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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.

    Science.gov (United States)

    Miotto, Olivo; Heiny, A T; Albrecht, Randy; García-Sastre, Adolfo; Tan, Tin Wee; August, J Thomas; Brusic, Vladimir

    2010-02-03

    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. 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. 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 unusually high number of adaptive mutations. However, these mutations appear

  2. Adaptive mutation: has the unicorn landed?

    Science.gov (United States)

    Foster, P L

    1998-01-01

    Reversion of an episomal Lac- allele during lactose selection has been studied as a model for adaptive mutation. Although recent results show that the mutations that arise during selection are not "adaptive" in the original sense, the mutagenic mechanism that produces these mutations may nonetheless be of evolutionary significance. In addition, a transient mutational state induced in a subpopulation of starving cells could provide a species with a mechanism for adaptive evolution. PMID:9560365

  3. Adaptive mutation: has the unicorn landed?

    Science.gov (United States)

    Foster, P L

    1998-04-01

    Reversion of an episomal Lac- allele during lactose selection has been studied as a model for adaptive mutation. Although recent results show that the mutations that arise during selection are not "adaptive" in the original sense, the mutagenic mechanism that produces these mutations may nonetheless be of evolutionary significance. In addition, a transient mutational state induced in a subpopulation of starving cells could provide a species with a mechanism for adaptive evolution.

  4. 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...

  5. Variable mutation rates as an adaptive strategy in replicator populations.

    Directory of Open Access Journals (Sweden)

    Michael Stich

    2010-06-01

    Full Text Available For evolving populations of replicators, there is much evidence that the effect of mutations on fitness depends on the degree of adaptation to the selective pressures at play. In optimized populations, most mutations have deleterious effects, such that low mutation rates are favoured. In contrast to this, in populations thriving in changing environments a larger fraction of mutations have beneficial effects, providing the diversity necessary to adapt to new conditions. What is more, non-adapted populations occasionally benefit from an increase in the mutation rate. Therefore, there is no optimal universal value of the mutation rate and species attempt to adjust it to their momentary adaptive needs. In this work we have used stationary populations of RNA molecules evolving in silico to investigate the relationship between the degree of adaptation of an optimized population and the value of the mutation rate promoting maximal adaptation in a short time to a new selective pressure. Our results show that this value can significantly differ from the optimal value at mutation-selection equilibrium, being strongly influenced by the structure of the population when the adaptive process begins. In the short-term, highly optimized populations containing little variability respond better to environmental changes upon an increase of the mutation rate, whereas populations with a lower degree of optimization but higher variability benefit from reducing the mutation rate to adapt rapidly. These findings show a good agreement with the behaviour exhibited by actual organisms that replicate their genomes under broadly different mutation rates.

  6. High mutation rates limit evolutionary adaptation in Escherichia coli.

    Directory of Open Access Journals (Sweden)

    Kathleen Sprouffske

    2018-04-01

    Full Text Available Mutation is fundamental to evolution, because it generates the genetic variation on which selection can act. In nature, genetic changes often increase the mutation rate in systems that range from viruses and bacteria to human tumors. Such an increase promotes the accumulation of frequent deleterious or neutral alleles, but it can also increase the chances that a population acquires rare beneficial alleles. Here, we study how up to 100-fold increases in Escherichia coli's genomic mutation rate affect adaptive evolution. To do so, we evolved multiple replicate populations of asexual E. coli strains engineered to have four different mutation rates for 3000 generations in the laboratory. We measured the ability of evolved populations to grow in their original environment and in more than 90 novel chemical environments. In addition, we subjected the populations to whole genome population sequencing. Although populations with higher mutation rates accumulated greater genetic diversity, this diversity conveyed benefits only for modestly increased mutation rates, where populations adapted faster and also thrived better than their ancestors in some novel environments. In contrast, some populations at the highest mutation rates showed reduced adaptation during evolution, and failed to thrive in all of the 90 alternative environments. In addition, they experienced a dramatic decrease in mutation rate. Our work demonstrates that the mutation rate changes the global balance between deleterious and beneficial mutational effects on fitness. In contrast to most theoretical models, our experiments suggest that this tipping point already occurs at the modest mutation rates that are found in the wild.

  7. High mutation rates limit evolutionary adaptation in Escherichia coli

    Science.gov (United States)

    Wagner, Andreas

    2018-01-01

    Mutation is fundamental to evolution, because it generates the genetic variation on which selection can act. In nature, genetic changes often increase the mutation rate in systems that range from viruses and bacteria to human tumors. Such an increase promotes the accumulation of frequent deleterious or neutral alleles, but it can also increase the chances that a population acquires rare beneficial alleles. Here, we study how up to 100-fold increases in Escherichia coli’s genomic mutation rate affect adaptive evolution. To do so, we evolved multiple replicate populations of asexual E. coli strains engineered to have four different mutation rates for 3000 generations in the laboratory. We measured the ability of evolved populations to grow in their original environment and in more than 90 novel chemical environments. In addition, we subjected the populations to whole genome population sequencing. Although populations with higher mutation rates accumulated greater genetic diversity, this diversity conveyed benefits only for modestly increased mutation rates, where populations adapted faster and also thrived better than their ancestors in some novel environments. In contrast, some populations at the highest mutation rates showed reduced adaptation during evolution, and failed to thrive in all of the 90 alternative environments. In addition, they experienced a dramatic decrease in mutation rate. Our work demonstrates that the mutation rate changes the global balance between deleterious and beneficial mutational effects on fitness. In contrast to most theoretical models, our experiments suggest that this tipping point already occurs at the modest mutation rates that are found in the wild. PMID:29702649

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

    DEFF Research Database (Denmark)

    Bailey, Susan; Hinz, Aaron; Kassen, Rees

    2014-01-01

    Conventional wisdom holds that synonymous mutations, nucleotide changes that do not alter the encoded amino acid, have no detectable effect on phenotype or fitness. However, a growing body of evidence from both comparative and experimental studies suggests otherwise. Synonymous mutations have been...... shown to impact gene expression, protein folding and fitness, however, direct evidence that they can be positively selected, and so contribute to adaptation, is lacking. Here we report the recovery of two beneficial synonymous single base pair changes that arose spontaneously and independently...... 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...

  9. 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

  10. Rhodopsin mutations are scarcely implicated in autosomal ...

    African Journals Online (AJOL)

    Reem Mebed

    2015-04-23

    Apr 23, 2015 ... of the disorder in the male and female progeny of unaffected persons [29]. ... a light stimulus and is used for the diagnosis of various retinal diseases. Dim flash ERG is performed on a dark-adapted eye, so the response is ...

  11. Experiments on the role of deleterious mutations as stepping stones in adaptive evolution

    Science.gov (United States)

    Covert, Arthur W.; Lenski, Richard E.; Wilke, Claus O.; Ofria, Charles

    2013-01-01

    Many evolutionary studies assume that deleterious mutations necessarily impede adaptive evolution. However, a later mutation that is conditionally beneficial may interact with a deleterious predecessor before it is eliminated, thereby providing access to adaptations that might otherwise be inaccessible. It is unknown whether such sign-epistatic recoveries are inconsequential events or an important factor in evolution, owing to the difficulty of monitoring the effects and fates of all mutations during experiments with biological organisms. Here, we used digital organisms to compare the extent of adaptive evolution in populations when deleterious mutations were disallowed with control populations in which such mutations were allowed. Significantly higher fitness levels were achieved over the long term in the control populations because some of the deleterious mutations served as stepping stones across otherwise impassable fitness valleys. As a consequence, initially deleterious mutations facilitated the evolution of complex, beneficial functions. We also examined the effects of disallowing neutral mutations, of varying the mutation rate, and of sexual recombination. Populations evolving without neutral mutations were able to leverage deleterious and compensatory mutation pairs to overcome, at least partially, the absence of neutral mutations. Substantially raising or lowering the mutation rate reduced or eliminated the long-term benefit of deleterious mutations, but introducing recombination did not. Our work demonstrates that deleterious mutations can play an important role in adaptive evolution under at least some conditions. PMID:23918358

  12. Teaching the Fluctuation Test "In Silico" by Using Mutate: A Program to Distinguish between the Adaptive and Spontaneous Mutation Hypotheses

    Science.gov (United States)

    Carvajal-Rodriguez, Antonio

    2012-01-01

    Mutate is a program developed for teaching purposes to impart a virtual laboratory class for undergraduate students of Genetics in Biology. The program emulates the so-called fluctuation test whose aim is to distinguish between spontaneous and adaptive mutation hypotheses in bacteria. The plan is to train students in certain key multidisciplinary…

  13. Teaching the fluctuation test in silico by using mutate: a program to distinguish between the adaptive and spontaneous mutation hypotheses.

    Science.gov (United States)

    Carvajal-Rodríguez, Antonio

    2012-07-01

    Mutate is a program developed for teaching purposes to impart a virtual laboratory class for undergraduate students of Genetics in Biology. The program emulates the so-called fluctuation test whose aim is to distinguish between spontaneous and adaptive mutation hypotheses in bacteria. The plan is to train students in certain key multidisciplinary aspects of current genetics such as sequence databases, DNA mutations, and hypothesis testing, while introducing the fluctuation test. This seminal experiment was originally performed studying Escherichia coli resistance to the infection by bacteriophage T1. The fluctuation test initiated the modern bacterial genetics that 25 years later ushered in the era of the recombinant DNA. Nowadays we know that some deletions in fhuA, the gene responsible for E. coli membrane receptor of T1, could cause the E. coli resistance to this phage. For the sake of simplicity, we will introduce the assumption that a single mutation generates the resistance to T1. During the practical, the students use the program to download some fhuA gene sequences, manually introduce some stop codon mutations, and design a fluctuation test to obtain data for distinguishing between preadaptative (spontaneous) and induced (adaptive) mutation hypotheses. The program can be launched from a browser or, if preferred, its executable file can be downloaded from http://webs.uvigo.es/acraaj/MutateWeb/Mutate.html. It requires the Java 5.0 (or higher) Runtime Environment (freely available at http://www.java.com). Copyright © 2012 Wiley Periodicals, Inc.

  14. Contribution of silent mutations to thermal adaptation of RNA bacteriophage Qβ.

    Science.gov (United States)

    Kashiwagi, Akiko; Sugawara, Ryu; Sano Tsushima, Fumie; Kumagai, Tomofumi; Yomo, Tetsuya

    2014-10-01

    Changes in protein function and other biological properties, such as RNA structure, are crucial for adaptation of organisms to novel or inhibitory environments. To investigate how mutations that do not alter amino acid sequence may be positively selected, we performed a thermal adaptation experiment using the single-stranded RNA bacteriophage Qβ in which the culture temperature was increased from 37.2°C to 41.2°C and finally to an inhibitory temperature of 43.6°C in a stepwise manner in three independent lines. Whole-genome analysis revealed 31 mutations, including 14 mutations that did not result in amino acid sequence alterations, in this thermal adaptation. Eight of the 31 mutations were observed in all three lines. Reconstruction and fitness analyses of Qβ strains containing only mutations observed in all three lines indicated that five mutations that did not result in amino acid sequence changes but increased the amplification ratio appeared in the course of adaptation to growth at 41.2°C. Moreover, these mutations provided a suitable genetic background for subsequent mutations, altering the fitness contribution from deleterious to beneficial. These results clearly showed that mutations that do not alter the amino acid sequence play important roles in adaptation of this single-stranded RNA virus to elevated temperature. Recent studies using whole-genome analysis technology suggested the importance of mutations that do not alter the amino acid sequence for adaptation of organisms to novel environmental conditions. It is necessary to investigate how these mutations may be positively selected and to determine to what degree such mutations that do not alter amino acid sequences contribute to adaptive evolution. Here, we report the roles of these silent mutations in thermal adaptation of RNA bacteriophage Qβ based on experimental evolution during which Qβ showed adaptation to growth at an inhibitory temperature. Intriguingly, four synonymous mutations and

  15. 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.

  16. 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.

  17. 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

  18. Adaptive benefits from small mutation supplies in an antibiotic resistance enzyme

    NARCIS (Netherlands)

    Salverda, Merijn L.M.; Koomen, Jeroen; Koopmanschap, Bertha; Zwart, Mark P.; Visser, De J.A.G.M.

    2017-01-01

    Populations with large mutation supplies adapt via the “greedy” substitution of the fittest genotype available, leading to fast and repeatable short-term responses. At longer time scales, smaller mutation supplies may in theory lead to larger improvements when distant high-fitness genotypes more

  19. Understanding the role of p53 in adaptive response to radiation-induced germline mutations

    International Nuclear Information System (INIS)

    Langlois, N.L.; Quinn, J.S.; Somers, C.M.; Boreham, D.R.; Mitchel, R.E.J.

    2003-01-01

    Full text: Radiation-induced adaptive response is now a widely studied area of radiation biology. Studies have demonstrated reduced levels of radiation-induced biological damage when an 'adaptive dose' is given before a higher 'challenge dose' compared to when the challenge dose is given alone. It has been shown in some systems to be a result of inducible cellular repair systems. The adaptive response has been clearly demonstrated in many model systems, however its impact on heritable effects in the mammalian germline has never been studied. Expanded Simple Tandem Repeat (ESTR) loci have been used as markers demonstrating that induced heritable mutations in mice follow a dose-response relationship. Recent data in our laboratory show preliminary evidence of radiation-induced adaptive response suppressing germline mutations at ESTR loci in wild type mice. The frequency of heritable mutations was significantly reduced when a priming dose of 0.1 Gy was given 24 hours prior to a 1 Gy acute challenging dose. We are now conducting a follow-up study to attempt to understand the mechanism of this adaptive response. P53 is known to play a significant role in governing apoptosis, DNA repair and cancer induction. In order to determine what function p53 has in the adaptive response for heritable mutations, we have mated radiation treated Trp53+/- male mice (C57Bl) to untreated, normal females (C57Bl). Using DNA fingerprinting, we are investigating the rate of inherited radiation-induced mutations on pre- and post-meiotic radiation-treated gametocytes by examining mutation frequencies in offspring DNA. If p53 is integral in the mechanism of adaptive response, we should not see an adaptive response in radiation-induced heritable mutations in these mice. This research is significant in that it will provide insight to understanding the mechanism behind radiation-induced adaptive response in the mammalian germline

  20. 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

    , 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...... 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...

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

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    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.

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

    International Nuclear Information System (INIS)

    Lee, Yoon Jae; Jang, Yo Han; Kim, Paul; Lee, Yun Ha; Lee, Young Jae; Byun, Young Ho; Lee, Kwang-Hee; Kim, Kyusik; Seong, Baik Lin

    2016-01-01

    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.

  3. 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.

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

    Science.gov (United States)

    Egbert, Matthew D.; Pérez-Mercader, Juan

    2016-01-01

    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

  5. Lineage dynamics and mutation-selection balance in non-adapting asexual populations

    Science.gov (United States)

    Pénisson, Sophie; Sniegowski, Paul D.; Colato, Alexandre; Gerrish, Philip J.

    2013-02-01

    In classical population genetics, mutation-selection balance refers to the equilibrium frequency of a deleterious allele established and maintained under two opposing forces: recurrent mutation, which tends to increase the frequency of the allele; and selection, which tends to decrease its frequency. In a haploid population, if μ denotes the per capita rate of production of the deleterious allele by mutation and s denotes the selective disadvantage of carrying the allele, then the classical mutation-selection balance frequency of the allele is approximated by μ/s. This calculation assumes that lineages carrying the mutant allele in question—the ‘focal allele’—do not accumulate deleterious mutations linked to the focal allele. In principle, indirect selection against the focal allele caused by such additional mutations can decrease the frequency of the focal allele below the classical mutation-selection balance. This effect of indirect selection will be strongest in an asexual population, in which the entire genome is in linkage. Here, we use an approach based on a multitype branching process to investigate this effect, analyzing lineage dynamics under mutation, direct selection, and indirect selection in a non-adapting asexual population. We find that the equilibrium balance between recurrent mutation to the focal allele and the forces of direct and indirect selection against the focal allele is closely approximated by γμ/(s + U) (s = 0 if the focal allele is neutral), where γ ≈ eθθ-(ω+θ)(ω + θ)(Γ(ω + θ) - Γ(ω + θ,θ)), \\theta =U/\\tilde {s}, and \\omega =s/\\tilde {s}; U denotes the genomic deleterious mutation rate and \\tilde {s} denotes the geometric mean selective disadvantage of deleterious mutations elsewhere on the genome. This mutation-selection balance for asexual populations can remain surprisingly invariant over wide ranges of the mutation rate.

  6. Mutation spectrum of RB1 mutations in retinoblastoma cases from Singapore with implications for genetic management and counselling.

    Directory of Open Access Journals (Sweden)

    Swati Tomar

    Full Text Available Retinoblastoma (RB is a rare childhood malignant disorder caused by the biallelic inactivation of RB1 gene. Early diagnosis and identification of carriers of heritable RB1 mutations can improve disease outcome and management. In this study, mutational analysis was conducted on fifty-nine matched tumor and peripheral blood samples from 18 bilateral and 41 unilateral unrelated RB cases by a combinatorial approach of Multiplex Ligation-dependent Probe Amplification (MLPA assay, deletion screening, direct sequencing, copy number gene dosage analysis and methylation assays. Screening of both blood and tumor samples yielded a mutation detection rate of 94.9% (56/59 while only 42.4% (25/59 of mutations were detected if blood samples alone were analyzed. Biallelic mutations were observed in 43/59 (72.9% of tumors screened. There were 3 cases (5.1% in which no mutations could be detected and germline mutations were detected in 19.5% (8/41 of unilateral cases. A total of 61 point mutations were identified, of which 10 were novel. There was a high incidence of previously reported recurrent mutations, occurring at 38.98% (23/59 of all cases. Of interest were three cases of mosaic RB1 mutations detected in the blood from patients with unilateral retinoblastoma. Additionally, two germline mutations previously reported to be associated with low-penetrance phenotypes: missense-c.1981C>T and splice variant-c.607+1G>T, were observed in a bilateral and a unilateral proband, respectively. These findings have implications for genetic counselling and risk prediction for the affected families. This is the first published report on the spectrum of mutations in RB patients from Singapore and shows that further improved mutation screening strategies are required in order to provide a definitive molecular diagnosis for every case of RB. Our findings also underscore the importance of genetic testing in supporting individualized disease management plans for patients and

  7. 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......The JFH1 strain of hepatitis C virus (HCV) is unique among HCV isolates, in that the wild-type virus can traverse the entire replication cycle in cultured cells. However, without adaptive mutations, only low levels of infectious virus are produced. In the present study, the effects of five...

  8. Positive signature-tagged mutagenesis in Pseudomonas aeruginosa: tracking patho-adaptive mutations promoting airways chronic infection.

    Directory of Open Access Journals (Sweden)

    Irene Bianconi

    2011-02-01

    Full Text Available The opportunistic pathogen Pseudomonas aeruginosa can establish life-long chronic infections in the airways of cystic fibrosis (CF patients. Persistent lifestyle is established with P. aeruginosa patho-adaptive variants, which are clonal with the initially-acquired strains. Several reports indicated that P. aeruginosa adapts by loss-of-function mutations which enhance fitness in CF airways and sustain its clonal expansion during chronic infection. To validate this model of P. aeruginosa adaptation to CF airways and to identify novel genes involved in this microevolution, we designed a novel approach of positive-selection screening by PCR-based signature-tagged mutagenesis (Pos-STM in a murine model of chronic airways infection. A systematic positive-selection scheme using sequential rounds of in vivo screenings for bacterial maintenance, as opposed to elimination, generated a list of genes whose inactivation increased the colonization and persistence in chronic airways infection. The phenotypes associated to these Pos-STM mutations reflect alterations in diverse aspects of P. aeruginosa biology which include lack of swimming and twitching motility, lack of production of the virulence factors such as pyocyanin, biofilm formation, and metabolic functions. In addition, Pos-STM mutants showed altered invasion and stimulation of immune response when tested in human respiratory epithelial cells, indicating that P. aeruginosa is prone to revise the interaction with its host during persistent lifestyle. Finally, sequence analysis of Pos-STM genes in longitudinally P. aeruginosa isolates from CF patients identified signs of patho-adaptive mutations within the genome. This novel Pos-STM approach identified bacterial functions that can have important clinical implications for the persistent lifestyle and disease progression of the airway chronic infection.

  9. Structural Implications of Mutations Conferring Rifampin Resistance in Mycobacterium leprae.

    Science.gov (United States)

    Vedithi, Sundeep Chaitanya; Malhotra, Sony; Das, Madhusmita; Daniel, Sheela; Kishore, Nanda; George, Anuja; Arumugam, Shantha; Rajan, Lakshmi; Ebenezer, Mannam; Ascher, David B; Arnold, Eddy; Blundell, Tom L

    2018-03-22

    The rpoB gene encodes the β subunit of RNA polymerase holoenzyme in Mycobacterium leprae (M. leprae). Missense mutations in the rpoB gene were identified as etiological factors for rifampin resistance in leprosy. In the present study, we identified mutations corresponding to rifampin resistance in relapsed leprosy cases from three hospitals in southern India which treat leprosy patients. DNA was extracted from skin biopsies of 35 relapse/multidrug therapy non-respondent leprosy cases, and PCR was performed to amplify the 276 bp rifampin resistance-determining region of the rpoB gene. PCR products were sequenced, and mutations were identified in four out of the 35 cases at codon positions D441Y, D441V, S437L and H476R. The structural and functional effects of these mutations were assessed in the context of three-dimensional comparative models of wild-type and mutant M. leprae RNA polymerase holoenzyme (RNAP), based on the recently solved crystal structures of RNAP of Mycobacterium tuberculosis, containing a synthetic nucleic acid scaffold and rifampin. The resistance mutations were observed to alter the hydrogen-bonding and hydrophobic interactions of rifampin and the 5' ribonucleotide of the growing RNA transcript. This study demonstrates that rifampin-resistant strains of M. leprae among leprosy patients in southern India are likely to arise from mutations that affect the drug-binding site and stability of RNAP.

  10. 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].

  11. Design of 2-D Recursive Filters Using Self-adaptive Mutation Differential Evolution Algorithm

    Directory of Open Access Journals (Sweden)

    Lianghong Wu

    2011-08-01

    Full Text Available This paper investigates a novel approach to the design of two-dimensional recursive digital filters using differential evolution (DE algorithm. The design task is reformulated as a constrained minimization problem and is solved by an Self-adaptive Mutation DE algorithm (SAMDE, which adopts an adaptive mutation operator that combines with the advantages of the DE/rand/1/bin strategy and the DE/best/2/bin strategy. As a result, its convergence performance is improved greatly. Numerical experiment results confirm the conclusion. The proposedSAMDE approach is effectively applied to test a numerical example and is compared with previous design methods. The computational experiments show that the SAMDE approach can obtain better results than previous design methods.

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

    OpenAIRE

    Carrigan, Matthew; Duignan, Emma; Humphries, Pete; Palfi, Arpad; Kenna, Paul F; Farrar, G Jane

    2015-01-01

    Background The GNAT1 gene encodes the ? 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. Methods A panel of 182 retinopathy-associated genes was sequenced to locate disease-causing mutations in patients with inherited retinopathies. Results Sequencing revealed a ...

  13. Prognostic implications of mutation-specific QTc standard deviation in congenital long QT syndrome

    NARCIS (Netherlands)

    Mathias, Andrew; Moss, Arthur J.; Lopes, Coeli M.; Barsheshet, Alon; McNitt, Scott; Zareba, Wojciech; Robinson, Jennifer L.; Locati, Emanuela H.; Ackerman, Michael J.; Benhorin, Jesaia; Kaufman, Elizabeth S.; Platonov, Pyotr G.; Qi, Ming; Shimizu, Wataru; Towbin, Jeffrey A.; Michael Vincent, G.; Wilde, Arthur A. M.; Zhang, Li; Goldenberg, Ilan

    2013-01-01

    Individual corrected QT interval (QTc) may vary widely among carriers of the same long QT syndrome (LQTS) mutation. Currently, neither the mechanism nor the implications of this variable penetrance are well understood. To hypothesize that the assessment of QTc variance in patients with congenital

  14. 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

  15. Evolutionary adaptations: theoretical and practical implications for visual ergonomics.

    Science.gov (United States)

    Fostervold, Knut Inge; Watten, Reidulf G; Volden, Frode

    2014-01-01

    The literature discussing visual ergonomics often mention that human vision is adapted to light emitted by the sun. However, theoretical and practical implications of this viewpoint is seldom discussed or taken into account. The paper discusses some of the main theoretical implications of an evolutionary approach to visual ergonomics. Based on interactional theory and ideas from ecological psychology an evolutionary stress model is proposed as a theoretical framework for future research in ergonomics and human factors. The model stresses the importance of developing work environments that fits with our evolutionary adaptations. In accordance with evolutionary psychology, the environment of evolutionary adaptedness (EEA) and evolutionarily-novel environments (EN) are used as key concepts. Using work with visual display units (VDU) as an example, the paper discusses how this knowledge can be utilized in an ergonomic analysis of risk factors in the work environment. The paper emphasises the importance of incorporating evolutionary theory in the field of ergonomics. Further, the paper encourages scientific practices that further our understanding of any phenomena beyond the borders of traditional proximal explanations.

  16. 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...

  17. Adaptive Mutations in Influenza A/California/07/2009 Enhance Polymerase Activity and Infectious Virion Production

    Science.gov (United States)

    Slaine, Patrick D.; MacRae, Cara; Kleer, Mariel; Lamoureux, Emily; McAlpine, Sarah; Warhuus, Michelle; Comeau, André M.; Hatchette, Todd

    2018-01-01

    Mice are not natural hosts for influenza A viruses (IAVs), but they are useful models for studying antiviral immune responses and pathogenesis. Serial passage of IAV in mice invariably causes the emergence of adaptive mutations and increased virulence. Here, we report the adaptation of IAV reference strain A/California/07/2009(H1N1) (also known as CA/07) in outbred Swiss Webster mice. Serial passage led to increased virulence and lung titers, and dissemination of the virus to brains. We adapted a deep-sequencing protocol to identify and enumerate adaptive mutations across all genome segments. Among mutations that emerged during mouse-adaptation, we focused on amino acid substitutions in polymerase subunits: polymerase basic-1 (PB1) T156A and F740L and polymerase acidic (PA) E349G. These mutations were evaluated singly and in combination in minigenome replicon assays, which revealed that PA E349G increased polymerase activity. By selectively engineering three PB1 and PA mutations into the parental CA/07 strain, we demonstrated that these mutations in polymerase subunits decreased the production of defective viral genome segments with internal deletions and dramatically increased the release of infectious virions from mouse cells. Together, these findings increase our understanding of the contribution of polymerase subunits to successful host adaptation. PMID:29783694

  18. Genome Mutational and Transcriptional Hotspots Are Traps for Duplicated Genes and Sources of Adaptations.

    Science.gov (United States)

    Fares, Mario A; Sabater-Muñoz, Beatriz; Toft, Christina

    2017-05-01

    Gene duplication generates new genetic material, which has been shown to lead to major innovations in unicellular and multicellular organisms. A whole-genome duplication occurred in the ancestor of Saccharomyces yeast species but 92% of duplicates returned to single-copy genes shortly after duplication. The persisting duplicated genes in Saccharomyces led to the origin of major metabolic innovations, which have been the source of the unique biotechnological capabilities in the Baker's yeast Saccharomyces cerevisiae. What factors have determined the fate of duplicated genes remains unknown. Here, we report the first demonstration that the local genome mutation and transcription rates determine the fate of duplicates. We show, for the first time, a preferential location of duplicated genes in the mutational and transcriptional hotspots of S. cerevisiae genome. The mechanism of duplication matters, with whole-genome duplicates exhibiting different preservation trends compared to small-scale duplicates. Genome mutational and transcriptional hotspots are rich in duplicates with large repetitive promoter elements. Saccharomyces cerevisiae shows more tolerance to deleterious mutations in duplicates with repetitive promoter elements, which in turn exhibit higher transcriptional plasticity against environmental perturbations. Our data demonstrate that the genome traps duplicates through the accelerated regulatory and functional divergence of their gene copies providing a source of novel adaptations in yeast. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

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

    Directory of Open Access Journals (Sweden)

    Yasuha Arai

    2016-04-01

    Full Text Available 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. Prognostic implications of mutation-specific QTc standard deviation in congenital long QT syndrome.

    Science.gov (United States)

    Mathias, Andrew; Moss, Arthur J; Lopes, Coeli M; Barsheshet, Alon; McNitt, Scott; Zareba, Wojciech; Robinson, Jennifer L; Locati, Emanuela H; Ackerman, Michael J; Benhorin, Jesaia; Kaufman, Elizabeth S; Platonov, Pyotr G; Qi, Ming; Shimizu, Wataru; Towbin, Jeffrey A; Michael Vincent, G; Wilde, Arthur A M; Zhang, Li; Goldenberg, Ilan

    2013-05-01

    Individual corrected QT interval (QTc) may vary widely among carriers of the same long QT syndrome (LQTS) mutation. Currently, neither the mechanism nor the implications of this variable penetrance are well understood. To hypothesize that the assessment of QTc variance in patients with congenital LQTS who carry the same mutation provides incremental prognostic information on the patient-specific QTc. The study population comprised 1206 patients with LQTS with 95 different mutations and ≥ 5 individuals who carry the same mutation. Multivariate Cox proportional hazards regression analysis was used to assess the effect of mutation-specific standard deviation of QTc (QTcSD) on the risk of cardiac events (comprising syncope, aborted cardiac arrest, and sudden cardiac death) from birth through age 40 years in the total population and by genotype. Assessment of mutation-specific QTcSD showed large differences among carriers of the same mutations (median QTcSD 45 ms). Multivariate analysis showed that each 20 ms increment in QTcSD was associated with a significant 33% (P = .002) increase in the risk of cardiac events after adjustment for the patient-specific QTc duration and the family effect on QTc. The risk associated with QTcSD was pronounced among patients with long QT syndrome type 1 (hazard ratio 1.55 per 20 ms increment; P<.001), whereas among patients with long QT syndrome type 2, the risk associated with QTcSD was not statistically significant (hazard ratio 0.99; P = .95; P value for QTcSD-by-genotype interaction = .002). Our findings suggest that mutations with a wider variation in QTc duration are associated with increased risk of cardiac events. These findings appear to be genotype-specific, with a pronounced effect among patients with the long QT syndrome type 1 genotype. Copyright © 2013. Published by Elsevier Inc.

  1. Attachment in Middle Childhood: Predictors, Correlates, and Implications for Adaptation

    Science.gov (United States)

    Boldt, Lea J.; Kochanska, Grazyna; Grekin, Rebecca; Brock, Rebecca L.

    2016-01-01

    Middle childhood is a relative lacuna in behavioral attachment research. We examined antecedents, correlates, and implications of parent-child attachment at age 10 in a longitudinal study of community families from a Midwestern US state (N=102, mothers, fathers, and children). Dimensions of security, avoidance, ambivalence, and disorganization of children’s attachment to each parent were observed in lengthy naturalistic interactions and assessed using Iowa Attachment Behavioral Coding (IABC). IABC scores were meaningfully associated with history of parental responsiveness (7–80 months) and with earlier and concurrent attachment security, assessed with other established instruments (parent- and observer-rated Attachment Q-Set at 25 months, children’s reports at age 8 and 10). Structural equation modeling analyses revealed that the overall history of responsive care was meaningfully associated with Security, Avoidance, and Disorganization at age 10, in both mother-child and father-child relationships, and that most recent care uniquely predicted Security. IABC scores were also meaningfully related to a broad range of measures of child adaptation at ages 10–12. Cumulative history of children’s security from infancy to middle childhood, integrating measures across relationships and methodologies, also predicted child adaptation at ages 10–12. PMID:26673686

  2. 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

  3. BRAF V600E mutations are common in pleomorphic xanthoastrocytoma: diagnostic and therapeutic implications.

    Directory of Open Access Journals (Sweden)

    Dora Dias-Santagata

    2011-03-01

    Full Text Available Pleomorphic xanthoastrocytoma (PXA is low-grade glial neoplasm principally affecting children and young adults. Approximately 40% of PXA are reported to recur within 10 years of primary resection. Upon recurrence, patients receive radiation therapy and conventional chemotherapeutics designed for high-grade gliomas. Genetic changes that can be targeted by selective therapeutics have not been extensively evaluated in PXA and ancillary diagnostic tests to help discriminate PXA from other pleomorphic and often more aggressive astrocytic malignancies are limited. In this study, we apply the SNaPshot multiplexed targeted sequencing platform in the analysis of brain tumors to interrogate 60 genetic loci that are frequently mutated in 15 cancer genes. In our analysis we detect BRAF V600E mutations in 12 of 20 (60% WHO grade II PXA, in 1 of 6 (17% PXA with anaplasia and in 1 glioblastoma arising in a PXA. Phospho-ERK was detected in all tumors independent of the BRAF mutation status. BRAF duplication was not detected in any of the PXA cases. BRAF V600E mutations were identified in only 2 of 71 (2.8% glioblastoma (GBM analyzed, including 1 of 9 (11.1% giant cell GBM (gcGBM. The finding that BRAF V600E mutations are common in the majority of PXA has important therapeutic implications and may help in differentiating less aggressive PXAs from lethal gcGBMs and GBMs.

  4. Adaptive and Mutational Resistance: Role of Porins and Efflux Pumps in Drug Resistance

    Science.gov (United States)

    Fernández, Lucía

    2012-01-01

    Summary: The substantial use of antibiotics in the clinic, combined with a dearth of new antibiotic classes, has led to a gradual increase in the resistance of bacterial pathogens to these compounds. Among the various mechanisms by which bacteria endure the action of antibiotics, those affecting influx and efflux are of particular importance, as they limit the interaction of the drug with its intracellular targets and, consequently, its deleterious effects on the cell. This review evaluates the impact of porins and efflux pumps on two major types of resistance, namely, mutational and adaptive types of resistance, both of which are regarded as key phenomena in the global rise of antibiotic resistance among pathogenic microorganisms. In particular, we explain how adaptive and mutational events can dramatically influence the outcome of antibiotic therapy by altering the mechanisms of influx and efflux of antibiotics. The identification of porins and pumps as major resistance markers has opened new possibilities for the development of novel therapeutic strategies directed specifically against these mechanisms. PMID:23034325

  5. Functional implications of the p.Cys680Arg mutation in the MLH1 mismatch repair protein

    DEFF Research Database (Denmark)

    Dominguez-Valentin, Mev; Drost, Mark; Therkildsen, Christina

    2014-01-01

    >C missense mutation in exon 18 of the human MLH1 gene and biochemically characterization of the p.Cys680Arg mutant MLH1 protein to implicate it in the pathogenicity of the Lynch syndrome (LS). We show that the mutation is deficient in DNA mismatch repair and, therefore, contributing to LS in the carriers....

  6. Mapping the fitness landscape of gene expression uncovers the cause of antagonism and sign epistasis between adaptive mutations.

    Directory of Open Access Journals (Sweden)

    Hsin-Hung Chou

    2014-02-01

    Full Text Available How do adapting populations navigate the tensions between the costs of gene expression and the benefits of gene products to optimize the levels of many genes at once? Here we combined independently-arising beneficial mutations that altered enzyme levels in the central metabolism of Methylobacterium extorquens to uncover the fitness landscape defined by gene expression levels. We found strong antagonism and sign epistasis between these beneficial mutations. Mutations with the largest individual benefit interacted the most antagonistically with other mutations, a trend we also uncovered through analyses of datasets from other model systems. However, these beneficial mutations interacted multiplicatively (i.e., no epistasis at the level of enzyme expression. By generating a model that predicts fitness from enzyme levels we could explain the observed sign epistasis as a result of overshooting the optimum defined by a balance between enzyme catalysis benefits and fitness costs. Knowledge of the phenotypic landscape also illuminated that, although the fitness peak was phenotypically far from the ancestral state, it was not genetically distant. Single beneficial mutations jumped straight toward the global optimum rather than being constrained to change the expression phenotypes in the correlated fashion expected by the genetic architecture. Given that adaptation in nature often results from optimizing gene expression, these conclusions can be widely applicable to other organisms and selective conditions. Poor interactions between individually beneficial alleles affecting gene expression may thus compromise the benefit of sex during adaptation and promote genetic differentiation.

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

    Science.gov (United States)

    Carrigan, Matthew; Duignan, Emma; Humphries, Pete; Palfi, Arpad; Kenna, Paul F; Farrar, G Jane

    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. A panel of 182 retinopathy-associated genes was sequenced to locate disease-causing mutations in patients with inherited retinopathies. Sequencing revealed a novel homozygous truncating mutation in the GNAT1 gene in a patient with significant pigmentary disturbance and constriction of visual fields, a presentation consistent with retinitis pigmentosa. This is the first report of a patient homozygous for a complete loss-of-function GNAT1 mutation. The clinical data from this patient provide definitive evidence of retinitis pigmentosa with late onset in addition to the lifelong night-blindness that would be expected from a lack of transducin function. These data suggest that some truncating GNAT1 variants can indeed cause a recessive, mild, late-onset retinal degeneration in human beings rather than just stationary night-blindness as reported previously, with notable similarities to the phenotype of the Gnat1 knockout mouse. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  8. Mutational jackpot events generate effective frequency-dependent selection in adapting populations

    Science.gov (United States)

    Hallatschek, Oskar

    The site-frequency spectrum is one the most easily measurable quantities that characterize the genetic diversity of a population. While most neutral models predict that site frequency spectra should decay with increasing frequency, a high-frequency uptick has been reported in many populations. Anomalies in the high-frequency tail are particularly unsettling because the highest frequencies can be measured with greatest accuracy. Here, we show that an uptick in the spectrum of neutral mutations generally arises when mutant frequencies are dominated by rare jackpot events, mutational events with large descendant numbers. This leads to an effective pattern of frequency-dependent selection (or unstable internal equilibrium at one half frequency) that causes an accumulation of high-frequency polymorphic sites. We reproduce the known uptick occurring for recurrent hitchhiking (genetic draft) as well as rapid adaptation, and (in the future) generalize the shape of the high-frequency tail to other scenarios that are dominated by jackpot events, such as frequent range expansions. We also tackle (in the future) the inverse approach to use the high-frequency uptick for learning about the tail of the offspring number distribution. Positively selected alleles need to surpass, typically, an u NSF Career Award (PoLS), NIH NIGMS R01, Simons Foundation.

