity of the polymerase, the high replication rate and the overlapping reading frames, mutations occur throughout the genome and they have been identified both in the structural and not structural gene. The arise of mutations being to develop of a whole of viral variants called "quasi-species" and the prevalent population, which favors virus replication, was selected by viral fitness, host's immune pressure and external pressure, i.e., vaccination or antiviral therapy. Naturally occurring mutations were found both in acute and chronic subjects. In the present review we examine and discuss the most recent available data about HBV genetic variability and its significance.

  18. Crystal structure of the yeast TSC1 core domain and implications for tuberous sclerosis pathological mutations.

    Science.gov (United States)

    Sun, Wei; Zhu, Ye Julia; Wang, Zhizhi; Zhong, Qiang; Gao, Feng; Lou, Jizhong; Gong, Weimin; Xu, Wenqing

    2013-01-01

    Tuberous sclerosis complex is a disease caused by mutations in two tumor-suppressor genes, TSC1 and TSC2. The TSC1 protein, also known as hamartin, has a critical role in controlling mTOR signalling. TSC1 does not bear apparent sequence homology with other proteins. Here we show that the N-terminal half of yeast TSC1 forms a protease-resistant domain, which is evolutionarily conserved. The crystal structure of this yeast TSC1 core domain shows that it contains a pseudo-HEAT repeat fold with its C-terminal end capped by a helical subdomain. This allows us to model the three-dimensional structure of the human TSC1 N-terminal domain (TSC1-NTD), which anchors essentially all pathogenic TSC1 missense mutations found in tuberous sclerosis patients. Interestingly, most pathogenic mutations map inside of the folded TSC1-NTD structure, whereas most non-pathogenic variants are on the structural surface. This indicates that the disruption of the TSC1-NTD globular structure is a major cause of tuberous sclerosis.

  19. Single arginine mutation in two yeast isocitrate dehydrogenases: biochemical characterization and functional implication.

    Science.gov (United States)

    Song, Ping; Wei, Huanhuan; Cao, Zhengyu; Wang, Peng; Zhu, Guoping

    2014-01-01

    Isocitrate dehydrogenase (IDH), a housekeeping gene, has drawn the attention of cancer experts. Mutation of the catalytic Arg132 residue of human IDH1 (HcIDH) eliminates the enzyme's wild-type isocitrate oxidation activity, but confer the mutant an ability of reducing α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). To examine whether an analogous mutation in IDHs of other eukaryotes could cause similar effects, two yeast mitochondrial IDHs, Saccharomyces cerevisiae NADP+-IDH1 (ScIDH1) and Yarrowia lipolytica NADP+-IDH (YlIDH), were studied. The analogous Arg residues (Arg148 of ScIDH1 and Arg141 of YlIDH) were mutated to His. The Km values of ScIDH1 R148H and YlIDH R141H for isocitrate were determined to be 2.4-fold and 2.2-fold higher, respectively, than those of the corresponding wild-type enzymes. The catalytic efficiencies (kcat/Km) of ScIDH1 R148H and YlIDH R141H for isocitrate oxidation were drastically reduced by 227-fold and 460-fold, respectively, of those of the wild-type enzymes. As expected, both ScIDH1 R148H and YlIDH R141H acquired the neomorphic activity of catalyzing α-KG to 2-HG, and the generation of 2-HG was confirmed using gas chromatography/time of flight-mass spectrometry (GC/TOF-MS). Kinetic analysis showed that ScIDH1 R148H and YlIDH R141H displayed 5.2-fold and 3.3-fold higher affinities, respectively, for α-KG than the HcIDH R132H mutant. The catalytic efficiencies of ScIDH1 R148H and YlIDH R141H for α-KG were 5.5-fold and 4.5-fold, respectively, of that of the HcIDH R132H mutant. Since the HcIDH Arg132 mutation is associated with the tumorigenesis, this study provides fundamental information for further research on the physiological role of this IDH mutation in vivo using yeast.

  20. Single arginine mutation in two yeast isocitrate dehydrogenases: biochemical characterization and functional implication.

    Directory of Open Access Journals (Sweden)

    Ping Song

    Full Text Available Isocitrate dehydrogenase (IDH, a housekeeping gene, has drawn the attention of cancer experts. Mutation of the catalytic Arg132 residue of human IDH1 (HcIDH eliminates the enzyme's wild-type isocitrate oxidation activity, but confer the mutant an ability of reducing α-ketoglutarate (α-KG to 2-hydroxyglutarate (2-HG. To examine whether an analogous mutation in IDHs of other eukaryotes could cause similar effects, two yeast mitochondrial IDHs, Saccharomyces cerevisiae NADP+-IDH1 (ScIDH1 and Yarrowia lipolytica NADP+-IDH (YlIDH, were studied. The analogous Arg residues (Arg148 of ScIDH1 and Arg141 of YlIDH were mutated to His. The Km values of ScIDH1 R148H and YlIDH R141H for isocitrate were determined to be 2.4-fold and 2.2-fold higher, respectively, than those of the corresponding wild-type enzymes. The catalytic efficiencies (kcat/Km of ScIDH1 R148H and YlIDH R141H for isocitrate oxidation were drastically reduced by 227-fold and 460-fold, respectively, of those of the wild-type enzymes. As expected, both ScIDH1 R148H and YlIDH R141H acquired the neomorphic activity of catalyzing α-KG to 2-HG, and the generation of 2-HG was confirmed using gas chromatography/time of flight-mass spectrometry (GC/TOF-MS. Kinetic analysis showed that ScIDH1 R148H and YlIDH R141H displayed 5.2-fold and 3.3-fold higher affinities, respectively, for α-KG than the HcIDH R132H mutant. The catalytic efficiencies of ScIDH1 R148H and YlIDH R141H for α-KG were 5.5-fold and 4.5-fold, respectively, of that of the HcIDH R132H mutant. Since the HcIDH Arg132 mutation is associated with the tumorigenesis, this study provides fundamental information for further research on the physiological role of this IDH mutation in vivo using yeast.

  1. Reduced climbing and increased slipping adaptation in cochlear hair cells of mice with Myo7a mutations

    NARCIS (Netherlands)

    Kros, CJ; Marcotti, W; van Netten, SM; Self, TJ; Libby, RT; Brown, SDM; Richardson, GP; Steel, KP

    Mutations in Myo7a cause hereditary deafness in mice and humans. We describe the effects of two mutations, Myo7a(6J) and Myo7a(4626SB). on mechano-electrical transduction in cochlear hair cells. Both mutations result in two major functional abnormalities that would interfere with sound transduction.

  2. Evidence of genomic adaptation to climate in Eucalyptus microcarpa: implications for adaptive potential to projected climate change.

    Science.gov (United States)

    Jordan, Rebecca; Hoffmann, Ary A; Dillon, Shannon K; Prober, Suzanne M

    2017-09-01

    Understanding whether populations can adapt in situ or whether interventions are required is of key importance for biodiversity management under climate change. Landscape genomics is becoming an increasingly important and powerful tool for rapid assessments of climate adaptation, especially in long-lived species such as trees. We investigated climate adaptation in Eucalyptus microcarpa using the DArTseq genomic approach. A combination of FST outlier and environmental association analyses were performed using > 4,200 genome-wide single nucleotide polymorphisms (SNPs) from 26 populations spanning climate gradients in south-eastern Australia. Eighty-one SNPs were identified as putatively adaptive, based on significance in FST outlier tests and significant associations with one or more climate variables related to temperature (70 / 81), aridity (37 / 81) or precipitation (35 / 81). Adaptive SNPs were located on all 11 chromosomes, with no particular region associated with individual climate variables. Climate adaptation appeared to be characterized by subtle shifts in allele frequencies, with no consistent fixed differences identified. Based on these associations, we predict adaptation under projected changes in climate will include a suite of shifts in allele frequencies. Whether this can occur sufficiently rapidly through natural selection within populations, or would benefit from assisted gene migration, requires further evaluation. In some populations, the absence, or predicted increases to near fixation of particular adaptive alleles hint at potential limits to adaptive capacity. Together, these results reinforce the importance of standing genetic variation at the geographical level for maintaining species' evolutionary potential. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  3. Recessive mutations in SPTBN2 implicate β-III spectrin in both cognitive and motor development.

    Directory of Open Access Journals (Sweden)

    Stefano Lise

    Full Text Available β-III spectrin is present in the brain and is known to be important in the function of the cerebellum. Heterozygous mutations in SPTBN2, the gene encoding β-III spectrin, cause Spinocerebellar Ataxia Type 5 (SCA5, an adult-onset, slowly progressive, autosomal-dominant pure cerebellar ataxia. SCA5 is sometimes known as "Lincoln ataxia," because the largest known family is descended from relatives of the United States President Abraham Lincoln. Using targeted capture and next-generation sequencing, we identified a homozygous stop codon in SPTBN2 in a consanguineous family in which childhood developmental ataxia co-segregates with cognitive impairment. The cognitive impairment could result from mutations in a second gene, but further analysis using whole-genome sequencing combined with SNP array analysis did not reveal any evidence of other mutations. We also examined a mouse knockout of β-III spectrin in which ataxia and progressive degeneration of cerebellar Purkinje cells has been previously reported and found morphological abnormalities in neurons from prefrontal cortex and deficits in object recognition tasks, consistent with the human cognitive phenotype. These data provide the first evidence that β-III spectrin plays an important role in cortical brain development and cognition, in addition to its function in the cerebellum; and we conclude that cognitive impairment is an integral part of this novel recessive ataxic syndrome, Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1 (SPARCA1. In addition, the identification of SPARCA1 and normal heterozygous carriers of the stop codon in SPTBN2 provides insights into the mechanism of molecular dominance in SCA5 and demonstrates that the cell-specific repertoire of spectrin subunits underlies a novel group of disorders, the neuronal spectrinopathies, which includes SCA5, SPARCA1, and a form of West syndrome.

  4. ECEL1 mutation implicates impaired axonal arborization of motor nerves in the pathogenesis of distal arthrogryposis.

    Science.gov (United States)

    Nagata, Kenichi; Kiryu-Seo, Sumiko; Tamada, Hiromi; Okuyama-Uchimura, Fumi; Kiyama, Hiroshi; Saido, Takaomi C

    2016-07-01

    The membrane-bound metalloprotease endothelin-converting enzyme-like 1 (ECEL1) has been newly identified as a causal gene of a specific type of distal arthrogryposis (DA). In contrast to most causal genes of DA, ECEL1 is predominantly expressed in neuronal cells, suggesting a unique neurogenic pathogenesis in a subset of DA patients with ECEL1 mutation. The present study analyzed developmental motor innervation and neuromuscular junction formation in limbs of the rodent homologue damage-induced neuronal endopeptidase (DINE)-deficient mouse. Whole-mount immunostaining was performed in DINE-deficient limbs expressing motoneuron-specific GFP to visualize motor innervation throughout the limb. Although DINE-deficient motor nerves displayed normal trajectory patterns from the spinal cord to skeletal muscles, they indicated impaired axonal arborization in skeletal muscles in the forelimbs and hindlimbs. Systematic examination of motor innervation in over 10 different hindlimb muscles provided evidence that DINE gene disruption leads to insufficient arborization of motor nerves after arriving at the skeletal muscle. Interestingly, the axonal arborization defect in foot muscles appeared more severe than in other hindlimb muscles, which was partially consistent with the proximal-distal phenotypic discordance observed in DA patients. Additionally, the number of innervated neuromuscular junction was significantly reduced in the severely affected DINE-deficient muscle. Furthermore, we generated a DINE knock-in (KI) mouse model with a pathogenic mutation, which was recently identified in DA patients. Axonal arborization defects were clearly detected in motor nerves of the DINE KI limb, which was identical to the DINE-deficient limb. Given that the encoded sequences, as well as ECEL1 and DINE expression profiles, are highly conserved between mouse and human, abnormal arborization of motor axons and subsequent failure of NMJ formation could be a primary cause of DA with ECEL1

  5. Structural and Functional Implication of RAP80 ΔGlu81 Mutation

    Science.gov (United States)

    Vikrant; Kumar, Rajan; Yadav, Lumbini R.; Nakhwa, Pallavi; Waghmare, Sanjeev K.; Goyal, Peyush; Varma, Ashok K.

    2013-01-01

    Receptor Associated Protein 80 (RAP80) is a member of RAP80-BRCA1-CCDC98 complex family and helps in its recruitment to the DNA damage site for effective homologous recombination repair. It encompasses two tandem UIMs (UIM1 and UIM2) motif at its N-terminus, which interact with K-63 linked polyubiquitin chain(s) on H2AX and thereby assemble the RAP80-BRCA1 complex at the damage site. Nevertheless, how RAP80 helps in the structural integrity of BRCA1 complex is still elusive. Considering the role of RAP80 in the recruitment of BRCA1 complex at the DNA damage site, we attempted to explore the molecular mechanism associated with RAP80 and mutation that causes chromosomal aberrations due to its loss of function. There is a significant loss in structural characteristics of RAP80 ΔE81, which impairs its binding affinity with the polyubiquitin chain. This leads to the defective recruitment of RAP80 and BRCA1 complex at the DNA damage site. The results presented here are very useful in understanding the cause of various repair defects (chromosomal aberration) that arise due to this mutation. Comparative study of wild type and ΔE81 could be helpful in designing the small molecules that can potentially compensate the deleterious effect(s) of ΔE81 and hence useful for therapeutic application. PMID:24039796

  6. The frequencies and clinical implications of mutations in 33 kinase-related genes in locally advanced rectal cancer: a pilot study.

    LENUS (Irish Health Repository)

    Abdul-Jalil, Khairun I

    2014-08-01

    Locally advanced rectal cancer (LARC: T3\\/4 and\\/or node-positive) is treated with preoperative\\/neoadjuvant chemoradiotherapy (CRT), but responses are not uniform. The phosphatidylinositol 3-kinase (PI3K), MAP kinase (MAPK), and related pathways are implicated in rectal cancer tumorigenesis. Here, we investigated the association between genetic mutations in these pathways and LARC clinical outcomes.

  7. A novel pseudoderivative-based mutation operator for real-coded adaptive genetic algorithms [v2; ref status: indexed, http://f1000r.es/1td

    Directory of Open Access Journals (Sweden)

    Maxinder S Kanwal

    2013-11-01

    Full Text Available Recent development of large databases, especially those in genetics and proteomics, is pushing the development of novel computational algorithms that implement rapid and accurate search strategies. One successful approach has been to use artificial intelligence and methods, including pattern recognition (e.g. neural networks and optimization techniques (e.g. genetic algorithms. The focus of this paper is on optimizing the design of genetic algorithms by using an adaptive mutation rate that is derived from comparing the fitness values of successive generations. We propose a novel pseudoderivative-based mutation rate operator designed to allow a genetic algorithm to escape local optima and successfully continue to the global optimum. Once proven successful, this algorithm can be implemented to solve real problems in neurology and bioinformatics. As a first step towards this goal, we tested our algorithm on two 3-dimensional surfaces with multiple local optima, but only one global optimum, as well as on the N-queens problem, an applied problem in which the function that maps the curve is implicit. For all tests, the adaptive mutation rate allowed the genetic algorithm to find the global optimal solution, performing significantly better than other search methods, including genetic algorithms that implement fixed mutation rates.

  8. The quantitative genetic basis of adaptive divergence in the moor frog (Rana arvalis) and its implications for gene flow.

    Science.gov (United States)

    Hangartner, S; Laurila, A; Räsänen, K

    2012-08-01

    Knowledge on the relative contribution of direct genetic, maternal and environmental effects to adaptive divergence is important for understanding the drivers of biological diversification. The moor frog (Rana arvalis) shows adaptive divergence in embryonic and larval fitness traits along an acidification gradient in south-western Sweden. To understand the quantitative genetic basis of this divergence, we performed reciprocal crosses between three divergent population pairs and reared embryos and larvae at acid and neutral pH in the laboratory. Divergence in embryonic acid tolerance (survival) was mainly determined by maternal effects, whereas the relative contributions of maternal, additive and nonadditive genetic effects in larval life-history traits differed between traits, population pairs and rearing environments. These results emphasize the need to investigate the quantitative genetic basis of adaptive divergence in multiple populations and traits, as well as different environments. We discuss the implications of our findings for maintenance of local adaptation in the context of migrant and hybrid fitness.

  9. KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer.

    Science.gov (United States)

    De Roock, Wendy; De Vriendt, Veerle; Normanno, Nicola; Ciardiello, Fortunato; Tejpar, Sabine

    2011-06-01

    The discovery of mutant KRAS as a predictor of resistance to epidermal growth-factor receptor (EGFR) monoclonal antibodies brought a major change in the treatment of metastatic colorectal cancer. This seminal finding also highlighted our sparse knowledge about key signalling pathways in colorectal tumours. Drugs that inhibit oncogenic alterations such as phospho-MAP2K (also called MEK), phospho-AKT, and mutant B-RAF seem promising as single treatment or when given with EGFR inhibitors. However, our understanding of the precise role these potential drug targets have in colorectal tumours, and the oncogenic dependence that tumours might have on these components, has not progressed at the same rate. As a result, patient selection and prediction of treatment effects remain problematic. We review the role of mutations in genes other than KRAS on the efficacy of anti-EGFR therapy, and discuss strategies to target these oncogenic alterations alone or in combination with receptor tyrosine-kinase inhibition.

  10. Mutational analysis of VAMP domains implicated in Ca2+-induced insulin exocytosis.

    Science.gov (United States)

    Regazzi, R; Sadoul, K; Meda, P; Kelly, R B; Halban, P A; Wollheim, C B

    1996-01-01

    Vesicle-associated membrane protein-2 (VAMP-2) and cellubrevin are associated with the membrane of insulin-containing secretory granules and of gamma-aminobutyric acid (GABA)-containing synaptic-like vesicles of pancreatic beta-cells. We found that a point mutation in VAMP-2 preventing targeting to synaptic vesicles also impairs the localization on insulin-containing secretory granules, suggesting a similar requirement for vesicular targeting. Tetanus toxin (TeTx) treatment of permeabilized HIT-T15 cells leads to the proteolytic cleavage of VAMP-2 and cellubrevin and causes the inhibition of Ca2+-triggered insulin exocytosis. Transient transfection of HIT-T15 cells with VAMP-1, VAMP-2 or cellubrevin made resistant to the proteolytic action of TeTx by amino acid replacements in the cleavage site restored Ca2+-stimulated secretion. Wild-type VAMP-2, wild-type cellubrevin or a mutant of VAMP-2 resistant to TeTx but not targeted to secretory granules were unable to rescue Ca2+-evoked insulin release. The transmembrane domain and the N-terminal region of VAMP-2 were not essential for the recovery of stimulated exocytosis, but deletions preventing the binding to SNAP-25 and/or to syntaxin I rendered the protein inactive in the reconstitution assay. Mutations of putative phosphorylation sites or of negatively charged amino acids in the SNARE motif recognized by clostridial toxins had no effect on the ability of VAMP-2 to mediate Ca2+-triggered secretion. We conclude that: (i) both VAMP-2 and cellubrevin can participate in the exocytosis of insulin; (ii) the interaction of VAMP-2 with syntaxin and SNAP-25 is required for docking and/or fusion of secretory granules with the plasma membrane; and (iii) the phosphorylation of VAMP-2 is not essential for Ca2+-stimulated insulin exocytosis. Images PMID:9003771

  11. Mutation of the N-Terminal Region of Chikungunya Virus Capsid Protein: Implications for Vaccine Design

    Science.gov (United States)

    Liu, Xiang; Zaid, Ali; Goh, Lucas Y. H.; Hobson-Peters, Jody; Hall, Roy A.; Merits, Andres

    2017-01-01

    ABSTRACT Mosquito-transmitted chikungunya virus (CHIKV) is an arthritogenic alphavirus of the Togaviridae family responsible for frequent outbreaks of arthritic disease in humans. Capsid protein, a structural protein encoded by the CHIKV RNA genome, is able to translocate to the host cell nucleolus. In encephalitic alphaviruses, nuclear translocation induces host cell transcriptional shutoff; however, the role of capsid protein nucleolar localization in arthritogenic alphaviruses remains unclear. Using recombinant enhanced green fluorescent protein (EGFP)-tagged expression constructs and CHIKV infectious clones, we describe a nucleolar localization sequence (NoLS) in the N-terminal region of capsid protein, previously uncharacterized in CHIKV. Mutation of the NoLS by site-directed mutagenesis reduced efficiency of nuclear import of CHIKV capsid protein. In the virus, mutation of the capsid protein NoLS (CHIKV-NoLS) attenuated replication in mammalian and mosquito cells, producing a small-plaque phenotype. Attenuation of CHIKV-NoLS is likely due to disruption of the viral replication cycle downstream of viral RNA synthesis. In mice, CHIKV-NoLS infection caused no disease signs compared to wild-type CHIKV (CHIKV-WT)-infected mice; lack of disease signs correlated with significantly reduced viremia and decreased expression of proinflammatory factors. Mice immunized with CHIKV-NoLS, challenged with CHIKV-WT at 30 days postimmunization, develop no disease signs and no detectable viremia. Serum from CHIKV-NoLS-immunized mice is able to efficiently neutralize CHIKV infection in vitro. Additionally, CHIKV-NoLS-immunized mice challenged with the related alphavirus Ross River virus showed reduced early and peak viremia postchallenge, indicating a cross-protective effect. The high degree of CHIKV-NoLS attenuation may improve CHIKV antiviral and rational vaccine design. PMID:28223458

  12. Mutation of the N-Terminal Region of Chikungunya Virus Capsid Protein: Implications for Vaccine Design

    Directory of Open Access Journals (Sweden)

    Adam Taylor

    2017-02-01

    Full Text Available Mosquito-transmitted chikungunya virus (CHIKV is an arthritogenic alphavirus of the Togaviridae family responsible for frequent outbreaks of arthritic disease in humans. Capsid protein, a structural protein encoded by the CHIKV RNA genome, is able to translocate to the host cell nucleolus. In encephalitic alphaviruses, nuclear translocation induces host cell transcriptional shutoff; however, the role of capsid protein nucleolar localization in arthritogenic alphaviruses remains unclear. Using recombinant enhanced green fluorescent protein (EGFP-tagged expression constructs and CHIKV infectious clones, we describe a nucleolar localization sequence (NoLS in the N-terminal region of capsid protein, previously uncharacterized in CHIKV. Mutation of the NoLS by site-directed mutagenesis reduced efficiency of nuclear import of CHIKV capsid protein. In the virus, mutation of the capsid protein NoLS (CHIKV-NoLS attenuated replication in mammalian and mosquito cells, producing a small-plaque phenotype. Attenuation of CHIKV-NoLS is likely due to disruption of the viral replication cycle downstream of viral RNA synthesis. In mice, CHIKV-NoLS infection caused no disease signs compared to wild-type CHIKV (CHIKV-WT-infected mice; lack of disease signs correlated with significantly reduced viremia and decreased expression of proinflammatory factors. Mice immunized with CHIKV-NoLS, challenged with CHIKV-WT at 30 days postimmunization, develop no disease signs and no detectable viremia. Serum from CHIKV-NoLS-immunized mice is able to efficiently neutralize CHIKV infection in vitro. Additionally, CHIKV-NoLS-immunized mice challenged with the related alphavirus Ross River virus showed reduced early and peak viremia postchallenge, indicating a cross-protective effect. The high degree of CHIKV-NoLS attenuation may improve CHIKV antiviral and rational vaccine design.

  13. CIRCADIAN RHYTHMS IN EXERCISE PERFORMANCE: IMPLICATIONS FOR HORMONAL AND MUSCULAR ADAPTATION

    Directory of Open Access Journals (Sweden)

    Weipeng Teo

    2011-12-01

    Full Text Available Almost all physiological and biochemical processes within the human body follow a circadian rhythm (CR. In humans, the suprachiasmatic nucleus regulates sleep- wake cycle and other daily biorhythms in line with solar time. Due to such daily physiological fluctuations, several investigations on neuromuscular performance have reported a distinct CR during exercise. Generally, peak performances have been found to occur in the early evening, at approximately the peak of core body temperature. The increase in core body temperature has been found to increase energy metabolism, improve muscle compliance and facilitate actin-myosin crossbridging. In addition, steroidal hormones such as testosterone (T and cortisol (C also display a clear CR. The role of T within the body is to maintain anabolism through the process of protein synthesis. By contrast, C plays a catabolic function and is involved in the response of stress. Due to the anabolic and catabolic nature of both T and C, it has been postulated that a causal relationship may exist between the CR of T and C and muscular performance. This review will therefore discuss the effects of CR on physical performance and its implications for training. Furthermore, this review will examine the impact of muscular performance on CR in hormonal responses and whether could variations in T and C be potentially beneficial for muscular adaptation

  14. Prognostic implication of gene mutations on overall survival in the adult acute myeloid leukemia patients receiving or not receiving allogeneic hematopoietic stem cell transplantations.

    Science.gov (United States)

    Chou, Sheng-Chieh; Tang, Jih-Luh; Hou, Hsin-An; Chou, Wen-Chien; Hu, Fu-Chang; Chen, Chien-Yuan; Yao, Ming; Ko, Bor-Sheng; Huang, Shang-Yi; Tsay, Woei; Chen, Yao-Chang; Tien, Hwei-Fang

    2014-11-01

    Several gene mutations have been shown to provide clinical implications in patients with acute myeloid leukemia (AML). However, the prognostic impact of gene mutations in the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear. We retrospectively evaluated the clinical implications of 8 gene mutations in 325 adult AML patients; 100 of them received allo-HSCT and 225 did not. The genetic alterations analyzed included NPM1, FLT3-ITD, FLT3-TKD, CEBPA, RUNX1, RAS, MLL-PTD, and WT1. In patients who did not receive allo-HSCT, older age, higher WBC count, higher lactate dehydrogenase level, unfavorable karyotype, and RUNX1 mutation were significantly associated with poor overall survival (OS), while CEBPA double mutation (CEBPA(double-mut)) and NPM1(mut)/FLT3-ITD(neg) were associated with good outcome. However, in patients who received allo-HSCT, only refractory disease status at the time of HSCT and unfavorable karyotype were independent poor prognostic factors. Surprisingly, RUNX1 mutation was an independent good prognostic factor for OS in multivariate analysis. The prognostic impact of FLT3-ITD or NPM1(mut)/FLT3-ITD(neg) was lost in this group of patients receiving allo-HSCT, while CEBPA(double-mut) showed a trend to be a good prognostic factor. In conclusion, allo-HSCT can ameliorate the unfavorable influence of some poor-risk gene mutations in AML patients. Unexpectedly, the RUNX1 mutation showed a favorable prognostic impact in the context of allo-HSCT. These results need to be confirmed by further studies with more AML patients.

  15. Mutations in snail family genes enhance craniosynostosis of Twist1 haplo-insufficient mice: implications for Saethre-Chotzen Syndrome.

    Science.gov (United States)

    Oram, Kathleen F; Gridley, Thomas

    2005-06-01

    In Drosophila, mutations in the Twist gene interact with mutations in the Snail gene. We show that the mouse Twist1 mutation interacts with Snai1 and Snai2 mutations to enhance aberrant cranial suture fusion, demonstrating that genetic interactions between genes of the Twist and Snail families have been conserved during evolution.

  16. Mutations in Snail Family Genes Enhance Craniosynostosis of Twist1 Haplo-insufficient Mice: Implications for Saethre-Chotzen Syndrome

    OpenAIRE

    2005-01-01

    In Drosophila, mutations in the Twist gene interact with mutations in the Snail gene. We show that the mouse Twist1 mutation interacts with Snai1 and Snai2 mutations to enhance aberrant cranial suture fusion, demonstrating that genetic interactions between genes of the Twist and Snail families have been conserved during evolution.

  17. Cross-Culture Adaptation in Business Context:the Implication of Adap-tation Theory in Translation

    Institute of Scientific and Technical Information of China (English)

    何爱玲; 石美

    2014-01-01

    Translating in business context involves considerable factors like culture, idioms besides language itself. This paper em-ploys adaptation theory and posed several examples commonly-seen in product, trademark and advertisement translating to show the essentials of translating in business context.

  18. Clinal adaptation and adaptive plasticity in Artemisia californica: implications for the response of a foundation species to predicted climate change.

    Science.gov (United States)

    Pratt, Jessica D; Mooney, Kailen A

    2013-08-01

    Local adaptation and plasticity pose significant obstacles to predicting plant responses to future climates. Although local adaptation and plasticity in plant functional traits have been documented for many species, less is known about population-level variation in plasticity and whether such variation is driven by adaptation to environmental variation. We examined clinal variation in traits and performance - and plastic responses to environmental change - for the shrub Artemisia californica along a 700 km gradient characterized (from south to north) by a fourfold increase in precipitation and a 61% decrease in interannual precipitation variation. Plants cloned from five populations along this gradient were grown for 3 years in treatments approximating the precipitation regimes of the north and south range margins. Most traits varying among populations did so clinally; northern populations (vs. southern) had higher water-use efficiencies and lower growth rates, C : N ratios and terpene concentrations. Notably, there was variation in plasticity for plant performance that was strongly correlated with source site interannual precipitation variability. The high-precipitation treatment (vs. low) increased growth and flower production more for plants from southern populations (181% and 279%, respectively) than northern populations (47% and 20%, respectively). Overall, precipitation variability at population source sites predicted 86% and 99% of variation in plasticity in growth and flowering, respectively. These striking, clinal patterns in plant traits and plasticity are indicative of adaptation to both the mean and variability of environmental conditions. Furthermore, our analysis of long-term coastal climate data in turn indicates an increase in interannual precipitation variation consistent with most global change models and, unexpectedly, this increased variation is especially pronounced at historically stable, northern sites. Our findings demonstrate the

  19. Autozygosity reveals recessive mutations and novel mechanisms in dominant genes: implications in variant interpretation

    KAUST Repository

    Monies, Dorota

    2017-04-06

    The purpose of this study is to describe recessive alleles in strictly dominant genes. Identifying recessive mutations in genes for which only dominant disease or risk alleles have been reported can expand our understanding of the medical relevance of these genes both phenotypically and mechanistically. The Saudi population is enriched for autozygosity, which enhances the homozygous occurrence of alleles, including pathogenic alleles in genes that have been associated only with a dominant inheritance pattern.Exome sequencing of patients from consanguineous families with likely recessive phenotypes was performed. In one family, the genotype of the deceased children was inferred from their parents due to lack of available samples.We describe the identification of 11 recessive variants (5 of which are reported here for the first time) in 11 genes for which only dominant disease or risk alleles have been reported. The observed phenotypes for these recessive variants were novel (e.g., FBN2-related myopathy and CSF1R-related brain malformation and osteopetrosis), typical (e.g., ACTG2-related visceral myopathy), or an apparently healthy state (e.g., PDE11A), consistent with the corresponding mouse knockout phenotypes.Our results show that, in the era of genomic sequencing and

  20. Mutations and polymorphisms in FSH receptor: functional implications in human reproduction.

    Science.gov (United States)

    Desai, Swapna S; Roy, Binita Sur; Mahale, Smita D

    2013-12-01

    FSH brings about its physiological actions by activating a specific receptor located on target cells. Normal functioning of the FSH receptor (FSHR) is crucial for follicular development and estradiol production in females and for the regulation of Sertoli cell function and spermatogenesis in males. In the last two decades, the number of inactivating and activating mutations, single nucleotide polymorphisms, and spliced variants of FSHR gene has been identified in selected infertile cases. Information on genotype-phenotype correlation and in vitro functional characterization of the mutants has helped in understanding the possible genetic cause for female infertility in affected individuals. The information is also being used to dissect various extracellular and intracellular events involved in hormone-receptor interaction by studying the differences in the properties of the mutant receptor when compared with WT receptor. Studies on polymorphisms in the FSHR gene have shown variability in clinical outcome among women treated with FSH. These observations are being explored to develop molecular markers to predict the optimum dose of FSH required for controlled ovarian hyperstimulation. Pharmacogenetics is an emerging field in this area that aims at designing individual treatment protocols for reproductive abnormalities based on FSHR gene polymorphisms. The present review discusses the current knowledge of various genetic alterations in FSHR and their impact on receptor function in the female reproductive system.

  1. Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration.

    Science.gov (United States)

    Smid, Marcel; Rodríguez-González, F Germán; Sieuwerts, Anieta M; Salgado, Roberto; Prager-Van der Smissen, Wendy J C; Vlugt-Daane, Michelle van der; van Galen, Anne; Nik-Zainal, Serena; Staaf, Johan; Brinkman, Arie B; van de Vijver, Marc J; Richardson, Andrea L; Fatima, Aquila; Berentsen, Kim; Butler, Adam; Martin, Sancha; Davies, Helen R; Debets, Reno; Gelder, Marion E Meijer-Van; van Deurzen, Carolien H M; MacGrogan, Gaëtan; Van den Eynden, Gert G G M; Purdie, Colin; Thompson, Alastair M; Caldas, Carlos; Span, Paul N; Simpson, Peter T; Lakhani, Sunil R; Van Laere, Steven; Desmedt, Christine; Ringnér, Markus; Tommasi, Stefania; Eyford, Jorunn; Broeks, Annegien; Vincent-Salomon, Anne; Futreal, P Andrew; Knappskog, Stian; King, Tari; Thomas, Gilles; Viari, Alain; Langerød, Anita; Børresen-Dale, Anne-Lise; Birney, Ewan; Stunnenberg, Hendrik G; Stratton, Mike; Foekens, John A; Martens, John W M

    2016-09-26

    A recent comprehensive whole genome analysis of a large breast cancer cohort was used to link known and novel drivers and substitution signatures to the transcriptome of 266 cases. Here, we validate that subtype-specific aberrations show concordant expression changes for, for example, TP53, PIK3CA, PTEN, CCND1 and CDH1. We find that CCND3 expression levels do not correlate with amplification, while increased GATA3 expression in mutant GATA3 cancers suggests GATA3 is an oncogene. In luminal cases the total number of substitutions, irrespective of type, associates with cell cycle gene expression and adverse outcome, whereas the number of mutations of signatures 3 and 13 associates with immune-response specific gene expression, increased numbers of tumour-infiltrating lymphocytes and better outcome. Thus, while earlier reports imply that the sheer number of somatic aberrations could trigger an immune-response, our data suggests that substitutions of a particular type are more effective in doing so than others.

  2. Mutation of the distal arginine in Coprinus cinereus peroxidase--structural implications.

    Science.gov (United States)

    Neri, F; Indiani, C; Welinder, K G; Smulevich, G

    1998-02-01

    Heme peroxidases of prokaryotic, plant and fungal origin share the essential His and Arg catalytic residues of the distal cavity and a proximal His bound to heme iron. Spectroscopic techniques, in contrast to X-ray crystallography, are well suited to detect the precise structure, spin and coordination states of the heme as influenced by its near environment. Resonance Raman and electronic absorption spectra obtained at various pH values for Fe3+ and Fe2+ forms of distal Arg51 mutants of the fungal Coprinus cinereus peroxidase are reported, together with the fluoride adducts at pH 5.0. This basic catalytic residue has been replaced by the aliphatic residue Leu, the polar residues Asn and Gln and the basic residue Lys (Arg51-->Leu, Asn, Gln, and Lys, respectively). These mutations cause changes in the coordination and spin states of the heme iron, and in the v(Fe-Im) stretching frequency. The variations are explained in terms of pH-dependent changes, charge location, size and hydrogen-bonding acceptor/donor properties of the residue at position 51. The present work indicates that the hydrogen-bond capability of the residue in position 51 influences the occupancy of water molecules in the distal cavity and the ability to form stable complexes between anionic ligands and the heme Fe atom.

  3. Adaptation to the cost of resistance in a haploid clonally reproducing organism: The role of mutation, migration and selection

    NARCIS (Netherlands)

    Jeger, M.J.; Wijngaarden, P.J.; Hoekstra, R.F.

    2008-01-01

    A model of compensatory evolution with respect to fungicide resistance in a haploid clonally reproducing fungus is developed in which compensatory mutations mitigate fitness costs associated with resistance. The role of mutation, migration and selection in invasion of rare genotypes when the environ

  4. Organizational values and the implications for mainstreaming climate adaptation in Dutch municipalities : Using Q methodology

    NARCIS (Netherlands)

    Uittenbroek, Caroline J.; Janssen-Jansen, Leonie B.; Spit, Tejo J M; Runhaar, Hens A C

    2014-01-01

    Mainstreaming climate adaptation requires the inclusion of climate adaptation in the policies of various policy domains such as water management and spatial planning. This paper investigates the organizational values present in several municipal policy departments in order to explore their

  5. Myh11(R247C/R247C) mutations increase thoracic aorta vulnerability to intramural damage despite a general biomechanical adaptivity.

    Science.gov (United States)

    Bellini, Chiara; Wang, Shanzhi; Milewicz, Dianna M; Humphrey, Jay D

    2015-01-02

    Genetic studies in patients reveal that mutations to genes that encode contractile proteins in medial smooth muscle cells can cause thoracic aortic aneurysms and dissections. Mouse models of such mutations, including Acta2(-/-) and Myh11(R247C/R247C), surprisingly do not present with any severe vascular phenotype under normal conditions. This observation raises the question whether these mutations nevertheless render the thoracic aorta increasingly vulnerable to aneurysms or dissections in the presence of additional, epigenetic, factors such as hypertension, a known risk factor for thoracic aortic disease. Accordingly, we compared the structure and biaxial mechanical properties of the ascending and descending thoracic aorta from male wild-type and Myh11(R247C/R247C) mice under normotension and induced hypertension. On average, the mutant aortas exhibited near normal biomechanics under normotensive hemodynamics and near normal adaptations to hypertensive hemodynamics, yet the latter led to intramural delaminations or premature deaths in over 20% of these mice. Moreover, the delaminated vessels exhibited localized pools of mucoid material, similar to the common histopathologic characteristic observed in aortas from humans affected by thoracic aortic aneurysms and dissections. The present findings suggest, therefore, that mutations to smooth muscle cell contractile proteins may place the thoracic aorta at increased risk to epigenetic factors and that there is a need to focus on focal, not global, changes in aortic structure and properties, including the pooling of glycosaminoglycans/proteoglycans that may lead to thoracic aortic dissection.

  6. Myh11R247C/R247C Mutations Increase Thoracic Aorta Vulnerability to Intramural Damage Despite a General Biomechanical Adaptivity

    Science.gov (United States)

    Bellini, Chiara; Wang, Shanzhi; Milewicz, Dianna M.; Humphrey, Jay D.

    2014-01-01

    Genetic studies in patients reveal that mutations to genes that encode contractile proteins in medial smooth muscle cells can cause thoracic aortic aneurysms and dissections. Mouse models of such mutations, including Acta2−/− and Myh11 R247C/R247C, surprisingly do not present with any severe vascular phenotype under normal conditions. This observation raises the question whether these mutations nevertheless render the thoracic aorta increasingly vulnerable to aneurysms or dissections in the presence of additional, epigenetic, factors such as hypertension, a known risk factor for thoracic aortic disease. Accordingly, we compared the structure and biaxial mechanical properties of the ascending and descending thoracic aorta from male wild-type and Myh11 R247C/R247C mice under normotension and induced hypertension. On average, the mutant aortas exhibited near normal biomechanics under normotensive hemodynamics and near normal adaptations to hypertensive hemodynamics, yet the latter led to intramural delaminations or premature deaths in over 20 percent of these mice. Moreover, the delaminated vessels exhibited localized pools of mucoid material, similar to the common histopathologic characteristic observed in aortas from humans affected by thoracic aortic aneurysms and dissections. The present findings suggest, therefore, that mutations to smooth muscle cell contractile proteins may place the thoracic aorta at increased risk to epigenetic factors and that there is a need to focus on focal, not global, changes in aortic structure and properties, including the pooling of glycosaminoglycans / proteoglycans that may lead to thoracic aortic dissection. PMID:25433566

  7. Somatic mosaicism for a SLC2A1 mutation: implications for genetic counseling for GLUT1 deficiency syndrome.

    Science.gov (United States)

    Takahashi, S; Matsufuji, M; Yonee, C; Tsuru, H; Sano, N; Oguni, H

    2017-06-01

    A heterozygous SLC2A1 mutation in the severely affected child was inherited from his less severely affected mother who was mosaic for the mutation. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Justice and Equity Implications of Climate Change Adaptation: A Theoretical Evaluation Framework

    Science.gov (United States)

    Boeckmann, Melanie; Zeeb, Hajo

    2016-01-01

    Climate change affects human health, and climate change adaptation aims to reduce these risks through infrastructural, behavioral, and technological measures. However, attributing direct human health effects to climate change adaptation is difficult, causing an ethical dilemma between the need for evidence of strategies and their precautionary implementation before such evidence has been generated. In the absence of conclusive evidence for individual adaptation strategies, alternative approaches to the measurement of adaptation effectiveness need to be developed. This article proposes a theoretical framework and a set of guiding questions to assess effects of adaptation strategies on seven domains of health determinants, including social, economic, infrastructure, institutional, community, environmental, and cultural determinants of health. Its focus on advancing gender equity and environmental justice concurrently with the implementation of health-related adaptation could serve as a template for policymakers and researchers. PMID:27618121

  9. Justice and Equity Implications of Climate Change Adaptation: A Theoretical Evaluation Framework.

    Science.gov (United States)

    Boeckmann, Melanie; Zeeb, Hajo

    2016-09-07

    Climate change affects human health, and climate change adaptation aims to reduce these risks through infrastructural, behavioral, and technological measures. However, attributing direct human health effects to climate change adaptation is difficult, causing an ethical dilemma between the need for evidence of strategies and their precautionary implementation before such evidence has been generated. In the absence of conclusive evidence for individual adaptation strategies, alternative approaches to the measurement of adaptation effectiveness need to be developed. This article proposes a theoretical framework and a set of guiding questions to assess effects of adaptation strategies on seven domains of health determinants, including social, economic, infrastructure, institutional, community, environmental, and cultural determinants of health. Its focus on advancing gender equity and environmental justice concurrently with the implementation of health-related adaptation could serve as a template for policymakers and researchers.

  10. Justice and Equity Implications of Climate Change Adaptation: A Theoretical Evaluation Framework

    Directory of Open Access Journals (Sweden)

    Melanie Boeckmann

    2016-09-01

    Full Text Available Climate change affects human health, and climate change adaptation aims to reduce these risks through infrastructural, behavioral, and technological measures. However, attributing direct human health effects to climate change adaptation is difficult, causing an ethical dilemma between the need for evidence of strategies and their precautionary implementation before such evidence has been generated. In the absence of conclusive evidence for individual adaptation strategies, alternative approaches to the measurement of adaptation effectiveness need to be developed. This article proposes a theoretical framework and a set of guiding questions to assess effects of adaptation strategies on seven domains of health determinants, including social, economic, infrastructure, institutional, community, environmental, and cultural determinants of health. Its focus on advancing gender equity and environmental justice concurrently with the implementation of health-related adaptation could serve as a template for policymakers and researchers.

  11. A Library of Infectious Hepatitis C Viruses with Engineered Mutations in the E2 Gene Reveals Growth-Adaptive Mutations That Modulate Interactions with Scavenger Receptor Class B Type I.

    Science.gov (United States)

    Zuiani, Adam; Chen, Kevin; Schwarz, Megan C; White, James P; Luca, Vincent C; Fremont, Daved H; Wang, David; Evans, Matthew J; Diamond, Michael S

    2016-12-01

    While natural hepatitis C virus (HCV) infection results in highly diverse quasispecies of related viruses over time, mutations accumulate more slowly in tissue culture, in part because of the inefficiency of replication in cells. To create a highly diverse population of HCV particles in cell culture and identify novel growth-enhancing mutations, we engineered a library of infectious HCV with all codons represented at most positions in the ectodomain of the E2 gene. We identified many putative growth-adaptive mutations and selected nine highly represented E2 mutants for further study: Q412R, T416R, S449P, T563V, A579R, L619T, V626S, K632T, and L644I. We evaluated these mutants for changes in particle-to-infectious-unit ratio, sensitivity to neutralizing antibody or CD81 large extracellular loop (CD81-LEL) inhibition, entry factor usage, and buoyant density profiles. Q412R, T416R, S449P, T563V, and L619T were neutralized more efficiently by anti-E2 antibodies and T416R, T563V, and L619T by CD81-LEL. Remarkably, all nine variants showed reduced dependence on scavenger receptor class B type I (SR-BI) for infection. This shift from SR-BI usage did not correlate with a change in the buoyant density profiles of the variants, suggesting an altered E2-SR-BI interaction rather than changes in the virus-associated lipoprotein-E2 interaction. Our results demonstrate that residues influencing SR-BI usage are distributed across E2 and support the development of large-scale mutagenesis studies to identify viral variants with unique functional properties. Characterizing variant viruses can reveal new information about the life cycle of HCV and the roles played by different viral genes. However, it is difficult to recapitulate high levels of diversity in the laboratory because of limitations in the HCV culture system. To overcome this limitation, we engineered a library of mutations into the E2 gene in the context of an infectious clone of the virus. We used this library of viruses

  12. Mutations at KCNQ1 and an unknown locus cause long QT syndrome in a large Australian family: implications for genetic testing.

    Science.gov (United States)

    Summers, Kim M; Bokil, Nilesh J; Lu, Foong Teng; Low, Jiun Tsuen; Baisden, John M; Duffy, David; Radford, Dorothy J

    2010-03-01

    A large Australian family affected with long QT syndrome (LQTS) was studied. The medical characteristics of the 16 clinically affected members were consistent with LQT1. A previously identified mutation in KCNQ1 was found in 12 affected individuals and 1 unaffected infant but absent in 4 affected family members. A haplotype consisting of specific alleles for microsatellites flanking in KCNQ1 was associated with the mutation. This was absent from the four affected individuals without the mutation, who had three different haplotypes in this region, indicating that LQTS is unlikely to be segregating with KCNQ1 in these anomalous family members. A genome scan revealed 12 regions where all four of these individuals shared alleles. One region on chromosome 21 contained the KCNE1, KCNE2, KCNJ6, and KCNJ15 genes. A common variant of KCNE1 was segregating in the family but did not explain the anomalous cases. A candidate region on chromosome 7 contained the AKAP9 and KCND2 genes. A previously reported mutation in the N-terminal Yotiao region of AKAP9 was absent from the family. No evidence was found implicating any other known or suspected LQTS gene. This family shows that there remain unidentified genetic causes of LQTS which are clinically significant and highlights the difficulties associated with genetic testing in LQTS, since we cannot rule out risk in individuals who are negative for the known mutation in KCNQ1 without knowing the second disease locus.

  13. Novel mutations and structural implications in R-type pyruvate kinase-deficient patients from Southern Italy.

    Science.gov (United States)

    Pastore, L; Della Morte, R; Frisso, G; Alfinito, F; Vitale, D; Calise, R M; Ferraro, F; Zagari, A; Rotoli, B; Salvatore, F

    1998-01-01

    Deficiency of the R-type pyruvate kinase (R-PK) causes an autosomal recessive, hereditary, nonspherocytic hemolytic anemia (HNSHA). We screened seven unrelated patients from the south of Italy for the known mutations and found one patient homozygous for the 1529A (R510Q) mutation, two others bearing the 1456T (R486W) mutation, one homozygous and another heterozygous, and two heterozygotes for the 994A mutation (G332S). We also found three novel mutations at the heterozygote status: a G to C transversion in position 1010 (1010C; R337P) and a C to T transition in position 1492 (1492T; R498C), which are missense, and a T to G transversion in position 1523 (1523G; L508Z), which produces a stop codon with a subsequent loss of the C-terminal protein domain. The structural features of R-PK in the mutation-bearing regions were examined. In all cases the mutations altered the local conformation of the enzyme. Both G332S and R337P are in highly conserved sequence regions. In particular, the R337P mutation significantly affects the intersubunit interactions, because it is located in a region subjected to a large conformational change that occurs during the R-->T allosteric transition, which is essential for the enzyme activity. The R486W mutation affects an external pocketlike region, producing only a local conformational change; the R498C mutation changes the interactions among neighbouring residues; the R510Q mutation involves the loss of interdomain interactions that may reduce enzyme stability and activity. Our data also indicate that in patients from Southern Italy, pyruvate kinase deficiency is heterogeneous, the 1529A mutation, which is the most frequent mutation in the U.S. Caucasian population, having a lower frequency.

  14. Comparison of KRAS/BRAF mutations between primary tumors and serum in colorectal cancer: Biological and clinical implications.

    Science.gov (United States)

    Pu, Xingxiang; Pan, Zhizhong; Huang, Ying; Tian, Ying; Guo, Hongqiang; Wu, Lin; He, Xuexing; Chen, Xinggui; Zhang, Shaodan; Lin, Tongyu

    2013-01-01

    In colorectal cancer (CRC), KRAS and BRAF mutations in primary tumors are associated with resistance to anti-epidermal growth factor receptor (anti-EGFR)-based therapies. However, the correlation between KRAS/BRAF mutation in primary tumors and serum has not been well studied. To evaluate the degree of concordance of KRAS/BRAF mutations between the primary tumors and the matched serum samples in CRC, serum and tumor tissues were collected from 115 patients with CRC and KRAS/BRAF mutations were examined by nested polymerase chain reaction (PCR) and direct sequencing. BRAF mutations were present in 3.5% (4/115) of the primary tumor tissue samples and 0.87% (1/115) of the serum samples. In the 4 primary tumors with BRAF mutations, identical mutations were not observed in the corresponding serum samples (κ=-0.016). KRAS mutations were observed in 32.2% (37/115) of the primary tumors and 11.3% (13/115) of the serum samples. Of the 37 tumor cases with KRAS mutations, 9 had identical mutations in the corresponding serum sample, with a concordance rate of 24.3% (9/37). Discordance was observed in 32 (27.8%) patients. The concordance between KRAS mutations in the primary tumors and KRAS mutations in the matched serums was low (κ=0.231). The results of the present study suggest that the possibility of differences in the mutational status of KRAS/BRAF between primary tumors and matched serum samples should be considered when patients are selected for anti-EGFR-based therapies.

  15. Organizational values and the implications for mainstreaming climate adaptation in Dutch municipalities : Using Q methodology

    NARCIS (Netherlands)

    Uittenbroek, Caroline J.; Janssen-Jansen, Leonie B.; Spit, Tejo J M; Runhaar, Hens A C

    2014-01-01

    Mainstreaming climate adaptation requires the inclusion of climate adaptation in the policies of various policy domains such as water management and spatial planning. This paper investigates the organizational values present in several municipal policy departments in order to explore their willingne

  16. Spatial perception changes associated with space flight: implications for adaptation to altered inertial environments.

    Science.gov (United States)

    Parker, Donald E

    2003-01-01

    Preparation for extended travel by astronauts within the Solar System, including a possible manned mission to Mars, requires more complete understanding of adaptation to altered inertial environments. Improved understanding is needed to support development and evaluation of interventions to facilitate adaptations during transitions between those environments. Travel to another planet escalates the adaptive challenge because astronauts will experience prolonged exposure to microgravity before encountering a novel gravitational environment. This challenge would have to be met without ground support at the landing site. Evaluation of current adaptive status as well as intervention efficacy can be performed using perceptual, eye movement and postural measures. Due to discrepancies of adaptation magnitude and time-course among these measures, complete understanding of adaptation processes, as well as intervention evaluation, requires examination of all three. Previous research and theory that provide models for comprehending adaptation to altered inertial environments are briefly examined. Reports from astronauts of selected pre- in- and postflight self-motion illusions are described. The currently controversial tilt-translation reinterpretation hypothesis is reviewed and possible resolutions to the controversy are proposed. Finally, based on apparent gaps in our current knowledge, further research is proposed to achieve a more complete understanding of adaptation as well as to develop effective counter-measures.

  17. Biological effects of the PINK1 c.1366C>T mutation: implications in Parkinson disease pathogenesis.

    Science.gov (United States)

    Grünewald, Anne; Breedveld, Guido J; Lohmann-Hedrich, Katja; Rohé, Christan F; König, Inke R; Hagenah, Johann; Vanacore, Nicola; Meco, Giuseppe; Antonini, Angelo; Goldwurm, Stefano; Lesage, Suzanne; Dürr, Alexandra; Binkofski, Ferdinand; Siebner, Hartwig; Münchau, Alexander; Brice, Alexis; Oostra, Ben A; Klein, Christine; Bonifati, Vincenzo

    2007-04-01

    PINK1 gene mutations are a cause of recessively inherited, early-onset Parkinson's disease. In some patients, a single heterozygous mutation has been identified, including the recurrent c.1366C>T transition. The interpretation of this finding remains controversial. Furthermore, the c.1366C>T mutation is associated with lower levels of PINK1 transcript, raising the question of whether mRNA levels correlate with the clinical status. We sequenced genomic DNA and copy DNA (cDNA) from 20 subjects carrying the c.1366C>T mutation in the homozygous (n = 5) or heterozygous (n = 15) state. In 17 mutation carriers, messenger RNA (mRNA) was quantified by real-time PCR using four different assays (PINK1 exon 5-6 or exon 7-8 relative to control genes SDHA or YWHAZ). Genomic sequencing confirmed the presence and zygosity of PINK1 mutations. cDNA sequencing in heterozygous mutation carriers revealed a strong wild-type and a much weaker or almost absent mutant signal, whereas in the homozygous patients, only the mutant signal was detected. Homozygous and heterozygous carriers showed PINK1 mRNA levels relative to a reference gene in the range of 0.1-0.2 and 0.5-0.6, respectively, compared with values of 0.9-1.0 in mutation-negative individuals. Treatment of lymphoblasts from a heterozygous mutation carrier with cycloheximide markedly increased the mutant transcript signal. We conclude that the recurrent PINK1 c.1366C>T mutation exerts a major effect at the mRNA level (80-90% reduction), most likely via nonsense-mediated mRNA decay. The absence of correlation between PINK1 mRNA levels and clinical status in heterozygous mutation carriers suggests that other genetic or environmental factors play a role in determining the phenotypic variability associated with the c.1366C>T mutation.

  18. Locomotor adaptations in Plio-Pleistocene large carnivores from the Italian Peninsula: Palaeoecological implications

    Directory of Open Access Journals (Sweden)

    Carlo MELORO

    2011-06-01

    Full Text Available Mammalian carnivores are rarely considered for environmental reconstructions because they are extremely adaptable and their geographic range is usually large. However, the functional morphology of carnivore long bones can be indicative of locomotor behaviour as well as adaptation to specific kind of habitats. Here, different long bone ratios belonging to a subsample of extant large carnivores are used to infer palaeoecology of a comparative sample of Plio-Pleistocene fossils belonging to Italian paleo-communities. A multivariate long bone shape space reveals similarities between extant and fossil carnivores and multiple logistic regression models suggest that specific indices (the brachial and the Mt/F can be applied to predict adaptations to grassland and tropical biomes. These functional indices exhibit also a phylogenetic signal to different degree. The brachial index is a significant predictor of adaptations to tropical biomes when phylogeny is taken into account, while Mt/F is not correlated anymore to habitat adaptations. However, the proportion of grassland-adapted carnivores in Italian paleo-communities exhibits a negative relationship with mean oxygen isotopic values, which are indicative of past climatic oscillations. As climate became more unstable during the Ice Ages, large carnivore guilds from the Italian peninsula were invaded by tropical/closed-adapted species. These species take advantage of the temperate forest cover that was more spread after 1.0 Ma than in the initial phase of the Quaternary (2.0 Ma when the climate was more arid [Current Zoology 57 (3: 269–283, 2011].