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

    Energy Technology Data Exchange (ETDEWEB)

    Manesh, Sara Shakeri; Sangsuwan, Traimate; Wojcik, Andrzej; Haghdoost, Siamak, E-mail: Siamak.haghdoost@su.se

    2015-10-15

    Highlights: • 50 mGy at 1.4 mGy/h induces adaptive response in MCF-10A at mutation level. • Low dose rate γ-radiation does not induce adaptive response at survival level. • Overall, a dose rate effect is absent at the level of mutation in MCF-10A cells. - Abstract: 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 50 mGy adapting dose administered acutely (0.40 Gy/min) or chronically (1.4 mGy/h or 4.1 mGy/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 100 mGy and 1 Gy 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 50 mGy at 1.4 mGy/h followed by 1 Gy acute exposure as challenging dose. Importantly, at single dose exposures (1 Gy or 100 mGy), no differences at the level of mutation were found comparing different dose rates.

  10. 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 c...... targets for additional ameliorating mutations. Overall, the results of this study provide insight into the adaptation process and yield lessons important for the future implementation of ALE as a tool for scientific research and engineering....

  11. Effects of Germline Mutations in the Ras/MAPK Signaling Pathway on Adaptive Behavior: Cardiofaciocutaneous Syndrome and Noonan Syndrome

    Science.gov (United States)

    Pierpont, Elizabeth I.; Pierpont, Mary Ella; Mendelsohn, Nancy J.; Roberts, Amy E.; Tworog-Dube, Erica; Rauen, Katherine A.; Seidenberg, Mark S.

    2011-01-01

    Cardiofaciocutaneous syndrome (CFC) and Noonan syndrome (NS) are two phenotypically overlapping genetic disorders whose underlying molecular etiologies affect a common signaling pathway. Mutations in the BRAF, MEK1 and MEK2 genes cause most cases of CFC and mutations in PTPN11, SOS1, KRAS and RAF1 typically cause NS. Although both syndromes are associated with developmental delays of varying severity, the extent to which the behavioral profiles differ may shed light on the different roles these respective genes play in development of skills necessary for everyday functioning. In this study, profiles of adaptive behavior of individuals with CFC and NS who had confirmed pathogenic mutations in Ras/MAPK pathway genes were investigated. Patterns of strengths and weaknesses, age-related differences, and risk factors for difficulties in adaptive skills were assessed. Although genes acting more downstream in the Ras/MAPK pathway were associated with more difficulties in adaptive functioning than genes more upstream in the pathway, several inconsistencies highlight the wide spectrum of possible developmental courses in CFC and NS. Along with clinical and genetic factors, variables such as chronological age, gestational age at birth and parental education levels accounted for significant variance in adaptive skills. Results indicate that there is wide heterogeneity in adaptive ability in CFC and NS, but that these abilities are correlated to some extent with the specific disease-causing genes. PMID:20186801

  12. Mutation breeding in Ajonjoli (Sesamum indicum, L.) for adaptation to the cropping system in Venezuela

    International Nuclear Information System (INIS)

    Oropeza, F.; Murty, B.R.; Bravo, R.M.

    1984-01-01

    Sesame, the main edible oil crop in Venezuela, is grown in a cropping system under peculiar ecological conditions after rice, sorghum or maize on residual moisture. The yields are variable with 350 to 500 Kg/Ha. The available varieties are not synchronous in flowering, have poor root development, and are susceptible to Fusarium sp, Phytophtora and Macrophomina. Some are very late (more than 115 days) with 1-3 capsules of variable size and unpredictable yield. A mutational rectification program using locally adapted varieties was started in 1981, to develop material suitable for the above ecological conditions. The main characteristics for improvement are: earliness, with maturity of 75 to 90 days, synchronous flowering, uniform ripening, indehiscence at harvesting but easy threshing, suitable plant type for mechanical harvesting, resistance specially to Macrophomina spp, without adverse effect on oil content, quality and yield and improved productivity and stability under moisture stress and improved fertilizer utilization. Eight varieties were treated with gamma radiation from Csub(o) 60 at 0, 20, 40, 60, 80 KR to determine varietal responses. The results show marked varietal differences in germination, growth and survival. The other three varieties: Aceitera, Arawaca, Turen were the most susceptible to radiation, while Glauca was the most resistant. Probit analysis of data for germination, vigor seedling height and survival revealed that no single character is adequate to determine LD 50 dose in mutation breeding. The need for taking all the parameters of regression analysis like b-tilde, and σ-circumflex to characterize varietal responses is discussed along with plans for the next stage of work. (author)

  13. Computer-Adaptive Testing: Implications for Students' Achievement, Motivation, Engagement, and Subjective Test Experience

    Science.gov (United States)

    Martin, Andrew J.; Lazendic, Goran

    2018-01-01

    The present study investigated the implications of computer-adaptive testing (operationalized by way of multistage adaptive testing; MAT) and "conventional" fixed order computer testing for various test-relevant outcomes in numeracy, including achievement, test-relevant motivation and engagement, and subjective test experience. It did so…

  14. 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...

  15. 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

    2009-08-01

    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

  16. 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.

  17. Computational analysis of KRAS mutations: implications for different effects on the KRAS p.G12D and p.G13D mutations.

    Directory of Open Access Journals (Sweden)

    Chih-Chieh Chen

    Full Text Available BACKGROUND: The issue of whether patients diagnosed with metastatic colorectal cancer who harbor KRAS codon 13 mutations could benefit from the addition of anti-epidermal growth factor receptor therapy remains under debate. The aim of the current study was to perform computational analysis to investigate the structural implications of the underlying mutations caused by c.38G>A (p.G13D on protein conformation. METHODS: Molecular dynamics (MD simulations were performed to understand the plausible structural and dynamical implications caused by c.35G>A (p.G12D and c.38G>A (p.G13D. The potential of mean force (PMF simulations were carried out to determine the free energy profiles of the binding processes of GTP interacting with wild-type (WT KRAS and its mutants (MT. RESULTS: Using MD simulations, we observed that the root mean square deviation (RMSD increased as a function of time for the MT c.35G>A (p.G12D and MT c.38G>A (p.G13D when compared with the WT. We also observed that the GTP-binding pocket in the c.35G>A (p.G12D mutant is more open than that of the WT and the c.38G>A (p.G13D proteins. Intriguingly, the analysis of atomic fluctuations and free energy profiles revealed that the mutation of c.35G>A (p.G12D may induce additional fluctuations in the sensitive sites (P-loop, switch I and II regions. Such fluctuations may promote instability in these protein regions and hamper GTP binding. CONCLUSIONS: Taken together with the results obtained from MD and PMF simulations, the present findings implicate fluctuations at the sensitive sites (P-loop, switch I and II regions. Our findings revealed that KRAS mutations in codon 13 have similar behavior as KRAS WT. To gain a better insight into why patients with metastatic colorectal cancer (mCRC and the KRAS c.38G>A (p.G13D mutation appear to benefit from anti-EGFR therapy, the role of the KRAS c.38G>A (p.G13D mutation in mCRC needs to be further investigated.

  18. 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....

  19. 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.

  20. The determinants of vulnerability and adaptive capacity at the national level and the implications for adaptation

    Energy Technology Data Exchange (ETDEWEB)

    Brooks, N.; Adger, W.N.; Kelly, P.M. [University of East Anglia, Norwich (United Kingdom). School of Environmental Sciences

    2005-07-01

    We present a set of indicators of vulnerability and capacity to adapt to climate variability, and by extension climate change, derived using a novel empirical analysis of data aggregated at the national level on a decadal timescale. The analysis is based on a conceptual framework in which risk is viewed in terms of outcome, and is a function of physically defined climate hazards and socially constructed vulnerability. Climate outcomes are represented by mortality from climate-related disasters, using the emergency events database data set, statistical relationships between mortality and a shortlist of potential proxies for vulnerability are used to identify key vulnerability indicators. We find that 11 key indicators exhibit a strong relationship with decadally aggregated mortality associated with climate-related disasters. Validation of indicators, relationships between vulnerability and adaptive capacity, and the sensitivity of subsequent vulnerability assessments to different sets of weightings are explored using expert judgement data, collected through a focus group exercise. The data are used to provide a robust assessment of vulnerability to climate-related mortality at the national level, and represent an entry point to more detailed explorations of vulnerability and adaptive capacity. They indicate that the most vulnerable nations are those situated in sub-Saharan Africa and those that have recently experienced conflict. Adaptive capacity - one element of vulnerability - is associated predominantly with governance, civil and political rights, and literacy. (author)

  1. The determinants of vulnerability and adaptive capacity at the national level and the implications for adaptation

    International Nuclear Information System (INIS)

    Brooks, N.; Adger, W.N.; Kelly, P.M.

    2005-01-01

    We present a set of indicators of vulnerability and capacity to adapt to climate variability, and by extension climate change, derived using a novel empirical analysis of data aggregated at the national level on a decadal timescale. The analysis is based on a conceptual framework in which risk is viewed in terms of outcome, and is a function of physically defined climate hazards and socially constructed vulnerability. Climate outcomes are represented by mortality from climate-related disasters, using the emergency events database data set, statistical relationships between mortality and a shortlist of potential proxies for vulnerability are used to identify key vulnerability indicators. We find that 11 key indicators exhibit a strong relationship with decadally aggregated mortality associated with climate-related disasters. Validation of indicators, relationships between vulnerability and adaptive capacity, and the sensitivity of subsequent vulnerability assessments to different sets of weightings are explored using expert judgement data, collected through a focus group exercise. The data are used to provide a robust assessment of vulnerability to climate-related mortality at the national level, and represent an entry point to more detailed explorations of vulnerability and adaptive capacity. They indicate that the most vulnerable nations are those situated in sub-Saharan Africa and those that have recently experienced conflict. Adaptive capacity - one element of vulnerability - is associated predominantly with governance, civil and political rights, and literacy. (author)

  2. Cell culture-adaptive mutations of NS5A affect replication of hepatitis C virus differentially depending on the viral genotypes.

    Science.gov (United States)

    Chung, Aeri; Jin, Bora; Han, Kwang-Hyub; Ahn, Sang Hoon; Kim, Seungtaek

    2017-01-01

    Most of HCV RNAs require cell culture-adaptive mutations for efficient replication in cell culture and a number of such mutations have been described including a well-known S2204I substitution mutation in NS5A protein. In contrast, the replication of genotype 2a JFH1 RNA in cell culture does not require any cell culture-adaptive mutation. Rather, the presence of S2204I mutation impaired the JFH1 RNA replication. In this study, we examined the effect of reversions and substitutions of NS5A cell culture-adaptive mutations on virus replication in different genotypic backgrounds after either placing genotype 1a NS5A in the genotype 2a JFH1 or vice versa. The results from this investigation suggest that the S2204I mutation affects HCV RNA replication differentially depending on the viral genotypes but that the effect was not simply explained by the genotypic background. Perhaps, the effect of the S2204I mutation on HCV replication reflects both intra- and intergenic interactions of NS5A protein. J. Med. Virol. 89:146-152, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  3. Placental transfer of antidepressant medications: implications for postnatal adaptation syndrome.

    Science.gov (United States)

    Ewing, Grace; Tatarchuk, Yekaterina; Appleby, Dina; Schwartz, Nadav; Kim, Deborah

    2015-04-01

    Seven to thirteen percent of women are either prescribed or taking (depending on the study) an antidepressant during pregnancy. Because antidepressants freely cross into the intrauterine environment, we aim to summarize the current findings on placental transfer of antidepressants. Although generally low risk, antidepressants have been associated with postnatal adaptation syndrome (PNAS). Specifically, we explore whether the antidepressants most closely associated with PNAS (paroxetine, fluoxetine, venlafaxine) cross the placenta to a greater extent than other antidepressants. We review research on antidepressants in the context of placental anatomy, placental transport mechanisms, placental metabolism, pharmacokinetics, as well as non-placental maternal and fetal factors. This provides insight into the complexity involved in understanding how placental transfer of antidepressants may relate to adverse perinatal outcomes. Ultimately, from this data there is no pattern in which PNAS is related to placental transfer of antidepressant medications. In general, there is large interindividual variability for each type of antidepressant. To make the most clinically informed decisions about the use of antidepressants in pregnancy, studies that link maternal, placental and fetal genetic polymorphisms, placental transfer rates and infant outcomes are needed.

  4. 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

    in terms of their mutational activity. Moreover, we highlight the importance of the genetic code and physico-chemical properties of the amino acid residues as likely causes of these inequalities and uncover serine as a mutational hot spot. Finally, we explore the consequences that these different......; it is typically assumed that all amino acid residues are equally likely to mutate or to result from a mutation. Here, by reconstructing ancestral sequences and computing mutational probabilities for all the amino acid residues, we refute this assumption and show extensive inequalities between different residues...... mutational properties have on phosphorylation site evolution, showing that a higher degree of evolvability exists for phosphorylated threonine and, to a lesser extent, serine in comparison with tyrosine residues. As exemplified by the suppression of serine's mutational activity in phosphorylation sites, our...

  5. 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.

  6. 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.

  7. Influence of smallholder farmers’ perceptions on adaptation strategies to climate change and policy implications in Zimbabwe

    Directory of Open Access Journals (Sweden)

    Jiri Obert

    2017-01-01

    Full Text Available Smallholder agricultural production is largely affected by climate change and variability. Despite the negative effects brought by climate variability, smallholder farmers are still able to derive livelihoods. An understanding of factors that influence farmers’ responses and adaptation to climate variability can improve decision making for governments and development partners. This study investigated farmers’ perceptions and adaptation strategies to climate change and how these influence adaptation policies at local level. A survey was conducted with 100 households randomly selected from Chiredzi district. Data collected was used to derive farmer perceptions to climate change as well as the influence of their perceptions and subsequent adaptation methods to ensuing local agricultural adaptation measures and policies. The results indicated that smallholder farmers perceived general reduction in long-term annual rainfall and rising local average temperatures. Adverse trends in rainfall and average temperature perceived by farmers were consistent with empirical data. These perceptions and other socio-economic factors helped to shape smallholder farmer agricultural adaptation strategies. Policy implications are that the government and development partners should seek ways to assist autonomous adaptations by farmers through investments in planned adaptation initiatives.

  8. 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.

  9. Mutation of a cuticular protein, BmorCPR2, alters larval body shape and adaptability in silkworm, Bombyx mori.

    Science.gov (United States)

    Qiao, Liang; Xiong, Gao; Wang, Ri-xin; He, Song-zhen; Chen, Jie; Tong, Xiao-ling; Hu, Hai; Li, Chun-lin; Gai, Ting-ting; Xin, Ya-qun; Liu, Xiao-fan; Chen, Bin; Xiang, Zhong-huai; Lu, Cheng; Dai, Fang-yin

    2014-04-01

    Cuticular proteins (CPs) are crucial components of the insect cuticle. Although numerous genes encoding cuticular proteins have been identified in known insect genomes to date, their functions in maintaining insect body shape and adaptability remain largely unknown. In the current study, positional cloning led to the identification of a gene encoding an RR1-type cuticular protein, BmorCPR2, highly expressed in larval chitin-rich tissues and at the mulberry leaf-eating stages, which is responsible for the silkworm stony mutant. In the Dazao-stony strain, the BmorCPR2 allele is a deletion mutation with significantly lower expression, compared to the wild-type Dazao strain. Dysfunctional BmorCPR2 in the stony mutant lost chitin binding ability, leading to reduced chitin content in larval cuticle, limitation of cuticle extension, abatement of cuticle tensile properties, and aberrant ratio between internodes and intersegmental folds. These variations induce a significant decrease in cuticle capacity to hold the growing internal organs in the larval development process, resulting in whole-body stiffness, tightness, and hardness, bulging intersegmental folds, and serious defects in larval adaptability. To our knowledge, this is the first study to report the corresponding phenotype of stony in insects caused by mutation of RR1-type cuticular protein. Our findings collectively shed light on the specific role of cuticular proteins in maintaining normal larval body shape and will aid in the development of pest control strategies for the management of Lepidoptera.

  10. 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.

  11. 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

    Hepatitis C virus (HCV) is an important cause of chronic liver disease, and interferon-based therapy cures only 40 to 80% of patients, depending on HCV genotype. Research was accelerated by genotype 2a (strain JFH1) infectious cell culture systems. We previously developed viable JFH1-based...... (HC-TN and DH6), 1b (DH1 and DH5), and 3a (DBN) isolates, using previously identified adaptive mutations. Introduction of mutations from isolates of the same subtype either led to immediate efficient virus production or accelerated culture adaptation. The DH6 and DH5 recombinants without introduced...... mutations did not adapt to culture. Universal adaptive effects of mutations in NS3 (Q1247L, I1312V, K1398Q, R1408W, and Q1496L) and NS5A (V2418L) were investigated for JFH1-based genotype 1 to 5 core-NS2 recombinants; several mutations conferred adaptation to H77C (1a), J4 (1b), S52 (3a), and SA13 (5a...

  12. Identification of novel mutations in X-linked retinitis pigmentosa families and implications for diagnostic testing

    Science.gov (United States)

    Glaus, Esther; Lorenz, Birgit; Netzer, Christian; Li, Yün; Schambeck, Maria; Wittmer, Mariana; Feil, Silke; Kirschner-Schwabe, Renate; Rosenberg, Thomas; Cremers, Frans P.M.; Bergen, Arthur A.B.; Barthelmes, Daniel; Baraki, Husnia; Schmid, Fabian; Tanner, Gaby; Fleischhauer, Johannes; Orth, Ulrike; Becker, Christian; Wegscheider, Erika; Nürnberg, Gudrun; Nürnberg, Peter; Bolz, Hanno Jörn; Gal, Andreas; Berger, Wolfgang

    2008-01-01

    Purpose The goal of this study was to identify mutations in X-chromosomal genes associated with retinitis pigmentosa (RP) in patients from Germany, The Netherlands, Denmark, and Switzerland. Methods In addition to all coding exons of RP2, exons 1 through 15, 9a, ORF15, 15a and 15b of RPGR were screened for mutations. PCR products were amplified from genomic DNA extracted from blood samples and analyzed by direct sequencing. In one family with apparently dominant inheritance of RP, linkage analysis identified an interval on the X chromosome containing RPGR, and mutation screening revealed a pathogenic variant in this gene. Patients of this family were examined clinically and by X-inactivation studies. Results This study included 141 RP families with possible X-chromosomal inheritance. In total, we identified 46 families with pathogenic sequence alterations in RPGR and RP2, of which 17 mutations have not been described previously. Two of the novel mutations represent the most 3’-terminal pathogenic sequence variants in RPGR and RP2 reported to date. In exon ORF15 of RPGR, we found eight novel and 14 known mutations. All lead to a disruption of open reading frame. Of the families with suggested X-chromosomal inheritance, 35% showed mutations in ORF15. In addition, we found five novel mutations in other exons of RPGR and four in RP2. Deletions in ORF15 of RPGR were identified in three families in which female carriers showed variable manifestation of the phenotype. Furthermore, an ORF15 mutation was found in an RP patient who additionally carries a 6.4 kbp deletion downstream of the coding region of exon ORF15. We did not identify mutations in 39 sporadic male cases from Switzerland. Conclusions RPGR mutations were confirmed to be the most frequent cause of RP in families with an X-chromosomal inheritance pattern. We propose a screening strategy to provide molecular diagnostics in these families. PMID:18552978

  13. 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.

  14. 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

    Background: A Saccharomyces cerevisiae strain carrying deletions in all three pyruvate decarboxylase (PDC) genes (also called Pdc negative yeast) represents a non-ethanol producing platform strain for the production of pyruvate derived biochemicals. However, it cannot grow on glucose as the sole...... 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...

  15. Calcium Sensing Receptor Mutations Implicated in Pancreatitis and Idiopathic Epilepsy Syndrome Disrupt an Arginine-rich Retention Motif

    Science.gov (United States)

    Stepanchick, Ann; McKenna, Jennifer; McGovern, Olivia; Huang, Ying; Breitwieser, Gerda E.

    2010-01-01

    Calcium sensing receptor (CaSR) mutations implicated in familial hypocalciuric hypercalcemia, pancreatitis and idiopathic epilepsy syndrome map to an extended arginine-rich region in the proximal carboxyl terminus. Arginine-rich motifs mediate endoplasmic reticulum retention and/or retrieval of multisubunit proteins so we asked whether these mutations, R886P, R896H or R898Q, altered CaSR targeting to the plasma membrane. Targeting was enhanced by all three mutations, and Ca2+-stimulated ERK1/2 phosphorylation was increased for R896H and R898Q. To define the role of the extended arginine-rich region in CaSR trafficking, we independently determined the contributions of R890/R891 and/or R896/K897/R898 motifs by mutation to alanine. Disruption of the motif(s) significantly increased surface expression and function relative to wt CaSR. The arginine-rich region is flanked by phosphorylation sites at S892 (protein kinase C) and S899 (protein kinase A). The phosphorylation state of S899 regulated recognition of the arginine-rich region; S899D showed increased surface localization. CaSR assembles in the endoplasmic reticulum as a covalent disulfide-linked dimer and we determined whether retention requires the presence of arginine-rich regions in both subunits. A single arginine-rich region within the dimer was sufficient to confer intracellular retention comparable to wt CaSR. We have identified an extended arginine-rich region in the proximal carboxyl terminus of CaSR (residues R890 - R898) which fosters intracellular retention of CaSR and is regulated by phosphorylation. Mutation(s) identified in chronic pancreatitis and idiopathic epilepsy syndrome therefore increase plasma membrane targeting of CaSR, likely contributing to the altered Ca2+ signaling characteristic of these diseases. PMID:20798521

  16. 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.

  17. Non-homologous end joining dependency of γ-irradiation-induced adaptive frameshift mutation formation in cell cycle-arrested yeast cells

    International Nuclear Information System (INIS)

    Heidenreich, Erich; Eisler, Herfried

    2004-01-01

    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 γ-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 γ-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

  18. Inter-disciplinary approach to selection in mutation breeding in local sorghums for adaptation and disease resistance

    International Nuclear Information System (INIS)

    Murty, B.R.; Taborda, F.; Reinoso, A.

    1984-01-01

    The present report of Mutational rectifications in local Sorghums involved improvement in adaptation and disease resistance. After seed treatment at 20, 30 and 40 kr the material now in the M 6 generation has given promising response to the above selection. Similarly, chemical mutagens with Na Azide + 5 kr γ-radiation of seeds also gave valuable mutants now in M 4 generation. More than 20 promising mutants are isolated with dwarf habit (100-125 cms), good head size, resistance to charcoal rot, good seed size and root development, more heads/unit area and yield increases (40%-100%) over the parents and much higher than the hybrids under cultivation. The mutants were also superior or equal to the parent in micronutrient uptake (Zn), protein content, nutrient uptake, light interception, photo-synthetic rate, and transfer to grain for N and P, root activities, regeneration capacity and disease resistance under artificial inoculation with better yield potential under close spacing (50 cm x 10 cm vs 75 cm x 10 cm). The multilocation test for wide adaptation in 3 locations revealed that at least 4 of the mutants have a wide range of adaptation. Biochemical studies of seed proteins by gel electrophoresis revealed distinct differences between the mutants and also the parents. Similar results were obtained for tannin content, Zn, phosphate (p 32 tracer) N uptake, indicating the presence of diverse mechanisms of adaptation and yield. Differences between the mutants in tillering, regeneration capacity rooting pattern, panicle no. and size, grain size and threshing % were observed. The integrated selection for the above attributes from M 3 to M 6 involved both field and laboratory testing demonstrating the utility of interdisciplinary approach in mutation breeding for effective selection in problem areas with complex ecological conditions and cropping patterns. The results of these studies are discussed with emphasis on selection methodology for the multiple traits involving

  19. Clinical implications of the BRAF mutation in papillary thyroid carcinoma and chronic lymphocytic thyroiditis.

    Science.gov (United States)

    Kim, Woon Won; Ha, Tae Kwun; Bae, Sung Kwon

    2018-01-09

    The purpose of this study was to examine the possible prognostics and clinicopathologic characteristics underlying the BRAFV600E mutation and papillary thyroid carcinoma (PTC) coexisting or in absence of chronic lymphocytic thyroiditis (CLT). This study was conducted on 172 patients who had undergone total thyroidectomy or unilateral total thyroidectomy for PTC; the patients were then examined for the BRAFV600E mutation using specimens obtained after their surgery from January 2013 to August 2015. BRAF mutations were found in 130 of 172 patients (75.6%). CLT was present in 27.9% of patients (48/172). The incidence of the BRAFV600E mutation was significantly increased in the group with no CLT (P = 0.001). The findings of the multivariate analysis pertaining to the coexistence of CLT and PTC showed no significant correlation other than the BRAFV600E mutation. No significant difference was noted in the clinicopathologic factors between the two groups based on the coexistence of CLT in univariate and multivariate analyses. The BRAFV600E mutation is less frequent in PTC coexisting with CLT presumably because CLT and the BRAFV600E mutation operate independently in the formation and progression of thyroid cancer.

  20. 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

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

    International Nuclear Information System (INIS)

    Preto, Ana; Soares, Paula; Sobrinho-Simões, Manuel; Gonçalves, Joana; Rebocho, Ana P; Figueiredo, Joana; Meireles, Ana M; Rocha, Ana S; Vasconcelos, Helena M; Seca, Hugo; Seruca, Raquel

    2009-01-01

    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. 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. Both BRAF RNAi and sorafenib inhibited proliferation in all the cell lines independently of the genetic background, mostly in cells with BRAF V600E mutation. In BRAF V600E mutated cells inhibition of BRAF pathway lead to a decrease in ERK1/2 phosphorylation and cyclin D1 levels and an increase in p27 Kip1 . Specific inhibition of BRAF by RNAi in cells with BRAF V600E mutation had no effect on apoptosis. In the case of sorafenib treatment, cells harbouring BRAF V600E mutation showed increase levels of apoptosis due to a balance of the anti-apoptotic proteins Mcl-1 and Bcl-2. Our results in thyroid cancer cells, namely those harbouring BRAF V600E mutation 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 BRAF V600E mutated cells which was independent of BRAF. These results suggest that sorafenib may prove useful in the treatment of thyroid carcinomas, particularly those refractory to conventional treatment and

  2. The Origin of Mutants Under Selection: How Natural Selection Mimics Mutagenesis (Adaptive Mutation)

    Science.gov (United States)

    Maisnier-Patin, Sophie; Roth, John R.

    2015-01-01

    Selection detects mutants but does not cause mutations. Contrary to this dictum, Cairns and Foster plated a leaky lac mutant of Escherichia coli on lactose medium and saw revertant (Lac+) colonies accumulate with time above a nongrowing lawn. This result suggested that bacteria might mutagenize their own genome when growth is blocked. However, this conclusion is suspect in the light of recent evidence that revertant colonies are initiated by preexisting cells with multiple copies the conjugative F′lac plasmid, which carries the lac mutation. Some plated cells have multiple copies of the simple F′lac plasmid. This provides sufficient LacZ activity to support plasmid replication but not cell division. In nongrowing cells, repeated plasmid replication increases the likelihood of a reversion event. Reversion to lac+ triggers exponential cell growth leading to a stable Lac+ revertant colony. In 10% of these plated cells, the high-copy plasmid includes an internal tandem lac duplication, which provides even more LacZ activity—sufficient to support slow growth and formation of an unstable Lac+ colony. Cells with multiple copies of the F′lac plasmid have an increased mutation rate, because the plasmid encodes the error-prone (mutagenic) DNA polymerase, DinB. Without DinB, unstable and stable Lac+ revertant types form in equal numbers and both types arise with no mutagenesis. Amplification and selection are central to behavior of the Cairns–Foster system, whereas mutagenesis is a system-specific side effect or artifact caused by coamplification of dinB with lac. Study of this system has revealed several broadly applicable principles. In all populations, gene duplications are frequent stable genetic polymorphisms, common near-neutral mutant alleles can gain a positive phenotype when amplified under selection, and natural selection can operate without cell division when variability is generated by overreplication of local genome subregions. PMID:26134316

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

    KAUST Repository

    Monies, Dorota; Maddirevula, Sateesh; Kurdi, Wesam; Alanazy, Mohammed H.; Alkhalidi, Hisham; Al-Owain, Mohammed; Sulaiman, Raashda A.; Faqeih, Eissa; Goljan, Ewa; Ibrahim, Niema; Abdulwahab, Firdous; Hashem, Mais; Abouelhoda, Mohamed; Shaheen, Ranad; Arold, Stefan T.; Alkuraya, Fowzan S.

    2017-01-01

    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

  4. Farmers’ Adaptation Strategies to Climate Change and Their Implications in the Zou Department of South Benin

    Directory of Open Access Journals (Sweden)

    Adégnandjou Mahouna Roland Fadina

    2018-01-01

    Full Text Available Climate change is a global phenomenon. Its impact on agricultural activities in developing countries has increased dramatically. Understanding how farmers perceive climate change and how they adapt to it is very important to the implementation of adequate policies for agricultural and food security. This paper aims to contribute to an understanding of farmers’ adaptation choices, determinants of the adaptation choices and the long-term implications of the adaptation choices. Data were collected from 120 respondents in the Zou Department of Benin. A binary logit model was used to analyze the factors influencing household decisions to adapt to climate change. Multinomial logistic regression analysis was estimated to analyze the factors influencing households’ choice of adaptation strategies to climate change. The results show that farmers have a developed perception of climate change. These changes are translated by rainfall disturbances (rainfall delays, early cessation, bad rainfall distribution etc., shortening of the small dry season, increasing of temperature and sometimes, violent winds. The survey reveals that Benin farmers adopt many strategies in response to climate change. These strategies include “Crop–livestock diversification and other good practices (mulching, organic fertilizer,” “Use of improved varieties, chemical fertilizers and pesticides,” “Agroforestry and perennial plantation” and “Diversification of income-generating activities.” The findings also reveal that most of the respondents use these strategies in combination. From the binary logit model, we know that “farming experience” and “educational level of household head” positively influence adaptation decisions. The result of the multinomial logit analysis shows that farming experience, educational level, farm size and gender have a significant impact on climate change adaptation strategies. Based on in-depth analysis of each strategy, we

  5. 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...... the adaptive profiles of mucoid and non-mucoid isolates from the two locations. METHODS: We studied the genetic basis of phenotypic diversification and gene expression profiles in sequential lung and sinus P. aeruginosa isolates from four chronically infected CF patients, including pre- and post-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...

  6. Factor V Leiden mutation in pregnancy.

    Science.gov (United States)

    Cohen, Susan Murphy

    2004-01-01

    Normal maternal adaptation to pregnancy significantly increases the risk for thrombus formation. Inherited thrombophilias further increase risk for deep venous thrombosis and adverse outcome in pregnancy. Factor V Leiden mutation is the most common inherited thrombophilia, occurring in approximately 5% of the White and 1% of the Black populations. Nurses should be knowledgeable about screening for and diagnosis of factor V Leiden mutation, risk reduction counseling, recommended care of the affected patient, and implications of anticoagulant therapy during the perinatal period.

  7. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  9. Clinical implications of somatic mutations in aplastic anemia and myelodysplastic syndrome in genomic age.

    Science.gov (United States)

    Maciejewski, Jaroslaw P; Balasubramanian, Suresh K

    2017-12-08

    Recent technological advances in genomics have led to the discovery of new somatic mutations and have brought deeper insights into clonal diversity. This discovery has changed not only the understanding of disease mechanisms but also the diagnostics and clinical management of bone marrow failure. The clinical applications of genomics include enhancement of current prognostic schemas, prediction of sensitivity or refractoriness to treatments, and conceptualization and selective application of targeted therapies. However, beyond these traditional clinical aspects, complex hierarchical clonal architecture has been uncovered and linked to the current concepts of leukemogenesis and stem cell biology. Detection of clonal mutations, otherwise typical of myelodysplastic syndrome, in the course of aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria has led to new pathogenic concepts in these conditions and created a new link between AA and its clonal complications, such as post-AA and paroxysmal nocturnal hemoglobinuria. Distinctions among founder vs subclonal mutations, types of clonal evolution (linear or branching), and biological features of individual mutations (sweeping, persistent, or vanishing) will allow for better predictions of the biologic impact they impart in individual cases. As clonal markers, mutations can be used for monitoring clonal dynamics of the stem cell compartment during physiologic aging, disease processes, and leukemic evolution. © 2016 by The American Society of Hematology. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    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.

  11. Predictive models for mutations in mismatch repair genes: implication for genetic counseling in developing countries

    Directory of Open Access Journals (Sweden)

    Monteiro Santos Erika

    2012-02-01

    Full Text Available Abstract Background Lynch syndrome (LS is the most common form of inherited predisposition to colorectal cancer (CRC, accounting for 2-5% of all CRC. LS is an autosomal dominant disease characterized by mutations in the mismatch repair genes mutL homolog 1 (MLH1, mutS homolog 2 (MSH2, postmeiotic segregation increased 1 (PMS1, post-meiotic segregation increased 2 (PMS2 and mutS homolog 6 (MSH6. Mutation risk prediction models can be incorporated into clinical practice, facilitating the decision-making process and identifying individuals for molecular investigation. This is extremely important in countries with limited economic resources. This study aims to evaluate sensitivity and specificity of five predictive models for germline mutations in repair genes in a sample of individuals with suspected Lynch syndrome. Methods Blood samples from 88 patients were analyzed through sequencing MLH1, MSH2 and MSH6 genes. The probability of detecting a mutation was calculated using the PREMM, Barnetson, MMRpro, Wijnen and Myriad models. To evaluate the sensitivity and specificity of the models, receiver operating characteristic curves were constructed. Results Of the 88 patients included in this analysis, 31 mutations were identified: 16 were found in the MSH2 gene, 15 in the MLH1 gene and no pathogenic mutations were identified in the MSH6 gene. It was observed that the AUC for the PREMM (0.846, Barnetson (0.850, MMRpro (0.821 and Wijnen (0.807 models did not present significant statistical difference. The Myriad model presented lower AUC (0.704 than the four other models evaluated. Considering thresholds of ≥ 5%, the models sensitivity varied between 1 (Myriad and 0.87 (Wijnen and specificity ranged from 0 (Myriad to 0.38 (Barnetson. Conclusions The Barnetson, PREMM, MMRpro and Wijnen models present similar AUC. The AUC of the Myriad model is statistically inferior to the four other models.

  12. Predictive models for mutations in mismatch repair genes: implication for genetic counseling in developing countries

    Energy Technology Data Exchange (ETDEWEB)

    Monteiro Santos, Erika Maria [Graduation Program, AC Camargo Hospital, Sao Paulo (Brazil); International Center of Research and Training (CIPE), AC Camargo Hospital, Sao Paulo (Brazil); Silva Junior, Wilson Araujo da [Sao Paulo University, Department of Genetics, Medical School of Ribeirao Preto, Ribeirao Preto (Brazil); Carraro, Dirce Maria [Graduation Program, AC Camargo Hospital, Sao Paulo (Brazil); International Center of Research and Training (CIPE), AC Camargo Hospital, Sao Paulo (Brazil); Rossi, Benedito Mauro; Valentin, Mev Dominguez [Graduation Program, AC Camargo Hospital, Sao Paulo (Brazil); Carneiro, Felipe [Graduation Program, AC Camargo Hospital, Sao Paulo (Brazil); International Center of Research and Training (CIPE), AC Camargo Hospital, Sao Paulo (Brazil); Oliveira, Ligia Petrolini de [Graduation Program, AC Camargo Hospital, Sao Paulo (Brazil); Oliveira Ferreira, Fabio de; Junior, Samuel Aguiar [Graduation Program, AC Camargo Hospital, Sao Paulo (Brazil); Hereditary Colorectal Cancer Registry, AC Camargo Hospital, Sao Paulo (Brazil); Nakagawa, Wilson Toshihiko [Hereditary Colorectal Cancer Registry, AC Camargo Hospital, Sao Paulo (Brazil); Gomy, Israel [Graduation Program, AC Camargo Hospital, Sao Paulo (Brazil); Sao Paulo University, Department of Genetics, Medical School of Ribeirao Preto, Ribeirao Preto (Brazil); Faria Ferraz, Victor Evangelista de [Sao Paulo University, Department of Genetics, Medical School of Ribeirao Preto, Ribeirao Preto (Brazil)

    2012-02-09

    Lynch syndrome (LS) is the most common form of inherited predisposition to colorectal cancer (CRC), accounting for 2-5% of all CRC. LS is an autosomal dominant disease characterized by mutations in the mismatch repair genes mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), postmeiotic segregation increased 1 (PMS1), post-meiotic segregation increased 2 (PMS2) and mutS homolog 6 (MSH6). Mutation risk prediction models can be incorporated into clinical practice, facilitating the decision-making process and identifying individuals for molecular investigation. This is extremely important in countries with limited economic resources. This study aims to evaluate sensitivity and specificity of five predictive models for germline mutations in repair genes in a sample of individuals with suspected Lynch syndrome. Blood samples from 88 patients were analyzed through sequencing MLH1, MSH2 and MSH6 genes. The probability of detecting a mutation was calculated using the PREMM, Barnetson, MMRpro, Wijnen and Myriad models. To evaluate the sensitivity and specificity of the models, receiver operating characteristic curves were constructed. Of the 88 patients included in this analysis, 31 mutations were identified: 16 were found in the MSH2 gene, 15 in the MLH1 gene and no pathogenic mutations were identified in the MSH6 gene. It was observed that the AUC for the PREMM (0.846), Barnetson (0.850), MMRpro (0.821) and Wijnen (0.807) models did not present significant statistical difference. The Myriad model presented lower AUC (0.704) than the four other models evaluated. Considering thresholds of ≥ 5%, the models sensitivity varied between 1 (Myriad) and 0.87 (Wijnen) and specificity ranged from 0 (Myriad) to 0.38 (Barnetson). The Barnetson, PREMM, MMRpro and Wijnen models present similar AUC. The AUC of the Myriad model is statistically inferior to the four other models.