  19. Adaptation to salinity in mangroves: Implication on the evolution of salt-tolerance

    Institute of Scientific and Technical Information of China (English)

    LIANG Shan; ZHOU RenChao; DONG SuiSui; SHI SuHua

    2008-01-01

    A plant's adaptation to its environment is one of the most important issues in evolutionary biology. Mangroves are trees that inhabit the intertidal zones with high salinity, while salt tolerance competence of different species varies. Even congeneric species usually occupy distinct positions of intertidal zones due to differential ability of salt tolerance. Some species have different ecotypes that adapt well to littoral and terrestrial environments, respectively. These characteristics of mangroves make them ideal ecological models to study adaptation of mangroves to salinity. Here, we briefly depict adaptive traits of salt tolerance in mangroves with respect to anatomy, physiology and biochemistry, and review the major advances recently made on both the genetic and genomic levels. Results from studies on individual genes or whole genomes of mangroves have confirmed conclusions drawn from studies on anatomy, physiology and biochemistry, and have further indicated that specific patterns of gene expression might contribute to adaptive evolution of mangroves under high salinity. By integrating all information from mangroves and performing comparisons among species of mangroves and non-mangroves, we could give a general picture of adaptation of mangroves to salinity, thus providing a new avenue for further studies on a molecular basis of adaptive evolution of mangroves.

  20. Locomotor adaptations in Plio-Pleistocene large carnivores from the Italian Peninsula: Palaeoecological implications

    Institute of Scientific and Technical Information of China (English)

    Carlo MELORO

    2011-01-01

    Mammalian carnivores are rarely considered for environmental reconstructions because they are extremely adaptable and their geographic range is usually large. However, the functional morphology of carnivore long bones can be indicative of locomotor behaviour as well as adaptation to specific kind of habitats. Here, different long bone ratios belonging to a subsample of extant large carnivores are used to infer palaeoecology of a comparative sample of Plio-Pleistocene fossils belonging to Italian paleo-communities. A multivariate long bone shape space reveals similarities between extant and fossil carnivores and multiple logistic regression models suggest that specific indices (the brachial and the Mt/F) can be applied to predict adaptations to grassland and tropical biomes. These functional indices exhibit also a phylogenetic signal to different degree. The brachial index is a significant predictor of adaptations to tropical biomes when phylogeny is taken into account, while Mt/F is not correlated anymore to habitat adaptations. However, the proportion of grassland-adapted carnivores in Italian paleo-communities exhibits a negative relationship with mean oxygen isotopic values, which are indicative of past climatic oscillations. As climate became more unstable during the Ice Ages, large carnivore guilds from the Italian peninsula were invaded by tropical/closed-adapted species. These species take advantage of the temperate forest cover that was more spread after 1.0 Ma than in the initial phase of the Quaternary (2.0 Ma) when the climate was more arid.

  1. Adaptive Immunity Dysregulation in Acute Coronary Syndromes: From Cellular and Molecular Basis to Clinical Implications.

    Science.gov (United States)

    Flego, Davide; Liuzzo, Giovanna; Weyand, Cornelia M; Crea, Filippo

    2016-11-08

    Although the early outcome of acute coronary syndrome (ACS) has considerably improved in the last decade, cardiovascular diseases still represent the main cause of morbidity and mortality worldwide. This is mainly because recurrence of ACS eventually leads to the pandemics of heart failure and sudden cardiac death, thus calling for a reappraisal of the mechanisms responsible for coronary instability. This review discusses recent advances in our understanding of how adaptive immunity contributes to the pathogenesis of ACS and the clinical implications that arise from these new pathogenic concepts. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  2. A case of IL-7R deficiency caused by a novel synonymous mutation and implications for mutation screening in SCID diagnosis.

    Directory of Open Access Journals (Sweden)

    FERNANDO GALLEGO-BUSTOS

    2016-10-01

    Full Text Available Reported synonymous substitutions are generally non-pathogenic and rare pathogenic synonymous variants may be disregarded unless there is a high index of suspicion. In a case of IL7 receptor deficiency SCID, the relevance of a non-reported synonymous variant was only suspected through the use of additional in silico computational tools which focused on the impact of mutations on gene splicing. The pathogenic nature of the variant was confirmed using experimental validation of the effect on mRNA splicing and IL7 pathway function. This case reinforces the need to use additional experimental methods to establish the functional impact of specific mutations, in particular for cases such as SCID where prompt diagnosis can greatly impact on diagnosis, treatment and survival.

  3. Low 2012-13 influenza vaccine effectiveness associated with mutation in the egg-adapted H3N2 vaccine strain not antigenic drift in circulating viruses.

    Directory of Open Access Journals (Sweden)

    Danuta M Skowronski

    Full Text Available BACKGROUND: Influenza vaccine effectiveness (VE is generally interpreted in the context of vaccine match/mismatch to circulating strains with evolutionary drift in the latter invoked to explain reduced protection. During the 2012-13 season, however, detailed genotypic and phenotypic characterization shows that low VE was instead related to mutations in the egg-adapted H3N2 vaccine strain rather than antigenic drift in circulating viruses. METHODS/FINDINGS: Component-specific VE against medically-attended, PCR-confirmed influenza was estimated in Canada by test-negative case-control design. Influenza A viruses were characterized genotypically by amino acid (AA sequencing of established haemagglutinin (HA antigenic sites and phenotypically through haemagglutination inhibition (HI assay. H3N2 viruses were characterized in relation to the WHO-recommended, cell-passaged vaccine prototype (A/Victoria/361/2011 as well as the egg-adapted strain as per actually used in vaccine production. Among the total of 1501 participants, influenza virus was detected in 652 (43%. Nearly two-thirds of viruses typed/subtyped were A(H3N2 (394/626; 63%; the remainder were A(H1N1pdm09 (79/626; 13%, B/Yamagata (98/626; 16% or B/Victoria (54/626; 9%. Suboptimal VE of 50% (95%CI: 33-63% overall was driven by predominant H3N2 activity for which VE was 41% (95%CI: 17-59%. All H3N2 field isolates were HI-characterized as well-matched to the WHO-recommended A/Victoria/361/2011 prototype whereas all but one were antigenically distinct from the egg-adapted strain as per actually used in vaccine production. The egg-adapted strain was itself antigenically distinct from the WHO-recommended prototype, and bore three AA mutations at antigenic sites B [H156Q, G186V] and D [S219Y]. Conversely, circulating viruses were identical to the WHO-recommended prototype at these positions with other genetic variation that did not affect antigenicity. VE was 59% (95%CI:16-80% against A(H1N1pdm09

  4. Rural Households’ Adaptation to Climate Change and its Implications for Policy Designs in Lijiang, China

    DEFF Research Database (Denmark)

    Zheng, Yuan

    As challenges and opportunities induced by climate change become increasingly manifested, adaptation strategies to these changes have received growing attention. While earlier studies focus on quantifying impacts of climate change or adaptation potential, empirical studies have been increasingly...... emphasised to document localised and actual adaptation practices. Although the latter has made important contributions to investigating people’s perceptions and interpretations of climate change, examining individual and collective climate responses as well as determinants of and barriers to adaptation...... changes in social-ecological systems. The PhD research demonstrates 1) the interwoven impacts of co-evolving socio-economic, political and environmental changes in shaping livelihood changes and households’ vulnerability; 2) the usefulness to accommodate key cognitive processes, such as risk perception...

  5. Adaptive genetic potential of coniferous forest tree species under climate change: implications for sustainable forest management

    Science.gov (United States)

    Mihai, Georgeta; Birsan, Marius-Victor; Teodosiu, Maria; Dumitrescu, Alexandru; Daia, Mihai; Mirancea, Ionel; Ivanov, Paula; Alin, Alexandru

    2017-04-01

    Mountain ecosystems are extremely vulnerable to climate change. The real potential for adaptation depends upon the existence of a wide genetic diversity in trees populations, upon the adaptive genetic variation, respectively. Genetic diversity offers the guarantee that forest species can survive, adapt and evolve under the influence of changing environmental conditions. The aim of this study is to evaluate the genetic diversity and adaptive genetic potential of two local species - Norway spruce and European silver fir - in the context of regional climate change. Based on data from a long-term provenance experiments network and climate variables spanning over more than 50 years, we have investigated the impact of climatic factors on growth performance and adaptation of tree species. Our results indicate that climatic and geographic factors significantly affect forest site productivity. Mean annual temperature and annual precipitation amount were found to be statistically significant explanatory variables. Combining the additive genetic model with the analysis of nuclear markers we obtained different images of the genetic structure of tree populations. As genetic indicators we used: gene frequencies, genetic diversity, genetic differentiation, genetic variance, plasticity. Spatial genetic analyses have allowed identifying the genetic centers holding high genetic diversity which will be valuable sources of gene able to buffer the negative effects of future climate change. Correlations between the marginal populations and in the optimal vegetation, between the level of genetic diversity and ecosystem stability, will allow the assessment of future risks arising from current genetic structure. Therefore, the strategies for sustainable forest management have to rely on the adaptive genetic variation and local adaptation of the valuable genetic resources. This work was realized within the framework of the project GENCLIM (Evaluating the adaptive potential of the main

  6. Use of adaptive laboratory evolution to discover key mutations enabling rapid growth of Escherichia coli K-12 MG1655 on glucose minimal medium.

    Science.gov (United States)

    LaCroix, Ryan A; Sandberg, Troy E; O'Brien, Edward J; Utrilla, Jose; Ebrahim, Ali; Guzman, Gabriela I; Szubin, Richard; Palsson, Bernhard O; Feist, Adam M

    2015-01-01

    Adaptive laboratory evolution (ALE) has emerged as an effective tool for scientific discovery and addressing biotechnological needs. Much of ALE's utility is derived from reproducibly obtained fitness increases. Identifying causal genetic changes and their combinatorial effects is challenging and time-consuming. Understanding how these genetic changes enable increased fitness can be difficult. A series of approaches that address these challenges was developed and demonstrated using Escherichia coli K-12 MG1655 on glucose minimal media at 37°C. By keeping E. coli in constant substrate excess and exponential growth, fitness increases up to 1.6-fold were obtained compared to the wild type. These increases are comparable to previously reported maximum growth rates in similar conditions but were obtained over a shorter time frame. Across the eight replicate ALE experiments performed, causal mutations were identified using three approaches: identifying mutations in the same gene/region across replicate experiments, sequencing strains before and after computationally determined fitness jumps, and allelic replacement coupled with targeted ALE of reconstructed strains. Three genetic regions were most often mutated: the global transcription gene rpoB, an 82-bp deletion between the metabolic pyrE gene and rph, and an IS element between the DNA structural gene hns and tdk. Model-derived classification of gene expression revealed a number of processes important for increased growth that were missed using a gene classification system alone. The methods described here represent a powerful combination of technologies to increase the speed and efficiency of ALE studies. The identified mutations can be examined as genetic parts for increasing growth rate in a desired strain and for understanding rapid growth phenotypes.

  7. Adaptation of lodgepole pine and interior spruce to climate: implications for reforestation in a warming world.

    Science.gov (United States)

    Liepe, Katharina J; Hamann, Andreas; Smets, Pia; Fitzpatrick, Connor R; Aitken, Sally N

    2016-02-01

    We investigated adaptation to climate in populations of two widespread tree species across a range of contrasting environments in western Canada. In a series of common garden experiments, bud phenology, cold hardiness, and seedling growth traits were assessed for 254 populations in the interior spruce complex (Picea glauca, P. engelmannii, and their hybrids) and for 281 populations of lodgepole pine (Pinus contorta). Complex multitrait adaptations to different ecological regions such as boreal, montane, coastal, and arid environments accounted for 15-20% of the total variance. This population differentiation could be directly linked to climate variables through multivariate regression tree analysis. Our results suggest that adaptation to climate does not always correspond linearly to temperature gradients. For example, opposite trait values (e.g., early versus late budbreak) may be found in response to apparently similar cold environments (e.g., boreal and montane). Climate change adaptation strategies may therefore not always be possible through a simple shift of seed sources along environmental gradients. For the two species in this study, we identified a relatively small number of uniquely adapted populations (11 for interior spruce and nine for lodgepole pine) that may be used to manage adaptive variation under current and expected future climates.

  8. Adaptation of Soybean mosaic virus avirulent chimeras containing P3 sequences from virulent strains to Rsv1-genotype soybeans is mediated by mutations in HC-Pro.

    Science.gov (United States)

    Hajimorad, M R; Eggenberger, A L; Hill, J H

    2008-07-01

    In Rsv1-genotype soybean, Soybean mosaic virus (SMV)-N (an avirulent isolate of strain G2) elicits extreme resistance (ER) whereas strain SMV-G7 provokes a lethal systemic hypersensitive response (LSHR). SMV-G7d, an experimentally evolved variant of SMV-G7, induces systemic mosaic. Thus, for Rsv1-genotype soybean, SMV-N is avirulent whereas SMV-G7 and SMV-G7d are both virulent. Exploiting these differential interactions, we recently mapped the elicitor functions of SMV provoking Rsv1-mediated ER and LSHR to the N-terminal 271 amino acids of P3 from SMV-N and SMV-G7, respectively. The phenotype of both SMV-G7 and SMV-G7d were rendered avirulent on Rsv1-genotype soybean when the part of the genome encoding the N-terminus or the entire P3 cistron was replaced with that from SMV-N; however, reciprocal exchanges did not confer virulence to SMV-N-derived P3 chimeras. Here, we describe virulent SMV-N-derived P3 chimeras containing the full-length or the N-terminal P3 from SMV-G7 or SMV-G7d, with or without additional mutations in P3, that were selected on Rsv1-genotype soybean by sequential transfers on rsv1 and Rsv1-genotype soybean. Sequence analyses of the P3 and helper-component proteinase (HC-Pro) cistrons of progeny recovered from Rsv1-genotype soybean consistently revealed the presence of mutations in HC-Pro. Interestingly, the precise mutations in HC-Pro required for the adaptation varied among the chimeras. No mutation was detected in the HC-Pro of progeny passaged continuously in rsv1-genotype soybean, suggesting that selection is a consequence of pressure imposed by Rsv1. Mutations in HC-Pro alone failed to confer virulence to SMV-N; however, reconstruction of mutations in HC-Pro of the SMV-N-derived P3 chimeras resulted in virulence. Taken together, the data suggest that HC-Pro complementation of P3 is essential for SMV virulence on Rsv1-genotype soybean.

  9. A novel LQT3 mutation implicates the human cardiac sodium channel domain IVS6 in inactivation kinetics

    NARCIS (Netherlands)

    Groenewegen, WA; Bezzina, CR; van Tintelen, JP; Hoorntje, TM; Mannens, MMAM; Wilde, AAM; Jongsma, HJ; Rook, MB

    2003-01-01

    The Long QT3 syndrome is associated with mutations in the cardiac sodium channel gene SCN5A. Objective: The aim of the present study was the identification and functional characterization of a mutation in a family with the long QT3 syndrome. Methods: The human cardiac sodium channel gene SCN5A was s

  10. Mechanisms responsible for the chromosome and gene mutations driving carcinogenesis: Implications for dose-response characteristics of mutagenic carcinogens

    Science.gov (United States)

    Through the use of high throughput DNA sequencing techniques, it has been possible to characterize a number of tumor types at the molcular level. This has led to the concept that there are "driver" mutations and "passenger" mutations, with an estimate of the number of the driver...

  11. Implications of newly-added N-glycosylation mutation of hepatitis B virus S-gene in patients with coexistence of HBsAg and antiHBs

    Directory of Open Access Journals (Sweden)

    Shan-shan LU

    2016-06-01

    Full Text Available Objective To analyze the characteristics of newly added N-glycosylation mutation in major hydrophilic region (MHR of HBV S gene in patients with coexistence of HBsAg and antiHBs, and reveal the generation mechanism and clinical implications of the coexistence. Methods HBV S genes from 284 patients with HBsAg+antiHBs and 314 patients with single HBsAg were amplified respectively for sequence analysis. A chronic hepatitis B (CHB patient with HBsAg+antiHBs in MHR was found to harbor a novel double N-glycosylation mutation and selected for further study. Recombinant vectors harboring the novel mutant or control PreS/S genes were constructed and transfected in HepG2 cells respectively for phenotypic analysis, and the effects of the mutations on HBV duplication and antigenicity were investigated. Results The detection rate of MHR N-glycosylation mutation was significantly higher in HBsAg+antiHBs group than in single HBsAg group (11.3% vs. 2.9%, P<0.01, respectively. In HBsAg+antiHBs cohort, the proportion of hepatocellular carcinoma (HCC patients accounted for 46.9%(15/32 in patients with N-glycosylation mutation at the time of testing; by contrast, the number was 22.6%(57/252 in patients with non-N-glycosylation mutation (P<0.01. N-glycosylation mutational pattern of the novel strain was s116-118TST NST+s131-133TSM NST concomitant with sP120 deletion+G145D mutation. The novel mutants accounted for 98.0%, 2.0% and 2.5%, respectively, of viral clones in three sequential serum samples. Mutants with single N-glycosylation mutation s130-132GTS NSS without sP120 deletion+G145D were detected in sample 2, accounting for 17.6% of viral clones. Compared to the wild-type, the novel mutant had an increase of 31% in replication capacity, but a decrease of 99% in HBsAg level. Immunofluorescence showed that elimination of the two additional N-glycosylation mutations only partly restored HBsAg detection by antiHBs, suggesting that sP120 deletion+G145D mutation also

  12. Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt.

    OpenAIRE

    Pelleau, Stéphane; Moss, Eli L; Dhingra, Satish K.; Volney, Béatrice; Casteras, Jessica; Gabryszewski, Stanislaw J.; Volkman, Sarah K.; Wirth, Dyann F.; Legrand, Eric; David A Fidock; Neafsey, Daniel E; Musset, Lise

    2015-01-01

    International audience; In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations ...

  13. WE-G-BRD-08: Motion Analysis for Rectal Cancer: Implications for Adaptive Radiotherapy On the MR-Linac

    Energy Technology Data Exchange (ETDEWEB)

    Kleijnen, J; Asselen, B van; Burbach, M; Intven, M; Philippens, M; Reerink, O; Lagendijk, J; Raaymakers, B [University Medical Center Utrecht, Utrecht (Netherlands)

    2015-06-15

    Purpose: Purpose of this study is to find the optimal trade-off between adaptation interval and margin reduction and to define the implications of motion for rectal cancer boost radiotherapy on a MR-linac. Methods: Daily MRI scans were acquired of 16 patients, diagnosed with rectal cancer, prior to each radiotherapy fraction in one week (N=76). Each scan session consisted of T2-weighted and three 2D sagittal cine-MRI, at begin (t=0 min), middle (t=9:30 min) and end (t=18:00 min) of scan session, for 1 minute at 2 Hz temporal resolution. Tumor and clinical target volume (CTV) were delineated on each T2-weighted scan and transferred to each cine-MRI. The start frame of the begin scan was used as reference and registered to frames at time-points 15, 30 and 60 seconds, 9:30 and 18:00 minutes and 1, 2, 3 and 4 days later. Per time-point, motion of delineated voxels was evaluated using the deformation vector fields of the registrations and the 95th percentile distance (dist95%) was calculated as measure of motion. Per time-point, the distance that includes 90% of all cases was taken as estimate of required planning target volume (PTV)-margin. Results: Highest motion reduction is observed going from 9:30 minutes to 60 seconds. We observe a reduction in margin estimates from 10.6 to 2.7 mm and 16.1 to 4.6 mm for tumor and CTV, respectively, when adapting every 60 seconds compared to not adapting treatment. A 75% and 71% reduction, respectively. Further reduction in adaptation time-interval yields only marginal motion reduction. For adaptation intervals longer than 18:00 minutes only small motion reductions are observed. Conclusion: The optimal adaptation interval for adaptive rectal cancer (boost) treatments on a MR-linac is 60 seconds. This results in substantial smaller PTV-margin estimates. Adaptation intervals of 18:00 minutes and higher, show little improvement in motion reduction.

  14. Biological Cost of Single and Multiple Norfloxacin Resistance Mutations in Escherichia coli Implicated in Urinary Tract Infections

    Science.gov (United States)

    Lindgren, Patricia Komp; Marcusson, Linda L.; Sandvang, Dorthe; Frimodt-Møller, Niels; Hughes, Diarmaid

    2005-01-01

    Resistance to fluoroquinolones in urinary tract infection (UTIs) caused by Escherichia coli is associated with multiple mutations, typically those that alter DNA gyrase and DNA topoisomerase IV and those that regulate AcrAB-TolC-mediated efflux. We asked whether a fitness cost is associated with the accumulation of these multiple mutations. Mutants of the susceptible E. coli UTI isolate Nu14 were selected through three to five successive steps with norfloxacin. Each selection was performed with the MIC of the selected strain. After each selection the MIC was measured; and the regions of gyrA, gyrB, parC, and parE, previously associated with resistance mutations, and all of marOR and acrR were sequenced. The first selection step yielded mutations in gyrA, gyrB, and marOR. Subsequent selection steps yielded mutations in gyrA, parE, and marOR but not in gyrB, parC, or acrR. Resistance-associated mutations were identified in almost all isolates after selection steps 1 and 2 but in less than 50% of isolates after subsequent selection steps. Selected strains were competed in vitro, in urine, and in a mouse UTI infection model against the starting strain, Nu14. First-step mutations were not associated with significant fitness costs. However, the accumulation of three or more resistance-associated mutations was usually associated with a large reduction in biological fitness, both in vitro and in vivo. Interestingly, in some lineages a partial restoration of fitness was associated with the accumulation of additional mutations in late selection steps. We suggest that the relative biological costs of multiple mutations may influence the evolution of E. coli strains that develop resistance to fluoroquinolones. PMID:15917531

  15. Structural analysis of alkaline β-mannanase from alkaliphilic Bacillus sp. N16-5: implications for adaptation to alkaline conditions.

    Directory of Open Access Journals (Sweden)

    Yueju Zhao

    Full Text Available Significant progress has been made in isolating novel alkaline β-mannanases, however, there is a paucity of information concerning the structural basis for alkaline tolerance displayed by these β-mannanases. We report the catalytic domain structure of an industrially important β-mannanase from the alkaliphilic Bacillus sp. N16-5 (BSP165 MAN at a resolution of 1.6 Å. This enzyme, classified into subfamily 8 in glycosyl hydrolase family 5 (GH5, has a pH optimum of enzymatic activity at pH 9.5 and folds into a classic (β/α(8-barrel. In order to gain insight into molecular features for alkaline adaptation, we compared BSP165 MAN with previously reported GH5 β-mannanases. It was revealed that BSP165 MAN and other subfamily 8 β-mannanases have significantly increased hydrophobic and Arg residues content and decreased polar residues, comparing to β-mannanases of subfamily 7 or 10 in GH5 which display optimum activities at lower pH. Further, extensive structural comparisons show alkaline β-mannanases possess a set of distinctive features. Position and length of some helices, strands and loops of the TIM barrel structures are changed, which contributes, to a certain degree, to the distinctly different shaped (β/α(8-barrels, thus affecting the catalytic environment of these enzymes. The number of negatively charged residues is increased on the molecular surface, and fewer polar residues are exposed to the solvent. Two amino acid substitutions in the vicinity of the acid/base catalyst were proposed to be possibly responsible for the variation in pH optimum of these homologous enzymes in subfamily 8 of GH5, identified by sequence homology analysis and pK(a calculations of the active site residues. Mutational analysis has proved that Gln91 and Glu226 are important for BSP165 MAN to function at high pH. These findings are proposed to be possible factors implicated in the alkaline adaptation of GH5 β-mannanases and will help to further

  16. Identification of KLHL41 Mutations Implicates BTB-Kelch-Mediated Ubiquitination as an Alternate Pathway to Myofibrillar Disruption in Nemaline Myopathy.

    Science.gov (United States)

    Gupta, Vandana A; Ravenscroft, Gianina; Shaheen, Ranad; Todd, Emily J; Swanson, Lindsay C; Shiina, Masaaki; Ogata, Kazuhiro; Hsu, Cynthia; Clarke, Nigel F; Darras, Basil T; Farrar, Michelle A; Hashem, Amal; Manton, Nicholas D; Muntoni, Francesco; North, Kathryn N; Sandaradura, Sarah A; Nishino, Ichizo; Hayashi, Yukiko K; Sewry, Caroline A; Thompson, Elizabeth M; Yau, Kyle S; Brownstein, Catherine A; Yu, Timothy W; Allcock, Richard J N; Davis, Mark R; Wallgren-Pettersson, Carina; Matsumoto, Naomichi; Alkuraya, Fowzan S; Laing, Nigel G; Beggs, Alan H

    2013-12-05

    Nemaline myopathy (NM) is a rare congenital muscle disorder primarily affecting skeletal muscles that results in neonatal death in severe cases as a result of associated respiratory insufficiency. NM is thought to be a disease of sarcomeric thin filaments as six of eight known genes whose mutation can cause NM encode components of that structure, however, recent discoveries of mutations in non-thin filament genes has called this model in question. We performed whole-exome sequencing and have identified recessive small deletions and missense changes in the Kelch-like family member 41 gene (KLHL41) in four individuals from unrelated NM families. Sanger sequencing of 116 unrelated individuals with NM identified compound heterozygous changes in KLHL41 in a fifth family. Mutations in KLHL41 showed a clear phenotype-genotype correlation: Frameshift mutations resulted in severe phenotypes with neonatal death, whereas missense changes resulted in impaired motor function with survival into late childhood and/or early adulthood. Functional studies in zebrafish showed that loss of Klhl41 results in highly diminished motor function and myofibrillar disorganization, with nemaline body formation, the pathological hallmark of NM. These studies expand the genetic heterogeneity of NM and implicate a critical role of BTB-Kelch family members in maintenance of sarcomeric integrity in NM. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  17. Cautious but committed: moving toward adaptive planning and operation strategies for renewable energy's wildlife implications.

    Science.gov (United States)

    Köppel, Johann; Dahmen, Marie; Helfrich, Jennifer; Schuster, Eva; Bulling, Lea

    2014-10-01

    Wildlife planning for renewable energy must cope with the uncertainties of potential wildlife impacts. Unfortunately, the environmental policies which instigate renewable energy and those which protect wildlife are not coherently aligned-creating a green versus green dilemma. Thus, climate mitigation efforts trigger renewable energy development, but then face substantial barriers from biodiversity protection instruments and practices. This article briefly reviews wind energy and wildlife interactions, highlighting the lively debated effects on bats. Today, planning and siting of renewable energy are guided by the precautionary principle in an attempt to carefully address wildlife challenges. However, this planning attitude creates limitations as it struggles to negotiate the aforementioned green versus green dilemma. More adaptive planning and management strategies and practices hold the potential to reconcile these discrepancies to some degree. This adaptive approach is discussed using facets of case studies from policy, planning, siting, and operational stages of wind energy in Germany and the United States, with one case showing adaptive planning in action for solar energy as well. This article attempts to highlight the benefits of more adaptive approaches as well as the possible shortcomings, such as reduced planning security for renewable energy developers. In conclusion, these studies show that adaptive planning and operation strategies can be designed to supplement and enhance the precautionary principle in wildlife planning for green energy.

  18. Fixation light hue bias revisited: implications for using adaptive optics to study color vision.

    Science.gov (United States)

    Hofer, H J; Blaschke, J; Patolia, J; Koenig, D E

    2012-03-01

    Current vision science adaptive optics systems use near infrared wavefront sensor 'beacons' that appear as red spots in the visual field. Colored fixation targets are known to influence the perceived color of macroscopic visual stimuli (Jameson, D., & Hurvich, L. M. (1967). Fixation-light bias: An unwanted by-product of fixation control. Vision Research, 7, 805-809.), suggesting that the wavefront sensor beacon may also influence perceived color for stimuli displayed with adaptive optics. Despite its importance for proper interpretation of adaptive optics experiments on the fine scale interaction of the retinal mosaic and spatial and color vision, this potential bias has not yet been quantified or addressed. Here we measure the impact of the wavefront sensor beacon on color appearance for dim, monochromatic point sources in five subjects. The presence of the beacon altered color reports both when used as a fixation target as well as when displaced in the visual field with a chromatically neutral fixation target. This influence must be taken into account when interpreting previous experiments and new methods of adaptive correction should be used in future experiments using adaptive optics to study color.

  19. Placental adaptations to the maternal-fetal environment: implications for fetal growth and developmental programming.

    Science.gov (United States)

    Sandovici, Ionel; Hoelle, Katharina; Angiolini, Emily; Constância, Miguel

    2012-07-01

    The placenta is a transient organ found in eutherian mammals that evolved primarily to provide nutrients for the developing fetus. The placenta exchanges a wide array of nutrients, endocrine signals, cytokines and growth factors with the mother and the fetus, thereby regulating intrauterine development. Recent studies show that the placenta is not just a passive organ mediating maternal-fetal exchange. It can adapt its capacity to supply nutrients in response to intrinsic and extrinsic variations in the maternal-fetal environment. These dynamic adaptations are thought to occur to maximize fetal growth and viability at birth in the prevailing conditions in utero. However, some of these adaptations may also affect the development of individual fetal tissues, with patho-physiological consequences long after birth. Here, this review summarizes current knowledge on the causes, possible mechanisms and consequences of placental adaptive responses, with a focus on the regulation of transporter-mediated processes for nutrients. This review also highlights the emerging roles that imprinted genes and epigenetic mechanisms of gene regulation may play in placental adaptations to the maternal-fetal environment. Copyright © 2012 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  20. The role of mitochondrial DNA mutations in aging and sarcopenia: implications for the mitochondrial vicious cycle theory of aging.

    Science.gov (United States)

    Hiona, Asimina; Leeuwenburgh, Christiaan

    2008-01-01

    Aging is associated with a progressive loss of skeletal muscle mass and strength and the mechanisms mediating these effects likely involve mitochondrial DNA (mtDNA) mutations, mitochondrial dysfunction and the activation of mitochondrial-mediated apoptosis. Because the mitochondrial genome is densely packed and close to the main generator of reactive oxygen species (ROS) in the cell, the electron transport chain (ETC), an important role for mtDNA mutations in aging has been proposed. Point mutations and deletions in mtDNA accumulate with age in a wide variety of tissues in mammals, including humans, and often coincide with significant tissue dysfunction. Here, we examine the evidence supporting a causative role for mtDNA mutations in aging and sarcopenia. We review experimental outcomes showing that mtDNA mutations, leading to mitochondrial dysfunction and possibly apoptosis, are causal to the process of sarcopenia. Moreover, we critically discuss and dispute an important part of the mitochondrial 'vicious cycle' theory of aging which proposes that accumulation of mtDNA mutations may lead to an enhanced mitochondrial ROS production and ever increasing oxidative stress which ultimately leads to tissue deterioration and aging. Potential mechanism(s) by which mtDNA mutations may mediate their pathological consequences in skeletal muscle are also discussed.

  1. The GULLS project: a comparison of vulnerabilities across selected ocean hotspots and implications for adaptation to global change.

    Science.gov (United States)

    Cochrane, K.; Hobday, A. J.; Aswani, S.; Byfield, V.; Dutra, L.; Gasalla, M.; Haward, M.; Paytan, A.; Pecl, G.; Plaganyi-Lloyd, E.; Popova, K.; Salim, S. S.; Savage, C.; Sauer, W.; van Putten, I. E.; Visser, N.; Team, T G

    2016-12-01

    The GULLS project, `Global learning for local solutions: Reducing vulnerability of marine-dependent coastal communities' has been underway since October 2014. The project has been investigating six regional `hotspots': marine areas experiencing rapid warming. These are south-east Australia, Brazil, India, Solomon Islands, South Africa, and the Mozambique Channel and Madagascar. Rapid warming could be expected to have social, cultural and economic impacts that could affect these countries in different ways and may already be doing so. GULLS has focused on contributing to assessing and reducing the vulnerability of coastal communities and other stakeholders dependent on marine resources and to facilitate adaptation to climate change and variability through an integrated and trans-disciplinary approach. It includes participants from Australia, Brazil, India, Madagascar, New Zealand, South Africa, the United Kingdom and the United States of America. The research programme has been divided into six inter-linked components: ocean models, biological and ecological sensitivity analyses, system models, social vulnerability, policy mapping, and communication and education. This presentation will provide a brief overview of each of these components and describe the benefits that have resulted from the collaborative and transdisciplinary approach of GULLS. Following the standard vulnerability elements of exposure, sensitivity and adaptive capacity, the vulnerabilities of coastal communities and other stakeholders dependent on marine resources in the five hotspots will be compared using a set of indicators derived and populated from results of the research programme. The implications of similarities and differences between the hotspots for adaptation planning and options will be described.

  2. Adaptive practices in heart failure care teams: implications for patient-centered care in the context of complexity

    Directory of Open Access Journals (Sweden)

    Tait GR

    2015-08-01

    member and could extend to other settings. Conclusion: Adaptive practices emerged unpredictably and were variably experienced by team members. Our study offers an empirically grounded explanation of how HF care teams self-organize and how adaptive practices emerge from nonlinear interdependencies among diverse agents. We use these insights to reframe the question of palliative care integration, to ask how best to foster palliative care-aligned adaptive practices in HF care. This work has implications for health care’s growing challenge of providing care to those with chronic medical illness in complex, team-based settings. Keywords: palliative care, qualitative, complex adaptive system, multimorbidity, health care teams

  3. P. aeruginosa in the paranasal sinuses and transplanted lungs have similar adaptive mutations as isolates from chronically infected CF lungs

    DEFF Research Database (Denmark)

    Ciofu, Oana; Johansen, Helle Krogh; Aanaes, Kasper;

    2013-01-01

    BACKGROUND: Pseudomonas aeruginosa cells are present as biofilms in the paranasal sinuses and the lungs of chronically infected cystic fibrosis (CF) patients. Since different inflammatory responses and selective antibiotic pressures are acting in the sinuses compared with the lungs, we compared......-lung transplantation isolates. RESULTS: The same phenotypes caused by similar mutations and similar gene expression profiles were found in mucoid and non-mucoid isolates from the paranasal sinuses and from the lungs before and after transplantation. CONCLUSION: Bilateral exchange of P. aeruginosa isolates between...... the paranasal sinuses and the lungs occurs in chronically infected patients and extensive sinus surgery before the lung transplantation might prevent infection of the new lung....

  4. Ebola Virus Altered Innate and Adaptive Immune Response Signalling Pathways: Implications for Novel Therapeutic Approaches.

    Science.gov (United States)

    Kumar, Anoop

    2016-01-01

    Ebola virus (EBOV) arise attention for their impressive lethality by the poor immune response and high inflammatory reaction in the patients. It causes a severe hemorrhagic fever with case fatality rates of up to 90%. The mechanism underlying this lethal outcome is poorly understood. In 2014, a major outbreak of Ebola virus spread amongst several African countries, including Leone, Sierra, and Guinea. Although infections only occur frequently in Central Africa, but the virus has the potential to spread globally. Presently, there is no vaccine or treatment is available to counteract Ebola virus infections due to poor understanding of its interaction with the immune system. Accumulating evidence indicates that the virus actively alters both innate and adaptive immune responses and triggers harmful inflammatory responses. In the literature, some reports have shown that alteration of immune signaling pathways could be due to the ability of EBOV to interfere with dendritic cells (DCs), which link innate and adaptive immune responses. On the other hand, some reports have demonstrated that EBOV, VP35 proteins act as interferon antagonists. So, how the Ebola virus altered the innate and adaptive immune response signaling pathways is still an open question for the researcher to be explored. Thus, in this review, I try to summarize the mechanisms of the alteration of innate and adaptive immune response signaling pathways by Ebola virus which will be helpful for designing effective drugs or vaccines against this lethal infection. Further, potential targets, current treatment and novel therapeutic approaches have also been discussed.

  5. Central adaptation to repeated galvanic vestibular stimulation: implications for pre-flight astronaut training.

    Directory of Open Access Journals (Sweden)

    Valentina Dilda

    Full Text Available Healthy subjects (N = 10 were exposed to 10-min cumulative pseudorandom bilateral bipolar Galvanic vestibular stimulation (GVS on a weekly basis for 12 weeks (120 min total exposure. During each trial subjects performed computerized dynamic posturography and eye movements were measured using digital video-oculography. Follow up tests were conducted 6 weeks and 6 months after the 12-week adaptation period. Postural performance was significantly impaired during GVS at first exposure, but recovered to baseline over a period of 7-8 weeks (70-80 min GVS exposure. This postural recovery was maintained 6 months after adaptation. In contrast, the roll vestibulo-ocular reflex response to GVS was not attenuated by repeated exposure. This suggests that GVS adaptation did not occur at the vestibular end-organs or involve changes in low-level (brainstem-mediated vestibulo-ocular or vestibulo-spinal reflexes. Faced with unreliable vestibular input, the cerebellum reweighted sensory input to emphasize veridical extra-vestibular information, such as somatosensation, vision and visceral stretch receptors, to regain postural function. After a period of recovery subjects exhibited dual adaption and the ability to rapidly switch between the perturbed (GVS and natural vestibular state for up to 6 months.

  6. Evidence-Based Practice in Special Education and Cultural Adaptations: Challenges and Implications for Research

    Science.gov (United States)

    Wang, Mian; Lam, Yeana

    2017-01-01

    Many issues arise in the discussion of the evidence-based practice (EBP) movement and implementation science in special education and specific educational practices for students with severe disabilities. Yet cultural adaptations of EBPs, which have emerged as an area of research in other fields, are being left out as a focus of EBP discourse. The…

  7. Language, Reading, and Readability Formulas: Implications for Developing and Adapting Tests

    Science.gov (United States)

    Oakland, Thomas; Lane, Holly B.

    2004-01-01

    Issues pertaining to language and reading while developing and adapting tests are examined. Strengths and limitations associated with the use of readability formulas are discussed. Their use should be confined to paragraphs and longer passages, not items. Readability methods that consider both quantitative and qualitative variables and are…

  8. Adapting Choral Singing Experiences for Older Adults: The Implications of Sensory, Perceptual, and Cognitive Changes

    Science.gov (United States)

    Yinger, Olivia Swedberg

    2014-01-01

    As people age, they naturally experience sensory, perceptual, and cognitive changes. Many of these changes necessitate adaptations in designing programs for older adults. Choral singing is an activity that has many potential benefits for older adults, yet the rehearsal environment, presentation style, and content of material presented may need to…

  9. Climate Change in the High Andes:implications and adaptation strategies for small-scale farmers

    NARCIS (Netherlands)

    Perez, C.; Nicklin, C.; Dangles, O.; Vanek, S.; Sherwood, S.G.; Halloy, S.; Garrett, K.A.; Forbes, G.A.

    2010-01-01

    Abstract: Global climate change represents a major threat to sustainable farming in the Andes. Farmers have used local ecological knowledge and intricate production systems to cope, adapt and reorganize to meet climate uncertainty and risk, which have always been a fact of life. Those traditional

  10. Adapting Choral Singing Experiences for Older Adults: The Implications of Sensory, Perceptual, and Cognitive Changes

    Science.gov (United States)

    Yinger, Olivia Swedberg

    2014-01-01

    As people age, they naturally experience sensory, perceptual, and cognitive changes. Many of these changes necessitate adaptations in designing programs for older adults. Choral singing is an activity that has many potential benefits for older adults, yet the rehearsal environment, presentation style, and content of material presented may need to…

  11. Implications of compound heterozygous insulin receptor mutations in congenital muscle fibre type disproportion myopathy for the receptor kinase activation

    DEFF Research Database (Denmark)

    Klein, H H; Müller, R; Vestergaard, H

    1999-01-01

    % of the receptors to become insulin-dependently activated. The mother carries a point mutation at the last base pair in exon 17 which, due to abnormal alternative splicing, could lead to normally transcribed receptor or truncated receptor lacking the kinase region. Kinase activation was normal in the mother......We studied insulin receptor kinase activation in two brothers with congenital muscle fibre type disproportion myopathy and compound heterozygous mutations of the insulin receptor gene, their parents, and their unaffected brother. In the father who has a heterozygote Arg1174-->Gln mutation, in situ......'s skeletal muscle, suggesting that virtually no truncated receptor was expressed. Receptor kinase activity was, however, reduced by 95 and 91% in the compound heterozygous brothers. This suggests that the mother's mutated allele contributes little to the generation of functional receptor protein...

  12. Depression as an evolutionary adaptation: implications for the development of preclinical models.

    Science.gov (United States)

    Hendrie, C A; Pickles, A R

    2009-03-01

    Several authors have suggested that rather than being a disease state, depression is an evolutionary adaptation to human social organization. Adaptations are produced in response to selection pressures and similar adaptations may easily have evolved in a range of other species. The current paper seeks to identify the social pressures that may lead to a species developing depression as an adaptation and the potential benefits that this may confer. It also examines whether rats and mice, the species most commonly used to model depression in the laboratory, have social organizations in which selection pressures towards the development of depression as an adaptation are likely to exist. It is proposed that depression is a useful adaptation in group-living animals, where there is competition for a social rank that gives reproductive advantage over others. The cluster of symptoms associated with depression include altered activity patterns, reduced sociability and appetite, and increased submissiveness. This combination strongly suggests that the function of depression is to reduce the likelihood of an individual being subject to further attack once they have lost social status and so increase their chances of survival in the period immediately following this. Successful transition from high to low status may provide further opportunities to reproduce. Hence, animals that become depressed during this critical period gain a reproductive advantage over those that do not, as these are either killed or expelled from the group. Wild mice do not have social hierarchies and are highly territorial. Wild rats do have social hierarchies however these only compete for reproductive advantage at the level of the sperm, and social status does not translate into significantly greater access to mates. Therefore, there are no selection pressures in these species towards the development of depression and so it is most unlikely that rats and mice have this adaptation. It is concluded that

  13. Sexually dimorphic adaptations in basal maternal stress physiology during pregnancy and implications for fetal development.

    Science.gov (United States)

    Giesbrecht, Gerald F; Campbell, Tavis; Letourneau, Nicole

    2015-06-01

    There is clear evidence of reciprocal exchange of information between the mother and fetus during pregnancy but the majority of research in this area has focussed on the fetus as a recipient of signals from the mother. Specifically, physiological signals produced by the maternal stress systems in response to the environment may carry valuable information about the state of the external world. Prenatal stress produces sex-specific adaptations within fetal physiology that have pervasive and long-lasting effects on development. Little is known, however, about the effects of sex-specific fetal signals on maternal adaptations to pregnancy. The current prospective study examined sexually dimorphic adaptations within maternal stress physiology, including the hypothalamic-adrenal-pituitary (HPA) axis and the autonomic nervous system (ANS) and associations with fetal growth. Using diurnal suites of saliva collected in early and late pregnancy, we demonstrate that basal cortisol and salivary alpha-amylase (sAA) differ by fetal sex. Women carrying female fetuses displayed greater autonomic arousal and flatter (but more elevated) diurnal cortisol patterns compared to women carrying males. Women with flatter daytime cortisol trajectories and more blunted sAA awakening responses also had infants with lower birth weight. These maternal adaptations are consistent with sexually dimorphic fetal developmental/evolutionary adaptation strategies that favor growth for males and conservation of resources for females. The findings provide new evidence to suggest that the fetus contributes to maternal HPA axis and ANS regulation during pregnancy and that these systems also contribute to the regulation of fetal growth. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. RET and EDNRB mutation screening in patients with Hirschsprung disease: Functional studies and its implications for genetic counseling.

    Science.gov (United States)

    Widowati, Titis; Melhem, Shamiram; Patria, Suryono Y; de Graaf, Bianca M; Sinke, Richard J; Viel, Martijn; Dijkhuis, Jos; Sadewa, Ahmad H; Purwohardjono, Rochadi; Soenarto, Yati; Hofstra, Robert Mw; Sribudiani, Yunia

    2016-06-01

    Hirschsprung disease (HSCR) is a major cause of chronic constipation in children. HSCR can be caused by germline mutations in RET and EDNRB. Defining causality of the mutations identified is difficult and almost exclusively based on in silico predictions. Therefore, the reported frequency of pathogenic mutations might be overestimated. We combined mutation analysis with functional assays to determine the frequencies of proven pathogenic RET and EDNRB mutations in HSCR. We sequenced RET and EDNRB in 57 HSCR patients. The identified RET-coding variants were introduced into RET constructs and these were transfected into HEK293 cells to determine RET phosphorylation and activation via ERK. An exon trap experiment was performed to check a possible splice-site mutation. We identified eight rare RET-coding variants, one possible splice-site variant, but no rare EDNRB variants. Western blotting showed that three coding variants p.(Pr270Leu), p.(Ala756Val) and p.(Tyr1062Cys) resulted in lower activation of RET. Moreover, only two RET variants (p.(Ala756Val) and p.(Tyr1062Cys)) resulted in reduced ERK activation. Splice-site assays on c.1880-11A>G could not confirm its pathogenicity. Our data suggest that indeed almost half of the identified rare variants are proven pathogenic and that, hence, functional studies are essential for proper genetic counseling.

  15. Identification of EGFR kinase domain mutations among lung cancer patients in China: implication for targeted cancer therapy

    Institute of Scientific and Technical Information of China (English)

    Bao Ming QIN; Xiao CHEN; Jing De ZHU; Duan Qing PEI

    2005-01-01

    Lung cancer is one of the leading causes of death with one of the lowest survival rates. However, a subset of lung cancer patients who are of Asian origin and carry somatic mutations in epidermal growth factor receptor or EGFR have responded remarkable well to two tyrosine kinase inhibitors, gefitinib and erlotinib. While EGFR mutation profiles have been reported from Japan, South Korea, and Taiwan, there is no such report from mainland of China where the largest pool of patients reside. In this report, we identified ten somatic mutations from a total of 41 lung cancer patients in China. Among them, seven mutations were found in 17 adenocarcinomas. In contrast to previous reports, eight of these mutations are deletions in exon 19 and two of these deletions are homozygous. These results suggest that a large portion of Chinese adenocarcinoma patients could benefit from gefitinib or erlotinib. This unique mutation profile provides a rationale to develop the next generation of EGFR inhibitors more suitable for the Chinese population.

  16. Assessment of genetic diversity among barley cultivars and breeding lines adapted to the US Pacific Northwest, and its implications in breeding barley for imidazolinone-resistance.

    Directory of Open Access Journals (Sweden)

    Sachin Rustgi

    Full Text Available Extensive application of imidazolinone (IMI herbicides had a significant impact on barley productivity contributing to a continuous decline in its acreage over the last two decades. A possible solution to this problem is to transfer IMI-resistance from a recently characterized mutation in the 'Bob' barley AHAS (acetohydroxy acid synthase gene to other food, feed and malting barley cultivars. We focused our efforts on transferring IMI-resistance to barley varieties adapted to the US Pacific Northwest (PNW, since it comprises ∼23% (335,000 ha of the US agricultural land under barley production. To effectively breed for IMI-resistance, we studied the genetic diversity among 13 two-rowed spring barley cultivars/breeding-lines from the PNW using 61 microsatellite markers, and selected six barley genotypes that showed medium to high genetic dissimilarity with the 'Bob' AHAS mutant. The six selected genotypes were used to make 29-53 crosses with the AHAS mutant and a range of 358-471 F1 seeds were obtained. To make informed selection for the recovery of the recipient parent genome, the genetic location of the AHAS gene was determined and its genetic nature assessed. Large F2 populations ranging in size from 2158-2846 individuals were evaluated for herbicide resistance and seedling vigor. Based on the results, F3 lines from the six most vigorous F2 genotypes per cross combination were evaluated for their genetic background. A range of 20%-90% recovery of the recipient parent genome for the carrier chromosome was observed. An effort was made to determine the critical dose of herbicide to distinguish between heterozygotes and homozygotes for the mutant allele. Results suggested that the mutant can survive up to the 10× field recommended dose of herbicide, and the 8× and 10× herbicide doses can distinguish between the two AHAS mutant genotypes. Finally, implications of this research in sustaining barley productivity in the PNW are discussed.

  17. The QoE implications of ultra-high definition video adaptation strategies

    Science.gov (United States)

    Nightingale, James; Awobuluyi, Olatunde; Wang, Qi; Alcaraz-Calero, Jose M.; Grecos, Christos

    2016-04-01

    As the capabilities of high-end consumer devices increase, streaming and playback of Ultra-High Definition (UHD) is set to become commonplace. The move to these new, higher resolution, video services is one of the main factors contributing to the predicted continuation of growth in video related traffic in the Internet. This massive increases in bandwidth requirement, even when mitigated by the use of new video compression standards such as H.265, will place an ever-increasing burden on network service providers. This will be especially true in mobile environments where users have come to expect ubiquitous access to content. Consequently, delivering UHD and Full UHD (FUHD) video content is one of the key drivers for future Fifth Generation (5G) mobile networks. One often voiced, but as yet unanswered question, is whether users of mobile devices with modest screen sizes (e.g. smartphones or smaller tablet) will actually benefit from consuming the much higher bandwidth required to watch online UHD video, in terms of an improved user experience. In this paper, we use scalable H.265 encoded video streams to conduct a subjective evaluation of the impact on a user's perception of video quality across a comprehensive range of adaptation strategies, covering each of the three adaptation domains, for UHD and FUHD video. The results of our subjective study provide insightful and useful indications of which methods of adapting UHD and FUHD streams have the least impact on user's perceived QoE. In particular, it was observed that, in over 70% of cases, users were unable to distinguish between full HD (1080p) and UHD (4K) videos when they were unaware of which version was being shown to them. Our results from this evaluation can be used to provide adaptation rule sets that will facilitate fast, QoE aware in-network adaptation of video streams in support of realtime adaptation objectives. Undoubtedly they will also promote discussion around how network service providers manage

  18. Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene mutations in North Egyptian population: implications for the genetic diagnosis in Egypt.

    Science.gov (United States)

    El-Seedy, A; Pasquet, M C; Shafiek, H; Morsi, T; Kitzis, A; Ladevèze, V

    2016-11-30

    Cystic fibrosis (CF) occurrence in Arab populations is not common and still remains underidentified. Furthermore, the lack of disease awareness and diagnosis facilities have mislead the identification of cystic fibrosis for decades. The knowledge about cystic fibrosis (CF) in Egypt is very limited, and a few reports have drawn attention to the existence of CF or CFTR-related disorders (CFTR-RDs) in the Egyptian population. Therefore a comprehensive genetic analysis of the CFTR gene was realized in patients of North Egypt. DNA samples of 56 Egyptian patients were screened for the CFTR gene mutations. The 27 exons and their flanking regions of the CFTR gene were amplified by PCR, using the published primer pairs, and were studied by automated direct DNA sequencing to detect disease-causing mutations. Moreover, large duplication/deletion was analysed by MLPA technique. CFTR screening revealed the identification of thirteen mutations including four novel ones: c.92G>A (p.Arg31His), c.2782G>C (p.Ala928Pro), c.3718-24G>A, c.4207A>G (p.Arg1403Gly) and nine previously reported mutations: c.454A>T (p.Met152Leu), c.902A>G (p.Tyr301Cys), c.1418delG, c.2620-15C>G, c.2997_3000delAATT, c.3154T>G (p.Phe1052Val), c.3872A>G (p.Gln1291Arg), c.3877G>A (p.Val1293Ile), c.4242+10T>C. Furthermore, eight polymorphisms were found: c.743+40A>G, c.869+11C>T, c.1408A>G, c.1584G>A, c.2562T>G, c.3870A>G, c.4272C>T, c.4389G>A. These mutations and polymorphisms were not previously described in the Egyptian population except for the c.1408A>G polymorphism. Here we demonstrate the importance of the newly discovered mutations in Egyptian patients and the presence of CF, whereas the p.Phe508del mutation is not detected. The identification of CFTR mutations will become increasingly important in undocumented populations. The current findings will help us expand the mutational spectrum of CF and establish the first panel of the CFTR gene mutations in the Egyptian population and design an appropriate

  19. Implications for the offspring of circulating factors involved in beta cell adaptation in pregnancy

    DEFF Research Database (Denmark)

    Nalla, Amarnadh; Ringholm, Lene; Søstrup, Birgitte

    2014-01-01

    is able to stimulate proliferation of rat beta cells. We have identified several circulating factors that may contribute to beta cell adaptation to pregnancy. Further studies are needed to elucidate their possible role in glucose homeostasis in the mother and her offspring.......OBJECTIVE: Several studies have shown an increase in beta cell mass during pregnancy. Somatolactogenic hormones are known to stimulate the proliferation of existing beta cells in rodents whereas the mechanism in humans is still unclear. We hypothesize that in addition to somatolactogenic hormones...... there are other circulating factors involved in beta cell adaptation to pregnancy. This study aimed at screening for potential pregnancy-associated circulating beta cell growth factors. SAMPLES: Serum samples from nonpregnant and pregnant women. METHODS: The effect of serum from pregnant women...

  20. Human physiological adaptation to extended Space Flight and its implications for Space Station

    Science.gov (United States)

    Kutyna, F. A.; Shumate, W. H.

    1985-01-01

    Current work evaluating short-term space flight physiological data on the homeostatic changes due to weightlessness is presented as a means of anticipating Space Station long-term effects. An integrated systems analysis of current data shows a vestibulo-sensory adaptation within days; a loss of body mass, fluids, and electrolytes, stabilizing in a month; and a loss in red cell mass over a month. But bone demineralization which did not level off is seen as the biggest concern. Computer algorithms have been developed to simulate the human adaptation to weightlessness. So far these paradigms have been backed up by flight data and it is hoped that they will provide valuable information for future Space Station design. A series of explanatory schematics is attached.

  1. Knowledge systems in upland farming practices in the Philippines and implications for climate change adaptation

    OpenAIRE

    Espaldon, Maria Victoria O.

    2008-01-01

    The paper focuses on the importance of multiple knowledge systems on enhancing the adaptive capacity of farming communities in the Philippines. It discusses the epistemologies of knowledge that are pertinent to strengthen the resilience of small farmers and farming households, who are one of the most vulnerable groups in the event of climatic variabilities, climatic extremes and climate change. It also brings to the discussion the need for effective communication systems to disseminate the kn...

  2. Leisure activities in Prader-Wlli syndrome: Implications for health, cognition and adaptive functioning

    Science.gov (United States)

    Dykens, Elisabeth M

    2012-01-01

    To this day, I can recite the Sara Sparrow definition of adaptive behavior. To this day, I recall Sara sitting on the other side of a one-way mirror observing me, an inexperienced clinical psychology intern, administer the Vineland Adaptive Behavior Scales to the mother of a child with learning disabilities. Talk about nervous-- the world’s expert on adaptive behavior held my very internship and career success in her hands! Even though I stumbled through it, Sara reassured me that I did great…all I needed was more practice. So, thousands of Vineland’s later, I was launched. Both my first and my latest publications in the disability field used assessment tools that I learned from Sara—primarily the Vineland, but also several cognitive tests. Beyond these tools, I cherish key insights from Sara that have stayed with me over the long haul. First and foremost, Sara taught me how to be a real psychologist, how to carefully observe and assess people with standardized tools and with my own eyes and ears. Second, she instilled a practical skill that I still am working on—always be on time even if others are late! Third, Sara imbued a sense of fun and adventure into our training and she continued to be a source of inspiration and fun in the years after I left Yale. For us data-driven types, the process of research and discovery is inherently fun—it is a total blast. Yet Sara modeled that fun and enjoyment need to come in other ways that are more balanced or well-rounded—that are, in a word, adaptive. It seems a fitting tribute to Sara to submit a paper that related her treasured Vineland Scales to how people with developmental disabilities have fun. Thank you, Sara. PMID:22484792

  3. Six missense mutations associated with type I and type II protein C deficiency and implications obtained from molecular modelling.