  13. Predictive models for mutations in mismatch repair genes: implication for genetic counseling in developing countries

    International Nuclear Information System (INIS)

    Monteiro Santos, Erika Maria; Silva Junior, Wilson Araujo da; Carraro, Dirce Maria; Rossi, Benedito Mauro; Valentin, Mev Dominguez; Carneiro, Felipe; Oliveira, Ligia Petrolini de; Oliveira Ferreira, Fabio de; Junior, Samuel Aguiar; Nakagawa, Wilson Toshihiko; Gomy, Israel; Faria Ferraz, Victor Evangelista de

    2012-01-01

    Lynch syndrome (LS) is the most common form of inherited predisposition to colorectal cancer (CRC), accounting for 2-5% of all CRC. LS is an autosomal dominant disease characterized by mutations in the mismatch repair genes mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), postmeiotic segregation increased 1 (PMS1), post-meiotic segregation increased 2 (PMS2) and mutS homolog 6 (MSH6). Mutation risk prediction models can be incorporated into clinical practice, facilitating the decision-making process and identifying individuals for molecular investigation. This is extremely important in countries with limited economic resources. This study aims to evaluate sensitivity and specificity of five predictive models for germline mutations in repair genes in a sample of individuals with suspected Lynch syndrome. Blood samples from 88 patients were analyzed through sequencing MLH1, MSH2 and MSH6 genes. The probability of detecting a mutation was calculated using the PREMM, Barnetson, MMRpro, Wijnen and Myriad models. To evaluate the sensitivity and specificity of the models, receiver operating characteristic curves were constructed. Of the 88 patients included in this analysis, 31 mutations were identified: 16 were found in the MSH2 gene, 15 in the MLH1 gene and no pathogenic mutations were identified in the MSH6 gene. It was observed that the AUC for the PREMM (0.846), Barnetson (0.850), MMRpro (0.821) and Wijnen (0.807) models did not present significant statistical difference. The Myriad model presented lower AUC (0.704) than the four other models evaluated. Considering thresholds of ≥ 5%, the models sensitivity varied between 1 (Myriad) and 0.87 (Wijnen) and specificity ranged from 0 (Myriad) to 0.38 (Barnetson). The Barnetson, PREMM, MMRpro and Wijnen models present similar AUC. The AUC of the Myriad model is statistically inferior to the four other models

  14. Diagnostic and therapeutic implications of genetic heterogeneity in myeloid neoplasms uncovered by comprehensive mutational analysis

    Directory of Open Access Journals (Sweden)

    Sarah M. Choi

    2017-01-01

    Full Text Available While growing use of comprehensive mutational analysis has led to the discovery of innumerable genetic alterations associated with various myeloid neoplasms, the under-recognized phenomenon of genetic heterogeneity within such neoplasms creates a potential for diagnostic confusion. Here, we describe two cases where expanded mutational testing led to amendment of an initial diagnosis of chronic myelogenous leukemia with subsequent altered treatment of each patient. We demonstrate the power of comprehensive testing in ensuring appropriate classification of genetically heterogeneous neoplasms, and emphasize thoughtful analysis of molecular and genetic data as an essential component of diagnosis and management.

  15. 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.

  16. NRASQ61K mutated primary leptomeningeal melanoma in a child: case presentation and discussion on clinical and diagnostic implications

    International Nuclear Information System (INIS)

    Angelino, Giulia; De Pasquale, Maria Debora; De Sio, Luigi; Serra, Annalisa; Massimi, Luca; De Vito, Rita; Marrazzo, Antonio; Lancella, Laura; Carai, Andrea; Antonelli, Manila; Giangaspero, Felice; Gessi, Marco; Menchini, Laura; Scarciolla, Laura; Longo, Daniela; Mastronuzzi, Angela

    2016-01-01

    Primary melanocytic neoplasms are rare in the pediatric age. Among them, the pattern of neoplastic meningitis represents a peculiar diagnostic challenge since neuroradiological features may be subtle and cerebrospinal fluid analysis may not be informative. Clinical misdiagnosis of neoplastic meningitis with tuberculous meningitis has been described in few pediatric cases, leading to a significant delay in appropriate management of patients. We describe the case of a child with primary leptomeningeal melanoma (LMM) that was initially misdiagnosed with tuberculous meningitis. We review the clinical and molecular aspects of LMM and discuss on clinical and diagnostic implications. A 27-month-old girl with a 1-week history of vomiting with mild intermittent strabismus underwent Magnetic Resonance Imaging, showing diffuse brainstem and spinal leptomeningeal enhancement. Cerebrospinal fluid analysis was unremarkable. Antitubercular treatment was started without any improvement. A spinal intradural biopsy was suggestive for primary leptomeningeal melanomatosis. Chemotherapy was started, but general clinical conditions progressively worsened and patient died 11 months after diagnosis. Molecular investigations were performed post-mortem on tumor tissue and revealed absence of BRAF V600E , GNAQ Q209 and GNA11 Q209 mutations but the presence of a NRAS Q61K mutation. Our case adds some information to the limited experience of the literature, confirming the presence of the NRAS Q61K mutation in children with melanomatosis. To our knowledge, this is the first case of leptomeningeal melanocytic neoplasms (LMN) without associated skin lesions to harbor this mutation. Isolated LMN presentation might be insidious, mimicking tuberculous meningitis, and should be suspected if no definite diagnosis is possible or if antitubercular treatment does not result in dramatic clinical improvement. Leptomeningeal biopsy should be considered, not only to confirm diagnosis of LMN but also to study

  17. 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. © 2014 WILEY PERIODICALS, INC.

  18. 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.

  19. Adaptation of soybeans to northern climatic conditions and modern harvesting technique by mutation breeding

    International Nuclear Information System (INIS)

    Krausse, G.W.

    1990-01-01

    Full text: For growing soybean in northern countries early ripening and cold tolerant varieties with stable yield are necessary. For combine harvesting these varieties have to have a sufficient plant length and the insertion height of the lower pods has to be high. Two directions were followed in mutation breeding: After mutagenic treatment of middle late, highly productive, long-stalked initial varieties (as for instance 'Maple Arrow') early ripening mutants were searched for. On the other hand, the extremely early ripening, but too short-stalked 'Fiskeby V' was the initial variety for selecting long-stalked mutants with higher insertion of the lowest pods. Methyl-nitrosourea, sodium azide (0,5...2 mM) or γ-rays (50...250 Gy) served as mutagens. In the period 1979-1987 the following quantities of material have been dealt with: 11 initial varieties, 356000 treated seeds, 38000 progeny rows (= 736,000 plants) in M 2 , 5519 lines in M 3 , 557 lines in M 4 and 226 lines in M 5 . Vegetation period of early mutants was 3-8 days shorter, grain yield being the same or slightly increased. Extremely early ripening mutants showed strong yield depression. These mutants are still not suitable for growing in the GDR, because they ripen only in October but they are used as crossing parents and tested in warmer regions. The induction and selection of long-stalked mutants with higher insertion of the lowest pods in the early ripening Swedish variety 'Fiskeby V' led to the release of a mutant variety 'Dorado' in 1988. Further mutants with a yield potential of 1,5-2 t/ha are tested in official trials. (author)

  20. PB2 mutations D701N and S714R promote adaptation of an influenza H5N1 virus to a mammalian host.

    Science.gov (United States)

    Czudai-Matwich, Volker; Otte, Anna; Matrosovich, Mikhail; Gabriel, Gülsah; Klenk, Hans-Dieter

    2014-08-01

    Mutation D701N in the PB2 protein is known to play a prominent role in the adaptation of avian influenza A viruses to mammalian hosts. In contrast, little is known about the nearby mutations S714I and S714R, which have been observed in some avian influenza viruses highly pathogenic for mammals. We have generated recombinant H5N1 viruses with PB2 displaying the avian signature 701D or the mammalian signature 701N and serine, isoleucine, and arginine at position 714 and compared them for polymerase activity and virus growth in avian and mammalian cells, as well as for pathogenicity in mice. Mutation D701N led to an increase in polymerase activity and replication efficiency in mammalian cells and in mouse pathogenicity, and this increase was significantly enhanced when mutation D701N was combined with mutation S714R. Stimulation by mutation S714I was less distinct. These observations indicate that PB2 mutation S714R, in combination with the mammalian signature at position 701, has the potential to promote the adaptation of an H5N1 virus to a mammalian host. Influenza A/H5N1 viruses are avian pathogens that have pandemic potential, since they are spread over large parts of Asia, Africa, and Europe and are occasionally transmitted to humans. It is therefore of high scientific interest to understand the mechanisms that determine the host specificity and pathogenicity of these viruses. It is well known that the PB2 subunit of the viral polymerase is an important host range determinant and that PB2 mutation D701N plays an important role in virus adaptation to mammalian cells. In the present study, we show that mutation S714R is also involved in adaptation and that it cooperates with D701N in exposing a nuclear localization signal that mediates importin-α binding and entry of PB2 into the nucleus, where virus replication and transcription take place. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  1. TRAIL receptor upregulation and the implication of KRAS/BRAF mutations in human colon cancer tumours

    Czech Academy of Sciences Publication Activity Database

    Oikonomou, E.; Kosmidou, V.; Katseli, A.; Kothonidis, K.; Mourtzoukou, D.; Kontogeorgos, G.; Anděra, Ladislav; Zografos, G.; Pintzas, A.

    2009-01-01

    Roč. 125, č. 9 (2009), s. 2127-2135 ISSN 0020-7136 R&D Projects: GA MŠk 1M0506 Grant - others:EC(XE) LSHC-CT-2006-037278 Institutional research plan: CEZ:AV0Z50520514 Keywords : colorectal tumours * TRAIL receptors expression * KRAS/ BRAF oncogenic mutations Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.722, year: 2009

  2. A reduced amino acid alphabet for understanding and designing protein adaptation to mutation.

    Science.gov (United States)

    Etchebest, C; Benros, C; Bornot, A; Camproux, A-C; de Brevern, A G

    2007-11-01

    Protein sequence world is considerably larger than structure world. In consequence, numerous non-related sequences may adopt similar 3D folds and different kinds of amino acids may thus be found in similar 3D structures. By grouping together the 20 amino acids into a smaller number of representative residues with similar features, sequence world simplification may be achieved. This clustering hence defines a reduced amino acid alphabet (reduced AAA). Numerous works have shown that protein 3D structures are composed of a limited number of building blocks, defining a structural alphabet. We previously identified such an alphabet composed of 16 representative structural motifs (5-residues length) called Protein Blocks (PBs). This alphabet permits to translate the structure (3D) in sequence of PBs (1D). Based on these two concepts, reduced AAA and PBs, we analyzed the distributions of the different kinds of amino acids and their equivalences in the structural context. Different reduced sets were considered. Recurrent amino acid associations were found in all the local structures while other were specific of some local structures (PBs) (e.g Cysteine, Histidine, Threonine and Serine for the alpha-helix Ncap). Some similar associations are found in other reduced AAAs, e.g Ile with Val, or hydrophobic aromatic residues Trp with Phe and Tyr. We put into evidence interesting alternative associations. This highlights the dependence on the information considered (sequence or structure). This approach, equivalent to a substitution matrix, could be useful for designing protein sequence with different features (for instance adaptation to environment) while preserving mainly the 3D fold.

  3. Implications of complex adaptive systems theory for interpreting research about health care organizations.

    Science.gov (United States)

    Jordon, Michelle; Lanham, Holly Jordan; Anderson, Ruth A; McDaniel, Reuben R

    2010-02-01

    Data about health care organizations (HCOs) are not useful until they are interpreted. Such interpretations are influenced by the theoretical lenses used by the researcher. Our purpose was to suggest the usefulness of theories of complex adaptive systems (CASs) in guiding research interpretation. Specifically, we addressed two questions: (1) What are the implications for interpreting research observations in HCOs of the fact that we are observing relationships among diverse agents? (2) What are the implications for interpreting research observations in HCOs of the fact that we are observing relationships among agents that learn? We defined diversity and learning and the implications of the non-linear relationships among agents from a CAS perspective. We then identified some common analytical practices that were problematic and may lead to conceptual and methodological errors. Then we described strategies for interpreting the results of research observations. We suggest that the task of interpreting research observations of HCOs could be improved if researchers take into account that the systems they study are CASs with non-linear relationships among diverse, learning agents. Our analysis points out how interpretation of research results might be shaped by the fact that HCOs are CASs. We described how learning is, in fact, the result of interactions among diverse agents and that learning can, by itself, reduce or increase agent diversity. We encouraged researchers to be persistent in their attempts to reason about complex systems and learn to attend not only to structures, but also to processes and functions of complex systems.

  4. Frequency and Clinical Implication of the R450H Mutation in the Thyrotropin Receptor Gene in the Japanese Population Detected by Smart Amplification Process 2

    Science.gov (United States)

    Yanagawa, Yoshimaro; Aoki, Tomoyuki; Morimura, Tadashi; Araki, Osamu; Kimura, Takao; Ogiwara, Takayuki; Kotajima, Nobuo; Yanagawa, Masumi; Murakami, Masami

    2014-01-01

    In Japanese pediatric patients with thyrotropin (TSH) resistance, the R450H mutation in TSH receptor gene (TSHR) is occasionally observed. We studied the frequency and clinical implication of the R450H mutation in TSHR in the general population of Japanese adults using smart amplification process 2 (SmartAmp2). We designed SmartAmp2 primer sets to detect this mutation using a drop of whole blood. We analyzed thyroid function, antithyroid antibodies, and this mutation in 429 Japanese participants who had not been found to have thyroid disease. Two cases without antithyroid antibodies were heterozygous for the R450H mutation in TSHR. Thus, the prevalence of this mutation was 0.47% in the general population and 0.63% among those without antithyroid antibodies. Their serum TSH concentrations were higher than the average TSH concentration not only in subjects without antithyroid antibodies but also in those with antithyroid antibodies. The R450H mutation in TSHR is relatively common in the Japanese population and potentially affects thyroid function. The present study demonstrates that the SmartAmp2 method is useful to detect the R450H mutation in TSHR, which is one of the common causes of TSH resistance in the Japanese population. PMID:24895636

  5. Health risks of climate change: An assessment of uncertainties and its implications for adaptation policies

    Science.gov (United States)

    2012-01-01

    Background Projections of health risks of climate change are surrounded with uncertainties in knowledge. Understanding of these uncertainties will help the selection of appropriate adaptation policies. Methods We made an inventory of conceivable health impacts of climate change, explored the type and level of uncertainty for each impact, and discussed its implications for adaptation policy. A questionnaire-based expert elicitation was performed using an ordinal scoring scale. Experts were asked to indicate the level of precision with which health risks can be estimated, given the present state of knowledge. We assessed the individual scores, the expertise-weighted descriptive statistics, and the argumentation given for each score. Suggestions were made for how dealing with uncertainties could be taken into account in climate change adaptation policy strategies. Results The results showed that the direction of change could be indicated for most anticipated health effects. For several potential effects, too little knowledge exists to indicate whether any impact will occur, or whether the impact will be positive or negative. For several effects, rough ‘order-of-magnitude’ estimates were considered possible. Factors limiting health impact quantification include: lack of data, multi-causality, unknown impacts considering a high-quality health system, complex cause-effect relations leading to multi-directional impacts, possible changes of present-day response-relations, and difficulties in predicting local climate impacts. Participants considered heat-related mortality and non-endemic vector-borne diseases particularly relevant for climate change adaptation. Conclusions For possible climate related health impacts characterised by ignorance, adaptation policies that focus on enhancing the health system’s and society’s capability of dealing with possible future changes, uncertainties and surprises (e.g. through resilience, flexibility, and adaptive capacity) are

  6. The evolutionary adaptation of the C282Y mutation to culture and climate during the European Neolithic.

    Science.gov (United States)

    Heath, Kathleen M; Axton, Jacob H; McCullough, John M; Harris, Nathan

    2016-05-01

    The C282Y allele is the major cause of hemochromatosis as a result of excessive iron absorption. The mutation arose in continental Europe no earlier than 6,000 years ago, coinciding with the arrival of the Neolithic agricultural revolution. Here we hypothesize that this new Neolithic diet, which originated in the sunny warm and dry climates of the Middle East, was carried by migrating farmers into the chilly and damp environments of Europe where iron is a critical micronutrient for effective thermoregulation. We argue that the C282Y allele was an adaptation to this novel environment. To address our hypothesis, we compiled C282Y allele frequencies, known Neolithic sites in Europe and climatic data on temperature and rainfall for statistical analysis. Our findings indicate that the geographic cline for C282Y frequency in Europe increases as average temperatures decrease below 16°C, a critical threshold for thermoregulation, with rainy days intensifying the trend. The results indicate that the deleterious C282Y allele, responsible for most cases of hemochromatosis, may have evolved as a selective advantage to culture and climate during the European Neolithic. © 2016 The Authors American Journal of Physical Anthropology Published by Wiley Periodicals, Inc.

  7. 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.

  8. Mutation scanning analysis of genetic variation within and among Echinococcus species: implications and future prospects.

    Science.gov (United States)

    Jabbar, Abdul; Gasser, Robin B

    2013-07-01

    Adult tapeworms of the genus Echinococcus (family Taeniidae) occur in the small intestines of carnivorous definitive hosts and are transmitted to particular intermediate mammalian hosts, in which they develop as fluid-filled larvae (cysts) in internal organs (usually lung and liver), causing the disease echinococcosis. Echinococcus species are of major medical importance and also cause losses to the meat and livestock industries, mainly due to the condemnation of infected offal. Decisions regarding the treatment and control of echinococcosis rely on the accurate identification of species and population variants (strains). Conventional, phenetic methods for specific identification have some significant limitations. Despite advances in the development of molecular tools, there has been limited application of mutation scanning methods to species of Echinococcus. Here, we briefly review key genetic markers used for the identification of Echinococcus species and techniques for the analysis of genetic variation within and among populations, and the diagnosis of echinococcosis. We also discuss the benefits of utilizing mutation scanning approaches to elucidate the population genetics and epidemiology of Echinococcus species. These benefits are likely to become more evident following the complete characterization of the genomes of E. granulosus and E. multilocularis.

  9. The shapes of the radiation dose-mutation response curves in drosophila: Mechanisms and implications

    International Nuclear Information System (INIS)

    Abrahamson, S.; DeJongh, C.; Meyer, H.U.

    1981-01-01

    This chapter proposes that radiation induced mutations, namely sex-linked recessive lethals in Drosophila and forward mutations at specific loci in Drosophila, mammals and lower eucaryotes, are the result of two sub-lesions or hits, induced by either single ionization tracks or by the interaction of two independent tracks for low LET radiations, when the dose is delivered in an acute fashion. Utilizes the well recognized linear quadratic expression Y=C+αD+βD 2 , where C is the spontaneous frequency of events scored and α and β represent the coefficients of the dose. Concludes that for low LET radiations, X or gamma rays, the linear-quadratic model can be used to predict the genetic response of germ cells and somatic cells to a variety of radiation regimes. Points out that the point of inflection in the curve, α/β value, can be determined specifically by target dimensions which vary with respect to DNA content. Considers the difference in RBE values observed for different species to be a reflection of their different target sizes

  10. Mutational analysis of S12 protein and implications for the accuracy of decoding by the ribosome.

    Science.gov (United States)

    Sharma, Divya; Cukras, Anthony R; Rogers, Elizabeth J; Southworth, Daniel R; Green, Rachel

    2007-12-07

    The fidelity of aminoacyl-tRNA selection by the ribosome depends on a conformational switch in the decoding center of the small ribosomal subunit induced by cognate but not by near-cognate aminoacyl-tRNA. The aminoglycosides paromomycin and streptomycin bind to the decoding center and induce related structural rearrangements that explain their observed effects on miscoding. Structural and biochemical studies have identified ribosomal protein S12 (as well as specific nucleotides in 16S ribosomal RNA) as a critical molecular contributor in distinguishing between cognate and near-cognate tRNA species as well as in promoting more global rearrangements in the small subunit, referred to as "closure." Here we use a mutational approach to define contributions made by two highly conserved loops in S12 to the process of tRNA selection. Most S12 variant ribosomes tested display increased levels of fidelity (a "restrictive" phenotype). Interestingly, several variants, K42A and R53A, were substantially resistant to the miscoding effects of paromomycin. Further characterization of the compromised paromomycin response identified a probable second, fidelity-modulating binding site for paromomycin in the 16S ribosomal RNA that facilitates closure of the small subunit and compensates for defects associated with the S12 mutations.

  11. 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.

  12. 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.

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

    OpenAIRE

    Maxinder S Kanwal; Avinash S Ramesh; Lauren A Huang

    2013-01-01

    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 ...

  14. Mirid (Hemiptera: Heteroptera) specialists of sticky plants: adaptations, interactions, and ecological implications.

    Science.gov (United States)

    Wheeler, Alfred G; Krimmel, Billy A

    2015-01-07

    Sticky plants-those having glandular trichomes (hairs) that produce adhesive, viscous exudates-can impede the movement of, and entrap, generalist insects. Disparate arthropod groups have adapted to these widespread and taxonomically diverse plants, yet their interactions with glandular hosts rarely are incorporated into broad ecological theory. Ecologists and entomologists might be unaware of even well-documented examples of insects that are sticky-plant specialists. The hemipteran family Miridae (more specifically, the omnivorous Dicyphini: Dicyphina) is the best-known group of arthropods that specializes on sticky plants. In the first synthesis of relationships with glandular plants for any insect family, we review mirid interactions with sticky hosts, including their adaptations (behavioral, morphological, and physiological) and mutualisms with carnivorous plants, and the ecological and agricultural implications of mirid-sticky plant systems. We propose that mirid research applies generally to tritrophic interactions on trichome-defended plants, enhances an understanding of insect-plant interactions, and provides information useful in managing crop pests.

  15. Adaptive learning can result in a failure to profit from good conditions: implications for understanding depression.

    Science.gov (United States)

    Trimmer, Pete C; Higginson, Andrew D; Fawcett, Tim W; McNamara, John M; Houston, Alasdair I

    2015-04-26

    Depression is a major medical problem diagnosed in an increasing proportion of people and for which commonly prescribed psychoactive drugs are frequently ineffective. Development of treatment options may be facilitated by an evolutionary perspective; several adaptive reasons for proneness to depression have been proposed. A common feature of many explanations is that depressive behaviour is a way to avoid costly effort where benefits are small and/or unlikely. However, this viewpoint fails to explain why low mood persists when the situation improves. We investigate whether a behavioural rule that is adapted to a stochastically changing world can cause inactivity which appears similar to the effect of depression, in that it persists after the situation has improved. We develop an adaptive learning model in which an individual has repeated choices of whether to invest costly effort that may result in a net benefit. Investing effort also provides information about the current conditions and rates of change of the conditions. An individual following the optimal behavioural strategy may sometimes remain inactive when conditions are favourable (i.e. when it would be better to invest effort) when it is poorly informed about the current environmental state. Initially benign conditions can predispose an individual to inactivity after a relatively brief period of negative experiences. Our approach suggests that the antecedent factors causing depressed behaviour could go much further back in an individual s history than is currently appreciated. The insights from our approach have implications for the ongoing debate about best treatment options for patients with depressive symptoms. © The Author(s) 2015. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health.

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

    Science.gov (United States)

    Taylor, Adam; Liu, Xiang; Zaid, Ali; Goh, Lucas Y H; Hobson-Peters, Jody; Hall, Roy A; Merits, Andres; Mahalingam, Suresh

    2017-02-21

    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. IMPORTANCE CHIKV is a mosquito-borne pathogen capable of causing explosive epidemics of incapacitating joint pain

  17. Induce mutations and adaptation

    International Nuclear Information System (INIS)

    Borojevicj, K.

    1987-01-01

    The effect of wheat irradiation has been studied through 20 generations. Radiation had deleterious effect in the year of treatment which genetic effect was traceable even 20 generations after treatment. (author). 11 refs.; 2 figs

  18. Cancer gene profiling in non-small cell lung cancers reveals activating mutations in JAK2 and JAK3 with therapeutic implications

    Directory of Open Access Journals (Sweden)

    Shuyu D. Li

    2017-10-01

    Full Text Available Abstract Background Next-generation sequencing (NGS of cancer gene panels are widely applied to enable personalized cancer therapy and to identify novel oncogenic mutations. Methods We performed targeted NGS on 932 clinical cases of non-small-cell lung cancers (NSCLCs using the Ion AmpliSeq™ Cancer Hotspot panel v2 assay. Results Actionable mutations were identified in 65% of the cases with available targeted therapeutic options, including 26% of the patients with mutations in National Comprehensive Cancer Network (NCCN guideline genes. Most notably, we discovered JAK2 p.V617F somatic mutation, a hallmark of myeloproliferative neoplasms, in 1% (9/932 of the NSCLCs. Analysis of cancer cell line pharmacogenomic data showed that a high level of JAK2 expression in a panel of NSCLC cell lines is correlated with increased sensitivity to a selective JAK2 inhibitor. Further analysis of TCGA genomic data revealed JAK2 gain or loss due to genetic alterations in NSCLC clinical samples are associated with significantly elevated or reduced PD-L1 expression, suggesting that the activating JAK2 p.V617F mutation could confer sensitivity to both JAK inhibitors and anti-PD1 immunotherapy. We also detected JAK3 germline activating mutations in 6.7% (62/932 of the patients who may benefit from anti-PD1 treatment, in light of recent findings that JAK3 mutations upregulate PD-L1 expression. Conclusion Taken together, this study demonstrated the clinical utility of targeted NGS with a focused hotspot cancer gene panel in NSCLCs and identified activating mutations in JAK2 and JAK3 with clinical implications inferred through integrative analysis of cancer genetic, genomic, and pharmacogenomic data. The potential of JAK2 and JAK3 mutations as response markers for the targeted therapy against JAK kinases or anti-PD1 immunotherapy warrants further investigation.

  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. Implications of health as 'the ability to adapt and self-manage' for public health policy: a qualitative study

    NARCIS (Netherlands)

    Jambroes, Marielle; Nederland, Trudi; Kaljouw, Marian; van Vliet, Katja; Essink-Bot, Marie-Louise; Ruwaard, Dirk

    2016-01-01

    To explore the implications for public health policy of a new conceptualisation of health as 'The ability to adapt and to self-manage, in the face of social, physical and emotional challenges'. Secondary qualitative data analysis of 28 focus group interviews, with 277 participants involved in public

  2. Implications of health as 'the ability to adapt and self-manage' for public health policy : A qualitative study

    NARCIS (Netherlands)

    Jambroes, Marielle; Nederland, Trudi; Kaljouw, Marian; Van Vliet, Katja; Essink-Bot, Marie Louise; Ruwaard, Dirk

    2016-01-01

    Background: To explore the implications for public health policy of a new conceptualisation of health as 'The ability to adapt and to self-manage, in the face of social, physical and emotional challenges'. Methods: Secondary qualitative data analysis of 28 focus group interviews, with 277

  3. The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management

    DEFF Research Database (Denmark)

    Tranebjærg, Lisbeth; Strenzke, Nicola; Lindholm, Sture

    2018-01-01

    obtained in the pure tone audiograms in several of the patients presented here. Molecular modelling and in vitro electrophysiological studies of the specific CAPOS mutation were performed. Heterologous expression studies of α3 with the p.Glu818Lys mutation affects sodium binding to, and release from...... of electrical impulses along the spiral ganglion neurons. This has implications for diagnosis and patient management. Auditory neuropathy is difficult to treat with conventional hearing aids, but preliminary improvement in speech perception in some patients suggests that cochlear implantation may be effective...

  4. Using iron studies to predict HFE mutations in New Zealand: implications for laboratory testing.

    Science.gov (United States)

    O'Toole, Rebecca; Romeril, Kenneth; Bromhead, Collette

    2017-04-01

    The diagnosis of hereditary haemochromatosis (HH) is not straightforward because symptoms are often absent or non-specific. Biochemical markers of iron-overloading may be affected by other conditions. To measure the correlation between iron studies and HFE genotype to inform evidence-based recommendations for laboratory testing in New Zealand. Results from 2388 patients genotyped for C282Y, H63D and S65C in Wellington, New Zealand from 2007 to 2013 were compared with their biochemical phenotype as quantified by serum ferritin (SF), transferrin saturation (TS), serum iron (SI) and serum transferrin (ST). The predictive power of these markers was evaluated by receiver operator characteristic (ROC) curve analysis, and if a statistically significant association for a variable was seen, sensitivity, specificity and predictive values were calculated. Test ordering patterns showed that 62% of HFE genotyping tests were ordered because of an elevated SF alone and only 11% of these had a C-reactive protein test to rule out an acute phase reaction. The association between SF and significant HFE genotypes SF was low. However, TS values ≥45% predicted HH mutations with the highest sensitivity and specificity. A SF of >1000 µg/L was found in one at-risk patient (C282Y homozygote) who had a TS <45%. Our analysis highlights the need for clear guidelines for investigation of hyperferritinaemia and HH in New Zealand. Using our findings, we developed an evidence-based laboratory testing algorithm based on a TS ≥45%, a SF ≥1000 µg/L and/or a family history of HH which identified all C282Y homozygotes in this study. © 2016 Royal Australasian College of Physicians.

  5. Adaptation.

    Science.gov (United States)

    Broom, Donald M

    2006-01-01

    The term adaptation is used in biology in three different ways. It may refer to changes which occur at the cell and organ level, or at the individual level, or at the level of gene action and evolutionary processes. Adaptation by cells, especially nerve cells helps in: communication within the body, the distinguishing of stimuli, the avoidance of overload and the conservation of energy. The time course and complexity of these mechanisms varies. Adaptive characters of organisms, including adaptive behaviours, increase fitness so this adaptation is evolutionary. The major part of this paper concerns adaptation by individuals and its relationships to welfare. In complex animals, feed forward control is widely used. Individuals predict problems and adapt by acting before the environmental effect is substantial. Much of adaptation involves brain control and animals have a set of needs, located in the brain and acting largely via motivational mechanisms, to regulate life. Needs may be for resources but are also for actions and stimuli which are part of the mechanism which has evolved to obtain the resources. Hence pigs do not just need food but need to be able to carry out actions like rooting in earth or manipulating materials which are part of foraging behaviour. The welfare of an individual is its state as regards its attempts to cope with its environment. This state includes various adaptive mechanisms including feelings and those which cope with disease. The part of welfare which is concerned with coping with pathology is health. Disease, which implies some significant effect of pathology, always results in poor welfare. Welfare varies over a range from very good, when adaptation is effective and there are feelings of pleasure or contentment, to very poor. A key point concerning the concept of individual adaptation in relation to welfare is that welfare may be good or poor while adaptation is occurring. Some adaptation is very easy and energetically cheap and

  6. Association of Mismatch Repair Mutation With Age at Cancer Onset in Lynch Syndrome: Implications for Stratified Surveillance Strategies.

    Science.gov (United States)

    Ryan, Neil A J; Morris, Julie; Green, Kate; Lalloo, Fiona; Woodward, Emma R; Hill, James; Crosbie, Emma J; Evans, D Gareth

    2017-12-01

    Lynch syndrome is caused by dominantly inherited germline mutations that predispose individuals to colorectal, endometrial, ovarian, and other cancers through inactivation of the cellular mismatch repair system. Lynch syndrome–associated cancers are amenable to surveillance strategies that may improve survival. The age at which surveillance should start is disputed. To determine whether mutated gene and type of mutation influence age at onset of Lynch syndrome–associated cancers. A retrospective cohort study of individuals with Lynch syndrome–associated colorectal, endometrial, and/or ovarian cancers whose medical records were included in the clinical database of a large quaternary referral center for genomic medicine in the Northwest of England. Mutated gene (MLH1, MSH2, MSH6, and/or PMS2) and type of mutation (truncating, splicing, or large rearrangement). Age at cancer diagnosis. A total of 1063 individuals with proven Lynch syndrome were included, 495 male and 568 female (mean age 52 years; age range, 10-93 years [children were included in the database, but no children developed cancer]). There were 546 men and women with colorectal cancer, 162 women with endometrial cancer, and 49 women with ovarian cancer; mean follow-up was 68.2 months. Among MLH1 mutation carriers, mutations in MLH1 were associated with colorectal cancer in 249 (61%) of 409 men and women; endometrial cancer in 53 of 196 (27%) women; and ovarian cancer in 15 (8%) of 196 women. Among MSH2 mutation carriers, mutations in MSH2 (the most prevalent mutations overall) were most commonly associated with female-specific cancers: endometrial cancer in 83 (30%) of 279 women; ovarian cancer in 28 (10%) of 279 women; and colorectal cancer in 239 (50%) 479 men and women. Mutations in MSH6 were less prevalent, and MSH6 mutation carriers presented with colorectal and endometrial cancer at later ages than carriers of mutations in MSH2 or MLH1. When stratified by mutation type, women with truncating

  7. Metabolic Alterations Caused by KRAS Mutations in Colorectal Cancer Contribute to Cell Adaptation to Glutamine Depletion by Upregulation of Asparagine Synthetase

    Directory of Open Access Journals (Sweden)

    Kosuke Toda

    2016-11-01

    Full Text Available A number of clinical trials have shown that KRAS mutations of colorectal cancer (CRC can predict a lack of responses to anti-epidermal growth factor receptor–based therapy. Recently, there have been several studies to elucidate metabolism reprogramming in cancer. However, it remains to be investigated how mutated KRAS can coordinate the metabolic shift to sustain CRC tumor growth. In this study, we found that KRAS mutation in CRC caused alteration in amino acid metabolism. KRAS mutation causes a marked decrease in aspartate level and an increase in asparagine level in CRC. Using several human CRC cell lines and clinical specimens of primary CRC, we demonstrated that the expression of asparagine synthetase (ASNS, an enzyme that synthesizes asparagine from aspartate, was upregulated by mutated KRAS and that ASNS expression was induced by KRAS-activated signaling pathway, in particular PI3K-AKT-mTOR pathway. Importantly, we demonstrated that KRAS-mutant CRC cells could become adaptive to glutamine depletion through asparagine biosynthesis by ASNS and that asparagine addition could rescue the inhibited growth and viability of cells grown under the glutamine-free condition in vitro. Notably, a pronounced growth suppression of KRAS-mutant CRC was observed upon ASNS knockdown in vivo. Furthermore, combination of L-asparaginase plus rapamycin markedly suppressed the growth of KRAS-mutant CRC xenografts in vivo, whereas either L-asparaginase or rapamycin alone was not effective. These results indicate ASNS might be a novel therapeutic target against CRCs with mutated KRAS.

  8. Adaptation

    International Development Research Centre (IDRC) Digital Library (Canada)

    building skills, knowledge or networks on adaptation, ... the African partners leading the AfricaAdapt network, together with the UK-based Institute of Development Studies; and ... UNCCD Secretariat, Regional Coordination Unit for Africa, Tunis, Tunisia .... 26 Rural–urban Cooperation on Water Management in the Context of.

  9. Structural implications of mutations in the pea SYM8 symbiosis gene, the DMI1 ortholog, encoding a predicted ion channel

    DEFF Research Database (Denmark)

    Edwards, Anne; Heckmann, Anne Birgitte Lau; Yousafzai, Faridoon

    2007-01-01

    the aspartate to valine and identified a missense mutation (changing alanine to valine adjacent to the aspartate residues) in this predicted filter region; both mutations caused a loss of function. We also identified a loss-of-function missense mutation (changing arginine to isoleucine) in a domain proposed...

  10. 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

  11. Radon-induced lung cancer in smokers and non-smokers: risk implications using a two-mutation carcinogenesis model

    International Nuclear Information System (INIS)

    Leenhouts, H.P.

    1999-01-01

    Three sets of data (population statistics in non-smokers, data from an investigation of the smoking habits of British doctors and a study of Colorado uranium miners) were used to analyse lung cancer in humans as a function of exposure to radon and smoking. One of the aims was to derive implications for radon risk estimates. The data were analysed using a two-mutation radiation carcinogenesis model and a stepwise determination of the model parameters. The basic model parameters for lung cancer were derived from the age dependence fit of the spontaneous lung cancer incidence in non-smokers. The effect of smoking was described by two additional parameters and, subsequently, the effect of radon by three other parameters; these five parameters define the dependence of the two mutation steps on smoking and exposure to radon. Using this approach, a consistent fit and comprehensive description of the three sets of data have been achieved, and the parameters could, at least partly, be related to cellular radiobiological data. The model results explain the different effect of radon on non-smokers and smokers as seen in epidemiological data. Although the analysis was only applied to a limited number of populations, lung cancer incidence as a result of radon exposure is estimated to be about ten times higher for people exposed at the age of about 15 than at about 50, although this effect is masked (especially for smokers) by the high lung cancer incidence from smoking. Using the model to calculate the lung cancer risks from lifetime exposure to radon, as is the case for indoor radon, higher risks were estimated than previously derived from epidemiological studies of the miners' data. The excess absolute risk per unit exposure of radon is about 1.7 times higher for smokers of 30 cigarettes per day than for non-smokers, even though, as a result of the low spontaneous tumour incidence in the non-smokers, the excess relative risk per unit exposure for the smokers is about 20 times

  12. Impacts of local adaptation of forest trees on associations with herbivorous insects: implications for adaptive forest management

    Czech Academy of Sciences Publication Activity Database

    Sinclair, F. H.; Stone, G. N.; Nicholls, J. A.; Cavers, S.; Gibbs, M.; Butterill, Philip T.; Wagner, S.; Ducousso, A.; Gerber, S.; Petit, R. J.; Kremer, A.; Schönrogge, K.

    2015-01-01

    Roč. 8, č. 10 (2015), s. 972-987 ISSN 1752-4571 Institutional support: RVO:60077344 Keywords : adaptive forest management * climate matching * gallwasp Subject RIV: EH - Ecology, Behaviour Impact factor: 4.572, year: 2015 http://onlinelibrary.wiley.com/doi/10.1111/eva.12329/epdf

  13. Adapt

    Science.gov (United States)

    Bargatze, L. F.

    2015-12-01

    Active Data Archive Product Tracking (ADAPT) is a collection of software routines that permits one to generate XML metadata files to describe and register data products in support of the NASA Heliophysics Virtual Observatory VxO effort. ADAPT is also a philosophy. The ADAPT concept is to use any and all available metadata associated with scientific data to produce XML metadata descriptions in a consistent, uniform, and organized fashion to provide blanket access to the full complement of data stored on a targeted data server. In this poster, we present an application of ADAPT to describe all of the data products that are stored by using the Common Data File (CDF) format served out by the CDAWEB and SPDF data servers hosted at the NASA Goddard Space Flight Center. These data servers are the primary repositories for NASA Heliophysics data. For this purpose, the ADAPT routines have been used to generate data resource descriptions by using an XML schema named Space Physics Archive, Search, and Extract (SPASE). SPASE is the designated standard for documenting Heliophysics data products, as adopted by the Heliophysics Data and Model Consortium. The set of SPASE XML resource descriptions produced by ADAPT includes high-level descriptions of numerical data products, display data products, or catalogs and also includes low-level "Granule" descriptions. A SPASE Granule is effectively a universal access metadata resource; a Granule associates an individual data file (e.g. a CDF file) with a "parent" high-level data resource description, assigns a resource identifier to the file, and lists the corresponding assess URL(s). The CDAWEB and SPDF file systems were queried to provide the input required by the ADAPT software to create an initial set of SPASE metadata resource descriptions. Then, the CDAWEB and SPDF data repositories were queried subsequently on a nightly basis and the CDF file lists were checked for any changes such as the occurrence of new, modified, or deleted

  14. Identification of somatic mutations in postmortem human brains by whole genome sequencing and their implications for psychiatric disorders.

    Science.gov (United States)

    Nishioka, Masaki; Bundo, Miki; Ueda, Junko; Katsuoka, Fumiki; Sato, Yukuto; Kuroki, Yoko; Ishii, Takao; Ukai, Wataru; Murayama, Shigeo; Hashimoto, Eri; Nagasaki, Masao; Yasuda, Jun; Kasai, Kiyoto; Kato, Tadafumi; Iwamoto, Kazuya

    2018-04-01

    Somatic mutations in the human brain are hypothesized to contribute to the functional diversity of brain cells as well as the pathophysiology of neuropsychiatric diseases. However, there are still few reports on somatic mutations in non-neoplastic human brain tissues. This study attempted to unveil the landscape of somatic mutations in the human brain. We explored the landscape of somatic mutations in human brain tissues derived from three individuals with no neuropsychiatric diseases by whole-genome deep sequencing at a depth of around 100. The candidate mutations underwent multi-layered filtering, and were validated by ultra-deep target amplicon sequencing at a depth of around 200 000. Thirty-one somatic mutations were identified in the human brain, demonstrating the utility of whole-genome sequencing of bulk brain tissue. The mutations were enriched in neuron-expressed genes, and two-thirds of the identified somatic single nucleotide variants in the brain tissues were cytosine-to-thymine transitions, half of which were in CpG dinucleotides. Our developed filtering and validation approaches will be useful to identify somatic mutations in the human brain. The vulnerability of neuron-expressed genes to mutational events suggests their potential relevance to neuropsychiatric diseases. © 2017 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.

  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

  16. Multi-objective differential evolution with adaptive Cauchy mutation for short-term multi-objective optimal hydro-thermal scheduling

    Energy Technology Data Exchange (ETDEWEB)

    Qin Hui [College of Hydropower and Information Engineering, Huazhong University of Science and Technology, Wuhan 430074 (China); Zhou Jianzhong, E-mail: jz.zhou@hust.edu.c [College of Hydropower and Information Engineering, Huazhong University of Science and Technology, Wuhan 430074 (China); Lu Youlin; Wang Ying; Zhang Yongchuan [College of Hydropower and Information Engineering, Huazhong University of Science and Technology, Wuhan 430074 (China)

    2010-04-15

    A new multi-objective optimization method based on differential evolution with adaptive Cauchy mutation (MODE-ACM) is presented to solve short-term multi-objective optimal hydro-thermal scheduling (MOOHS) problem. Besides fuel cost, the pollutant gas emission is also optimized as an objective. The water transport delay between connected reservoirs and the effect of valve-point loading of thermal units are also taken into account in the presented problem formulation. The proposed algorithm adopts an elitist archive to retain non-dominated solutions obtained during the evolutionary process. It modifies the DE's operators to make it suit for multi-objective optimization (MOO) problems and improve its performance. Furthermore, to avoid premature convergence, an adaptive Cauchy mutation is proposed to preserve the diversity of population. An effective constraints handling method is utilized to handle the complex equality and inequality constraints. The effectiveness of the proposed algorithm is tested on a hydro-thermal system consisting of four cascaded hydro plants and three thermal units. The results obtained by MODE-ACM are compared with several previous studies. It is found that the results obtained by MODE-ACM are superior in terms of fuel cost as well as emission output, consuming a shorter time. Thus it can be a viable alternative to generate optimal trade-offs for short-term MOOHS problem.

  17. Targeted next-generation sequencing reveals novel USH2A mutations associated with diverse disease phenotypes: implications for clinical and molecular diagnosis.

    Science.gov (United States)

    Chen, Xue; Sheng, Xunlun; Liu, Xiaoxing; Li, Huiping; Liu, Yani; Rong, Weining; Ha, Shaoping; Liu, Wenzhou; Kang, Xiaoli; Zhao, Kanxing; Zhao, Chen

    2014-01-01

    USH2A mutations have been implicated in the disease etiology of several inherited diseases, including Usher syndrome type 2 (USH2), nonsyndromic retinitis pigmentosa (RP), and nonsyndromic deafness. The complex genetic and phenotypic spectrums relevant to USH2A defects make it difficult to manage patients with such mutations. In the present study, we aim to determine the genetic etiology and to characterize the correlated clinical phenotypes for three Chinese pedigrees with nonsyndromic RP, one with RP sine pigmento (RPSP), and one with USH2. Family histories and clinical details for all included patients were reviewed. Ophthalmic examinations included best corrected visual acuities, visual field measurements, funduscopy, and electroretinography. Targeted next-generation sequencing (NGS) was applied using two sequence capture arrays to reveal the disease causative mutations for each family. Genotype-phenotype correlations were also annotated. Seven USH2A mutations, including four missense substitutions (p.P2762A, p.G3320C, p.R3719H, and p.G4763R), two splice site variants (c.8223+1G>A and c.8559-2T>C), and a nonsense mutation (p.Y3745*), were identified as disease causative in the five investigated families, of which three reported to have consanguineous marriage. Among all seven mutations, six were novel, and one was recurrent. Two homozygous missense mutations (p.P2762A and p.G3320C) were found in one individual family suggesting a potential double hit effect. Significant phenotypic divergences were revealed among the five families. Three families of the five families were affected with early, moderated, or late onset RP, one with RPSP, and the other one with USH2. Our study expands the genotypic and phenotypic variability relevant to USH2A mutations, which would help with a clear insight into the complex genetic and phenotypic spectrums relevant to USH2A defects, and is complementary for a better management of patients with such mutations. We have also

  18. Targeted next-generation sequencing reveals novel USH2A mutations associated with diverse disease phenotypes: implications for clinical and molecular diagnosis.

    Directory of Open Access Journals (Sweden)

    Xue Chen

    Full Text Available USH2A mutations have been implicated in the disease etiology of several inherited diseases, including Usher syndrome type 2 (USH2, nonsyndromic retinitis pigmentosa (RP, and nonsyndromic deafness. The complex genetic and phenotypic spectrums relevant to USH2A defects make it difficult to manage patients with such mutations. In the present study, we aim to determine the genetic etiology and to characterize the correlated clinical phenotypes for three Chinese pedigrees with nonsyndromic RP, one with RP sine pigmento (RPSP, and one with USH2. Family histories and clinical details for all included patients were reviewed. Ophthalmic examinations included best corrected visual acuities, visual field measurements, funduscopy, and electroretinography. Targeted next-generation sequencing (NGS was applied using two sequence capture arrays to reveal the disease causative mutations for each family. Genotype-phenotype correlations were also annotated. Seven USH2A mutations, including four missense substitutions (p.P2762A, p.G3320C, p.R3719H, and p.G4763R, two splice site variants (c.8223+1G>A and c.8559-2T>C, and a nonsense mutation (p.Y3745*, were identified as disease causative in the five investigated families, of which three reported to have consanguineous marriage. Among all seven mutations, six were novel, and one was recurrent. Two homozygous missense mutations (p.P2762A and p.G3320C were found in one individual family suggesting a potential double hit effect. Significant phenotypic divergences were revealed among the five families. Three families of the five families were affected with early, moderated, or late onset RP, one with RPSP, and the other one with USH2. Our study expands the genotypic and phenotypic variability relevant to USH2A mutations, which would help with a clear insight into the complex genetic and phenotypic spectrums relevant to USH2A defects, and is complementary for a better management of patients with such mutations. We have

  19. 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

    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 sit...

  20. Identification of the bovine Arachnomelia mutation by massively parallel sequencing implicates sulfite oxidase (SUOX in bone development.

    Directory of Open Access Journals (Sweden)

    Cord Drögemüller

    2010-08-01

    Full Text Available Arachnomelia is a monogenic recessive defect of skeletal development in cattle. The causative mutation was previously mapped to a ∼7 Mb interval on chromosome 5. Here we show that array-based sequence capture and massively parallel sequencing technology, combined with the typical family structure in livestock populations, facilitates the identification of the causative mutation. We re-sequenced the entire critical interval in a healthy partially inbred cow carrying one copy of the critical chromosome segment in its ancestral state and one copy of the same segment with the arachnomelia mutation, and we detected a single heterozygous position. The genetic makeup of several partially inbred cattle provides extremely strong support for the causality of this mutation. The mutation represents a single base insertion leading to a premature stop codon in the coding sequence of the SUOX gene and is perfectly associated with the arachnomelia phenotype. Our findings suggest an important role for sulfite oxidase in bone development.

  1. Identification of the Bovine Arachnomelia Mutation by Massively Parallel Sequencing Implicates Sulfite Oxidase (SUOX) in Bone Development

    Science.gov (United States)

    Drögemüller, Cord; Tetens, Jens; Sigurdsson, Snaevar; Gentile, Arcangelo; Testoni, Stefania; Lindblad-Toh, Kerstin; Leeb, Tosso

    2010-01-01

    Arachnomelia is a monogenic recessive defect of skeletal development in cattle. The causative mutation was previously mapped to a ∼7 Mb interval on chromosome 5. Here we show that array-based sequence capture and massively parallel sequencing technology, combined with the typical family structure in livestock populations, facilitates the identification of the causative mutation. We re-sequenced the entire critical interval in a healthy partially inbred cow carrying one copy of the critical chromosome segment in its ancestral state and one copy of the same segment with the arachnomelia mutation, and we detected a single heterozygous position. The genetic makeup of several partially inbred cattle provides extremely strong support for the causality of this mutation. The mutation represents a single base insertion leading to a premature stop codon in the coding sequence of the SUOX gene and is perfectly associated with the arachnomelia phenotype. Our findings suggest an important role for sulfite oxidase in bone development. PMID:20865119

  2. alpha-Adducin mutations increase Na/K pump activity in renal cells by affecting constitutive endocytosis: implications for tubular Na reabsorption.

    Science.gov (United States)

    Torielli, Lucia; Tivodar, Simona; Montella, Rosa Chiara; Iacone, Roberto; Padoani, Gloria; Tarsini, Paolo; Russo, Ornella; Sarnataro, Daniela; Strazzullo, Pasquale; Ferrari, Patrizia; Bianchi, Giuseppe; Zurzolo, Chiara

    2008-08-01

    Genetic variation in alpha-adducin cytoskeletal protein is implicated in the polymerization and bundling of actin and alteration of the Na/K pump, resulting in abnormal renal sodium transport and hypertension in Milan hypertensive rats and humans. To investigate the molecular involvement of alpha-adducin in controlling Na/K pump activity, wild-type or mutated rat and human alpha-adducin forms were, respectively, transfected into several renal cell lines. Through multiple experimental approaches (microscopy, enzymatic assays, coimmunoprecipitation), we showed that rat and human mutated forms increased Na/K pump activity and the number of pump units; moreover, both variants coimmunoprecipitate with Na/K pump. The increased Na/K pump activity was not due to changes in its basolateral localization, but to an alteration of Na/K pump residential time on the plasma membrane. Indeed, both rat and human mutated variants reduced constitutive Na/K pump endocytosis and similarly affected transferrin receptor trafficking and fluid-phase endocytosis. In fact, alpha-adducin was detected in clathrin-coated vesicles and coimmunoprecipitated with clathrin. These results indicate that adducin, besides its modulatory effects on actin cytoskeleton dynamics, might play a direct role in clathrin-dependent endocytosis. The constitutive reduction of the Na/K pump endocytic rate induced by mutated adducin variants may be relevant in Na-dependent hypertension.

  3. The evolutionary adaptation of the C282Y mutation to culture and climate during the European Neolithic

    OpenAIRE

    Heath, Kathleen M.; Axton, Jacob H.; McCullough, John M.; Harris, Nathan

    2016-01-01

    ABSTRACT Objectives The C282Y allele is the major cause of hemochromatosis as a result of excessive iron absorption. The mutation arose in continental Europe no earlier than 6,000 years ago, coinciding with the arrival of the Neolithic agricultural revolution. Here we hypothesize that this new Neolithic diet, which originated in the sunny warm and dry climates of the Middle East, was carried by migrating farmers into the chilly and damp environments of Europe where iron is a critical micronut...

  4. 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

  5. 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.

  6. Adaptation to High Ethanol Reveals Complex Evolutionary Pathways.

    Directory of Open Access Journals (Sweden)

    Karin Voordeckers

    2015-11-01

    Full Text Available Tolerance to high levels of ethanol is an ecologically and industrially relevant phenotype of microbes, but the molecular mechanisms underlying this complex trait remain largely unknown. Here, we use long-term experimental evolution of isogenic yeast populations of different initial ploidy to study adaptation to increasing levels of ethanol. Whole-genome sequencing of more than 30 evolved populations and over 100 adapted clones isolated throughout this two-year evolution experiment revealed how a complex interplay of de novo single nucleotide mutations, copy number variation, ploidy changes, mutator phenotypes, and clonal interference led to a significant increase in ethanol tolerance. Although the specific mutations differ between different evolved lineages, application of a novel computational pipeline, PheNetic, revealed that many mutations target functional modules involved in stress response, cell cycle regulation, DNA repair and respiration. Measuring the fitness effects of selected mutations introduced in non-evolved ethanol-sensitive cells revealed several adaptive mutations that had previously not been implicated in ethanol tolerance, including mutations in PRT1, VPS70 and MEX67. Interestingly, variation in VPS70 was recently identified as a QTL for ethanol tolerance in an industrial bio-ethanol strain. Taken together, our results show how, in contrast to adaptation to some other stresses, adaptation to a continuous complex and severe stress involves interplay of different evolutionary mechanisms. In addition, our study reveals functional modules involved in ethanol resistance and identifies several mutations that could help to improve the ethanol tolerance of industrial yeasts.

  7. The Dynamics of Vulnerability and Implications for Climate Change Adaptation: Lessons from Urban Water Management

    Science.gov (United States)

    Dilling, L.; Daly, M.; Travis, W.; Wilhelmi, O.; Klein, R.; Kenney, D.; Ray, A. J.; Miller, K.

    2013-12-01

    Recent reports and scholarship have suggested that adapting to current climate variability may represent a "no regrets" strategy for adapting to climate change. Filling "adaptation deficits" and other approaches that rely on addressing current vulnerabilities are of course helpful for responding to current climate variability, but we find here that they are not sufficient for adapting to climate change. First, following a comprehensive review and unique synthesis of the natural hazards and climate adaptation literatures, we advance six reasons why adapting to climate variability is not sufficient for adapting to climate change: 1) Vulnerability is different at different levels of exposure; 2) Coping with climate variability is not equivalent to adaptation to longer term change; 3) The socioeconomic context for vulnerability is constantly changing; 4) The perception of risk associated with climate variability does not necessarily promote adaptive behavior in the face of climate change; 5) Adaptations made to short term climate variability may reduce the flexibility of the system in the long term; and 6) Adaptive actions may shift vulnerabilities to other parts of the system or to other people. Instead we suggest that decision makers faced with choices to adapt to climate change must consider the dynamics of vulnerability in a connected system-- how choices made in one part of the system might impact other valued outcomes or even create new vulnerabilities. Furthermore we suggest that rather than expressing climate change adaptation as an extension of adaptation to climate variability, the research and practice communities would do well to articulate adaptation as an imperfect policy, with tradeoffs and consequences and that decisions be prioritized to preserve flexibility be revisited often as climate change unfolds. We then present the results of a number of empirical studies of decision making for drought in urban water systems in the United States to understand

  8. Spectrum of novel mutations found in Waardenburg syndrome types 1 and 2: implications for molecular genetic diagnostics

    Science.gov (United States)

    Wildhardt, Gabriele; Zirn, Birgit; Graul-Neumann, Luitgard M; Wechtenbruch, Juliane; Suckfüll, Markus; Buske, Annegret; Bohring, Axel; Kubisch, Christian; Vogt, Stefanie; Strobl-Wildemann, Gertrud; Greally, Marie; Bartsch, Oliver; Steinberger, Daniela

    2013-01-01

    Objectives Till date, mutations in the genes PAX3 and MITF have been described in Waardenburg syndrome (WS), which is clinically characterised by congenital hearing loss and pigmentation anomalies. Our study intended to determine the frequency of mutations and deletions in these genes, to assess the clinical phenotype in detail and to identify rational priorities for molecular genetic diagnostics procedures. Design Prospective analysis. Patients 19 Caucasian patients with typical features of WS underwent stepwise investigation of PAX3 and MITF. When point mutations and small insertions/deletions were excluded by direct sequencing, copy number analysis by multiplex ligation-dependent probe amplification was performed to detect larger deletions and duplications. Clinical data and photographs were collected to facilitate genotype–phenotype analyses. Setting All analyses were performed in a large German laboratory specialised in genetic diagnostics. Results 15 novel and 4 previously published heterozygous mutations in PAX3 and MITF were identified. Of these, six were large deletions or duplications that were only detectable by copy number analysis. All patients with PAX3 mutations had typical phenotype of WS with dystopia canthorum (WS1), whereas patients with MITF gene mutations presented without dystopia canthorum (WS2). In addition, one patient with bilateral hearing loss and blue eyes with iris stroma dysplasia had a de novo missense mutation (p.Arg217Ile) in MITF. MITF 3-bp deletions at amino acid position 217 have previously been described in patients with Tietz syndrome (TS), a clinical entity with hearing loss and generalised hypopigmentation. Conclusions On the basis of these findings, we conclude that sequencing and copy number analysis of both PAX3 and MITF have to be recommended in the routine molecular diagnostic setting for patients, WS1 and WS2. Furthermore, our genotype–phenotype analyses indicate that WS2 and TS correspond to a clinical spectrum

  9. Spectrum of novel mutations found in Waardenburg syndrome types 1 and 2: implications for molecular genetic diagnostics.

    Science.gov (United States)

    Wildhardt, Gabriele; Zirn, Birgit; Graul-Neumann, Luitgard M; Wechtenbruch, Juliane; Suckfüll, Markus; Buske, Annegret; Bohring, Axel; Kubisch, Christian; Vogt, Stefanie; Strobl-Wildemann, Gertrud; Greally, Marie; Bartsch, Oliver; Steinberger, Daniela

    2013-03-18

    Till date, mutations in the genes PAX3 and MITF have been described in Waardenburg syndrome (WS), which is clinically characterised by congenital hearing loss and pigmentation anomalies. Our study intended to determine the frequency of mutations and deletions in these genes, to assess the clinical phenotype in detail and to identify rational priorities for molecular genetic diagnostics procedures. Prospective analysis. 19 Caucasian patients with typical features of WS underwent stepwise investigation of PAX3 and MITF. When point mutations and small insertions/deletions were excluded by direct sequencing, copy number analysis by multiplex ligation-dependent probe amplification was performed to detect larger deletions and duplications. Clinical data and photographs were collected to facilitate genotype-phenotype analyses. All analyses were performed in a large German laboratory specialised in genetic diagnostics. 15 novel and 4 previously published heterozygous mutations in PAX3 and MITF were identified. Of these, six were large deletions or duplications that were only detectable by copy number analysis. All patients with PAX3 mutations had typical phenotype of WS with dystopia canthorum (WS1), whereas patients with MITF gene mutations presented without dystopia canthorum (WS2). In addition, one patient with bilateral hearing loss and blue eyes with iris stroma dysplasia had a de novo missense mutation (p.Arg217Ile) in MITF. MITF 3-bp deletions at amino acid position 217 have previously been described in patients with Tietz syndrome (TS), a clinical entity with hearing loss and generalised hypopigmentation. On the basis of these findings, we conclude that sequencing and copy number analysis of both PAX3 and MITF have to be recommended in the routine molecular diagnostic setting for patients, WS1 and WS2. Furthermore, our genotype-phenotype analyses indicate that WS2 and TS correspond to a clinical spectrum that is influenced by MITF mutation type and position.

  10. Epitope-positive truncating MLH1 mutation and loss of PMS2: implications for IHC-directed genetic testing for Lynch syndrome.

    Science.gov (United States)

    Zighelboim, Israel; Powell, Matthew A; Babb, Sheri A; Whelan, Alison J; Schmidt, Amy P; Clendenning, Mark; Senter, Leigha; Thibodeau, Stephen N; de la Chapelle, Albert; Goodfellow, Paul J

    2009-01-01

    We assessed mismatch repair by immunohistochemistry (IHC) and microsatellite instability (MSI) analysis in an early onset endometrial cancer and a sister's colon cancer. We demonstrated high-level MSI and normal expression for MLH1, MSH2 and MSH6. PMS2 failed to stain in both tumors, strongly implicating a PMS2 defect. This family did not meet clinical criteria for Lynch syndrome. However, early onset endometrial cancers in the proband and her sister, a metachronous colorectal cancer in the sister as well as MSI in endometrial and colonic tumors suggested a heritable mismatch repair defect. PCR-based direct exonic sequencing and multiplex ligation-dependent probe amplification (MLPA) were undertaken to search for PMS2 mutations in the germline DNA from the proband and her sister. No mutation was identified in the PMS2 gene. However, PMS2 exons 3, 4, 13, 14, 15 were not evaluated by MLPA and as such, rearrangements involving those exons cannot be excluded. Clinical testing for MLH1 and MSH2 mutation revealed a germline deletion of MLH1 exons 14 and 15. This MLH1 germline deletion leads to an immunodetectable stable C-terminal truncated MLH1 protein which based on the IHC staining must abrogate PMS2 stabilization. To the best of our knowledge, loss of PMS2 in MLH1 truncating mutation carriers that express MLH1 in their tumors has not been previously reported. This family points to a potential limitation of IHC-directed gene testing for suspected Lynch syndrome and the need to consider comprehensive MLH1 testing for individuals whose tumors lack PMS2 but for whom PMS2 mutations are not identified.

  11. Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability.

    Science.gov (United States)

    Musante, Luciana; Püttmann, Lucia; Kahrizi, Kimia; Garshasbi, Masoud; Hu, Hao; Stehr, Henning; Lipkowitz, Bettina; Otto, Sabine; Jensen, Lars R; Tzschach, Andreas; Jamali, Payman; Wienker, Thomas; Najmabadi, Hossein; Ropers, Hans Hilger; Kuss, Andreas W

    2017-06-01

    Intellectual disability (ID) is the hallmark of an extremely heterogeneous group of disorders that comprises a wide variety of syndromic and non-syndromic phenotypes. Here, we report on mutations in two aminoacyl-tRNA synthetases that are associated with ID in two unrelated Iranian families. In the first family, we identified a homozygous missense mutation (c.514G>A, p.Asp172Asn) in the cytoplasmic seryl-tRNA synthetase (SARS) gene. The mutation affects the enzymatic core domain of the protein and impairs its enzymatic activity, probably leading to reduced cytoplasmic tRNA Ser concentrations. The mutant protein was predicted to be unstable, which could be substantiated by investigating ectopic mutant SARS in transfected HEK293T cells. In the second family, we found a compound heterozygous genotype of the mitochondrial tryptophanyl-tRNA synthetase (WARS2) gene, comprising a nonsense mutation (c.325delA, p.Ser109Alafs*15), which very likely entails nonsense-mediated mRNA decay and a missense mutation (c.37T>G, p.Trp13Gly). The latter affects the mitochondrial localization signal of WARS2, causing protein mislocalization. Including AIMP1, which we have recently implicated in the etiology of ID, three genes with a role in tRNA-aminoacylation are now associated with this condition. We therefore suggest that the functional integrity of tRNAs in general is an important factor in the development and maintenance of human cognitive functions. © 2017 Wiley Periodicals, Inc.

  12. Transition from positive to neutral in mutation fixation along with continuing rising fitness in thermal adaptive evolution.

    Science.gov (United States)

    Kishimoto, Toshihiko; Iijima, Leo; Tatsumi, Makoto; Ono, Naoaki; Oyake, Ayana; Hashimoto, Tomomi; Matsuo, Moe; Okubo, Masato; Suzuki, Shingo; Mori, Kotaro; Kashiwagi, Akiko; Furusawa, Chikara; Ying, Bei-Wen; Yomo, Tetsuya

    2010-10-21

    It remains to be determined experimentally whether increasing fitness is related to positive selection, while stationary fitness is related to neutral evolution. Long-term laboratory evolution in Escherichia coli was performed under conditions of thermal stress under defined laboratory conditions. The complete cell growth data showed common continuous fitness recovery to every 2°C or 4°C stepwise temperature upshift, finally resulting in an evolved E. coli strain with an improved upper temperature limit as high as 45.9°C after 523 days of serial transfer, equivalent to 7,560 generations, in minimal medium. Two-phase fitness dynamics, a rapid growth recovery phase followed by a gradual increasing growth phase, was clearly observed at diverse temperatures throughout the entire evolutionary process. Whole-genome sequence analysis revealed the transition from positive to neutral in mutation fixation, accompanied with a considerable escalation of spontaneous substitution rate in the late fitness recovery phase. It suggested that continually increasing fitness not always resulted in the reduction of genetic diversity due to the sequential takeovers by fit mutants, but caused the accumulation of a considerable number of mutations that facilitated the neutral evolution.

  13. 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.

  14. 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].

  15. Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy.

    Science.gov (United States)

    Goh, Gerald; Walradt, Trent; Markarov, Vladimir; Blom, Astrid; Riaz, Nadeem; Doumani, Ryan; Stafstrom, Krista; Moshiri, Ata; Yelistratova, Lola; Levinsohn, Jonathan; Chan, Timothy A; Nghiem, Paul; Lifton, Richard P; Choi, Jaehyuk

    2016-01-19

    Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine carcinoma, associated with the Merkel cell polyomavirus (MCPyV) in 80% of cases. To define the genetic basis of MCCs, we performed exome sequencing of 49 MCCs. We show that MCPyV-negative MCCs have a high mutation burden (median of 1121 somatic single nucleotide variants (SSNVs) per-exome with frequent mutations in RB1 and TP53 and additional damaging mutations in genes in the chromatin modification (ASXL1, MLL2, and MLL3), JNK (MAP3K1 and TRAF7), and DNA-damage pathways (ATM, MSH2, and BRCA1). In contrast, MCPyV-positive MCCs harbor few SSNVs (median of 12.5 SSNVs/tumor) with none in the genes listed above. In both subgroups, there are rare cancer-promoting mutations predicted to activate the PI3K pathway (HRAS, KRAS, PIK3CA, PTEN, and TSC1) and to inactivate the Notch pathway (Notch1 and Notch2). TP53 mutations appear to be clinically relevant in virus-negative MCCs as 37% of these tumors harbor potentially targetable gain-of-function mutations in TP53 at p.R248 and p.P278. Moreover, TP53 mutational status predicts death in early stage MCC (5-year survival in TP53 mutant vs wild-type stage I and II MCCs is 20% vs. 92%, respectively; P = 0.0036). Lastly, we identified the tumor neoantigens in MCPyV-negative and MCPyV-positive MCCs. We found that virus-negative MCCs harbor more tumor neoantigens than melanomas or non-small cell lung cancers (median of 173, 65, and 111 neoantigens/sample, respectively), two cancers for which immune checkpoint blockade can produce durable clinical responses. Collectively, these data support the use of immunotherapies for virus-negative MCCs.

  16. CONSTRUCTION AND ADAPTATION OF GENETIC SEXING STRAIN OF THE MEDFLY CERATITIS CAPITATA (WIED.)BASED ON TEMPERATURE SENSITIVE MUTATION IN THE EGYPTIAN FRUITFLY LABORATORIES

    International Nuclear Information System (INIS)

    SHOMAN, A.A.

    2007-01-01

    Special strains that produce only males are used now for the control of the medfly Ceratitis capitata using the sterile insect technique. The use of these strains has a major impact on the overall efficiency of SIT, by increasing significantly the amount of sterility induced in field population comparing by using bisexual strains. Genetic sexing strains (GSS) are based on the use of male-linked chromosomal translocations which enable selectable marker genes to be linked to the male sex. Two basic components are required in the medfly to construct and adapt a laboratory strain which exhibits genetic sexing properties. The first is Y-auto some translocation strain, which enables male and female pupae to be differentiated on the basis of colour and the second is temperature sensitive lethal (tsl) mutation strain, which enables females to be killed by an increase in ambient temperature

  17. TSC1/2 mutations define a molecular subset of HCC with aggressive behaviour and treatment implication.

    Science.gov (United States)

    Ho, Daniel W H; Chan, Lo K; Chiu, Yung T; Xu, Iris M J; Poon, Ronnie T P; Cheung, Tan T; Tang, Chung N; Tang, Victor W L; Lo, Irene L O; Lam, Polly W Y; Yau, Derek T W; Li, Miao X; Wong, Chun M; Ng, Irene O L

    2017-08-01

    We investigated the mutational landscape of mammalian target of rapamycin (mTOR) signalling cascade in hepatocellular carcinomas (HCCs) with chronic HBV background, aiming to evaluate and delineate mutation-dependent mechanism of mTOR hyperactivation in hepatocarcinogenesis. We performed next-generation sequencing on human HCC samples and cell line panel. Systematic mutational screening of mTOR pathway-related genes was undertaken and mutant genes were evaluated based on their recurrence. Protein expressions of tuberous sclerosis complex (TSC)1, TSC2 and pRPS6 were assessed by immunohistochemistry in human HCC samples. Rapamycin sensitivity was estimated by colony-formation assay in HCC cell lines and the treatment was further tested using our patient-derived tumour xenograft (PDTX) models. We identified and confirmed multiple mTOR components as recurrently mutated in HBV-associated HCCs. Of significance, we detected frequent (16.2%, n=18/111) mutations of TSC1 and TSC2 genes in the HCC samples. The spectrum of TSC1/2 mutations likely disrupts the endogenous gene functions in suppressing the downstream mTOR activity through different mechanisms and leads to more aggressive tumour behaviour. Mutational disruption of TSC1 and TSC2 was also observed in HCC cell lines and our PDTX models. TSC -mutant cells exhibited reduced colony-forming ability on rapamycin treatment. With the use of biologically relevant TSC2 -mutant PDTXs, we demonstrated the therapeutic benefits of the hypersensitivity towards rapamycin treatment. Taken together, our findings suggest the significance of previously undocumented mutation-dependent mTOR hyperactivation and frequent TSC1/2 mutations in HBV-associated HCCs. They define a molecular subset of HCC having genetic aberrations in mTOR signalling, with potential significance of effective specific drug therapy. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  18. Two novel mutations in the SLC40A1 and HFE genes implicated in iron overload in a Spanish man.

    Science.gov (United States)

    Del-Castillo-Rueda, Alejandro; Moreno-Carralero, María-Isabel; Alvarez-Sala-Walther, Luis-Antonio; Cuadrado-Grande, Nuria; Enríquez-de-Salamanca, Rafael; Méndez, Manuel; Morán-Jiménez, María-Josefa

    2011-03-01

    The most common form of hemochromatosis is caused by mutations in the HFE gene. Rare forms of the disease are caused by mutations in other genes. We present a patient with hyperferritinemia and iron overload, and facial flushing. Magnetic resonance imaging was performed to measure hepatic iron overload, and a molecular study of the genes involved in iron metabolism was undertaken. The iron overload was similar to that observed in HFE hemochromatosis, and the patient was double heterozygous for two novel mutations, c.-20G>A and c.718A>G (p.K240E), in the HFE and ferroportin (FPN1 or SLC40A1) genes, respectively. Hyperferritinemia and facial flushing improved after phlebotomy. Two of the patient's children were also studied, and the daughter was heterozygous for the mutation in the SLC40A1 gene, although she did not have hyperferritinemia. The patient presented a mild iron overload phenotype probably because of the two novel mutations in the HFE and SLC40A1 genes. © 2011 John Wiley & Sons A/S.

  19. 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

  20. Psychosocial Adaptation and Depressive Manifestations in High-Risk Pregnant Women: Implications for Clinical Practice.

    Science.gov (United States)

    Fiskin, Gamze; Kaydirak, Meltem Mecdi; Oskay, Umran Yesiltepe

    2017-02-01

    High-risk pregnancy research has focused primarily on psychological well-being. The aim is to determine psychosocial adaptation and depression levels of pregnant women who were admitted to hospital with diagnosis of high-risk pregnancy. This study was descriptive. Sampling was composed of 122 high-risk pregnant women who were hospitalized in the perinatology service of Istanbul University Medical School, Department of Obstetrics and Gynecology between January 1, 2014, and May 31, 2014, and met the study criteria. The Pregnant Introduction Form, Psychosocial Adjustment of Illness Scale-Self Report, and CES Depression Scale were used. Of high-risk pregnant women, 47% were found to have a poor level of psychosocial adaptation and 57% presented with depressive symptoms. There were statistically significant difference found between the levels of psychosocial adaptation and status of depressive manifestations. The difference between the average scores increased as the adaptation levels weaken and the pregnant women with a poor level of psychosocial adaptation showed more depressive manifestations. The results of this study indicate that, depending on the high-risk pregnancy status, pregnant women experience difficulty in adaptation to their current status and pregnant women with a poor level of psychosocial adaptation showed more depressive manifestations. Nurses should deliver care in high-risk pregnancies with the awareness of physiological needs as well the psychosocial needs of pregnant women, and information meetings should be held in order to increase the psychosocial support of their families and decrease their tendency toward depression. Nursing initiatives should be developed with further studies for the psychosocial adaptation of high-risk pregnancy and reduction of the depressive manifestations. © 2016 Sigma Theta Tau International.

  1. 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.

  2. Adaptive capacity based water quality resilience transformation and policy implications in rapidly urbanizing landscapes

    International Nuclear Information System (INIS)

    Li, Yi; Degener, Jan; Gaudreau, Matthew; Li, Yangfan; Kappas, Martin

    2016-01-01

    Resilience-based management focuses on specific attributes or drivers of complex social-ecological systems, in order to operationalize and promote guiding principles for water quality management in urban systems. We therefore propose a resilience lens drawing on the theory of adaptive capacity and adaptive cycle to evaluate the urban resilience between water quality and land use type. Our findings show that the resilience of water quality variables, which were calculated based on their adaptive capacities, showed adaptive and sustainable trends with dramatic fluctuation. NH_3-N, Cadmium and Total Phosphorus experienced the most vulnerable shifts in the built-up area, agricultural areas, and on bare land. Our framework provided a consistent and repeatable approach to address uncertainty inherent in the resilience of water quality in different landscapes, as well as an approach to monitor variables over time with respect to national water quality standards. Ultimately, we pointed to the political underpinnings for risk mitigation and managing resilient urban system in a particular coastal urban setting. - Highlights: • Integrated framework to analyze the resilience of urban land-water systems • Addressed the changes of adaptive capacity based resilience and transitions • Applied four transition phases of adaptive cycle to water quality management

  3. Adaptive capacity based water quality resilience transformation and policy implications in rapidly urbanizing landscapes

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yi, E-mail: ly463526@gmail.com [Department of Cartography, GIS and Remote Sensing, Institute of Geography, Georg-August University of Goettingen, Goettingen 37077 (Germany); Key Laboratory of Coastal and Wetland Ecosystems (Ministry of Education), College of the Environment and Ecology, Xiamen University, Xiamen 361102 (China); Degener, Jan [Department of Cartography, GIS and Remote Sensing, Institute of Geography, Georg-August University of Goettingen, Goettingen 37077 (Germany); Gaudreau, Matthew [Balsillie School of International Affairs, Faculty of Environment, University of Waterloo, 67 Erb Street West, Waterloo, ON N2L 6C2 (Canada); Li, Yangfan, E-mail: yangf@xmu.edu.cn [Key Laboratory of Coastal and Wetland Ecosystems (Ministry of Education), College of the Environment and Ecology, Xiamen University, Xiamen 361102 (China); Kappas, Martin [Department of Cartography, GIS and Remote Sensing, Institute of Geography, Georg-August University of Goettingen, Goettingen 37077 (Germany)

    2016-11-01

    Resilience-based management focuses on specific attributes or drivers of complex social-ecological systems, in order to operationalize and promote guiding principles for water quality management in urban systems. We therefore propose a resilience lens drawing on the theory of adaptive capacity and adaptive cycle to evaluate the urban resilience between water quality and land use type. Our findings show that the resilience of water quality variables, which were calculated based on their adaptive capacities, showed adaptive and sustainable trends with dramatic fluctuation. NH{sub 3}-N, Cadmium and Total Phosphorus experienced the most vulnerable shifts in the built-up area, agricultural areas, and on bare land. Our framework provided a consistent and repeatable approach to address uncertainty inherent in the resilience of water quality in different landscapes, as well as an approach to monitor variables over time with respect to national water quality standards. Ultimately, we pointed to the political underpinnings for risk mitigation and managing resilient urban system in a particular coastal urban setting. - Highlights: • Integrated framework to analyze the resilience of urban land-water systems • Addressed the changes of adaptive capacity based resilience and transitions • Applied four transition phases of adaptive cycle to water quality management.

  4. 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

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

    Science.gov (United States)

    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

    2009-07-01

    Aicardi-Goutières 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 DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid. Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response.

  6. 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.