    Science.gov (United States)

    Zheng, Y Z; Sakata, T; Matsusue, T; Umeyama, H; Kato, H; Miyata, T

    1994-10-01

    The molecular basis of protein C deficiency was studied in three type I and three type II heterozygotes. Three probands showed thrombotic complications. All the exons and intron/exon junctions of the protein C gene were studied using a strategy combining by the polymerase chain reaction (PCR) amplification, single-strand conformational polymorphism (SSCP) analysis, and DNA sequencing of the PCR-amplified fragments. Six missense mutations were identified, including three novel ones. One was located in exon II, in which the initiating translation codon (ATG) encoding for Met at position -42 was replaced by ACG encoding for Thr. The other five were located in exon IX, and included TAC(Tyr399)-->CAC(His), CCG(Pro327)-->CTG(Leu), GAC(Asp359)-->AAC(Asn) in two cases, and GGG(Gly350)-->AGG(Arg). Four of the six missense mutations occurred in CG dinucleotide. Sequence analysis of the other exons excluded additional mutations. By restriction enzyme analysis, co-segregation of the mutation with protein C deficiency was observed in four families. The other two mutations at amino acid positions -42 and 350 were also considered to be associated with protein C deficiency due to the absence of these mutations in 50 normal individuals. A structural model of the protease domain of mutant activated protein C was constructed by the chimeric modelling method, and the resultant model suggested conformational changes due to each missense mutation identified in protein C deficiency. The present data also provide some evidence regarding the genetic heterogeneity of protein C deficiency.

  4. Adaptive transgenerational plasticity in plants: case studies, mechanisms, and implications for natural populations

    Directory of Open Access Journals (Sweden)

    Jacob J. Herman

    2011-12-01

    Full Text Available Plants respond to environmental conditions not only by plastic changes to their own development and physiology, but also by altering the phenotypes expressed by their offspring. This transgenerational plasticity was initially considered to entail only negative effects of stressful parental environments, such as production of smaller seeds by resource- or temperature-stressed parent plants, and was therefore viewed as environmental noise. Recent evolutionary ecology studies have shown that in some cases, these inherited environmental effects can include specific growth adjustments that are functionally adaptive to the parental conditions that induced them, which can range from contrasting states of controlled laboratory environments to the complex habitat variation encountered by natural plant populations. Preliminary findings suggest that adaptive transgenerational effects can be transmitted by means of diverse mechanisms including changes to seed provisioning and biochemistry, and epigenetic modifications such as DNA methylation that can persist across multiple generations. These non-genetically inherited adaptations can influence the ecological breadth and evolutionary dynamics of plant taxa and promote the spread of invasive plants. Interdisciplinary studies that join mechanistic and evolutionary ecology approaches will be an important source of future insights.

  5. Low Genetic Quality Alters Key Dimensions of the Mutational Spectrum.

    Directory of Open Access Journals (Sweden)

    Nathaniel P Sharp

    2016-03-01

    Full Text Available Mutations affect individual health, population persistence, adaptation, diversification, and genome evolution. There is evidence that the mutation rate varies among genotypes, but the causes of this variation are poorly understood. Here, we link differences in genetic quality with variation in spontaneous mutation in a Drosophila mutation accumulation experiment. We find that chromosomes maintained in low-quality genetic backgrounds experience a higher rate of indel mutation and a lower rate of gene conversion in a manner consistent with condition-based differences in the mechanisms used to repair DNA double strand breaks. These aspects of the mutational spectrum were also associated with body mass, suggesting that the effect of genetic quality on DNA repair was mediated by overall condition, and providing a mechanistic explanation for the differences in mutational fitness decline among these genotypes. The rate and spectrum of substitutions was unaffected by genetic quality, but we find variation in the probability of substitutions and indels with respect to several aspects of local sequence context, particularly GC content, with implications for models of molecular evolution and genome scans for signs of selection. Our finding that the chances of mutation depend on genetic context and overall condition has important implications for how sequences evolve, the risk of extinction, and human health.

  6. Low Genetic Quality Alters Key Dimensions of the Mutational Spectrum

    Science.gov (United States)

    Sharp, Nathaniel P.; Agrawal, Aneil F.

    2016-01-01

    Mutations affect individual health, population persistence, adaptation, diversification, and genome evolution. There is evidence that the mutation rate varies among genotypes, but the causes of this variation are poorly understood. Here, we link differences in genetic quality with variation in spontaneous mutation in a Drosophila mutation accumulation experiment. We find that chromosomes maintained in low-quality genetic backgrounds experience a higher rate of indel mutation and a lower rate of gene conversion in a manner consistent with condition-based differences in the mechanisms used to repair DNA double strand breaks. These aspects of the mutational spectrum were also associated with body mass, suggesting that the effect of genetic quality on DNA repair was mediated by overall condition, and providing a mechanistic explanation for the differences in mutational fitness decline among these genotypes. The rate and spectrum of substitutions was unaffected by genetic quality, but we find variation in the probability of substitutions and indels with respect to several aspects of local sequence context, particularly GC content, with implications for models of molecular evolution and genome scans for signs of selection. Our finding that the chances of mutation depend on genetic context and overall condition has important implications for how sequences evolve, the risk of extinction, and human health. PMID:27015430

  7. An adaptive mutation simulated annealing based investigation of Coulombic explosion and identification of dissociation patterns in (CO2)n(2+) clusters.

    Science.gov (United States)

    Naskar, Pulak; Talukder, Srijeeta; Chaudhury, Pinaki

    2017-04-05

    In this communication, we would like to discuss the advantages of adaptive mutation simulated annealing (AMSA) over standard simulated annealing (SA) in studying the Coulombic explosion of (CO2)n(2+) clusters for n = 20-68, where 'n' is the size of the cluster. We have demonstrated how AMSA itself can overcome the predicaments which can arise in conventional SA and carry out the search for better results by adapting the parameters (only when needed) dynamically during the simulations so that the search process can come out of high energy basins and not go astray for better exploration and convergence, respectively. This technique also has in-built properties for getting more than one minimum in a single run. For a (CO2)n(2+) cluster system we have found the critical limit to be n = 43, above which the attractive forces between individual units become greater in value than that of the large repulsive forces and the clusters stay intact as the energetically favoured isomers. This result is in good concurrence with earlier studies. Moreover, we have studied the fragmentation patterns for the entire size range and we have found fission type fragmentation as the favoured mechanism nearly for all sizes.

  8. Shared ACVR1 mutations in FOP and DIPG: Opportunities and challenges in extending biological and clinical implications across rare diseases.

    Science.gov (United States)

    Han, Harry J; Jain, Payal; Resnick, Adam C

    2017-08-02

    Gain-of-function mutations in the Type I Bone Morphogenic Protein (BMP) receptor ACVR1 have been identified in two diseases: Fibrodysplasia Ossificans Progressiva (FOP), a rare autosomal dominant disorder characterized by genetically driven heterotopic ossification, and in 20-25% of Diffuse Intrinsic Pontine Gliomas (DIPGs), a pediatric brain tumor with no effective therapies and dismal median survival. While the ACVR1 mutation is causal for FOP, its role in DIPG tumor biology remains under active investigation. Here, we discuss cross-fertilization between the FOP and DIPG fields, focusing on the biological mechanisms and principles gleaned from FOP that can be applied to DIPG biology. We highlight our current knowledge of ACVR1 in both diseases, and then describe the growing opportunities and barriers to effectively investigate ACVR1 in DIPG. Importantly, learning from other seemingly unrelated diseases harboring similar mutations may uncover novel mechanisms or processes for future investigation. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. MYBPC3's alternate ending: consequences and therapeutic implications of a highly prevalent 25 bp deletion mutation

    Science.gov (United States)

    Kuster, Diederik W. D.

    2014-01-01

    Hypertrophic cardiomyopathy (HCM) is the most common form of inherited cardiac disease and the leading cause of sudden cardiac death in young people. HCM is caused by mutations in genes encoding contractile proteins. Cardiac myosin binding protein-C (cMyBP-C) is a thick filament contractile protein that regulates sarcomere organization and cardiac contractility. About 200 different mutations in the cMyBP-C gene (MYBPC3) have thus far been reported as causing HCM. Among them, a 25 base pair deletion in the branch point of intron 32 of MYBPC3 is widespread, particularly in South Asia, where it affects ≈4% of South Asian descendants worldwide. This polymorphic mutation results in skipping of exon 33 and a reading frame shift, which, in turn, replaces the last 65 amino acids of the C-terminal C10 domain of cMyBP-C (cMyBP-CC10mut) with a novel sequence of 58 residues. Carriers of the 25 base pair deletion mutation are at increased risk of developing cardiomyopathy and heart failure. Because of the high prevalence of this mutation in certain populations, genetic screening of at-risk groups might be beneficial. Scientifically, the functional consequences of C-terminal mutations and the precise mechanisms leading to HCM should be defined using induced pluripotent stem cells and engineered heart tissue in vitro, or mouse models in vivo. Most importantly, therapeutic strategies that include pharmacology, gene repair and gene therapy should be developed to prevent the adverse clinical effects of cMyBP-CC10mut. This review article aims to examine the effects of cMyBP-CC10mut on cardiac function, emphasizing the need for the development of genetic testing and expanded therapeutic strategies. PMID:24327208

  10. Setal morphology and cirral setation of thoracican barnacle cirri: adaptations and implications for thoracican evolution

    DEFF Research Database (Denmark)

    Chan, B.K.K.; Garm, A.; Høeg, Jens Thorvald

    2008-01-01

    Thoracic cirripedes are sessile crustaceans that use six pairs of thoracic appendages (the cirri) to catch and handle food. We used scanning electron microscopy to examine the cirri, which include one to three pairs of maxillipeds in six species of thoracican barnacles, in search of correlations...... in the mantle cavity using the setae on their three pairs of maxillipeds. Our results indicate that in thoracican barnacles, adaptations in feeding behaviour are associated with changes in the setation pattern of the cirri. In addition, the setal types and their distribution on the cirri are potential new...

  11. User adaptation in long-term, open-loop myoelectric training: implications for EMG pattern recognition in prosthesis control

    Science.gov (United States)

    He, Jiayuan; Zhang, Dingguo; Jiang, Ning; Sheng, Xinjun; Farina, Dario; Zhu, Xiangyang

    2015-08-01

    Objective. Recent studies have reported that the classification performance of electromyographic (EMG) signals degrades over time without proper classification retraining. This problem is relevant for the applications of EMG pattern recognition in the control of active prostheses. Approach. In this study we investigated the changes in EMG classification performance over 11 consecutive days in eight able-bodied subjects and two amputees. Main results. It was observed that, when the classifier was trained on data from one day and tested on data from the following day, the classification error decreased exponentially but plateaued after four days for able-bodied subjects and six to nine days for amputees. The between-day performance became gradually closer to the corresponding within-day performance. Significance. These results indicate that the relative changes in EMG signal features over time become progressively smaller when the number of days during which the subjects perform the pre-defined motions are increased. The performance of the motor tasks is thus more consistent over time, resulting in more repeatable EMG patterns, even if the subjects do not have any external feedback on their performance. The learning curves for both able-bodied subjects and subjects with limb deficiencies could be modeled as an exponential function. These results provide important insights into the user adaptation characteristics during practical long-term myoelectric control applications, with implications for the design of an adaptive pattern recognition system.

  12. The adaptive response of bacterial food-borne pathogens in the environment, host and food: Implications for food safety.

    Science.gov (United States)

    Alvarez-Ordóñez, Avelino; Broussolle, Véronique; Colin, Pierre; Nguyen-The, Christophe; Prieto, Miguel

    2015-11-20

    Bacteria are constantly faced to stress situations in their ecological niches, the food and the host gastrointestinal tract. The capacity to detect and respond to surrounding changes is crucial for bacterial pathogens to survive or grow in changing environments. To this purpose, cells have evolved various sophisticated networks designed to protect against stressors or repair damage caused by them. Challenges can occur during production of foods when subjected to processing, and after food ingestion when confronted with host defensive barriers. Some pathogenic bacteria have shown the capacity to develop stable resistance against extreme conditions within a defined genomic context and a limited number of generations. On the other hand, bacteria can also respond to adverse conditions in a transient manner, through the so-called stress tolerance responses. Bacterial stress tolerance responses include both structural and physiological modifications in the cell and are mediated by complex genetic regulatory machinery. Major aspects in the adaptive response are the sensing mechanisms, the characterization of cell defensive systems, such as the operation of regulatory proteins (e.g. RpoS), the induction of homeostatic and repair systems, the synthesis of shock response proteins, and the modifications of cell membranes, particularly in their fatty acid composition and physical properties. This article reviews certain strategies used by food-borne bacteria to respond to particular stresses (acid, cold stress, extreme pressure) in a permanent or transient manner and discusses the implications that such adaptive responses pose for food safety.

  13. Dietary and physical activity adaptations to alternate day modified fasting: implications for optimal weight loss

    Directory of Open Access Journals (Sweden)

    Klempel Monica C

    2010-09-01

    Full Text Available Abstract Background Alternate day modified fasting (ADMF is an effective strategy for weight loss in obese adults. Objective The objective of this study was to examine the dietary and physical activity adaptations that occur during short-term ADMF, and to determine how these modulations affect rate of weight loss. Methods Sixteen obese subjects (12 women/4 men completed a 10-week trial consisting of 3 phases: 1 2-week control phase, 2 4-week ADMF controlled feeding phase, and 3 4-week ADMF self-selected feeding phase. Results Body weight decreased (P r = 0.42, P = 0.01. Dietary fat intake decreased (36% to 33% of kcal, P r = 0.38, P = 0.03. Hunger on the fast day decreased (P Conclusion These findings indicate that obese subjects quickly adapt to ADMF, and that changes in energy/macronutrient intake, hunger, and maintenance of physical activity play a role in influencing rate of weight loss by ADMF.

  14. Adaptive Evolution of cry Genes in Bacillus thuringiensis:Implications for Their Specificity Determination

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The cry gene family, produced during the late exponential phase of growth in Bacillus thuringiensis, is a large, still-growing family of homologous genes, in which each gene encodes a protein with strong specific activity against only one or a few insect species. Extensive studies are mostly focusing on the structural and functional relationships of Cry proteins, and have revealed several residues or domains that are important for the target recognition and receptor attachment. In this study,we have employed a maximum likelihood method to detect evidence of adaptive evolution in Cry proteins, and have identified 24 positively selected residues, which are all located in Domain Ⅱ or Ⅲ. Combined with known data from mutagenesis studies, the majority of these residues, at the molecular level, contribute much to the insect specificity determination. We postulate that the potential pressures driving the diversification of Cry proteins may be in an attempt to adapt for the "arm race" between δ-endotoxins and the targeted insects, or to enlarge their target spectra, hence result in the functional divergence. The sites identified to be under positive selection would provide targets for further structural and functional analyses on Cry proteins.

  15. Neuromuscular adaptations to training, injury and passive interventions: implications for running economy.

    Science.gov (United States)

    Bonacci, Jason; Chapman, Andrew; Blanch, Peter; Vicenzino, Bill

    2009-01-01

    Performance in endurance sports such as running, cycling and triathlon has long been investigated from a physiological perspective. A strong relationship between running economy and distance running performance is well established in the literature. From this established base, improvements in running economy have traditionally been achieved through endurance training. More recently, research has demonstrated short-term resistance and plyometric training has resulted in enhanced running economy. This improvement in running economy has been hypothesized to be a result of enhanced neuromuscular characteristics such as improved muscle power development and more efficient use of stored elastic energy during running. Changes in indirect measures of neuromuscular control (i.e. stance phase contact times, maximal forward jumps) have been used to support this hypothesis. These results suggest that neuromuscular adaptations in response to training (i.e. neuromuscular learning effects) are an important contributor to enhancements in running economy. However, there is no direct evidence to suggest that these adaptations translate into more efficient muscle recruitment patterns during running. Optimization of training and run performance may be facilitated through direct investigation of muscle recruitment patterns before and after training interventions. There is emerging evidence that demonstrates neuromuscular adaptations during running and cycling vary with training status. Highly trained runners and cyclists display more refined patterns of muscle recruitment than their novice counterparts. In contrast, interference with motor learning and neuromuscular adaptation may occur as a result of ongoing multidiscipline training (e.g. triathlon). In the sport of triathlon, impairments in running economy are frequently observed after cycling. This impairment is related mainly to physiological stress, but an alteration in lower limb muscle coordination during running after cycling

  16. Identifying activating mutations in the EGFR gene: prognostic and therapeutic implications in non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Gabriel Lima Lopes

    2015-08-01

    Full Text Available AbstractLung cancer is the leading cause of cancer-related deaths worldwide. Promising new therapies have recently emerged from the development of molecular targeted drugs; particularly promising are those blocking the signal transduction machinery of cancer cells. One of the most widely studied cell signaling pathways is that of EGFR, which leads to uncontrolled cell proliferation, increased cell angiogenesis, and greater cell invasiveness. Activating mutations in the EGFR gene (deletions in exon 19 and mutation L858R in exon 21, first described in 2004, have been detected in approximately 10% of all non-squamous non-small cell lung cancer (NSCLC patients in Western countries and are the most important predictors of a response to EGFR tyrosine-kinase inhibitors (EGFR-TKIs. Studies of the EGFR-TKIs gefitinib, erlotinib, and afatinib, in comparison with platinum-based regimens, as first-line treatments in chemotherapy-naïve patients have shown that the EGFR-TKIs produce gains in progression-free survival and overall response rates, although only in patients whose tumors harbor activating mutations in the EGFR gene. Clinical trials have also shown EGFR-TKIs to be effective as second- and third-line therapies in advanced NSCLC. Here, we review the main aspects of EGFR pathway activation in NSCLC, underscore the importance of correctly identifying activating mutations in the EGFR gene, and discuss the main outcomes of EGFR-TKI treatment in NSCLC.

  17. Substrate compositional variation with tissue/region and Gba1 mutations in mouse models--implications for Gaucher disease.

    Directory of Open Access Journals (Sweden)

    Ying Sun

    Full Text Available Gaucher disease results from GBA1 mutations that lead to defective acid β-glucosidase (GCase mediated cleavage of glucosylceramide (GC and glucosylsphingosine as well as heterogeneous manifestations in the viscera and CNS. The mutation, tissue, and age-dependent accumulations of different GC species were characterized in mice with Gba1 missense mutations alone or in combination with isolated saposin C deficiency (C*. Gba1 heteroallelism for D409V and null alleles (9V/null led to GC excesses primarily in the visceral tissues with preferential accumulations of lung GC24∶0, but not in liver, spleen, or brain. Age-dependent increases of different GC species were observed. The combined saposin C deficiency (C* with V394L homozygosity (4L;C* showed major GC18:0 degradation defects in the brain, whereas the analogous mice with D409H homozygosity and C* (9H;C* led to all GC species accumulating in visceral tissues. Glucosylsphingosine was poorly degraded in brain by V394L and D409H GCases and in visceral tissues by D409V GCase. The neonatal lethal N370S/N370S genotype had insignificant substrate accumulations in any tissue. These results demonstrate age, organ, and mutation-specific quantitative differences in GC species and glucosylsphingosine accumulations that can have influence in the tissue/regional expression of Gaucher disease phenotypes.

  18. Mutations involved in Aicardi-Goutieres syndrome implicate SAMHD1 as regulator of the innate immune response

    NARCIS (Netherlands)

    Rice, Gillian I.; Bond, Jacquelyn; Asipu, Aruna; Brunette, Rebecca L.; Manfield, Iain W.; Carr, Ian M.; Fuller, Jonathan C.; Jackson, Richard M.; Lamb, Teresa; Briggs, Tracy A.; Ali, Manir; Gornall, Hannah; Couthard, Lydia R.; Aeby, Alec; Attard-Montalto, Simon P.; Bertini, Enrico; Bodemer, Christine; Brockmann, Knut; Brueton, Louise A.; Corry, Peter C.; Desguerre, Isabelle; Fazzi, Elisa; Cazorla, Angels Garcia; Gener, Blanca; Hamel, Ben C. J.; Heiberg, Arvid; Hunter, Matthew; van der Knaap, Marjo S.; Kumar, Ram; Lagae, Lieven; Landrieu, Pierre G.; Lourenco, Charles M.; Marom, Daphna; McDermott, Michael F.; van der Merwe, William; Orcesi, Simona; Prendiville, Julie S.; Rasmussen, Magnhild; Shalev, Stavit A.; Soler, Doriette M.; Shinawi, Marwan; Spiegel, Ronen; Tan, Tiong Y.; Vanderver, Adeline; Wakeling, Emma L.; Wassmer, Evangeline; Whittaker, Elizabeth; Lebon, Pierre; Stetson, Daniel B.; Bonthron, David T.; Crow, Yanick J.

    2009-01-01

    Aicardi-Goutieres syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The recent identification of mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DN

  19. Identifying activating mutations in the EGFR gene: prognostic and therapeutic implications in non-small cell lung cancer *

    Science.gov (United States)

    Lopes, Gabriel Lima; Vattimo, Edoardo Filippo de Queiroz; de Castro, Gilberto

    2015-01-01

    Abstract Lung cancer is the leading cause of cancer-related deaths worldwide. Promising new therapies have recently emerged from the development of molecular targeted drugs; particularly promising are those blocking the signal transduction machinery of cancer cells. One of the most widely studied cell signaling pathways is that of EGFR, which leads to uncontrolled cell proliferation, increased cell angiogenesis, and greater cell invasiveness. Activating mutations in the EGFR gene (deletions in exon 19 and mutation L858R in exon 21), first described in 2004, have been detected in approximately 10% of all non-squamous non-small cell lung cancer (NSCLC) patients in Western countries and are the most important predictors of a response to EGFR tyrosine-kinase inhibitors (EGFR-TKIs). Studies of the EGFR-TKIs gefitinib, erlotinib, and afatinib, in comparison with platinum-based regimens, as first-line treatments in chemotherapy-naïve patients have shown that the EGFR-TKIs produce gains in progression-free survival and overall response rates, although only in patients whose tumors harbor activating mutations in the EGFR gene. Clinical trials have also shown EGFR-TKIs to be effective as second- and third-line therapies in advanced NSCLC. Here, we review the main aspects of EGFR pathway activation in NSCLC, underscore the importance of correctly identifying activating mutations in the EGFR gene, and discuss the main outcomes of EGFR-TKI treatment in NSCLC. PMID:26398757

  20. Implications of prion adaptation and evolution paradigm for human neurodegenerative diseases.

    Science.gov (United States)

    Kabir, M Enamul; Safar, Jiri G

    2014-01-01

    There is a growing body of evidence indicating that number of human neurodegenerative diseases, including Alzheimer disease, Parkinson disease, fronto-temporal dementias, and amyotrophic lateral sclerosis, propagate in the brain via prion-like intercellular induction of protein misfolding. Prions cause lethal neurodegenerative diseases in humans, the most prevalent being sporadic Creutzfeldt-Jakob disease (sCJD); they self-replicate and spread by converting the cellular form of prion protein (PrP(C)) to a misfolded pathogenic conformer (PrP(Sc)). The extensive phenotypic heterogeneity of human prion diseases is determined by polymorphisms in the prion protein gene, and by prion strain-specific conformation of PrP(Sc). Remarkably, even though informative nucleic acid is absent, prions may undergo rapid adaptation and evolution in cloned cells and upon crossing the species barrier. In the course of our investigation of this process, we isolated distinct populations of PrP(Sc) particles that frequently co-exist in sCJD. The human prion particles replicate independently and undergo competitive selection of those with lower initial conformational stability. Exposed to mutant substrate, the winning PrP(Sc) conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to the lowest stability. Thus, the evolution and adaptation of human prions is enabled by a dynamic collection of distinct populations of particles, whose evolution is governed by the selection of progressively less stable, faster replicating PrP(Sc) conformers. This fundamental biological mechanism may explain the drug resistance that some prions gained after exposure to compounds targeting PrP(Sc). Whether the phenotypic heterogeneity of other neurodegenerative diseases caused by protein misfolding is determined by the spectrum of misfolded conformers (strains) remains to be established. However, the prospect that these conformers may evolve and

  1. Adaptability of protein structures to enable functional interactions and evolutionary implications.

    Science.gov (United States)

    Haliloglu, Turkan; Bahar, Ivet

    2015-12-01

    Several studies in recent years have drawn attention to the ability of proteins to adapt to intermolecular interactions by conformational changes along structure-encoded collective modes of motions. These so-called soft modes, primarily driven by entropic effects, facilitate, if not enable, functional interactions. They represent excursions on the conformational space along principal low-ascent directions/paths away from the original free energy minimum, and they are accessible to the protein even before protein-protein/ligand interactions. An emerging concept from these studies is the evolution of structures or modular domains to favor such modes of motion that will be recruited or integrated for enabling functional interactions. Structural dynamics, including the allosteric switches in conformation that are often stabilized upon formation of complexes and multimeric assemblies, emerge as key properties that are evolutionarily maintained to accomplish biological activities, consistent with the paradigm sequence→structure→dynamics→function where 'dynamics' bridges structure and function.

  2. Complex adaptive HIV/AIDS risk reduction: Plausible implications from findings in Limpopo Province, South Africa.

    Science.gov (United States)

    Burman, Chris J; Aphane, Marota A

    2016-05-16

    This article emphasises that when working with complex adaptive systems it is possible to stimulate new social practices and/or cognitive perspectives that contribute to risk reduction, associated with reducing aggregate community viral loads. The process of achieving this is highly participatory and is methodologically possible because evidence of 'attractors' that influence the social practices can be identified using qualitative research techniques. Using findings from Limpopo Province, South Africa, we argue that working with 'wellness attractors' and increasing their presence within the HIV/AIDS landscape could influence aggregate community viral loads. While the analysis that is presented is unconventional, it is plausible that this perspective may hold potential to develop a biosocial response - which the Joint United Nations Programme on HIV and AIDS (UNAIDS) has called for - that reinforces the biomedical opportunities that are now available to achieve the ambition of ending AIDS by 2030.

  3. Impact of maraviroc-resistant and low-CCR5-adapted mutations induced by in vitro passage on sensitivity to anti-envelope neutralizing antibodies.

    Science.gov (United States)

    Yoshimura, Kazuhisa; Harada, Shigeyoshi; Boonchawalit, Samatchaya; Kawanami, Yoko; Matsushita, Shuzo

    2014-08-01

    The aim of this study was to generate maraviroc (MVC)-resistant viruses in vitro using a human immunodeficiency virus type 1 subtype B clinical isolate (HIV-1KP-5) to understand the mechanism(s) of resistance to MVC. To select HIV-1 variants resistant to MVC in vitro, we exposed high-chemokine (C-C motif) receptor 5 (CCR5)-expressing PM1/CCR5 cells to HIV-1KP-5 followed by serial passage in the presence of MVC. We also passaged HIV-1KP-5 in PM1 cells, which were low CCR5 expressing to determine low-CCR5-adapted substitutions and compared the Env sequences of the MVC-selected variants. Following 48 passages with MVC (10 µM), HIV-1KP-5 acquired a resistant phenotype [maximal per cent inhibition (MPI) 24%], whilst the low-CCR5-adapted variant had low sensitivity to MVC (IC50 ~200 nM), but not reduction of the MPI. The common substitutions observed in both the MVC-selected and low-CCR5-adapted variants were selected from the quasi-species, in V1, V3 and V5. After 14 passages, the MVC-selected variants harboured substitutions around the CCR5 N-terminal-binding site and V3 (V200I, T297I, K305R and M434I). The low-CCR5-adapted infectious clone became sensitive to anti-CD4bs and CD4i mAbs, but not to anti-V3 mAb and autologous plasma IgGs. Conversely, the MVC-selected clone became highly sensitive to the anti-envelope (Env) mAbs tested and the autologous plasma IgGs. These findings suggest that the four MVC-resistant mutations required for entry using MVC-bound CCR5 result in a conformational change of Env that is associated with a phenotype sensitive to anti-Env neutralizing antibodies.

  4. The framing of two major flood episodes in the Irish print news media: Implications for societal adaptation to living with flood risk.

    Science.gov (United States)

    Devitt, Catherine; O'Neill, Eoin

    2017-10-01

    Societal adaptation to flooding is a critical component of contemporary flood policy. Using content analysis, this article identifies how two major flooding episodes (2009 and 2014) are framed in the Irish broadsheet news media. The article considers the extent to which these frames reflect shifts in contemporary flood policy away from protection towards risk management, and the possible implications for adaptation to living with flood risk. Frames help us make sense of the social world, and within the media, framing is an essential tool for communication. Five frames were identified: flood resistance and structural defences, politicisation of flood risk, citizen as risk manager, citizen as victim and emerging trade-offs. These frames suggest that public debates on flood management do not fully reflect shifts in contemporary flood policy, with negative implications for the direction of societal adaptation. Greater discussion is required on the influence of the media on achieving policy objectives.

  5. Reproductive seasonality in captive wild ruminants: implications for biogeographical adaptation, photoperiodic control, and life history.

    Science.gov (United States)

    Zerbe, Philipp; Clauss, Marcus; Codron, Daryl; Bingaman Lackey, Laurie; Rensch, Eberhard; Streich, Jürgen W; Hatt, Jean-Michel; Müller, Dennis W H

    2012-11-01

    Many ruminant species show seasonal patterns of reproduction. Causes for this are widely debated, and include adaptations to seasonal availability of resources (with cues either from body condition in more tropical, or from photoperiodism in higher latitude habitats) and/or defence strategies against predators. Conclusions so far are limited to datasets with less than 30 species. Here, we use a dataset on 110 wild ruminant species kept in captivity in temperate-zone zoos to describe their reproductive patterns quantitatively [determining the birth peak breadth (BPB) as the number of days in which 80% of all births occur]; then we link this pattern to various biological characteristics [latitude of origin, mother-young-relationship (hider/follower), proportion of grass in the natural diet (grazer/browser), sexual size dimorphism/mating system], and compare it with reports for free-ranging animals. When comparing taxonomic subgroups, variance in BPB is highly correlated to the minimum, but not the maximum BPB, suggesting that a high BPB (i.e. an aseasonal reproductive pattern) is the plesiomorphic character in ruminants. Globally, latitude of natural origin is highly correlated to the BPB observed in captivity, supporting an overruling impact of photoperiodism on ruminant reproduction. Feeding type has no additional influence; the hider/follower dichotomy, associated with the anti-predator strategy of 'swamping', has additional influence in the subset of African species only. Sexual size dimorphism and mating system are marginally associated with the BPB, potentially indicating a facilitation of polygamy under seasonal conditions. The difference in the calculated Julian date of conception between captive populations and that reported for free-ranging ones corresponds to the one expected if absolute day length was the main trigger in highly seasonal species: calculated day length at the time of conception between free-ranging and captive populations followed a y = x

  6. Evolution of motion uncertainty in rectal cancer: implications for adaptive radiotherapy

    Science.gov (United States)

    Kleijnen, Jean-Paul J. E.; van Asselen, Bram; Burbach, Johannes P. M.; Intven, Martijn; Philippens, Marielle E. P.; Reerink, Onne; Lagendijk, Jan J. W.; Raaymakers, Bas W.

    2016-01-01

    Reduction of motion uncertainty by applying adaptive radiotherapy strategies depends largely on the temporal behavior of this motion. To fully optimize adaptive strategies, insight into target motion is needed. The purpose of this study was to analyze stability and evolution in time of motion uncertainty of both the gross tumor volume (GTV) and clinical target volume (CTV) for patients with rectal cancer. We scanned 16 patients daily during one week, on a 1.5 T MRI scanner in treatment position, prior to each radiotherapy fraction. Single slice sagittal cine MRIs were made at the beginning, middle, and end of each scan session, for one minute at 2 Hz temporal resolution. GTV and CTV motion were determined by registering a delineated reference frame to time-points later in time. The 95th percentile of observed motion (dist95%) was taken as a measure of motion. The stability of motion in time was evaluated within each cine-MRI separately. The evolution of motion was investigated between the reference frame and the cine-MRIs of a single scan session and between the reference frame and the cine-MRIs of several days later in the course of treatment. This observed motion was then converted into a PTV-margin estimate. Within a one minute cine-MRI scan, motion was found to be stable and small. Independent of the time-point within the scan session, the average dist95% remains below 3.6 mm and 2.3 mm for CTV and GTV, respectively 90% of the time. We found similar motion over time intervals from 18 min to 4 days. When reducing the time interval from 18 min to 1 min, a large reduction in motion uncertainty is observed. A reduction in motion uncertainty, and thus the PTV-margin estimate, of 71% and 75% for CTV and tumor was observed, respectively. Time intervals of 15 and 30 s yield no further reduction in motion uncertainty compared to a 1 min time interval.

  7. Conformational adaptability of Redbeta during DNA annealing and implications for its structural relationship with Rad52.

    Science.gov (United States)

    Erler, Axel; Wegmann, Susanne; Elie-Caille, Celine; Bradshaw, Charles Richard; Maresca, Marcello; Seidel, Ralf; Habermann, Bianca; Muller, Daniel J; Stewart, A Francis

    2009-08-21

    Single-strand annealing proteins, such as Redbeta from lambda phage or eukaryotic Rad52, play roles in homologous recombination. Here, we use atomic force microscopy to examine Redbeta quaternary structure and Redbeta-DNA complexes. In the absence of DNA, Redbeta forms a shallow right-handed helix. The presence of single-stranded DNA (ssDNA) disrupts this structure. Upon addition of a second complementary ssDNA, annealing generates a left-handed helix that incorporates 14 Redbeta monomers per helical turn, with each Redbeta monomer annealing approximately 11 bp of DNA. The smallest stable annealing intermediate requires 20 bp DNA and two Redbeta monomers. Hence, we propose that Redbeta promotes base pairing by first increasing the number of transient interactions between ssDNAs. Then, annealing is promoted by the binding of a second Redbeta monomer, which nucleates the formation of a stable annealing intermediate. Using threading, we identify sequence similarities between the RecT/Redbeta and the Rad52 families, which strengthens previous suggestions, based on similarities of their quaternary structures, that they share a common mode of action. Hence, our findings have implications for a common mechanism of DNA annealing mediated by single-strand annealing proteins including Rad52.

  8. DEVELOPMENTAL CHANGES IN SEROTONIN SIGNALING: IMPLICATIONS FOR EARLY BRAIN FUNCTION, BEHAVIOR AND ADAPTATION

    Science.gov (United States)

    BRUMMELTE, S.; GLANAGHY, E. MC; BONNIN, A.; OBERLANDER, T. F.

    2017-01-01

    The neurotransmitter serotonin (5-HT) plays a central role in brain development, regulation of mood, stress reactivity and risk of psychiatric disorders, and thus alterations in 5-HT signaling early in life have critical implications for behavior and mental health across the life span. Drawing on preclinical and emerging human evidence this narrative review paper will examine three key aspects when considering the consequences of early life changes in 5-HT: (1) developmental origins of variations of 5-HT signaling; (2) influence of genetic and epigenetic factors; and (3) preclinical and clinical consequences of 5-HT-related changes associated with antidepressant exposure (SSRIs). The developmental consequences of altered prenatal 5-HT signaling varies greatly and outcomes depend on an ongoing interplay between biological (genetic/epigenetic variations) and environmental factors, both pre and postnatally. Emerging evidence suggests that variations in 5-HT signaling may increase sensitivity to risky home environments, but may also amplify a positive response to a nurturing environment. In this sense, factors that change central 5-HT levels may act as ‘plasticity’ rather than ‘risk’ factors associated with developmental vulnerability. Understanding the impact of early changes in 5-HT levels offers critical insights that might explain the variations in early typical brain development that underlies behavioral risk. PMID:26905950

  9. Androgen Induces Adaptation to Oxidative Stress in Prostate Cancer: Implications for Treatment with Radiation Therapy

    Directory of Open Access Journals (Sweden)

    Jehonathan H. Pinthus

    2007-01-01

    Full Text Available Radiation therapy is a standard treatment for prostate cancer (PC. The postulated mechanism of action for radiation therapy is the generation of reactive oxygen species (ROS. Adjuvant androgen deprivation (AD therapy has been shown to confer a survival advantage over radiation alone in high-risk localized PC. However, the mechanism of this interaction is unclear. We hypothesize that androgens modify the radioresponsiveness of PC through the regulation of cellular oxidative homeostasis. Using androgen receptor (AR+ 22rv1 and AR− PC3 human PC cell lines, we demonstrated that testosterone increased basal reactive oxygen species (bROS levels, resulting in dose-dependent activation of phospho-p38 and pAKT, increased expression of clusterin, catalase, manganese superoxide dismutase. Similar data were obtained in three human PC xenografts; WISH-PC14, WISH-PC23, CWR22, growing in testosterone-supplemented or castrated SCID mice. These effects were reversible through AD or through incubation with a reducing agent. Moreover, testosterone increased the activity of catalase, superoxide dismutases, glutathione reductase. Consequently, AD significantly facilitated the response of AR+ cells to oxidative stress challenge. Thus, testosterone induces a preset cellular adaptation to radiation through the generation of elevated bROS, which is modified by AD. These findings provide a rational for combined hormonal and radiation therapy for localized PC.

  10. Oxytocin and arginine vasopressin receptor evolution: implications for adaptive novelties in placental mammals

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    Pamela Paré

    Full Text Available Abstract Oxytocin receptor (OXTR and arginine vasopressin receptors (AVPR1a, AVPR1b, and AVPR2 are paralogous genes that emerged through duplication events; along the evolutionary timeline, owing to speciation, numerous orthologues emerged as well. In order to elucidate the evolutionary forces that shaped these four genes in placental mammals and to reveal specific aspects of their protein structures, 35 species were selected. Specifically, we investigated their molecular evolutionary history and intrinsic protein disorder content, and identified the presence of short linear interaction motifs. OXTR seems to be under evolutionary constraint in placental mammals, whereas AVPR1a, AVPR1b, and AVPR2 exhibit higher evolutionary rates, suggesting that they have been under relaxed or experienced positive selection. In addition, we describe here, for the first time, that the OXTR, AVPR1a, AVPR1b, and AVPR2 mammalian orthologues preserve their disorder content, while this condition varies among the paralogues. Finally, our results reveal the presence of short linear interaction motifs, indicating possible functional adaptations related to physiological and/or behavioral taxa-specific traits.

  11. Oxytocin and arginine vasopressin receptor evolution: implications for adaptive novelties in placental mammals

    Science.gov (United States)

    Paré, Pamela; Paixão-Côrtes, Vanessa R.; Tovo-Rodrigues, Luciana; Vargas-Pinilla, Pedro; Viscardi, Lucas Henriques; Salzano, Francisco Mauro; Henkes, Luiz E.; Bortolini, Maria Catira

    2016-01-01

    Abstract Oxytocin receptor (OXTR) and arginine vasopressin receptors (AVPR1a, AVPR1b, and AVPR2) are paralogous genes that emerged through duplication events; along the evolutionary timeline, owing to speciation, numerous orthologues emerged as well. In order to elucidate the evolutionary forces that shaped these four genes in placental mammals and to reveal specific aspects of their protein structures, 35 species were selected. Specifically, we investigated their molecular evolutionary history and intrinsic protein disorder content, and identified the presence of short linear interaction motifs. OXTR seems to be under evolutionary constraint in placental mammals, whereas AVPR1a, AVPR1b, and AVPR2 exhibit higher evolutionary rates, suggesting that they have been under relaxed or experienced positive selection. In addition, we describe here, for the first time, that the OXTR, AVPR1a, AVPR1b, and AVPR2 mammalian orthologues preserve their disorder content, while this condition varies among the paralogues. Finally, our results reveal the presence of short linear interaction motifs, indicating possible functional adaptations related to physiological and/or behavioral taxa-specific traits. PMID:27505307

  12. Implication of adaptive smoothness constraint and Helmert variance component estimation in seismic slip inversion

    Science.gov (United States)

    Fan, Qingbiao; Xu, Caijun; Yi, Lei; Liu, Yang; Wen, Yangmao; Yin, Zhi

    2017-03-01

    When ill-posed problems are inverted, the regularization process is equivalent to adding constraint equations or prior information from a Bayesian perspective. The veracity of the constraints (or the regularization matrix R) significantly affects the solution, and a smoothness constraint is usually added in seismic slip inversions. In this paper, an adaptive smoothness constraint (ASC) based on the classic Laplacian smoothness constraint (LSC) is proposed. The ASC not only improves the smoothness constraint, but also helps constrain the slip direction. A series of experiments are conducted in which different magnitudes of noise are imposed and different densities of observation are assumed, and the results indicated that the ASC was superior to the LSC. Using the proposed ASC, the Helmert variance component estimation method is highlighted as the best for selecting the regularization parameter compared with other methods, such as generalized cross-validation or the mean squared error criterion method. The ASC may also benefit other ill-posed problems in which a smoothness constraint is required.

  13. Adaptive Plasticity in the Healthy Language Network: Implications for Language Recovery after Stroke

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    Gesa Hartwigsen

    2016-01-01

    Full Text Available Across the last three decades, the application of noninvasive brain stimulation (NIBS has substantially increased the current knowledge of the brain’s potential to undergo rapid short-term reorganization on the systems level. A large number of studies applied transcranial magnetic stimulation (TMS and transcranial direct current stimulation (tDCS in the healthy brain to probe the functional relevance and interaction of specific areas for different cognitive processes. NIBS is also increasingly being used to induce adaptive plasticity in motor and cognitive networks and shape cognitive functions. Recently, NIBS has been combined with electrophysiological techniques to modulate neural oscillations of specific cortical networks. In this review, we will discuss recent advances in the use of NIBS to modulate neural activity and effective connectivity in the healthy language network, with a special focus on the combination of NIBS and neuroimaging or electrophysiological approaches. Moreover, we outline how these results can be transferred to the lesioned brain to unravel the dynamics of reorganization processes in poststroke aphasia. We conclude with a critical discussion on the potential of NIBS to facilitate language recovery after stroke and propose a phase-specific model for the application of NIBS in language rehabilitation.

  14. Comparison of Mutation Profiles in the Duchenne Muscular Dystrophy Gene among Populations: Implications for Potential Molecular Therapies

    Directory of Open Access Journals (Sweden)

    Luz Berenice López-Hernández

    2015-03-01

    Full Text Available Novel therapeutic approaches are emerging to restore dystrophin function in Duchenne Muscular Dystrophy (DMD, a severe neuromuscular disease characterized by progressive muscle wasting and weakness. Some of the molecular therapies, such as exon skipping, stop codon read-through and internal ribosome entry site-mediated translation rely on the type and location of mutations. Hence, their potential applicability worldwide depends on mutation frequencies within populations. In view of this, we compared the mutation profiles of the populations represented in the DMD Leiden Open-source Variation Database with original data from Mexican patients (n = 162 with clinical diagnosis of the disease. Our data confirm that applicability of exon 51 is high in most populations, but also show that differences in theoretical applicability of exon skipping may exist among populations; Mexico has the highest frequency of potential candidates for the skipping of exons 44 and 46, which is different from other populations (p < 0.001. To our knowledge, this is the first comprehensive comparison of theoretical applicability of exon skipping targets among specific populations.

  15. Comparison of mutation profiles in the Duchenne muscular dystrophy gene among populations: implications for potential molecular therapies.

    Science.gov (United States)

    López-Hernández, Luz Berenice; Gómez-Díaz, Benjamín; Luna-Angulo, Alexandra Berenice; Anaya-Segura, Mónica; Bunyan, David John; Zúñiga-Guzman, Carolina; Escobar-Cedillo, Rosa Elena; Roque-Ramírez, Bladimir; Ruano-Calderón, Luis Angel; Rangel-Villalobos, Héctor; López-Hernández, Julia Angélica; Estrada-Mena, Francisco Javier; García, Silvia; Coral-Vázquez, Ramón Mauricio

    2015-03-09

    Novel therapeutic approaches are emerging to restore dystrophin function in Duchenne Muscular Dystrophy (DMD), a severe neuromuscular disease characterized by progressive muscle wasting and weakness. Some of the molecular therapies, such as exon skipping, stop codon read-through and internal ribosome entry site-mediated translation rely on the type and location of mutations. Hence, their potential applicability worldwide depends on mutation frequencies within populations. In view of this, we compared the mutation profiles of the populations represented in the DMD Leiden Open-source Variation Database with original data from Mexican patients (n = 162) with clinical diagnosis of the disease. Our data confirm that applicability of exon 51 is high in most populations, but also show that differences in theoretical applicability of exon skipping may exist among populations; Mexico has the highest frequency of potential candidates for the skipping of exons 44 and 46, which is different from other populations (p < 0.001). To our knowledge, this is the first comprehensive comparison of theoretical applicability of exon skipping targets among specific populations.

  16. A Foxp2 Mutation Implicated in Human Speech Deficits Alters Sequencing of Ultrasonic Vocalizations in Adult Male Mice

    Science.gov (United States)

    Chabout, Jonathan; Sarkar, Abhra; Patel, Sheel R.; Radden, Taylor; Dunson, David B.; Fisher, Simon E.; Jarvis, Erich D.

    2016-01-01

    Development of proficient spoken language skills is disrupted by mutations of the FOXP2 transcription factor. A heterozygous missense mutation in the KE family causes speech apraxia, involving difficulty producing words with complex learned sequences of syllables. Manipulations in songbirds have helped to elucidate the role of this gene in vocal learning, but findings in non-human mammals have been limited or inconclusive. Here, we performed a systematic study of ultrasonic vocalizations (USVs) of adult male mice carrying the KE family mutation. Using novel statistical tools, we found that Foxp2 heterozygous mice did not have detectable changes in USV syllable acoustic structure, but produced shorter sequences and did not shift to more complex syntax in social contexts where wildtype animals did. Heterozygous mice also displayed a shift in the position of their rudimentary laryngeal motor cortex (LMC) layer-5 neurons. Our findings indicate that although mouse USVs are mostly innate, the underlying contributions of FoxP2 to sequencing of vocalizations are conserved with humans.

  17. Numerical Simulations of Optical Turbulence Using an Advanced Atmospheric Prediction Model: Implications for Adaptive Optics Design

    Science.gov (United States)

    Alliss, R.

    2014-09-01

    Optical turbulence (OT) acts to distort light in the atmosphere, degrading imagery from astronomical telescopes and reducing the data quality of optical imaging and communication links. Some of the degradation due to turbulence can be corrected by adaptive optics. However, the severity of optical turbulence, and thus the amount of correction required, is largely dependent upon the turbulence at the location of interest. Therefore, it is vital to understand the climatology of optical turbulence at such locations. In many cases, it is impractical and expensive to setup instrumentation to characterize the climatology of OT, so numerical simulations become a less expensive and convenient alternative. The strength of OT is characterized by the refractive index structure function Cn2, which in turn is used to calculate atmospheric seeing parameters. While attempts have been made to characterize Cn2 using empirical models, Cn2 can be calculated more directly from Numerical Weather Prediction (NWP) simulations using pressure, temperature, thermal stability, vertical wind shear, turbulent Prandtl number, and turbulence kinetic energy (TKE). In this work we use the Weather Research and Forecast (WRF) NWP model to generate Cn2 climatologies in the planetary boundary layer and free atmosphere, allowing for both point-to-point and ground-to-space seeing estimates of the Fried Coherence length (ro) and other seeing parameters. Simulations are performed using a multi-node linux cluster using the Intel chip architecture. The WRF model is configured to run at 1km horizontal resolution and centered on the Mauna Loa Observatory (MLO) of the Big Island. The vertical resolution varies from 25 meters in the boundary layer to 500 meters in the stratosphere. The model top is 20 km. The Mellor-Yamada-Janjic (MYJ) TKE scheme has been modified to diagnose the turbulent Prandtl number as a function of the Richardson number, following observations by Kondo and others. This modification

  18. A decision framework for the adaptive management of an exploited species with implications for marine reserves.

    Science.gov (United States)

    Gerber, Leah R; Wielgus, Jeffrey; Sala, Enric

    2007-12-01

    Marine reserves have both conservation and fishery benefits. Nevertheless, there are no general criteria about when and where to establish new reserves, how to evaluate their efficacy, and how to conduct adaptive management to achieve conservation goals. We applied a decision-theory framework to optimally allocate conservation resources between improving data on population status and establishing a reserve for species conservation. Our goal was to maximize reserve benefits given the constraints of a population growth rate that would permit sustainability of resources. We illustrate our decision framework with a retrospective analysis of a 7-year time series on abundance of the leopard grouper (Mycteroperca rosacea) in the Sea of Cortés, Mexico. We used the lower bound of the distribution of the population growth rate (lambda) as a decision rule for determining how many years of monitoring are needed to detect reserve effects. We determined the minimum time frame needed to estimate lambda based on a stated level of risk tolerance for four sites. As expected, the coefficient of variation for the lambda declined with the number of years of data. This increased precision with additional years of data resulted from the high degree of annual variability in the system. Where populations were slow to respond to reserves, more data were needed to detect a positive lambda value. For the leopard grouper case study, confidence in the estimate of lambda increased with the number of years of data. Our decision framework may be used to identify the minimum number of years of data needed before a management decision about reserve establishment could be made that is reasonably likely to meet its management objectives.

  19. Sensitivity and adaptability of methanogens to perchlorates: Implications for life on Mars

    Science.gov (United States)

    Kral, Timothy A.; Goodhart, Timothy H.; Harpool, Joshua D.; Hearnsberger, Christopher E.; McCracken, Graham L.; McSpadden, Stanley W.

    2016-01-01

    % indicating some success in adapting cells to concentrations higher than 1%. The results reported here indicate that the presence of perchlorate on Mars does not rule out the possible existence of methanogens.

  20. Assessment of trophic ecomorphology in non-alligatoroid crocodylians and its adaptive and taxonomic implications.

    Science.gov (United States)

    Iijima, Masaya

    2017-08-01

    Although the establishment of trophic ecomorphology in living crocodylians can contribute to estimating feeding habits of extinct large aquatic reptiles, assessment of ecomorphological traits other than the snout shape has scarcely been conducted in crocodylians. Here, I tested the validity of the proposed trophic ecomorphological traits in crocodylians by examining the correlation between those traits and the snout shape (an established trophic ecomorphology), using 10 non-alligatoroid crocodylian species with a wide range of snout shape. I then compared the ontogenetic scaling of trophic ecomorphology to discuss its adaptive and taxonomic significance. The results demonstrated that degree of heterodonty, tooth spacing, size of supratemporal fenestra (STF), ventral extension of pterygoid flange and length of lower jaw symphysis are significantly correlated with snout shape by both non-phylogenetic and phylogenetic regression analyses. Gavialis gangeticus falls outside of 95% prediction intervals for the relationships of some traits and the snout shape, suggesting that piscivorous specialization involves the deviation from the typical transformation axis of skull characters. The comparative snout shape ontogeny revealed a universal trend of snout widening through growth in the sampled crocodylians, implying the existence of a shared size-dependent biomechanical constraint in non-alligatoroid crocodylians. Growth patterns of other traits indicated that G. gangeticus shows atypical trends for degree of heterodonty, size of STF, and symphysis length, whereas the same trends are shared for tooth spacing and ventral extension of pterygoid flange among non-alligatoroid crocodylians. These suggest that some characters are ontogenetically labile in response to prey preference shifts through growth, but other characters are in keeping with the conserved biomechanics among non-alligatoroid crocodylians. Some important taxonomic characters such as the occlusal pattern are

  1. A transcriptomic analysis of Echinococcus granulosus larval stages: implications for parasite biology and host adaptation.

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    John Parkinson

    Full Text Available BACKGROUND: The cestode Echinococcus granulosus--the agent of cystic echinococcosis, a zoonosis affecting humans and domestic animals worldwide--is an excellent model for the study of host-parasite cross-talk that interfaces with two mammalian hosts. To develop the molecular analysis of these interactions, we carried out an EST survey of E. granulosus larval stages. We report the salient features of this study with a focus on genes reflecting physiological adaptations of different parasite stages. METHODOLOGY/PRINCIPAL FINDINGS: We generated ~10,000 ESTs from two sets of full-length enriched libraries (derived from oligo-capped and trans-spliced cDNAs prepared with three parasite materials: hydatid cyst wall, larval worms (protoscoleces, and pepsin/H(+-activated protoscoleces. The ESTs were clustered into 2700 distinct gene products. In the context of the biology of E. granulosus, our analyses reveal: (i a diverse group of abundant long non-protein coding transcripts showing homology to a middle repetitive element (EgBRep that could either be active molecular species or represent precursors of small RNAs (like piRNAs; (ii an up-regulation of fermentative pathways in the tissue of the cyst wall; (iii highly expressed thiol- and selenol-dependent antioxidant enzyme targets of thioredoxin glutathione reductase, the functional hub of redox metabolism in parasitic flatworms; (iv candidate apomucins for the external layer of the tissue-dwelling hydatid cyst, a mucin-rich structure that is critical for survival in the intermediate host; (v a set of tetraspanins, a protein family that appears to have expanded in the cestode lineage; and (vi a set of platyhelminth-specific gene products that may offer targets for novel pan-platyhelminth drug development. CONCLUSIONS/SIGNIFICANCE: This survey has greatly increased the quality and the quantity of the molecular information on E. granulosus and constitutes a valuable resource for gene prediction on the

  2. Reconstructing the ups and downs of primate brain evolution: implications for adaptive hypotheses and Homo floresiensis.