  7. Non-climatic thermal adaptation: implications for species' responses to climate warming.

    Science.gov (United States)

    Marshall, David J; McQuaid, Christopher D; Williams, Gray A

    2010-10-23

    There is considerable interest in understanding how ectothermic animals may physiologically and behaviourally buffer the effects of climate warming. Much less consideration is being given to how organisms might adapt to non-climatic heat sources in ways that could confound predictions for responses of species and communities to climate warming. Although adaptation to non-climatic heat sources (solar and geothermal) seems likely in some marine species, climate warming predictions for marine ectotherms are largely based on adaptation to climatically relevant heat sources (air or surface sea water temperature). Here, we show that non-climatic solar heating underlies thermal resistance adaptation in a rocky-eulittoral-fringe snail. Comparisons of the maximum temperatures of the air, the snail's body and the rock substratum with solar irradiance and physiological performance show that the highest body temperature is primarily controlled by solar heating and re-radiation, and that the snail's upper lethal temperature exceeds the highest climatically relevant regional air temperature by approximately 22°C. Non-climatic thermal adaptation probably features widely among marine and terrestrial ectotherms and because it could enable species to tolerate climatic rises in air temperature, it deserves more consideration in general and for inclusion into climate warming models.

  8. 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.

  9. 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.

  10. Adaptation of the chlorophycean Dictyosphaerium chlorelloides to stressful acidic, mine metal-rich waters as result of pre-selective mutations.

    Science.gov (United States)

    López-Rodas, Victoria; Marvá, Fernando; Rouco, Mónica; Costas, Eduardo; Flores-Moya, Antonio

    2008-06-01

    Several species of microalgae, closely related to mesophilic lineages, inhabit the extreme environment (pH 2.5, high levels of metals) of the Spain's Aguas Agrias Stream water (AASW). Consequently, AASW constitutes an interesting natural laboratory for analysis of adaptation by microalgae to extremely stressful conditions. To distinguish between the pre-selective or post-selective origin of adaptation processes allowing the existence of microalgae in AASW, a Luria-Delbrück fluctuation analysis was performed with the chlorophycean Dictyosphaerium chlorelloides isolated from non-acidic waters. In the analysis, AASW was used as selective factor. Preselective, resistant D. chlorelloides cells appeared with a frequency of 1.1 x 10(-6) per cell per generation. AASW-resistant mutants, with a diminished Malthusian fitness, are maintained in non-extreme waters as the result of a balance between new AASW-resistant cells arising by mutation and AASW-resistant mutants eliminated by natural selection (equilibrium at c. 12 AASW-resistants per 10(7) wild-type cells). We propose that the microalgae inhabiting this stressful environment could be the descendents of chance mutants that arrived in the past or are even arriving at the present.

  11. 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.

  12. 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.

    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

  13. 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; Castro Junior, Gilberto de

    2015-01-01

    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.

  14. 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.

  15. 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

  16. A screen of a large Czech cohort of oligodontia patients implicates a novel mutation in the PAX9 gene

    Czech Academy of Sciences Publication Activity Database

    Šerý, Omar; Bonczek, Ondřej; Hloušková, A.; Černochová, P.; Vaněk, J.; Míšek, Ivan; Krejčí, J.; Izakovičová Hollá, L.

    2015-01-01

    Roč. 123, č. 2 (2015), s. 65-71 ISSN 0909-8836 R&D Projects: GA ČR GB14-37368G; GA MZd(CZ) NT11420 Institutional support: RVO:67985904 Keywords : monozygotic twins * mutation screening * oligodontia Subject RIV: FF - HEENT, Dentistry Impact factor: 1.607, year: 2015

  17. Policy implications of greenhouse warming: Mitigation, adaptation, and the science base

    International Nuclear Information System (INIS)

    Anon.

    1992-01-01

    This book discusses the policy implications of greenhouse warming by examining three major areas: general summary of information about the greenhouse effect leading to a framework for policy; the science basis for the greenhouse effect; mitigation of greenhouse warming. Each section contains 9-13 chapters on specific subjects including the following: overview of greenhouse gases; policy implications; internations considerations; climate records and models; sea levels; temperature rise estimation; energy management at several levels; nonenergy emission reduction; human populations; deforestation. Conclusions are summarized at the end of each section

  18. Multiple Concurrent Visual-Motor Mappings: Implications for Models of Adaptation

    Science.gov (United States)

    Cunningham, H. A.; Welch, Robert B.

    1994-01-01

    Previous research on adaptation to visual-motor rearrangement suggests that the central nervous system represents accurately only 1 visual-motor mapping at a time. This idea was examined in 3 experiments where subjects tracked a moving target under repeated alternations between 2 initially interfering mappings (the 'normal' mapping characteristic of computer input devices and a 108' rotation of the normal mapping). Alternation between the 2 mappings led to significant reduction in error under the rotated mapping and significant reduction in the adaptation aftereffect ordinarily caused by switching between mappings. Color as a discriminative cue, interference versus decay in adaptation aftereffect, and intermanual transfer were also examined. The results reveal a capacity for multiple concurrent visual-motor mappings, possibly controlled by a parametric process near the motor output stage of processing.

  19. 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.

  20. 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

  1. Embedded Culture and Intercultural Adaptation: Implications for Managing the Needs of Chinese Students

    Science.gov (United States)

    Bodycott, Peter

    2012-01-01

    Students who travel abroad for study bring with them a wealth of cultural resources and expectations that influence their ability to adapt and acculturate into their new environment. While the ability to fit into their new context is a largely personal endeavour, for students from Confucian heritage societies, the cultural expectations of family…

  2. 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…

  3. Health risks of climate change: An assessment of uncertainties and its implications for adaption policies

    NARCIS (Netherlands)

    Wardekker, J.A.; de Jong, A.; van Bree, L.; Turkenburg, W.C.; van der Sluijs, J.P.

    2012-01-01

    Background: Projections of health risks of climate change are surrounded with uncertainties in knowledge. Understanding of these uncertainties will help the selection of appropriate adaptation policies. Methods: We made an inventory of conceivable health impacts of climate change, explored the type

  4. Rational Adaptation under Task and Processing Constraints: Implications for Testing Theories of Cognition and Action

    Science.gov (United States)

    Howes, Andrew; Lewis, Richard L.; Vera, Alonso

    2009-01-01

    The authors assume that individuals adapt rationally to a utility function given constraints imposed by their cognitive architecture and the local task environment. This assumption underlies a new approach to modeling and understanding cognition--cognitively bounded rational analysis--that sharpens the predictive acuity of general, integrated…

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

    Science.gov (United States)

    Dilda, Valentina; Morris, Tiffany R; Yungher, Don A; MacDougall, Hamish G; Moore, Steven T

    2014-01-01

    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.

  7. 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.

  8. Mutations in the VLGR1 Gene Implicate G-Protein Signaling in the Pathogenesis of Usher Syndrome Type II

    Science.gov (United States)

    Weston, Michael D.; Luijendijk, Mirjam W. J.; Humphrey, Kurt D.; Möller, Claes; Kimberling, William J.

    2004-01-01

    Usher syndrome type II (USH2) is a genetically heterogeneous autosomal recessive disorder with at least three genetic subtypes (USH2A, USH2B, and USH2C) and is classified phenotypically as congenital hearing loss and progressive retinitis pigmentosa. The VLGR1 (MASS1) gene in the 5q14.3-q21.1 USH2C locus was considered a likely candidate on the basis of its protein motif structure and expressed-sequence-tag representation from both cochlear and retinal subtracted libraries. Denaturing high-performance liquid chromatography and direct sequencing of polymerase-chain-reaction products amplified from 10 genetically independent patients with USH2C and 156 other patients with USH2 identified four isoform-specific VLGR1 mutations (Q2301X, I2906FS, M2931FS, and T6244X) from three families with USH2C, as well as two sporadic cases. All patients with VLGR1 mutations are female, a significant deviation from random expectations. The ligand(s) for the VLGR1 protein is unknown, but on the basis of its potential extracellular and intracellular protein-protein interaction domains and its wide mRNA expression profile, it is probable that VLGR1 serves diverse cellular and signaling processes. VLGR1 mutations have been previously identified in both humans and mice and are associated with a reflex-seizure phenotype in both species. The identification of additional VLGR1 mutations to test whether a phenotype/genotype correlation exists, akin to that shown for other Usher syndrome disease genes, is warranted. PMID:14740321

  9. A Foxp2 mutation implicated in human speech deficits alters sequencing of ultrasonic vocalizations in adult male mice

    Directory of Open Access Journals (Sweden)

    Jonathan Chabout

    2016-10-01

    Full Text Available 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 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.

  10. First implication of STRA6 mutations in isolated anophthalmia, microphthalmia, and coloboma: a new dimension to the STRA6 phenotype.

    Science.gov (United States)

    Casey, Jillian; Kawaguchi, Riki; Morrissey, Maria; Sun, Hui; McGettigan, Paul; Nielsen, Jens E; Conroy, Judith; Regan, Regina; Kenny, Elaine; Cormican, Paul; Morris, Derek W; Tormey, Peter; Chróinín, Muireann Ní; Kennedy, Breandan N; Lynch, SallyAnn; Green, Andrew; Ennis, Sean

    2011-12-01

    Microphthalmia, anophthalmia, and coloboma (MAC) are structural congenital eye malformations that cause a significant proportion of childhood visual impairments. Several disease genes have been identified but do not account for all MAC cases, suggesting that additional risk loci exist. We used single nucleotide polymorphism (SNP) homozygosity mapping (HM) and targeted next-generation sequencing to identify the causative mutation for autosomal recessive isolated colobomatous microanophthalmia (MCOPCB) in a consanguineous Irish Traveller family. We identified a double-nucleotide polymorphism (g.1157G>A and g.1156G>A; p.G304K) in STRA6 that was homozygous in all of the MCOPCB patients. The STRA6 p.G304K mutation was subsequently detected in additional MCOPCB patients, including one individual with Matthew-Wood syndrome (MWS; MCOPS9). STRA6 encodes a transmembrane receptor involved in vitamin A uptake, a process essential to eye development and growth. We have shown that the G304K mutant STRA6 protein is mislocalized and has severely reduced vitamin A uptake activity. Furthermore, we reproduced the MCOPCB phenotype in a zebrafish disease model by inhibiting retinoic acid (RA) synthesis, suggesting that diminished RA levels account for the eye malformations in STRA6 p.G304K patients. The current study demonstrates that STRA6 mutations can cause isolated eye malformations in addition to the congenital anomalies observed in MWS. © 2011 Wiley Periodicals, Inc.

  11. Identification of a Novel Homozygous Nonsense Mutation Confirms the Implication of GNAT1 in Rod-Cone Dystrophy.

    Directory of Open Access Journals (Sweden)

    Cécile Méjécase

    Full Text Available GNAT1, encoding the transducin subunit Gα, is an important element of the phototransduction cascade. Mutations in this gene have been associated with autosomal dominant and autosomal recessive congenital stationary night blindness. Recently, a homozygous truncating GNAT1 mutation was identified in a patient with late-onset rod-cone dystrophy. After exclusion of mutations in genes underlying progressive inherited retinal disorders, by targeted next generation sequencing, a 32 year-old male sporadic case with severe rod-cone dystrophy and his unaffected parents were investigated by whole exome sequencing. This led to the identification of a homozygous nonsense variant, c.963C>A p.(Cys321* in GNAT1, which was confirmed by Sanger sequencing. The mother was heterozygous for this variant whereas the variant was absent in the father. c.963C>A p.(Cys321* is predicted to produce a shorter protein that lacks critical sites for the phototransduction cascade. Our work confirms that the phenotype and the mode of inheritance associated with GNAT1 variants can vary from autosomal dominant, autosomal recessive congenital stationary night blindness to autosomal recessive rod-cone dystrophy.

  12. Reliability of kinetic visual field testing in children with mutation-proven retinal dystrophies: Implications for therapeutic clinical trials.

    Science.gov (United States)

    Dedania, Vaidehi S; Liu, Jerry Y; Schlegel, Dana; Andrews, Chris A; Branham, Kari; Khan, Naheed W; Musch, David C; Heckenlively, John R; Jayasundera, K Thiran

    2018-01-01

    Kinetic visual field testing is used to monitor disease course in retinal dystrophy clinical care and treatment response in treatment trials, which are increasingly recruiting children. This study investigates Goldmann visual field (GVF) changes in young children with mutation-proven retinal dystrophies as they age and with progression of the retinal degeneration. Retrospective review of children ≤ 17 years old with a mutation-proven retinal dystrophy. Objective clinical disease activity was assessed by a retinal degeneration specialist masked to GVF results. Digital quantification of GVF area was performed. Twenty-nine children (58 eyes), ages 5-16, were identified. GVF area increased with age despite progression in 20 children and clinical stability in nine children. Mean ± standard error increase in GVF area/year was 333 ± 130 mm 2 (I4e, p = 0.012), 720 ± 155 mm 2 (III4e, p children with mutation-proven retinal dystrophies, there is a significant increase in GVF area with age, particularly those children with retinal dystrophies can be an unreliable measure of response to treatment and on which to base appropriate counseling about visual impairment.

  13. The health policy implications of individual adaptive behavior responses to smog pollution in urban China.

    Science.gov (United States)

    Ban, Jie; Zhou, Lian; Zhang, Yi; Brooke Anderson, G; Li, Tiantian

    2017-09-01

    Smog pollution is a serious public health issue in urban China, where it is associated with public health through a range of respiratory and cardiovascular illnesses. Despite the negative health impacts of smog pollution, individual adaptive behaviors are poorly understood. This knowledge gap hinders the development of effective public policy to support and encourage the adoption of individual adaptive and mitigating behaviors to smog pollution. A questionnaire survey of 1141 randomly sampled individuals in a typical PM 2.5 -polluted Chinese city was designed to establish smog concerns and behavior changes during smog events. The results demonstrate a variety of behavior responses associated with risk perception, experience of smog, age, and gender of respondents. An understanding of these variations is critical to the development of effective public policy and ultimately to the improvement of public health in cities affected by smog. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Adaptive behaviors of experts in following standard protocol in trauma management: implications for developing flexible guidelines.

    Science.gov (United States)

    Vankipuram, Mithra; Ghaemmaghami, Vafa; Patel, Vimla L

    2012-01-01

    Critical care environments are complex and dynamic. To adapt to such environments, clinicians may be required to make alterations to their workflows resulting in deviations from standard procedures. In this work, deviations from standards in trauma critical care are studied. Thirty trauma cases were observed in a Level 1 trauma center. Activities tracked were compared to the Advance Trauma Life Support standard to determine (i) if deviations had occurred, (ii) type of deviations and (iii) whether deviations were initiated by individuals or collaboratively by the team. Results show that expert clinicians deviated to innovate, while deviations of novices result mostly in error. Experts' well developed knowledge allows for flexibility and adaptiveness in dealing with standards, resulting in innovative deviations while minimizing errors made. Providing informatics solution, in such a setting, would mean that standard protocols would have be flexible enough to "learn" from new knowledge, yet provide strong support for the trainees.

  15. 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...

  16. 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.

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

    Science.gov (United States)

    Herman, Jacob J; Sultan, Sonia E

    2011-01-01

    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.

  18. 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

    between cirral setation and feeding mode. The species studied comprise both pedunculate and sessile forms and represent a wide range of marine habitats as well as morphologies, viz., Ibla cumingi, Octolasmis warwickii, Capitulum mitella, Pollicipes polymerus, Tetraclita japonica japonica and Megabalanus...... 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...

  19. 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...... grades: wild-types (grade 0; frequency, 0.03) and infections with MOM grades of 1 to 5, with the following cumulative frequency; 0.97, 0.931, 0.866, 0.719, 0.121, respectively. There was no significant association between the MOM and SP response. Importantly, immunity, using age as a surrogate marker...

  20. From a distance: implications of spontaneous self-distancing for adaptive self-reflection.

    Science.gov (United States)

    Ayduk, Ozlem; Kross, Ethan

    2010-05-01

    Although recent experimental work indicates that self-distancing facilitates adaptive self-reflection, it remains unclear (a) whether spontaneous self-distancing leads to similar adaptive outcomes, (b) how spontaneous self-distancing relates to avoidance, and (c) how this strategy impacts interpersonal behavior. Three studies examined these issues demonstrating that the more participants spontaneously self-distanced while reflecting on negative memories, the less emotional (Studies 1-3) and cardiovascular (Study 2) reactivity they displayed in the short term. Spontaneous self-distancing was also associated with lower emotional reactivity and intrusive ideation over time (Study 1). The negative association between spontaneous self-distancing and emotional reactivity was mediated by how participants construed their experience (i.e., less recounting relative to reconstruing) rather than avoidance (Studies 1-2). In addition, spontaneous self-distancing was associated with more problem-solving behavior and less reciprocation of negativity during conflicts among couples in ongoing relationships (Study 3). Although spontaneous self-distancing was empirically related to trait rumination, it explained unique variance in predicting key outcomes. 2010 APA, all rights reserved

  1. Skin of the Cretaceous mosasaur Plotosaurus: implications for aquatic adaptations in giant marine reptiles.

    Science.gov (United States)

    Lindgren, Johan; Alwmark, Carl; Caldwell, Michael W; Fiorillo, Anthony R

    2009-08-23

    The physical nature of water and the environment it presents to an organism have long been recognized as important constraints on aquatic adaptation and evolution. Little is known about the dermal cover of mosasauroids (a group of secondarily aquatic reptiles that occupied a wide array of predatory niches in the Cretaceous marine ecosystems 92-65 Myr ago), a lack of information that has hindered inferences about the nature and level of their aquatic adaptations. A newly discovered Plotosaurus skeleton with integument preserved in three dimensions represents not only the first documented squamation in a mosasaurine mosasaur but also the first record of skin in an advanced member of the Mosasauroidea. The dermal cover comprises keeled and possibly osteoderm-reinforced scales that presumably contributed to an anterior-posterior channelling of the water flow and a reduction of microturbulent burst activities along the surface of the skin. Thus, hydrodynamic requirements of life in the water might have influenced the evolution of multiple-keeled body scales in advanced mosasauroids.

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. A founder large deletion mutation in Xeroderma pigmentosum-Variant form in Tunisia: implication for molecular diagnosis and therapy.

    Science.gov (United States)

    Ben Rekaya, Mariem; Laroussi, Nadia; Messaoud, Olfa; Jones, Mariem; Jerbi, Manel; Naouali, Chokri; Bouyacoub, Yosra; Chargui, Mariem; Kefi, Rym; Fazaa, Becima; Boubaker, Mohamed Samir; Boussen, Hamouda; Mokni, Mourad; Abdelhak, Sonia; Zghal, Mohamed; Khaled, Aida; Yacoub-Youssef, Houda

    2014-01-01

    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.

  7. 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

  8. Genetic Variation and Adaptation in Africa: Implications for Human Evolution and Disease

    Science.gov (United States)

    Gomez, Felicia; Hirbo, Jibril; Tishkoff, Sarah A.

    2014-01-01

    Because modern humans originated in Africa and have adapted to diverse environments, African populations have high levels of genetic and phenotypic diversity. Thus, genomic studies of diverse African ethnic groups are essential for understanding human evolutionary history and how this leads to differential disease risk in all humans. Comparative studies of genetic diversity within and between African ethnic groups creates an opportunity to reconstruct some of the earliest events in human population history and are useful for identifying patterns of genetic variation that have been influenced by recent natural selection. Here we describe what is currently known about genetic variation and evolutionary history of diverse African ethnic groups. We also describe examples of recent natural selection in African genomes and how these data are informative for understanding the frequency of many genetic traits, including those that cause disease susceptibility in African populations and populations of recent African descent. PMID:24984772

  9. SUSTAINABLE DIVERSIFIED AGRICULTURE AND LAND MANAGEMENT IN THE HIMALAYA: IMPLICATIONS FOR CLIMATE CHANGE ADAPTATION AND MITIGATION

    Directory of Open Access Journals (Sweden)

    R. M. Bajracharya

    2016-08-01

    Full Text Available The soil and land resources play a vital role in sustaining the local livelihoods of rural communities in the Himalaya. Most of the arable land has already been brought under cultivation, hence the ever-increasing demand for food and fiber has left farmers with no choice but to intensify agriculture. However, producing more crops and greater quantities of food, fiber and other materials on the same parcel of land can to soil fertility and productivity decline with overall degradation of land quality. Therefore, ways and means to intensify agriculture to enhance productivity without degrading the soil and land resource base have become imperative. Agro-forestry, agro-slivi-pastoral systems, and the adoption of a variety of crop, soil and water management and conservation practices offer potential to deliver multiple benefits without sacrificing the very resource upon which the human population depends. Presented herein are findings on approaches to sustainable intensification of agriculture and land management related to soil OM management and C sequestration for multiple benefits, and, agro-forestry as a crop diversification strategy with both livelihood, and climate change adaptation/mitigation benefits. The results indicate that sustainable soil management practices could lead to significant SOC accumulations (4-8 t/ha over 6 yrs. SOC and soil C stocks tend to increase with elevation due to cooler climate and slow decomposition rates. Carbon stocks for the 3 LU types was in the order CF>AF/LH>AG, suggesting that diversified cropping practices including agro-forestry have good potential sequester C while providing livelihood opportunities and climate adaptive capacity for local farming communities. Biochar amendment increased growth of both coffee plants and radish with mixed grass/weed biochar being most effective. Biochar application also significantly decreased emission of GHGs, especially N2O.

  10. Understanding stakeholder preferences for flood adaptation alternatives with natural capital implications

    Directory of Open Access Journals (Sweden)

    Jonathon R. Loos

    2016-09-01

    Full Text Available Inland flood risks are defined by a range of environmental and social factors, including land use and floodplain management. Shifting patterns of storm intensity and precipitation, attributed to climate change, are exacerbating flood risk in regions across North America. Strategies for adapting to growing flood risks and climate change must account for a community's specific vulnerabilities, and its local economic, environmental, and social conditions. Through a stakeholder-engaged methodology, we designed an interactive decision exercise to enable stakeholders to evaluate alternatives for addressing specific community flood vulnerabilities. We used a multicriteria framework to understand what drives stakeholder preferences for flood mitigation and adaptation alternatives, including ecosystem-based projects. Results indicated strong preferences for some ecosystem-based projects that utilize natural capital, generated a useful discussion on the role of individual values in driving decisions and a critique of local environmental and hazard planning procedure, and uncovered support for a river management alternative that had previously been considered socially infeasible. We conclude that a multicriteria decision framework may help ensure that the multiple benefit qualities of natural capital projects are considered by decision makers. Application of a utility function can demonstrate the role of individual decision-maker values in decision outcomes and help illustrate why one alternative may be a better choice than another. Although designing an efficient and accurate multicriteria exercise is quite challenging and often data intensive, we imagine that this method is applicable elsewhere. It may be especially suitable to group decisions that involve varying levels of expertise and competing values, as is often the case in planning for the ecological and human impacts of climate change.

  11. 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.

  12. 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

  13. 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.

  14. Genome-wide analysis of protein disorder in Arabidopsis thaliana: implications for plant environmental adaptation.

    Science.gov (United States)

    Pietrosemoli, Natalia; García-Martín, Juan A; Solano, Roberto; Pazos, Florencio

    2013-01-01

    Intrinsically disordered proteins/regions (IDPs/IDRs) are currently recognized as a widespread phenomenon having key cellular functions. Still, many aspects of the function of these proteins need to be unveiled. IDPs conformational flexibility allows them to recognize and interact with multiple partners, and confers them larger interaction surfaces that may increase interaction speed. For this reason, molecular interactions mediated by IDPs/IDRs are particularly abundant in certain types of protein interactions, such as those of signaling and cell cycle control. We present the first large-scale study of IDPs in Arabidopsis thaliana, the most widely used model organism in plant biology, in order to get insight into the biological roles of these proteins in plants. The work includes a comparative analysis with the human proteome to highlight the differential use of disorder in both species. Results show that while human proteins are in general more disordered, certain functional classes, mainly related to environmental response, are significantly more enriched in disorder in Arabidopsis. We propose that because plants cannot escape from environmental conditions as animals do, they use disorder as a simple and fast mechanism, independent of transcriptional control, for introducing versatility in the interaction networks underlying these biological processes so that they can quickly adapt and respond to challenging environmental conditions.

  15. Sovereign Adaptive Risk Modeling and Implications for the Eurozone GREXIT Case

    Directory of Open Access Journals (Sweden)

    Morgan Escalera

    2018-05-01

    Full Text Available In the wake of the 2008 financial crisis, the Financial Stability Board (FSB and the Basel Committee on Banking Supervision (BCBS created a list of systemically important financial institutions (SIFIs with the intention of determining which financial institutions were important enough to the global market that their failure would result in systemic collapse. In this work, we create a model that modifies the BCBS’s five indicators of size, interconnectedness, cross-jurisdictional activities, complexity, and substitutability and apply these measures of systemic stress to governments. Although the cross-jurisdictional activities and size were almost identical to the SIFI calculations, the others had to be adapted to mirror the intent of the BCBS. Interconnectedness is calculated by simulation of what would happen to nearby countries if a country defaulted. Substitutability is estimated by the number of services that would no longer be provided if the government ceased to exist. Complexity is market-based and is derived from credit default swap (CDS spreads. The original application of the model was to track the systemic interdependence of the Eurozone, with particular emphasis on the case of Greece. We anticipate that this model can be used in regional fiscal situations beyond the Eurozone.

  16. Role of sufficient statistics in stochastic thermodynamics and its implication to sensory adaptation

    Science.gov (United States)

    Matsumoto, Takumi; Sagawa, Takahiro

    2018-04-01

    A sufficient statistic is a significant concept in statistics, which means a probability variable that has sufficient information required for an inference task. We investigate the roles of sufficient statistics and related quantities in stochastic thermodynamics. Specifically, we prove that for general continuous-time bipartite networks, the existence of a sufficient statistic implies that an informational quantity called the sensory capacity takes the maximum. Since the maximal sensory capacity imposes a constraint that the energetic efficiency cannot exceed one-half, our result implies that the existence of a sufficient statistic is inevitably accompanied by energetic dissipation. We also show that, in a particular parameter region of linear Langevin systems there exists the optimal noise intensity at which the sensory capacity, the information-thermodynamic efficiency, and the total entropy production are optimized at the same time. We apply our general result to a model of sensory adaptation of E. coli and find that the sensory capacity is nearly maximal with experimentally realistic parameters.

  17. 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.

  18. Rational adaptation under task and processing constraints: implications for testing theories of cognition and action.

    Science.gov (United States)

    Howes, Andrew; Lewis, Richard L; Vera, Alonso

    2009-10-01

    The authors assume that individuals adapt rationally to a utility function given constraints imposed by their cognitive architecture and the local task environment. This assumption underlies a new approach to modeling and understanding cognition-cognitively bounded rational analysis-that sharpens the predictive acuity of general, integrated theories of cognition and action. Such theories provide the necessary computational means to explain the flexible nature of human behavior but in doing so introduce extreme degrees of freedom in accounting for data. The new approach narrows the space of predicted behaviors through analysis of the payoff achieved by alternative strategies, rather than through fitting strategies and theoretical parameters to data. It extends and complements established approaches, including computational cognitive architectures, rational analysis, optimal motor control, bounded rationality, and signal detection theory. The authors illustrate the approach with a reanalysis of an existing account of psychological refractory period (PRP) dual-task performance and the development and analysis of a new theory of ordered dual-task responses. These analyses yield several novel results, including a new understanding of the role of strategic variation in existing accounts of PRP and the first predictive, quantitative account showing how the details of ordered dual-task phenomena emerge from the rational control of a cognitive system subject to the combined constraints of internal variance, motor interference, and a response selection bottleneck.

  19. 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.

  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. Decision Trees Predicting Tumor Shrinkage for Head and Neck Cancer: Implications for Adaptive Radiotherapy.

    Science.gov (United States)

    Surucu, Murat; Shah, Karan K; Mescioglu, Ibrahim; Roeske, John C; Small, William; Choi, Mehee; Emami, Bahman

    2016-02-01

    To develop decision trees predicting for tumor volume reduction in patients with head and neck (H&N) cancer using pretreatment clinical and pathological parameters. Forty-eight patients treated with definitive concurrent chemoradiotherapy for squamous cell carcinoma of the nasopharynx, oropharynx, oral cavity, or hypopharynx were retrospectively analyzed. These patients were rescanned at a median dose of 37.8 Gy and replanned to account for anatomical changes. The percentages of gross tumor volume (GTV) change from initial to rescan computed tomography (CT; %GTVΔ) were calculated. Two decision trees were generated to correlate %GTVΔ in primary and nodal volumes with 14 characteristics including age, gender, Karnofsky performance status (KPS), site, human papilloma virus (HPV) status, tumor grade, primary tumor growth pattern (endophytic/exophytic), tumor/nodal/group stages, chemotherapy regimen, and primary, nodal, and total GTV volumes in the initial CT scan. The C4.5 Decision Tree induction algorithm was implemented. The median %GTVΔ for primary, nodal, and total GTVs was 26.8%, 43.0%, and 31.2%, respectively. Type of chemotherapy, age, primary tumor growth pattern, site, KPS, and HPV status were the most predictive parameters for primary %GTVΔ decision tree, whereas for nodal %GTVΔ, KPS, site, age, primary tumor growth pattern, initial primary GTV, and total GTV volumes were predictive. Both decision trees had an accuracy of 88%. There can be significant changes in primary and nodal tumor volumes during the course of H&N chemoradiotherapy. Considering the proposed decision trees, radiation oncologists can select patients predicted to have high %GTVΔ, who would theoretically gain the most benefit from adaptive radiotherapy, in order to better use limited clinical resources. © The Author(s) 2015.

  2. 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

  3. A Transcriptomic Analysis of Echinococcus granulosus Larval Stages: Implications for Parasite Biology and Host Adaptation

    Science.gov (United States)

    Parkinson, John; Wasmuth, James D.; Salinas, Gustavo; Bizarro, Cristiano V.; Sanford, Chris; Berriman, Matthew; Ferreira, Henrique B.; Zaha, Arnaldo; Blaxter, Mark L.; Maizels, Rick M.; Fernández, Cecilia

    2012-01-01

    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 parasite genome

  4. 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

  5. In vitro techniques for selection of radiation induced mutations adapted to adverse environmental conditions. Proceedings of a final research co-ordination meeting

    International Nuclear Information System (INIS)

    2001-06-01

    The ever increasing human population and dwindling land and water resources worldwide make it essential to produce more food, fibre and fodder from less and less land. During the last century, plant breeding contributed remarkably to increasing food by producing varieties which give higher yield, have improved quality and nutrition, and resist diseases and pests. Nearly 50% of the increase in food production in Asia during the last fifty years can be attributed to the high yielding, short height varieties of rice and wheat, the remaining to the improved agronomic inputs and management. Many crops, such as cassava, potato, pineapple, sweet potato, sugarcane, banana and plantain are major food crops, and others such as sugarcane and pineapple are important to the economies of many developing countries. One of the solutions to have a sustainable and secure food production is to breed varieties which are tolerant of stress conditions during their growth and development. Hence a Co-ordinated Research Project on In vitro Techniques for Selection of Radiation Induced Mutations Adapted to Adverse Environmental Conditions was initiated and focused primarily on the improvement of vegetatively propagated plants. Since the inception of this project, several participating scientists established the optimal dose requirement for in vitro cultured material. Investigations were carried out on the effect of radiation to alter traits which affect survival under stress conditions and high temperature stress in potato, pineapple, sweet potato and garlic. The possibility to change traits such as tolerance to saline and water logged soils in sugarcane and gene regulation for salinity tolerance were studied. The limited number of available reports suggest that callus cultures are much more sensitive to radiation treatment and require much lower doses (2 to 5 Gy) than stem cuttings or seeds, and that relatively higher doses (15 to 20 Gy) cause necrosis or loss of regenerative capacity. The

  6. In vitro techniques for selection of radiation induced mutations adapted to adverse environmental conditions. Proceedings of a final research co-ordination meeting

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2001-06-01

    The ever increasing human population and dwindling land and water resources worldwide make it essential to produce more food, fibre and fodder from less and less land. During the last century, plant breeding contributed remarkably to increasing food by producing varieties which give higher yield, have improved quality and nutrition, and resist diseases and pests. Nearly 50% of the increase in food production in Asia during the last fifty years can be attributed to the high yielding, short height varieties of rice and wheat, the remaining to the improved agronomic inputs and management. Many crops, such as cassava, potato, pineapple, sweet potato, sugarcane, banana and plantain are major food crops, and others such as sugarcane and pineapple are important to the economies of many developing countries. One of the solutions to have a sustainable and secure food production is to breed varieties which are tolerant of stress conditions during their growth and development. Hence a Co-ordinated Research Project on In vitro Techniques for Selection of Radiation Induced Mutations Adapted to Adverse Environmental Conditions was initiated and focused primarily on the improvement of vegetatively propagated plants. Since the inception of this project, several participating scientists established the optimal dose requirement for in vitro cultured material. Investigations were carried out on the effect of radiation to alter traits which affect survival under stress conditions and high temperature stress in potato, pineapple, sweet potato and garlic. The possibility to change traits such as tolerance to saline and water logged soils in sugarcane and gene regulation for salinity tolerance were studied. The limited number of available reports suggest that callus cultures are much more sensitive to radiation treatment and require much lower doses (2 to 5 Gy) than stem cuttings or seeds, and that relatively higher doses (15 to 20 Gy) cause necrosis or loss of regenerative capacity. The

  7. Role of pleiotropy during adaptation of TEM-1 β-lactamase to two novel antibiotics

    NARCIS (Netherlands)

    Schenk, M.F.; Witte, Sariette; Salverda, M.L.M.; Koopmanschap, Bertha; Krug, Joachim; Visser, de J.A.G.M.

    2015-01-01

    Pleiotropy is a key feature of the genotype-phenotype map, and its form and extent have many evolutionary implications, including for the dynamics of adaptation and the evolution of specialization. Similarly, pleiotropic effects of antibiotic resistance mutations may affect the evolution of

  8. 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.

  9. Adaptive mutations enhance assembly and cell-to-cell transmission of a high-titer hepatitis C virus genotype 5a Core-NS2 JFH1-based recombinant

    DEFF Research Database (Denmark)

    Mathiesen, Christian K; Prentoe, Jannick; Meredith, Luke W

    2015-01-01

    UNLABELLED: Recombinant hepatitis C virus (HCV) clones propagated in human hepatoma cell cultures yield relatively low infectivity titers. Here, we adapted the JFH1-based Core-NS2 recombinant SA13/JFH1C3405G,A3696G (termed SA13/JFH1orig), of the poorly characterized genotype 5a, to Huh7.5 cells......-titer production of diverse HCV strains would be advantageous. Our study offers important functional data on how cell culture-adaptive mutations identified in genotype 5a JFH1-based HCVcc permit high-titer culture by affecting HCV genesis through increasing virus assembly and HCV fitness by enhancing the virus...... specific infectivity and cell-to-cell transmission ability, without influencing the biophysical particle properties. High-titer HCVcc like the one described in this study may be pivotal in future vaccine-related studies where large quantities of infectious HCV particles are necessary....

  10. The Intrauterine Growth Restriction Phenotype: Fetal Adaptations and Potential Implications for Later Life Insulin Resistance and Diabetes

    Science.gov (United States)

    Thorn, Stephanie R.; Rozance, Paul J.; Brown, Laura D.; Hay, William W.

    2011-01-01

    The intrauterine growth restricted (IUGR) fetus develops unique metabolic adaptations in response to exposure to reduced nutrient supply. These adaptations provide survival value for the fetus by enhancing the capacity of the fetus to take up and use nutrients, thereby reducing the need for nutrient supply. Each organ and tissue in the fetus adapts differently, with the brain showing the greatest capacity for maintaining nutrient supply and growth. Such adaptations, if persistent, also have the potential in later life to promote nutrient uptake and storage, which directly lead to complications of obesity, insulin resistance, reduced insulin production, and type 2 diabetes. PMID:21710398

  11. Complement factor 5 (C5) p.A252T mutation is prevalent in, but not restricted to, sub-Saharan Africa: implications for the susceptibility to meningococcal disease.

    Science.gov (United States)

    Franco-Jarava, C; Comas, D; Orren, A; Hernández-González, M; Colobran, R

    2017-08-01

    Complement C5 deficiency (C5D) is a rare primary immunodeficiency associated with recurrent infections, particularly meningitis, by Neisseria species. To date, studies to elucidate the molecular basis of hereditary C5D have included fewer than 40 families, and most C5 mutations (13 of 17) have been found in single families. However, the recently described C5 p.A252T mutation is reported to be associated with approximately 7% of meningococcal disease cases in South Africa. This finding raises the question of whether the mutation may be prevalent in other parts of Africa or other continental regions. The aim of this study was to investigate the prevalence of C5 p.A252T in Africa and other regions and discuss the implications for prophylaxis against meningococcal disease. In total, 2710 samples from healthy donors within various populations worldwide were analysed by quantitative polymerase chain reaction (qPCR) assay to detect the C5 p.A252T mutation. Eleven samples were found to be heterozygous for p.A252T, and nine of these samples were from sub-Saharan African populations (allele frequency 0·94%). Interestingly, two other heterozygous samples were from individuals in populations outside Africa (Israel and Pakistan). These findings, together with data from genomic variation databases, indicate a 0·5-2% prevalence of the C5 p.A252T mutation in heterozygosity in sub-Saharan Africa. Therefore, this mutation may have a relevant role in meningococcal disease susceptibility in this geographical area. © 2017 British Society for Immunology.

  12. Screening for germline mutations of MLH1, MSH2, MSH6 and PMS2 genes in Slovenian colorectal cancer patients: implications for a population specific detection strategy of Lynch syndrome.