    Science.gov (United States)

    Montgomery, Stephen H; Capellini, Isabella; Barton, Robert A; Mundy, Nicholas I

    2010-01-27

    Brain size is a key adaptive trait. It is often assumed that increasing brain size was a general evolutionary trend in primates, yet recent fossil discoveries have documented brain size decreases in some lineages, raising the question of how general a trend there was for brains to increase in mass over evolutionary time. We present the first systematic phylogenetic analysis designed to answer this question. We performed ancestral state reconstructions of three traits (absolute brain mass, absolute body mass, relative brain mass) using 37 extant and 23 extinct primate species and three approaches to ancestral state reconstruction: parsimony, maximum likelihood and Bayesian Markov-chain Monte Carlo. Both absolute and relative brain mass generally increased over evolutionary time, but body mass did not. Nevertheless both absolute and relative brain mass decreased along several branches. Applying these results to the contentious case of Homo floresiensis, we find a number of scenarios under which the proposed evolution of Homo floresiensis' small brain appears to be consistent with patterns observed along other lineages, dependent on body mass and phylogenetic position. Our results confirm that brain expansion began early in primate evolution and show that increases occurred in all major clades. Only in terms of an increase in absolute mass does the human lineage appear particularly striking, with both the rate of proportional change in mass and relative brain size having episodes of greater expansion elsewhere on the primate phylogeny. However, decreases in brain mass also occurred along branches in all major clades, and we conclude that, while selection has acted to enlarge primate brains, in some lineages this trend has been reversed. Further analyses of the phylogenetic position of Homo floresiensis and better body mass estimates are required to confirm the plausibility of the evolution of its small brain mass. We find that for our dataset the Bayesian analysis for

  3. Reconstructing the ups and downs of primate brain evolution: implications for adaptive hypotheses and Homo floresiensis

    Directory of Open Access Journals (Sweden)

    Barton Robert A

    2010-01-01

    Full Text Available Abstract Background Brain size is a key adaptive trait. It is often assumed that increasing brain size was a general evolutionary trend in primates, yet recent fossil discoveries have documented brain size decreases in some lineages, raising the question of how general a trend there was for brains to increase in mass over evolutionary time. We present the first systematic phylogenetic analysis designed to answer this question. Results We performed ancestral state reconstructions of three traits (absolute brain mass, absolute body mass, relative brain mass using 37 extant and 23 extinct primate species and three approaches to ancestral state reconstruction: parsimony, maximum likelihood and Bayesian Markov-chain Monte Carlo. Both absolute and relative brain mass generally increased over evolutionary time, but body mass did not. Nevertheless both absolute and relative brain mass decreased along several branches. Applying these results to the contentious case of Homo floresiensis, we find a number of scenarios under which the proposed evolution of Homo floresiensis' small brain appears to be consistent with patterns observed along other lineages, dependent on body mass and phylogenetic position. Conclusions Our results confirm that brain expansion began early in primate evolution and show that increases occurred in all major clades. Only in terms of an increase in absolute mass does the human lineage appear particularly striking, with both the rate of proportional change in mass and relative brain size having episodes of greater expansion elsewhere on the primate phylogeny. However, decreases in brain mass also occurred along branches in all major clades, and we conclude that, while selection has acted to enlarge primate brains, in some lineages this trend has been reversed. Further analyses of the phylogenetic position of Homo floresiensis and better body mass estimates are required to confirm the plausibility of the evolution of its small brain

  4. Reconstructing the ups and downs of primate brain evolution: implications for adaptive hypotheses and Homo floresiensis

    Science.gov (United States)

    2010-01-01

    Background Brain size is a key adaptive trait. It is often assumed that increasing brain size was a general evolutionary trend in primates, yet recent fossil discoveries have documented brain size decreases in some lineages, raising the question of how general a trend there was for brains to increase in mass over evolutionary time. We present the first systematic phylogenetic analysis designed to answer this question. Results We performed ancestral state reconstructions of three traits (absolute brain mass, absolute body mass, relative brain mass) using 37 extant and 23 extinct primate species and three approaches to ancestral state reconstruction: parsimony, maximum likelihood and Bayesian Markov-chain Monte Carlo. Both absolute and relative brain mass generally increased over evolutionary time, but body mass did not. Nevertheless both absolute and relative brain mass decreased along several branches. Applying these results to the contentious case of Homo floresiensis, we find a number of scenarios under which the proposed evolution of Homo floresiensis' small brain appears to be consistent with patterns observed along other lineages, dependent on body mass and phylogenetic position. Conclusions Our results confirm that brain expansion began early in primate evolution and show that increases occurred in all major clades. Only in terms of an increase in absolute mass does the human lineage appear particularly striking, with both the rate of proportional change in mass and relative brain size having episodes of greater expansion elsewhere on the primate phylogeny. However, decreases in brain mass also occurred along branches in all major clades, and we conclude that, while selection has acted to enlarge primate brains, in some lineages this trend has been reversed. Further analyses of the phylogenetic position of Homo floresiensis and better body mass estimates are required to confirm the plausibility of the evolution of its small brain mass. We find that for our

  5. Null steering of adaptive beamforming using linear constraint minimum variance assisted by particle swarm optimization, dynamic mutated artificial immune system, and gravitational search algorithm.

    Science.gov (United States)

    Darzi, Soodabeh; Kiong, Tiong Sieh; Islam, Mohammad Tariqul; Ismail, Mahamod; Kibria, Salehin; Salem, Balasem

    2014-01-01

    Linear constraint minimum variance (LCMV) is one of the adaptive beamforming techniques that is commonly applied to cancel interfering signals and steer or produce a strong beam to the desired signal through its computed weight vectors. However, weights computed by LCMV usually are not able to form the radiation beam towards the target user precisely and not good enough to reduce the interference by placing null at the interference sources. It is difficult to improve and optimize the LCMV beamforming technique through conventional empirical approach. To provide a solution to this problem, artificial intelligence (AI) technique is explored in order to enhance the LCMV beamforming ability. In this paper, particle swarm optimization (PSO), dynamic mutated artificial immune system (DM-AIS), and gravitational search algorithm (GSA) are incorporated into the existing LCMV technique in order to improve the weights of LCMV. The simulation result demonstrates that received signal to interference and noise ratio (SINR) of target user can be significantly improved by the integration of PSO, DM-AIS, and GSA in LCMV through the suppression of interference in undesired direction. Furthermore, the proposed GSA can be applied as a more effective technique in LCMV beamforming optimization as compared to the PSO technique. The algorithms were implemented using Matlab program.

  6. The Self-Adaptive Monkey Algorithm Based on Gaussian Mutation%基于高斯变异的自适应猴群算法

    Institute of Scientific and Technical Information of China (English)

    周志鹏; 谢瑾秋; 程佰健

    2014-01-01

    由于原猴群算法中的参数过多且固定,若设置不准确,会丧失猴群多样性且易陷入局部最优值。针对这些不足,本文提出了一种新型的自适应猴群算法---基于高斯变异的自适应猴群算法(GAMA)。 GAMA改变了原本固定的步长及视“,使其随着迭代次数的变化而变化,这样无论在算法的前期或者后期,都有较强的搜索能力。对于猴群算法容易陷入局部最优的缺点,本文采用高斯变异的方法,对数次迭代过程中未改变的局部最优值进行高斯变异,不仅使猴群能够有效摆脱局部极值的束缚,也加强了对局域再搜索能力。最后通过对多峰测试函数验证,结果表明GAMA算法无论在精度,稳定性,克服早熟及收敛速度方面都有显著提高。%Due to so much fixed parametersof the monkey algorithm , if the setting is not accurate, especially makes the loss of diversity,falling into the most superior con- ditions easily. Aiming at this shortcoming, this paper proposes a novel adaptive monkey algorithm---The Self-Adaptive Monkey Algorithm based on gaussian mutation (GAMA), change the original fixed step length and the field of vision, make its changes with the change of the number of iterations, so no matter early or late in the algorithm, has a strong ability of search;Especially for the algorithm easy to fall into local optimum of faults , this paper USES the method of gauss-ian mutation did not change in the process of this method for several iterations gauss mutation localoptimal value, not only make monkeys can effectively get rid of the bondage of local extremum, but also strengthened the ability of local LAN to search again. Finally by using functions to exam, the resul-ts show that theopyimization precision, algorithm stability ,overcome the premature and convergence speed of GAMA algorithm are improved significantly.

  7. Germline Mutations in NFKB2 Implicate the Noncanonical NF-κB Pathway in the Pathogenesis of Common Variable Immunodeficiency

    OpenAIRE

    Chen, Karin; Coonrod, Emily M.; Kumánovics, Attila; Franks, Zechariah F.; Durtschi, Jacob D.; Margraf, Rebecca L.; Wu, Wilfred; Heikal, Nahla M.; Augustine, Nancy H.; Ridge, Perry G.; Hill, Harry R.; Jorde, Lynn B.; Weyrich, Andrew S.; Zimmerman, Guy A.; Gundlapalli, Adi V.

    2013-01-01

    Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by antibody deficiency, poor humoral response to antigens, and recurrent infections. To investigate the molecular cause of CVID, we carried out exome sequence analysis of a family diagnosed with CVID and identified a heterozygous frameshift mutation, c.2564delA (p.Lys855Serfs∗7), in NFKB2 affecting the C terminus of NF-κB2 (also known as p100/p52 or p100/p49). Subsequent screening of NFKB2 in 33 unrelated CVID-a...

  8. Temperature-sensitive mutations for live-attenuated Rift Valley fever vaccines: Implications from other RNA viruses

    Directory of Open Access Journals (Sweden)

    Shoko eNishiyama

    2015-08-01

    Full Text Available Rift Valley fever (RVF is a mosquito-borne zoonotic disease endemic to the African continent. RVF is characterized by high rate of abortions in ruminants and hemorrhagic fever, encephalitis or blindness in humans. RVF is caused by the Rift Valley fever virus (RVFV: genus Phlebovirus, family Bunyaviridae. Vaccination is the only known effective strategy to prevent the disease, but there are no licensed RVF vaccines available for humans. A live-attenuated vaccine candidate derived from the wild-type pathogenic Egyptian ZH548 strain, MP-12, has been conditionally licensed for veterinary use in the United States. MP-12 displays a temperature-sensitive (ts phenotype and does not replicate at 41oC. The ts mutation limits viral replication at a specific body temperature and may lead to an attenuation of the virus. Here we will review well-characterized ts mutations for RNA viruses, and further discuss the potential in designing novel live-attenuated vaccines for RVF.

  9. A Founder Large Deletion Mutation in Xeroderma Pigmentosum-Variant Form in Tunisia: Implication for Molecular Diagnosis and Therapy

    Directory of Open Access Journals (Sweden)

    Mariem Ben Rekaya

    2014-01-01

    Full Text Available Xeroderma pigmentosum Variant (XP-V form is characterized by a late onset of skin symptoms. Our aim is the clinical and genetic investigations of XP-V Tunisian patients in order to develop a simple tool for early diagnosis. We investigated 16 suspected XP patients belonging to ten consanguineous families. Analysis of the POLH gene was performed by linkage analysis, long range PCR, and sequencing. Genetic analysis showed linkage to the POLH gene with a founder haplotype in all affected patients. Long range PCR of exon 9 to exon 11 showed a 3926 bp deletion compared to control individuals. Sequence analysis demonstrates that this deletion has occurred between two Alu-Sq2 repetitive sequences in the same orientation, respectively, in introns 9 and 10. We suggest that this mutation POLH NG_009252.1: g.36847_40771del3925 is caused by an equal crossover event that occurred between two homologous chromosomes at meiosis. These results allowed us to develop a simple test based on a simple PCR in order to screen suspected XP-V patients. In Tunisia, the prevalence of XP-V group seems to be underestimated and clinical diagnosis is usually later. Cascade screening of this founder mutation by PCR in regions with high frequency of XP provides a rapid and cost-effective tool for early diagnosis of XP-V in Tunisia and North Africa.

  10. MRX87 family with Aristaless X dup24bp mutation and implication for polyAlanine expansions

    Directory of Open Access Journals (Sweden)

    D'Urso Michele

    2007-05-01

    Full Text Available Abstract Background Cognitive impairments are heterogeneous conditions, and it is estimated that 10% may be caused by a defect of mental function genes on the X chromosome. One of those genes is Aristaless related homeobox (ARX encoding a polyA-rich homeobox transcription factor essential for cerebral patterning and its mutations cause different neurologic disorders. We reported on the clinical and genetic analysis of an Italian family with X-linked mental retardation (XLMR and intra-familial heterogeneity, and provided insight into its molecular defect. Methods We carried out on linkage-candidate gene studies in a new MRX family (MRX87. All coding regions and exon-intron boundaries of ARX gene were analysed by direct sequencing. Results MRX87 patients had moderate to profound cognition impairment and a combination of minor congenital anomalies. The disease locus, MRX87, was mapped between DXS7104 and DXS1214, placing it in Xp22-p21 interval, a hot spot region for mental handicap. An in frame duplication of 24 bp (ARXdup24 in the second polyAlanine tract (polyA_II in ARX was identified. Conclusion Our study underlines the role of ARXdup24 as a critical mutational site causing mental retardation linked to Xp22. Phenotypic heterogeneity of MRX87 patients represents a new observation relevant to the functional consequences of polyAlanine expansions enriching the puzzling complexity of ARXdup24-linked diseases.

  11. IMPLICATION OF THE CYTOCHROME B NUCLEOTIDE AND PROTEIN MUTATIONS IN THE OCCURRENCE OF BREAST CANCER IN SENEGAL

    Directory of Open Access Journals (Sweden)

    Fatimata Mbaye

    2012-05-01

    Full Text Available The reports provided by OMS in 2011 have showed that cancer is a major cause ofdeath in the world, causing 7.6 million deaths in 2008. Breast cancer is in the world, the most commonneoplasia of women, and it appears that low penetrance genes, but frequently mutated in the generalpopulation play an important role in the development of this cancer. The objective of this study is toevaluate the involvement of Cytochrome b mutations (mitochondrial gene in the occurrence of breastcancer in the Senegalese women. We have analyzed by PCR-sequencing the variability of theCytochrome b gene in thirty Senegalese patients suffering from breast cancer. The results of molecularanalysis of a portion of Cytochrome B indicate the existence of nucleotide variability at intra and inter-individual with a genetic differentiation between healthy and cancerous tissue, as well as theexistence ofa correlation between this genetic differentiation at the age of the patients and location oftumors (right breast or left breast. Changes of one or more Tryptophan to other amino acids,rangingnormal tissue to cancerous tissue, are noted in some individuals with a penetrance of72.41%.Our results also show a significant increase (79.3% the number of Phenylalanine in canceroustissues with very different proportions between individuals. Any increase in the rate of Tryptophanand Phenylalanine in cancerous tissues could be correlated with an increased risk of developing breastcancer.

  12. Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction.

    Science.gov (United States)

    Antoniou, Antonis C; Beesley, Jonathan; McGuffog, Lesley; Sinilnikova, Olga M; Healey, Sue; Neuhausen, Susan L; Ding, Yuan Chun; Rebbeck, Timothy R; Weitzel, Jeffrey N; Lynch, Henry T; Isaacs, Claudine; Ganz, Patricia A; Tomlinson, Gail; Olopade, Olufunmilayo I; Couch, Fergus J; Wang, Xianshu; Lindor, Noralane M; Pankratz, Vernon S; Radice, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Barile, Monica; Viel, Alessandra; Allavena, Anna; Dall'Olio, Valentina; Peterlongo, Paolo; Szabo, Csilla I; Zikan, Michal; Claes, Kathleen; Poppe, Bruce; Foretova, Lenka; Mai, Phuong L; Greene, Mark H; Rennert, Gad; Lejbkowicz, Flavio; Glendon, Gord; Ozcelik, Hilmi; Andrulis, Irene L; Thomassen, Mads; Gerdes, Anne-Marie; Sunde, Lone; Cruger, Dorthe; Birk Jensen, Uffe; Caligo, Maria; Friedman, Eitan; Kaufman, Bella; Laitman, Yael; Milgrom, Roni; Dubrovsky, Maya; Cohen, Shimrit; Borg, Ake; Jernström, Helena; Lindblom, Annika; Rantala, Johanna; Stenmark-Askmalm, Marie; Melin, Beatrice; Nathanson, Kate; Domchek, Susan; Jakubowska, Ania; Lubinski, Jan; Huzarski, Tomasz; Osorio, Ana; Lasa, Adriana; Durán, Mercedes; Tejada, Maria-Isabel; Godino, Javier; Benitez, Javier; Hamann, Ute; Kriege, Mieke; Hoogerbrugge, Nicoline; van der Luijt, Rob B; van Asperen, Christi J; Devilee, Peter; Meijers-Heijboer, E J; Blok, Marinus J; Aalfs, Cora M; Hogervorst, Frans; Rookus, Matti; Cook, Margaret; Oliver, Clare; Frost, Debra; Conroy, Don; Evans, D Gareth; Lalloo, Fiona; Pichert, Gabriella; Davidson, Rosemarie; Cole, Trevor; Cook, Jackie; Paterson, Joan; Hodgson, Shirley; Morrison, Patrick J; Porteous, Mary E; Walker, Lisa; Kennedy, M John; Dorkins, Huw; Peock, Susan; Godwin, Andrew K; Stoppa-Lyonnet, Dominique; de Pauw, Antoine; Mazoyer, Sylvie; Bonadona, Valérie; Lasset, Christine; Dreyfus, Hélène; Leroux, Dominique; Hardouin, Agnès; Berthet, Pascaline; Faivre, Laurence; Loustalot, Catherine; Noguchi, Tetsuro; Sobol, Hagay; Rouleau, Etienne; Nogues, Catherine; Frénay, Marc; Vénat-Bouvet, Laurence; Hopper, John L; Daly, Mary B; Terry, Mary B; John, Esther M; Buys, Saundra S; Yassin, Yosuf; Miron, Alexander; Goldgar, David; Singer, Christian F; Dressler, Anne Catharina; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; Hansen, Thomas V O; Jønson, Lars; Agnarsson, Bjarni A; Kirchhoff, Tomas; Offit, Kenneth; Devlin, Vincent; Dutra-Clarke, Ana; Piedmonte, Marion; Rodriguez, Gustavo C; Wakeley, Katie; Boggess, John F; Basil, Jack; Schwartz, Peter E; Blank, Stephanie V; Toland, Amanda Ewart; Montagna, Marco; Casella, Cinzia; Imyanitov, Evgeny; Tihomirova, Laima; Blanco, Ignacio; Lazaro, Conxi; Ramus, Susan J; Sucheston, Lara; Karlan, Beth Y; Gross, Jenny; Schmutzler, Rita; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Lochmann, Magdalena; Arnold, Norbert; Heidemann, Simone; Varon-Mateeva, Raymonda; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Dorothea; Preisler-Adams, Sabine; Kast, Karin; Schönbuchner, Ines; Caldes, Trinidad; de la Hoya, Miguel; Aittomäki, Kristiina; Nevanlinna, Heli; Simard, Jacques; Spurdle, Amanda B; Holland, Helene; Chen, Xiaoqing; Platte, Radka; Chenevix-Trench, Georgia; Easton, Douglas F

    2010-12-01

    The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

  13. Germline Mutation in EXPH5 Implicates the Rab27B Effector Protein Slac2-b in Inherited Skin Fragility

    Science.gov (United States)

    McGrath, John A.; Stone, Kristina L.; Begum, Rumena; Simpson, Michael A.; Dopping-Hepenstal, Patricia J.; Liu, Lu; McMillan, James R.; South, Andrew P.; Pourreyron, Celine; McLean, W.H. Irwin; Martinez, Anna E.; Mellerio, Jemima E.; Parsons, Maddy

    2012-01-01

    The Rab GTPase Rab27B and one of its effector proteins, Slac2-b (also known as EXPH5, exophilin-5), have putative roles in intracellular vesicle trafficking but their relevance to human disease is not known. By using whole-exome sequencing, we identified a homozygous frameshift mutation in EXPH5 in three siblings with inherited skin fragility born to consanguineous Iraqi parents. All three individuals harbor the mutation c.5786delC (p.Pro1929Leufs∗8) in EXPH5, which truncates the 1,989 amino acid Slac2-b protein by 52 residues. The clinical features comprised generalized scale-crusts and occasional blisters, mostly induced by trauma, as well as mild diffuse pigmentary mottling on the trunk and proximal limbs. There was no increased bleeding tendency, no neurologic abnormalities, and no increased incidence of infection. Analysis of an affected person's skin showed loss of Slac2-b immunostaining (C-terminal antibody), disruption of keratinocyte adhesion within the lower epidermis, and an increased number of perinuclear vesicles. A role for Slac2-b in keratinocyte biology was supported by findings of cytoskeletal disruption (mainly keratin intermediate filaments) and decreased keratinocyte adhesion in both keratinocytes from an affected subject and after shRNA knockdown of Slac2-b in normal keratinocytes. Slac2-b was also shown to colocalize with Rab27B and β4 integrin to early adhesion initiation sites in spreading normal keratinocytes. Collectively, our findings identify an unexpected role for Slac2-b in inherited skin fragility and expand the clinical spectrum of human disorders of GTPase effector proteins. PMID:23176819

  14. High-throughput oncogene mutation profiling shows demographic differences in BRAF mutation rates among melanoma patients.

    Science.gov (United States)

    van den Hurk, Karin; Balint, Balazs; Toomey, Sinead; O'Leary, Patrick C; Unwin, Louise; Sheahan, Kieran; McDermott, Enda W; Murphy, Ian; van den Oord, Joost J; Rafferty, Mairin; FitzGerald, Dara M; Moran, Julie; Cummins, Robert; MacEneaney, Owen; Kay, Elaine W; O'Brien, Cathal P; Finn, Stephen P; Heffron, Cynthia C B B; Murphy, Michelle; Yela, Ruben; Power, Derek G; Regan, Padraic J; McDermott, Clodagh M; O'Keeffe, Allan; Orosz, Zsolt; Donnellan, Paul P; Crown, John P; Hennessy, Bryan T; Gallagher, William M

    2015-06-01

    Because of advances in targeted therapies, the clinical evaluation of cutaneous melanoma is increasingly based on a combination of traditional histopathology and molecular pathology. Therefore, it is necessary to expand our knowledge of the molecular events that accompany the development and progression of melanoma to optimize clinical management. The central objective of this study was to increase our knowledge of the mutational events that complement melanoma progression. High-throughput genotyping was adapted to query 159 known single nucleotide mutations in 33 cancer-related genes across two melanoma cohorts from Ireland (n=94) and Belgium (n=60). Results were correlated with various clinicopathological characteristics. A total of 23 mutations in 12 genes were identified, that is--BRAF, NRAS, MET, PHLPP2, PIK3R1, IDH1, KIT, STK11, CTNNB1, JAK2, ALK, and GNAS. Unexpectedly, we discovered significant differences in BRAF, MET, and PIK3R1 mutations between the cohorts. That is, cases from Ireland showed significantly lower (PBRAF(V600E) mutation rates (19%) compared with the mutation frequency observed in Belgian patients (43%). Moreover, MET mutations were detected in 12% of Irish cases, whereas none of the Belgian patients harbored these mutations, and Irish patients significantly more often (P=0.027) had PIK3R1-mutant (33%) melanoma versus 17% of Belgian cases. The low incidence of BRAF(V600E)(-) mutant melanoma among Irish patients was confirmed in five independent Irish cohorts, and in total, only 165 of 689 (24%) Irish cases carried mutant BRAF(V600E). Together, our data show that melanoma-driving mutations vary by demographic area, which has important implications for the clinical management of this disease.

  15. Mutator suppression and escape from replication error-induced extinction in yeast.

    Directory of Open Access Journals (Sweden)

    Alan J Herr

    2011-10-01

    Full Text Available Cells rely on a network of conserved pathways to govern DNA replication fidelity. Loss of polymerase proofreading or mismatch repair elevates spontaneous mutation and facilitates cellular adaptation. However, double mutants are inviable, suggesting that extreme mutation rates exceed an error threshold. Here we combine alleles that affect DNA polymerase δ (Pol δ proofreading and mismatch repair to define the maximal error rate in haploid yeast and to characterize genetic suppressors of mutator phenotypes. We show that populations tolerate mutation rates 1,000-fold above wild-type levels but collapse when the rate exceeds 10⁻³ inactivating mutations per gene per cell division. Variants that escape this error-induced extinction (eex rapidly emerge from mutator clones. One-third of the escape mutants result from second-site changes in Pol δ that suppress the proofreading-deficient phenotype, while two-thirds are extragenic. The structural locations of the Pol δ changes suggest multiple antimutator mechanisms. Our studies reveal the transient nature of eukaryotic mutators and show that mutator phenotypes are readily suppressed by genetic adaptation. This has implications for the role of mutator phenotypes in cancer.

  16. Architecture of the Flagellar Switch Complex of Escherichia coli: Conformational Plasticity of FliG and Implications for Adaptive Remodeling.

    Science.gov (United States)

    Kim, Eun A; Panushka, Joseph; Meyer, Trevor; Carlisle, Ryan; Baker, Samantha; Ide, Nicholas; Lynch, Michael; Crane, Brian R; Blair, David F

    2017-03-01

    Structural models of the complex that regulates the direction of flagellar rotation assume either ~34 or ~25 copies of the protein FliG. Support for ~34 came from cross-linking experiments identifying an inter-subunit contact most consistent with that number; support for ~25 came from the observation that flagella can assemble and rotate when FliG is genetically fused to FliF, for which the accepted number is ~25. Here, we have undertaken cross-linking and other experiments to address more fully the question of FliG number. The results indicate a copy number of ~25 for FliG. An interaction between the C-terminal and middle domains, which has been taken to support a model with ~34 copies, is also supported. To reconcile the interaction with a FliG number of ~25, we hypothesize conformational plasticity in an inter-domain segment of FliG that allows some subunits to bridge gaps created by the number mismatch. This proposal is supported by mutant phenotypes and other results indicating that the normally helical segment adopts a more extended conformation in some subunits. The FliG amino-terminal domain is organized in a regular array with dimensions matching a ring in the upper part of the complex. The model predicts that FliG copy number should be tied to that of FliF, whereas FliM copy number can increase or decrease according to the number of FliG subunits that adopt the extended conformation. This has implications for the phenomenon of adaptive switch remodeling, in which FliM the copy number varies to adjust the bias of the switch.

  17. A POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus.

    Science.gov (United States)

    Takai, Hiroyuki; Jenkinson, Emma; Kabir, Shaheen; Babul-Hirji, Riyana; Najm-Tehrani, Nasrin; Chitayat, David A; Crow, Yanick J; de Lange, Titia

    2016-04-01

    Coats plus (CP) can be caused by mutations in the CTC1 component of CST, which promotes polymerase α (polα)/primase-dependent fill-in throughout the genome and at telomeres. The cellular pathology relating to CP has not been established. We identified a homozygous POT1 S322L substitution (POT1(CP)) in two siblings with CP. POT1(CP)induced a proliferative arrest that could be bypassed by telomerase. POT1(CP)was expressed at normal levels, bound TPP1 and telomeres, and blocked ATR signaling. POT1(CP)was defective in regulating telomerase, leading to telomere elongation rather than the telomere shortening observed in other telomeropathies. POT1(CP)was also defective in the maintenance of the telomeric C strand, causing extended 3' overhangs and stochastic telomere truncations that could be healed by telomerase. Consistent with shortening of the telomeric C strand, metaphase chromosomes showed loss of telomeres synthesized by leading strand DNA synthesis. We propose that CP is caused by a defect in POT1/CST-dependent telomere fill-in. We further propose that deficiency in the fill-in step generates truncated telomeres that halt proliferation in cells lacking telomerase, whereas, in tissues expressing telomerase (e.g., bone marrow), the truncations are healed. The proposed etiology can explain why CP presents with features distinct from those associated with telomerase defects (e.g., dyskeratosis congenita).

  18. Adaptation of cancer cells from different entities to the MDM2 inhibitor nutlin-3 results in the emergence of p53-mutated multi-drug-resistant cancer cells

    NARCIS (Netherlands)

    Michaelis, M.; Rothweiler, F.; Barth, S.; Cinatl, J.; van Rikxoort, M.; Loeschmann, N.; Voges, Y.; Breitling, R.; von Deimling, A.; Roedel, F.; Weber, K.; Fehse, B.; Mack, E.; Stiewe, T.; Doerr, H. W.; Speidel, D.; Cinatl, J.; Cinatl jr., J.; Stephanou, A.

    2011-01-01

    Six p53 wild-type cancer cell lines from infrequently p53-mutated entities (neuroblastoma, rhabdomyosarcoma, and melanoma) were continuously exposed to increasing concentrations of the murine double minute 2 inhibitor nutlin-3, resulting in the emergence of nutlin-3-resistant, p53-mutated sublines d

  19. Distribution of MED12 mutations in fibroadenomas and phyllodes tumors of the breast--implications for tumor biology and pathological diagnosis.

    Science.gov (United States)

    Pfarr, Nicole; Kriegsmann, Mark; Sinn, Peter; Klauschen, Frederick; Endris, Volker; Herpel, Esther; Muckenhuber, Alexander; Jesinghaus, Moritz; Klosterhalfen, Bernd; Penzel, Roland; Lennerz, Jochen K; Weichert, Wilko; Stenzinger, Albrecht

    2015-07-01

    Somatic mutations in exon 2 of MED12 have been described in benign and malignant smooth muscle cell tumors suggesting a functional role in these neoplasms. Recently fibroadenomas of the breast were also reported to harbor MED12 mutations. Hence, we explored MED12 mutations in fibroepithelial tumors of the breast, histological subtypes of fibroadenomas and phyllodes tumors, to validate and extend previous efforts. Using conventional Sanger sequencing, we profiled 39 cases of fibroepithelial breast tumors comprising classic histological subtypes of fibroadenomas as well as benign and malignant phyllodes tumors for mutations in exon 2 of MED12. MED12 mutations were detected in 60% of all tumor samples with the majority being missense mutations affecting codon 44. Additionally, we report novel in-frame deletions that have not been described previously. Sixty-two percent of the fibroadenomas harbored mutated MED12 with intracanalicular fibroadenomas being the most frequently mutated histological subtype (82%). Of note, 8/11 of benign phyllodes tumors had MED12 mutations while only 1/5 of malignant phyllodes tumors showed mutations in exon 2 of MED12. In conclusion, we confirm the frequent occurrence of MED12 mutations in fibroadenomas, provide evidence that most intracanalicular fibroadenomas closely resembling benign phyllodes as well as benign phyllodes tumors harbor MED12 mutations, and conclude that MED12 mutations in malignant phyllodes tumors appear to be relatively rare.

  20. Artificial glowworm swarm optimization algorithm based on adaptive t distribution mixed mutation%基于自适应t分布混合变异的人工萤火虫算法

    Institute of Scientific and Technical Information of China (English)

    杜晓昕; 张剑飞; 孙明

    2013-01-01

    The convergence speed of Artificial Glowworm Swarm Optimization (AGSO) algorithm declines,even falls into local minimums,when some glowworms gather in non whole extreme points or some glowworms wander around aimlessly.Concerning this problem,an AGSO algorithm based on adaptive t distribution mixed mutation was proposed.Adaptive t distribution mutation and optimization adjustment mutation was introduced into the AGSO algorithm to improve the diversity of glowworm swarm,and prevent the AGSO algorithm from falling into local minimums.Mutation control factor was defined.Combining history status information,the description of adaptive t distribution mixed mutation was given.The mutation method could enhance ability of global exploration and local development.The emulation results of representative test functions and many application examples show that the proposed algorithm is reliable and efficient.Meanwhile,this algorithm is better than tradition algorithm in terms of speed and precision for seeking the optimum.%针对人工萤火虫(AGSO)算法中存在一些漫无目的随机运动的萤火虫及一些萤火虫在非全局极值点出现严重聚集时,收敛速度降低,甚至陷入局部极值的问题,提出一种基于自适应t分布混合变异的人工萤火虫算法.用自适应t分布变异和最优调教变异来增强种群的多样性,限制算法陷入局部最优;定义了变异控制因子对变异的运行进行控制,结合历史状态信息给出了自适应t分布混合变异描述.该变异方法能使算法同时提高全局探索能力和局部开发能力.通过典型函数算例和实际应用算例实验结果表明,该算法是可行有效的,比传统算法具有较快的寻优速度和较高的寻优精度.

  1. High-level ciprofloxacin resistance from point mutations in gyrA and parC confined to global hospital-adapted clonal lineage CC17 of Enterococcus faecium.

    Science.gov (United States)

    Leavis, Helen L; Willems, Rob J L; Top, Janetta; Bonten, Marc J M

    2006-03-01

    To substantiate a common genetic background of ciprofloxacin-resistant Enterococcus faecium, 32 ciprofloxacin-resistant (Cip(r)) and 31 ciprofloxacin-susceptible (Cip(s)) isolates from outbreaks, clinical infections, surveillances, and animals from 10 different countries were genotyped by multilocus sequence typing. Additionally, susceptibilities to ampicillin and vancomycin and the presence of esp were determined and the quinolone resistance-determining regions of parC, gyrA, parB, and gyrE were sequenced. High-level Cip(r) (MIC > or = 64 microg/ml) due to point mutations in the quinolone resistance-determining region was unique to a distinct hospital-adapted genetic complex in E. faecium, previously designated CC17. Low-level Cip(r) (MIC = 4 microg/ml) in non-CC17 strains is not attributable to point mutations in any subunit of the topoisomerase genes, and the mechanism of resistance remains unclear. Acquisition of mutations in parC and gyrA, leading to high-level Cip(r), is, in addition to ampicillin resistance and the presence of a putative pathogenicity island, another cumulative step in hospital adaptation of CC17.

  2. Biochemical and molecular characterization of GALT gene from Indian galactosemia patients: identification of 10 novel mutations and their structural and functional implications.

    Science.gov (United States)

    Singh, Ramandeep; Thapa, Babu R; Kaur, Gurjit; Prasad, Rajendra

    2012-12-24

    Classical Galactosemia is an autosomal recessive disorder of galactose metabolism caused by severe reduction or absence of the galactose-1-phosphate uridyl transferase (GALT) enzyme. Till date, no reports are available on clinical and molecular spectrum of galactosemia from Indian population. The characterization of underlying GALT gene lesions was performed in 55 unrelated galactosemia patients. The GALT mutational spectrum comprised 16 distinct mutations including 10 previously unreported mutations. N314D was the most common mutation with a frequency of 40% followed by Q188R at 2.7%. The novel GALT gene mutations included 6 missense mutations viz. Y89H, Q103R, P166A, S181F, K285R, R333L; one nonsense mutation, S307X and 3 silent mutations--Q103Q, K210K and H319H. The functional significance of the novel GALT missense mutations was investigated using SNPs&GO and SIFT tools. Further, modeling studies using 3D models of mutant and wild type GALT proteins revealed mutations to exert their effects at the molecular level by altering H-bonds, salt bridges, secondary structure or surface features. The study highlighted the heterogeneity of classical galactosemia in the Indian population and also emphasizes the importance of GALT gene analysis in diagnosis of galactosemia. It also revealed that the Indian GALT mutational profile differs significantly from other populations studied.

  3. A Founder Mutation in MYO7A Underlies a Significant Proportion of Usher Syndrome in Indigenous South Africans: Implications for the African Diaspora.

    Science.gov (United States)

    Roberts, Lisa; George, Siddiqah; Greenberg, Jacquie; Ramesar, Raj S

    2015-10-01

    Research over the past 25 years at the University of Cape Town has led to the identification of causative mutations in 17% of the 1416 families in the Retinal Degenerative Diseases (RDD) biorepository in South Africa. A low rate of mutation detection has been observed in patients of indigenous African origin, hinting at novel genes and mutations in this population. Recently, however, data from our translational research program showed two unrelated indigenous African families with Usher syndrome (USH), with the same homozygous MYO7A mutation. Therefore, the extent to which this mutation contributes toward the disease burden in South Africa was investigated. Cohorts of unrelated indigenous South African probands with different RDD diagnoses were tested for the MYO7A c.6377delC mutation. Familial cosegregation analysis was performed for homozygous probands, clinical data were evaluated, and SNP haplotypes were analyzed. This homozygous MYO7A mutation underlies a remarkable 43% of indigenous African USH cases investigated in this study, the majority of which (60%) were diagnosed clinically with Type 2 USH. All homozygotes shared a common haplotype. This mutation does not appear to cause nonsyndromic vision loss. Of interest is the origin of this common mutation relevant to the Bantu population migration into southern Africa. Further investigation of the phenotype may elucidate the disease biology, and perhaps reveal a larger cohort with the same mutation, with which to assess the impact of environmental and genetic modifiers and evaluate therapeutic trials.

  4. Mutations of C-reactive protein (CRP) -286 SNP, APC and p53 in colorectal cancer: implication for a CRP-Wnt crosstalk.

    Science.gov (United States)

    Su, Hai-Xiang; Zhou, Hai-Hong; Wang, Ming-Yu; Cheng, Jin; Zhang, Shi-Chao; Hui, Feng; Chen, Xue-Zhong; Liu, Shan-Hui; Liu, Qin-Jiang; Zhu, Zi-Jiang; Hu, Qing-Rong; Wu, Yi; Ji, Shang-Rong

    2014-01-01

    C-reactive protein (CRP) is an established marker of inflammation with pattern-recognition receptor-like activities. Despite the close association of the serum level of CRP with the risk and prognosis of several types of cancer, it remains elusive whether CRP contributes directly to tumorigenesis or just represents a bystander marker. We have recently identified recurrent mutations at the SNP position -286 (rs3091244) in the promoter of CRP gene in several tumor types, instead suggesting that locally produced CRP is a potential driver of tumorigenesis. However, it is unknown whether the -286 site is the sole SNP position of CRP gene targeted for mutation and whether there is any association between CRP SNP mutations and other frequently mutated genes in tumors. Herein, we have examined the genotypes of three common CRP non-coding SNPs (rs7553007, rs1205, rs3093077) in tumor/normal sample pairs of 5 cancer types (n = 141). No recurrent somatic mutations are found at these SNP positions, indicating that the -286 SNP mutations are preferentially selected during the development of cancer. Further analysis reveals that the -286 SNP mutations of CRP tend to co-occur with mutated APC particularly in rectal cancer (p = 0.04; n = 67). By contrast, mutations of CRP and p53 or K-ras appear to be unrelated. There results thus underscore the functional importance of the -286 mutation of CRP in tumorigenesis and imply an interaction between CRP and Wnt signaling pathway.

  5. Adaptation Independent Modulation of Auditory Hair Cell Mechanotransduction Channel Open Probability Implicates a Role for the Lipid Bilayer.

    Science.gov (United States)

    Peng, Anthony W; Gnanasambandam, Radhakrishnan; Sachs, Frederick; Ricci, Anthony J

    2016-03-09

    The auditory system is able to detect movement down to atomic dimensions. This sensitivity comes in part from mechanisms associated with gating of hair cell mechanoelectric transduction (MET) channels. MET channels, located at the tops of stereocilia, are poised to detect tension induced by hair bundle deflection. Hair bundle deflection generates a force by pulling on tip-link proteins connecting adjacent stereocilia. The resting open probability (P(open)) of MET channels determines the linearity and sensitivity to mechanical stimulation. Classically, P(open) is regulated by a calcium-sensitive adaptation mechanism in which lowering extracellular calcium or depolarization increases P(open). Recent data demonstrated that the fast component of adaptation is independent of both calcium and voltage, thus requiring an alternative explanation for the sensitivity of P(open) to calcium and voltage. Using rat auditory hair cells, we characterize a mechanism, separate from fast adaptation, whereby divalent ions interacting with the local lipid environment modulate resting P(open). The specificity of this effect for different divalent ions suggests binding sites that are not an EF-hand or calmodulin model. GsMTx4, a lipid-mediated modifier of cationic stretch-activated channels, eliminated the voltage and divalent sensitivity with minimal effects on adaptation. We hypothesize that the dual mechanisms (lipid modulation and adaptation) extend the dynamic range of the system while maintaining adaptation kinetics at their maximal rates.

  6. Use of Adaptive Laboratory Evolution To Discover Key Mutations Enabling Rapid Growth of Escherichia coli K-12 MG1655 on Glucose Minimal Medium

    DEFF Research Database (Denmark)

    LaCroix, Ryan A.; Sandberg, Troy E.; O'Brien, Edward J.

    2015-01-01

    and exponential growth, fitness increases up to 1.6-fold were obtained compared to the wild type. These increases are comparable to previously reported maximum growth rates in similar conditions but were obtained over a shorter time frame. Across the eight replicate ALE experiments performed, causal mutations...... using a gene classification system alone. The methods described here represent a powerful combination of technologies to increase the speed and efficiency of ALE studies. The identified mutations can be examined as genetic parts for increasing growth rate in a desired strain and for understanding rapid...... often mutated: the global transcription gene rpoB, an 82-bp deletion between the metabolic pyrE gene and rph, and an IS element between the DNA structural gene hns and tdk. Model-derived classification of gene expression revealed a number of processes important for increased growth that were missed...

  7. Functional analysis of non-hotspot AKT1 mutants found in human breast cancers identifies novel driver mutations: implications for personalized medicine

    OpenAIRE

    Yi, Kyung H.; Axtmayer, Jossette; Gustin, John P.; Rajpurohit, Anandita; Lauring, Josh

    2012-01-01

    The phosphatidylinositol 3-kinase (PI3-kinase)-Akt-mTOR pathway is mutated at high frequency in human breast cancer, and this pathway is the focus of active drug discovery and clinical investigation. Trials of personalized cancer therapy seek to leverage knowledge of cancer gene mutations by using mutations to guide the choice of targeted therapies. At the same time, cancer genome sequencing studies are identifying low frequency variants of unknown significance in known cancer genes, as well ...

  8. The adapter protein APPL1 links FSH receptor to inositol 1,4,5-trisphosphate production and is implicated in intracellular Ca(2+) mobilization.

    Science.gov (United States)

    Thomas, Richard M; Nechamen, Cheryl A; Mazurkiewicz, Joseph E; Ulloa-Aguirre, Alfredo; Dias, James A

    2011-04-01

    FSH binds to its receptor (FSHR) on target cells in the ovary and testis, to regulate oogenesis and spermatogenesis, respectively. The signaling cascades activated after ligand binding are extremely complex and have been shown to include protein kinase A, mitogen-activated protein kinase, phosphatidylinositol 3-kinase/protein kinase B, and inositol 1,4,5-trisphosphate-mediated calcium signaling pathways. The adapter protein APPL1 (Adapter protein containing Pleckstrin homology domain, Phosphotyrosine binding domain and Leucine zipper motif), which has been linked to an assortment of other signaling proteins, was previously identified as an interacting protein with FSHR. Thus, alanine substitution mutations in the first intracellular loop of FSHR were generated to determine which residues are essential for FSHR-APPL1 interaction. Three amino acids were essential; when any one of them was altered, APPL1 association with FSHR mutants was abrogated. Two of the mutants (L377A and F382A) that displayed poor cell-surface expression were not studied further. Substitution of FSHR-K376A did not affect FSH binding or agonist-stimulated cAMP production in either transiently transfected human embryonic kidney cells or virally transduced human granulosa cells (KGN). In the KGN line, as well as primary cultures of rat granulosa cells transduced with wild type or mutant receptor, FSH-mediated progesterone or estradiol production was not affected by the mutation. However, in human embryonic kidney cells inositol 1,4,5-trisphosphate production was curtailed and KGN cells transduced with FSHR-K376A evidenced reduced Ca(2+) mobilization from intracellular stores after FSH treatment.

  9. Microanatomical and histological features in the long bones of Mosasaurine mosasaurs (Reptilia, Squamata)--implications for aquatic adaptation and growth rates.

    Science.gov (United States)

    Houssaye, Alexandra; Lindgren, Johan; Pellegrini, Rodrigo; Lee, Andrew H; Germain, Damien; Polcyn, Michael J

    2013-01-01

    During their evolution in the Late Cretaceous, mosasauroids attained a worldwide distribution, accompanied by a marked increase in body size and open ocean adaptations. This transition from land-dwellers to highly marine-adapted forms is readily apparent not only at the gross anatomic level but also in their inner bone architecture, which underwent profound modifications. The present contribution describes, both qualitatively and quantitatively, the internal organization (microanatomy) and tissue types and characteristics (histology) of propodial and epipodial bones in one lineage of mosasauroids; i.e., the subfamily Mosasaurinae. By using microanatomical and histological data from limb bones in combination with recently acquired knowledge on the inner structure of ribs and vertebrae, and through comparisons with extant squamates and semi-aquatic to fully marine amniotes, we infer possible implications on mosasaurine evolution, aquatic adaptation, growth rates, and basal metabolic rates. Notably, we observe the occurrence of an unusual type of parallel-fibered bone, with large and randomly shaped osteocyte lacunae (otherwise typical of fibrous bone) and particular microanatomical features in Dallasaurus, which displays, rather than a spongious inner organization, bone mass increase in its humeri and a tubular organization in its femora and ribs. The dominance of an unusual type of parallel-fibered bone suggests growth rates and, by extension, basal metabolic rates intermediate between that of the extant leatherback turtle, Dermochelys, and those suggested for plesiosaur and ichthyosaur reptiles. Moreover, the microanatomical features of the relatively primitive genus Dallasaurus differ from those of more derived mosasaurines, indicating an intermediate stage of adaptation for a marine existence. The more complete image of the various microanatomical trends observed in mosasaurine skeletal elements supports the evolutionary convergence between this lineage of

  10. Microanatomical and Histological Features in the Long Bones of Mosasaurine Mosasaurs (Reptilia, Squamata) – Implications for Aquatic Adaptation and Growth Rates

    Science.gov (United States)

    Houssaye, Alexandra; Lindgren, Johan; Pellegrini, Rodrigo; Lee, Andrew H.; Germain, Damien; Polcyn, Michael J.

    2013-01-01

    Background During their evolution in the Late Cretaceous, mosasauroids attained a worldwide distribution, accompanied by a marked increase in body size and open ocean adaptations. This transition from land-dwellers to highly marine-adapted forms is readily apparent not only at the gross anatomic level but also in their inner bone architecture, which underwent profound modifications. Methodology/Principal Findings The present contribution describes, both qualitatively and quantitatively, the internal organization (microanatomy) and tissue types and characteristics (histology) of propodial and epipodial bones in one lineage of mosasauroids; i.e., the subfamily Mosasaurinae. By using microanatomical and histological data from limb bones in combination with recently acquired knowledge on the inner structure of ribs and vertebrae, and through comparisons with extant squamates and semi-aquatic to fully marine amniotes, we infer possible implications on mosasaurine evolution, aquatic adaptation, growth rates, and basal metabolic rates. Notably, we observe the occurrence of an unusual type of parallel-fibered bone, with large and randomly shaped osteocyte lacunae (otherwise typical of fibrous bone) and particular microanatomical features in Dallasaurus, which displays, rather than a spongious inner organization, bone mass increase in its humeri and a tubular organization in its femora and ribs. Conclusions/Significance The dominance of an unusual type of parallel-fibered bone suggests growth rates and, by extension, basal metabolic rates intermediate between that of the extant leatherback turtle, Dermochelys, and those suggested for plesiosaur and ichthyosaur reptiles. Moreover, the microanatomical features of the relatively primitive genus Dallasaurus differ from those of more derived mosasaurines, indicating an intermediate stage of adaptation for a marine existence. The more complete image of the various microanatomical trends observed in mosasaurine skeletal elements

  11. How hard they hit? Perception, adaptation and public health implications of heat waves in urban and peri-urban Pakistan.

    Science.gov (United States)

    Rauf, Sara; Bakhsh, Khuda; Abbas, Azhar; Hassan, Sarfraz; Ali, Asghar; Kächele, Harald

    2017-04-01

    Heat waves threaten human health given the fast changing climatic scenarios in the recent past. Adaptation to heat waves would take place when people perceive their impacts based on their knowledge. The present study examines perception level and its determinants resulting in adaptation to heat waves in Pakistan. The study used cross-sectional data from urban and peri-urban respondents of Faisalabad District. The study employs a health belief model to assess risk perception among the respondents. Logistic model is used to determine factors affecting level of knowledge, perception and adaptation to heat waves. Around 30% of peri-urban respondents have a low level of knowledge about the fatal impacts of heat waves. Risk perception of heat waves is very low among urban (57%) and peri-urban (66%) respondents. Households' knowledge on heat waves is significantly related to age, gender, education, wealth and access to health services. Determinants of perception include knowledge of heat waves, age and joint effect of marital status and knowledge while income level, family size, urban/peri-urban background, perceived barriers, perceived benefits and cues to action significantly affect adaptation to heat waves. To reduce deadly health impacts, mass awareness campaigns are needed to build perception and improve adaptation to heat waves.

  12. A limited spectrum of phenylalanine hydroxylase mutations is observed in phenylketonuria patients in western Poland and implications for treatment with 6R tetrahydrobiopterin.

    Science.gov (United States)

    Dobrowolski, Steven F; Borski, K; Ellingson, C C; Koch, R; Levy, H L; Naylor, E W

    2009-06-01

    Phenylketonuria (PKU) is an autosomal recessive defect in hepatic metabolism of phenylalanine, which is secondary to mutations in the phenylalanine hydroxylase (PAH) gene. Sixty-seven ethnically Polish PKU patients, followed at the Outpatient Department of Pediatrics and Developmental Medicine in Poznan, Poland, were assessed for mutations in the PAH gene. Two mutations were identified in 61 of 67 patients and a single mutation was identified in the remaining six patients. The four most prevalent mutations (p.R408W, 68%; c.1066-11G>A, 6%; c.1315+1G>A, 5.2%; c.822-832delGCCCATGTATA, 3.7%) accounted for 83% of the mutant alleles. Fifteen additional mutations were identified of which most (13/15) were observed in an individual patient. Before knowledge of PAH genotypes, 19 patients were challenged with a 20 mg kg(-1) dose of 6R tetrahydrobiopterin (BH(4)) and serum phenylalanine concentration was monitored in hospital over 24 h. Two patients responded to the BH(4) challenge with a reduction of serum phenylalanine concentration >30% from baseline. PAH genotypes of the two responsive patients would have been predicted, as they contained mutations recognized as BH(4) responsive, whereas the 17 patients who were unresponsive would have been predicted as their mutations were either recognized as non-responsive or were highly deleterious frame-shift mutations. Overall, only 7.5% (5/ 67) of patients had PAH mutations recognized as responsive to co-factor therapy. Among the PKU patients from western Poland, PAH mutations responsive to BH(4) therapy are poorly represented; therefore, genotyping may be useful for identifying candidate patients likely to respond to BH(4) before physiological challenge.

  13. Mutations in the Arabidopsis homolog of LST8/GβL, a partner of the target of Rapamycin kinase, impair plant growth, flowering, and metabolic adaptation to long days.

    Science.gov (United States)

    Moreau, Manon; Azzopardi, Marianne; Clément, Gilles; Dobrenel, Thomas; Marchive, Chloé; Renne, Charlotte; Martin-Magniette, Marie-Laure; Taconnat, Ludivine; Renou, Jean-Pierre; Robaglia, Christophe; Meyer, Christian

    2012-02-01

    The conserved Target of Rapamycin (TOR) kinase forms high molecular mass complexes and is a major regulator of cellular adaptations to environmental cues. The Lethal with Sec Thirteen 8/G protein β subunit-like (LST8/GβL) protein is a member of the TOR complexes, and two putative LST8 genes are present in Arabidopsis thaliana, of which only one (LST8-1) is significantly expressed. The Arabidopsis LST8-1 protein is able to complement yeast lst8 mutations and interacts with the TOR kinase. Mutations in the LST8-1 gene resulted in reduced vegetative growth and apical dominance with abnormal development of flowers. Mutant plants were also highly sensitive to long days and accumulated, like TOR RNA interference lines, higher amounts of starch and amino acids, including proline and glutamine, while showing reduced concentrations of inositol and raffinose. Accordingly, transcriptomic and enzymatic analyses revealed a higher expression of genes involved in nitrate assimilation when lst8-1 mutants were shifted to long days. The transcriptome of lst8-1 mutants in long days was found to share similarities with that of a myo-inositol 1 phosphate synthase mutant that is also sensitive to the extension of the light period. It thus appears that the LST8-1 protein has an important role in regulating amino acid accumulation and the synthesis of myo-inositol and raffinose during plant adaptation to long days.

  14. Combination of Whole Genome Sequencing, Linkage and Functional Studies Implicates a Missense Mutation in Titin as a Cause of Autosomal Dominant Cardiomyopathy with Features of Left Ventricular Non-Compaction

    Science.gov (United States)

    Hooper, Charlotte; Ormondroyd, Liz; Pagnamenta, Alistair; Lise, Stefano; Salatino, Silvia; Knight, Samantha JL; Taylor, Jenny C.; Thomson, Kate L.; Arnold, Linda; Chatziefthimiou, Spyros D.; Konarev, Petr V.; Wilmanns, Matthias; Ehler, Elisabeth; Ghisleni, Andrea; Gautel, Mathias; Blair, Edward; Watkins, Hugh; Gehmlich, Katja

    2016-01-01

    Background High throughput next generation sequencing techniques have made whole genome sequencing accessible in clinical practice, however, the abundance of variation in the human genomes makes the identification of a disease-causing mutation on a background of benign rare variants challenging. Methods and Results Here we combine whole genome sequencing with linkage analysis in a three-generation family affected by cardiomyopathy with features of autosomal dominant left-ventricular non-compaction cardiomyopathy. A missense mutation in the giant protein titin is the only plausible disease-causing variant that segregates with disease amongst the eight surviving affected individuals, with interrogation of the entire genome excluding other potential causes. This A178D missense mutation, affecting a conserved residue in the second immunoglobulin-like domain of titin, was introduced in a bacterially expressed recombinant protein fragment and biophysically characterised in comparison to its wild-type counterpart. Multiple experiments, including size exclusion chromatography, small angle X-ray scattering and circular dichroism spectroscopy suggest partial unfolding and domain destabilisation in the presence of the mutation. Moreover, binding experiments in mammalian cells show that the mutation markedly impairs binding to the titin ligand telethonin. Conclusions Here we present genetic and functional evidence implicating the novel A178D missense mutation in titin as the cause of a highly penetrant familial cardiomyopathy with features of left-ventricular non-compaction. This expands the spectrum of titin’s roles in cardiomyopathies. It furthermore highlights that rare titin missense variants, currently often ignored or left un-interpreted, should be considered to be relevant for cardiomyopathies and can be identified by the approach presented here. PMID:27625337

  15. Detection of the mtDNA 14484 mutation on an African-specific haplotype: Implications about its role in causing Leber hereditary optic neuropathy

    Energy Technology Data Exchange (ETDEWEB)

    Torroni, A.; Petrozzi, M.; Terracina, M. [Universita` di Roma (Italy)] [and others

    1996-07-01

    Leber hereditary optic neuropathy (LHON) is a maternally transmitted disease whose primary clinical manifestation is acute or subacute bilateral loss of central vision leading to central scotoma and blindness. To date, LHON has been associated with 18 mtDNA missense mutations, even though, for many of these mutations, it remains unclear whether they cause the disease, contribute to the pathology, or are nonpathogenic mtDNA polymorphisms. On the basis of numerous criteria, which include the specificity for LHON, the frequency in the general population, and the penetrance within affected pedigrees, the detection of associated defects in the respiratory chain, mutations at three nucleotide positions (nps), 11778 (G{r_arrow}A), 3460 (G{r_arrow}A), and 14484 (T{r_arrow}C) have been classified as high-risk and primary LHON mutations. Overall, these three mutations encompass {ge}90% of the LHON cases. 29 refs., 1 fig.

  16. Low prevalence of K-RAS, EGF-R and BRAF mutations in sinonasal adenocarcinomas. Implications for anti-EGFR treatments.

    Science.gov (United States)

    Franchi, Alessandro; Innocenti, Duccio Rossi Degli; Palomba, Annarita; Miligi, Lucia; Paiar, Fabiola; Franzese, Ciro; Santucci, Marco

    2014-07-01

    We have previously shown that a subset of sinonasal intestinal-type adenocarcinomas (ITAC) shows activation of the epidermal growth factor-receptor (EGFR) pathway. In this study we examine the status of the EGFR, KRAS and BRAF genes in a series of sinonasal intestinal (ITAC) and non-intestinal type adenocarcinomas (non-ITAC). Eighteen ITACs and 12 non-ITACs were studied immunohistochemically for EGFR expression. Point mutations were analyzed for EGFR exons 19 and 21, KRAS exon 2 and BRAF exon 15 by direct sequencing. Non-ITACs showed significantly higher expression of EGFR (p = 0.015). Mutation analysis revealed one ITAC with EGFR and one ITAC with KRAS mutation, while two non-ITACs presented mutation of BRAF. We conclude that a subset of sinonasal adenocarcinomas shows overexpression of EGFR, while activating mutations of the signaling cascade downstream of EGFR are rare, suggesting that these tumors could be good candidates for anti-EGFR therapies.

  17. Mutations of C-reactive protein (CRP -286 SNP, APC and p53 in colorectal cancer: implication for a CRP-Wnt crosstalk.

    Directory of Open Access Journals (Sweden)

    Hai-Xiang Su

    Full Text Available C-reactive protein (CRP is an established marker of inflammation with pattern-recognition receptor-like activities. Despite the close association of the serum level of CRP with the risk and prognosis of several types of cancer, it remains elusive whether CRP contributes directly to tumorigenesis or just represents a bystander marker. We have recently identified recurrent mutations at the SNP position -286 (rs3091244 in the promoter of CRP gene in several tumor types, instead suggesting that locally produced CRP is a potential driver of tumorigenesis. However, it is unknown whether the -286 site is the sole SNP position of CRP gene targeted for mutation and whether there is any association between CRP SNP mutations and other frequently mutated genes in tumors. Herein, we have examined the genotypes of three common CRP non-coding SNPs (rs7553007, rs1205, rs3093077 in tumor/normal sample pairs of 5 cancer types (n = 141. No recurrent somatic mutations are found at these SNP positions, indicating that the -286 SNP mutations are preferentially selected during the development of cancer. Further analysis reveals that the -286 SNP mutations of CRP tend to co-occur with mutated APC particularly in rectal cancer (p = 0.04; n = 67. By contrast, mutations of CRP and p53 or K-ras appear to be unrelated. There results thus underscore the functional importance of the -286 mutation of CRP in tumorigenesis and imply an interaction between CRP and Wnt signaling pathway.

  18. M-Learning: Implications in Learning Domain Specificities, Adaptive Learning, Feedback, Augmented Reality, and the Future of Online Learning

    Science.gov (United States)

    Squires, David R.

    2014-01-01

    The aim of this paper is to examine the potential and effectiveness of m-learning in the field of Education and Learning domains. The purpose of this research is to illustrate how mobile technology can and is affecting novel change in instruction, from m-learning and the link to adaptive learning, to the uninitiated learner and capacities of…

  19. Situational variations in ethnic identity across immigration generations: Implications for acculturative change and cross-cultural adaptation.

    Science.gov (United States)

    Noels, Kimberly A; Clément, Richard

    2015-12-01

    This study examined whether the acculturation of ethnic identity is first evident in more public situations with greater opportunity for intercultural interaction and eventually penetrates more intimate situations. It also investigated whether situational variations in identity are associated with cross-cultural adaptation. First-generation (G1), second-generation (G2) and mixed-parentage second-generation (G2.5) young adult Canadians (n = 137, n = 169, and n = 91, respectively) completed a questionnaire assessing their heritage and Canadian identities across four situational domains (family, friends, university and community), global heritage identity and cross-cultural adaptation. Consistent with the acculturation penetration hypothesis, the results showed Canadian identity was stronger than heritage identity in public domains, but the converse was true in the family domain; moreover, the difference between the identities in the family domain was attenuated in later generations. Situational variability indicated better adaptation for the G1 cohort, but poorer adaptation for the G2.5 cohort. For the G2 cohort, facets of global identity moderated the relation, such that those with a weaker global identity experienced greater difficulties and hassles with greater identity variability but those with a stronger identity did not. These results are interpreted in light of potential interpersonal issues implied by situational variation for each generation cohort.

  20. Adaptations of lichens to conditions in tropical forests of South-East Asia and their taxonomic implications

    NARCIS (Netherlands)

    Wolseley, P.A.; Hawksworth, D.L.

    2009-01-01

    Lichens are fungi with a specialized nutritional mode involving algae, or cyanobacteria, or both. Classification is based on the fungal partner, and around 13 500 species are known. The association is ancient, and the first ascomycete fungi with fruit bodies may have been lichenized. Adaptations to

  1. Adaptations of lichens to conditions in tropical forests of South-East Asia and their taxonomic implications

    NARCIS (Netherlands)

    Wolseley, P.A.; Hawksworth, D.L.

    2009-01-01

    Lichens are fungi with a specialized nutritional mode involving algae, or cyanobacteria, or both. Classification is based on the fungal partner, and around 13 500 species are known. The association is ancient, and the first ascomycete fungi with fruit bodies may have been lichenized. Adaptations to

  2. Non-Western Students' Causal Reasoning about Biologically Adaptive Changes in Humans, Other Animals and Plants: Instructional and Curricular Implications

    Science.gov (United States)

    Mbajiorgu, Ngozika; Anidu, Innocent

    2017-01-01

    Senior secondary school students (N = 360), 14- to 18-year-olds, from the Igbo culture of eastern Nigeria responded to a questionnaire requiring them to give causal explanations of biologically adaptive changes in humans, other animals and plants. A student subsample (n = 36) was, subsequently, selected for in-depth interviews. Significant…

  3. De novo COX2 mutation in a LHON family of Caucasian origin: implication for the role of mtDNA polymorphism in human pathology.

    Science.gov (United States)

    Zhadanov, Sergey I; Atamanov, Vasiliy V; Zhadanov, Nikolay I; Schurr, Theodore G

    2006-01-01

    Recent studies suggest that certain mutations with phylogeographic importance as haplogroup markers may also influence the phenotypic expression of particular mitochondrial disorders. One such disorder, Leber's hereditary optic neuropathy (LHON), demonstrates a clear expression bias in mtDNAs belonging to haplogroup J, a West Eurasian maternal lineage defined by polymorphic markers that have been called 'secondary' disease mutations. In this report, we present evidence for a de novo heteroplasmic COX2 mutation associated with a LHON clinical phenotype. This particular mutation-at nucleotide position 7,598-occurs in West Eurasian haplogroup H, the most common maternal lineage among individuals of European descent, whereas previous studies have detected this mutation only in East Eurasian haplogroup E. A review of the available mtDNA sequence data indicates that the COX2 7598 mutation occurs as a homoplasic event at the tips of these phylogenetic branches, suggesting that it could be a variant that is rapidly eliminated by selection. This finding points to the potential background influence of polymorphisms on the expression of mild deleterious mutations such as LHON mtDNA defects and further highlights the difficulties in distinguishing deleterious mtDNA changes from neutral polymorphisms and their significance in the development of mitochondriopathies.

  4. C-kit mutation screening in patients with acute myeloid leukaemia: adaptation of a Giemsa-stained bone-marrow smear DNA extraction technique.

    Science.gov (United States)

    Court, E L; Davidson, K; Smith, M A; Inman, L; Marriott, S A; Smith, J G; Pallister, C J

    2001-01-01

    The scarcity of viable tissue samples for leukaemia research is widely recognised and currently restrictive. Archival bone-marrow smears present a valuable resource that can be exploited easily for mutational analysis. Here, a modified technique to extract DNA is described, and used subsequently for mutation/polymorphism screening of the stem-cell factor receptor proto-oncogene c-kit in 23 patients with acute myeloid leukaemia (AML). The selected method was straightforward and used bone-marrow material scraped from periodic acid-Schiff, sudan black B and May-Grünwald/Giemsa-stained preparations, and treated initially with proteinase K prepared in digestion buffer to digest all proteinaceous matter. Following incubation, saturated sodium chloride was added and DNA extracted from the supernatant by phenol/chloroform/isoamyl alcohol treatment. Retrieved DNA was precipitated with ethanol at -20 degrees C overnight, washed with 95% ethanol, air-dried, resuspended using purite water and stored at -20 degrees C prior to use in mutational analysis. The extraction method described was compared with a commercial reagent for combined DNA, RNA and protein isolation using cryopreserved cells from 20 patients with AML. The quality of extracted DNA isolated by the two methods was comparable by polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) techniques. Bone-marrow biopsies are performed regularly on each AML patient to monitor the disease; therefore, an extraction method using this resource could liberate a valuable source of DNA for study (e.g. molecular investigations, including mutation/polymorphism screening etc.). This would allow fresh and programme-frozen cells to be reserved for those investigations requiring intact, viable cells. The use of archived bone-marrow smears would permit vast increase in the scope for retrospective testing and large-scale analyses.

  5. The Implication and Application of Communicative Approach to Designing and Adapting ELT Materials for Chinese College Students

    Institute of Scientific and Technical Information of China (English)

    张靓

    2009-01-01

    The Communicative approach is a main stream in current ELT classroom.This approach mainly aims at developing leamers'communicative competences to equip them to be,proficient in real life communication in English.The communicative approach influences the belief of language learning,teaching,methodology and inevitably the syllabus and also ELT materials.However.communicative materials are not quite suitable for Chinese learners all the time,cause it can not meet the some specific expectations and competences of Chinese learners and teachers.Thus,adaptation is needed to make materials more.workable and help learners to develop their language proficiency.This essay will first introduce the communicative approach and materials briefly and then analyses the reasons of adaptation according to the specific context of Chinese college learners.

  6. The Implication and Application of Communicative Approach to Designing and Adapting ELT Materials for Chinese College Students

    Institute of Scientific and Technical Information of China (English)

    张靓

    2009-01-01

    The Communicative approach is a main stream in current ELT classroom.This approach mainly aims at developing learners'communicative competences to equip them to be proficient in real life communication in English.The communicative approach influences the belief of language learning,teaching,methodology and inevitably the syllabus and also ELT materials.However,communicative materials are not quite suitable for Chinese learners all the time,cause it can not meet the some specific expectations and competences of Chinese learners and teachers.Thus,adaptation is needed to make materials more workable and help learners to develop their language proficiency.This essay will first introduce the communicative approach and materials briefly and then analyses the reasons of adaptation according to the specific context of Chinese college learners.

  7. An assessment of implications of adaptive licensing for pharmaceutical intellectual property and regulatory exclusivity rights in the European Union.

    Science.gov (United States)

    Meier, A; Faulkner, S D; Schoonderbeek, C; Jong, B; Kung, J; Brindley, D; Barker, R

    2016-12-01

    One of the key advantages of adaptive licensing (AL) is to align the licensing of new medicines more closely with patient needs for earlier access to beneficial treatments. From an innovators perspective, "earlier" market access may seem an obvious incentive to gain earlier revenue generation. However, this is offset with an "earlier" start to patent and regulatory protection periods, which, depending on the technology, disease, population, and timing of subsequent asset protection periods, can present a conflict.

  8. Shared human-chimpanzee pattern of perinatal femoral shaft morphology and its implications for the evolution of hominin locomotor adaptations.

    Directory of Open Access Journals (Sweden)

    Naoki Morimoto

    Full Text Available BACKGROUND: Acquisition of bipedality is a hallmark of human evolution. How bipedality evolved from great ape-like locomotor behaviors, however, is still highly debated. This is mainly because it is difficult to infer locomotor function, and even more so locomotor kinematics, from fossil hominin long bones. Structure-function relationships are complex, as long bone morphology reflects phyletic history, developmental programs, and loading history during an individual's lifetime. Here we discriminate between these factors by investigating the morphology of long bones in fetal and neonate great apes and humans, before the onset of locomotion. METHODOLOGY/PRINCIPAL FINDINGS: Comparative morphometric analysis of the femoral diaphysis indicates that its morphology reflects phyletic relationships between hominoid taxa to a greater extent than taxon-specific locomotor adaptations. Diaphyseal morphology in humans and chimpanzees exhibits several shared-derived features, despite substantial differences in locomotor adaptations. Orangutan and gorilla morphologies are largely similar, and likely represent the primitive hominoid state. CONCLUSIONS/SIGNIFICANCE: These findings are compatible with two possible evolutionary scenarios. Diaphyseal morphology may reflect retained adaptive traits of ancestral taxa, hence human-chimpanzee shared-derived features may be indicative of the locomotor behavior of our last common ancestor. Alternatively, diaphyseal morphology might reflect evolution by genetic drift (neutral evolution rather than selection, and might thus be more informative about phyletic relationships between taxa than about locomotor adaptations. Both scenarios are consistent with the hypothesis that knuckle-walking in chimpanzees and gorillas resulted from convergent evolution, and that the evolution of human bipedality is unrelated to extant great ape locomotor specializations.

  9. Impacts of Climate Change on Vector Borne Diseases in the Mediterranean Basin — Implications for Preparedness and Adaptation Policy

    OpenAIRE

    Maya Negev; Shlomit Paz; Alexandra Clermont; Noemie Groag Pri-Or; Uri Shalom; Tamar Yeger; Green, Manfred S

    2015-01-01

    The Mediterranean region is vulnerable to climatic changes. A warming trend exists in the basin with changes in rainfall patterns. It is expected that vector-borne diseases (VBD) in the region will be influenced by climate change since weather conditions influence their emergence. For some diseases (i.e., West Nile virus) the linkage between emergence andclimate change was recently proved; for others (such as dengue) the risk for local transmission is real. Consequently, adaptation and prepar...

  10. Adaptation to flooding during emergence and seedling growth in rice and weeds, and implications for crop establishment

    Science.gov (United States)

    Ismail, Abdelbagi M.; Johnson, David E.; Ella, Evangelina S.; Vergara, Georgina V.; Baltazar, Aurora M.

    2012-01-01

    Background and aims Direct seeding of rice is being adopted in rainfed and irrigated lowland ecosystems because it reduces labour costs in addition to other benefits. However, early flooding due to uneven fields or rainfall slows down seed germination and hinders crop establishment. Conversely, early flooding helps suppress weeds and reduces the costs of manual weeding and/or dependence on herbicides; however, numerous weed species are adapted to lowlands and present challenges for the use of flooding to control weeds. Advancing knowledge on the mechanisms of tolerance of flooding during germination and early growth in rice and weeds could facilitate the development of improved rice varieties and effective weed management practices for direct-seeded rice. Principal results Rice genotypes with a greater ability to germinate and establish in flooded soils were identified, providing opportunities to develop varieties suitable for direct seeding in flooded soils. Tolerance of flooding in these genotypes was mostly attributed to traits associated with better ability to mobilize stored carbohydrates and anaerobic metabolism. Limited studies were undertaken in weeds associated with lowland rice systems. Remaining studies compared rice and weeds and related weed species such as Echinochloa crus-galli and E. colona or compared ecotypes of the same species of Cyperus rotundus adapted to either aerobic or flooded soils. Conclusions Tolerant weeds and rice genotypes mostly developed similar adaptive traits that allow them to establish in flooded fields, including the ability to germinate and elongate faster under hypoxia, mobilize stored starch reserves and generate energy through fermentation pathways. Remarkably, some weeds developed additional traits such as larger storage tubers that enlarge further in deeper flooded soils (C. rotundus). Unravelling the mechanisms involved in adaptation to flooding will help design management options that will allow tolerant rice genotypes

  11. Pressure Induced Changes in Adaptive Immune Function in Belugas (Delphinapterus leucas; implications for dive physiology and health

    Directory of Open Access Journals (Sweden)

    Laura A Thompson

    2016-09-01

    Full Text Available Increased pressure, associated with diving, can alter cell function through several mechanisms and has been shown to impact immune functions performed by peripheral blood mononuclear cells (PBMC in humans. While marine mammals possess specific adaptations which protect them from dive related injury, it is unknown how their immune system is adapted to the challenges associated with diving. The purpose of this study was to measure PBMC activation (IL2R expression and Concanavalin A induced lymphocyte proliferation (BrdU incorporation in belugas following in vitro pressure exposures during baseline, Out of Water Examination (OWE and capture/release conditions. Beluga blood samples (n=4 were obtained from animals at the Mystic Aquarium and from free ranging animals in Alaska (n=9. Human blood samples (n=4 (Biological Specialty Corporation were run for comparison. In vivo catecholamines and cortisol were measured in belugas to characterize the neuroendocrine response. Comparison of cellular responses between controls and pressure exposed cells, between conditions in belugas, between belugas and humans as well as between dive profiles, were run using mixed generalized linear models (α=0.05. Cortisol was significantly higher in wild belugas and OWE samples as compared with baseline for aquarium animals. Both IL2R expression and proliferation displayed significant pressure induced changes, and these responses varied between conditions in belugas. Both belugas and humans displayed increased IL2R expression, while lymphocyte proliferation decreased for aquarium animals and increased for humans and wild belugas. Results suggest beluga PBMC function is altered during diving and changes may represent dive adaptation as the response differs from humans, a non-dive adapted mammal. In addition, characteristics of a dive (i.e., duration, depth as well as neuroendocrine activity can alter the response of beluga cells, potentially impacting the ability of animals

  12. Chronic stress and brain plasticity: mechanisms underlying adaptive and maladaptive changes and implications for stress-related CNS disorders

    Science.gov (United States)

    Radley, Jason; Morilak, David; Viau, Victor; Campeau, Serge

    2015-01-01

    Stress responses entail neuroendocrine, autonomic, and behavioral changes to promote effective coping with real or perceived threats to one’s safety. While these responses are critical for the survival of the individual, adverse effects of repeated exposure to stress are widely known to have deleterious effects on health. Thus, a considerable effort in the search for treatments to stress-related CNS disorders necessitates unraveling the brain mechanisms responsible for adaptation under acute conditions and their perturbations following chronic stress exposure. This paper is based upon a symposium from the 2014 International Behavioral Neuroscience Meeting, summarizing some recent advances in understanding the effects of stress on adaptive and maladaptive responses subserved by limbic forebrain networks. An important theme highlighted in this review is that the same networks mediating neuroendocrine, autonomic, and behavioral processes during adaptive coping also comprise targets of the effects of repeated stress exposure in the development of maladaptive states. Where possible, reference is made to the similarity of neurobiological substrates and effects observed following repeated exposure to stress in laboratory animals and the clinical features of stress-related disorders in humans. PMID:26116544

  13. Expression of HIF-1α and Its Target Genes in the Nanorana parkeri Heart:Implications for High Altitude Adaptation

    Institute of Scientific and Technical Information of China (English)

    Qiong ZHANG; Xingzhi HAN; Yinzi YE; Robert H S KRAUS; Liqing FAN; Le YANG; Yi TAO

    2016-01-01

    Hypoxia-inducible factor 1 alpha (HIF-1α) and its target genes vascular endothelial growth factor (VEGF) and transferrins (TF) play an important role in native endothermic animals’ adaptation to the high altitude environments. For ectothermic animals – especially frogs – it remains undetermined whether HIF-1α and its target genes (VEGF and TF) play an important role in high altitude adaptation, too. In this study, we compared the gene sequences and expression of HIF-1α and its target genes (VEGF and TF) between three Nanorana parkeri populations from different altitudes (3008 m a.s.l., 3440 m a.s.l. and 4312 m a.s.l.). We observed that the cDNA sequences of HIF-1A exhibited high sequence similarity (99.38%) among the three altitudinally separated populations; but with increasing altitude, the expression of HIF-1A and its target genes (VEGF and TF) increased significantly. These results indicate that HIF-1αplays an important role in N. parkeri adaptation to the high altitude, similar to its role in endothermic animals.

  14. Prevalence of BRCA1 mutations among 403 women with triple-negative breast cancer: implications for genetic screening selection criteria: a Hellenic Cooperative Oncology Group Study.

    Science.gov (United States)

    Fostira, Florentia; Tsitlaidou, Marianthi; Papadimitriou, Christos; Pertesi, Maroulio; Timotheadou, Eleni; Stavropoulou, Alexandra V; Glentis, Stavros; Bournakis, Evangelos; Bobos, Mattheos; Pectasides, Dimitrios; Papakostas, Pavlos; Pentheroudakis, George; Gogas, Helen; Skarlos, Pantelis; Samantas, Epaminontas; Bafaloukos, Dimitrios; Kosmidis, Paris A; Koutras, Angelos; Yannoukakos, Drakoulis; Konstantopoulou, Irene; Fountzilas, George

    2012-07-01

    In spite the close association of the triple-negative breast cancer immunophenotype with hereditary breast cancers and the BRCA1 pathway, there is a lack of population studies that determine the frequency of BRCA1 mutations among triple-negative breast cancer patients. To address this, we have screened a large sample of 403 women diagnosed with triple-negative invasive breast cancer, independently of their age or family history, for germline BRCA1 mutations. Median age at diagnosis was 50 years (range 20-83). The overall prevalence of triple-negative cases among the initial patient group with invasive breast cancer was 8%. BRCA1 was screened by direct DNA sequencing in all patients, including all exons where a mutation was previously found in the Greek population (exons 5, 11, 12, 16, 20, 21, 22, 23, 24-77% of the BRCA1 coding region), including diagnostic PCRs to detect the three Greek founder large genomic rearrangements. Sixty-five deleterious BRCA1 mutations were identified among the 403 triple-negative breast cancer patients (16%). Median age of onset for mutation carriers was 39 years. Among a total of 106 women with early-onset triple-negative breast cancer (<40 years), 38 (36%) had a BRCA1 mutation, while 27% of women with triple-negative breast cancer diagnosed before 50 years (56/208) had a BRCA1 mutation. A mutation was found in 48% (50/105) of the triple-negative breast cancer patients with family history of breast or ovarian cancer. It is noteworthy, however, that of the 65 carriers, 15 (23%) had no reported family history of related cancers. All but one of the carriers had grade III tumors (98%). These results indicate that women with early-onset triple-negative breast cancer, and ideally all triple-negative breast cancer patients, are candidates for BRCA1 genetic testing even in the absence of a family history of breast or ovarian cancer.

  15. Identification of KLHL41 Mutations Implicates BTB-Kelch-Mediated Ubiquitination as an Alternate Pathway to Myofibrillar Disruption in Nemaline Myopathy

    OpenAIRE

    Gupta, Vandana A.; Ravenscroft, Gianina; Shaheen, Ranad; Todd, Emily J.; Swanson, Lindsay C.; Shiina, Masaaki; Ogata, Kazuhiro; Hsu, Cynthia; Clarke, Nigel F.; Darras, Basil T.; Farrar, Michelle A.; Hashem, Amal; Manton, Nicholas D.; Muntoni, Francesco; North, Kathryn N.

    2013-01-01

    Nemaline myopathy (NM) is a rare congenital muscle disorder primarily affecting skeletal muscles that results in neonatal death in severe cases as a result of associated respiratory insufficiency. NM is thought to be a disease of sarcomeric thin filaments as six of eight known genes whose mutation can cause NM encode components of that structure, however, recent discoveries of mutations in non-thin filament genes has called this model in question. We performed whole-exome sequencing and have ...

  16. Agro-ecosystem and socio-economic role of homegarden agroforestry in Jabithenan District, North-Western Ethiopia: implication for climate change adaptation.

    Science.gov (United States)

    Linger, Ewuketu

    2014-01-01

    Homegarden agroforestry is believed to be more diverse and provide multiple services for household than other monocropping system and this is due to the combination of crops, trees and livestock. The aim of this study was to assess socio-economic and agro-ecological role of homegardens in Jabithenan district, North-western Ethiopia. Two sites purposively and two villages randomly from each site were selected. Totally 96 households; in which 48 from homegarden agroforestry user and 48 from non-tree based garden user were selected for this study. Socio-economic data and potential economic and agro-ecosystem role of homegarden agroforestry over non-tree based garden were collected by using semi-structured and structured questionnaires to the households. Homegarden agroforestry significantly (P homegarden agroforestry practice provides good socio-economical and agro-ecological service for farmers which have a higher implication for climate change adaptation than non-tree based garden.

  17.  Mutations of noncollagen genes in osteogenesis imperfecta – implications of the gene products in collagen biosynthesis and pathogenesis of disease

    Directory of Open Access Journals (Sweden)

    Anna Galicka

    2012-06-01

    Full Text Available  Recent investigations revealed that the “brittle bone” phenotype in osteogenesis imperfecta (OI is caused not only by dominant mutations in collagen type I genes, but also by recessively inherited mutations in genes responsible for the post-translational processing of type I procollagen as well as for bone formation. The phenotype of patients with mutations in noncollagen genes overlaps with very severe type III and lethal type II OI caused by mutations in collagen genes. Mutations in genes that encode proteins involved in collagen prolyl 3-hydroxylation (P3H1/CRTAP/CyPB eliminated Pro986 hydroxylation and caused an increase in modification of collagen helix by prolyl 4-hydroxylase and lysyl hydroxylase. However, the importance of these disturbances in the disease pathomechanism is not known. Loss of complex proteins’ function as collagen chaperones may dominate the disease mechanism. The latest findings added to the spectrum of OI-causing and collagen-influencing factors other chaperones (HSP47 and FKBP65 and protein BMP-1, which emphasizes the complexity of collagen folding and secretion as well as their importance in bone formation. Furthermore, mutations in genes encoding transcription factor SP7/Osterix and pigment epithelium-derived factor (PEDF constitute a novel mechanism for OI, which is independent of changes in biosynthesis and processing of collagen.

  18. Stoichiometric imbalances between terrestrial decomposer communities and their resources: mechanisms and implications of microbial adaptations to their resources

    Directory of Open Access Journals (Sweden)

    Maria eMooshammer

    2014-02-01

    Full Text Available Terrestrial microbial decomposer communities thrive on a wide range of organic matter types that rarely ever meet their elemental demands. In this review we synthesize the current state-of-the-art of microbial adaptations to resource stoichiometry, in order to gain a deeper understanding of the interactions between heterotrophic microbial communities and their chemical environment. The stoichiometric imbalance between microbial communities and their organic substrates generally decreases from wood to leaf litter and further to topsoil and subsoil organic matter. Microbial communities can respond to these imbalances in four ways: first, they adapt their biomass composition towards their resource in a non-homeostatic behaviour. Such changes are, however, only moderate, and occur mainly because of changes in microbial community structure and less so due to cellular storage of elements in excess. Second, microbial communities can mobilize resources that meet their elemental demand by producing specific extracellular enzymes, which, in turn, is restricted by the C and N requirement for enzyme production itself. Third, microbes can regulate their element use efficiencies (ratio of element invested in growth over total element uptake, such that they release elements in excess depending on their demand (e.g., respiration and N mineralization. Fourth, diazotrophic bacteria and saprotrophic fungi may trigger the input of external N and P to decomposer communities. Theoretical considerations show that adjustments in element use efficiencies may be the most important mechanism by which microbes regulate their biomass stoichiometry. This review summarizes different views on how microbes cope with imbalanced supply of C, N and P, thereby providing a framework for integrating and linking microbial adaptation to resource imbalances to ecosystem scale fluxes across scales and ecosystems.

  19. Molecular evolution of the hyaluronan synthase 2 gene in mammals: implications for adaptations to the subterranean niche and cancer resistance.

    Science.gov (United States)

    Faulkes, Christopher G; Davies, Kalina T J; Rossiter, Stephen J; Bennett, Nigel C

    2015-05-01

    The naked mole-rat (NMR) Heterocephalus glaber is a unique and fascinating mammal exhibiting many unusual adaptations to a subterranean lifestyle. The recent discovery of their resistance to cancer and exceptional longevity has opened up new and important avenues of research. Part of this resistance to cancer has been attributed to the fact that NMRs produce a modified form of hyaluronan--a key constituent of the extracellular matrix--that is thought to confer increased elasticity of the skin as an adaptation for living in narrow tunnels. This so-called high molecular mass hyaluronan (HMM-HA) stems from two apparently unique substitutions in the hyaluronan synthase 2 enzyme (HAS2). To test whether other subterranean mammals with similar selection pressures also show molecular adaptation in their HAS2 gene, we sequenced the HAS2 gene for 11 subterranean mammals and closely related species, and combined these with data from 57 other mammals. Comparative screening revealed that one of the two putatively important HAS2 substitutions in the NMR predicted to have a significant effect on hyaluronan synthase function was uniquely shared by all African mole-rats. Interestingly, we also identified multiple other amino acid substitutions in key domains of the HAS2 molecule, although the biological consequences of these for hyaluronan synthesis remain to be determined. Despite these results, we found evidence of strong purifying selection acting on the HAS2 gene across all mammals, and the NMR remains unique in its particular HAS2 sequence. Our results indicate that more work is needed to determine whether the apparent cancer resistance seen in NMR is shared by other members of the African mole-rat clade. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

  20. Impacts of Climate Change on Vector Borne Diseases in the Mediterranean Basin - Implications for Preparedness and Adaptation Policy.

    Science.gov (United States)

    Negev, Maya; Paz, Shlomit; Clermont, Alexandra; Pri-Or, Noemie Groag; Shalom, Uri; Yeger, Tamar; Green, Manfred S

    2015-06-15

    The Mediterranean region is vulnerable to climatic changes. A warming trend exists in the basin with changes in rainfall patterns. It is expected that vector-borne diseases (VBD) in the region will be influenced by climate change since weather conditions influence their emergence. For some diseases (i.e., West Nile virus) the linkage between emergence andclimate change was recently proved; for others (such as dengue) the risk for local transmission is real. Consequently, adaptation and preparation for changing patterns of VBD distribution is crucial in the Mediterranean basin. We analyzed six representative Mediterranean countries and found that they have started to prepare for this threat, but the preparation levels among them differ, and policy mechanisms are limited and basic. Furthermore, cross-border cooperation is not stable and depends on international frameworks. The Mediterranean countries should improve their adaptation plans, and develop more cross-sectoral, multidisciplinary and participatory approaches. In addition, based on experience from existing local networks in advancing national legislation and trans-border cooperation, we outline recommendations for a regional cooperation framework. We suggest that a stable and neutral framework is required, and that it should address the characteristics and needs of African, Asian and European countries around the Mediterranean in order to ensure participation. Such a regional framework is essential to reduce the risk of VBD transmission, since the vectors of infectious diseases know no political borders.

  1. Photosystem II Photochemistry and Phycobiliprotein of the Red Algae Kappaphycus alvarezii and Their Implications for Light Adaptation

    Directory of Open Access Journals (Sweden)

    Xiangyu Guan

    2013-01-01

    Full Text Available Photosystem II photochemistry and phycobiliprotein (PBP genes of red algae Kappaphycus alvarezii, raw material of κ-carrageenan used in food and pharmaceutical industries, were analyzed in this study. Minimum saturating irradiance (Ik of this algal species was less than 115 μmol m−2 s−1. Its actual PSII efficiency (yield II increased when light intensity enhanced and decreased when light intensity reached 200 μmol m−2 s−1. Under dim light, yield II declined at first and then increased on the fourth day. Under high light, yield II retained a stable value. These results indicate that K. alvarezii is a low-light-adapted species but possesses regulative mechanisms in response to both excessive and deficient light. Based on the PBP gene sequences, K. alvarezii, together with other red algae, assembled faster and showed a closer relationship with LL-Prochlorococcus compared to HL-Prochlorococcus. Many amino acid loci in PBP sequences of K. alvarezii were conserved with those of LL-Prochlorococcus. However, loci conserved with HL-Prochlorococcus but divergent with LL-Prochlorococcus were also found. The diversities of PE and PC are proposed to have played some roles during the algal evolution and divergence of light adaption.

  2. Photosystem II photochemistry and phycobiliprotein of the red algae Kappaphycus alvarezii and their implications for light adaptation.

    Science.gov (United States)

    Guan, Xiangyu; Wang, Jinfeng; Zhu, Jianyi; Yao, Chunyan; Liu, Jianguo; Qin, Song; Jiang, Peng

    2013-01-01

    Photosystem II photochemistry and phycobiliprotein (PBP) genes of red algae Kappaphycus alvarezii, raw material of κ -carrageenan used in food and pharmaceutical industries, were analyzed in this study. Minimum saturating irradiance (I k) of this algal species was less than 115 μmol m(-2) s(-1). Its actual PSII efficiency (yield II) increased when light intensity enhanced and decreased when light intensity reached 200 μmol m(-2) s(-1). Under dim light, yield II declined at first and then increased on the fourth day. Under high light, yield II retained a stable value. These results indicate that K. alvarezii is a low-light-adapted species but possesses regulative mechanisms in response to both excessive and deficient light. Based on the PBP gene sequences, K. alvarezii, together with other red algae, assembled faster and showed a closer relationship with LL-Prochlorococcus compared to HL-Prochlorococcus. Many amino acid loci in PBP sequences of K. alvarezii were conserved with those of LL-Prochlorococcus. However, loci conserved with HL-Prochlorococcus but divergent with LL-Prochlorococcus were also found. The diversities of PE and PC are proposed to have played some roles during the algal evolution and divergence of light adaption.

  3. Dark-adaptation functions in molecularly confirmed achromatopsia and the implications for assessment in retinal therapy trials.

    Science.gov (United States)

    Aboshiha, Jonathan; Luong, Vy; Cowing, Jill; Dubis, Adam M; Bainbridge, James W; Ali, Robin R; Webster, Andrew R; Moore, Anthony T; Fitzke, Frederick W; Michaelides, Michel

    2014-08-28

    To describe the dark-adaptation (DA) functions in subjects with molecularly proven achromatopsia (ACHM) using refined testing conditions with a view to guiding assessment in forthcoming gene therapy trials. The DA functions of nine subjects with ACHM were measured and compared with those of normal observers. The size and retinal location of the stimuli used to measure DA sensitivities were varied in four distinct testing condition sets, and the effect of altering these parameters assessed. In three of the four testing condition sets, achromats had significantly higher mean final thresholds than normal observers, whereas in the fourth condition set they did not. A larger, more central stimulus revealed the greatest difference between the final DA thresholds of achromat and normal subjects, and also demonstrated the slowest rate of recovery among the achromat group. In this, the largest study of DA functions in molecularly proven ACHM to date, we have identified optimal testing conditions that accentuate the relative difference between achromats and normal observers. These findings can help optimize DA testing in future trials, as well as help resolve the dichotomy in the literature regarding the normality or otherwise of DA functions in ACHM. Furthermore, the shorter testing time and less intense adaptation light used in these experiments may prove advantageous for more readily and reliably probing scotopic function in retinal disease, and be particularly valuable in the frequent post therapeutic assessments required in the context of the marked photophobia in ACHM. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

  4. Impacts of Climate Change on Vector Borne Diseases in the Mediterranean Basin — Implications for Preparedness and Adaptation Policy

    Directory of Open Access Journals (Sweden)

    Maya Negev

    2015-06-01

    Full Text Available The Mediterranean region is vulnerable to climatic changes. A warming trend exists in the basin with changes in rainfall patterns. It is expected that vector-borne diseases (VBD in the region will be influenced by climate change since weather conditions influence their emergence. For some diseases (i.e., West Nile virus the linkage between emergence andclimate change was recently proved; for others (such as dengue the risk for local transmission is real. Consequently, adaptation and preparation for changing patterns of VBD distribution is crucial in the Mediterranean basin. We analyzed six representative Mediterranean countries and found that they have started to prepare for this threat, but the preparation levels among them differ, and policy mechanisms are limited and basic. Furthermore, cross-border cooperation is not stable and depends on international frameworks. The Mediterranean countries should improve their adaptation plans, and develop more cross-sectoral, multidisciplinary and participatory approaches. In addition, based on experience from existing local networks in advancing national legislation and trans-border cooperation, we outline recommendations for a regional cooperation framework. We suggest that a stable and neutral framework is required, and that it should address the characteristics and needs of African, Asian and European countries around the Mediterranean in order to ensure participation. Such a regional framework is essential to reduce the risk of VBD transmission, since the vectors of infectious diseases know no political borders.

  5. The number of CGG repeats of the FMR1 locus in premutated and fully mutated heterozygotes and their offspring: Implications for the origin of mosaicism

    Energy Technology Data Exchange (ETDEWEB)

    Mingroni-Netto, R.C.; Vianna-Morgante, A.M. [Universidade de Sao Paulo (Brazil); Haddad, L.A. [Universidade Federal de Minas Gerais (Brazil)

    1996-08-09

    The size of the CGG repeat of the FMRl gene was investigated with probe StB12.3 in 154 transmissions to the offspring of heterozygotes for the premutation and the full mutation. Among the 135 offspring of premutated heterozygotes there were three decreases in size of the repeats: in two of these cases a full mutation was present along with the decreased premutation, and in a third mosaic (46,fra(X)(q27.3),Y), a normal allele was observed. In the 19 offspring of fully mutated females with no detected mosaicism, there were three mosaics and three individuals who had full mutations that included a number of repeats smaller than those present in their mothers. Among the 32 offspring who received a premutation from their premutated mothers, 27 alleles were increased in size and 5 remained unaltered. Among 11 mosaic offspring of premutated mothers, the premutation increased in 4, decreased in 3, and was unchanged in 4. In contrast to the trend of an increasing premutation size in the non-mosaic offspring, the premutation present in mosaics can be smaller, larger, or of unaltered size with approximately equal frequencies. These data suggest that the premutations present in mosaics result from mitotic instability of the inherited full mutations. This is further supported by the finding of a mosaic male with a normal sized allele. 17 refs., 3 figs., 1 tab.

  6. Transformation of the mechanism of triple-helix peptide folding in the absence of a C-terminal nucleation domain and its implications for mutations in collagen disorders.

    Science.gov (United States)

    Buevich, Alexei V; Silva, Teresita; Brodsky, Barbara; Baum, Jean

    2004-11-05

    Folding abnormalities of the triple helix have been demonstrated in collagen diseases such as osteogenesis imperfecta in which the mutation leads to the substitution of a single Gly in the (Gly-X-Y)n sequence pattern by a larger residue. Model peptides can be used to clarify the details of normal collagen folding and the consequences of the interruption of that folding by a Gly substitution. NMR and CD studies show that placement of a (GPO)4 nucleation domain at the N terminus rather than the C terminus of a native collagen sequence allows the formation of a stable triple helix but alters the folding mechanism. Although C- to N-terminal directional folding occurs when the nucleation domain is at the C terminus, there is no preferential folding direction when the nucleation domain is at the N terminus. The lack of zipper-like directional folding does not interfere with triple-helix formation, and when a Gly residue is replaced by Ser to model an osteogenesis imperfecta mutation, the peptide with the N-terminal (GPO)4 domain can still form a good triple helix N-terminal to the mutation site. These peptide studies raise the possibility that mutant collagen could fold in a C to N direction in a zipper-like manner up to the mutation site and that completion of the triple helix N-terminal to the mutation would involve an alternative mechanism.

  7. Sheep grazing causes shift in sex ratio and cohort structure of Brandt's vole: Implication of their adaptation to food shortage.

    Science.gov (United States)

    Li, Guoliang; Hou, Xianglei; Wan, Xinrong; Zhang, Zhibin

    2016-01-01

    Livestock grazing has been demonstrated to affect the population abundance of small rodents in grasslands, but the causative mechanism of grazing on demographic parameters, particularly the age structure and sex ratio, is rarely investigated. In this study, we examined the effects of sheep grazing on the cohort structure and sex ratio of Brandt's vole (Lasiopodomys brandtii) in Inner Mongolia of China by using large manipulative experimental enclosures during 2010-2013. Our results indicated that sheep grazing significantly decreased the proportion of the spring-born cohort, but increased the proportion of the summer-born cohort. Grazing increased the proportion of males in both spring and summer cohorts. In addition, we found a negative relation between population density and the proportion of the overwinter cohort. Our results suggest that a shift in the cohort structure and the sex ratio may be an important strategy for small rodents to adapt to changes in food resources resulting from livestock grazing.

  8. Modeled Sea Level Rise Impacts on Coastal Ecosystems at Six Major Estuaries on Florida's Gulf Coast: Implications for Adaptation Planning.

    Science.gov (United States)

    Geselbracht, Laura L; Freeman, Kathleen; Birch, Anne P; Brenner, Jorge; Gordon, Doria R

    2015-01-01

    The Sea Level Affecting Marshes Model (SLAMM) was applied at six major estuaries along Florida's Gulf Coast (Pensacola Bay, St. Andrews/Choctawhatchee Bays, Apalachicola Bay, Southern Big Bend, Tampa Bay and Charlotte Harbor) to provide quantitative and spatial information on how coastal ecosystems may change with sea level rise (SLR) and to identify how this information can be used to inform adaption planning. High resolution LiDAR-derived elevation data was utilized under three SLR scenarios: 0.7 m, 1 m and 2 m through the year 2100 and uncertainty analyses were conducted on selected input parameters at three sites. Results indicate that the extent, spatial orientation and relative composition of coastal ecosystems at the study areas may substantially change with SLR. Under the 1 m SLR scenario, total predicted impacts for all study areas indicate that coastal forest (-69,308 ha; -18%), undeveloped dry land (-28,444 ha; -2%) and tidal flat (-25,556 ha; -47%) will likely face the greatest loss in cover by the year 2100. The largest potential gains in cover were predicted for saltmarsh (+32,922 ha; +88%), transitional saltmarsh (+23,645 ha; na) and mangrove forest (+12,583 ha; +40%). The Charlotte Harbor and Tampa Bay study areas were predicted to experience the greatest net loss in coastal wetlands The uncertainty analyses revealed low to moderate changes in results when some numerical SLAMM input parameters were varied highlighting the value of collecting long-term sedimentation, accretion and erosion data to improve SLAMM precision. The changes predicted by SLAMM will affect exposure of adjacent human communities to coastal hazards and ecosystem functions potentially resulting in impacts to property values, infrastructure investment and insurance rates. The results and process presented here can be used as a guide for communities vulnerable to SLR to identify and prioritize adaptation strategies that slow and/or accommodate the changes underway.

  9. Modeled Sea Level Rise Impacts on Coastal Ecosystems at Six Major Estuaries on Florida's Gulf Coast: Implications for Adaptation Planning.

    Directory of Open Access Journals (Sweden)

    Laura L Geselbracht

    Full Text Available The Sea Level Affecting Marshes Model (SLAMM was applied at six major estuaries along Florida's Gulf Coast (Pensacola Bay, St. Andrews/Choctawhatchee Bays, Apalachicola Bay, Southern Big Bend, Tampa Bay and Charlotte Harbor to provide quantitative and spatial information on how coastal ecosystems may change with sea level rise (SLR and to identify how this information can be used to inform adaption planning. High resolution LiDAR-derived elevation data was utilized under three SLR scenarios: 0.7 m, 1 m and 2 m through the year 2100 and uncertainty analyses were conducted on selected input parameters at three sites. Results indicate that the extent, spatial orientation and relative composition of coastal ecosystems at the study areas may substantially change with SLR. Under the 1 m SLR scenario, total predicted impacts for all study areas indicate that coastal forest (-69,308 ha; -18%, undeveloped dry land (-28,444 ha; -2% and tidal flat (-25,556 ha; -47% will likely face the greatest loss in cover by the year 2100. The largest potential gains in cover were predicted for saltmarsh (+32,922 ha; +88%, transitional saltmarsh (+23,645 ha; na and mangrove forest (+12,583 ha; +40%. The Charlotte Harbor and Tampa Bay study areas were predicted to experience the greatest net loss in coastal wetlands The uncertainty analyses revealed low to moderate changes in results when some numerical SLAMM input parameters were varied highlighting the value of collecting long-term sedimentation, accretion and erosion data to improve SLAMM precision. The changes predicted by SLAMM will affect exposure of adjacent human communities to coastal hazards and ecosystem functions potentially resulting in impacts to property values, infrastructure investment and insurance rates. The results and process presented here can be used as a guide for communities vulnerable to SLR to identify and prioritize adaptation strategies that slow and/or accommodate the changes underway.

  10. Driven by Mutations: The Predictive Value of Mutation Subtype in EGFR-Mutated Non-Small Cell Lung Cancer.

    Science.gov (United States)

    Castellanos, Emily; Feld, Emily; Horn, Leora

    2016-12-23

    EGFR-mutated NSCLC is a genetically heterogeneous disease that includes more than 200 distinct mutations. The implications of mutational subtype for both prognostic and predictive value are being increasingly understood. Although the most common EGFR mutations-exon 19 deletions or L858R mutations-predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs), it is now being recognized that outcomes may be improved in patients with exon 19 deletions. Additionally, 10% of patients will have an uncommon EGFR mutation, and response to EGFR TKI therapy is highly variable depending on the mutation. Given the growing recognition of the genetic and clinical variation seen in this disease, the development of comprehensive bioinformatics-driven tools to both analyze response in uncommon mutation subtypes and inform clinical decision making will be increasingly important. Clinical trials of novel EGFR TKIs should prospectively account for the presence of uncommon mutation subtypes in study design.

  11. Dengue type four viruses with E-Glu345Lys adaptive mutation from MRC-5 cells induce low viremia but elicit potent neutralizing antibodies in rhesus monkeys.

    Science.gov (United States)

    Lin, Hsiao-Han; Lee, Hsiang-Chi; Li, Xiao-Feng; Tsai, Meng-Ju; Hsiao, Hung-Ju; Peng, Jia-Guan; Sue, Shih-Che; Qin, Cheng-Feng; Wu, Suh-Chin

    2014-01-01

    Knowledge of virulence and immunogenicity is important for development of live-attenuated dengue vaccines. We previously reported that an infectious clone-derived dengue type 4 virus (DENV-4) passaged in MRC-5 cells acquired a Glu345Lys (E-E345K) substitution in the E protein domain III (E-DIII). The same cloned DENV-4 was found to yield a single E-Glu327Gly (E-E327G) mutation after passage in FRhL cells and cause the loss of immunogenicity in rhesus monkeys. Here, we used site-directed mutagenesis to generate the E-E345K and E-E327G mutants from DENV-4 and DENV-4Δ30 infectious clones and propagated in Vero or MRC-5 cells. The E-E345K mutations were consistently presented in viruses recovered from MRC-5 cells, but not Vero cells. Recombinant E-DIII proteins of E345K and E327G increased heparin binding correlated with the reduced infectivity by heparin treatment in cell cultures. Different from the E-E327G mutant viruses to lose the immunogencity in rhesus monkeys, the E-E345K mutant viruses were able to induce neutralizing antibodies in rhesus monkeys with an almost a 10-fold lower level of viremia as compared to the wild type virus. Monkeys immunized with the E-E345K mutant virus were completely protected with no detectable viremia after live virus challenges with the wild type DENV-4. These results suggest that the E-E345K mutant virus propagated in MRC-5 cells may have potential for the use in live-attenuated DENV vaccine development.

  12. Calreticulin Mutations in Myeloproliferative Neoplasms

    Directory of Open Access Journals (Sweden)

    Noa Lavi

    2014-10-01

    Full Text Available With the discovery of the JAK2V617F mutation in patients with Philadelphia chromosome-negative (Ph− myeloproliferative neoplasms (MPNs in 2005, major advances have been made in the diagnosis of MPNs, in understanding of their pathogenesis involving the JAK/STAT pathway, and finally in the development of novel therapies targeting this pathway. Nevertheless, it remains unknown which mutations exist in approximately one-third of patients with non-mutated JAK2 or MPL essential thrombocythemia (ET and primary myelofibrosis (PMF. At the end of 2013, two studies identified recurrent mutations in the gene encoding calreticulin (CALR using whole-exome sequencing. These mutations were revealed in the majority of ET and PMF patients with non-mutated JAK2 or MPL but not in polycythemia vera patients. Somatic 52-bp deletions (type 1 mutations and recurrent 5-bp insertions (type 2 mutations in exon 9 of the CALR gene (the last exon encoding the C-terminal amino acids of the protein calreticulin were detected and found always to generate frameshift mutations. All detected mutant calreticulin proteins shared a novel amino acid sequence at the C-terminal. Mutations in CALR are acquired early in the clonal history of the disease, and they cause activation of JAK/STAT signaling. The CALR mutations are the second most frequent mutations in Ph− MPN patients after the JAK2V617F mutation, and their detection has significantly improved the diagnostic approach for ET and PMF. The characteristics of the CALR mutations as well as their diagnostic, clinical, and pathogenesis implications are discussed in this review.

  13. The spatial architecture of protein function and adaptation

    Science.gov (United States)

    McLaughlin, Richard N.; Poelwijk, Frank J.; Raman, Arjun; Gosal, Walraj S.; Ranganathan, Rama

    2014-01-01

    Statistical analysis of protein evolution suggests a design for natural proteins in which sparse networks of coevolving amino acids (termed sectors) comprise the essence of three-dimensional structure and function1, 2, 3, 4, 5. However, proteins are also subject to pressures deriving from the dynamics of the evolutionary process itself—the ability to tolerate mutation and to be adaptive to changing selection pressures6, 7, 8, 9, 10. To understand the relationship of the sector architecture to these properties, we developed a high-throughput quantitative method for a comprehensive single-mutation study in which every position is substituted individually to every other amino acid. Using a PDZ domain (PSD95pdz3) model system, we show that sector positions are functionally sensitive to mutation, whereas non-sector positions are more tolerant to substitution. In addition, we find that adaptation to a new binding specificity initiates exclusively through variation within sector residues. A combination of just two sector mutations located near and away from the ligand-binding site suffices to switch the binding specificity of PSD95pdz3 quantitatively towards a class-switching ligand. The localization of functional constraint and adaptive variation within the sector has important implications for understanding and engineering proteins. PMID:23041932

  14. Saccharomyces cerevisiae strain improvement using selection, mutation, and adaptation for the resistance to lignocellulose-derived fermentation inhibitor for ethanol production.

    Science.gov (United States)

    Jang, Youri; Lim, Younghoon; Kim, Keun

    2014-05-01

    Twenty-five Saccharomyces cerevisiae strains were screened for the highest sugar tolerance, ethanol-tolerance, ethanol production, and inhibitor resistance, and S. cerevisiae KL5 was selected as the best strain. Inhibitor cocktail (100%) was composed of 75 mM formic acid, 75 mM acetic acid, 30 mM furfural, 30 mM hydroxymethyl furfural (HMF), and 2.7 mM vanillin. The cells of strain KL5 were treated with γ-irradiation, and among the survivals, KL5- G2 with improved inhibitor resistance and the highest ethanol yield in the presence of inhibitor cocktail was selected. The KL5-G2 strain was adapted to inhibitor cocktail by sequential transfer of cultures to a minimal YNB medium containing increasing concentrations of inhibitor cocktail. After 10 times of adaptation, most of the isolated colonies could grow in YNB with 80% inhibitor cocktail, whereas the parental KL5 strain could not grow at all. Among the various adapted strains, the best strain (KL5-G2-A9) producing the highest ethanol yield in the presence of inhibitor cocktail was selected. In a complex YP medium containing 60% inhibitor cocktail and 5% glucose, the theoretical yield and productivity (at 48 h) of KL5- G2-A9 were 81.3% and 0.304 g/l/h, respectively, whereas those of KL5 were 20.8% and 0.072 g/l/h, respectively. KL5-G2-A9 reduced the concentrations of HMF, furfural, and vanillin in the medium in much faster rates than KL5.

  15. Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: Implications for risk prediction

    NARCIS (Netherlands)

    A.C. Antoniou (Antonis); J. Beesley (Jonathan); L. McGuffog (Lesley); O. Sinilnikova (Olga); S. Healey (Sue); S.L. Neuhausen (Susan); Y.C. Ding (Yuan); R. Rebbeck (Timothy); J.N. Weitzel (Jeffrey); H. Lynch (Henry); C. Isaacs (Claudine); P.A. Ganz (Patricia); G. Tomlinson (Gail); O.I. Olopade (Olofunmilayo); F.J. Couch (Fergus); X. Wang (Xing); N.M. Lindor (Noralane); V.S. Pankratz (Shane); P. Radice (Paolo); S. Manoukian (Siranoush); B. Peissel (Bernard); D. Zaffaroni (D.); M. Barile (Monica); A. Viel (Alessandra); A. Allavena (Anna); V. Dall'Olio (Valentina); P. Peterlongo (Paolo); C. Szabo (Csilla); M. Zikan (Michal); K. Claes (Kathleen); B. Poppe (Bruce); L. Foretova (Lenka); P.L. Mai (Phuong); M.H. Greene (Mark); G. Rennert (Gad); F. Lejbkowicz (Flavio); G. Glendon (Gord); H. Ozcelik (Hilmi); I.L. Andrulis (Irene); M. Thomassen (Mads); A-M. Gerdes (Anne-Marie); L. Sunde (Lone); D. Cruger (Dorthe); U.B. Jensen; M.A. Caligo (Maria); E. Friedman (Eitan); B. Kaufman (Bella); Y. Laitman (Yael); R. Milgrom (Roni); M. Dubrovsky (Maya); S. Cohen (Shimrit); Å. Borg (Åke); H. Jernström (H.); A. Lindblom (Annika); J. Rantala (Johanna); M. Stenmark-Askmalm (M.); B. Melin (Beatrice); K.L. Nathanson (Katherine); S.M. Domchek (Susan); A. Jakubowska (Anna); J. Lubinski (Jan); T. Huzarski (Tomasz); A. Osorio (Ana); A. Lasa (Adriana); M. Durán (Mercedes); M.I. Tejada; J. Godino (Javier); J. Benitez (Javier); U. Hamann (Ute); M. Kriege (Mieke); N. Hoogerbrugge (Nicoline); R.B. van der Luijt (Rob); C.J. van Asperen (Christi); P. Devilee (Peter); E.J. Meijers-Heijboer (Hanne); M.J. Blok (Marinus); C.M. Aalfs (Cora); F.B.L. Hogervorst (Frans); M.A. Rookus (Matti); M. Cook (Margaret); C.T. Oliver (Clare); D. Frost (Debra); D. Conroy (Don); D.G. Evans (Gareth); F. Lalloo (Fiona); G. Pichert (Gabriella); R. Davidson (Rosemarie); T.J. Cole (Trevor); J. Paterson (Joan); S.V. Hodgson (Shirley); P.J. Morrison (Patrick); M.E. Porteous (Mary); L.J. Walker (Lisa); M.J. Kennedy (John); H. Dorkins (Huw); S. Peock (Susan); A.K. Godwin (Andrew); D. Stoppa-Lyonnet (Dominique); A. de Pauw (Antoine); S. Mazoyer (Sylvie); V. Bonadona (Valérie); C. Lasset (Christine); H. Dreyfus (Hélène); D. Leroux (Dominique); A. hardouin (Agnès); P. Berthet (Pascaline); L. Faivre (Laurence); C. Loustalot (Catherine); T. Noguchi (Tetsuro); H. Sobol (Hagay); E. Rouleau (Etienne); C. Nogues (Catherine); M. Frenay (Marc); L. Vénat-Bouvet (Laurence); J. Hopper (John); M.J. Daly (Mark); M-B. Terry (Mary-beth); E.M. John (Esther); S.S. Buys (Saundra); Y. Yassin (Yosuf); A. Miron (Alexander); D. Goldgar (David); C.F. Singer (Christian); C. Dressler (Catherina); D. Gschwantler-Kaulich (Daphne); G. Pfeiler (Georg); T.V.O. Hansen (Thomas); L. Jnson (Lars); B.A. Agnarsson (Bjarni); T. Kircchoff (Tomas); K. Offit (Kenneth); V. Devlin (Vincent); A. Dutra-Clarke (Ana); M. Piedmonte (Marion); G.C. Rodriguez (Gustavo); K. Wakeley (Katie); J.F. Boggess (John); J. Basil (Jack); P.E. Schwartz (Peter); S.V. Blank (Stephanie); A.E. Toland (Amanda); M. Montagna (Marco); C. Casella (Cinzia); E.N. Imyanitov (Evgeny); L. Tihomirova (Laima); I. Blanco (Ignacio); C. Lazaro (Conxi); S.J. Ramus (Susan); L. Sucheston (Lara); B.Y. Karlan (Beth); J. Gross (Jenny); R.K. Schmutzler (Rita); B. Wapenschmidt (Barbara); C. Engel (Christoph); A. Meindl (Alfons); M. Lochmann (Magdalena); N. Arnold (Norbert); S. Heidemann (Simone); R. Varon-Mateeva (Raymonda); D. Niederacher (Dieter); C. Sutter (Christian); H. Deissler (Helmut); D. Gadzicki (Dorothea); S. Preisler-Adams (Sabine); K. Kast (Karin); I. Schönbuchner (Ines); T. Caldes (Trinidad); M. de La Hoya (Miguel); K. Aittomäki (Kristiina); H. Nevanlinna (Heli); J. Simard (Jacques); A.B. Spurdle (Amanda); H. Holland (Helene); G. Chenevix-Trench (Georgia); R. Platte (Radka); D.F. Easton (Douglas)

    2010-01-01

    textabstractThe known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10,

  16. Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: Implications for risk prediction

    NARCIS (Netherlands)

    A.C. Antoniou (Antonis); J. Beesley (Jonathan); L. McGuffog (Lesley); O. Sinilnikova (Olga); S. Healey (Sue); S.L. Neuhausen (Susan); Y.C. Ding (Yuan); R. Rebbeck (Timothy); J.N. Weitzel (Jeffrey); H. Lynch (Henry); C. Isaacs (Claudine); P.A. Ganz (Patricia); G. Tomlinson (Gail); O.I. Olopade (Olofunmilayo); F.J. Couch (Fergus); X. Wang (Xing); N.M. Lindor (Noralane); V.S. Pankratz (Shane); P. Radice (Paolo); S. Manoukian (Siranoush); B. Peissel (Bernard); D. Zaffaroni (D.); M. Barile (Monica); A. Viel (Alessandra); A. Allavena (Anna); V. Dall'Olio (Valentina); P. Peterlongo (Paolo); C. Szabo (Csilla); M. Zikan (Michal); K. Claes (Kathleen); B. Poppe (Bruce); L. Foretova (Lenka); P.L. Mai (Phuong); M.H. Greene (Mark); G. Rennert (Gad); F. Lejbkowicz (Flavio); G. Glendon (Gord); H. Ozcelik (Hilmi); I.L. Andrulis (Irene); M. Thomassen (Mads); A-M. Gerdes (Anne-Marie); L. Sunde (Lone); D. Cruger (Dorthe); U.B. Jensen; M.A. Caligo (Maria); E. Friedman (Eitan); B. Kaufman (Bella); Y. Laitman (Yael); R. Milgrom (Roni); M. Dubrovsky (Maya); S. Cohen (Shimrit); Å. Borg (Åke); H. Jernström (H.); A. Lindblom (Annika); J. Rantala (Johanna); M. Stenmark-Askmalm (M.); B. Melin (Beatrice); K.L. Nathanson (Katherine); S.M. Domchek (Susan); A. Jakubowska (Anna); J. Lubinski (Jan); T. Huzarski (Tomasz); A. Osorio (Ana); A. Lasa (Adriana); M. Durán (Mercedes); M.I. Tejada; J. Godino (Javier); J. Benitez (Javier); U. Hamann (Ute); M. Kriege (Mieke); N. Hoogerbrugge (Nicoline); R.B. van der Luijt (Rob); C.J. van Asperen (Christi); P. Devilee (Peter); E.J. Meijers-Heijboer (Hanne); M.J. Blok (Marinus); C.M. Aalfs (Cora); F.B.L. Hogervorst (Frans); M.A. Rookus (Matti); M. Cook (Margaret); C.T. Oliver (Clare); D. Frost (Debra); D. Conroy (Don); D.G. Evans (Gareth); F. Lalloo (Fiona); G. Pichert (Gabriella); R. Davidson (Rosemarie); T.J. Cole (Trevor); J. Paterson (Joan); S.V. Hodgson (Shirley); P.J. Morrison (Patrick); M.E. Porteous (Mary); L.J. Walker (Lisa); M.J. Kennedy (John); H. Dorkins (Huw); S. Peock (Susan); A.K. Godwin (Andrew); D. Stoppa-Lyonnet (Dominique); A. de Pauw (Antoine); S. Mazoyer (Sylvie); V. Bonadona (Valérie); C. Lasset (Christine); H. Dreyfus (Hélène); D. Leroux (Dominique); A. hardouin (Agnès); P. Berthet (Pascaline); L. Faivre (Laurence); C. Loustalot (Catherine); T. Noguchi (Tetsuro); H. Sobol (Hagay); E. Rouleau (Etienne); C. Nogues (Catherine); M. Frenay (Marc); L. Vénat-Bouvet (Laurence); J. Hopper (John); M.J. Daly (Mark); M-B. Terry (Mary-beth); E.M. John (Esther); S.S. Buys (Saundra); Y. Yassin (Yosuf); A. Miron (Alexander); D. Goldgar (David); C.F. Singer (Christian); C. Dressler (Catherina); D. Gschwantler-Kaulich (Daphne); G. Pfeiler (Georg); T.V.O. Hansen (Thomas); L. Jnson (Lars); B.A. Agnarsson (Bjarni); T. Kircchoff (Tomas); K. Offit (Kenneth); V. Devlin (Vincent); A. Dutra-Clarke (Ana); M. Piedmonte (Marion); G.C. Rodriguez (Gustavo); K. Wakeley (Katie); J.F. Boggess (John); J. Basil (Jack); P.E. Schwartz (Peter); S.V. Blank (Stephanie); A.E. Toland (Amanda); M. Montagna (Marco); C. Casella (Cinzia); E.N. Imyanitov (Evgeny); L. Tihomirova (Laima); I. Blanco (Ignacio); C. Lazaro (Conxi); S.J. Ramus (Susan); L. Sucheston (Lara); B.Y. Karlan (Beth); J. Gross (Jenny); R.K. Schmutzler (Rita); B. Wapenschmidt (Barbara); C. Engel (Christoph); A. Meindl (Alfons); M. Lochmann (Magdalena); N. Arnold (Norbert); S. Heidemann (Simone); R. Varon-Mateeva (Raymonda); D. Niederacher (Dieter); C. Sutter (Christian); H. Deissler (Helmut); D. Gadzicki (Dorothea); S. Preisler-Adams (Sabine); K. Kast (Karin); I. Schönbuchner (Ines); T. Caldes (Trinidad); M. de La Hoya (Miguel); K. Aittomäki (Kristiina); H. Nevanlinna (Heli); J. Simard (Jacques); A.B. Spurdle (Amanda); H. Holland (Helene); G. Chenevix-Trench (Georgia); R. Platte (Radka); D.F. Easton (Douglas)

    2010-01-01

    textabstractThe known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10,

  17. Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Beesley, Jonathan; McGuffog, Lesley;

    2010-01-01

    The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs650495...