    Science.gov (United States)

    Berginc, Gasper; Bracko, Matej; Ravnik-Glavac, Metka; Glavac, Damjan

    2009-01-01

    Microsatellite instability (MSI) is present in more than 90% of colorectal cancers of patients with Lynch syndrome, and is therefore a feasible marker for the disease. Mutations in MLH1, MSH2, MSH6 and PMS2, which are one of the main causes of deficient mismatch repair and subsequent MSI, have been linked to the disease. In order to establish the role of each of the 4 genes in Slovenian Lynch syndrome patients, we performed MSI analysis on 593 unselected CRC patients and subsequently searched for the presence of point mutations, larger genomic rearrangements and MLH1 promoter hypermethylation in patients with MSI-high tumours. We detected 43 (7.3%) patients with MSI-H tumours, of which 7 patients (1.3%) harboured germline defects: 2 in MLH1, 4 in MSH2, 1 in PMS2 and none in MSH6. Twenty-nine germline sequence variations of unknown significance and 17 deleterious somatic mutations were found. MLH1 promoter methylation was detected in 56% of patients without detected germline defects and in 1 (14%) suspected Lynch syndrome. Due to the minor role of germline MSH6 mutations, we adapted the Lynch syndrome detection strategy for the Slovenian population of CRC patients, whereby germline alterations should be first sought in MLH1 and MSH2 followed by a search for larger genomic rearrangements in these two genes. When no germline mutations are found tumors should be further tested for the presence of germline defects in PMS2 and MSH6. The choice about which gene should be tested first can be guided more accurately by the immunohistochemical analysis. Our study demonstrates that the incidence of MMR mutations in a population should be known prior to the application of one of several suggested strategies for detection of Lynch syndrome.

  13. Co-inheritance of HNF1a and GCK mutations in a family with maturity-onset diabetes of the young (MODY): implications for genetic testing.

    Science.gov (United States)

    López-Garrido, M P; Herranz-Antolín, S; Alija-Merillas, M J; Giralt, P; Escribano, J

    2013-09-01

    To determine the genetic basis of dominant early-onset diabetes mellitus in two families. Molecular analysis by PCR sequencing of the promoter, the 5' untranslated region (UTR) and exons of both GCK and HNF1A genes was carried out in two families with clinically diagnosed dominant diabetes mellitus. The novel HNF1A c.-154_-160TGGGGGT mutation, located in the 5' UTR, was present in several members of the two families in the heterozygous state. Interestingly, the GCK p.Y61X mutation was also identified in three members of one of the families, and two of them carried both mutations in heterozygosis. To the best of our knowledge, this is the first report of the co-inheritance of GCK and HNF1A mutations and the coexistence of maturity-onset diabetes of the young (MODY) 2, MODY 3 and unusual MODY 2-3 genotypes in the same family. Carriers of both GCK and HNF1A mutations manifested a typical MODY 3 phenotype and showed that the presence of a second mutation in the GCK gene apparently did not modify the clinical outcome, at least at the time of this study. Our data show that co-inheritance of MODY 2 and MODY 3 mutations should be considered, at least in some cases, for accurate genetic testing. © 2012 John Wiley & Sons Ltd.

  14. Selective Bottlenecks Shape Evolutionary Pathways Taken during Mammalian Adaptation of a 1918-like Avian Influenza Virus.

    Science.gov (United States)

    Moncla, Louise H; Zhong, Gongxun; Nelson, Chase W; Dinis, Jorge M; Mutschler, James; Hughes, Austin L; Watanabe, Tokiko; Kawaoka, Yoshihiro; Friedrich, Thomas C

    2016-02-10

    Avian influenza virus reassortants resembling the 1918 human pandemic virus can become transmissible among mammals by acquiring mutations in hemagglutinin (HA) and polymerase. Using the ferret model, we trace the evolutionary pathway by which an avian-like virus evolves the capacity for mammalian replication and airborne transmission. During initial infection, within-host HA diversity increased drastically. Then, airborne transmission fixed two polymerase mutations that do not confer a detectable replication advantage. In later transmissions, selection fixed advantageous HA1 variants. Transmission initially involved a "loose" bottleneck, which became strongly selective after additional HA mutations emerged. The stringency and evolutionary forces governing between-host bottlenecks may therefore change throughout host adaptation. Mutations occurred in multiple combinations in transmitted viruses, suggesting that mammalian transmissibility can evolve through multiple genetic pathways despite phenotypic constraints. Our data provide a glimpse into avian influenza virus adaptation in mammals, with broad implications for surveillance on potentially zoonotic viruses. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. P2X2 Dominant Deafness Mutations Have No Negative Effect on Wild-Type Isoform: Implications for Functional Rescue and in Deafness Mechanism

    Directory of Open Access Journals (Sweden)

    Yan Zhu

    2017-11-01

    Full Text Available The P2X2 receptor is an ATP-gated ion channel, assembled by three subunits. Recently, it has been found that heterozygous mutations of P2X2 V60L and G353R can cause autosomal dominant nonsyndromic hearing loss. However, the underlying mechanism remains unclear. The fact that heterozygous mutations cause deafness suggests that the mutations may have dominant-negative effect (DNE on wild-type (WT P2X2 isoforms and/or other partners leading to hearing loss. In this study, the effect of these dominant deafness P2X2 mutations on WT P2X2 was investigated. We found that sole transfection of both V60L and G353R deafness mutants could efficiently target to the plasma membrane, like WT P2X2, but exhibit a significantly reduced response to ATP stimulation. Both mutants reduced the channel conductance, but G353R mutation also altered the voltage dependency. Co-expression with WT P2X2 could restore the response to ATP. As the ratio of WT P2X2 vs. mutants increased, the response to ATP was also increased. Computer modeling confirmed that both V60L and G353R dominant-deafness mutant subunits do not have any negative effect on WT P2X2 subunit, when assembled as a heterotrimer. Improper docking or defective gating is the more likely mechanism for impaired channel function by these P2X2 deafness mutations. These results suggest that P2X2 dominant deafness mutations do not have negative effects on WT P2X2 isoforms, and that adding additional WT P2X2 could rescue the lost channel function caused by the deafness mutations. These P2X2 dominant deafness mutations may have negative-effects on other partners leading to hearing loss.

  16. 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

    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...

  17. Different effects of dose rate on radiation-induced mutation frequency in various germ-cell stages of the mouse, and their implications for the analysis of tumorigenesis

    International Nuclear Information System (INIS)

    Russell, W.L.

    1979-01-01

    The following factors affecting mutation induction by radiation in mice are discussed: dose rate, cell stage, and sex. It is suggested that for cancers of presumed mutational origin, the risk from chronic radiation exposure may be only one-third the risk from acute exposure. This is based only on responses of spermatogonia; other cell types behave quite differently. Specific and general applications are discussed

  18. Adaptive landscape and functional diversity of Neotropical cichlids: implications for the ecology and evolution of Cichlinae (Cichlidae; Cichliformes).

    Science.gov (United States)

    Arbour, J H; López-Fernández, H

    2014-11-01

    Morphological, lineage and ecological diversity can vary substantially even among closely related lineages. Factors that influence morphological diversification, especially in functionally relevant traits, can help to explain the modern distribution of disparity across phylogenies and communities. Multivariate axes of feeding functional morphology from 75 species of Neotropical cichlid and a stepwise-AIC algorithm were used to estimate the adaptive landscape of functional morphospace in Cichlinae. Adaptive landscape complexity and convergence, as well as the functional diversity of Cichlinae, were compared with expectations under null evolutionary models. Neotropical cichlid feeding function varied primarily between traits associated with ram feeding vs. suction feeding/biting and secondarily with oral jaw muscle size and pharyngeal crushing capacity. The number of changes in selective regimes and the amount of convergence between lineages was higher than expected under a null model of evolution, but convergence was not higher than expected under a similarly complex adaptive landscape. Functional disparity was compatible with an adaptive landscape model, whereas the distribution of evolutionary change through morphospace corresponded with a process of evolution towards a single adaptive peak. The continentally distributed Neotropical cichlids have evolved relatively rapidly towards a number of adaptive peaks in functional trait space. Selection in Cichlinae functional morphospace is more complex than expected under null evolutionary models. The complexity of selective constraints in feeding morphology has likely been a significant contributor to the diversity of feeding ecology in this clade. © 2014 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2014 European Society For Evolutionary Biology.

  19.  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.

  20. 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.

  1. The Role of Social Networks in Agricultural Adaptation to Climate Change: Implications for Sustainable Agriculture in Pakistan

    Directory of Open Access Journals (Sweden)

    Muhammad Abid

    2017-11-01

    Full Text Available Incorporating adaptation into subsistence farming systems is an important strategy to reduce damages related to climate change and to protect livelihoods in developing countries. Using a dataset of 450 farm households collected from three agro-ecological zones, this study examines rural networks, assesses farm-level institutional support and documents any existing structural gaps on climate change adaptation in the agricultural sector of Pakistan. For this purpose, a social network analysis method is used. The study findings reveal that farmers reported a decrease in crop production and increase in pests and diseases due to climate change. Further, changing crop varieties, sowing dates, input mixes and planting trees are the key measures adopted by farmers. Lack of information, finances and resources are the key adaptation constraints. The study findings show that only 28% and 13% of the respondents do not have access to financial services and climate adaptation knowledge, respectively. Support to farmers mainly consists of marketing information and farm equipment from community-based organizations, while private institutions offer weather forecasting services. Public institutions are poorly represented in the network analysis. We also found that extension services are key institutions in the climate adaptation network, while agricultural credits, post-harvest services and marketing of produce were dominant but weakly connected in the financial support network. We also found that with an increase in the provision of services at the farm level, farmers not only adapt more but also move from low-cost and short-term measures to advanced measures. This study proposes an integrated framework to improve the stakeholders’ networking through different kind of partnerships and better adaptation to climate change.

  2. Tumor heterogeneity of fibroblast growth factor receptor 3 (FGFR3) mutations in invasive bladder cancer: implications for perioperative anti-FGFR3 treatment.

    Science.gov (United States)

    Pouessel, D; Neuzillet, Y; Mertens, L S; van der Heijden, M S; de Jong, J; Sanders, J; Peters, D; Leroy, K; Manceau, A; Maille, P; Soyeux, P; Moktefi, A; Semprez, F; Vordos, D; de la Taille, A; Hurst, C D; Tomlinson, D C; Harnden, P; Bostrom, P J; Mirtti, T; Horenblas, S; Loriot, Y; Houédé, N; Chevreau, C; Beuzeboc, P; Shariat, S F; Sagalowsky, A I; Ashfaq, R; Burger, M; Jewett, M A S; Zlotta, A R; Broeks, A; Bapat, B; Knowles, M A; Lotan, Y; van der Kwast, T H; Culine, S; Allory, Y; van Rhijn, B W G

    2016-07-01

    Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer. Preclinical studies show that anti-FGFR3 treatment slows down tumor growth, suggesting that this tyrosine kinase receptor is a candidate for personalized bladder cancer treatment, particularly in patients with mutated FGFR3. We addressed tumor heterogeneity in a large multicenter, multi-laboratory study, as this may have significant impact on therapeutic response. We evaluated possible FGFR3 heterogeneity by the PCR-SNaPshot method in the superficial and deep compartments of tumors obtained by transurethral resection (TUR, n = 61) and in radical cystectomy (RC, n = 614) specimens and corresponding cancer-positive lymph nodes (LN+, n = 201). We found FGFR3 mutations in 13/34 (38%) T1 and 8/27 (30%) ≥T2-TUR samples, with 100% concordance between superficial and deeper parts in T1-TUR samples. Of eight FGFR3 mutant ≥T2-TUR samples, only 4 (50%) displayed the mutation in the deeper part. We found 67/614 (11%) FGFR3 mutations in RC specimens. FGFR3 mutation was associated with pN0 (P < 0.001) at RC. In 10/201 (5%) LN+, an FGFR3 mutation was found, all concordant with the corresponding RC specimen. In the remaining 191 cases, RC and LN+ were both wild type. FGFR3 mutation status seems promising to guide decision-making on adjuvant anti-FGFR3 therapy as it appeared homogeneous in RC and LN+. Based on the results of TUR, the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. We conclude that studies on the heterogeneity of actionable molecular targets should precede clinical trials with these drugs in the perioperative setting. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  3. Extremely low penetrance of deafness associated with the mitochondrial 12S rRNA mutation in 16 Chinese families: Implication for early detection and prevention of deafness

    International Nuclear Information System (INIS)

    Dai Pu; Liu Xin; Han Dongyi; Qian Yaping; Huang Deliang; Yuan Huijun; Li Weiming; Yu Fei; Zhang Ruining; Lin Hongyan; He Yong; Yu Youjun; Sun Quanzhu; Qin Huaiyi; Li Ronghua; Zhang Xin; Kang Dongyang; Cao Juyang; Young Wieyen; Guan Minxin

    2006-01-01

    Mutations in mitochondrial DNA (mtDNA) have been found to be associated with sensorineural hearing loss. We report here the clinical, genetic, and molecular characterization of 16 Chinese pedigrees (a total of 246 matrilineal relatives) with aminoglycoside-induced impairment. Clinical evaluation revealed the variable phenotype of hearing impairment including audiometric configuration in these subjects, although these subjects share some common features: being bilateral and sensorineural hearing impairment. Strikingly, these Chinese pedigrees exhibited extremely low penetrance of hearing loss, ranging from 4% to 18%, with an average of 8%. In particular, nineteen of 246 matrilineal relatives in these pedigrees had aminoglycoside-induced hearing loss. Mutational analysis of the mtDNA in these pedigrees showed the presence of homoplasmic 12S rRNA A1555G mutation, which has been associated with hearing impairment in many families worldwide. The extremely low penetrance of hearing loss in these Chinese families carrying the A1555G mutation strongly supports the notion that the A1555G mutation itself is not sufficient to produce the clinical phenotype. Children carrying the A1555G mutation are susceptible to the exposure of aminoglycosides, thereby inducing or worsening hearing impairment, as in the case of these Chinese families. Using those genetic and molecular approaches, we are able to diagnose whether children carry the ototoxic mtDNA mutation. Therefore, these data have been providing valuable information and technology to predict which individuals are at risk for ototoxicity, to improve the safety of aminoglycoside therapy, and eventually to decrease the incidence of deafness

  4. 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

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

    Directory of Open Access Journals (Sweden)

    Alexandra Houssaye

    Full Text Available 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

  6. Metabolic engineering of an ATP-neutral Embden-Meyerhof-Parnas pathway in Corynebacterium glutamicum: growth restoration by an adaptive point mutation in NADH dehydrogenase.

    Science.gov (United States)

    Komati Reddy, Gajendar; Lindner, Steffen N; Wendisch, Volker F

    2015-03-01

    Corynebacterium glutamicum uses the Embden-Meyerhof-Parnas pathway of glycolysis and gains 2 mol of ATP per mol of glucose by substrate-level phosphorylation (SLP). To engineer glycolysis without net ATP formation by SLP, endogenous phosphorylating NAD-dependent glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was replaced by nonphosphorylating NADP-dependent glyceraldehyde-3-phosphate dehydrogenase (GapN) from Clostridium acetobutylicum, which irreversibly converts glyceraldehyde-3-phosphate (GAP) to 3-phosphoglycerate (3-PG) without generating ATP. As shown recently (S. Takeno, R. Murata, R. Kobayashi, S. Mitsuhashi, and M. Ikeda, Appl Environ Microbiol 76:7154-7160, 2010, http://dx.doi.org/10.1128/AEM.01464-10), this ATP-neutral, NADPH-generating glycolytic pathway did not allow for the growth of Corynebacterium glutamicum with glucose as the sole carbon source unless hitherto unknown suppressor mutations occurred; however, these mutations were not disclosed. In the present study, a suppressor mutation was identified, and it was shown that heterologous expression of udhA encoding soluble transhydrogenase from Escherichia coli partly restored growth, suggesting that growth was inhibited by NADPH accumulation. Moreover, genome sequence analysis of second-site suppressor mutants that were able to grow faster with glucose revealed a single point mutation in the gene of non-proton-pumping NADH:ubiquinone oxidoreductase (NDH-II) leading to the amino acid change D213G, which was shared by these suppressor mutants. Since related NDH-II enzymes accepting NADPH as the substrate possess asparagine or glutamine residues at this position, D213G, D213N, and D213Q variants of C. glutamicum NDH-II were constructed and were shown to oxidize NADPH in addition to NADH. Taking these findings together, ATP-neutral glycolysis by the replacement of endogenous NAD-dependent GAPDH with NADP-dependent GapN became possible via oxidation of NADPH formed in this pathway by mutant NADPH

  7. Stepping reaction time and gait adaptability are significantly impaired in people with Parkinson's disease: Implications for fall risk.

    Science.gov (United States)

    Caetano, Maria Joana D; Lord, Stephen R; Allen, Natalie E; Brodie, Matthew A; Song, Jooeun; Paul, Serene S; Canning, Colleen G; Menant, Jasmine C

    2018-02-01

    Decline in the ability to take effective steps and to adapt gait, particularly under challenging conditions, may be important reasons why people with Parkinson's disease (PD) have an increased risk of falling. This study aimed to determine the extent of stepping and gait adaptability impairments in PD individuals as well as their associations with PD symptoms, cognitive function and previous falls. Thirty-three older people with PD and 33 controls were assessed in choice stepping reaction time, Stroop stepping and gait adaptability tests; measurements identified as fall risk factors in older adults. People with PD had similar mean choice stepping reaction times to healthy controls, but had significantly greater intra-individual variability. In the Stroop stepping test, the PD participants were more likely to make an error (48 vs 18%), took 715 ms longer to react (2312 vs 1517 ms) and had significantly greater response variability (536 vs 329 ms) than the healthy controls. People with PD also had more difficulties adapting their gait in response to targets (poorer stepping accuracy) and obstacles (increased number of steps) appearing at short notice on a walkway. Within the PD group, higher disease severity, reduced cognition and previous falls were associated with poorer stepping and gait adaptability performances. People with PD have reduced ability to adapt gait to unexpected targets and obstacles and exhibit poorer stepping responses, particularly in a test condition involving conflict resolution. Such impaired stepping responses in Parkinson's disease are associated with disease severity, cognitive impairment and falls. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. TH-CD-202-11: Implications for Online Adaptive and Non-Adaptive Radiotherapy of Gastic and Gastroesophageal Junction Cancers Using MRI-Guided Radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Mittauer, K; Geurts, M; Toya, R; Bassetti, M; Harari, P; Paliwal, B; Bayouth, J [University of Wisconsin, Madison, WI (United States)

    2016-06-15

    Purpose: Radiotherapy for gastric and gastroesophageal junction (GEJ) tumors commonly requires large margins due to deformation, motion and variable changes of the stomach anatomy, at the risk of increased normal tissue toxicities. This work quantifies the interfraction variation of stomach deformation from daily MRI-guided radiotherapy to allow for a more targeted determination of margin expansion in the treatment of gastric and GEJ tumors. Methods: Five patients treated for gastric (n=3) and gastroesophageal junction (n=2) cancers with conventionally fractionated radiotherapy underwent daily MR imaging on a clinical MR-IGRT system. Treatment planning and contours were performed based on the MR simulation. The stomach was re-contoured on each daily volumetric setup MR. Dice similarity coefficients (DSC) of the daily stomach were computed to evaluate the stomach interfraction deformation. To evaluate the stomach margin, the maximum Hausdorff distance (HD) between the initial and fractional stomach surface was measured for each fraction. The margin expansion, needed to encompass all fractions, was evaluated from the union of all fractional stomachs. Results: In total, 94 fractions with daily stomach contours were evaluated. For the interfraction stomach differences, the average DSC was 0.67±0.1 for gastric and 0.62±0.1 for GEJ cases. The maximum HD of each fraction was 3.5±2.0cm (n=94) with mean HD of 0.8±0.4cm (across all surface voxels for all fractions). The margin expansion required to encompass all individual fractions (averaged across 5 patients) was 1.4 cm(superior), 2.3 cm(inferior), 2.5 cm(right), 3.2 cm(left), 3.7 cm(anterior), 3.4 cm(posterior). Maximum observed difference for margin expansion was 8.7cm(posterior) among one patient. Conclusion: We observed a notable interfractional change in daily stomach shape (i.e., mean DSC of 0.67, p<0.0001) in both gastric and GEJ patients, for which adaptive radiotherapy is indicated. A minimum PTV margin of 3

  9. TH-CD-202-11: Implications for Online Adaptive and Non-Adaptive Radiotherapy of Gastic and Gastroesophageal Junction Cancers Using MRI-Guided Radiotherapy

    International Nuclear Information System (INIS)

    Mittauer, K; Geurts, M; Toya, R; Bassetti, M; Harari, P; Paliwal, B; Bayouth, J

    2016-01-01

    Purpose: Radiotherapy for gastric and gastroesophageal junction (GEJ) tumors commonly requires large margins due to deformation, motion and variable changes of the stomach anatomy, at the risk of increased normal tissue toxicities. This work quantifies the interfraction variation of stomach deformation from daily MRI-guided radiotherapy to allow for a more targeted determination of margin expansion in the treatment of gastric and GEJ tumors. Methods: Five patients treated for gastric (n=3) and gastroesophageal junction (n=2) cancers with conventionally fractionated radiotherapy underwent daily MR imaging on a clinical MR-IGRT system. Treatment planning and contours were performed based on the MR simulation. The stomach was re-contoured on each daily volumetric setup MR. Dice similarity coefficients (DSC) of the daily stomach were computed to evaluate the stomach interfraction deformation. To evaluate the stomach margin, the maximum Hausdorff distance (HD) between the initial and fractional stomach surface was measured for each fraction. The margin expansion, needed to encompass all fractions, was evaluated from the union of all fractional stomachs. Results: In total, 94 fractions with daily stomach contours were evaluated. For the interfraction stomach differences, the average DSC was 0.67±0.1 for gastric and 0.62±0.1 for GEJ cases. The maximum HD of each fraction was 3.5±2.0cm (n=94) with mean HD of 0.8±0.4cm (across all surface voxels for all fractions). The margin expansion required to encompass all individual fractions (averaged across 5 patients) was 1.4 cm(superior), 2.3 cm(inferior), 2.5 cm(right), 3.2 cm(left), 3.7 cm(anterior), 3.4 cm(posterior). Maximum observed difference for margin expansion was 8.7cm(posterior) among one patient. Conclusion: We observed a notable interfractional change in daily stomach shape (i.e., mean DSC of 0.67, p<0.0001) in both gastric and GEJ patients, for which adaptive radiotherapy is indicated. A minimum PTV margin of 3

  10. Mapping of the X-linked cataract (Xcat) mutation, the gene implicated in the Nance Horan syndrome, on the mouse X chromosome.

    Science.gov (United States)

    Stambolian, D; Favor, J; Silvers, W; Avner, P; Chapman, V; Zhou, E

    1994-07-15

    The Xcat mutation in the mouse, an X-linked inherited disorder, is characterized by the congenital onset of cataracts. The cataracts have morphologies similar to those of cataracts found in the human Nance Horan (X-linked cataract dental) syndrome, suggesting that Xcat is an animal model for Nance Horan. The Xcat mutation provides an opportunity to investigate, at the molecular level, the pathogenesis of cataract. As a first step to cloning the Xcat gene, we report the localization of the Xcat mutation with respect to known molecular markers on the mouse X chromosome. Back-cross progeny carrying the Xcat mutation were obtained from an interspecific cross. Genomic DNA from each mouse was subjected to Southern and PCR analysis to identify restriction fragment length polymorphisms and simple sequence length polymorphisms, respectively. Our results refine the location of Xcat to a 2-cM region, eliminate several genes from consideration as the Xcat mutation, identify molecular probes tightly linked with Xcat, and suggest candidate genes responsible for the Xcat phenotype.

  11. 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

    + CHL and CHL + CIP). We find that lineages evolved to antibiotic combinations exhibit different resistance allele dynamics compared with those of single-drug evolved lineages, especially for a drug pair with reciprocal collateral sensitivity. During adaptation, we observed interfering, superimposing...

  12. Hypervariable region 1 deletion and required adaptive envelope mutations confer decreased dependency on scavenger receptor class B type I and low-density lipoprotein receptor for hepatitis C virus

    DEFF Research Database (Denmark)

    Prentoe, Jannick; Serre, Stéphanie B N; Ramirez, Santseharay

    2014-01-01

    -deleted viruses. Apolipoprotein E (ApoE)-specific HCV neutralization was similar for H77, J6, and S52 viruses with and without HVR1. In conclusion, HVR1 and HVR1-related adaptive envelope mutations appeared to be involved in LDLr and SR-BI dependency, respectively. Also, LDLr served Apo....../S733F), S52(ΔHVR1/A369V), and S52(A369V), but not for J6(ΔHVR1). Low-density lipoprotein receptor (LDLr) dependency was decreased for HVR1-deleted viruses, but not for H77(N476D/S733F) and S52(A369V). Soluble LDLr neutralization revealed strong inhibition of parental HCV but limited effect against HVR1...

  13. 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…

  14. 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

  15. 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. © 2015 International Union of Psychological Science.

  16. An innovative approach for Predicting Farmers' Adaptive Behavior at the Large Watershed Scale: Implications for Water Quality and Crop Yields

    Science.gov (United States)

    Valcu-Lisman, A. M.; Gassman, P. W.; Arritt, R. W.; Kling, C.; Arbuckle, J. G.; Roesch-McNally, G. E.; Panagopoulos, Y.

    2017-12-01

    Projected changes in the climatic patterns (higher temperatures, changes in extreme precipitation events, and higher levels of humidity) will affect agricultural cropping and management systems in major agricultural production areas. The concept of adaption to new climatic or economic conditions is an important aspect of the agricultural decision-making process. Adopting cover crops, reduced tillage, extending the drainage systems and adjusting crop management are only a few examples of adaptive actions. These actions can be easily implemented as long as they have private benefits (increased profits, reduced risk). However, each adaptive action has a different impact on water quality. Cover crops and no till usually have a positive impact on water quality, but increased tile drainage typically results in more degraded water quality due primarily to increased export of soluble nitrogen and phosphorus. The goal of this research is to determine the changes in water quality as well in crop yields as farmers undertake these adaptive measures. To answer this research question, we need to estimate the likelihood that these actions will occur, identify the agricultural areas where these actions are most likely to be implemented, and simulate the water quality impacts associated with each of these scenarios. We apply our modeling efforts to the whole Upper-Mississippi River Basin Basin (UMRB) and the Ohio-Tennessee River Basin (OTRB). These two areas are critical source regions for the re-occurring hypoxic zone in the gulf of Mexico. The likelihood of each adaptive agricultural action is estimated using data from a survey conducted in 2012. A large, representative sample of farmers in the Corn Belt was used in the survey to elicit behavioral intentions regarding three of the most important agricultural adaptation strategies (no-till, cover crops and tile drainage). We use these data to study the relationship between intent to adapt, farmer characteristics, farm

  17. 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

  18. 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...

  19. 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 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.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.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.

  20. 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

  1. Low prevalence of transmitted K65R and other tenofovir resistance mutations across different HIV-1 subtypes: implications for pre-exposure prophylaxis.

    Science.gov (United States)

    Chan, Philip A; Huang, Austin; Kantor, Rami

    2012-10-15

    Tenofovir-containing regimens have demonstrated potential efficacy as pre-exposure prophylaxis (PrEP) in preventing HIV-1 infection. Transmitted drug resistance mutations associated with tenofovir, specifically the reverse transcriptase (RT) mutation K65R, may impact the effectiveness of PrEP. The worldwide prevalence of transmitted tenofovir resistance in different HIV-1 subtypes is unknown. Sequences from treatment-naïve studies and databases were aggregated and analyzed by Stanford Database tools and as per the International AIDS Society (IAS-USA) resistance criteria. RT sequences were collected from GenBank, the Stanford HIV Sequence Database and the Los Alamos HIV Sequence Database. Sequences underwent rigorous quality control measures. Tenofovir-associated resistance mutations included K65R, K70E, T69-insertion and ≥3 thymidine analogue mutations (TAMs), inclusive of M41L or L210W. A total of 19,823 sequences were evaluated across diverse HIV-1 subtypes (Subtype A: 1549 sequences, B: 9783, C: 3198, D: 483, F: 372, G: 594, H: 41, J: 69, K: 239, CRF01_AE: 1797 and CRF02_AG: 1698). Overall, tenofovir resistance prevalence was 0.4% (n=77/19,823, 95% confidence interval or CI: 0.3 to 0.5). K65R was found in 20 sequences (0.1%, 95% CI: 0.06 to 0.15). Differences in the prevalence of K65R between HIV-1 subtypes were not statistically significant. K70E and ≥3 TAMs were found in 0.015% (95% CI: 0.004 to 0.04) and 0.27% (95% CI: 0.2 to 0.4) of sequences, respectively. Prevalence of transmitted K65R and other tenofovir resistance mutations across diverse HIV-1 subtypes and recombinants is low, suggesting minimal effect on tenofovir-containing PrEP regimens.

  2. 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.

  3. 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 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.

  4. Neutral mutation as the source of genetic variation in life history traits.

    Science.gov (United States)

    Brcić-Kostić, Krunoslav

    2005-08-01

    The mechanism underlying the maintenance of adaptive genetic variation is a long-standing question in evolutionary genetics. There are two concepts (mutation-selection balance and balancing selection) which are based on the phenotypic differences between alleles. Mutation - selection balance and balancing selection cannot properly explain the process of gene substitution, i.e. the molecular evolution of quantitative trait loci affecting fitness. I assume that such loci have non-essential functions (small effects on fitness), and that they have the potential to evolve into new functions and acquire new adaptations. Here I show that a high amount of neutral polymorphism at these loci can exist in real populations. Consistent with this, I propose a hypothesis for the maintenance of genetic variation in life history traits which can be efficient for the fixation of alleles with very small selective advantage. The hypothesis is based on neutral polymorphism at quantitative trait loci and both neutral and adaptive gene substitutions. The model of neutral - adaptive conversion (NAC) assumes that neutral alleles are not neutral indefinitely, and that in specific and very rare situations phenotypic (relative fitness) differences between them can appear. In this paper I focus on NAC due to phenotypic plasticity of neutral alleles. The important evolutionary consequence of NAC could be the increased adaptive potential of a population. Loci responsible for adaptation should be fast evolving genes with minimally discernible phenotypic effects, and the recent discovery of genes with such characteristics implicates them as suitable candidates for loci involved in adaptation.

  5. Ancient genes establish stress-induced mutation as a hallmark of cancer.

    Science.gov (United States)

    Cisneros, Luis; Bussey, Kimberly J; Orr, Adam J; Miočević, Milica; Lineweaver, Charles H; Davies, Paul

    2017-01-01

    stress that evolved among prokaryotes was co-opted to maintain diversity in the germline and immune system, while the original phenotype is restored in cancer. Reversion to a stress-induced mutational response is a hallmark of cancer that allows for effectively searching "protected" genome space where genes causally implicated in cancer are located and underlies the high adaptive potential and concomitant therapeutic resistance that is characteristic of cancer.

  6. Older American Indians' Perspectives on Health, Arthritis, and Physical Activity: Implications for Adapting Evidence-Based Interventions, Oregon, 2013.

    Science.gov (United States)

    Conte, Kathleen P; Schure, Marc B; Goins, R Turner

    2016-06-23

    Despite the high prevalence of arthritis and physical disability among older American Indians, few evidence-based interventions that improve arthritis self-management via physical activity have been adapted for use in this population. The purpose of this study was to identify beliefs about health, arthritis, and physical activity among older American Indians living in a rural area in Oregon to help select and adapt an arthritis self-management program. In partnership with a tribal health program, we conducted surveys, a focus group, and individual interviews with older American Indians with arthritis. Our sample comprised 6 focus group participants and 18 interviewees. The 24 participants were aged 48 to 82 years, of whom 67% were women. Forms B and C of the Multidimensional Health Locus of Control (MHLC) instrument, modified for arthritis, measured MHLC. The concepts of health, arthritis, and physical activity overlapped in that health was a holistic concept informed by cultural teachings that included living a healthy lifestyle, socializing, and being functionally independent. Arthritis inhibited health and healthy behaviors. Participants identified barriers such as unreliable transportation and recruiting challenges that would make existing interventions challenging to implement in this setting. The Doctor subscale had the highest MHLC (mean = 4.4 [standard deviation (SD), 1.0]), followed by the Internal subscale (3.9 [SD, 1.4]) and the Other People subscale (2.8 [SD, 1.1]). Existing evidence-based programs for arthritis should be adapted to address implementation factors, such as access to transportation, and incorporate cultural values that emphasize holistic wellness and social interconnectedness. Culturally sensitive programs that build on indigenous values and practices to promote active coping strategies for older American Indians with arthritis are needed.

  7. 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.

  8. Impacts of ozone air pollution and temperature extremes on crop yields: Spatial variability, adaptation and implications for future food security

    Science.gov (United States)

    Tai, Amos P. K.; Val Martin, Maria

    2017-11-01

    Ozone air pollution and climate change pose major threats to global crop production, with ramifications for future food security. Previous studies of ozone and warming impacts on crops typically do not account for the strong ozone-temperature correlation when interpreting crop-ozone or crop-temperature relationships, or the spatial variability of crop-to-ozone sensitivity arising from varietal and environmental differences, leading to potential biases in their estimated crop losses. Here we develop an empirical model, called the partial derivative-linear regression (PDLR) model, to estimate the spatial variations in the sensitivities of wheat, maize and soybean yields to ozone exposures and temperature extremes in the US and Europe using a composite of multidecadal datasets, fully correcting for ozone-temperature covariation. We find generally larger and more spatially varying sensitivities of all three crops to ozone exposures than are implied by experimentally derived concentration-response functions used in most previous studies. Stronger ozone tolerance is found in regions with high ozone levels and high consumptive crop water use, reflecting the existence of spatial adaptation and effect of water constraints. The spatially varying sensitivities to temperature extremes also indicate stronger heat tolerance in crops grown in warmer regions. The spatial adaptation of crops to ozone and temperature we find can serve as a surrogate for future adaptation. Using the PDLR-derived sensitivities and 2000-2050 ozone and temperature projections by the Community Earth System Model, we estimate that future warming and unmitigated ozone pollution can combine to cause an average decline in US wheat, maize and soybean production by 13%, 43% and 28%, respectively, and a smaller decline for European crops. Aggressive ozone regulation is shown to offset such decline to various extents, especially for wheat. Our findings demonstrate the importance of considering ozone regulation

  9. Mutation D816V alters the internal structure and dynamics of c-KIT receptor cytoplasmic region: implications for dimerization and activation mechanisms.

    Directory of Open Access Journals (Sweden)

    Elodie Laine

    2011-06-01

    Full Text Available The type III receptor tyrosine kinase (RTK KIT plays a crucial role in the transmission of cellular signals through phosphorylation events that are associated with a switching of the protein conformation between inactive and active states. D816V KIT mutation is associated with various pathologies including mastocytosis and cancers. D816V-mutated KIT is constitutively active, and resistant to treatment with the anti-cancer drug Imatinib. To elucidate the activating molecular mechanism of this mutation, we applied a multi-approach procedure combining molecular dynamics (MD simulations, normal modes analysis (NMA and binding site prediction. Multiple 50-ns MD simulations of wild-type KIT and its mutant D816V were recorded using the inactive auto-inhibited structure of the protein, characteristic of type III RTKs. Computed free energy differences enabled us to quantify the impact of D816V on protein stability in the inactive state. We evidenced a local structural alteration of the activation loop (A-loop upon mutation, and a long-range structural re-organization of the juxta-membrane region (JMR followed by a weakening of the interaction network with the kinase domain. A thorough normal mode analysis of several MD conformations led to a plausible molecular rationale to propose that JMR is able to depart its auto-inhibitory position more easily in the mutant than in wild-type KIT and is thus able to promote kinase mutant dimerization without the need for extra-cellular ligand binding. Pocket detection at the surface of NMA-displaced conformations finally revealed that detachment of JMR from the kinase domain in the mutant was sufficient to open an access to the catalytic and substrate binding sites.

  10. 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.

  11. 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.

  12. 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.

  13. Detection of high frequency of mutations in a breast and/or ovarian cancer cohort: implications of embracing a multi-gene panel in molecular diagnosis in India.

    Science.gov (United States)

    Mannan, Ashraf U; Singh, Jaya; Lakshmikeshava, Ravikiran; Thota, Nishita; Singh, Suhasini; Sowmya, T S; Mishra, Avshesh; Sinha, Aditi; Deshwal, Shivani; Soni, Megha R; Chandrasekar, Anbukayalvizhi; Ramesh, Bhargavi; Ramamurthy, Bharat; Padhi, Shila; Manek, Payal; Ramalingam, Ravi; Kapoor, Suman; Ghosh, Mithua; Sankaran, Satish; Ghosh, Arunabha; Veeramachaneni, Vamsi; Ramamoorthy, Preveen; Hariharan, Ramesh; Subramanian, Kalyanasundaram

    2016-06-01

    Breast and/or ovarian cancer (BOC) are among the most frequently diagnosed forms of hereditary cancers and leading cause of death in India. This emphasizes on the need for a cost-effective method for early detection of these cancers. We sequenced 141 unrelated patients and families with BOC using the TruSight Cancer panel, which includes 13 genes strongly associated with risk of inherited BOC. Multi-gene sequencing was done on the Illumina MiSeq platform. Genetic variations were identified using the Strand NGS software and interpreted using the StrandOmics platform. We were able to detect pathogenic mutations in 51 (36.2%) cases, out of which 19 were novel mutations. When we considered familial breast cancer cases only, the detection rate increased to 52%. When cases were stratified based on age of diagnosis into three categories, ⩽40 years, 40-50 years and >50 years, the detection rates were higher in the first two categories (44.4% and 53.4%, respectively) as compared with the third category, in which it was 26.9%. Our study suggests that next-generation sequencing-based multi-gene panels increase the sensitivity of mutation detection and help in identifying patients with a high risk of developing cancer as compared with sequential tests of individual genes.

  14. The landscape of cancer genes and mutational processes in breast cancer

    NARCIS (Netherlands)

    Stephens, Philip J.; Tarpey, Patrick S.; Davies, Helen; van Loo, Peter; Greenman, Chris; Wedge, David C.; Nik-Zainal, Serena; Martin, Sancha; Varela, Ignacio; Bignell, Graham R.; Yates, Lucy R.; Papaemmanuil, Elli; Beare, David; Butler, Adam; Cheverton, Angela; Gamble, John; Hinton, Jonathan; Jia, Mingming; Jayakumar, Alagu; Jones, David; Latimer, Calli; Lau, King Wai; McLaren, Stuart; McBride, David J.; Menzies, Andrew; Mudie, Laura; Raine, Keiran; Rad, Roland; Chapman, Michael Spencer; Teague, Jon; Easton, Douglas; Langerød, Anita; Lee, Ming Ta Michael; Shen, Chen-Yang; tee, Benita Tan Kiat; Huimin, Bernice Wong; Broeks, Annegien; Vargas, Ana Cristina; Turashvili, Gulisa; Martens, John; Fatima, Aquila; Miron, Penelope; Chin, Suet-Feung; Thomas, Gilles; Boyault, Sandrine; Mariani, Odette; Lakhani, Sunil R.; van de Vijver, Marc; van 't Veer, Laura; Foekens, John

    2012-01-01

    All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis(1), and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast

  15. Molecular evolution of the odorant and gustatory receptor genes in lepidopteran insects: implications for their adaptation and speciation.

    Science.gov (United States)

    Engsontia, Patamarerk; Sangket, Unitsa; Chotigeat, Wilaiwan; Satasook, Chutamas

    2014-08-01

    Lepidoptera (comprised of butterflies and moths) is one of the largest groups of insects, including more than 160,000 described species. Chemoreception plays important roles in the adaptation of these species to a wide range of niches, e.g., plant hosts, egg-laying sites, and mates. This study investigated the molecular evolution of the lepidopteran odorant (Or) and gustatory receptor (Gr) genes using recently identified genes from Bombyx mori, Danaus plexippus, Heliconius melpomene, Plutella xylostella, Heliothis virescens, Manduca sexta, Cydia pomonella, and Spodoptera littoralis. A limited number of cases of large lineage-specific gene expansion are observed (except in the P. xylostella lineage), possibly due to selection against tandem gene duplication. There has been strong purifying selection during the evolution of both lepidopteran odorant and gustatory genes, as shown by the low ω values estimated through CodeML analysis, ranging from 0.0093 to 0.3926. However, purifying selection has been relaxed on some amino acid sites in these receptors, leading to sequence divergence, which is a precursor of positive selection on these sequences. Signatures of positive selection were detected only in a few loci from the lineage-specific analysis. Estimation of gene gains and losses suggests that the common ancestor of the Lepidoptera had fewer Or genes compared to extant species and an even more reduced number of Gr genes, particularly within the bitter receptor clade. Multiple gene gains and a few gene losses occurred during the evolution of Lepidoptera. Gene family expansion may be associated with the adaptation of lepidopteran species to plant hosts, especially after angiosperm radiation. Phylogenetic analysis of the moth sex pheromone receptor genes suggested that chromosomal translocations have occurred several times. New sex pheromone receptors have arisen through tandem gene duplication. Positive selection was detected at some amino acid sites predicted to be

  16. 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.

  17. 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.

  18. Kinetic Stability of Proteins in Beans and Peas: Implications for Protein Digestibility, Seed Germination, and Plant Adaptation.

    Science.gov (United States)

    Xia, Ke; Pittelli, Sandy; Church, Jennifer; Colón, Wilfredo

    2016-10-12

    Kinetically stable proteins (KSPs) are resistant to the denaturing detergent sodium dodecyl sulfate (SDS). Such resilience makes KSPs resistant to proteolytic degradation and may have arisen in nature as a mechanism for organismal adaptation and survival against harsh conditions. Legumes are well-known for possessing degradation-resistant proteins that often diminish their nutritional value. Here we applied diagonal two-dimensional (D2D) SDS-polyacrylamide gel electrophoresis (PAGE), a method that allows for the proteomics-level identification of KSPs, to a group of 12 legumes (mostly beans and peas) of agricultural and nutritional importance. Our proteomics results show beans that are more difficult to digest, such as soybean, lima beans, and various common beans, have high contents of KSPs. In contrast, mung bean, red lentil, and various peas that are highly digestible contain low amounts of KSPs. Identified proteins with high kinetic stability are associated with warm-season beans, which germinate at higher temperatures. In contrast, peas and red lentil, which are cool-season legumes, contain low levels of KSPs. Thus, our results show protein kinetic stability is an important factor in the digestibility of legume proteins and may relate to nutrition efficiency, timing of seed germination, and legume resistance to biotic stressors. Furthermore, we show D2D SDS-PAGE is a powerful method that could be applied for determining the abundance and identity of KSPs in engineered and wild legumes and for advancing basic research and associated applications.

  19. 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

    2017-06-01

    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 differences were found between prompts within the prompt categories, suggesting item feature effects. However, the most coherent pattern was found within the plant category as patterns differed for the mechanistic proximate (MP) reasoning category only. Patterns also differed highly significantly between the prompt categories, with patterns for teleology, MP, mechanistic ultimate and don't know categories similar for plants and other animals but different for the human category. Both urban and rural students recognise commonalities in causality between the three prompt categories, in that their preferences for causal explanations were similar across four reasoning categories. The rural students, however, were more likely than their urban counterparts to give multiple causal explanations in the span of a single response and less likely to attribute causal agency to God. Two factors, religious belief and language, for all the students; and one factor, ecological closeness to nature, for rural students were suspected to have produced these patterns.

  20. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus

    Science.gov (United States)

    Graham, Deborah S Cunninghame; Pinder, Christopher L; Tombleson, Philip; Behrens, Timothy W; Martín, Javier; Fairfax, Benjamin P; Knight, Julian C; Chen, Lingyan; Replogle, Joseph; Syvänen, Ann-Christine; Rönnblom, Lars; Graham, Robert R; Wither, Joan E; Rioux, John D; Alarcón-Riquelme, Marta E; Vyse, Timothy J

    2015-01-01

    Systemic lupus erythematosus (SLE; OMIM 152700) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry: a new GWAS, meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including 10 novel associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n=16) of transcription factors among SLE susceptibility genes. This supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE. PMID:26502338

  1. 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.

  2. Adaptive hearing in the vocal plainfin midshipman fish: getting in tune for the breeding season and implications for acoustic communication.

    Science.gov (United States)

    Sisneros, Joseph A

    2009-03-01

    The plainfin midshipman fish (Porichthys notatus Girard, 1854) is a vocal species of batrachoidid fish that generates acoustic signals for intraspecific communication during social and reproductive activity and has become a good model for investigating the neural and endocrine mechanisms of vocal-acoustic communication. Reproductively active female plainfin midshipman fish use their auditory sense to detect and locate "singing" males, which produce a multiharmonic advertisement call to attract females for spawning. The seasonal onset of male advertisement calling in the midshipman fish coincides with an increase in the range of frequency sensitivity of the female's inner ear saccule, the main organ of hearing, thus leading to enhanced encoding of the dominant frequency components of male advertisement calls. Non-reproductive females treated with either testosterone or 17β-estradiol exhibit a dramatic increase in the inner ear's frequency sensitivity that mimics the reproductive female's auditory phenotype and leads to an increased detection of the male's advertisement call. This novel form of auditory plasticity provides an adaptable mechanism that enhances coupling between sender and receiver in vocal communication. This review focuses on recent evidence for seasonal reproductive-state and steroid-dependent plasticity of auditory frequency sensitivity in the peripheral auditory system of the midshipman fish. The potential steroid-dependent mechanism(s) that lead to this novel form of auditory and behavioral plasticity are also discussed. © 2009 ISZS, Blackwell Publishing and IOZ/CAS.

  3. 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.

  4. 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

  5. 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

  6. Confocal Adaptive Optics Imaging of Peripapillary Nerve Fiber Bundles: Implications for Glaucomatous Damage Seen on Circumpapillary OCT Scans.

    Science.gov (United States)

    Hood, Donald C; Chen, Monica F; Lee, Dongwon; Epstein, Benjamin; Alhadeff, Paula; Rosen, Richard B; Ritch, Robert; Dubra, Alfredo; Chui, Toco Y P

    2015-04-01

    To improve our understanding of glaucomatous damage as seen on circumpapillary disc scans obtained with frequency-domain optical coherence tomography (fdOCT), fdOCT scans were compared to images of the peripapillary retinal nerve fiber (RNF) bundles obtained with an adaptive optics-scanning light ophthalmoscope (AO-SLO). The AO-SLO images and fdOCT scans were obtained on 6 eyes of 6 patients with deep arcuate defects (5 points ≤-15 db) on 10-2 visual fields. The AO-SLO images were montaged and aligned with the fdOCT images to compare the RNF bundles seen with AO-SLO to the RNF layer thickness measured with fdOCT. All 6 eyes had an abnormally thin (1% confidence limit) RNF layer (RNFL) on fdOCT and abnormal (hyporeflective) regions of RNF bundles on AO-SLO in corresponding regions. However, regions of abnormal, but equal, RNFL thickness on fdOCT scans varied in appearance on AO-SLO images. These regions could be largely devoid of RNF bundles (5 eyes), have abnormal-appearing bundles of lower contrast (6 eyes), or have isolated areas with a few relatively normal-appearing bundles (2 eyes). There also were local variations in reflectivity of the fdOCT RNFL that corresponded to the variations in AO-SLO RNF bundle appearance. Relatively similar 10-2 defects with similar fdOCT RNFL thickness profiles can have very different degrees of RNF bundle damage as seen on fdOCT and AO-SLO. While the results point to limitations of fdOCT RNFL thickness as typically analyzed, they also illustrate the potential for improving fdOCT by attending to variations in local intensity.

  7. Geographic body size variation in the periodical cicadas Magicicada: implications for life cycle divergence and local adaptation.

    Science.gov (United States)

    Koyama, T; Ito, H; Kakishima, S; Yoshimura, J; Cooley, J R; Simon, C; Sota, T

    2015-06-01

    Seven species in three species groups (Decim, Cassini and Decula) of periodical cicadas (Magicicada) occupy a wide latitudinal range in the eastern United States. To clarify how adult body size, a key trait affecting fitness, varies geographically with climate conditions and life cycle, we analysed the relationships of population mean head width to geographic variables (latitude, longitude, altitude), habitat annual mean temperature (AMT), life cycle and species differences. Within species, body size was larger in females than males and decreased with increasing latitude (and decreasing habitat AMT), following the converse Bergmann's rule. For the pair of recently diverged 13- and 17-year species in each group, 13-year cicadas were equal in size or slightly smaller on average than their 17-year counterparts despite their shorter developmental time. This fact suggests that, under the same climatic conditions, 17-year cicadas have lowered growth rates compared to their 13-years counterparts, allowing 13-year cicadas with faster growth rates to achieve body sizes equivalent to those of their 17-year counterparts at the same locations. However, in the Decim group, which includes two 13-year species, the more southerly, anciently diverged 13-year species (Magicicada tredecim) was characterized by a larger body size than the other, more northerly 13- and 17-year species, suggesting that local adaptation in warmer habitats may ultimately lead to evolution of larger body sizes. Our results demonstrate how geographic clines in body size may be maintained in sister species possessing different life cycles. © 2015 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2015 European Society For Evolutionary Biology.

  8. A new look at ichthyosaur long bone microanatomy and histology: implications for their adaptation to an aquatic life.

    Directory of Open Access Journals (Sweden)

    Alexandra Houssaye

    Full Text Available BACKGROUND: Ichthyosaurs are Mesozoic reptiles considered as active swimmers highly adapted to a fully open-marine life. They display a wide range of morphologies illustrating diverse ecological grades. Data concerning their bone microanatomical and histological features are rather limited and suggest that ichthyosaurs display a spongious, "osteoporotic-like" bone inner structure, like extant cetaceans. However, some taxa exhibit peculiar features, suggesting that the analysis of the microanatomical and histological characteristics of various ichthyosaur long bones should match the anatomical diversity and provide information about their diverse locomotor abilities and physiology. METHODOLOGY/PRINCIPAL FINDINGS: The material analyzed for this study essentially consists of mid-diaphyseal transverse sections from stylopod bones of various ichthyosaurs and of a few microtomographic (both conventional and synchrotron data. The present contribution discusses the histological and microanatomical variation observed within ichthyosaurs and the peculiarities of some taxa (Mixosaurus, Pessopteryx. Four microanatomical types are described. If Mixosaurus sections differ from those of the other taxa analyzed, the other microanatomical types, characterized by the relative proportion of compact and loose spongiosa of periosteal and endochondral origin respectively, seem to rather especially illustrate variation along the diaphysis in taxa with similar microanatomical features. Our analysis also reveals that primary bone in all the ichthyosaur taxa sampled (to the possible exception of Mixosaurus is spongy in origin, that cyclical growth is a common pattern among ichthyosaurs, and confirms the previous assumptions of high growth rates in ichthyosaurs. CONCLUSIONS/SIGNIFICANCE: The occurrence of two types of remodelling patterns along the diaphysis, characterized by bone mass decrease and increase respectively is described for the first time. It raises questions

  9. Induced pluripotent stem cells with NOTCH1 gene mutation show impaired differentiation into smooth muscle and endothelial cells: Implications for bicuspid aortic valve-related aortopathy.

    Science.gov (United States)

    Jiao, Jiao; Tian, Weihua; Qiu, Ping; Norton, Elizabeth L; Wang, Michael M; Chen, Y Eugene; Yang, Bo

    2018-03-12

    The NOTCH1 gene mutation has been identified in bicuspid aortic valve patients. We developed an in vitro model with human induced pluripotent stem cells (iPSCs) to evaluate the role of NOTCH1 in smooth muscle and endothelial cell (EC) differentiation. The iPSCs were derived from a patient with a normal tricuspid aortic valve and aorta. The NOTCH1 gene was targeted in iPSCs with the Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9 nuclease (Cas9) system. The NOTCH1 -/- (NOTCH1 homozygous knockout) and isogenic control iPSCs (wild type) were differentiated into neural crest stem cells (NCSCs) and into cardiovascular progenitor cells (CVPCs). The NCSCs were differentiated into smooth muscle cells (SMCs). The CVPCs were differentiated into ECs. The differentiations of SMCs and ECs were compared between NOTCH1 -/- and wild type cells. The expression of NCSC markers (SRY-related HMG-box 10 and transcription factor AP-2 alpha) was significantly lower in NOTCH1 -/- NCSCs than in wild type NCSCs. The SMCs derived from NOTCH1 -/- NCSCs showed immature morphology with smaller size and decreased expression of all SMC-specific contractile proteins. In NOTCH1 -/- CVPCs, the expression of ISL1, NKX2.5, and MYOCD was significantly lower than that in isogenic control CVPCs, indicating impaired differentiation from iPSCs to CVPCs. The NOTCH1 -/- ECs derived from CVPCs showed significantly lower expression of cluster of differentiation 105 and cluster of differentiation 31 mRNA and protein, indicating a defective differentiation process. NOTCH1 is critical in SMC and EC differentiation of iPSCs through NCSCs and CVPCs, respectively. NOTCH1 gene mutations might potentially contribute to the development of thoracic aortic aneurysms by affecting SMC differentiation in some patients with bicuspid aortic valve. Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

  10. 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

  11. Screening for calreticulin mutations in a cohort of patients suspected ...

    African Journals Online (AJOL)

    Of the 36 types of insertions and deletions identified, type 1 (a. 52-base pair deletion) and type 2 (a 5-base pair insertion) mutations account for >80% of CALR mutations.[7] Phenotypic differences between type 1 and type 2 carriers have been implicated. [3] All recurrent mutations cause a frameshift in the region encoding.

  12. Climate change mitigation through adaptation

    NARCIS (Netherlands)

    Hof, Anouschka R.; Dymond, Caren C.; Mladenoff, David J.

    2017-01-01

    Climate change is projected to have negative implications for forest ecosystems and their dependent communities and industries. Adaptation studies of forestry practices have focused on maintaining the provisioning of ecosystem services; however, those practices may have implications for climate

  13. 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

  14. Mutation breeding in soybean

    International Nuclear Information System (INIS)

    Baradjanegara, A.A.

    1983-01-01

    In Indonesia, soybean is one of the important crop after rice. It is generally cultivated in the lowlands and rarely in the highlands. Seeds of soybean variety ORBA were treated with various doses of fast neutrons, gamma rays, EMS and NaN 3 with the aims of studying the mutagen effects in M-1 and M-2 generations and also to select mutants adapted to highland conditions. D-50 doses for gamma rays, fast neutrons and EMS were around 23 krad, 2,300 rad, 0.3%, respectively. Much higher chlorophyll mutation frequency was observed in EMS treatment of 0.3%. Seven mutants were shorter and four early mutants matured from 4 to 20 days earlier than the control plants. Two early mutants were quite adaptable in both the low and highlands and produced better yields than the parental material. (author)

  15. 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

  16. Epistasis increases the rate of conditionally neutral substitution in an adapting population.

    Science.gov (United States)

    Draghi, Jeremy A; Parsons, Todd L; Plotkin, Joshua B

    2011-04-01

    Kimura observed that the rate of neutral substitution should equal the neutral mutation rate. This classic result is central to our understanding of molecular evolution, and it continues to influence phylogenetics, genomics, and the interpretation of evolution experiments. By demonstrating that neutral mutations substitute at a rate independent of population size and selection at linked sites, Kimura provided an influential justification for the idea of a molecular clock and emphasized the importance of genetic drift in shaping molecular evolution. But when epistasis among sites is common, as numerous empirical studies suggest, do neutral mutations substitute according to Kimura's expectation? Here we study simulated, asexual populations of RNA molecules, and we observe that conditionally neutral mutations--i.e., mutations that do not alter the fitness of the individual in which they arise, but that may alter the fitness effects of subsequent mutations--substitute much more often than expected while a population is adapting. We quantify these effects using a simple population-genetic model that elucidates how the substitution rate at conditionally neutral sites depends on the population size, mutation rate, strength of selection, and prevalence of epistasis. We discuss the implications of these results for our understanding of the molecular clock, and for the interpretation of molecular variation in laboratory and natural populations.

  17. 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.

  18. 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.

    Directory of Open Access Journals (Sweden)

    Di Feng

    Full Text Available 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.

  19. 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. © 2013.

  20. Real-time resolution of point mutations that cause phenovariance in mice

    Science.gov (United States)

    Wang, Tao; Zhan, Xiaowei; Bu, Chun-Hui; Lyon, Stephen; Pratt, David; Hildebrand, Sara; Choi, Jin Huk; Zhang, Zhao; Zeng, Ming; Wang, Kuan-wen; Turer, Emre; Chen, Zhe; Zhang, Duanwu; Yue, Tao; Wang, Ying; Shi, Hexin; Wang, Jianhui; Sun, Lei; SoRelle, Jeff; McAlpine, William; Hutchins, Noelle; Zhan, Xiaoming; Fina, Maggy; Gobert, Rochelle; Quan, Jiexia; Kreutzer, McKensie; Arnett, Stephanie; Hawkins, Kimberly; Leach, Ashley; Tate, Christopher; Daniel, Chad; Reyna, Carlos; Prince, Lauren; Davis, Sheila; Purrington, Joel; Bearden, Rick; Weatherly, Jennifer; White, Danielle; Russell, Jamie; Sun, Qihua; Tang, Miao; Li, Xiaohong; Scott, Lindsay; Moresco, Eva Marie Y.; McInerney, Gerald M.; Karlsson Hedestam, Gunilla B.; Xie, Yang; Beutler, Bruce

    2015-01-01

    With the wide availability of massively parallel sequencing technologies, genetic mapping has become the rate limiting step in mammalian forward genetics. Here we introduce a method for real-time identification of N-ethyl-N-nitrosourea-induced mutations that cause phenotypes in mice. All mutations are identified by whole exome G1 progenitor sequencing and their zygosity is established in G2/G3 mice before phenotypic assessment. Quantitative and qualitative traits, including lethal effects, in single or multiple combined pedigrees are then analyzed with Linkage Analyzer, a software program that detects significant linkage between individual mutations and aberrant phenotypic scores and presents processed data as Manhattan plots. As multiple alleles of genes are acquired through mutagenesis, pooled “superpedigrees” are created to analyze the effects. Our method is distinguished from conventional forward genetic methods because it permits (1) unbiased declaration of mappable phenotypes, including those that are incompletely penetrant (2), automated identification of causative mutations concurrent with phenotypic screening, without the need to outcross mutant mice to another strain and backcross them, and (3) exclusion of genes not involved in phenotypes of interest. We validated our approach and Linkage Analyzer for the identification of 47 mutations in 45 previously known genes causative for adaptive immune phenotypes; our analysis also implicated 474 genes not previously associated with immune function. The method described here permits forward genetic analysis in mice, limited only by the rates of mutant production and screening. PMID:25605905

  1. Multiple origins of knockdown resistance mutations in the Afrotropical mosquito vector Anopheles gambiae.

    Directory of Open Access Journals (Sweden)

    João Pinto

    2007-11-01

    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.

  2. Evolutionary invasion and escape in the presence of deleterious mutations.

    Directory of Open Access Journals (Sweden)

    Claude Loverdo

    Full Text Available Replicators such as parasites invading a new host species, species invading a new ecological niche, or cancer cells invading a new tissue often must mutate to adapt to a new environment. It is often argued that a higher mutation rate will favor evolutionary invasion and escape from extinction. However, most mutations are deleterious, and even lethal. We study the probability that the lineage will survive and invade successfully as a function of the mutation rate when both the initial strain and an adaptive mutant strain are threatened by lethal mutations. We show that mutations are beneficial, i.e. a non-zero mutation rate increases survival compared to the limit of no mutations, if in the no-mutation limit the survival probability of the initial strain is smaller than the average survival probability of the strains which are one mutation away. The mutation rate that maximizes survival depends on the characteristics of both the initial strain and the adaptive mutant, but if one strain is closer to the threshold governing survival then its properties will have greater influence. These conclusions are robust for more realistic or mechanistic depictions of the fitness landscapes such as a more detailed viral life history, or non-lethal deleterious mutations.

  3. 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 ...

  4. 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

    2017-01-24

    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.

  5. How Large Asexual Populations Adapt

    Science.gov (United States)

    Desai, Michael

    2007-03-01

    We often think of beneficial mutations as being rare, and of adaptation as a sequence of selected substitutions: a beneficial mutation occurs, spreads through a population in a selective sweep, then later another beneficial mutation occurs, and so on. This simple picture is the basis for much of our intuition about adaptive evolution, and underlies a number of practical techniques for analyzing sequence data. Yet many large and mostly asexual populations -- including a wide variety of unicellular organisms and viruses -- live in a very different world. In these populations, beneficial mutations are common, and frequently interfere or cooperate with one another as they all attempt to sweep simultaneously. This radically changes the way these populations adapt: rather than an orderly sequence of selective sweeps, evolution is a constant swarm of competing and interfering mutations. I will describe some aspects of these dynamics, including why large asexual populations cannot evolve very quickly and the character of the diversity they maintain. I will explain how this changes our expectations of sequence data, how sex can help a population adapt, and the potential role of ``mutator'' phenotypes with abnormally high mutation rates. Finally, I will discuss comparisons of these predictions with evolution experiments in laboratory yeast populations.

  6. Cone structure in patients with usher syndrome type III and mutations in the Clarin 1 gene.

    Science.gov (United States)

    Ratnam, Kavitha; Västinsalo, Hanna; Roorda, Austin; Sankila, Eeva-Marja K; Duncan, Jacque L

    2013-01-01

    To study macular structure and function in patients with Usher syndrome type III (USH3) caused by mutations in the Clarin 1 gene (CLRN1). High-resolution macular images were obtained by adaptive optics scanning laser ophthalmoscopy and spectral domain optical coherence tomography in 3 patients with USH3 and were compared with those of age-similar control subjects. Vision function measures included best-corrected visual acuity, kinetic and static perimetry, and full-field electroretinography. Coding regions of the CLRN1 gene were sequenced. CLRN1 mutations were present in all the patients; a 20-year-old man showed compound heterozygous mutations (p.N48K and p.S188X), and 2 unrelated women aged 25 and 32 years had homozygous mutations (p.N48K). Best-corrected visual acuity ranged from 20/16 to 20/40, with scotomas beginning at 3° eccentricity. The inner segment-outer segment junction or the inner segment ellipsoid band was disrupted within 1° to 4° of the fovea, and the foveal inner and outer segment layers were significantly thinner than normal. Cones near the fovea in patients 1 and 2 showed normal spacing, and the preserved region ended abruptly. Retinal pigment epithelial cells were visible in patient 3 where cones were lost. Cones were observed centrally but not in regions with scotomas, and retinal pigment epithelial cells were visible in regions without cones in patients with CLRN1 mutations. High-resolution measures of retinal structure demonstrate patterns of cone loss associated with CLRN1 mutations. These findings provide insight into the effect of CLRN1 mutations on macular cone structure, which has implications for the development of treatments for USH3. clinicaltrials.gov Identifier: NCT00254605.

  7. Cone Structure in Patients With Usher Syndrome Type III and Mutations in the Clarin 1 Gene

    Science.gov (United States)

    Ratnam, Kavitha; Västinsalo, Hanna; Roorda, Austin; Sankila, Eeva-Marja K.; Duncan, Jacque L.

    2015-01-01

    Objective To study macular structure and function in patients with Usher syndrome type III (USH3) caused by mutations in the Clarin 1 gene (CLRN1). Methods High-resolution macular images were obtained by adaptive optics scanning laser ophthalmoscopy and spectral domain optical coherence tomography in 3 patients with USH3 and were compared with those of age-similar control subjects. Vision function measures included best-corrected visual acuity, kinetic and static perimetry, and full-field electroretinography. Coding regions of the CLRN1 gene were sequenced. Results CLRN1 mutations were present in all the patients; a 20-year-old man showed compound heterozygous mutations (p.N48K and p.S188X), and 2 unrelated women aged 25 and 32 years had homozygous mutations (p.N48K). Best-corrected visual acuity ranged from 20/16 to 20/40, with scotomas beginning at 3° eccentricity. The inner segment-outer segment junction or the inner segment ellipsoid band was disrupted within 1° to 4° of the fovea, and the foveal inner and outer segment layers were significantly thinner than normal. Cones near the fovea in patients 1 and 2 showed normal spacing, and the preserved region ended abruptly. Retinal pigment epithelial cells were visible in patient 3 where cones were lost. Conclusions Cones were observed centrally but not in regions with scotomas, and retinal pigment epithelial cells were visible in regions without cones in patients with CLRN1 mutations. High-resolution measures of retinal structure demonstrate patterns of cone loss associated with CLRN1 mutations. Clinical Relevance These findings provide insight into the effect of CLRN1 mutations on macular cone structure, which has implications for the development of treatments for USH3. Trial Registration clinicaltrials.gov Identifier: NCT00254605 PMID:22964989

  8. 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

  9. 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.

  10. POLE somatic mutations in advanced colorectal cancer.

    Science.gov (United States)

    Guerra, Joana; Pinto, Carla; Pinto, Diana; Pinheiro, Manuela; Silva, Romina; Peixoto, Ana; Rocha, Patrícia; Veiga, Isabel; Santos, Catarina; Santos, Rui; Cabreira, Verónica; Lopes, Paula; Henrique, Rui; Teixeira, Manuel R

    2017-12-01

    Despite all the knowledge already gathered, the picture of somatic genetic changes in colorectal tumorigenesis is far from complete. Recently, germline and somatic mutations in the exonuclease domain of polymerase epsilon, catalytic subunit (POLE) gene have been reported in a small subset of microsatellite-stable and hypermutated colorectal carcinomas (CRCs), affecting the proofreading activity of the enzyme and leading to misincorporation of bases during DNA replication. To evaluate the role of POLE mutations in colorectal carcinogenesis, namely in advanced CRC, we searched for somatic mutations by Sanger sequencing in tumor DNA samples from 307 cases. Microsatellite instability and mutation analyses of a panel of oncogenes were performed in the tumors harboring POLE mutations. Three heterozygous mutations were found in two tumors, the c.857C>G, p.Pro286Arg, the c.901G>A, p.Asp301Asn, and the c.1376C>T, p.Ser459Phe. Of the POLE-mutated CRCs, one tumor was microsatellite-stable and the other had low microsatellite instability, whereas KRAS and PIK3CA mutations were found in one tumor each. We conclude that POLE somatic mutations exist but are rare in advanced CRC, with further larger studies being necessary to evaluate its biological and clinical implications. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  11. Mutation breeding in chickpea

    International Nuclear Information System (INIS)

    Sagel, Z.; Tutluer, M. I.; Peskircioglu, H.; Kantoglu, Y.; Kunter, B.

    2009-01-01

    Chickpea is an important food legume in Turkey. Turkey is one of the most important gene centers in the world for legumes. Realizing the potential of induced mutations, a mutation breeding programme was initiated at the Nuclear Agriculture Section of the Saraykoy Nuclear Research and Training Center in 1994. The purpose of the study was to obtain high yielding chickpea mutants with large seeds, good cooking quality and high protein content. Beside this some characters such as higher adaptation ability, tolerant to cold and drought, increased machinery harvest type, higher yield, resistant to diseases especially to antracnose and pest were investigated too. Parent varieties were ILC-482, AK-7114 and AKCIN-91 had been used in these experiments. The irradiation doses were 0 (control), 50, 100, 150, 200, 250, 300, 350 and 400 Gy for field experiments, respectively. As a result of these experiments, two promising mutant lines were chosen and given to the Seed Registration and Certification Center for official registration These two promising mutants were tested at five different locations of Turkey, in 2004 and 2005 years. After 2 years of registration experiments one of outstanding mutants was officially released as mutant chickpea variety under the name TAEK-SAGEL, in 2006. Some basic characteristics of this mutant are; earliness (95-100 day), high yield capacity (180-220 kg/da), high seed protein (22-25 %), first pot height (20-25 cm), 100 seeds weight (42-48 g), cooking time (35-40 min) and resistance to Ascochyta blight.

  12. Survival of mutations arising during invasions.

    Science.gov (United States)

    Miller, Judith R

    2010-03-01

    When a neutral mutation arises in an invading population, it quickly either dies out or 'surfs', i.e. it comes to occupy almost all the habitat available at its time of origin. Beneficial mutations can also surf, as can deleterious mutations over finite time spans. We develop descriptive statistical models that quantify the relationship between the probability that a mutation will surf and demographic parameters for a cellular automaton model of surfing. We also provide a simple analytic model that performs well at predicting the probability of surfing for neutral and beneficial mutations in one dimension. The results suggest that factors - possibly including even abiotic factors - that promote invasion success may also increase the probability of surfing and associated adaptive genetic change, conditioned on such success.

  13. Molecular Clock of Neutral Mutations in a Fitness-Increasing Evolutionary Process

    OpenAIRE

    Kishimoto, Toshihiko; Ying, Bei-Wen; Tsuru, Saburo; Iijima, Leo; Suzuki, Shingo; Hashimoto, Tomomi; Oyake, Ayana; Kobayashi, Hisaka; Someya, Yuki; Narisawa, Dai; Yomo, Tetsuya

    2015-01-01

    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 e...

  14. Molecular mechanisms of induced-mutations

    International Nuclear Information System (INIS)

    Kato, Takeshi

    1985-01-01

    The outcome of recent studies on mechanisms of induced-mutations is outlined with particular emphasis on the dependence of recA gene function in Escherichia coli. Genes involved in spontaneous mutation and x-ray- and chemical-induced mutation and genes involved in adaptive response are presented. As for SOS mutagenesis, SOS-induced regulation mechanisms and mutagenic routes are described. Furthermore, specificity of mutagens themselves are discussed in relation to mechanisms of base substitution, frameshift, and deletion mutagenesis. (Namekawa, K.)

  15. Mutation breeding in chickpea

    International Nuclear Information System (INIS)

    2009-01-01

    Chickpea is an important food legume in Turkey. Turkey is one of the most important gene centers in the world for legumes. The most widely known characteristic of chickpea is that it is an important vegetable protein source used in human and animal nutrition. However, the dry grains of chickpea, has 2-3 times more protein than our traditional food of wheat. In addition, cheakpea is also energy source because of its high carbohydrate content. It is very rich in some vitamin and mineral basis. In the plant breeding, mutation induction has become an effective way of supplementing existing germplasm and improving cultivars. Many successful examples of mutation induction have proved that mutation breeding is an effective and important approach to food legume improvement. The induced mutation technique in chickpea has proved successful and good results have been attained. Realizing the potential of induced mutations, a mutation breeding programme was initiated at the Nuclear Agriculture Section of the Saraykoey Nuclear Research and Training Center in 1994. The purpose of the study was to obtain high yielding chickpea mutants with large seeds, good cooking quality and high protein content. Beside this some characters such as higher adaptation ability, tolerant to cold and drought, increased machinery harvest type, higher yield, resistant to diseases especially to antracnose and pest were investigated too. Parents varieties were ILC-482, AK-7114 and AKCIN-91 (9 % seed moisture content and germination percentage 98 %) in these experiments. The irradiation doses were 0 (control), 50, 100, 150, 200, 250, 300, 350, 400, 500 ve 600 Gy for greenhouse experiments and 0 (control), 50, 100, 150, 200, 250, 300, 350 ve 400 Gy for field experiments, respectively. One thousand seeds for per treatment were sown in the field for the M 1 . At maturity, 3500 single plants were harvested and 20 seeds were taken from each M 1 plant and planted in the following season. During plant growth

  16. 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.

  17. 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.

  18. 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.

  19. The Formation of Rational and Irrational Behaviors in Risky Investment Decision Making: Laboratory Experiment of Coping Theory Implication in Investors' Adaptation Model

    OpenAIRE

    Wendy Wendy; Marwan Asri; Jogiyanto Hartono

    2012-01-01

    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-...

  20. Prognostic implications of c-Ki-ras2 mutations in patients with advanced colorectal cancer treated with 5-fluorouracil and interferon: a study of the eastern cooperative oncology group (EST 2292)

    Science.gov (United States)

    Wadler, S; Bajaj, R; Neuberg, D; Agarwal, V; Haynes, H; Benson, A B

    1997-01-01

    Mutations in c-Ki-ras2 (ras) occur in about 40% of patients with colorectal cancers and occur early in the pathogenesis of this disease. To evaluate the prognostic value of mutations in ras, the Eastern Cooperative Oncology Group (ECOG) conducted a retrospective study (EST 2292) to determine the frequency of mutations in patients with advanced colorectal cancer, and to determine whether ras mutations were associated with altered response to therapy and survival. Patients were enrolled from four studies: P-Z289, an ECOG phase II trial of 5-fluorouracil (5-FU) and interferon (IFN) in patients with advanced colorectal cancer; P-Z991, an ECOG phase I trial of 5-FU and IFN in patients with advanced malignancies; and two trials from the Albert Einstein College of Medicine in patients with advanced colorectal cancer treated with 5-FU and either IFN-alpha or IFN-beta. All patients had advanced colorectal carcinoma and had sufficient histologic material available for analysis for the presence and type of ras, using polymerase chain reaction and dot-blot analysis with sets of probes sufficient to detect all the common mutations of ras at codons 12, 13, and 61. Seventy-two patients were enrolled in this trial. Mutations in ras were detected in 25 (35%), including 17 (23%) in codon 12, four (6%) in codon 13, and four (6%) in codon 61. There was no correlation between the presence of a ras mutation and age, sex, Dukes' stage, histology, or tumor markers. Thirty-one of 72 patients (43%) responded to therapy with 5-FU and IFN, and 10 of 31 responders (32%) and 15 of 41 nonresponders (37%) had mutations in ras. There was no difference in response rates or overall survival between the groups with and without ras mutations. It is unlikely that ras mutations will have significant prognostic value for either response to therapy or survival in patients with colorectal carcinomas treated with 5-FU and IFN.

  1. High incidence of GJB2 gene mutations among assortatively mating ...

    Indian Academy of Sciences (India)

    High incidence of GJB2 gene mutations among assortatively mating hearing impaired families in Kerala: future implications. Amritkumar Pavithra, Justin Margret Jeffrey, Jayasankaran Chandru, Arabandi Ramesh and C. R. Srikumari Srisailapathy. J. Genet. 93, 207–213. Table 1. Consolidated table of GJB2 mutation status ...

  2. 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.

  3. Polyploidy can drive rapid adaptation in yeast

    Science.gov (United States)

    Selmecki, Anna M.; Maruvka, Yosef E.; Richmond, Phillip A.; Guillet, Marie; Shoresh, Noam; Sorenson, Amber L.; de, Subhajyoti; Kishony, Roy; Michor, Franziska; Dowell, Robin; Pellman, David

    2015-03-01

    Polyploidy is observed across the tree of life, yet its influence on evolution remains incompletely understood. Polyploidy, usually whole-genome duplication, is proposed to alter the rate of evolutionary adaptation. This could occur through complex effects on the frequency or fitness of beneficial mutations. For example, in diverse cell types and organisms, immediately after a whole-genome duplication, newly formed polyploids missegregate chromosomes and undergo genetic instability. The instability following whole-genome duplications is thought to provide adaptive mutations in microorganisms and can promote tumorigenesis in mammalian cells. Polyploidy may also affect adaptation independently of beneficial mutations through ploidy-specific changes in cell physiology. Here we perform in vitro evolution experiments to test directly whether polyploidy can accelerate evolutionary adaptation. Compared with haploids and diploids, tetraploids undergo significantly faster adaptation. Mathematical modelling suggests that rapid adaptation of tetraploids is driven by higher rates of beneficial mutations with stronger fitness effects, which is supported by whole-genome sequencing and phenotypic analyses of evolved clones. Chromosome aneuploidy, concerted chromosome loss, and point mutations all provide large fitness gains. We identify several mutations whose beneficial effects are manifest specifically in the tetraploid strains. Together, these results provide direct quantitative evidence that in some environments polyploidy can accelerate evolutionary adaptation.

  4. Exploring the common molecular basis for the universal DNA mutation bias: Revival of Loewdin mutation model

    International Nuclear Information System (INIS)

    Fu, Liang-Yu; Wang, Guang-Zhong; Ma, Bin-Guang; Zhang, Hong-Yu

    2011-01-01

    Highlights: → There exists a universal G:C → A:T mutation bias in three domains of life. → This universal mutation bias has not been sufficiently explained. → A DNA mutation model proposed by Loewdin 40 years ago offers a common explanation. -- Abstract: Recently, numerous genome analyses revealed the existence of a universal G:C → A:T mutation bias in bacteria, fungi, plants and animals. To explore the molecular basis for this mutation bias, we examined the three well-known DNA mutation models, i.e., oxidative damage model, UV-radiation damage model and CpG hypermutation model. It was revealed that these models cannot provide a sufficient explanation to the universal mutation bias. Therefore, we resorted to a DNA mutation model proposed by Loewdin 40 years ago, which was based on inter-base double proton transfers (DPT). Since DPT is a fundamental and spontaneous chemical process and occurs much more frequently within GC pairs than AT pairs, Loewdin model offers a common explanation for the observed universal mutation bias and thus has broad biological implications.