  18. Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers : Implications for Risk Prediction

    NARCIS (Netherlands)

    Antoniou, Antonis C.; Beesley, Jonathan; McGuffog, Lesley; Sinilnikova, Olga M.; Healey, Sue; Neuhausen, Susan L.; Ding, Yuan Chun; Rebbeck, Timothy R.; Weitzel, Jeffrey N.; Lynch, Henry T.; Isaacs, Claudine; Ganz, Patricia A.; Tomlinson, Gail; Olopade, Olufunmilayo I.; Couch, Fergus J.; Wang, Xianshu; Lindor, Noralane M.; Pankratz, Vernon S.; Radice, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Barile, Monica; Viel, Alessandra; Allavena, Anna; Dall'Olio, Valentina; Peterlongo, Paolo; Szabo, Csilla I.; Zikan, Michal; Claes, Kathleen; Poppe, Bruce; Foretova, Lenka; Mai, Phuong L.; Greene, Mark H.; Rennert, Gad; Lejbkowicz, Flavio; Glendon, Gord; Ozcelik, Hilmi; Andrulis, Irene L.; Thomassen, Mads; Gerdes, Anne-Marie; Sunde, Lone; Cruger, Dorthe; Jensen, Uffe Birk; Caligo, Maria; Friedman, Eitan; Kaufman, Bella; Laitman, Yael; Milgrom, Roni; Dubrovsky, Maya; Cohen, Shimrit; Borg, Ake; Jernstroem, Helena; Lindblom, Annika; Rantala, Johanna; Stenmark-Askmalm, Marie; Melin, Beatrice; Nathanson, Kate; Domchek, Susan; Jakubowska, Ania; Lubinski, Jan; Huzarski, Tomasz; Osorio, Ana; Lasa, Adriana; Duran, Mercedes; Tejada, Maria-Isabel; Godino, Javier; Benitez, Javier; Hamann, Ute; Kriege, Mieke; Hoogerbrugge, Nicoline; van der Luijt, Rob B.; van Asperen, Christi J.; Devilee, Peter; Meijers-Heijboer, E. J.; Blok, Marinus J.; Aalfs, Cora M.; Hogervorst, Frans; Rookus, Matti; Cook, Margaret; Oliver, Clare; Frost, Debra; Conroy, Don; Evans, D. Gareth; Lalloo, Fiona; Pichert, Gabriella; Davidson, Rosemarie; Cole, Trevor; Cook, Jackie; Paterson, Joan; Hodgson, Shirley; Morrison, Patrick J.; Porteous, Mary E.; Walker, Lisa; Kennedy, M. John; Dorkins, Huw; Peock, Susan; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; de Pauw, Antoine; Mazoyer, Sylvie; Bonadona, Valerie; Lasset, Christine; Dreyfus, Helene; Leroux, Dominique; Hardouin, Agnes; Berthet, Pascaline; Faivre, Laurence; Loustalot, Catherine; Noguchi, Tetsuro; Sobol, Hagay; Rouleau, Etienne; Nogues, Catherine; Frenay, Marc; Venat-Bouvet, Laurence; Hopper, John L.; Daly, Mary B.; Terry, Mary B.; John, Esther M.; Buys, Saundra S.; Yassin, Yosuf; Miron, Alexander; Goldgar, David; Singer, Christian F.; Dressler, Anne Catharina; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; Hansen, Thomas V. O.; Jnson, Lars; Agnarsson, Bjarni A.; Kirchhoff, Tomas; Offit, Kenneth; Devlin, Vincent; Dutra-Clarke, Ana; Piedmonte, Marion; Rodriguez, Gustavo C.; Wakeley, Katie; Boggess, John F.; Basil, Jack; Schwartz, Peter E.; Blank, Stephanie V.; Toland, Amanda Ewart; Montagna, Marco; Casella, Cinzia; Imyanitov, Evgeny; Tihomirova, Laima; Blanco, Ignacio; Lazaro, Conxi; Ramus, Susan J.; Sucheston, Lara; Karlan, Beth Y.; Gross, Jenny; Schmutzler, Rita; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Lochmann, Magdalena; Arnold, Norbert; Heidemann, Simone; Varon-Mateeva, Raymonda; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Dorothea; Preisler-Adams, Sabine; Kast, Karin; Schoenbuchner, Ines; Caldes, Trinidad; de la Hoya, Miguel; Aittomaeki, Kristiina; Nevanlinna, Heli; Simard, Jacques; Spurdle, Amanda B.; Holland, Helene; Chen, Xiaoqing; Platte, Radka; Chenevix-Trench, Georgia; Easton, Douglas F.

    2010-01-01

    The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 i

  19. Structural implications of a G170R mutation of alanine:glyoxylate aminotransferase that is associated with peroxisome-to-mitochondrion mistargeting

    OpenAIRE

    Djordjevic, Snezana; Zhang, Xiaoxuan; Bartlam, Mark; Ye, Sheng; Rao, Zihe; Danpure, Christopher J

    2010-01-01

    The crystal structure of the G170R mutant form of human alanine:glyoxylate aminotransferase has been determined at 2.6 Å resolution. This mutation is associated with enzyme mistargeting in the hereditary kidney-stone disease primary hyperoxaluria type 1.

  20. Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers : Implications for Risk Prediction

    NARCIS (Netherlands)

    Antoniou, Antonis C.; Beesley, Jonathan; McGuffog, Lesley; Sinilnikova, Olga M.; Healey, Sue; Neuhausen, Susan L.; Ding, Yuan Chun; Rebbeck, Timothy R.; Weitzel, Jeffrey N.; Lynch, Henry T.; Isaacs, Claudine; Ganz, Patricia A.; Tomlinson, Gail; Olopade, Olufunmilayo I.; Couch, Fergus J.; Wang, Xianshu; Lindor, Noralane M.; Pankratz, Vernon S.; Radice, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Barile, Monica; Viel, Alessandra; Allavena, Anna; Dall'Olio, Valentina; Peterlongo, Paolo; Szabo, Csilla I.; Zikan, Michal; Claes, Kathleen; Poppe, Bruce; Foretova, Lenka; Mai, Phuong L.; Greene, Mark H.; Rennert, Gad; Lejbkowicz, Flavio; Glendon, Gord; Ozcelik, Hilmi; Andrulis, Irene L.; Thomassen, Mads; Gerdes, Anne-Marie; Sunde, Lone; Cruger, Dorthe; Jensen, Uffe Birk; Caligo, Maria; Friedman, Eitan; Kaufman, Bella; Laitman, Yael; Milgrom, Roni; Dubrovsky, Maya; Cohen, Shimrit; Borg, Ake; Jernstroem, Helena; Lindblom, Annika; Rantala, Johanna; Stenmark-Askmalm, Marie; Melin, Beatrice; Nathanson, Kate; Domchek, Susan; Jakubowska, Ania; Lubinski, Jan; Huzarski, Tomasz; Osorio, Ana; Lasa, Adriana; Duran, Mercedes; Tejada, Maria-Isabel; Godino, Javier; Benitez, Javier; Hamann, Ute; Kriege, Mieke; Hoogerbrugge, Nicoline; van der Luijt, Rob B.; van Asperen, Christi J.; Devilee, Peter; Meijers-Heijboer, E. J.; Blok, Marinus J.; Aalfs, Cora M.; Hogervorst, Frans; Rookus, Matti; Cook, Margaret; Oliver, Clare; Frost, Debra; Conroy, Don; Evans, D. Gareth; Lalloo, Fiona; Pichert, Gabriella; Davidson, Rosemarie; Cole, Trevor; Cook, Jackie; Paterson, Joan; Hodgson, Shirley; Morrison, Patrick J.; Porteous, Mary E.; Walker, Lisa; Kennedy, M. John; Dorkins, Huw; Peock, Susan; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; de Pauw, Antoine; Mazoyer, Sylvie; Bonadona, Valerie; Lasset, Christine; Dreyfus, Helene; Leroux, Dominique; Hardouin, Agnes; Berthet, Pascaline; Faivre, Laurence; Loustalot, Catherine; Noguchi, Tetsuro; Sobol, Hagay; Rouleau, Etienne; Nogues, Catherine; Frenay, Marc; Venat-Bouvet, Laurence; Hopper, John L.; Daly, Mary B.; Terry, Mary B.; John, Esther M.; Buys, Saundra S.; Yassin, Yosuf; Miron, Alexander; Goldgar, David; Singer, Christian F.; Dressler, Anne Catharina; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; Hansen, Thomas V. O.; Jnson, Lars; Agnarsson, Bjarni A.; Kirchhoff, Tomas; Offit, Kenneth; Devlin, Vincent; Dutra-Clarke, Ana; Piedmonte, Marion; Rodriguez, Gustavo C.; Wakeley, Katie; Boggess, John F.; Basil, Jack; Schwartz, Peter E.; Blank, Stephanie V.; Toland, Amanda Ewart; Montagna, Marco; Casella, Cinzia; Imyanitov, Evgeny; Tihomirova, Laima; Blanco, Ignacio; Lazaro, Conxi; Ramus, Susan J.; Sucheston, Lara; Karlan, Beth Y.; Gross, Jenny; Schmutzler, Rita; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Lochmann, Magdalena; Arnold, Norbert; Heidemann, Simone; Varon-Mateeva, Raymonda; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Dorothea; Preisler-Adams, Sabine; Kast, Karin; Schoenbuchner, Ines; Caldes, Trinidad; de la Hoya, Miguel; Aittomaeki, Kristiina; Nevanlinna, Heli; Simard, Jacques; Spurdle, Amanda B.; Holland, Helene; Chen, Xiaoqing; Platte, Radka; Chenevix-Trench, Georgia; Easton, Douglas F.

    2010-01-01

    The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 i

  1. Assessing Climate Vulnerabilities of Food Distribution Center Sites in Greater Boston and Their Regional Implications: Climate Adaptation Planning in Practice

    Science.gov (United States)

    Teferra, A.; Watson, C.; Douglas, E. M.

    2016-12-01

    The Metro Boston region, an area whose civic leaders have been at the forefront of climate resilience initiatives in recent years, is finalizing a flood vulnerability assessment of food distribution center sites located north of Boston, with the support of the University of Massachusetts Boston and the American Geophysical Union's Thriving Earth Exchange program. The community-scientist collaboration emerged because of the need for more local analyses of the area to inform climate resiliency policy and planning actions for the region. A significant amount of the metro region's food supply passes through two major distribution centers in the cities of Everett and Chelsea, just north of the Mystic River. The Metropolitan Area Planning Council (MAPC), on behalf of the Metro Boston Climate Preparedness Taskforce, is working with Chris Watson and Ellen Douglas of UMass Boston to build on existing analyses of the region's food system and climate vulnerabilities and to develop a report identifying flood risk exposure to the sites. The analysis brings in dynamic modeling techniques that incorporate storm surge and sea level rise projections under different climate scenarios, and aims to align methodologies with those of other regional analyses, such as Climate Ready Boston and the City of Cambridge's Vulnerability Assessment. The study is helping to inform MAPC's and the Metro Boston Climate Preparedness Taskforce's understanding of this critical food distribution infrastructure, illustrate the larger regional implications of climate impacts on food distribution in the Greater Boston area, and guide the development of site-specific strategies for addressing identified vulnerabilities.

  2. Adaptation of high-growth influenza H5N1 vaccine virus in Vero cells: implications for pandemic preparedness.

    Directory of Open Access Journals (Sweden)

    Yu-Fen Tseng

    Full Text Available Current egg-based influenza vaccine production technology can't promptly meet the global demand during an influenza pandemic as shown in the 2009 H1N1 pandemic. Moreover, its manufacturing capacity would be vulnerable during pandemics caused by highly pathogenic avian influenza viruses. Therefore, vaccine production using mammalian cell technology is becoming attractive. Current influenza H5N1 vaccine strain (NIBRG-14, a reassortant virus between A/Vietnam/1194/2004 (H5N1 virus and egg-adapted high-growth A/PR/8/1934 virus, could grow efficiently in eggs and MDCK cells but not Vero cells which is the most popular cell line for manufacturing human vaccines. After serial passages and plaque purifications of the NIBRG-14 vaccine virus in Vero cells, one high-growth virus strain (Vero-15 was generated and can grow over 10(8 TCID(50/ml. In conclusion, one high-growth H5N1 vaccine virus was generated in Vero cells, which can be used to manufacture influenza H5N1 vaccines and prepare reassortant vaccine viruses for other influenza A subtypes.

  3. Collaborative implementation for ecological restoration on US Public Lands: implications for legal context, accountability, and adaptive management.

    Science.gov (United States)

    Butler, William H; Monroe, Ashley; McCaffrey, Sarah

    2015-03-01

    The Collaborative Forest Landscape Restoration Program (CFLRP), established in 2009, encourages collaborative landscape scale ecosystem restoration efforts on United States Forest Service (USFS) lands. Although the USFS employees have experience engaging in collaborative planning, CFLRP requires collaboration in implementation, a domain where little prior experience can be drawn on for guidance. The purpose of this research is to identify the ways in which CFLRP's collaborative participants and agency personnel conceptualize how stakeholders can contribute to implementation on landscape scale restoration projects, and to build theory on dynamics of collaborative implementation in environmental management. This research uses a grounded theory methodology to explore collaborative implementation from the perspectives and experiences of participants in landscapes selected as part of the CFLRP in 2010. Interviewees characterized collaborative implementation as encompassing three different types of activities: prioritization, enhancing treatments, and multiparty monitoring. The paper describes examples of activities in each of these categories and then identifies ways in which collaborative implementation in the context of CFLRP (1) is both hindered and enabled by overlapping legal mandates about agency collaboration, (2) creates opportunities for expanded accountability through informal and relational means, and, (3) creates feedback loops at multiple temporal and spatial scales through which monitoring information, prioritization, and implementation actions shape restoration work both within and across projects throughout the landscape creating more robust opportunities for adaptive management.

  4. Collaborative Implementation for Ecological Restoration on US Public Lands: Implications for Legal Context, Accountability, and Adaptive Management

    Science.gov (United States)

    Butler, William H.; Monroe, Ashley; McCaffrey, Sarah

    2015-03-01

    The Collaborative Forest Landscape Restoration Program (CFLRP), established in 2009, encourages collaborative landscape scale ecosystem restoration efforts on United States Forest Service (USFS) lands. Although the USFS employees have experience engaging in collaborative planning, CFLRP requires collaboration in implementation, a domain where little prior experience can be drawn on for guidance. The purpose of this research is to identify the ways in which CFLRP's collaborative participants and agency personnel conceptualize how stakeholders can contribute to implementation on landscape scale restoration projects, and to build theory on dynamics of collaborative implementation in environmental management. This research uses a grounded theory methodology to explore collaborative implementation from the perspectives and experiences of participants in landscapes selected as part of the CFLRP in 2010. Interviewees characterized collaborative implementation as encompassing three different types of activities: prioritization, enhancing treatments, and multiparty monitoring. The paper describes examples of activities in each of these categories and then identifies ways in which collaborative implementation in the context of CFLRP (1) is both hindered and enabled by overlapping legal mandates about agency collaboration, (2) creates opportunities for expanded accountability through informal and relational means, and, (3) creates feedback loops at multiple temporal and spatial scales through which monitoring information, prioritization, and implementation actions shape restoration work both within and across projects throughout the landscape creating more robust opportunities for adaptive management.

  5. Stratification of archaeal membrane lipids in the ocean and implications for adaptation and chemotaxonomy of planktonic archaea.

    Science.gov (United States)

    Zhu, Chun; Wakeham, Stuart G; Elling, Felix J; Basse, Andreas; Mollenhauer, Gesine; Versteegh, Gerard J M; Könneke, Martin; Hinrichs, Kai-Uwe

    2016-12-01

    Membrane lipids of marine planktonic archaea have provided unique insights into archaeal ecology and paleoceanography. However, past studies of archaeal lipids in suspended particulate matter (SPM) and sediments mainly focused on a small class of fully saturated glycerol dibiphytanyl glycerol tetraether (GDGT) homologues identified decades ago. The apparent low structural diversity of GDGTs is in strong contrast to the high diversity of metabolism and taxonomy among planktonic archaea. Furthermore, adaptation of archaeal lipids in the deep ocean remains poorly constrained. We report the archaeal lipidome in SPM from diverse oceanic regimes. We extend the known inventory of planktonic archaeal lipids to include numerous unsaturated archaeal ether lipids (uns-AELs). We further reveal (i) different thermal regulations and polar headgroup compositions of membrane lipids between the epipelagic (≤ 100 m) and deep (>100 m) populations of archaea, (ii) stratification of unsaturated GDGTs with varying redox conditions, and (iii) enrichment of tetra-unsaturated archaeol and fully saturated GDGTs in epipelagic and deep oxygenated waters, respectively. Such stratified lipid patterns are consistent with the typical distribution of archaeal phylotypes in marine environments. We, thus, provide an ecological context for GDGT-based paleoclimatology and bring about the potential use of uns-AELs as biomarkers for planktonic Euryarchaeota. © 2016 Society for Applied Microbiology and John Wiley & Sons Ltd.

  6. Mitigation/adaptation and health: health policymaking in the global response to climate change and implications for other upstream determinants.

    Science.gov (United States)

    Wiley, Lindsay F

    2010-01-01

    The time is ripe for innovation in global health governance if we are to achieve global health and development objectives in the face of formidable challenges. Integration of global health concerns into the law and governance of other, related disciplines should be given high priority. This article explores opportunities for health policymaking in the global response to climate change. Climate change and environmental degradation will affect weather disasters, food and water security, infectious disease patterns, and air pollution. Although scientific research has pointed to the interdependence of the global environment and human health, policymakers have been slow to integrate their approaches to environmental and health concerns. A robust response to climate change will require improved integration on two fronts: health concerns must be given higher priority in the response to climate change and threats associated with climate change and environmental degradation must be more adequately addressed by global health law and governance. The mitigation/adaptation response paradigm developing within and beyond the United Nations Framework Convention on Climate Change provides a useful framework for thinking about global health law and governance with respect to climate change, environmental degradation, and possibly other upstream determinants of health as well.

  7. Diagnostic exome sequencing identifies two novel IQSEC2 mutations associated with X-linked intellectual disability with seizures: implications for genetic counseling and clinical diagnosis.

    Science.gov (United States)

    Gandomi, Stephanie K; Farwell Gonzalez, K D; Parra, M; Shahmirzadi, L; Mancuso, J; Pichurin, P; Temme, R; Dugan, S; Zeng, W; Tang, Sha

    2014-06-01

    Intellectual disability is a heterogeneous disorder with a wide phenotypic spectrum. Over 1,700 OMIM genes have been associated with this condition, many of which reside on the X-chromosome. The IQSEC2 gene is located on chromosome Xp11.22 and is known to play a significant role in the maintenance and homeostasis of the brain. Mutations in IQSEC2 have been historically associated with nonsyndromic X-linked intellectual disability. Case reports of affected probands show phenotypic overlap with conditions associated with pathogenic MECP2, FOXG1, CDKL5, and MEF2C gene mutations. Affected individuals, however, have also been identified as presenting with additional clinical features including seizures, autistic-behavior, psychiatric problems, and delayed language skills. To our knowledge, only 5 deleterious mutations and 2 intragenic duplications have been previously reported in IQSEC2. Here we report two novel IQSEC2 de novo truncating mutations identified through diagnostic exome sequencing in two severely affected unrelated male probands manifesting developmental delay, seizures, hypotonia, plagiocephaly, and abnormal MRI findings. Overall, diagnostic exome sequencing established a molecular diagnosis for two patients in whom traditional testing methods were uninformative while expanding on the mutational and phenotypic spectrum. In addition, our data suggests that IQSEC2 may be more common than previously appreciated, accounting for approximately 9 % (2/22) of positive findings among patients with seizures referred for diagnostic exome sequencing. Further, these data supports recently published data suggesting that IQSEC2 plays a more significant role in the development of X-linked intellectual disability with seizures than previously anticipated.

  8. Lower carrier rate of GJB2 W24X ancestral Indian mutation in Roma samples from Hungary: implication for public health intervention.

    Science.gov (United States)

    Sipeky, Csilla; Matyas, Petra; Melegh, Marton; Janicsek, Ingrid; Szalai, Renata; Szabo, Istvan; Varnai, Reka; Tarlos, Greta; Ganczer, Alma; Melegh, Bela

    2014-09-01

    The purpose of this work was to characterise the W24X mutation of the GJB2 gene in order to provide more representative and geographicaly relevant carrier rates of healthy Roma subisolates and the Hungarian population. 493 Roma and 498 Hungarian healthy subjects were genotyped for the GJB2 c.71G>A (rs104894396, W24X) mutation by PCR-RFLP assay and direct sequencing. This is the first report on GJB2 W24X mutation in geographically subisolated Roma population of Hungary compared to local Hungarians. Comparing the genotype and allele frequencies of GJB2 rs104894396 mutation, significant difference was found in GG (98.4 vs. 99.8 %), GA (1.62 vs. 0.20 %) genotypes and A (0.8 vs. 0.1 %) allele between the Roma and Hungarian populations, respectively (p Roma and Hungarian samples carried the GJB2 W24X AA genotype. Considerable result of our study, that the proportion of GJB2 W24X GA heterozygotes and the A allele frequency was eight times higher in Roma than in Hungarians. Considering the results, the mutant allele frequency both in Roma (0.8 %) and in Hungarian (0.1 %) populations is lower than expected from previous results, likely reflecting local differentiated subisolates of these populations and a suspected lower risk for GJB2 mutation related deafness. However, the significant difference in GJB2 W24X carrier rates between the Roma and Hungarians may initiate individual diagnostic investigations and effective public health interventions.

  9. TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

    NARCIS (Netherlands)

    M. Remke (Marc); E.A. Ramaswamy; M. Peacock (Munro); D.J.H. Shih (David J.); C. Koelsche (Christian); P.A. Northcott (Paul A.); N. Hill (Nadia); S. Cavalli (Silvia); M. Kool (Marcel); X. Wang (Xin); S. Mack (Stephen); M. Barszczyk (Mark); A.S. Morrissy (A. Sorana); X. Wu (Xiaochong); S. Agnihotri (Sameer); P. Luu (Phan); D. Jones (David); L. Garzia (Livia); A.M. Dubuc (Adrian); N. Zhukova (Nataliya); R. Vanner (Robert); J.M. Kros (Johan); P.J. French (Pim); E.G. van Meir (Erwin); R. Vibhakar (Rajeev); K. Zitterbart (Karel); J.A. Chan (Jennifer); L. Bognár (László); A. Klekner (Almos); B. Lach (Boleslaw); S. Jung (Shin); F. Saad (Fred); L.M. Liau (Linda); S. Albrecht (Steffen); M. Zollo (Maurizio); M.K. Cooper (Michael); R.C. Thompson (Reid); O. Delattre (Olivier); F. Bourdeaut (Franck); F.F. Doz (François); M. Garami (Miklós); P. Hauser (Peter); C.G. Carlotti (Carlos); T.E. Van Meter (Timothy); L. Massimi (Luca); D. Fults (Daniel); L.W. Pomeroy (Laura); T. Kumabe (Toshiro); Y.S. Ra (Young Shin); J.R. Leonard (Jeffrey); S.K. Elbabaa (Samer); J. Mora (Jaume); J.B. Rubin (Joshua); Y.-J. Cho (Yoon-Jae); R.E. McLendon (Roger); D.D. Bigner (Darell); C.G. Eberhart (Charles); M. Fouladi (Maryam); R.J. Wechsler-Reya (Robert); R. Faria (Rui); S.E. Croul (Sidney); A. Huang (Anding); E. Bouffet (Eric); C.E. Hawkins (Cynthia); M. Dirks (Maaike); W.A. Weiss (William); U. Schüller (Ulrich); A. Pollack (Aaron); P. Rutkowski (Piotr); D. Meyronet (David); A. Jouvet (Anne); M. Fèvre-Montange (Michelle); N. Jabado (Nada); M. Perek-Polnik (Marta); W.A. Grajkowska (Wieslawa); S.-K. Kim (Seung-Ki); J.T. Rutka (James); E. Malkin (Elissa); U. Tabori (Uri); S.M. Pfister (Stefan); A. Korshunov (Andrey); A. von Deimling (Andreas); M.D. Taylor (Michael)

    2013-01-01

    textabstractTelomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought

  10. TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

    NARCIS (Netherlands)

    M. Remke (Marc); E.A. Ramaswamy; M. Peacock (Munro); D.J.H. Shih (David J.); C. Koelsche (Christian); P.A. Northcott (Paul A.); N. Hill (Nadia); S. Cavalli (Silvia); M. Kool (Marcel); X. Wang (Xin); S. Mack (Stephen); M. Barszczyk (Mark); A.S. Morrissy (A. Sorana); X. Wu (Xiaochong); S. Agnihotri (Sameer); P. Luu (Phan); D. Jones (David); L. Garzia (Livia); A.M. Dubuc (Adrian); N. Zhukova (Nataliya); R. Vanner (Robert); J.M. Kros (Johan); P.J. French (Pim); E.G. van Meir (Erwin); R. Vibhakar (Rajeev); K. Zitterbart (Karel); J.A. Chan (Jennifer); L. Bognár (László); A. Klekner (Almos); B. Lach (Boleslaw); S. Jung (Shin); F. Saad (Fred); L.M. Liau (Linda); S. Albrecht (Steffen); M. Zollo (Maurizio); M.K. Cooper (Michael); R.C. Thompson (Reid); O. Delattre (Olivier); F. Bourdeaut (Franck); F.F. Doz (François); M. Garami (Miklós); P. Hauser (Peter); C.G. Carlotti (Carlos); T.E. Van Meter (Timothy); L. Massimi (Luca); D. Fults (Daniel); L.W. Pomeroy (Laura); T. Kumabe (Toshiro); Y.S. Ra (Young Shin); J.R. Leonard (Jeffrey); S.K. Elbabaa (Samer); J. Mora (Jaume); J.B. Rubin (Joshua); Y.-J. Cho (Yoon-Jae); R.E. McLendon (Roger); D.D. Bigner (Darell); C.G. Eberhart (Charles); M. Fouladi (Maryam); R.J. Wechsler-Reya (Robert); R. Faria (Rui); S.E. Croul (Sidney); A. Huang (Anding); E. Bouffet (Eric); C.E. Hawkins (Cynthia); M. Dirks (Maaike); W.A. Weiss (William); U. Schüller (Ulrich); A. Pollack (Aaron); P. Rutkowski (Piotr); D. Meyronet (David); A. Jouvet (Anne); M. Fèvre-Montange (Michelle); N. Jabado (Nada); M. Perek-Polnik (Marta); W.A. Grajkowska (Wieslawa); S.-K. Kim (Seung-Ki); J.T. Rutka (James); E. Malkin (Elissa); U. Tabori (Uri); S.M. Pfister (Stefan); A. Korshunov (Andrey); A. von Deimling (Andreas); M.D. Taylor (Michael)

    2013-01-01

    textabstractTelomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought

  11. Projecting Future Land Use Changes in West Africa Driven by Climate and Socioeconomic Factors: Uncertainties and Implications for Adaptation

    Science.gov (United States)

    Wang, G.; Ahmed, K. F.; You, L.

    2015-12-01

    Land use changes constitute an important regional climate change forcing in West Africa, a region of strong land-atmosphere coupling. At the same time, climate change can be an important driver for land use, although its importance relative to the impact of socio-economic factors may vary significant from region to region. This study compares the contributions of climate change and socioeconomic development to potential future changes of agricultural land use in West Africa and examines various sources of uncertainty using a land use projection model (LandPro) that accounts for the impact of socioeconomic drivers on the demand side and the impact of climate-induced crop yield changes on the supply side. Future crop yield changes were simulated by a process-based crop model driven with future climate projections from a regional climate model, and future changes of food demand is projected using a model for policy analysis of agricultural commodities and trade. The impact of human decision-making on land use was explicitly considered through multiple "what-if" scenarios to examine the range of uncertainties in projecting future land use. Without agricultural intensification, the climate-induced decrease of crop yield together with increase of food demand are found to cause a significant increase in agricultural land use at the expense of forest and grassland by the mid-century, and the resulting land use land cover changes are found to feed back to the regional climate in a way that exacerbates the negative impact of climate on crop yield. Analysis of results from multiple decision-making scenarios suggests that human adaptation characterized by science-informed decision making to minimize land use could be very effective in many parts of the region.

  12. A Hospital Is Not Just a Factory, but a Complex Adaptive System-Implications for Perioperative Care.

    Science.gov (United States)

    Mahajan, Aman; Islam, Salim D; Schwartz, Michael J; Cannesson, Maxime

    2017-07-01

    Many methods used to improve hospital and perioperative services productivity and quality of care have assumed that the hospital is essentially a factory, and therefore, that industrial engineering and manufacturing-derived redesign approaches such as Six Sigma and Lean can be applied to hospitals and perioperative services just as they have been applied in factories. However, a hospital is not merely a factory but also a complex adaptive system (CAS). The hospital CAS has many subsystems, with perioperative care being an important one for which concepts of factory redesign are frequently advocated. In this article, we argue that applying only factory approaches such as lean methodologies or process standardization to complex systems such as perioperative care could account for difficulties and/or failures in improving performance in care delivery. Within perioperative services, only noncomplex/low-variance surgical episodes are amenable to manufacturing-based redesign. On the other hand, complex surgery/high-variance cases and preoperative segmentation (the process of distinguishing between normal and complex cases) can be viewed as CAS-like. These systems tend to self-organize, often resist or react unpredictably to attempts at control, and therefore require application of CAS principles to modify system behavior. We describe 2 examples of perioperative redesign to illustrate the concepts outlined above. These examples present complementary and contrasting cases from 2 leading delivery systems. The Mayo Clinic example illustrates the application of manufacturing-based redesign principles to a factory-like (high-volume, low-risk, and mature practice) clinical program, while the Kaiser Permanente example illustrates the application of both manufacturing-based and self-organization-based approaches to programs and processes that are not factory-like but CAS-like. In this article, we describe how factory-like processes and CAS can coexist within a hospital and how

  13. Burkitt’s lymphoma-associated c-Myc mutations converge on a dramatically altered target gene response and implicate Nol5a/Nop56 in oncogenesis

    Science.gov (United States)

    Cowling, Victoria H.; Turner, Scott A.; Cole, Michael D.

    2016-01-01

    Burkitt’s Lymphomas (BLs) acquire consistent point mutations in a conserved domain of Myc, Myc Box I. We report that the enhanced transforming activity of BL-associated Myc mutants can be uncoupled from loss of phosphorylation and increased protein stability. Furthermore, two different BL-associated Myc mutations induced similar gene expression profiles independently of T58 phosphorylation, and these profiles are dramatically different from MycWT. Nol5a/Nop56, which is required for rRNA methylation, was identified as a gene hyperactivated by the BL-associated Myc mutants. We show that Nol5a is necessary for Myc-induced cell transformation, enhances MycWT-induced cell transformation, and increases the size of MycWT induced tumors. Thus, Nol5a expands the link between Myc-induced regulation of nucleolar target genes which are rate-limiting for cell transformation and tumor growth. PMID:24013231

  14. Diverse Drought Spatiotemporal Trends, Diverse Etic-Emic Perceptions and Knowledge: Implications for Adaptive Capacity and Resource Management for Indigenous Maasai-Pastoralism in the Rangelands of Kenya

    Directory of Open Access Journals (Sweden)

    Margaret Mwangi

    2016-04-01

    Full Text Available The study examined the spatiotemporal distribution of drought in the Maasai rangelands of Kenya. The implications of this distribution, in concert with the documented existing and/or projected social and biophysical factors, on critical rangeland resources in Maasai-pastoralism are discussed using an integrated approach. Participatory interviews with the Maasai, retrieval from archives, and acquisition from instrument measurements provided data for the study. Empirical evidence of the current study reveals that drought occurrences in this rangeland have been recurrent, widespread, cyclic, sometimes temporally clustered, and have manifested with varying intensities across spatial, temporal, and, occasionally, social scales; and they have more intensity in lower than higher agroecological areas. An estimated 86% of drought occurrences in this rangeland, over the last three decades alone, were of major drought category. The 2000s, with four major drought events including two extreme droughts, are an important drought period. A strong consensus exists among the Maasai regarding observed drought events. In Maasai-pastoralism, the phenomenon called drought, pastoralist drought, is simultaneously multivariate and multiscalar: its perception comprises the simultaneous manifestation of cross-scale meteorological, socioeconomic, and environmental factors and processes, and their various combinations. The inherent simultaneous multivariate and scalar nature of the pastoralist drought distinguishes it from the conventional drought types, particularly the meteorological drought that predominantly guides drought and resource management in the rangelands of Kenya. In Maasai-pastoralism, the scarcely used (33% meteorological drought is construed as rainfall delay/failure across spatial and/or temporal scale, and never its reduced amount. Collectively, the current findings reveal that knowledge about drought affects the way the manifestation of this climatic

  15. Acceleration of 5-methylcytosine deamination in cyclobutane dimers by G and its implications for UV-induced C-to-T mutation hotspots.

    Science.gov (United States)

    Cannistraro, Vincent J; Taylor, John-Stephen

    2009-10-01

    Sunlight-induced C-->T mutation hotspots occur most frequently at methylated CpG sites in tumor suppressor genes and are thought to arise from translesion synthesis past deaminated cyclobutane pyrimidine dimers (CPDs). While it is known that methylation enhances CPD formation in sunlight, little is known about the effect of methylation and sequence context on the deamination of 5-methylcytosine ((m)C) and its contribution to mutagenesis at these hotspots. Using an enzymatic method, we have determined the yields and deamination rates of C and (m)C in CPDs and find that the frequency of UVB-induced CPDs correlates with the oxidation potential of the flanking bases. We also found that the deamination of T(m)C and (m)CT CPDs is about 25-fold faster when flanked by G's than by A's, C's or T's in duplex DNA and appears to involve catalysis by the O6 group of guanine. In contrast, the first deamination of either C or (m)C in AC(m)CG with a flanking G was much slower (t(1/2) >250 h) and rate limiting, while the second deamination was much faster. The observation that C(m)CG dimers deaminate very slowly but at the same time correlate with C-->T mutation hotspots suggests that their repair must be slow enough to allow sufficient time for deamination. There are, however, a greater number of single C-->T mutations than CC-->TT mutations at C(m)CG sites even though the second deamination is very fast, which could reflect faster repair of doubly deaminated dimers.

  16. Germline mutations of the RET proto-oncogene in pedigree with MEN type 2A: DNA analysis and its implications for pediatric surgery.

    Science.gov (United States)

    Shimotake, T; Iwai, N; Inoue, K; Inazawa, J; Nishisho, I

    1996-06-01

    To assess the feasibility of screening for multiple endocrine neoplasia type 2A (MEN 2A), the authors used DNA sequence analysis to evaluate the RET proto-oncogene in a kindred with MEN 2A. The kindred consisted of 95 members (1 to 79 years of age) and their spouses, and spanned five generations. Genomic DNA was extracted from peripheral blood lymphocytes or lymphoblastoid cell lines established from the family members, and the RET gene was amplified by polymerase chain reaction (PCR) using RET-specific primers (10q 11.2) and was sequenced. Periodic endocrine screening also was performed, by measuring the plasma calcitonin concentration after provocation with pentagastrin (0.5 microgram/kg intravenously) to assess its reliability for detecting the associated neoplasms. Nineteen patients were confirmed to have MEN 2A by medical records or the screening program. The DNA sequence of the PCR products from clinically established MEN 2A patients showed a mutation at codon 634 (TGC-->CGC) that resulted in an amino acid change from cysteine to arginine. Endocrine screening tests showed that six other family members had a mutated RET protooncogene. DNA sequencing can detect high-risk cases at a preclinical stage of the disease. The establishment of mutated MEN 2A gene carriers allows pediatric surgeons to consider total thyroidectomy at a very early stage of neoplasm development (C-cell hyperplasia) or even prophylactically.

  17. Cell size variations of large granular lymphocyte leukemia: Implication of a small cell subtype of granular lymphocyte leukemia with STAT3 mutations.

    Science.gov (United States)

    Tanahashi, Takahiro; Sekiguchi, Nodoka; Matsuda, Kazuyuki; Takezawa, Yuka; Ito, Toshiro; Kobayashi, Hikaru; Ichikawa, Naoaki; Nishina, Sayaka; Senoo, Noriko; Sakai, Hitoshi; Nakazawa, Hideyuki; Ishida, Fumihiro

    2016-06-01

    Large granular lymphocyte leukemia (LGL-L) has been morphologically defined as a group of lymphoproliferative disorders, including T-cell large granular lymphocytic leukemia (T-LGL-L), chronic lymphoproliferative disorders of NK cells (CLPD-NK) and aggressive NK cell leukemia. We investigated the morphological features of LGL leukemic cells in 26 LGL-L patients in order to elucidate relationships with current classifications and molecular backgrounds. LGL-L cells were mostly indistinguishable from normal LGL. Patients with STAT3 SH2 domain mutations showed significantly smaller cells compared with patients without STAT3 mutations. Four patients with T-LGL-L showed smaller granular lymphocytes with a median diameter of less than 13μm, which were rarely seen in normal subjects. This small subtype of T-LGL-L was recognized among rather young patients and was associated with D661Y mutations in the STAT3 gene SH2 domain. In addition, all of them showed anemia including two cases with pure red cell aplasia. These results suggest the heterogeneity of T-LGL-L and a specific subtype with small variants of T-LGL-L. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Impaired training-induced adaptation of blood pressure in COPD patients: implication of the muscle capillary bed

    Directory of Open Access Journals (Sweden)

    Gouzi F

    2016-09-01

    exercise BP was reduced in CSs (DP: 89±10 mmHg vs 85±9 mmHg; P<0.001/SP: 204±25 mmHg vs 196±27 mmHg; P<0.05, it did not change in COPD patients (DP: 94±14 mmHg vs 97±16 mmHg; P=0.46/SP: 202±27 mmHg vs 208±24 mmHg; P=0.13. The change in muscle C/F ratio was negatively correlated with maximal exercise SP in CSs and COPD patients (r=-0.41; P=0.02. Conclusion: COPD patients showed impaired training-induced BP adaptation related to a change in muscle capillarization, suggesting the possibility of blunted angiogenesis. Keywords: angiogenesis, hypertension, pulmonary rehabilitation

  19. Adaptation Reactions of Siderophilic Cyanobacteria to High and Low Levels Of Environmental Iron: Implications for Biosphere History

    Science.gov (United States)

    Brown, I. I.; Bryant, D.; Sarkisova, S.; Shen, G.; Garrison, D.; McKay, D. S.

    2009-01-01

    Of all extant environments, iron-depositing hot springs may constitute the most appropriate natural models (Pierson and Parenteau, 2000) for analysis of the ecophysiology of ancient cyanobacteria (CB) which may have emerged in association with hydrothermal activity (Brown et al., 2007) and elevated levels of environmental Fe (Rouxel et al., 2005). Elevated environmental Fe2+ posed a significant challenge to the first oxygenic phototrophs - CB - because reduced Fe2+ induces toxic Fenton reactions (Wiedenheft et al., 2005). Ancient CB could have also been stressed by occasional migrations from the Fe2+-rich Ocean to the basaltic land which was almost devoid of dissolved Fe2+. That is why the study of the adaptation reactions of siderophilic CB, which inhabit iron-depositing hot springs, to up and down shifts in levels of dissolved Fe may shed light on the paleophysiology of ancient oxygenic prokaryotes. Methods. Siderophilic CB (Brown et al., 2007) were cultivated in media with different concentrations of added Fe3+. In some cases basaltic rocks were used as a source of Fe and trace elements. The processes of Fe mineralization and rock dissolution were studied using TEM, SEM and EDS techniques. Fluorescence spectroscopy was used for checking chlorophyll-protein complexes. Results. It was found that five siderophilic isolates Chroogloeocystis siderophila, JSC-1, JSC-3, JSC-11 and JSC-12 precipitated Fe-bearing phases on the exopolymeric sheaths of their cells if [Fe3+] was approx. 400-600 M (high Fe). Same [Fe3+] was most optimal one for the cultures proliferation rate (Brown et al., 2005; Brown et al., 2007). Higher concentrations of Fe3+ repressed the growth of some siderophilic CB (Brown et al., 2005). No mineralized Fe3+ was observed on the sheath of freshwater isolates Synechocystis sp. PCC 6803 and Phormidium aa. Scanning TEM in conjunction with thin-window energy dispersive X-ray spectroscopy (EDS) revealed intracellular Fe-rich phases within all three isolates

  20. Cellular adaptation to nutrient deprivation: crosstalk between the mTORC1 and eIF2α signaling pathways and implications for autophagy.

    Science.gov (United States)

    Wengrod, Jordan C; Gardner, Lawrence B

    2015-01-01

    The hostile tumor microenvironment results in the generation of intracellular stresses including hypoxia and nutrient deprivation. In order to adapt to such conditions, the cell utilizes several stress-response mechanisms, including the attenuation of protein synthesis, the inhibition of cellular proliferation, and induction of autophagy. Autophagy leads to the degradation of cellular contents, including damaged organelles and mutant proteins, which the cell can then use as an alternate energy source. Two integral changes to the signaling milieu to promote such a response include inhibition of the mammalian target of rapamycin complex 1 (mTORC1) and phosphorylation of eIF2α. This review will describe how conditions found in the tumor microenvironment regulate mTORC1 as well as eIF2α, the downstream impact of these modifications, and the implications in tumorigenesis. We will then discuss the remarkable similarities and overlapping function of these 2 signaling pathways, focusing on the response to amino acid deprivation, and present a new model involving crosstalk between them based on our recent work.

  1. An integrative genomic and proteomic analysis of PIK3CA, PTEN and AKT mutations in breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Stemke-Hale, Katherine; Gonzalez-Angulo, Ana Maria; Lluch, Ana; Neve, Richard M.; Kuo, Wen-Lin; Davies, Michael; Carey, Mark; Hu, Zhi; Guan, Yinghui; Sahin, Aysegul; Symmans, W. Fraser; Pusztai, Lajos; Nolden, Laura K.; Horlings, Hugo; Berns, Katrien; Hung, Mien-Chie; van de Vijver, Marc J.; Valero, Vicente; Gray, Joe W.; Bernards, Rene; Mills, Gordon B.; Hennessy, Bryan T.

    2008-05-06

    Phosphatidylinositol-3-kinase (PI3K)/AKT pathway aberrations are common in cancer. By applying mass spectroscopy-based sequencing and reverse phase protein arrays to 547 human breast cancers and 41 cell lines, we determined the subtype specificity and signaling effects of PIK3CA, AKT and PTEN mutations, and the effects of PIK3CA mutations on responsiveness to PI3K inhibition in-vitro and on outcome after adjuvant tamoxifen. PIK3CA mutations were more common in hormone receptor positive (33.8%) and HER2-positive (24.6%) than in basal-like tumors (8.3%). AKT1 (1.4%) and PTEN (2.3%) mutations were restricted to hormone receptor-positive cancers with PTEN protein levels also being significantly lower in hormone receptor-positive cancers. Unlike AKT1 mutations, PIK3CA (39%) and PTEN (20%) mutations were more common in cell lines than tumors, suggesting a selection for these but not AKT1 mutations during adaptation to culture. PIK3CA mutations did not have a significant impact on outcome in 166 hormone receptor-positive breast cancer patients after adjuvant tamoxifen. PIK3CA mutations, in comparison with PTEN loss and AKT1 mutations, were associated with significantly less and indeed inconsistent activation of AKT and of downstream PI3K/AKT signaling in tumors and cell lines, and PTEN loss and PIK3CA mutation were frequently concordant, suggesting different contributions to pathophysiology. PTEN loss but not PIK3CA mutations rendered cells sensitive to growth inhibition by the PI3K inhibitor LY294002. Thus, PI3K pathway aberrations likely play a distinct role in the pathogenesis of different breast cancer subtypes. The specific aberration may have implications for the selection of PI3K-targeted therapies in hormone receptor-positive breast cancer.

  2. Effects of new mutations on fitness: insights from models and data.

    Science.gov (United States)

    Bataillon, Thomas; Bailey, Susan F

    2014-07-01

    The rates and properties of new mutations affecting fitness have implications for a number of outstanding questions in evolutionary biology. Obtaining estimates of mutation rates and effects has historically been challenging, and little theory has been available for predicting the distribution of fitness effects (DFE); however, there have been recent advances on both fronts. Extreme-value theory predicts the DFE of beneficial mutations in well-adapted populations, while phenotypic fitness landscape models make predictions for the DFE of all mutations as a function of the initial level of adaptation and the strength of stabilizing selection on traits underlying fitness. Direct experimental evidence confirms predictions on the DFE of beneficial mutations and favors distributions that are roughly exponential but bounded on the right. A growing number of studies infer the DFE using genomic patterns of polymorphism and divergence, recovering a wide range of DFE. Future work should be aimed at identifying factors driving the observed variation in the DFE. We emphasize the need for further theory explicitly incorporating the effects of partial pleiotropy and heterogeneity in the environment on the expected DFE.

  3. RAS Mutations, and RET/PTC and PAX8/PPAR-gamma Chromosomal Rearrangements Are Also Prevalent in Benign Thyroid Lesions: Implications Thereof and A Systematic Review.

    Science.gov (United States)

    Najafian, Alireza; Noureldine, Salem; Azar, Faris; Atallah, Chady; Trinh, Gina; Schneider, Eric B; Tufano, Ralph P; Zeiger, Martha A

    2017-01-01

    Molecular markers associated with thyroid malignancy are increasingly being used as differential diagnostic tools for thyroid nodules. However, little has been reported recently regarding the prevalence of these markers in benign lesions. The literature was systematically reviewed to examine studies that reported on the prevalence of these markers in benign thyroid lesions. Appropriate studies published between January 1, 2000, and April 30, 2015, and cataloged in PubMed, Embase, Cochrane, Scopus, and Web of Science databases were searched for by combining different keywords for "thyroid tumor" with both general and specific keywords for "molecular marker" by using "AND" as the Boolean operator. All studies meeting criteria that reported the prevalence of RAS mutations, and RET/PTC and PAX8/PPAR-gamma chromosomal rearrangements in benign thyroid lesions were included for study. A total of 64 articles (including 8162 patients, of whom 42.5% had benign lesions) that met all the study criteria were systematically reviewed and abstracted. Among 35 studies examining RAS mutations, the reported prevalence of RAS mutation in benign lesions ranged from 0% to 48%. In 38 studies examining RET/PTC rearrangements, the prevalence in benign lesions ranged from 0% to 68%. PAX8/PPAR-gamma rearrangements were examined in 27 studies, with the prevalence in benign lesions ranging from 0% to 55%. The presence of these biomarkers and the tremendous variation in reports of their prevalence in benign lesions suggests the need for caution when including these markers in diagnostic decisions. Further understanding of the importance of these markers, as well as newly discovered markers of thyroid malignancy, may be required in order to avoid overtreatment of patients with benign thyroid tumors.

  4. The Impact of Mutation Rate on the Computation Time of Evolutionary Dynamic Optimization

    CERN Document Server

    Chen, Tianshi; Tang, Ke; Chen, Guoliang; Yao, Xin

    2011-01-01

    Mutation has traditionally been regarded as an important operator in evolutionary algorithms. In particular, there have been many experimental studies which showed the effectiveness of adapting mutation rates for various static optimization problems. Given the perceived effectiveness of adaptive and self-adaptive mutation for static optimization problems, there have been speculations that adaptive and self-adaptive mutation can benefit dynamic optimization problems even more since adaptation and self-adaptation are capable of following a dynamic environment. However, few theoretical results are available in analyzing rigorously evolutionary algorithms for dynamic optimization problems. It is unclear when adaptive and self-adaptive mutation rates are likely to be useful for evolutionary algorithms in solving dynamic optimization problems. This paper provides the first rigorous analysis of adaptive mutation and its impact on the computation times of evolutionary algorithms in solving certain dynamic optimizatio...

  5. Fitness seascapes and adaptive evolution of the influenza virus

    Science.gov (United States)

    Lassig, Michael

    2014-03-01

    The seasonal human influenza A virus undergoes rapid genome evolution. This process is triggered by interactions with the host immune system and produces significant year-to-year sequence turnover in the population of circulating viral strains. We develop a dynamical fitness model that predicts the evolution of the viral population from one year to the next. Two factors are shown to determine the fitness of a viral strain: adaptive changes, which are under positive selection, and deleterious mutations, which affect conserved viral functions such as protein stability. Combined with the influenza strain tree, this fitness model maps the adaptive history of influenza A. We discuss the implications of our results for the statistical theory of adaptive evolution in asexual populations. Based on this and related systems, we touch upon the fundamental question of when evolution can be predicted. Joint work with Marta Luksza, Columbia University.

  6. Centrosomal-ciliary gene CEP290/NPHP6 mutations result in blindness with unexpected sparing of photoreceptors and visual brain: implications for therapy of Leber congenital amaurosis.

    Science.gov (United States)

    Cideciyan, Artur V; Aleman, Tomas S; Jacobson, Samuel G; Khanna, Hemant; Sumaroka, Alexander; Aguirre, Geoffrey K; Schwartz, Sharon B; Windsor, Elizabeth A M; He, Shirley; Chang, Bo; Stone, Edwin M; Swaroop, Anand

    2007-11-01

    Mutations in the centrosomal-ciliary gene CEP290/NPHP6 are associated with Joubert syndrome and are the most common cause of the childhood recessive blindness known as Leber congenital amaurosis (LCA). An in-frame deletion in Cep290 shows rapid degeneration in the rod-rich mouse retina. To explore the mechanisms of the human retinal disease, we studied CEP290-LCA in patients of different ages (7-48 years) and compared results to Cep290-mutant mice. Unexpectedly, blind CEP290-mutant human retinas retained photoreceptor and inner laminar architecture in the cone-rich central retina, independent of severity of visual loss. Surrounding the cone-rich island was photoreceptor loss and distorted retina, suggesting neural-glial remodeling. The mutant mouse retina at 4-6 weeks of age showed similar features of retinal remodeling, with altered neural and synaptic laminae and Muller glial activation. The visual brain pathways in CEP290-LCA were anatomically intact. Our findings of preserved foveal cones and visual brain anatomy in LCA with CEP290 mutations, despite severe blindness and rapid rod cell death, suggest an opportunity for visual restoration of central vision in this common form of inherited blindness.

  7. Restoration of correct splicing in IVSI-110 mutation of β-globin gene with antisense oligonucleotides: implications and applications in functional assay development

    Directory of Open Access Journals (Sweden)

    Sima Mansoori Derakhshan

    2017-06-01

    Full Text Available Objective(s: The use of antisense oligonucleotides (AOs to restore normal splicing by blocking the recognition of aberrant splice sites by the spliceosome represents an innovative means of potentially controlling certain inherited disorders affected by aberrant splicing. Selection of the appropriate target site is essential in the success of an AO therapy. In this study, in search for a splice model system to facilitate the evaluation of AOs to redirect defective splicing of IVSI-110 β-globin intron, an EGFP-based IVSI-110 specific cellular reporter assay system has been developed and a number of AOs were tested in this cellular splicing assay. Materials and Methods: A recombinant plasmid (pEGFP/I-110 carrying the EGFP gene interrupted by a mutated human β-globin intron 1 (IVSI-110 was developed and transfected into K562 cells. A number of AOs with a 2’-O-methyl oligoribonucleotide (2’-O-Me backbone system were systematically tested in this cellular splicing assay. Results: The mutation in the intron causes aberrant splicing of EGFP pre-mRNA, preventing translation of EGFP; however, treatment of the cells with specific concentration of a sequence specific 2’-O-Me AO targeted to the aberrant splice site induced correct splicing and resulted in restoring of EGFP activity. Conclusion: This cellular splicing assay provides a novel functional assay system in assessing the cellular delivery efficiency of AOs and therapeutic effect of AOs in restoration of aberrant splicing.

  8. Sequential emergence and clinical implications of viral mutants with K70E and K65R mutation in reverse transcriptase during prolonged tenofovir monotherapy in rhesus macaques with chronic RT-SHIV infection

    Directory of Open Access Journals (Sweden)

    Pedersen Niels C

    2007-04-01

    Full Text Available Abstract Background We reported previously on the emergence and clinical implications of simian immunodeficiency virus (SIVmac251 mutants with a K65R mutation in reverse transcriptase (RT, and the role of CD8+ cell-mediated immune responses in suppressing viremia during tenofovir therapy. Because of significant sequence differences between SIV and HIV-1 RT that affect drug susceptibilities and mutational patterns, it is unclear to what extent findings with SIV can be extrapolated to HIV-1 RT. Accordingly, to model HIV-1 RT responses, 12 macaques were inoculated with RT-SHIV, a chimeric SIV containing HIV-1 RT, and started on prolonged tenofovir therapy 5 months later. Results The early virologic response to tenofovir correlated with baseline viral RNA levels and expression of the MHC class I allele Mamu-A*01. For all animals, sensitive real-time PCR assays detected the transient emergence of K70E RT mutants within 4 weeks of therapy, which were then replaced by K65R mutants within 12 weeks of therapy. For most animals, the occurrence of these mutations preceded a partial rebound of plasma viremia to levels that remained on average 10-fold below baseline values. One animal eventually suppressed K65R viremia to undetectable levels for more than 4 years; sequential experiments using CD8+ cell depletion and tenofovir interruption demonstrated that both CD8+ cells and continued tenofovir therapy were required for sustained suppression of viremia. Conclusion This is the first evidence that tenofovir therapy can select directly for K70E viral mutants in vivo. The observations on the clinical implications of the K65R RT-SHIV mutants were consistent with those of SIVmac251, and suggest that for persons infected with K65R HIV-1 both immune-mediated and drug-dependent antiviral activities play a role in controlling viremia. These findings suggest also that even in the presence of K65R virus, continuation of tenofovir treatment as part of HAART may be

  9. Molecular evolution of rbcL in three gymnosperm families: identifying adaptive and coevolutionary patterns

    LENUS (Irish Health Repository)

    Sen, Lin

    2011-06-03

    Abstract Background The chloroplast-localized ribulose-1, 5-biphosphate carboxylase\\/oxygenase (Rubisco), the primary enzyme responsible for autotrophy, is instrumental in the continual adaptation of plants to variations in the concentrations of CO2. The large subunit (LSU) of Rubisco is encoded by the chloroplast rbcL gene. Although adaptive processes have been previously identified at this gene, characterizing the relationships between the mutational dynamics at the protein level may yield clues on the biological meaning of such adaptive processes. The role of such coevolutionary dynamics in the continual fine-tuning of RbcL remains obscure. Results We used the timescale and phylogenetic analyses to investigate and search for processes of adaptive evolution in rbcL gene in three gymnosperm families, namely Podocarpaceae, Taxaceae and Cephalotaxaceae. To understand the relationships between regions identified as having evolved under adaptive evolution, we performed coevolutionary analyses using the software CAPS. Importantly, adaptive processes were identified at amino acid sites located on the contact regions among the Rubisco subunits and on the interface between Rubisco and its activase. Adaptive amino acid replacements at these regions may have optimized the holoenzyme activity. This hypothesis was pinpointed by evidence originated from our analysis of coevolution that supported the correlated evolution between Rubisco and its activase. Interestingly, the correlated adaptive processes between both these proteins have paralleled the geological variation history of the concentration of atmospheric CO2. Conclusions The gene rbcL has experienced bursts of adaptations in response to the changing concentration of CO2 in the atmosphere. These adaptations have emerged as a result of a continuous dynamic of mutations, many of which may have involved innovation of functional Rubisco features. Analysis of the protein structure and the functional implications of such

  10. Norm comparisons of the Spanish-language and English-language WAIS-III: Implications for clinical assessment and test adaptation.

    Science.gov (United States)

    Funes, Cynthia M; Rodriguez, Juventino Hernandez; Lopez, Steven Regeser

    2016-12-01

    This study provides a systematic comparison of the norms of 3 Spanish-language Wechsler Adult Intelligence Scales (WAIS-III) batteries from Mexico, Spain, and Puerto Rico, and the U.S. English-language WAIS-III battery. Specifically, we examined the performance of the 4 normative samples on 2 identical subtests (Digit Span and Digit Symbol-Coding) and 1 nearly identical subtest (Block Design). We found that across most age groups the means associated with the Spanish-language versions of the 3 subtests were lower than the means of the U.S. English-language version. In addition, we found that for most age ranges the Mexican subsamples scored lower than the Spanish subsamples. Lower educational levels of Mexicans and Spaniards compared to U.S. residents are consistent with the general pattern of findings. These results suggest that because of the different norms, applying any of the 3 Spanish-language versions of the WAIS-III generally risks underestimating deficits, and that applying the English-language WAIS-III norms risks overestimating deficits of Spanish-speaking adults. There were a few exceptions to these general patterns. For example, the Mexican subsample ages 70 years and above performed significantly better on the Digit Symbol and Block Design than did the U.S. and Spanish subsamples. Implications for the clinical assessment of U.S. Spanish-speaking Latinos and test adaptation are discussed with an eye toward improving the clinical care for this community. (PsycINFO Database Record

  11. Pigment pattern in jaguar/obelix zebrafish is caused by a Kir7.1 mutation: implications for the regulation of melanosome movement.

    Directory of Open Access Journals (Sweden)

    Motoko Iwashita

    2006-11-01

    Full Text Available Many animals have a variety of pigment patterns, even within a species, and these patterns may be one of the driving forces of speciation. Recent molecular genetic studies on zebrafish have revealed that interaction among pigment cells plays a key role in pattern formation, but the mechanism of pattern formation is unclear. The zebrafish jaguar/obelix mutant has broader stripes than wild-type fish. In this mutant, the development of pigment cells is normal but their distribution is altered, making these fish ideal for studying the process of pigment pattern formation. Here, we utilized a positional cloning method to determine that the inwardly rectifying potassium channel 7.1 (Kir7.1 gene is responsible for pigment cell distribution among jaguar/obelix mutant fish. Furthermore, in jaguar/obelix mutant alleles, we identified amino acid changes in the conserved region of Kir7.1, each of which affected K(+ channel activity as demonstrated by patch-clamp experiments. Injection of a bacterial artificial chromosome containing the wild-type Kir7.1 genomic sequence rescued the jaguar/obelix phenotype. From these results, we conclude that mutations in Kir7.1 are responsible for jaguar/obelix. We also determined that the ion channel function defect of melanophores expressing mutant Kir7.1 altered the cellular response to external signals. We discovered that mutant melanophores cannot respond correctly to the melanosome dispersion signal derived from the sympathetic neuron and that melanosome aggregation is constitutively activated. In zebrafish and medaka, it is well known that melanosome aggregation and subsequent melanophore death increase when fish are kept under constant light conditions. These observations indicate that melanophores of jaguar/obelix mutant fish have a defect in the signaling pathway downstream of the alpha2-adrenoceptor. Taken together, our results suggest that the cellular defect of the Kir7.1 mutation is directly responsible for

  12. Pigment pattern in jaguar/obelix zebrafish is caused by a Kir7.1 mutation: implications for the regulation of melanosome movement.

    Science.gov (United States)

    Iwashita, Motoko; Watanabe, Masakatsu; Ishii, Masaru; Chen, Tim; Johnson, Stephen L; Kurachi, Yoshihisa; Okada, Norihiro; Kondo, Shigeru

    2006-11-24

    Many animals have a variety of pigment patterns, even within a species, and these patterns may be one of the driving forces of speciation. Recent molecular genetic studies on zebrafish have revealed that interaction among pigment cells plays a key role in pattern formation, but the mechanism of pattern formation is unclear. The zebrafish jaguar/obelix mutant has broader stripes than wild-type fish. In this mutant, the development of pigment cells is normal but their distribution is altered, making these fish ideal for studying the process of pigment pattern formation. Here, we utilized a positional cloning method to determine that the inwardly rectifying potassium channel 7.1 (Kir7.1) gene is responsible for pigment cell distribution among jaguar/obelix mutant fish. Furthermore, in jaguar/obelix mutant alleles, we identified amino acid changes in the conserved region of Kir7.1, each of which affected K(+) channel activity as demonstrated by patch-clamp experiments. Injection of a bacterial artificial chromosome containing the wild-type Kir7.1 genomic sequence rescued the jaguar/obelix phenotype. From these results, we conclude that mutations in Kir7.1 are responsible for jaguar/obelix. We also determined that the ion channel function defect of melanophores expressing mutant Kir7.1 altered the cellular response to external signals. We discovered that mutant melanophores cannot respond correctly to the melanosome dispersion signal derived from the sympathetic neuron and that melanosome aggregation is constitutively activated. In zebrafish and medaka, it is well known that melanosome aggregation and subsequent melanophore death increase when fish are kept under constant light conditions. These observations indicate that melanophores of jaguar/obelix mutant fish have a defect in the signaling pathway downstream of the alpha2-adrenoceptor. Taken together, our results suggest that the cellular defect of the Kir7.1 mutation is directly responsible for the pattern change

  13. A P-loop Mutation in G[alpha] Subunits Prevents Transition to the Active State: Implications for G-protein Signaling in Fungal Pathogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Bosch, Dustin E.; Willard, Francis S.; Ramanujam, Ravikrishna; Kimple, Adam J.; Willard, Melinda D.; Naqvi, Naweed I.; Siderovski, David P. (UNC); (Singapore)

    2012-10-23

    Heterotrimeric G-proteins are molecular switches integral to a panoply of different physiological responses that many organisms make to environmental cues. The switch from inactive to active G{alpha}{beta}{gamma} heterotrimer relies on nucleotide cycling by the G{alpha} subunit: exchange of GTP for GDP activates G{alpha}, whereas its intrinsic enzymatic activity catalyzes GTP hydrolysis to GDP and inorganic phosphate, thereby reverting G{alpha} to its inactive state. In several genetic studies of filamentous fungi, such as the rice blast fungus Magnaporthe oryzae, a G42R mutation in the phosphate-binding loop of G{alpha} subunits is assumed to be GTPase-deficient and thus constitutively active. Here, we demonstrate that G{alpha}(G42R) mutants are not GTPase deficient, but rather incapable of achieving the activated conformation. Two crystal structure models suggest that Arg-42 prevents a typical switch region conformational change upon G{alpha}{sub i1}(G42R) binding to GDP {center_dot} AlF{sub 4}{sup -} or GTP, but rotameric flexibility at this locus allows for unperturbed GTP hydrolysis. G{alpha}(G42R) mutants do not engage the active state-selective peptide KB-1753 nor RGS domains with high affinity, but instead favor interaction with G{beta}{gamma} and GoLoco motifs in any nucleotide state. The corresponding G{alpha}{sub q}(G48R) mutant is not constitutively active in cells and responds poorly to aluminum tetrafluoride activation. Comparative analyses of M. oryzae strains harboring either G42R or GTPase-deficient Q/L mutations in the G{alpha} subunits MagA or MagB illustrate functional differences in environmental cue processing and intracellular signaling outcomes between these two G{alpha} mutants, thus demonstrating the in vivo functional divergence of G42R and activating G-protein mutants.

  14. Markov models for accumulating mutations

    CERN Document Server

    Beerenwinkel, Niko

    2007-01-01

    We introduce and analyze a waiting time model for the accumulation of genetic changes. The continuous time conjunctive Bayesian network is defined by a partially ordered set of mutations and by the rate of fixation of each mutation. The partial order encodes constraints on the order in which mutations can fixate in the population, shedding light on the mutational pathways underlying the evolutionary process. We study a censored version of the model and derive equations for an EM algorithm to perform maximum likelihood estimation of the model parameters. We also show how to select the maximum likelihood poset. The model is applied to genetic data from different cancers and from drug resistant HIV samples, indicating implications for diagnosis and treatment.

  15. 基于非均匀变异和自适应逃逸的果蝇优化算法%Fruit fly optimization algorithm based on non-uniform mutation and adaptive escape

    Institute of Scientific and Technical Information of China (English)

    张彩宏; 潘广贞

    2016-01-01

    Aiming at the problems of low convergence precision and easily relapsing into local extremum caused by olfaction searching random blind and only learning from the optimal fruit fly in basic fruit fly optimization algorithm (FOA),an improved FOA called fruit fly optimization algorithm based on non-uniform mutation and adaptive escape (NAFOA)was proposed.Non-uniform mutation operator was introduced into olfaction searching phase to adj ust dynamically searching step of each iteration. States of population were divided into premature state and normal state by setting threshold.If population was in normal state, basic FOA was adopted to evolve.Otherwise,it fell into premature,perturbations dimension by dimension for the global optimal fruit was adopted to generate new solution.The ability to escape from local optimum was enhanced and the balance between ex-ploring and developing was well processed.Test of six classic functions was designed.Experimental results show that the algo-rithm in terms of accuracy and robustness were better than FOA and other several improved algorithms.%基本果蝇优化算法(FOA)存在嗅觉搜索随机盲目、迭代寻优只学习最优个体的问题,导致收敛精度低、易陷入局部极值,为此提出基于非均匀变异和自适应逃逸的果蝇优化算法(NAFOA)。在嗅觉搜索阶段引入非均匀变异算子,动态调整每次迭代的搜索步长。通过设置阈值将种群划分为“早熟”状态和正常状态,若处于正常状态,采用基本的 FOA模式进化;若处于“早熟”状态,对全局最优果蝇进行逐维扰动,逃离局部最优,平衡果蝇探索和开发的能力。设计实验,测试6个经典函数,实验结果表明,该算法在精度和鲁棒性方面均优于基本的果蝇算法及其它几种改进算法。

  16. Culture adaptation of malaria parasites selects for convergent loss-of-function mutants

    Science.gov (United States)

    Claessens, Antoine; Affara, Muna; Assefa, Samuel A.; Kwiatkowski, Dominic P.; Conway, David J.

    2017-01-01

    Cultured human pathogens may differ significantly from source populations. To investigate the genetic basis of laboratory adaptation in malaria parasites, clinical Plasmodium falciparum isolates were sampled from patients and cultured in vitro for up to three months. Genome sequence analysis was performed on multiple culture time point samples from six monoclonal isolates, and single nucleotide polymorphism (SNP) variants emerging over time were detected. Out of a total of five positively selected SNPs, four represented nonsense mutations resulting in stop codons, three of these in a single ApiAP2 transcription factor gene, and one in SRPK1. To survey further for nonsense mutants associated with culture, genome sequences of eleven long-term laboratory-adapted parasite strains were examined, revealing four independently acquired nonsense mutations in two other ApiAP2 genes, and five in Epac. No mutants of these genes exist in a large database of parasite sequences from uncultured clinical samples. This implicates putative master regulator genes in which multiple independent stop codon mutations have convergently led to culture adaptation, affecting most laboratory lines of P. falciparum. Understanding the adaptive processes should guide development of experimental models, which could include targeted gene disruption to adapt fastidious malaria parasite species to culture. PMID:28117431

  17. Atrazine dissipation in s-triazine-adapted and nonadapted soil from Colorado and Mississippi: implications of enhanced degradation on atrazine fate and transport parameters.

    Science.gov (United States)

    Krutz, L Jason; Shaner, Dale L; Accinelli, Cesare; Zablotowicz, Robert M; Henry, W Brien

    2008-01-01

    Soil bacteria have developed novel metabolic abilities resulting in enhanced atrazine degradation. Consequently, there is a need to evaluate the effects of enhanced degradation on parameters used to model atrazine fate and transport. The objectives of this study were (i) to screen Colorado (CO) and Mississippi (MS) atrazine-adapted and non-adapted soil for genes that code for enzymes able to rapidly catabolize atrazine and (ii) to compare atrazine persistence, Q(10), beta, and metabolite profiles between adapted and non-adapted soils. The atzABC and/or trzN genes were detected only in adapted soil. Atrazine's average half-life in adapted soil was 10-fold lower than that of the non-adapted soil and 18-fold lower than the USEPA estimate of 3 to 4 mo. Q(10) was greater in adapted soil. No difference in beta was observed between soils. The accumulation and persistence of mono-N-dealkylated metabolites was lower in adapted soil; conversely, under suboptimal moisture levels in CO adapted soil, hydroxyatrazine concentrations exceeded 30% of the parent compounds' initial mass. Results indicate that (i) enhanced atrazine degradation and atzABC and/or trzN genes are likely widespread across the Western and Southern corn-growing regions of the USA; (ii) persistence of atrazine and its mono-N-dealkylated metabolites is significantly reduced in adapted soil; (iii) hydroxyatrazine can be a major degradation product in adapted soil; and (iv) fate, transport, and risk assessment models that assume historic atrazine degradation pathways and persistence estimates will likely overpredict the compounds' transport potential in adapted soil.

  18. The adaptive evolution of the mammalian mitochondrial genome

    Directory of Open Access Journals (Sweden)

    O'Brien Stephen J

    2008-03-01

    Full Text Available Abstract Background The mitochondria produce up to 95% of a eukaryotic cell's energy through oxidative phosphorylation. The proteins involved in this vital process are under high functional constraints. However, metabolic requirements vary across species, potentially modifying selective pressures. We evaluate the adaptive evolution of 12 protein-coding mitochondrial genes in 41 placental mammalian species by assessing amino acid sequence variation and exploring the functional implications of observed variation in secondary and tertiary protein structures. Results Wide variation in the properties of amino acids were observed at functionally important regions of cytochrome b in species with more-specialized metabolic requirements (such as adaptation to low energy diet or large body size, such as in elephant, dugong, sloth, and pangolin, and adaptation to unusual oxygen requirements, for example diving in cetaceans, flying in bats, and living at high altitudes in alpacas. Signatures of adaptive variation in the NADH dehydrogenase complex were restricted to the loop regions of the transmembrane units which likely function as protons pumps. Evidence of adaptive variation in the cytochrome c oxidase complex was observed mostly at the interface between the mitochondrial and nuclear-encoded subunits, perhaps evidence of co-evolution. The ATP8 subunit, which has an important role in the assembly of F0, exhibited the highest signal of adaptive variation. ATP6, which has an essential role in rotor performance, showed a high adaptive variation in predicted loop areas. Conclusion Our study provides insight into the adaptive evolution of the mtDNA genome in mammals and its implications for the molecular mechanism of oxidative phosphorylation. We present a framework for future experimental characterization of the impact of specific mutations in the function, physiology, and interactions of the mtDNA encoded proteins involved in oxidative phosphorylation.

  19. IMPLICATION DE CERTAINES MUTATIONS DANS LES GENES BRCA1 ET BRCA2 SUR LA PRÉDISPOSITION AU CANCER DU SEIN ET AU CANCER OVARIEN

    Directory of Open Access Journals (Sweden)

    Lucian Negura

    2007-08-01

    Full Text Available Le cancer du sein, ainsi que celui ovarien, est une maladie fréquente chez les femmes, ayant un traitement assez difficile et, malheureusement, de sérieuses répercutions sur le physique ; c’est pourquoi il s’avère essentiel que la maladie soit dépistée dès les phases précoces. La prédisposition génétique est responsable de 5% des cancers et de 25% des cas apparus avant l’age de 30 ans [Breast Cancer Linkage Consortium, 1997]. Nous présentons ici l’implication des gènes suppresseurs des tumeurs BRCA1 et BRCA2 sur cette prédisposition.

  20. Biogenic sediments from coastal ecosystems to beach-dune systems: implications for the adaptation of mixed and carbonate beaches to future sea level rise

    Science.gov (United States)

    De Falco, Giovanni; Molinaroli, Emanuela; Conforti, Alessandro; Simeone, Simone; Tonielli, Renato

    2017-07-01

    century-1, 28 % (15 % / 34 %) of which is transported to the beach-dune system, thus significantly contributing to the beach sediment budget. The contribution to the beach sediment budget represents a further ecosystem service, which our data can help quantify, provided by P. oceanica. The value of this sediment-supply service is in addition to the other important ecological services provided by seagrass meadows. The dependence of the beach sediment budget on carbonate production associated with coastal ecosystems has several implications for the adaptation of mixed and carbonate beaches to the loss of seagrass meadows due to local impacts and the changes expected to occur over the next few decades in coastal ecosystems following sea level rise.

  1. Is The Ribosome Targeted By Adaptive Mutations

    DEFF Research Database (Denmark)

    Jimenez Fernandez, Alicia; Molin, Søren; Johansen, Helle Krogh

    2015-01-01

    Introduction: RNA polymerase and ribosomes, composing the macromolecular synthesis machinery (MMSM), carry out the central processes of transcription and translation, but are usually seen as mechanical elements with no regulatory function. Extensive investigations of gene regulation and the high...

  2. Costs and benefits of mutational robustness in RNA viruses.

    Science.gov (United States)

    Stern, Adi; Bianco, Simone; Yeh, Ming Te; Wright, Caroline; Butcher, Kristin; Tang, Chao; Nielsen, Rasmus; Andino, Raul

    2014-08-21

    The accumulation of mutations in RNA viruses is thought to facilitate rapid adaptation to changes in the environment. However, most mutations have deleterious effects on fitness, especially for viruses. Thus, tolerance to mutations should determine the nature and extent of genetic diversity that can be maintained in the population. Here, we combine population genetics theory, computer simulation, and experimental evolution to examine the advantages and disadvantages of tolerance to mutations, also known as mutational robustness. We find that mutational robustness increases neutral diversity and, as expected, can facilitate adaptation to a new environment. Surprisingly, under certain conditions, robustness may also be an impediment for viral adaptation, if a highly diverse population contains a large proportion of previously neutral mutations that are deleterious in the new environment. These findings may inform therapeutic strategies that cause extinction of otherwise robust viral populations.

  3. Costs and Benefits of Mutational Robustness in RNA Viruses

    Directory of Open Access Journals (Sweden)

    Adi Stern

    2014-08-01

    Full Text Available The accumulation of mutations in RNA viruses is thought to facilitate rapid adaptation to changes in the environment. However, most mutations have deleterious effects on fitness, especially for viruses. Thus, tolerance to mutations should determine the nature and extent of genetic diversity that can be maintained in the population. Here, we combine population genetics theory, computer simulation, and experimental evolution to examine the advantages and disadvantages of tolerance to mutations, also known as mutational robustness. We find that mutational robustness increases neutral diversity and, as expected, can facilitate adaptation to a new environment. Surprisingly, under certain conditions, robustness may also be an impediment for viral adaptation, if a highly diverse population contains a large proportion of previously neutral mutations that are deleterious in the new environment. These findings may inform therapeutic strategies that cause extinction of otherwise robust viral populations.

  4. Functional Validation of an Alpha-Actinin-4 Mutation as a Potential Cause of an Aggressive Presentation of Adolescent Focal Segmental Glomerulosclerosis: Implications for Genetic Testing

    Science.gov (United States)

    Steinke, Julia M.; Krishnan, Ramaswamy; Birrane, Gabriel; Pollak, Martin R.

    2016-01-01

    Genetic testing in the clinic and research lab is becoming more routinely used to identify rare genetic variants. However, attributing these rare variants as the cause of disease in an individual patient remains challenging. Here, we report a patient who presented with nephrotic syndrome and focal segmental glomerulosclerosis (FSGS) with collapsing features at age 14. Despite treatment, her kidney disease progressed to end-stage within a year of diagnosis. Through genetic testing, an Y265H variant with unknown clinical significance in alpha-actinin-4 gene (ACTN4) was identified. This variant has not been seen previously in FSGS patients nor is it present in genetic databases. Her clinical presentation is different from previous descriptions of ACTN4 mediated FSGS, which is characterized by sub-nephrotic proteinuria and slow progression to end stage kidney disease. We performed in vitro and cellular assays to characterize this novel ACTN4 variant before attributing causation. We found that ACTN4 with either Y265H or K255E (a known disease-causing mutation) increased the actin bundling activity of ACTN4 in vitro, was associated with the formation of intracellular aggregates, and increased podocyte contractile force. Despite the absence of a familial pattern of inheritance, these similar biological changes caused by the Y265H and K255E amino acid substitutions suggest that this new variant is potentially the cause of FSGS in this patient. Our studies highlight that functional validation in complement with genetic testing may be required to confirm the etiology of rare disease, especially in the setting of unusual clinical presentations. PMID:27977723

  5. Spliceosome mutations exhibit specific associations with epigenetic modifiers and proto-oncogenes mutated in myelodysplastic syndrome.

    Science.gov (United States)

    Mian, Syed A; Smith, Alexander E; Kulasekararaj, Austin G; Kizilors, Aytug; Mohamedali, Azim M; Lea, Nicholas C; Mitsopoulos, Konstantinos; Ford, Kevin; Nasser, Erick; Seidl, Thomas; Mufti, Ghulam J

    2013-07-01

    The recent identification of acquired mutations in key components of the spliceosome machinery strongly implicates abnormalities of mRNA splicing in the pathogenesis of myelodysplastic syndromes. However, questions remain as to how these aberrations functionally combine with the growing list of mutations in genes involved in epigenetic modification and cell signaling/transcription regulation identified in these diseases. In this study, amplicon sequencing was used to perform a mutation screen in 154 myelodysplastic syndrome patients using a 22-gene panel, including commonly mutated spliceosome components (SF3B1, SRSF2, U2AF1, ZRSR2), and a further 18 genes known to be mutated in myeloid cancers. Sequencing of the 22-gene panel revealed that 76% (n=117) of the patients had mutations in at least one of the genes, with 38% (n=59) having splicing gene mutations and 49% (n=75) patients harboring more than one gene mutation. Interestingly, single and specific epigenetic modifier mutations tended to coexist with SF3B1 and SRSF2 mutations (P<0.03). Furthermore, mutations in SF3B1 and SRSF2 were mutually exclusive to TP53 mutations both at diagnosis and at the time of disease transformation. Moreover, mutations in FLT3, NRAS, RUNX1, CCBL and C-KIT were more likely to co-occur with splicing factor mutations generally (P<0.02), and SRSF2 mutants in particular (P<0.003) and were significantly associated with disease transformation (P<0.02). SF3B1 and TP53 mutations had varying impacts on overall survival with hazard ratios of 0.2 (P<0.03, 95% CI, 0.1-0.8) and 2.1 (P<0.04, 95% CI, 1.1-4.4), respectively. Moreover, patients with splicing factor mutations alone had a better overall survival than those with epigenetic modifier mutations, or cell signaling/transcription regulator mutations with and without coexisting mutations of splicing factor genes, with worsening prognosis (P<0.001). These findings suggest that splicing factor mutations are maintained throughout disease

  6. Mutational profiling reveals PIK3CA mutations in gallbladder carcinoma

    Directory of Open Access Journals (Sweden)

    Bardeesy Nabeel

    2011-02-01

    Full Text Available Abstract Background The genetics of advanced biliary tract cancers (BTC, which encompass intra- and extra-hepatic cholangiocarcinomas as well as gallbladder carcinomas, are heterogeneous and remain to be fully defined. Methods To better characterize mutations in established known oncogenes and tumor suppressor genes we tested a mass spectrometric based platform to interrogate common cancer associated mutations across a panel of 77 formalin fixed paraffin embedded archived BTC cases. Results Mutations among three genes, KRAS, NRAS and PIK3CA were confirmed in this cohort. Activating mutations in PIK3CA were identified exclusively in GBC (4/32, 12.5%. KRAS mutations were identified in 3 (13% intra-hepatic cholangiocarcinomas and 1 (33% perihillar cholangiocarcinoma but were not identified in gallbladder carcinomas and extra-hepatic cholangiocarcinoma. Conclusions The presence of activating mutations in PIK3CA specifically in GBC has clinical implications in both the diagnosis of this cancer type, as well as the potential utility of targeted therapies such as PI3 kinase inhibitors.

  7. Prognostic role and implications of mutation status of tumor suppressor gene ARID1A in cancer: a systematic review and meta-analysis.

    Science.gov (United States)

    Luchini, Claudio; Veronese, Nicola; Solmi, Marco; Cho, Hanbyoul; Kim, Jae-Hoon; Chou, Angela; Gill, Anthony J; Faraj, Sheila F; Chaux, Alcides; Netto, George J; Nakayama, Kentaro; Kyo, Satoru; Lee, Soo Young; Kim, Duck-Woo; Yousef, George M; Scorilas, Andreas; Nelson, Gregg S; Köbel, Martin; Kalloger, Steve E; Schaeffer, David F; Yan, Hai-Bo; Liu, Feng; Yokoyama, Yoshihito; Zhang, Xianyu; Pang, Da; Lichner, Zsuzsanna; Sergi, Giuseppe; Manzato, Enzo; Capelli, Paola; Wood, Laura D; Scarpa, Aldo; Correll, Christoph U

    2015-11-17

    Loss of the tumor suppressor gene AT-rich interactive domain-containing protein 1A (ARID1A) has been demonstrated in several cancers, but its prognostic role is unknown. We aimed to investigate the risk associated with loss of ARID1A (ARID1A-) for all-cause mortality, cancer-specific mortality and recurrence of disease in subjects with cancer. PubMed and SCOPUS search from database inception until 01/31/2015 without language restriction was conducted, contacting authors for unpublished data. Eligible were prospective studies reporting data on prognostic parameters in subjects with cancer, comparing participants with presence of ARID1A (ARID1A+) vs. ARID1A-, assessed either via immunohistochemistry (loss of expression) or with genetic testing (presence of mutation). Data were summarized using risk ratios (RR) for number of deaths/recurrences and hazard ratios (HR) for time-dependent risk related to ARID1A- adjusted for potential confounders. Of 136 hits, 25 studies with 5,651 participants (28 cohorts; ARID1A-: n = 1,701; ARID1A+: n = 3,950), with a mean follow-up period of 4.7 ± 1.8 years, were meta-analyzed. Compared to ARID1A+, ARID1A- significantly increased cancer-specific mortality (studies = 3; RR = 1.55, 95% confidence interval (CI) = 1.19-2.00, I(2) = 31%). Using HRs adjusted for potential confounders, ARID1A- was associated with a greater risk of cancer-specific mortality (studies = 2; HR = 2.55, 95%CI = 1.19-5.45, I(2) = 19%) and cancer recurrence (studies = 10; HR = 1.93, 95%CI = 1.22-3.05, I(2) = 76%). On the basis of these results, we have demonstrated that loss of ARID1A shortened time to cancer-specific mortality, and to recurrence of cancer when adjusting for potential confounders. For its role, this gene should be considered as an important potential target for personalized medicine in cancer treatment.

  8. B-Raf mutation: a key player in molecular biology of cancer.

    Science.gov (United States)

    Rahman, M A; Salajegheh, A; Smith, R A; Lam, A K-Y

    2013-12-01

    B-Raf is one of the more commonly mutated proto-oncogenes implicated in the development of cancers. In this review, we consider the mechanisms and clinical impacts of B-Raf mutations in cancer and discuss the implications for the patient in melanoma, thyroid cancer and colorectal cancer, where B-Raf mutations are particularly common.

  9. Multiple origins of knockdown resistance mutations in the Afrotropical mosquito vector Anopheles gambiae.

    Directory of Open Access Journals (Sweden)

    João Pinto

    Full Text Available How often insecticide resistance mutations arise in natural insect populations is a fundamental question for understanding the evolution of resistance and also for modeling its spread. Moreover, the development of resistance is regarded as a favored model to study the molecular evolution of adaptive traits. In the malaria vector Anopheles gambiae two point mutations (L1014F and L1014S in the voltage-gated sodium channel gene, that confer knockdown resistance (kdr to DDT and pyrethroid insecticides, have been described. In order to determine whether resistance alleles result from single or multiple mutation events, genotyping of the kdr locus and partial sequencing of the upstream intron-1 was performed on a total of 288 A. gambiae S-form collected from 28 localities in 15 countries. Knockdown resistance alleles were found to be widespread in West Africa with co-occurrence of both 1014S and 1014F in West-Central localities. Differences in intron-1 haplotype composition suggest that kdr alleles may have arisen from at least four independent mutation events. Neutrality tests provided evidence for a selective sweep acting on this genomic region, particularly in West Africa. The frequency and distribution of these kdr haplotypes varied geographically, being influenced by an interplay between different mutational occurrences, gene flow and local selection. This has important practical implications for the management and sustainability of malaria vector control programs.

  10. Service composition in cloud manufacturing based on adaptive mutation particle swarm optimization%基于自适应粒子群算法的制造云服务组合研究

    Institute of Scientific and Technical Information of China (English)

    刘卫宁; 李一鸣; 刘波

    2012-01-01

    To cope with Multi-objective Programming on Manufacturing Cloud Service Composition ( MOP-MCSC) problem in cloud manufacturing (CMfg) system, a mathematical model and a solution algorithm were proposed and studied. Firstly, inspired by the resource service composition technology in manufacturing grid, a QoS-aware MOP-MCSC model in CMfg system had been explored and described. Secondly, by analyzing the characteristics of manufacturing cloud services according to the domain knowledge of manufacturing, an eight-dimensional QoS evaluation criterion with corresponding quantitative calculation formulas was defined. Then, the QoS expression of manufacturing cloud service was eventually formulated. Lastly, the MOP-MCSC model was built, and an Adaptive Mutation Particle Swarm Optimization (AMPSO) was designed to realize this model. The simulation experimental results suggest that the proposed algorithm could solve the MOP-MCSC problem efficiently and effectively with a better performance than conventional particle swarm optimization.%针对云制造系统中制造云服务组合的多目标规划问题,研究建立了问题模型并提出了求解方法.首先引入了网格制造模式的制造资源服务组合技术,探讨并描述了云制造模式中基于服务质量(QoS)的制造云服务组合过程;接着通过分析云制造模式下制造云服务的特征并基于制造领域知识,研究定义了制造云服务的八维QoS评估标准及计算表达式,推导出制造组合云服务的QoS表达,进而建立了制造云服务组合的多目标规划问题模型.最终设计了自适应粒子群算法来解决该多目标规划问题.仿真实验表明,该算法能有效并高效地解决该问题,且求解效率优于传统粒子群算法.

  11. The Formation of Rational and Irrational Behaviors in Risky Investment Decision Making: Laboratory Experiment of Coping Theory Implication in Investors’ Adaptation Model

    Directory of Open Access Journals (Sweden)

    Wendy Wendy

    2014-08-01

    Full Text Available This study analyzes the stock investor's rational and irrational behavior formation through Investor's Adaptation model. Hypotheses testings were conducted by manipulating four market conditions using between-subject experimental design. The results supported the hypotheses proposed in this study. When given treatment one (opportunity-high control, investors tended to adapt the profit maximizing strategy (rational. Meanwhile, when given treatment two (opportunity-low control, three (threat-high control and four (threat-low control, they tended to adapt the profit satisfying strategy (rational-emotional, bad news handling strategy (emotional-rational, and self-preserving strategy (irrational respectively. The application of rational strategies are intended to obtain personal benefits and profit, while adapting irrational strategy is intended to recover emotional stability and reduce some other tensions. Another finding showed that for the investors, the relatively irrational decision formation was "harder" than that of rational.

  12. Allele-specific suppression of the temperature sensitivity of fitA/fitB mutants of Escherichia coli by a new mutation (fitC4): isolation, characterization and its implications in transcription control

    Indian Academy of Sciences (India)

    S Vidya; B Praveen Kamalakar; M Hussain Munavar; L Sathish Kumar; R Jayaraman

    2006-03-01

    The temperature sensitive transcription defective mutant of Escherichia coli originally called fitA76 has been shown to harbour two missense mutations namely pheS5 and fit95. In order to obtain a suppressor of fitA76, possibly mapping in rpoD locus, a Ts+ derivative (JV4) was isolated from a fitA76 mutant. It was found that JV4 neither harbours the lesions present in the original fitA76 nor a suppressor that maps in or near rpoD. We show that JV4 harbours a modified form of fitA76 (designated fitA76*) together with its suppressor. The results presented here indicate that the fit95 lesion is intact in the fitA76* mutant and the modification should be at the position of pheS5. Based on the cotransduction of the suppressor mutation and/or its wild type allele with pps, aroD and zdj-3124::Tn10 kan we have mapped its location to 39⋅01 min on the E. coli chromosome. We tentatively designate the locus defined by this new extragenic suppressor as fitC and the suppressor allele as fitC4. While fitC4 could suppress the Ts phenotype of fitA76* present in JV4, it fails to suppress the Ts phenotype of the original fitA76 mutant (harbouring pheS5 and fit95). Also fitC4 could suppress the Ts phenotype of a strain harbouring only pheS5. Interestingly, the fitC4 Ts phenotype could also be suppressed by fit95. The pattern of decay of pulse labelled RNA in the strains harbouring fitC4 and the fitA76* resembles that of the original fitA76 mutant implying a transcription defect similar to that of fitA76 in both these mutants. The implications of these findings with special reference to transcription control by Fit factors in vivo are discussed.

  13. Sensitive detection of pre-existing BCR-ABL kinase domain mutations in CD34+ cells of newly diagnosed chronic-phase chronic myeloid leukemia patients is associated with imatinib resistance: implications in the post-imatinib era.

    Directory of Open Access Journals (Sweden)

    Zafar Iqbal

    Full Text Available BACKGROUND: BCR-ABL kinase domain mutations are infrequently detected in newly diagnosed chronic-phase chronic myeloid leukemia (CML patients. Recent studies indicate the presence of pre-existing BCR-ABL mutations in a higher percentage of CML patients when CD34+ stem/progenitor cells are investigated using sensitive techniques, and these mutations are associated with imatinib resistance and disease progression. However, such studies were limited to smaller number of patients. METHODS: We investigated BCR-ABL kinase domain mutations in CD34+ cells from 100 chronic-phase CML patients by multiplex allele-specific PCR and sequencing at diagnosis. Mutations were re-investigated upon manifestation of imatinib resistance using allele-specific PCR and direct sequencing of BCR-ABL kinase domain. RESULTS: Pre-existing BCR-ABL mutations were detected in 32/100 patients and included F311L, M351T, and T315I. After a median follow-up of 30 months (range 8-48, all patients with pre-existing BCR-ABL mutations exhibited imatinib resistance. Of the 68 patients without pre-existing BCR-ABL mutations, 24 developed imatinib resistance; allele-specific PCR and BCR-ABL kinase domain sequencing detected mutations in 22 of these patients. All 32 patients with pre-existing BCR-ABL mutations had the same mutations after manifestation of imatinib-resistance. In imatinib-resistant patients without pre-existing BCR-ABL mutations, we detected F311L, M351T, Y253F, and T315I mutations. All imatinib-resistant patients except T315I and Y253F mutations responded to imatinib dose escalation. CONCLUSION: Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid

  14. Intraspecific variation of a dominant grass and local adaptation in reciprocal garden communities along a US Great Plains' precipitation gradient: implications for grassland restoration with climate change.

    Science.gov (United States)

    Johnson, Loretta C; Olsen, Jacob T; Tetreault, Hannah; DeLaCruz, Angel; Bryant, Johnny; Morgan, Theodore J; Knapp, Mary; Bello, Nora M; Baer, Sara G; Maricle, Brian R

    2015-08-01

    Identifying suitable genetic stock for restoration often employs a 'best guess' approach. Without adaptive variation studies, restoration may be misguided. We test the extent to which climate in central US grasslands exerts selection pressure on a foundation grass big bluestem (Andropogon gerardii), widely used in restorations, and resulting in local adaptation. We seeded three regional ecotypes of A. gerardii in reciprocal transplant garden communities across 1150 km precipitation gradient. We measured ecological responses over several timescales (instantaneous gas exchange, medium-term chlorophyll absorbance, and long-term responses of establishment and cover) in response to climate and biotic factors and tested if ecotypes could expand range. The ecotype from the driest region exhibited greatest cover under low rainfall, suggesting local adaptation under abiotic stress. Unexpectedly, no evidence for cover differences between ecotypes exists at mesic sites where establishment and cover of all ecotypes were low, perhaps due to strong biotic pressures. Expression of adaptive differences is strongly environment specific. Given observed adaptive variation, the most conservative restoration strategy would be to plant the local ecotype, especially in drier locations. With superior performance of the most xeric ecotype under dry conditions and predicted drought, this ecotype may migrate eastward, naturally or with assistance in restorations.

  15. Implications of Childhood Experiences for the Health and Adaptation of Lesbian, Gay, and Bisexual Individuals: Sensitivity to Developmental Process in Future Research

    Science.gov (United States)

    Rosario, Margaret

    2015-01-01

    The empirical literature on lesbian, gay, and bisexual (LGB) individuals has predominantly focused on sexual-orientation disparities between LGB and heterosexual individuals on health and adaptation, as well as on the role of gay-related or minority stress in the health and adaptation of LGB individuals. Aside from demographic control variables, the initial predictor is a marker of sexual orientation or LGB-related experience (e.g., minority stress). Missing are potential strengths and vulnerabilities that LGB individuals develop over time and bring to bear on their sexual identity development and other LGB-related experiences. Those strengths and vulnerabilities may have profound consequences for the sexual identity development, health, and adaptation of LGB individuals. Here, I focus on one such set of strengths and vulnerabilities derived from attachment. I conclude by emphasizing the importance of attachment in the lives of LGB individuals and the need to identify other developmental processes that may be equally consequential. PMID:26900586

  16. Hypermutation and stress adaptation in bacteria

    Indian Academy of Sciences (India)

    R. Jayaraman

    2011-08-01

    Hypermutability is a phenotype characterized by a moderate to high elevation of spontaneous mutation rates and could result from DNA replication errors, defects in error correction mechanisms and many other causes. The elevated mutation rates are helpful to organisms to adapt to sudden and unforeseen threats to survival. At the same time hypermutability also leads to the generation of many deleterious mutations which offset its adaptive value and therefore disadvantageous. Nevertheless, it is very common in nature, especially among clinical isolates of pathogens. Hypermutability is inherited by indirect (second order) selection along with the beneficial mutations generated. At large population sizes and high mutation rates many cells in the population could concurrently acquire beneficial mutations of varying adaptive (fitness) values. These lineages compete with the ancestral cells and also among themselves for fixation. The one with the ‘fittest’ mutation gets fixed ultimately while the others are lost. This has been called ‘clonal interference’ which puts a speed limit on adaptation. The original clonal interference hypothesis has been modified recently. Nonheritable (transient) hypermtability conferring significant adaptive benefits also occur during stress response although its molecular basis remains controversial. The adaptive benefits of heritable hypermutability are discussed with emphasis on host–pathogen interactions.

  17. CF Mutation Panel

    Science.gov (United States)

    ... Testing; Cystic Fibrosis Transmembrane Conductance Regulator Mutation Analysis; CFTR Mutation Analysis Formal name: Cystic Fibrosis Gene Mutation ... an elevated immunoreactive trypsinogen (IRT) or positive sweat chloride test , to confirm the diagnosis of cystic fibrosis. ...

  18. Generation of mutation hotspots in ageing bacterial colonies

    DEFF Research Database (Denmark)

    Sekowska, Agnieszka; Wendel, Sofie; Christian Fischer, Emil

    2016-01-01

    How do ageing bacterial colonies generate adaptive mutants? Over a period of two months, we isolated on ageing colonies outgrowing mutants able to use a new carbon source, and sequenced their genomes. This allowed us to uncover exquisite details on the molecular mechanism behind their adaptation......: most mutations were located in just a few hotspots in the genome, and over time, mutations increasingly were consistent with the involvement of 8-oxo-guanosine, formed exclusively on the transcribed strand. This work provides strong support for retromutagenesis as a general process creating adaptive...... mutations during ageing....

  19. Physicochemical evolution and molecular adaptation of the cetacean osmoregulation-related gene UT-A2 and implications for functional studies.

    Science.gov (United States)

    Wang, Jingzhen; Yu, Xueying; Hu, Bo; Zheng, Jinsong; Xiao, Wuhan; Hao, Yujiang; Liu, Wenhua; Wang, Ding

    2015-03-12

    Cetaceans have an enigmatic evolutionary history of re-invading aquatic habitats. One of their essential adaptabilities that has enabled this process is their homeostatic strategy adjustment. Here, we investigated the physicochemical evolution and molecular adaptation of the cetacean urea transporter UT-A2, which plays an important role in urine concentration and water homeostasis. First, we cloned UT-A2 from the freshwater Yangtze finless porpoise, after which bioinformatics analyses were conducted based on available datasets (including freshwater baiji and marine toothed and baleen whales) using MEGA, PAML, DataMonkey, TreeSAAP and Consurf. Our findings suggest that the UT-A2 protein shows folding similar to that of dvUT and UT-B, whereas some variations occurred in the functional So and Si regions of the selectivity filter. Additionally, several regions of the cetacean UT-A2 protein have experienced molecular adaptations. We suggest that positive-destabilizing selection could contribute to adaptations by influencing its biochemical and conformational character. The conservation of amino acid residues within the selectivity filter of the urea conduction pore is likely to be necessary for urea conduction, whereas the non-conserved amino acid replacements around the entrance and exit of the conduction pore could potentially affect the activity, which could be interesting target sites for future mutagenesis studies.

  20. Rhodopsin mutations are scarcely implicated in autosomal ...

    African Journals Online (AJOL)

    Reem Mebed

    2015-04-23

    Apr 23, 2015 ... d National Institute of Laser Enhanced Sciences, Cairo University, ... Rhodopsin is considered the most mutant protein causing ... dominant transmission were either the presence of three or .... Direct forward and reverse.

  1. Trade-Offs of Escherichia coli Adaptation to an Intracellular Lifestyle in Macrophages.

    Directory of Open Access Journals (Sweden)

    M Azevedo

    Full Text Available The bacterium Escherichia coli exhibits remarkable genomic and phenotypic variation, with some pathogenic strains having evolved to survive and even replicate in the harsh intra-macrophage environment. The rate and effects of mutations that can cause pathoadaptation are key determinants of the pace at which E. coli can colonize such niches and become pathogenic. We used experimental evolution to determine the speed and evolutionary paths undertaken by a commensal strain of E. coli when adapting to intracellular life. We estimated the acquisition of pathoadaptive mutations at a rate of 10-6 per genome per generation, resulting in the fixation of more virulent strains in less than a hundred generations. Whole genome sequencing of independently evolved clones showed that the main targets of intracellular adaptation involved loss of function mutations in genes implicated in the assembly of the lipopolysaccharide core, iron metabolism and di- and tri-peptide transport, namely rfaI, fhuA and tppB, respectively. We found a substantial amount of antagonistic pleiotropy in evolved populations, as well as metabolic trade-offs, commonly found in intracellular bacteria with reduced genome sizes. Overall, the low levels of clonal interference detected indicate that the first steps of the transition of a commensal E. coli into intracellular pathogens are dominated by a few pathoadaptive mutations with very strong effects.

  2. A nonsymbiotic root hair tip growth phenotype in NORK-mutated legumes: implications for nodulation factor-induced signaling and formation of a multifaceted root hair pocket for bacteria

    NARCIS (Netherlands)

    Esseling, J.J.; Lhuissier, F.G.P.; Emons, A.M.C.

    2004-01-01

    The Medicago truncatula Does not Make Infections (DMI2) mutant is mutated in the nodulation receptor-like kinase, NORK. Here, we report that NORK-mutated legumes of three species show an enhanced touch response to experimental handling, which results in a nonsymbiotic root hair phenotype. When care

  3. Role of positron emission tomography and bone scintigraphy in the evaluation of bone involvement in metastatic pheochromocytoma and paraganglioma: specific implications for succinate dehydrogenase enzyme subunit B gene mutations.

    NARCIS (Netherlands)

    Zelinka, T.; Timmers, H.J.L.M.; Kozupa, A.; Chen, C.C.; Carrasquillo, J.A.; Reynolds, J.C.; Ling, A.; Eisenhofer, G.; Lazurova, I.; Adams, K.T.; Whatley, M.A.; Widimsky, J.Jr.; Pacak, K.

    2008-01-01

    We performed a retrospective analysis of 71 subjects with metastatic pheochromocytoma and paraganglioma (30 subjects with mutation of succinate dehydrogenase enzyme subunit B (SDHB) gene and 41 subjects without SDHB mutation). Sixty-nine percent presented with bone metastases (SDHB +/-: 77% vs 63%),

  4. Cross-cultural adaptation and preliminary psychometric properties of the Affective Reactivity Index in Brazilian Youth: implications for DSM-5 measured irritability

    Directory of Open Access Journals (Sweden)

    Diogo Araújo DeSousa

    2013-01-01

    Full Text Available Objective: To describe the cross-cultural adaptation of the Affective Reactivity Index (ARI to Brazilian Portuguese and to investigate preliminary psychometric properties of the adapted version. Methods: Cross-cultural adaptation was based on the investigation of the theoretical and operational equivalences of the original ARI in the Brazilian context, followed by a process of translation, back-translation, and review by a committee of experts. Data analysis was carried out in a community sample of 133 schoolchildren aged 8 to 17 years to investigate the following characteristics of the ARI: 1 factor structure; 2 internal consistency; 3 construct validity comparing differential relationships between irritability and anxiety dimensions and impairment; and 4 item response theory (IRT parameters. Results: A final Brazilian Portuguese version of the instrument was defined and is presented. Internal consistency was good, and our analysis supported the original single-factor structure of the ARI. Correlations of the ARI with distress-related anxiety dimensions were higher than with phobic-related anxiety dimensions, supporting its construct validity. In addition, higher ARI scores were associated with higher irritability-related impairment. IRT analysis underscored frequency of loss of temper as essential to inform about pathological states of irritability. Conclusion: The Brazilian Portuguese version of the ARI seems to be very similar to the original instrument in terms of conceptual, item, semantic, and operational equivalence. Our preliminary analysis replicates and extends previous evidence confirming promising psychometric properties for the ARI.

  5. Environmental change drives accelerated adaptation through stimulated copy number variation

    Science.gov (United States)

    Hull, Ryan M.; Cruz, Cristina; Jack, Carmen V.

    2017-01-01

    Copy number variation (CNV) is rife in eukaryotic genomes and has been implicated in many human disorders, particularly cancer, in which CNV promotes both tumorigenesis and chemotherapy resistance. CNVs are considered random mutations but often arise through replication defects; transcription can interfere with replication fork progression and stability, leading to increased mutation rates at highly transcribed loci. Here we investigate whether inducible promoters can stimulate CNV to yield reproducible, environment-specific genetic changes. We propose a general mechanism for environmentally-stimulated CNV and validate this mechanism for the emergence of copper resistance in budding yeast. By analysing a large cohort of individual cells, we directly demonstrate that CNV of the copper-resistance gene CUP1 is stimulated by environmental copper. CNV stimulation accelerates the formation of novel alleles conferring enhanced copper resistance, such that copper exposure actively drives adaptation to copper-rich environments. Furthermore, quantification of CNV in individual cells reveals remarkable allele selectivity in the rate at which specific environments stimulate CNV. We define the key mechanistic elements underlying this selectivity, demonstrating that CNV is regulated by both promoter activity and acetylation of histone H3 lysine 56 (H3K56ac) and that H3K56ac is required for CUP1 CNV and efficient copper adaptation. Stimulated CNV is not limited to high-copy CUP1 repeat arrays, as we find that H3K56ac also regulates CNV in 3 copy arrays of CUP1 or SFA1 genes. The impact of transcription on DNA damage is well understood, but our research reveals that this apparently problematic association forms a pathway by which mutations can be directed to particular loci in particular environments and furthermore that this mutagenic process can be regulated through histone acetylation. Stimulated CNV therefore represents an unanticipated and remarkably controllable pathway

  6. Molecular Clock of Neutral Mutations in a Fitness-Increasing Evolutionary Process.

    Directory of Open Access Journals (Sweden)

    Toshihiko Kishimoto

    2015-07-01

    Full Text Available The molecular clock of neutral mutations, which represents linear mutation fixation over generations, is theoretically explained by genetic drift in fitness-steady evolution or hitchhiking in adaptive evolution. The present study is the first experimental demonstration for the molecular clock of neutral mutations in a fitness-increasing evolutionary process. The dynamics of genome mutation fixation in the thermal adaptive evolution of Escherichia coli were evaluated in a prolonged evolution experiment in duplicated lineages. The cells from the continuously fitness-increasing evolutionary process were subjected to genome sequencing and analyzed at both the population and single-colony levels. Although the dynamics of genome mutation fixation were complicated by the combination of the stochastic appearance of adaptive mutations and clonal interference, the mutation fixation in the population was simply linear over generations. Each genome in the population accumulated 1.6 synonymous and 3.1 non-synonymous neutral mutations, on average, by the spontaneous mutation accumulation rate, while only a single genome in the population occasionally acquired an adaptive mutation. The neutral mutations that preexisted on the single genome hitchhiked on the domination of the adaptive mutation. The successive fixation processes of the 128 mutations demonstrated that hitchhiking and not genetic drift were responsible for the coincidence of the spontaneous mutation accumulation rate in the genome with the fixation rate of neutral mutations in the population. The molecular clock of neutral mutations to the fitness-increasing evolution suggests that the numerous neutral mutations observed in molecular phylogenetic trees may not always have been fixed in fitness-steady evolution but in adaptive evolution.

  7. Molecular Clock of Neutral Mutations in a Fitness-Increasing Evolutionary Process.

    Science.gov (United States)

    Kishimoto, Toshihiko; Ying, Bei-Wen; Tsuru, Saburo; Iijima, Leo; Suzuki, Shingo; Hashimoto, Tomomi; Oyake, Ayana; Kobayashi, Hisaka; Someya, Yuki; Narisawa, Dai; Yomo, Tetsuya

    2015-07-01

    The molecular clock of neutral mutations, which represents linear mutation fixation over generations, is theoretically explained by genetic drift in fitness-steady evolution or hitchhiking in adaptive evolution. The present study is the first experimental demonstration for the molecular clock of neutral mutations in a fitness-increasing evolutionary process. The dynamics of genome mutation fixation in the thermal adaptive evolution of Escherichia coli were evaluated in a prolonged evolution experiment in duplicated lineages. The cells from the continuously fitness-increasing evolutionary process were subjected to genome sequencing and analyzed at both the population and single-colony levels. Although the dynamics of genome mutation fixation were complicated by the combination of the stochastic appearance of adaptive mutations and clonal interference, the mutation fixation in the population was simply linear over generations. Each genome in the population accumulated 1.6 synonymous and 3.1 non-synonymous neutral mutations, on average, by the spontaneous mutation accumulation rate, while only a single genome in the population occasionally acquired an adaptive mutation. The neutral mutations that preexisted on the single genome hitchhiked on the domination of the adaptive mutation. The successive fixation processes of the 128 mutations demonstrated that hitchhiking and not genetic drift were responsible for the coincidence of the spontaneous mutation accumulation rate in the genome with the fixation rate of neutral mutations in the population. The molecular clock of neutral mutations to the fitness-increasing evolution suggests that the numerous neutral mutations observed in molecular phylogenetic trees may not always have been fixed in fitness-steady evolution but in adaptive evolution.

  8. Role of positron emission tomography and bone scintigraphy in the evaluation of bone involvement in metastatic pheochromocytoma and paraganglioma: specific implications for succinate dehydrogenase enzyme subunit B gene mutations.

    Science.gov (United States)

    Zelinka, Tomás; Timmers, Henri J L M; Kozupa, Anna; Chen, Clara C; Carrasquillo, Jorge A; Reynolds, James C; Ling, Alexander; Eisenhofer, Graeme; Lazúrová, Ivica; Adams, Karen T; Whatley, Millie A; Widimsky, Jirí; Pacak, Karel

    2008-03-01

    We performed a retrospective analysis of 71 subjects with metastatic pheochromocytoma and paraganglioma (30 subjects with mutation of succinate dehydrogenase enzyme subunit B (SDHB) gene and 41 subjects without SDHB mutation). Sixty-nine percent presented with bone metastases (SDHB +/-: 77% vs 63%), 39% with liver metastases (SDHB +/-: 27% vs 47%), and 32% with lung metastases (SDHB +/-: 37% vs 29%). The most common sites of bone involvement were thoracic spine (80%; SDHB+/-: 83% vs 77%), lumbar spine (78%; SDHB +/-: 78% vs 75%), and pelvic and sacral bones (78%; SDHB +/-: 91% vs 65%, P=0.04). Subjects with SDHB mutation also showed significantly higher involvement of long bones (SDHB +/-: 78% vs 30%, P=0.007) than those without the mutation. The best overall sensitivity in detecting bone metastases demonstrated positron emission tomography (PET) with 6-[(18)F]-fluorodopamine ([(18)F]-FDA; 90%), followed by bone scintigraphy (82%), computed tomography or magnetic resonance imaging (CT/MRI; 78%), 2-[(18)F]-fluoro-2-deoxy-d-glucose ([(18)F]-FDG) PET (76%), and scintigraphy with [(123/131)I]-metaiodobenzylguanidine (71%). In subjects with SDHB mutation, imaging modalities with best sensitivities for detecting bone metastases were CT/MRI (96%), bone scintigraphy (95%), and [(18)F]-FDG PET (92%). In subjects without SDHB mutations, the modality with the best sensitivity for bone metastases was [(18)F]-FDA PET (100%). In conclusion, bone scintigraphy should be used in the staging of patients with malignant pheochromocytoma and paraganglioma, particularly in patients with SDHB mutations. As for PET imaging, [(18)F]-FDG PET is highly recommended in SDHB mutation patients, whereas [(18)F]-FDA PET is recommended in patients without the mutation.

  9. Mutation Clusters from Cancer Exome.

    Science.gov (United States)

    Kakushadze, Zura; Yu, Willie

    2017-08-15

    We apply our statistically deterministic machine learning/clustering algorithm *K-means (recently developed in https://ssrn.com/abstract=2908286) to 10,656 published exome samples for 32 cancer types. A majority of cancer types exhibit a mutation clustering structure. Our results are in-sample stable. They are also out-of-sample stable when applied to 1389 published genome samples across 14 cancer types. In contrast, we find in- and out-of-sample instabilities in cancer signatures extracted from exome samples via nonnegative matrix factorization (NMF), a computationally-costly and non-deterministic method. Extracting stable mutation structures from exome data could have important implications for speed and cost, which are critical for early-stage cancer diagnostics, such as novel blood-test methods currently in development.

  10. Short-Term Local Adaptation of Historical Common Bean (Phaseolus vulgaris L. Varieties and Implications for In Situ Management of Bean Diversity

    Directory of Open Access Journals (Sweden)

    Stephanie M. Klaedtke

    2017-02-01

    Full Text Available Recognizing both the stakes of traditional European common bean diversity and the role farmers’ and gardeners’ networks play in maintaining this diversity, the present study examines the role that local adaptation plays for the management of common bean diversity in situ. To the purpose, four historical bean varieties and one modern control were multiplied on two organic farms for three growing seasons. The fifteen resulting populations, the initial ones and two populations of each variety obtained after the three years of multiplication, were then grown in a common garden. Twenty-two Simple Sequence Repeat (SSR markers and 13 phenotypic traits were assessed. In total, 68.2% of tested markers were polymorphic and a total of 66 different alleles were identified. FST analysis showed that the genetic composition of two varieties multiplied in different environments changed. At the phenotypic level, differences were observed in flowering date and leaf length. Results indicate that three years of multiplication suffice for local adaptation to occur. The spatial dynamics of genetic and phenotypic bean diversity imply that the maintenance of diversity should be considered at the scale of the network, rather than individual farms and gardens. The microevolution of bean populations within networks of gardens and farms emerges as a research perspective.

  11. Short-Term Local Adaptation of Historical Common Bean (Phaseolus vulgaris L.) Varieties and Implications for In Situ Management of Bean Diversity.

    Science.gov (United States)

    Klaedtke, Stephanie M; Caproni, Leonardo; Klauck, Julia; de la Grandville, Paul; Dutartre, Martin; Stassart, Pierre M; Chable, Véronique; Negri, Valeria; Raggi, Lorenzo

    2017-02-28

    Recognizing both the stakes of traditional European common bean diversity and the role farmers' and gardeners' networks play in maintaining this diversity, the present study examines the role that local adaptation plays for the management of common bean diversity in situ. To the purpose, four historical bean varieties and one modern control were multiplied on two organic farms for three growing seasons. The fifteen resulting populations, the initial ones and two populations of each variety obtained after the three years of multiplication, were then grown in a common garden. Twenty-two Simple Sequence Repeat (SSR) markers and 13 phenotypic traits were assessed. In total, 68.2% of tested markers were polymorphic and a total of 66 different alleles were identified. FST analysis showed that the genetic composition of two varieties multiplied in different environments changed. At the phenotypic level, differences were observed in flowering date and leaf length. Results indicate that three years of multiplication suffice for local adaptation to occur. The spatial dynamics of genetic and phenotypic bean diversity imply that the maintenance of diversity should be considered at the scale of the network, rather than individual farms and gardens. The microevolution of bean populations within networks of gardens and farms emerges as a research perspective.

  12. A pox on thee! Manipulation of the host immune system by myxoma virus and implications for viral-host co-adaptation.

    Science.gov (United States)

    Zúñiga, Martha C

    2002-09-01

    The poxviruses have evolved a diverse array of proteins which serve to subvert innate and adaptive host responses that abort or at least limit viral infections. Myxoma virus and its rabbit host are considered to represent an ideal poxvirus-host system in which to study the effects of these immunomodulatory proteins. Studies of laboratory rabbits (Oryctolagus cuniculus) infected with gene knockout variants of myxoma virus have provided compelling evidence that several myxoma virus gene products contribute to the pathogenic condition known as myxomatosis. However, myxomatosis, which is characterized by skin lesions, systemic immunosuppression, and a high mortality rate, does not occur in the virus' natural South American host, Sylvilogus brasiliensis. Moreover, in Australia where myxoma virus was willfully introduced to control populations of O. cuniculus, myxomatosis-resistant rabbits emerged within a year of myxoma virus introduction into the field. In this review I discuss the characterized immunomodulatory proteins of myxoma virus, their biochemical properties, their pathogenic effects in laboratory rabbits, the role of the host immune system in the susceptibility or resistance to myxomatosis, and the evidence that immunomodulatory genes may have been attenuated during the co-adaptation of myxoma virus and O. cuniculus in Australia.

  13. Molecular evolution and thermal adaptation

    Science.gov (United States)

    Chen, Peiqiu

    2011-12-01

    In this thesis, we address problems in molecular evolution, thermal adaptation, and the kinetics of adaptation of bacteria and viruses to elevated environmental temperatures. We use a nearly neutral fitness model where the replication speed of an organism is proportional to the copy number of folded proteins. Our model reproduces the distribution of stabilities of natural proteins in excellent agreement with experiment. We find that species with high mutation rates tend to have less stable proteins compared to species with low mutation rate. We found that a broad distribution of protein stabilities observed in the model and in experiment is the key determinant of thermal response for viruses and bacteria. Our results explain most of the earlier experimental observations: striking asymmetry of thermal response curves, the absence of evolutionary trade-off which was expected but not found in experiments, correlation between denaturation temperature for several protein families and the Optimal Growth Temperature (OGT) of their carrier organisms, and proximity of bacterial or viral OGTs to their evolutionary temperatures. Our theory quantitatively and with high accuracy described thermal response curves for 35 bacterial species. The model also addresses the key to adaptation is in weak-link genes (WLG), which encode least thermodynamically stable essential proteins in the proteome. We observe, as in experiment, a two-stage adaptation process. The first stage is a Luria-Delbruck type of selection, whereby rare WLG alleles, whose proteins are more stable than WLG proteins of the majority of the population (either due to standing genetic variation or due to an early acquired mutation), rapidly rise to fixation. The second stage constitutes subsequent slow accumulation of mutations in an adapted population. As adaptation progresses, selection regime changes from positive to neutral: Selection coefficient of beneficial mutations scales as a negative power of number of

  14. Salivary miRNA profiles identify children with autism spectrum disorder, correlate with adaptive behavior, and implicate ASD candidate genes involved in neurodevelopment.

    Science.gov (United States)

    Hicks, Steven D; Ignacio, Cherry; Gentile, Karen; Middleton, Frank A

    2016-04-22

    Autism spectrum disorder (ASD) is a common neurodevelopmental disorder that lacks adequate screening tools, often delaying diagnosis and therapeutic interventions. Despite a substantial genetic component, no single gene variant accounts for >1 % of ASD incidence. Epigenetic mechanisms that include microRNAs (miRNAs) may contribute to the ASD phenotype by altering networks of neurodevelopmental genes. The extracellular availability of miRNAs allows for painless, noninvasive collection from biofluids. In this study, we investigated the potential for saliva-based miRNAs to serve as diagnostic screening tools and evaluated their potential functional importance. Salivary miRNA was purified from 24 ASD subjects and 21 age- and gender-matched control subjects. The ASD group included individuals with mild ASD (DSM-5 criteria and Autism Diagnostic Observation Schedule) and no history of neurologic disorder, pre-term birth, or known chromosomal abnormality. All subjects completed a thorough neurodevelopmental assessment with the Vineland Adaptive Behavior Scales at the time of saliva collection. A total of 246 miRNAs were detected and quantified in at least half the samples by RNA-Seq and used to perform between-group comparisons with non-parametric testing, multivariate logistic regression and classification analyses, as well as Monte-Carlo Cross-Validation (MCCV). The top miRNAs were examined for correlations with measures of adaptive behavior. Functional enrichment analysis of the highest confidence mRNA targets of the top differentially expressed miRNAs was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID), as well as the Simons Foundation Autism Database (AutDB) of ASD candidate genes. Fourteen miRNAs were differentially expressed in ASD subjects compared to controls (p ASD demonstrated differential expression of 14 miRNAs that are expressed in the developing brain, impact mRNAs related to brain development, and correlate with

  15. Modulation of allele leakiness and adaptive mutability in Escherichia coli

    Indian Academy of Sciences (India)

    R. Jayaraman

    2000-08-01

    It is shown that partial phenotypic suppression of two ochre mutations (argE3 and lacZU118) and an amber mutation (in argE) by sublethal concentrations of streptomycin in an rpsL+ (streptomycin-sensitive) derivative of the Escherichia coli strain AB1157 greatly enhances their adaptive mutability under selection. Streptomycin also increases adaptive mutability brought about by the ppm mutation described earlier. Inactivation of recA affects neither phenotypic suppression by streptomycin nor replication-associated mutagenesis but abolishes adaptive mutagenesis. These results indicate a causal relationship between allele leakiness and adaptive mutability.

  16. The Adaptation Finance Gap Report

    DEFF Research Database (Denmark)

    UNEP’s Adaptation Gap Report series focuses on Finance, Technology and Knowledge gaps in climate change adaptation. It compliments the Emissions Gap Report series, and explores the implications of failing to close the emissions gap. The report builds on a 2014 assessment by the United Nations...... Environment Programme (UNEP), which laid out the concept of ‘adaptation gaps’ and outlined three such gaps: technology, finance and knowledge. The 2016 Adaptation Gap Report assesses the difference between the financial costs of adapting to climate change in developing countries and the amount of money...... actually available to meet these costs – a difference known as the “adaptation finance gap”. Like the 2014 report, the 2016 report focuses on developing countries, where adaptation capacity is often the lowest and needs the highest, and concentrates on the period up to 2050. The report identifies trends...

  17. Interactions Between Snow-Adapted Organisms, Minerals and Snow in a Mars-Analog Environment, and Implications for the Possible Formation of Mineral Biosignatures

    Science.gov (United States)

    Hausrath, E.; Bartlett, C. L.; Garcia, A. H.; Tschauner, O. D.; Murray, A. E.; Raymond, J. A.

    2015-12-01

    Increasing evidence suggests that icy environments on bodies such as Mars, Europa, and Enceladus may be important potential habitats in our solar system. Life in icy environments faces many challenges, including water limitation, temperature extremes, and nutrient limitation. Understanding how life has adapted to withstand these challenges on Earth may help understand potential life on other icy worlds, and understanding the interactions of such life with minerals may help shed light on the detection of possible mineral biosignatures. Snow environments, being particularly nutrient limited, may require specific adaptations by the microbiota living there. Previous observations have suggested that associated minerals and microorganisms play an important role in snow algae micronutrient acquisition. Here, in order to interpret micronutrient uptake by snow algae, and potential formation of mineral biosignatures, we present observations of interactions between snow algae and associated microorganisms and minerals in both natural, Mars-analog environments, and laboratory experiments. Samples of snow, dust, snow algae, and microorganisms were collected from Mount Anderson Ridge, CA. Some samples were DAPI-stained and analyzed by epifluorescent microscopy, and others were freeze-dried and examined by scanning electron microscopy, synchrotron X-ray diffraction (XRD) and synchrotron X-ray fluorescence (XRF). Xenic cultures of the snow alga Chloromonas brevispina were also grown under Fe-limiting conditions with and without the Fe-containing mineral nontronite to determine impacts of the mineral on algal growth. Observations from epifluorescent microscopy show bacteria closely associated with the snow algae, consistent with a potential role in micronutrient acquisition. Particles are also present on the algal cell walls, and synchrotron-XRD and XRF observations indicate that they are Fe-rich, and may therefore be a micronutrient source. Laboratory experiments indicated

  18. Parotid Glands Dose–Effect Relationships Based on Their Actually Delivered Doses: Implications for Adaptive Replanning in Radiation Therapy of Head-and-Neck Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Hunter, Klaudia U. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Fernandes, Laura L. [Department of Biostatistics, University of Michigan, Ann Arbor, Michigan (United States); Vineberg, Karen A.; McShan, Daniel; Antonuk, Alan E. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Cornwall, Craig [Department of Hospital Dentistry, University of Michigan, Ann Arbor, Michigan (United States); Feng, Mary [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Schipper, Mathew J. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Department of Biostatistics, University of Michigan, Ann Arbor, Michigan (United States); Balter, James M. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Eisbruch, Avraham, E-mail: eisbruch@umich.edu [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States)

    2013-11-15

    Purpose: Doses actually delivered to the parotid glands during radiation therapy often exceed planned doses. We hypothesized that the delivered doses correlate better with parotid salivary output than the planned doses, used in all previous studies, and that determining these correlations will help make decisions regarding adaptive radiation therapy (ART) aimed at reducing the delivered doses. Methods and Materials: In this prospective study, oropharyngeal cancer patients treated definitively with chemoirradiation underwent daily cone-beam computed tomography (CBCT) with clinical setup alignment based on the C2 posterior edge. Parotid glands in the CBCTs were aligned by deformable registration to calculate cumulative delivered doses. Stimulated salivary flow rates were measured separately from each parotid gland pretherapy and periodically posttherapy. Results: Thirty-six parotid glands of 18 patients were analyzed. Average mean planned doses was 32 Gy, and differences from planned to delivered mean gland doses were −4.9 to +8.4 Gy, median difference +2.2 Gy in glands in which delivered doses increased relative to planned. Both planned and delivered mean doses were significantly correlated with posttreatment salivary outputs at almost all posttherapy time points, without statistically significant differences in the correlations. Large dispersions (on average, SD 3.6 Gy) characterized the dose–effect relationships for both. The differences between the cumulative delivered doses and planned doses were evident at first fraction (r=.92, P<.0001) because of complex setup deviations (eg, rotations and neck articulations), uncorrected by the translational clinical alignments. Conclusions: After daily translational setup corrections, differences between planned and delivered doses in most glands were small relative to the SDs of the dose–saliva data, suggesting that ART is not likely to gain measurable salivary output improvement in most cases. These differences were

  19. In-host adaptation and acquired triazole resistance in Aspergillus fumigatus: a dilemma for clinical management.

    Science.gov (United States)

    Verweij, Paul E; Zhang, Jianhua; Debets, Alfons J M; Meis, Jacques F; van de Veerdonk, Frank L; Schoustra, Sijmen E; Zwaan, Bas J; Melchers, Willem J G

    2016-11-01

    Aspergillus fumigatus causes a range of diseases in human beings, some of which are characterised by fungal persistence. A fumigatus can persist by adapting to the human lung environment through physiological and genomic changes. The physiological changes are based on the large biochemical versatility of the fungus, and the genomic changes are based on the capacity of the fungus to generate genetic diversity by spontaneous mutations or recombination and subsequent selection of the genotypes that are most adapted to the new environment. In this Review, we explore the adaptation strategies of A fumigatus in relation to azole resistance selection and the clinical implications thereof for management of diseases caused by Aspergillus spp. We hypothesise that the current diagnostic tools and treatment strategies do not take into account the biology of the fungus and might result in an increased likelihood of fungal persistence in patients. Stress factors, such as triazole exposure, cause mutations that render resistance. The process of reproduction-ie, sexual, parasexual, or asexual-is probably crucial for the adaptive potential of Aspergillus spp. As any change in the environment can provoke adaptation, switching between triazoles in patients with chronic pulmonary aspergillosis might result in a high-level pan-triazole-resistant phenotype through the accumulation of resistance mutations. Alternatively, when triazole therapy is stopped, an azole-free environment is created that could prompt selection for compensatory mutations that overcome any fitness costs that are expected to accompany resistance development. As a consequence, starting, switching, and stopping azole therapy has the risk of selecting for highly resistant strains with wildtype fitness. A similar adaptation is expected to occur in response to other stress factors, such as endogenous antimicrobial peptides; over time the fungus will become increasingly adapted to the lung environment, thereby limiting

  20. Bacterial adaptation through loss of function.

    Directory of Open Access Journals (Sweden)

    Alison K Hottes

    Full Text Available The metabolic capabilities and regulatory networks of bacteria have been optimized by evolution in response to selective pressures present in each species' native ecological niche. In a new environment, however, the same bacteria may grow poorly due to regulatory constraints or biochemical deficiencies. Adaptation to such conditions can proceed through the acquisition of new cellular functionality due to gain of function mutations or via modulation of cellular networks. Using selection experiments on transposon-mutagenized libraries of bacteria, we illustrate that even under conditions of extreme nutrient limitation, substantial adaptation can be achieved solely through loss of function mutations, which rewire the metabolism of the cell without gain of enzymatic or sensory function. A systematic analysis of similar experiments under more than 100 conditions reveals that adaptive loss of function mutations exist for many environmental challenges. Drawing on a wealth of examples from published articles, we detail the range of mechanisms through which loss-of-function mutations can generate such beneficial regulatory changes, without the need for rare, specific mutations to fine-tune enzymatic activities or network connections. The high rate at which loss-of-function mutations occur suggests that null mutations play an underappreciated role in the early stages of adaption of bacterial populations to new environments.

  1. Recorded Step Directional Mutation for Faster Convergence

    CERN Document Server

    Dunning, Ted

    2008-01-01

    Two meta-evolutionary optimization strategies described in this paper accelerate the convergence of evolutionary programming algorithms while still retaining much of their ability to deal with multi-modal problems. The strategies, called directional mutation and recorded step in this paper, can operate independently but together they greatly enhance the ability of evolutionary programming algorithms to deal with fitness landscapes characterized by long narrow valleys. The directional mutation aspect of this combined method uses correlated meta-mutation but does not introduce a full covariance matrix. These new methods are thus much more economical in terms of storage for problems with high dimensionality. Additionally, directional mutation is rotationally invariant which is a substantial advantage over self-adaptive methods which use a single variance per coordinate for problems where the natural orientation of the problem is not oriented along the axes.

  2. Comparison of low-salinity adaptability and morphological development during the early life history of five pleuronectid flatfishes, and implications for migration and recruitment to their nurseries

    Science.gov (United States)

    Wada, Toshihiro; Aritaki, Masato; Yamashita, Yoh; Tanaka, Masaru

    2007-10-01

    The nursery habitats of flatfishes range from offshore areas to rivers, with salinity conditions varying significantly between the habitats selected by larvae and juveniles. Morphological characteristics of larvae also contribute to the successful recruitment to specific nursery areas. In the present study, ontogenetic developments of low-salinity tolerance and morphology of five pleuronectid flatfishes were examined, and compared with their previously described ontogenetic migrations. Species examined were starry flounder Platichthys stellatus, stone flounder Platichthys bicoloratus, spotted halibut Verasper variegatus, marbled flounder Pseudopleuronectes yokohamae and slime flounder Microstomus achne. The first three were categorised as 'cross-shelf species', marbled flounder as 'demersal-egg species' and slime flounder as 'offshore species'. Their typical nurseries were rivers, estuaries, tidal flats, coastal areas and offshore areas, respectively. Low-salinity tolerance from hatching to juvenile stage was examined by survival 48 h after transfer (A to I stage) and seven days after transfer (I stage) from seawater to various salinities (0, 1, 2, 4, 8, 16 and 32 ppt). High survival in 4 ppt was found in all yolk-sac larvae, but decreased in mid-larval development. During metamorphosis, starry flounder, stone flounder and spotted halibut developed strong low-salinity tolerance and juveniles were able to survive in 0, 1 and 2 ppt, respectively. In contrast, marbled flounder and slime flounder did not show these clear developments and juveniles could only survive in 4 and 8 ppt, respectively. In the morphological development, differences in standard length (SL) and relative body depth (BD) to SL (%BD/SL, an indicator of locomotive adaptation of flatfish larvae showing tilt swimming behaviour during the eye translocation) increased with larval development, and the greatest SL and %BD/SL were observed at the metamorphic climax H stage in the order of slime flounder

  3. Systemic epidermal nevus with involvement of the oral mucosa due to FGFR3 mutation

    DEFF Research Database (Denmark)

    Bygum, Anette; Fagerberg, Christina R; Clemmensen, Ole J

    2011-01-01

    Epidermal nevi (EN) represent benign congenital skin lesions following the lines of Blaschko. They result from genetic mosaicism, and activating FGFR3 and PIK3CA mutations have been implicated.......Epidermal nevi (EN) represent benign congenital skin lesions following the lines of Blaschko. They result from genetic mosaicism, and activating FGFR3 and PIK3CA mutations have been implicated....

  4. Changing Water and Nitrogen Use Efficiency over Agricultural Lands of the Inland Pacific Northwest During the 21th Century: Implications for Adaptation and Mitigation

    Science.gov (United States)

    Liu, M.; Malek, K.; Adam, J. C.; Stockle, C. O.; Rajagopalan, K.; Nelson, R.

    2014-12-01

    As water is the primary resource limitation for cropping systems over the inland Pacific Northwest (PNW), water use efficiency impacts regional water availability, crop yields, and net carbon sequestration. Furthermore, nitrogen (N) use efficiency affects the cost of farming and the total N flux to the environment (including leaching to aquatic ecosystems and greenhouse gas emissions to the atmosphere). Climate change affects water and nitrogen use efficiencies due to the combined effects of warming (reducing snowpack water storage, increasing ET, earlier leaf-on, shortening or lengthening plant growth season, etc.), the CO2 fertilization effects (increasing net primary productivity and leaf-level water and energy use efficiencies for C3 crops), and extreme climate events (drought and flood). Cropland conservation management (rotation, tillage, irrigation, and fertilization) is widely practiced in this region for maintaining high productivity of agricultural lands. To reduce vulnerability to weather extremes and long-term climate change, management regimes will likely need to be adapted for a changing environment. Here, we applied the coupled macro-scale hydrologic and crop growth model (VIC-CropSyst) to study how climate change in the 21st century will change water and nitrogen use efficiencies over the PNW. Simulation experiments with different combinations of management options and climate scenarios are used for attributing effects of climate factors and management options on long-term trends and fluctuations on water and nitrogen use efficiency. Preliminary simulation results indicate that there is a trend of decreasing water and nitrogen use efficiency over the inner PNW domain during the 21th century because of increasing ET, a seasonal shift in water availability, and the intensification of extreme climate events. Effective managements, including no-tillage and conservational tillage and optimized irrigation can eliminate the decrease or even increase water

  5. Evaluating the Photoprotective Effects of Ochre on Human Skin by In Vivo SPF Assessment: Implications for Human Evolution, Adaptation and Dispersal.

    Science.gov (United States)

    Rifkin, Riaan F; Dayet, Laure; Queffelec, Alain; Summers, Beverley; Lategan, Marlize; d'Errico, Francesco

    2015-01-01

    Archaeological indicators of cognitively modern behaviour become increasingly prevalent during the African Middle Stone Age (MSA). Although the exploitation of ochre is viewed as a key feature of the emergence of modern human behaviour, the uses to which ochre and ochre-based mixtures were put remain ambiguous. Here we present the results of an experimental study exploring the efficacy of ochre as a topical photoprotective compound. This is achieved through the in vivo calculation of the sun protection factor (SPF) values of ochre samples obtained from Ovahimba women (Kunene Region, Northern Namibia) and the Palaeozoic Bokkeveld Group deposits of the Cape Supergroup (Western Cape Province, South Africa). We employ visible spectroscopy, energy-dispersive X-ray fluorescence (ED-XRF), X-ray diffraction (XRD) and granulometric analyses to characterise ochre samples. The capacity of ochre to inhibit the susceptibility of humans to the harmful effects of exposure to ultraviolet radiation (UVR) is confirmed and the mechanisms implicated in the efficacy of ochre as a sunscreen identified. It is posited that the habitual application of ochre may have represented a crucial innovation for MSA humans by limiting the adverse effects of ultraviolet exposure. This may have facilitated the colonisation of geographic regions largely unfavourable to the constitutive skin colour of newly arriving populations.

  6. Evaluating the Photoprotective Effects of Ochre on Human Skin by In Vivo SPF Assessment: Implications for Human Evolution, Adaptation and Dispersal.

    Directory of Open Access Journals (Sweden)

    Riaan F Rifkin

    Full Text Available Archaeological indicators of cognitively modern behaviour become increasingly prevalent during the African Middle Stone Age (MSA. Although the exploitation of ochre is viewed as a key feature of the emergence of modern human behaviour, the uses to which ochre and ochre-based mixtures were put remain ambiguous. Here we present the results of an experimental study exploring the efficacy of ochre as a topical photoprotective compound. This is achieved through the in vivo calculation of the sun protection factor (SPF values of ochre samples obtained from Ovahimba women (Kunene Region, Northern Namibia and the Palaeozoic Bokkeveld Group deposits of the Cape Supergroup (Western Cape Province, South Africa. We employ visible spectroscopy, energy-dispersive X-ray fluorescence (ED-XRF, X-ray diffraction (XRD and granulometric analyses to characterise ochre samples. The capacity of ochre to inhibit the susceptibility of humans to the harmful effects of exposure to ultraviolet radiation (UVR is confirmed and the mechanisms implicated in the efficacy of ochre as a sunscreen identified. It is posited that the habitual application of ochre may have represented a crucial innovation for MSA humans by limiting the adverse effects of ultraviolet exposure. This may have facilitated the colonisation of geographic regions largely unfavourable to the constitutive skin colour of newly arriving populations.

  7. Adaptation of the ToxRTool to Assess the Reliability of Toxicology Studies Conducted with Genetically Modified Crops and Implications for Future Safety Testing.

    Science.gov (United States)

    Koch, Michael S; DeSesso, John M; Williams, Amy Lavin; Michalek, Suzanne; Hammond, Bruce

    2016-01-01

    To determine the reliability of food safety studies carried out in rodents with genetically modified (GM) crops, a Food Safety Study Reliability Tool (FSSRTool) was adapted from the European Centre for the Validation of Alternative Methods' (ECVAM) ToxRTool. Reliability was defined as the inherent quality of the study with regard to use of standardized testing methodology, full documentation of experimental procedures and results, and the plausibility of the findings. Codex guidelines for GM crop safety evaluations indicate toxicology studies are not needed when comparability of the GM crop to its conventional counterpart has been demonstrated. This guidance notwithstanding, animal feeding studies have routinely been conducted with GM crops, but their conclusions on safety are not always consistent. To accurately evaluate potential risks from GM crops, risk assessors need clearly interpretable results from reliable studies. The development of the FSSRTool, which provides the user with a means of assessing the reliability of a toxicology study to inform risk assessment, is discussed. Its application to the body of literature on GM crop food safety studies demonstrates that reliable studies report no toxicologically relevant differences between rodents fed GM crops or their non-GM comparators.

  8. Climate change effects on nitrogen loading from cultivated catchments in Europe: implications for nitrogen retention, ecological state of lakes and adaptation

    DEFF Research Database (Denmark)

    Jeppesen, Erik; Kronvang, Brian; Olesen, Jørgen E;

    2011-01-01

    Climate change might have profound effects on the nitrogen (N) dynamics in the cultivated landscape as well as on N transport in streams and the eutrophication of lakes. N loading from land to streams is expected to increase in North European temperate lakes due to higher winter rainfall and chan......Climate change might have profound effects on the nitrogen (N) dynamics in the cultivated landscape as well as on N transport in streams and the eutrophication of lakes. N loading from land to streams is expected to increase in North European temperate lakes due to higher winter rainfall...... and changes in cropping patterns. Scenario (IPCC, A2) analyses using a number of models of various complexity for Danish streams and lakes suggest an increase in runoff and N transport on an annual basis (higher during winter and typically lower during summer) in streams, a slight increase in N concentrations...... agricultural practices for reducing the loss of nutrients to surface waters, to improve sewage treatment and to reduce the storm-water nutrient runoff. In north temperate zones adaptations may also include re-establishment of artificial and natural wetlands, introduction of riparian buffer zones and re...

  9. Life cycle, feeding and adaptive strategy implications on the co-occurrence of Argyrodiaptomus furcatus and Notodiaptomus iheringi in Lobo-Broa Reservoir (SP, Brazil

    Directory of Open Access Journals (Sweden)

    RIETZLER A. C.

    2002-01-01

    Full Text Available The population dynamics, life cycle and feeding of Argyrodiaptomus furcatus and Notodiaptomus iheringi, were studied in Broa reservoir from August 1988 to August 1989, period when a replacement of A. furcatus by N. iheringi was observed. Some abiotic factors such as temperature, dissolved oxygen, pH and conductivity were measured to characterize the limnological conditions of the reservoir. Also, phytoplankton composition was analyzed and related to the feeding of the two species. Experimental data on developmental time and reproduction of A. furcatus and N. iheringi under different temperatures showed that lower temperatures were responsible for density decreasing of both populations in the reservoir during the dry season. Chlorophyta and Chrysophyta smaller than 20 mum were the most abundant phytoplankton groups in the reservoir as well as in the gut content of A. furcatus and N. iheringi, representing an important food source for both species. The temporary disappearance of Argyrodiaptomus furcatus, observed between 1988 and 1989 and its replacement by Notodiaptomus iheringi was related to mining activities upstream, modifying the water turbidity, pH and conductivity. However, the reappearance and maintenance of A. furcatus for another ten years and a recent replacement re-incidence indicates that these two calanoids do not coexist in this environment. Adaptive strategies of both species, related to changes in environmental conditions, are discussed. Probably, Argyrodiaptomus furcatus is an indicator of less eutrophic environments, while Notodiaptomus iheringi of more eutrophic systems.

  10. Life cycle, feeding and adaptive strategy implications on the co-occurrence of Argyrodiaptomus furcatus and Notodiaptomus iheringi in Lobo-Broa Reservoir (SP, Brazil

    Directory of Open Access Journals (Sweden)

    A. C. RIETZLER

    Full Text Available The population dynamics, life cycle and feeding of Argyrodiaptomus furcatus and Notodiaptomus iheringi, were studied in Broa reservoir from August 1988 to August 1989, period when a replacement of A. furcatus by N. iheringi was observed. Some abiotic factors such as temperature, dissolved oxygen, pH and conductivity were measured to characterize the limnological conditions of the reservoir. Also, phytoplankton composition was analyzed and related to the feeding of the two species. Experimental data on developmental time and reproduction of A. furcatus and N. iheringi under different temperatures showed that lower temperatures were responsible for density decreasing of both populations in the reservoir during the dry season. Chlorophyta and Chrysophyta smaller than 20 mum were the most abundant phytoplankton groups in the reservoir as well as in the gut content of A. furcatus and N. iheringi, representing an important food source for both species. The temporary disappearance of Argyrodiaptomus furcatus, observed between 1988 and 1989 and its replacement by Notodiaptomus iheringi was related to mining activities upstream, modifying the water turbidity, pH and conductivity. However, the reappearance and maintenance of A. furcatus for another ten years and a recent replacement re-incidence indicates that these two calanoids do not coexist in this environment. Adaptive strategies of both species, related to changes in environmental conditions, are discussed. Probably, Argyrodiaptomus furcatus is an indicator of less eutrophic environments, while Notodiaptomus iheringi of more eutrophic systems.

  11. Transgenic Animal Mutation Assays

    Institute of Scientific and Technical Information of China (English)

    Tao Chen; Ph.D.D.A.B.T.

    2005-01-01

    @@ The novel transgenic mouse and rat mutation assays have provided a tool for analyzing in vivo mutation in any tissue, thus permitting the direct comparison of cancer incidence with mutant frequency.

  12. Arteriovenous malformation within an isocitrate dehydrogenase 1 mutated anaplastic oligodendroglioma

    Directory of Open Access Journals (Sweden)

    Grace Lai

    2015-01-01

    Full Text Available Background: The co-occurrence of intracranial arteriovenous malformations (AVMs and cerebral neoplasms is exceedingly rare but may harbor implications pertaining to the molecular medicine of brain cancer pathogenesis. Case Description: Here, we present a case of de novo AVM within an isocitrate dehydrogenase 1 mutated anaplastic oligodendroglioma (WHO Grade III and review the potential contribution of this mutation to aberrant angiogenesis as an interesting case study in molecular medicine. Conclusion: The co-occurrence of an IDH1 mutated neoplasm and AVM supports the hypothesis that IDH1 mutations may contribute to aberrant angiogenesis and vascular malformation.

  13. Braf V600E mutation in melanoma: translational current scenario.

    Science.gov (United States)

    Guadarrama-Orozco, J A; Ortega-Gómez, A; Ruiz-García, E B; Astudillo-de la Vega, H; Meneses-García, A; Lopez-Camarillo, C

    2016-09-01

    Melanoma was one of the translational cancer examples in clinic, including target therapy related to specific biomarkers impacting in the outcome of melanoma patients. Melanomagenesis involved a wide variety of mutations during his evolution; many of these mutated proteins have a kinase activity. One of the most cited proteins in melanoma is BRAF (about 50-60 % of melanomas harbors activating BRAF mutations), for these the most common is a substitution of valine to glutamic acid at codon 600 (p.V600E). Therefore, the precise identification of this underlying somatic mutation is essential; knowing the translational implications has opened a wide view of melanoma biology and therapy.

  14. INDIGENOUS PERCEPTIONS OF SOIL EROSION, ADAPTATIONS AND LIVELIHOOD IMPLICATIONS: THE CASE OF MAIZE FARMERS IN THE ZAMPE COMMUNITY OF BOLE IN THE NORTHERN REGION OF GHANA.

    Directory of Open Access Journals (Sweden)

    Bukari Francis Issahaku Malongza

    2013-10-01

    Full Text Available Soil is an important natural resource which when effectively managed, could increase the livelihoods of households in sedentary agricultural communities. Soil erosion is however an emerging challenge as a cause of environmental degradation and this paper sought to ascertain the nature of soil erosion on maize farms, the effects of soil erosion on maize crop farmers and the effectiveness of local control measures on output levels and the livelihoods of the farmers. A cross-section of the community was taken and participants were selected non-probabilistically by snow-balling for questionnaire administration and focus group discussions. The study revealed that the local farmers perceived soil erosion as the wearing away of the top soil and nutrients, under the influence of running water during rainy periods and the slope of the land. The major effects of soil erosion were found to be the loss of fertile soils, reduction in the cultivable land area, the reduction in the crop yield and a fall in the living standards of farmers’ households. The findings also indicated that some of the adaptive strategies to reduce the effects of soil erosion include shifting cultivation, ridging across slopes, planting on raised mounds and avoidance of deep ploughing. It was further revealed that farmers who successfully applied the traditional methods improved upon their output levels per land area and the standards of living of their families It was recommended that modern agricultural extension services were needed, not to replace, but to complement the local knowledge systems in order to ensure sustainability.

  15. Catalytic properties of Phr family members of cell wall glucan remodeling enzymes: implications for the adaptation of Candida albicans to ambient pH.

    Science.gov (United States)

    Kováčová, Kristína; Degani, Genny; Stratilová, Eva; Farkaš, Vladimír; Popolo, Laura

    2015-03-01

    Fungal wall formation is a dynamic process involving several categories of enzymes. The GH72 family of β(1,3)-glucanosyltransferases is essential for the determination of cell shape, for cell integrity and for virulence in pathogenic fungi. Candida albicans has five GH72 genes: PHR1 and PHR2 are pH dependent, the first being expressed at pH ≥ 6 and repressed at lower pH and the second regulated in the opposite manner, PGA4 is transcribed independently of pH whereas PHR3 and PGA5 have low expression levels. To characterize the catalytic properties of Phr1p-2p and probe the activity of Pga4p, we heterologously expressed these proteins and used a fluorescent assay based on the transfer of oligosaccharyl units from a donor to a sulforhodamine-labeled acceptor. Phr1p-2p used exclusively β-1,3-glucan or cell wall glucan as donor and laminarin-derived oligosaccharides as acceptor. The acceptor efficiency increased with the length of the oligosaccharide. The temperature optimum was 30°C. The pH optimum was 5.8 for Phr1p and 3 for Phr2p. Overall, adaptation to pH of C. albicans appears to involve a fine interplay among the pH-dependent activity of Phr1p and Phr2p, the pH-regulated expression of their genes and protein stability. Unexpectedly, Pga4p was inactive suggesting that it turned into a structural mannoprotein.

  16. Siting and Sizing of Distributed Generation Planning Based on Adaptive Mutation Particle Swarm Optimization Algorithm%基于自适应变异粒子群算法的分布式电源选址与容量确定

    Institute of Scientific and Technical Information of China (English)

    叶德意; 何正友; 臧天磊

    2011-01-01

    TO carry out the planning of siting and sizing of DGs in distribution network without considering the newly increased load nodes, an economical model that takes the minimum annual operating cost of distribution network as objective function is built In allusion to the operation cost of DGS. the weight factor of fixed installation cost is led into the proposed medel to describe the cost variation of distribution network after DGs are connected in. Meanwhile, to remedy the premature convergence of panicle swarm oplimization (PSO)algorithm, the adaptive mutation particle swarm optimization algorithm is utilized to optimize the siting and sizing of DGs in distributio network. Calculation results Of IEEE 33 bus radial distribution test system show that the proposed model is correct and the solving algorithm is effective%在不考虑负荷新增节点的情况下进行分布式发电的布点规划,建立了以配电网年运行费用最小为目标的经济模型.模型中针对分布式电源运行费用引入固定安装费用权重因子,更准确地刻画了分布式电源接入后配电网费用的变化.同时,为克服粒子群算法存在的早熟问题,采用自适应变异的粒子群算法(adaptive mutation particle swarmoptimization algorithm,AMPSO)对配电网中的DG选址和定容进行了优化.通过对IEEE 33节点配电网测试系统进行分析,验证了上述模型的准确性和求解算法的有效性.

  17. Mutation analysis and prenatal diagnosis of EXT1 gene mutations in Chinese patients with multiple osteochondromas

    Institute of Scientific and Technical Information of China (English)

    ZHU Hai-yan; HU Ya-li; YANG Ying; WU Xing; ZHU Rui-fang; ZHU Xiang-yu; DUAN Hong-lei; ZHANG Ying; ZHOU Jin-yong

    2011-01-01

    Background Multiple osteochondromas (MO), an inherited autosomal dominant disorder, is characterized by the presence of multiple exostoses on the long bones. MO is caused by mutations in the EXT1 or EXT2 genes which encode glycosyltransferases implicated in heparin sulfate biosynthesis.Methods In this study, efforts were made to identify the underlying disease-causing mutations in patients from two MO families in China.Results Two novel EXT1 gene mutations were identified and no mutation was found in EXT2 gene. The mutation c.497T>A in exon 1 of the EXT1 gene was cosegregated with the disease phenotype in family 1 and formed a stop codon at amino acid site 166. The fetus of the proband was diagnosed negative. In family 2, the mutation c. 1430-1431delCC in exon 6 of the EXT1 gene would cause frameshift and introduce a premature stop codon after the reading frame being open for 42 amino acids. The fetus of this family inherited this mutation from the father.Conclusions Mutation analysis of two MO families in this study demonstrates its further application in MO genetic counseling and prenatal diagnosis.

  18. Adaptive Lighting

    DEFF Research Database (Denmark)

    Petersen, Kjell Yngve; Søndergaard, Karin; Kongshaug, Jesper

    2015-01-01

    Adaptive Lighting Adaptive lighting is based on a partial automation of the possibilities to adjust the colour tone and brightness levels of light in order to adapt to people’s needs and desires. IT support is key to the technical developments that afford adaptive control systems. The possibilities...... offered by adaptive lighting control are created by the ways that the system components, the network and data flow can be coordinated through software so that the dynamic variations are controlled in ways that meaningfully adapt according to people’s situations and design intentions. This book discusses...... differently into an architectural body. We also examine what might occur when light is dynamic and able to change colour, intensity and direction, and when it is adaptive and can be brought into interaction with its surroundings. In short, what happens to an architectural space when artificial lighting ceases...

  19. Genetic Adaptation of Achromobacter sp. during Persistence in the Lungs of Cystic Fibrosis Patients.

    Directory of Open Access Journals (Sweden)

    Winnie Ridderberg

    Full Text Available Achromobacter species are increasingly isolated from the respiratory tract of cystic fibrosis patients and often a chronic infection is established. How Achromobacter sp. adapts to the human host remains uncharacterised. By comparing longitudinally collected isolates of Achromobacter sp. isolated from five CF patients, we have investigated the within-host evolution of clonal lineages. The majority of identified mutations were isolate-specific suggesting co-evolution of several subpopulations from the original infecting isolate. The largest proportion of mutated genes were involved in the general metabolism of the bacterium, but genes involved in virulence and antimicrobial resistance were also affected. A number of virulence genes required for initiation of acute infection were selected against, e.g. genes of the type I and type III secretion systems and genes related to pilus and flagellum formation or function. Six antimicrobial resistance genes or their regulatory genes were mutated, including large deletions affecting the repressor genes of an RND-family efflux pump and a beta-lactamase. Convergent evolution was observed for five genes that were all implicated in bacterial virulence. Characterisation of genes involved in adaptation of Achromobacter to the human host is required for understanding the pathogen-host interaction and facilitate design of future therapeutic interventions.

  20. Phenotypic effect of mutations in evolving populations of RNA molecules

    Directory of Open Access Journals (Sweden)

    Manrubia Susanna C

    2010-02-01

    Full Text Available Abstract Background The secondary structure of folded RNA sequences is a good model to map phenotype onto genotype, as represented by the RNA sequence. Computational studies of the evolution of ensembles of RNA molecules towards target secondary structures yield valuable clues to the mechanisms behind adaptation of complex populations. The relationship between the space of sequences and structures, the organization of RNA ensembles at mutation-selection equilibrium, the time of adaptation as a function of the population parameters, the presence of collective effects in quasispecies, or the optimal mutation rates to promote adaptation all are issues that can be explored within this framework. Results We investigate the effect of microscopic mutations on the phenotype of RNA molecules during their in silico evolution and adaptation. We calculate the distribution of the effects of mutations on fitness, the relative fractions of beneficial and deleterious mutations and the corresponding selection coefficients for populations evolving under different mutation rates. Three different situations are explored: the mutation-selection equilibrium (optimized population in three different fitness landscapes, the dynamics during adaptation towards a goal structure (adapting population, and the behavior under periodic population bottlenecks (perturbed population. Conclusions The ratio between the number of beneficial and deleterious mutations experienced by a population of RNA sequences increases with the value of the mutation rate μ at which evolution proceeds. In contrast, the selective value of mutations remains almost constant, independent of μ, indicating that adaptation occurs through an increase in the amount of beneficial mutations, with little variations in the average effect they have on fitness. Statistical analyses of the distribution of fitness effects reveal that small effects, either beneficial or deleterious, are well described by a Pareto

  1. Maize Mutator transposon

    Institute of Scientific and Technical Information of China (English)

    Yijun WANG; Mingliang XU; Dexiang DENG; Yunlong BIAN

    2008-01-01

    Transposable elements are widely distributed in eukaryotes. Due to its high copy numbers, high forward mutation rate and preferential insertion into low-copy DNA sequences, among others, the Mutator system has been widely used as a mutagen in genomic research. The discovery, classification, transposition specificity and epige-netic regulation of Mutator transposons were described. The application of Mutator tagging in plant genomic research was also presented. The role of Mu-like elements in genome evolution was briefly depicted. Moreover, the direction of Mutator transposon research in the future was discussed.

  2. Uniparental disomy of chromosome 8 leading to homozygosity of a CYP11B1 mutation in a patient with congenital adrenal hyperplasia: implication for a rare etiology of an autosomal recessive disorder.

    Science.gov (United States)

    Matsubara, Keiko; Kataoka, Naoki; Ogita, Satoko; Sano, Shinichiro; Ogata, Tsutomu; Fukami, Maki; Katsumata, Noriyuki

    2014-01-01

    Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder that usually results from paternally and maternally transmitted mutations in genes for steroidogenic enzymes. Recent studies on steroid 21-hydroxylase deficiency, the most common form of CAH, have revealed that a small percentage of patients have a non-carrier parent; uniparental disomy (UPD) and de novo mutations were reported as disease-causing mechanisms in these patients. However, it remains unknown whether UPD and de novo mutations underlie other forms of CAH. Here, we report a male patient with steroid 11β-hydroxylase deficiency (11OHD) born to a non-carrier mother. The patient was identified by an elevated 17-hydroxyprogesterone level at a neonatal mass-screening test. His clinical features were comparable to those of previously reported patients with 11OHD. Direct sequencing of CYP11B1 identified a homozygous IVS7+1G>A mutation in the patient, which was not shared by his mother. Comparative genomic hybridization of the patient detected UPD of chromosome 8 [UPD(8)]. Microsatellite analysis indicated non-maternal origin of the UPD(8) and confirmed parentage of other chromosomes. This study shows for the first time that 11OHD can be caused by UPD in the presence of a non-carrier parent. Awareness of such rare cases should improve the accuracy of genetic counseling for families with CAH. Our data support the importance of UPD as an underlying mechanism of autosomal recessive disorders.

  3. Mutation@A Glance : an integrative web application for analysing mutations from human genetic diseases

    NARCIS (Netherlands)

    Hijikata, A.; Raju, R.; Keerthikumar, S.; Ramabadran, S.; Balakrishnan, L.; Ramadoss, S.K.; Pandey, A.; Mohan, S.; Ohara, O.

    2010-01-01

    Although mutation analysis serves as a key part in making a definitive diagnosis about a genetic disease, it still remains a time-consuming step to interpret their biological implications through integration of various lines of archived information about genes in question. To expedite this evaluatio

  4. Mutation trend of hemagglutinin of influenza A virus: a review from a computational mutation viewpoint

    Institute of Scientific and Technical Information of China (English)

    Guang WU; Shao-min YAN

    2006-01-01

    Since 1999 we have developed two computational mutation approaches to analyze the protein primary structure whose methodology and implications were reviewed in 2002.Our first approach is the calculation of predictable and unpredictable portions of amino-acid pairs in a protein, and the second iS the calculation of amino-acid distribution rank in a protein. Both approaches provide quantitative measures to present a protein, which we have used to study a number of proteins with numerous mutations such as p53 proteins. More recently, we focussed our efforts on analyzing the proteins mutating frequently over time such as hemagglutinins of influenza A viruses. In this review we summarise our findings and their implications for hemagglutinin mutations in combination with some newly available data. Our approaches throw light on the true nature of genetic heterogeneity of influenza virus hemagglutinins; that is, the protein variability is highly relevant to its amino-acid construction. Using these approaches, we can monitor new mutations from influenza virus hemaggtutinins and may predict their mutations in the future.

  5. Adapting to a changing world: RAG genomics and evolution

    Directory of Open Access Journals (Sweden)

    de Camargo Maristela

    2005-06-01

    Full Text Available Abstract The origin of the recombination-activating genes (RAGs is considered to be a foundation hallmark for adaptive immunity, characterised by the presence of antigen receptor genes that provide the ability to recognise and respond to specific peptide antigens. In vertebrates, a diverse repertoire of antigen-specific receptors, T cell receptors and immunoglobulins is generated by V(DJ recombination performed by the RAG-1 and RAG-2 protein complex. RAG homologues were identified in many jawed vertebrates. Despite their crucial importance, no homologues have been found in jawless vertebrates and invertebrates. This paper focuses on the RAG homologues in humans and other vertebrates for which the genome is completely sequenced, and also discuses the main contribution of the use of RAG homologues in phylogenetics and vertebrate evolution. Since mutations in both genes cause a spectrum of severe combined immunodeficiencies, including the Omenn syndrome (OS, these topics are discussed in detail. Finally, the relevance to genomic diversity and implications to immunomics are addressed. The search for homologues could enlighten us about the evolutionary processes that shaped the adaptive immune system. Understanding the diversity of the adaptive immune system is crucially important for the design and development of new therapies to modulate the immune responses in humans and/or animal models.

  6. BRCA1 and BRCA2 germline mutation analysis among Indian women from south India: identification of four novel mutations and high-frequency occurrence of 185delAG mutation

    Indian Academy of Sciences (India)

    Kannan Vaidyanathan; Smita Lakhotia; H M Ravishankar; Umaira Tabassum; Geetashree Mukherjee; Kumaravel Somasundaram

    2009-09-01

    Mutations in the BRCA1 and BRCA2 genes profoundly increase the risk of developing breast and/or ovarian cancer among women. To explore the contribution of BRCA1 and BRCA2 mutations in the development of hereditary breast cancer among Indian women, we carried out mutation analysis of the BRCA1 and BRCA2 genes in 61 breast or ovarian cancer patients from south India with a positive family history of breast and/or ovarian cancer. Mutation analysis was carried out using conformation-sensitive gel electrophoresis (CSGE) followed by sequencing. Mutations were identified in 17 patients (28.0%); 15 (24.6%) had BRCA1 mutations and two (3.28%) had BRCA2 mutations. While no specific association between BRCA1 or BRCA2 mutations with cancer type was seen, mutations were more often seen in families with ovarian cancer. While 40% (4/10) and 30.8% (4/12) of families with ovarian or breast and ovarian cancer had mutations, only 23.1% (9/39) of families with breast cancer carried mutations in the BRCA1 and BRCA2 genes. In addition, while BRCA1 mutations were found in all age groups, BRCA2 mutations were found only in the age group of ≤ 40 years. Of the BRCA1 mutations, there were three novel mutations (295delCA; 4213T → A; 5267T → G) and three mutations that have been reported earlier. Interestingly, 185delAG, a BRCA1 mutation which occurs at a very high frequency in Ashkenazi Jews, was found at a frequency of 16.4% (10/61). There was one novel mutation (4866insT) and one reported mutation in BRCA2. Thus, our study emphasizes the importance of mutation screening in familial breast and/or ovarian cancers, and the potential implications of these findings in genetic counselling and preventive therapy.

  7. [Stress-induced cellular adaptive mutagenesis].

    Science.gov (United States)

    Zhu, Linjiang; Li, Qi

    2014-04-01

    The adaptive mutations exist widely in the evolution of cells, such as antibiotic resistance mutations of pathogenic bacteria, adaptive evolution of industrial strains, and cancerization of human somatic cells. However, how these adaptive mutations are generated is still controversial. Based on the mutational analysis models under the nonlethal selection conditions, stress-induced cellular adaptive mutagenesis is proposed as a new evolutionary viewpoint. The hypothetic pathway of stress-induced mutagenesis involves several intracellular physiological responses, including DNA damages caused by accumulation of intracellular toxic chemicals, limitation of DNA MMR (mismatch repair) activity, upregulation of general stress response and activation of SOS response. These responses directly affect the accuracy of DNA replication from a high-fidelity manner to an error-prone one. The state changes of cell physiology significantly increase intracellular mutation rate and recombination activity. In addition, gene transcription under stress condition increases the instability of genome in response to DNA damage, resulting in transcription-associated DNA mutagenesis. In this review, we summarize these two molecular mechanisms of stress-induced mutagenesis and transcription-associated DNA mutagenesis to help better understand the mechanisms of adaptive mutagenesis.

  8. RELN Mutations in Autism Spectrum Disorder.

    Science.gov (United States)

    Lammert, Dawn B; Howell, Brian W

    2016-01-01

    RELN encodes a large, secreted glycoprotein integral to proper neuronal positioning during development and regulation of synaptic function postnatally. Rare, homozygous, null mutations lead to lissencephaly with cerebellar hypoplasia (LCH), accompanied by developmental delay and epilepsy. Until recently, little was known about the frequency or consequences of heterozygous mutations. Several lines of evidence from multiple studies now implicate heterozygous mutations in RELN in autism spectrum disorders (ASD). RELN maps to the AUTS1 locus on 7q22, and at this time over 40 distinct mutations have been identified that would alter the protein sequence, four of which are de novo. The RELN mutations that are most clearly consequential are those that are predicted to inactivate the signaling function of the encoded protein and those that fall in a highly conserved RXR motif found at the core of the 16 Reelin subrepeats. Despite the growing evidence of RELN dysfunction in ASD, it appears that these mutations in isolation are insufficient and that secondary genetic or environmental factors are likely required for a diagnosis.