  5. Generation of mutation hotspots in ageing bacterial colonies

    DEFF Research Database (Denmark)

    Sekowska, Agnieszka; Wendel, Sofie; Christian Fischer, Emil

    2016-01-01

    : 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...

  6. Acromelic frontonasal dysostosis and ZSWIM6 mutation

    DEFF Research Database (Denmark)

    Twigg, Stephen R F; Ousager, Lilian Bomme; Miller, Kerry A

    2016-01-01

    Acromelic frontonasal dysostosis (AFND) is a distinctive and rare frontonasal malformation that presents in combination with brain and limb abnormalities. A single recurrent heterozygous missense substitution in ZSWIM6, encoding a protein of unknown function, was previously shown to underlie this...... sequencing of DNA isolated from a variety of tissues, which each contain different levels of mutation. This has important implications for genetic counselling....

  7. 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.

  8. Death and population dynamics affect mutation rate estimates and evolvability under stress in bacteria.

    Science.gov (United States)

    Frenoy, Antoine; Bonhoeffer, Sebastian

    2018-05-01

    The stress-induced mutagenesis hypothesis postulates that in response to stress, bacteria increase their genome-wide mutation rate, in turn increasing the chances that a descendant is able to better withstand the stress. This has implications for antibiotic treatment: exposure to subinhibitory doses of antibiotics has been reported to increase bacterial mutation rates and thus probably the rate at which resistance mutations appear and lead to treatment failure. More generally, the hypothesis posits that stress increases evolvability (the ability of a population to generate adaptive genetic diversity) and thus accelerates evolution. Measuring mutation rates under stress, however, is problematic, because existing methods assume there is no death. Yet subinhibitory stress levels may induce a substantial death rate. Death events need to be compensated by extra replication to reach a given population size, thus providing more opportunities to acquire mutations. We show that ignoring death leads to a systematic overestimation of mutation rates under stress. We developed a system based on plasmid segregation that allows us to measure death and division rates simultaneously in bacterial populations. Using this system, we found that a substantial death rate occurs at the tested subinhibitory concentrations previously reported to increase mutation rate. Taking this death rate into account lowers and sometimes removes the signal for stress-induced mutagenesis. Moreover, even when antibiotics increase mutation rate, we show that subinhibitory treatments do not increase genetic diversity and evolvability, again because of effects of the antibiotics on population dynamics. We conclude that antibiotic-induced mutagenesis is overestimated because of death and that understanding evolvability under stress requires accounting for the effects of stress on population dynamics as much as on mutation rate. Our goal here is dual: we show that population dynamics and, in particular, the

  9. Systematic Analysis of Splice-Site-Creating Mutations in Cancer

    Directory of Open Access Journals (Sweden)

    Reyka G. Jayasinghe

    2018-04-01

    Full Text Available Summary: For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for the large-scale discovery of splice-site-creating mutations (SCMs across 8,656 TCGA tumors. We report 1,964 originally mis-annotated mutations having clear evidence of creating alternative splice junctions. TP53 and GATA3 have 26 and 18 SCMs, respectively, and ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function. Notably, we found that neoantigens induced by SCMs are likely several folds more immunogenic compared to missense mutations, exemplified by the recurrent GATA3 SCM. Further, high expression of PD-1 and PD-L1 was observed in tumors with SCMs, suggesting candidates for immune blockade therapy. Our work highlights the importance of integrating DNA and RNA data for understanding the functional and the clinical implications of mutations in human diseases. : Jayasinghe et al. identify nearly 2,000 splice-site-creating mutations (SCMs from over 8,000 tumor samples across 33 cancer types. They provide a more accurate interpretation of previously mis-annotated mutations, highlighting the importance of integrating data types to understand the functional and the clinical implications of splicing mutations in human disease. Keywords: splicing, RNA, mutations of clinical relevance

  10. EGFR and KRAS mutation coexistence in lung adenocarcinomas

    Directory of Open Access Journals (Sweden)

    Vitor Manuel Leitão de Sousa

    2015-04-01

    Full Text Available Lung cancer is one of the most common causes of cancer deaths. The development of EGFR targeted therapies, including monoclonal antibodies and tyrosine kinase inhibitors have generated an interest in the molecular characterization of these tumours. KRAS mutations are associated with resistance to EGFR TKIs. EGFR and KRAS mutations have been considered as mutually exclusive. This paper presents three bronchial-pulmonary carcinomas, two adenocarcinomas and one pleomorphic sarcomatoid carcinoma, harboring EGFR and KRAS mutations. Case 1 corresponded to an adenocarcinoma with EGFR exon 21 mutation (L858R and KRAS codon 12 point mutation (G12V; case 2, a  mucinous adenocarcinoma expressed coexistence of EGFR exon 21 mutation (L858R and KRAS codon 12 point mutation (G12V; and case 3 a sarcomatoid carcinoma with EGFR exon 19 deletion – del 9bp and KRAS codon 12 point mutation (G12C - cysteine. Based on our experience and on the literature, we conclude that EGFR and KRAS mutations can indeed coexist in the same bronchial-pulmonary carcinoma, either in the same histological type or in different patterns. The biological implications of this coexistence are still poorly understood mainly because these cases are not frequent or currently searched. It is therefore necessary to study larger series of cases with the two mutations to better understand the biological, clinical and therapeutic implications.

  11. High frequency of the recurrent c.1310_1313delAAGA BRCA2 mutation in the North-East of Morocco and implication for hereditary breast-ovarian cancer prevention and control.

    Science.gov (United States)

    Laarabi, Fatima-Zahra; Ratbi, Ilham; Elalaoui, Siham Chafai; Mezzouar, Loubna; Doubaj, Yassamine; Bouguenouch, Laila; Ouldim, Karim; Benjaafar, Noureddine; Sefiani, Abdelaziz

    2017-06-02

    To date, a limited number of BRCA1/2 germline mutations have been reported in hereditary breast and/or ovarian cancer in the Moroccan population. Less than 20 different mutations of these two genes have been identified in Moroccan patients, and recently we reported a further BRCA2 mutation (c.1310_1313delAAGA; p.Lys437IlefsX22) in three unrelated patients, all from the North-East of the country. We aimed in this study to evaluate the frequency and geographic distribution of this BRCA2 frameshift mutation, in order to access its use as the first-line BRCA genetic testing strategy for Moroccan patients. We enrolled in this study 122 patients from different regions of Morocco, with suggestive inherited predisposition to breast and ovarian cancers. All subjects gave written informed consent to BRCA1/2 genetic testing. According to available resources of our lab and enrolled families, 51 patients were analyzed by the conventional individual exon-by-exon Sanger sequencing, 23 patients were able to benefit from a BRCA next generation sequencing and a target screening for exon 10 of BRCA2 gene was performed in 48 patients. Overall, and among the 122 patients analyzed for at least the exon 10 of the BRCA2 gene, the c.1310_1313delAAGA frameshift mutation was found in 14 patients. Genealogic investigation revealed that all carriers of this mutation shared the same geographic origin and were descendants of the North-East of Morocco. In this study, we highlighted that c.1310_1313delAAGA mutation of BRCA2 gene is recurrent with high frequency in patients from the North-East region of Morocco. Therefore, we propose to use, in public health strategies, the detection of this mutation as the first-line screening tests in patients with breast and ovarian cancer originated from this region.

  12. The role of oxidative, inflammatory and neuroendocrinological systems during exercise stress in athletes: implications of antioxidant supplementation on physiological adaptation during intensified physical training.

    Science.gov (United States)

    Slattery, Katie; Bentley, David; Coutts, Aaron J

    2015-04-01

    During periods of intensified physical training, reactive oxygen species (ROS) release may exceed the protective capacity of the antioxidant system and lead to dysregulation within the inflammatory and neuroendocrinological systems. Consequently, the efficacy of exogenous antioxidant supplementation to maintain the oxidative balance in states of exercise stress has been widely investigated. The aim of this review was to (1) collate the findings of prior research on the effect of intensive physical training on oxidant-antioxidant balance; (2) summarise the influence of antioxidant supplementation on the reduction-oxidation signalling pathways involved in physiological adaptation; and (3) provide a synopsis on the interactions between the oxidative, inflammatory and neuroendocrinological response to exercise stimuli. Based on prior research, it is evident that ROS are an underlying aetiology in the adaptive process; however, the impact of antioxidant supplementation on physiological adaptation remains unclear. Equivocal results have been reported on the impact of antioxidant supplementation on exercise-induced gene expression. Further research is required to establish whether the interference of antioxidant supplementation consistently observed in animal-based and in vivo research extends to a practical sports setting. Moreover, the varied results reported within the literature may be due to the hormetic response of oxidative, inflammatory and neuroendocrinological systems to an exercise stimulus. The collective findings suggest that intensified physical training places substantial stress on the body, which can manifest as an adaptive or maladaptive physiological response. Additional research is required to determine the efficacy of antioxidant supplementation to minimise exercise-stress during intensive training and promote an adaptive state.

  13. STAT3 mutations correlated with hyper-IgE syndrome lead to ...

    Indian Academy of Sciences (India)

    Of all the causes identified for the disease hyper-immunoglobulinemia E syndrome (HIES), a homozygous mutation in tyrosine kinase2 (TYK2) and heterozygous mutations in STAT3 are implicated the defects in Jak/STAT signalling pathway in the pathogenesis of HIES. Mutations of STAT3 have been frequently clinically ...

  14. Pathoadaptation of a Human Pathogen Through Non-Coding Intergenic Mutations

    DEFF Research Database (Denmark)

    Khademi, Seyed Mohammad Hossein

    in CF adaptation of P. aeruginosa and their expressions are altered by the mutation. It was established that mutations upstream ampR increased tolerance of P. aeruginosa to some β-lactam antibiotics. Mutations in promoter of phuR, encoding receptor of pseudomonas heme uptake system, conferred growth...... advantage in the presence of hemoglobin demonstrating that P. aeruginosa has adapted towards utilization of iron from hemoglobin. Further investigation of phuR promoter mutation revealed pleiotropic effects on expression of many other genes. The pleiotropic effect by this mutation was contingent...

  15. 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.

  16. Mitochondrial mutations in adenoid cystic carcinoma of the salivary glands.

    Directory of Open Access Journals (Sweden)

    Suhail K Mithani

    Full Text Available BACKGROUND: The MitoChip v2.0 resequencing array is an array-based technique allowing for accurate and complete sequencing of the mitochondrial genome. No studies have investigated mitochondrial mutation in salivary gland adenoid cystic carcinomas. METHODOLOGY: The entire mitochondrial genome of 22 salivary gland adenoid cystic carcinomas (ACC of salivary glands and matched leukocyte DNA was sequenced to determine the frequency and distribution of mitochondrial mutations in ACC tumors. PRINCIPAL FINDINGS: Seventeen of 22 ACCs (77% carried mitochondrial mutations, ranging in number from 1 to 37 mutations. A disproportionate number of mutations occurred in the D-loop. Twelve of 17 tumors (70.6% carried mutations resulting in amino acid changes of translated proteins. Nine of 17 tumors (52.9% with a mutation carried an amino acid changing mutation in the nicotinamide adenine dinucleotide dehydrogenase (NADH complex. CONCLUSIONS/SIGNIFICANCE: Mitochondrial mutation is frequent in salivary ACCs. The high incidence of amino acid changing mutations implicates alterations in aerobic respiration in ACC carcinogenesis. D-loop mutations are of unclear significance, but may be associated with alterations in transcription or replication.

  17. N1303K (c.3909C>G) Mutation and Splicing: Implication of Its c.[744-33GATT(6); 869+11C>T] Complex Allele in CFTR Exon 7 Aberrant Splicing

    Science.gov (United States)

    Farhat, Raëd; Puissesseau, Géraldine; El-Seedy, Ayman; Pasquet, Marie-Claude; Adolphe, Catherine; Corbani, Sandra; Megarbané, André; Kitzis, Alain; Ladeveze, Véronique

    2015-01-01

    Cystic Fibrosis is the most common recessive autosomal rare disease found in Caucasians. It is caused by mutations on the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) that encodes a protein located on the apical membrane of epithelial cells. c.3909C>G (p.Asn1303Lys, old nomenclature: N1303K) is one of the most common worldwide mutations. This mutation has been found at high frequencies in the Mediterranean countries with the highest frequency in the Lebanese population. Therefore, on the genetic level, we conducted a complete CFTR gene screening on c.3909C>G Lebanese patients. The complex allele c.[744-33GATT(6); 869+11C>T] was always associated with the c.3909C>G mutation in cis in the Lebanese population. In cellulo splicing studies, realized by hybrid minigene constructs, revealed no impact of the c.3909C>G mutation on the splicing process, whereas the associated complex allele induces minor exon skipping. PMID:26075213

  18. Deletion mutations of bacteriophage

    International Nuclear Information System (INIS)

    Ryo, Yeikou

    1975-01-01

    Resolution of mutation mechanism with structural changes of DNA was discussed through the studies using bacteriophage lambda. One of deletion mutations inductions of phage lambda is the irradiation of ultraviolet ray. It is not clear if the inductions are caused by errors in reparation of ultraviolet-induced damage or by the activation of int gene. Because the effective site of int gene lies within the regions unnecessary for existing, it is considered that int gene is connected to deletion mutations induction. A certain system using prophage complementarity enables to detect deletion mutations at essential hereditary sites and to solve the relations of deletion mutations with other recombination system, DNA reproduction and repairment system. Duplication and multiplication of hereditary elements were discussed. If lambda deletion mutations of the system, which can control recombination, reproduction and repairment of added DNA, are constructed, mutations mechanism with great changes of DNA structure can be solved by phage lambda. (Ichikawa, K.)

  19. Mutation breeding in vegetable crops

    International Nuclear Information System (INIS)

    Yamaguchi, Takashi

    1984-01-01

    Vegetables breed by seeds and vegetative organs. In main vegetables, the differentiation of clopping types, the adoption of monoculture and year-round production and shipment are carried out, adapting to various socio-economic and cultivation conditions. Protected agriculture has advanced mainly for fruit vegetables, and the seeds for sale have become almost hybrid varieties. Reflecting the situation like this, the demand for breeding is diversified and characteristic, and the case of applying mutation breeding seems to be many. The present status of the mutation breeding of vegetables is not yet well under way, but about 40 raised varieties have been published in the world. The characters introduced by induced mutation and irradiation were compact form, harvesting aptitude, the forms and properties of stems and leaves, anti-lodging property, the size, form and uniformity of fruits, male sterility and so on. The radiation sources used were mostly gamma ray or X-ray, but sometimes, combined irradiation was used. As the results obtained in Japan, burdocks as an example of gamma ray irradiation to seeds, tomatoes as an example of inducing the compound resistance against disease injury and lettuces as an example of internal beta irradiation are reported. (Kako, I.)

  20. 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

  1. The Climate Adaptation Frontier

    Energy Technology Data Exchange (ETDEWEB)

    Preston, Benjamin L [ORNL

    2013-01-01

    Climate adaptation has emerged as a mainstream risk management strategy for assisting in maintaining socio-ecological systems within the boundaries of a safe operating space. Yet, there are limits to the ability of systems to adapt. Here, we introduce the concept of an adaptation frontier , which is defined as a socio-ecological system s transitional adaptive operating space between safe and unsafe domains. A number of driving forces are responsible for determining the sustainability of systems on the frontier. These include path dependence, adaptation/development deficits, values conflicts and discounting of future loss and damage. The cumulative implications of these driving forces are highly uncertain. Nevertheless, the fact that a broad range of systems already persist at the edge of their frontiers suggests a high likelihood that some limits will eventually be exceeded. The resulting system transformation is likely to manifest as anticipatory modification of management objectives or loss and damage. These outcomes vary significantly with respect to their ethical implications. Successful navigation of the adaptation frontier will necessitate new paradigms of risk governance to elicit knowledge that encourages reflexive reevaluation of societal values that enable or constrain sustainability.

  2. Diploid yeast cells yield homozygous spontaneous mutations

    Science.gov (United States)

    Esposito, M. S.; Bruschi, C. V.; Brushi, C. V. (Principal Investigator)

    1993-01-01

    A leucine-requiring hybrid of Saccharomyces cerevisiae, homoallelic at the LEU1 locus (leu1-12/leu1-12) and heterozygous for three chromosome-VII genetic markers distal to the LEU1 locus, was employed to inquire: (1) whether spontaneous gene mutation and mitotic segregation of heterozygous markers occur in positive nonrandom association and (2) whether homozygous LEU1/LEU1 mutant diploids are generated. The results demonstrate that gene mutation of leu1-12 to LEU1 and mitotic segregation of heterozygous chromosome-VII markers occur in strong positive nonrandom association, suggesting that the stimulatory DNA lesion is both mutagenic and recombinogenic. In addition, genetic analysis of diploid Leu+ revertants revealed that approximately 3% of mutations of leu1-12 to LEU1 result in LEU1/LEU1 homozygotes. Red-white sectored Leu+ colonies exhibit genotypes that implicate post-replicational chromatid breakage and exchange near the site of leu1-12 reversion, chromosome loss, and subsequent restitution of diploidy, in the sequence of events leading to mutational homozygosis. By analogy, diploid cell populations can yield variants homozygous for novel recessive gene mutations at biologically significant rates. Mutational homozygosis may be relevant to both carcinogenesis and the evolution of asexual diploid organisms.

  3. TOX3 mutations in breast cancer.

    Directory of Open Access Journals (Sweden)

    James Owain Jones

    Full Text Available TOX3 maps to 16q12, a region commonly lost in breast cancers and recently implicated in the risk of developing breast cancer. However, not much is known of the role of TOX3 itself in breast cancer biology. This is the first study to determine the importance of TOX3 mutations in breast cancers. We screened TOX3 for mutations in 133 breast tumours and identified four mutations (three missense, one in-frame deletion of 30 base pairs in six primary tumours, corresponding to an overall mutation frequency of 4.5%. One potentially deleterious missense mutation in exon 3 (Leu129Phe was identified in one tumour (genomic DNA and cDNA. Whilst copy number changes of 16q12 are common in breast cancer, our data show that mutations of TOX3 are present at low frequency in tumours. Our results support that TOX3 should be further investigated to elucidate its role in breast cancer biology.

  4. Effect of endogenous carotenoids on “adaptive” mutation in Escherichia coli FC40

    Science.gov (United States)

    Bridges, Bryn A.; Foster, Patricia L.; Timms, Andrew R.

    2010-01-01

    The appearance over many days of Lac+ frameshift mutations in Escherichia coli strain FC40 incubated on lactose selection plates is a classic example of apparent “adaptive” mutation in an episomal gene. We show that endogenously overproduced carotenoids reduce adaptive mutation under selective conditions by a factor of around two. Carotenoids are known to scavenge singlet oxygen suggesting that the accumulation of oxidative base damage may be an integral part of the adaptive mutation phenomenon. If so, the lesion cannot be 7,8-dihydro-8-oxoguanine since adaptive mutation in FC40 is unaffected by mutM and mutY mutations. If active oxygen species such as singlet oxygen are involved in adaptive mutation then they should also induce frameshift mutations in FC40 under non-selective conditions. We show that such mutations can be induced under non-selective conditions by protoporphyrin photosensitisation and that this photodynamic induction is reduced by a factor of just over two when endogenous carotenoids are present. We argue that the involvement of oxidative damage would in no way be inconsistent with current understanding of the mechanism of adaptive mutation and the role of DNA polymerases. PMID:11166030

  5. 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.

  6. 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.

  7. Clusters of community exposure to coastal flooding hazards based on storm and sea level rise scenarios—implications for adaptation networks in the San Francisco Bay region

    Science.gov (United States)

    Hummel, Michelle; Wood, Nathan J.; Schweikert, Amy; Stacey, Mark T.; Jones, Jeanne; Barnard, Patrick L.; Erikson, Li H.

    2018-01-01

    Sea level is projected to rise over the coming decades, further increasing the extent of flooding hazards in coastal communities. Efforts to address potential impacts from climate-driven coastal hazards have called for collaboration among communities to strengthen the application of best practices. However, communities currently lack practical tools for identifying potential partner communities based on similar hazard exposure characteristics. This study uses statistical cluster analysis to identify similarities in community exposure to flooding hazards for a suite of sea level rise and storm scenarios. We demonstrate this approach using 63 jurisdictions in the San Francisco Bay region of California (USA) and compare 21 distinct exposure variables related to residents, employees, and structures for six hazard scenario combinations of sea level rise and storms. Results indicate that cluster analysis can provide an effective mechanism for identifying community groupings. Cluster compositions changed based on the selected societal variables and sea level rise scenarios, suggesting that a community could participate in multiple networks to target specific issues or policy interventions. The proposed clustering approach can serve as a data-driven foundation to help communities identify other communities with similar adaptation challenges and to enhance regional efforts that aim to facilitate adaptation planning and investment prioritization.

  8. Changes associated with Ebola virus adaptation to novel species.

    OpenAIRE

    Pappalardo, Morena; Reddin, Ian; Cantoni, Diego; Rossman, Jeremy S.; Michaelis, Martin; Wass, Mark N.

    2017-01-01

    Motivation: Ebola viruses are not pathogenic but can be adapted to replicate and cause disease in rodents. Here, we used a structural bioinformatics approach to analyze the mutations associated with Ebola virus adaptation to rodents to elucidate the determinants of host-specific Ebola virus pathogenicity.\\ud Results: We identified 33 different mutations associated with Ebola virus adaptation to rodents in the proteins GP, NP, L, VP24, and VP35. Only VP24, GP and NP were consistently found mut...

  9. Mutation directional selection sheds light on prion pathogenesis

    International Nuclear Information System (INIS)

    Shen, Liang; Ji, Hong-Fang

    2011-01-01

    Highlights: → Most pathogenic mutations possess strong directional selection, i.e., enhancing hydrophobicity or decreasing negative and increasing positive charge. → Mutation-induced changes may strengthen the interactions between PrP and facilitating factors. → The findings also have significant implications for exploring potential regions involved in the conformational transition from PrP C to PrP Sc . -- Abstract: As mutations in the PRNP gene account for human hereditary prion diseases (PrDs), it is crucial to elucidating how these mutations affect the central pathogenic conformational transition of normal cellular prion protein (PrP C ) to abnormal scrapie isoform (PrP Sc ). Many studies proposed that these pathogenic mutations may make PrP more susceptible to conformational change through altering its structure stability. By evaluating the most recent observations regarding pathogenic mutations, it was found that the pathogenic mutations do not exert a uniform effect on the thermodynamic stability of the human PrP's structure. Through analyzing the reported PrDs-related mutations, we found that 25 out of 27 mutations possess strong directional selection, i.e., enhancing hydrophobicity or decreasing negative and increasing positive charge. Based on the triggering role reported by previous studies of facilitating factors in PrP C conversion, e.g., lipid and polyanion, we proposed that the mutation-induced changes may strengthen the interaction between PrP and facilitating factors, which will accelerate PrP conversion and cause PrDs.

  10. Better plants through mutations

    International Nuclear Information System (INIS)

    1988-01-01

    This is a public relations film describing problems associated with the genetic improvement of crop plants through induced mutations. Mutations are the ultimate source of genetic variation in plants. Mutation induction is now established as a practical tool in plant breeding. The Joint FAO/IAEA Division and the IAEA's laboratory at Seibersdorf have supported research and practical implementation of mutation breeding of both seed propagated and vegetatively propagated plants. Plant biotechnology based on in vitro culture and recombinant DNA technology will make a further significant contribution to plant breeding

  11. 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

    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...... shifts from clear to turbid in a warmer North European temperate climate. However, it must be emphasised that the prediction of N transport and thus effects is uncertain as the prediction of regional precipitation and changes in land-use is uncertain. By contrast, N loading is expected to decline in warm...... 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...

  12. 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)

    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. PMID:26207914

  13. 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

  14. 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

  15. TEMPERAMENTAL ADAPTABILITY, PERSISTENCE, AND REGULARITY: PARENTAL RATINGS OF NORWEGIAN INFANTS AGED 6 TO 12 MONTHS, WITH SOME IMPLICATIONS FOR PREVENTIVE PRACTICE.

    Science.gov (United States)

    Olafsen, Kåre S; Ulvund, Stein Erik; Torgersen, Anne Mari; Wentzel-Larsen, Tore; Smith, Lars; Moe, Vibeke

    2018-03-01

    There is a need for standardized measures of infant temperament to strengthen current practices in prevention and early intervention. The present study provides Norwegian data on the Cameron-Rice Infant Temperament Questionnaire (CRITQ; J.R. Cameron & D.C. Rice, 1986a), which comprises 46 items and is used within a U.S. health maintenance organization. The CRITQ was filled out by mothers and fathers at 6 and again at 12 months as part of a longitudinal study of mental health during the first years of life (the "Little in Norway" study, N = 1,041 families enrolled; V. Moe & L. Smith, 2010). Results showed that internal consistencies were comparable with U.S. The temperament dimensions of persistence, adaptability, and regularity had acceptable or close-to-acceptable reliabilities in the U.S. study as well as in this study, and also were unifactorial in confirmatory factor analysis. These dimensions are the focus in this article. Findings concerning parents' differential ratings of their infants on the three dimensions are reported, as is the stability of parents' ratings of temperament from 6 to 12 months. In addition, results on the relation between temperament and parenting stress are presented. The study suggests that temperamental adaptability, persistence, and regularity may be relevant when assessing infant behavior, and may be applied in systematic prevention trials for families with infants. The inclusion of concepts related to individual differences in response tendencies and regulatory efforts may broaden the understanding of parent-infant transactions, and thus enrich prevention and sensitizing interventions with the aim of assisting infants' development. © 2018 Michigan Association for Infant Mental Health.

  16. Fixation probability of a nonmutator in a large population of asexual mutators.

    Science.gov (United States)

    Jain, Kavita; James, Ananthu

    2017-11-21

    In an adapted population of mutators in which most mutations are deleterious, a nonmutator that lowers the mutation rate is under indirect selection and can sweep to fixation. Using a multitype branching process, we calculate the fixation probability of a rare nonmutator in a large population of asexual mutators. We show that when beneficial mutations are absent, the fixation probability is a nonmonotonic function of the mutation rate of the mutator: it first increases sublinearly and then decreases exponentially. We also find that beneficial mutations can enhance the fixation probability of a nonmutator. Our analysis is relevant to an understanding of recent experiments in which a reduction in the mutation rates has been observed. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. LRIG2 mutations cause urofacial syndrome.

    Science.gov (United States)

    Stuart, Helen M; Roberts, Neil A; Burgu, Berk; Daly, Sarah B; Urquhart, Jill E; Bhaskar, Sanjeev; Dickerson, Jonathan E; Mermerkaya, Murat; Silay, Mesrur Selcuk; Lewis, Malcolm A; Olondriz, M Beatriz Orive; Gener, Blanca; Beetz, Christian; Varga, Rita E; Gülpınar, Omer; Süer, Evren; Soygür, Tarkan; Ozçakar, Zeynep B; Yalçınkaya, Fatoş; Kavaz, Aslı; Bulum, Burcu; Gücük, Adnan; Yue, Wyatt W; Erdogan, Firat; Berry, Andrew; Hanley, Neil A; McKenzie, Edward A; Hilton, Emma N; Woolf, Adrian S; Newman, William G

    2013-02-07

    Urofacial syndrome (UFS) (or Ochoa syndrome) is an autosomal-recessive disease characterized by congenital urinary bladder dysfunction, associated with a significant risk of kidney failure, and an abnormal facial expression upon smiling, laughing, and crying. We report that a subset of UFS-affected individuals have biallelic mutations in LRIG2, encoding leucine-rich repeats and immunoglobulin-like domains 2, a protein implicated in neural cell signaling and tumorigenesis. Importantly, we have demonstrated that rare variants in LRIG2 might be relevant to nonsyndromic bladder disease. We have previously shown that UFS is also caused by mutations in HPSE2, encoding heparanase-2. LRIG2 and heparanase-2 were immunodetected in nerve fascicles growing between muscle bundles within the human fetal bladder, directly implicating both molecules in neural development in the lower urinary tract. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  18. PMS2 mutations in childhood cancer.

    Science.gov (United States)

    De Vos, Michel; Hayward, Bruce E; Charlton, Ruth; Taylor, Graham R; Glaser, Adam W; Picton, Susan; Cole, Trevor R; Maher, Eamonn R; McKeown, Carole M E; Mann, Jill R; Yates, John R; Baralle, Diana; Rankin, Julia; Bonthron, David T; Sheridan, Eamonn

    2006-03-01

    Until recently, the PMS2 DNA mismatch repair gene has only rarely been implicated as a cancer susceptibility locus. New studies have shown, however, that earlier analyses of this gene have had technical limitations and also that the genetic behavior of mutant PMS2 alleles is unusual, in that, unlike MLH1 or MSH2 mutations, PMS2 mutations show low heterozygote penetrance. As a result, a dominantly inherited cancer predisposition has not been a feature reported in families with PMS2 mutations. Such families have instead been ascertained through childhood-onset cancers in homozygotes or through apparently sporadic colorectal cancer in heterozygotes. We present further information on the phenotype associated with homozygous PMS2 deficiency in 13 patients from six families of Pakistani origin living in the United Kingdom. This syndrome is characterized by café-au-lait skin pigmentation and a characteristic tumor spectrum, including leukemias, lymphomas, cerebral malignancies (such as supratentorial primitive neuroectodermal tumors, astrocytomas, and glioblastomas), and colorectal neoplasia with an onset in early adult life. We present evidence for a founder effect in five families, all of which carried the same R802-->X mutation (i.e., arginine-802 to stop) in PMS2. This cancer syndrome can be mistaken for neurofibromatosis type 1, with important management implications including the risk of the disorder occurring in siblings and the likelihood of tumor development in affected individuals.

  19. Mutational Analysis of Merkel Cell Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Erstad, Derek J. [Department of Surgery, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114 (United States); Cusack, James C. Jr., E-mail: jcusack@mgh.harvard.edu [Division of Surgical Oncology, Harvard Medical School, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114 (United States)

    2014-10-17

    Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine malignancy that is associated with a poor prognosis. The pathogenesis of MCC is not well understood, and despite a recent plethora of mutational analyses, we have yet to find a set of signature mutations implicated in the majority of cases. Mutations, including TP53, Retinoblastoma and PIK3CA, have been documented in subsets of patients. Other mechanisms are also likely at play, including infection with the Merkel cell polyomavirus in a subset of patients, dysregulated immune surveillance, epigenetic alterations, aberrant protein expression, posttranslational modifications and microRNAs. In this review, we summarize what is known about MCC genetic mutations and chromosomal abnormalities, and their clinical significance. We also examine aberrant protein function and microRNA expression, and discuss the therapeutic and prognostic implications of these findings. Multiple clinical trials designed to selectively target overexpressed oncogenes in MCC are currently underway, though most are still in early phases. As we accumulate more molecular data on MCC, we will be better able to understand its pathogenic mechanisms, develop libraries of targeted therapies, and define molecular prognostic signatures to enhance our clinicopathologic knowledge.

  20. Mutational Analysis of Merkel Cell Carcinoma

    International Nuclear Information System (INIS)

    Erstad, Derek J.; Cusack, James C. Jr.

    2014-01-01

    Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine malignancy that is associated with a poor prognosis. The pathogenesis of MCC is not well understood, and despite a recent plethora of mutational analyses, we have yet to find a set of signature mutations implicated in the majority of cases. Mutations, including TP53, Retinoblastoma and PIK3CA, have been documented in subsets of patients. Other mechanisms are also likely at play, including infection with the Merkel cell polyomavirus in a subset of patients, dysregulated immune surveillance, epigenetic alterations, aberrant protein expression, posttranslational modifications and microRNAs. In this review, we summarize what is known about MCC genetic mutations and chromosomal abnormalities, and their clinical significance. We also examine aberrant protein function and microRNA expression, and discuss the therapeutic and prognostic implications of these findings. Multiple clinical trials designed to selectively target overexpressed oncogenes in MCC are currently underway, though most are still in early phases. As we accumulate more molecular data on MCC, we will be better able to understand its pathogenic mechanisms, develop libraries of targeted therapies, and define molecular prognostic signatures to enhance our clinicopathologic knowledge

  1. 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...

  2. 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.

  3. Biomonitoring role of some cellular markers during heat stress-induced changes in highly representative fresh water mollusc, Bellamya bengalensis: Implication in climate change and biological adaptation.

    Science.gov (United States)

    Dutta, Sangita Maiti; Mustafi, Soumyajit Banerjee; Raha, Sanghamitra; Chakraborty, Susanta Kumar

    2018-08-15

    Owing to increasing concern of global climate-change, temperature rise is of great interest which can be primarily evaluated from the seasonal variations in some organisms. Aquatic environment can be extremely stressful to its inhabitants because most of them are poikilothermous. In the present study, attempt was made to evaluate the biological effects of oxidative-stress and adaptive/antioxidant capacities during temperature variations (36-40 °C for 24hrs to 72hrs) in Bellamya bengalensis both in environmental and laboratory conditions by testing some biomarkers like HSP70, catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH) and glutathione reductase (GR). The biomarker potency of the molecules and the anti-oxidative metabolic-network was postulated and extrapolated to find its resemblance to the climate-change associated organismal variations. In a natural and eco-restored environment in the Eastern part of India, 10-20 fold increases in CAT, SOD and HSP70 protein expressions (Western blot results) were noticed in Bellamya paralleling to their increased enzymatic activities (gel zymogram studies) due to the seasonal (summer versus winter) temperature variation. It is evident from the consecutive three years' study that this variation resulted in the unfavorable physico-chemical changes of water quality parameters like dissolved oxygen, biochemical oxygen demand, alkalinity and consequently decreased the animal density in summer. And that was revived due to their higher reproduction-rate in post rainy/winter season when temperature normalizes resulting in a restoration of favorable environment. In laboratory condition, the reduced GR and increased GPx indicated the oxidative damage as evident by higher tissue MDA level following to higher mortality. Changes in SOD and CAT activities suggest activation of physiological mechanism to scavenge the ROS produced during heat stress. However, when mortality increased at different time points (36

  4. The biomechanical, chemical and physiological adaptations of the eggs of two Australian megapodes to their nesting strategies and their implications for extinct titanosaur dinosaurs.

    Science.gov (United States)

    Grellet-Tinner, G; Lindsay, S; Thompson, M B

    2017-08-01

    Megapodes are galliform birds endemic to Australasia and unusual among modern birds in that they bury their eggs for incubation in diverse substrates and using various strategies. Alectura lathami and Leipoa ocellata are Australian megapodes that build and nest in mounds of soil and organic matter. Such unusual nesting behaviours have resulted in particular evolutionary adaptations of their eggs and eggshells. We used a combination of scanning electron microscopy, including electron backscatter diffraction and energy-dispersive X-ray spectroscopy, to determine the fine structure of the eggshells and micro-CT scanning to map the structure of pores. We discovered that the surface of the eggshell of A. lathami displays nodes similar to those of extinct titanosaur dinosaurs from Transylvania and Auca Mahuevo egg layer #4. We propose that this pronounced nodular ornamentation is an adaptation to an environment rich in organic acids from their nest mound, protecting the egg surface from chemical etching and leaving the eggshell thickness intact. By contrast, L. ocellata nests in mounds of sand with less organic matter in semiarid environments and has eggshells with weakly defined nodes, like those of extinct titanosaurs from AM L#3 that also lived in a semiarid environment. We suggest the internode spaces in both megapode and titanosaur species act as funnels, which concentrate the condensed water vapour between the nodes. This water funnelling in megapodes through the layer of calcium phosphate reduces the likelihood of bacterial infection by creating a barrier to microbial invasion. In addition, the accessory layer of both species possesses sulphur, which reinforces the calcium phosphate barrier to bacterial and fungal contamination. Like titanosaurs, pores through the eggshell are Y-shaped in both species, but A. lathami displays unique mid-shell connections tangential to the eggshell surface and that connect some adjacent pores, like the eggshells of titanosaur of AM

  5. Challenging a dogma: co-mutations exist in MAPK pathway genes in colorectal cancer.

    Science.gov (United States)

    Grellety, Thomas; Gros, Audrey; Pedeutour, Florence; Merlio, Jean-Philippe; Duranton-Tanneur, Valerie; Italiano, Antoine; Soubeyran, Isabelle

    2016-10-01

    Sequencing of genes encoding mitogen-activated protein kinase (MAPK) pathway proteins in colorectal cancer (CRC) has established as dogma that of the genes in a pathway only a single one is ever mutated. We searched for cases with a mutation in more than one MAPK pathway gene (co-mutations). Tumor tissue samples of all patients presenting with CRC, and referred between 01/01/2008 and 01/06/2015 to three French cancer centers for determination of mutation status of RAS/RAF+/-PIK3CA, were retrospectively screened for co-mutations using Sanger sequencing or next-generation sequencing. We found that of 1791 colorectal patients with mutations in the MAPK pathway, 20 had a co-mutation, 8 of KRAS/NRAS, and some even with a third mutation. More than half of the mutations were in codons 12 and 13. We also found 3 cases with a co-mutation of NRAS/BRAF and 9 with a co-mutation of KRAS/BRAF. In 2 patients with a co-mutation of KRAS/NRAS, the co-mutation existed in the primary as well as in a metastasis, which suggests that co-mutations occur early during carcinogenesis and are maintained when a tumor disseminates. We conclude that co-mutations exist in the MAPK genes but with low frequency and as yet with unknown outcome implications.

  6. Adaptations of lumbar biomechanics after four weeks of running training with minimalist footwear and technique guidance: Implications for running-related lower back pain.

    Science.gov (United States)

    Lee, Szu-Ping; Bailey, Joshua P; Smith, Jo Armour; Barton, Stephanie; Brown, David; Joyce, Talia

    2018-01-01

    To investigate the changes in lumbar kinematic and paraspinal muscle activation before, during, and after a 4-week minimalist running training. Prospective cohort study. University research laboratory. Seventeen habitually shod recreational runners who run 10-50 km per week. During stance phases of running, sagittal lumbar kinematics was recorded using an electrogoniometer, and activities of the lumbar paraspinal muscles were assessed by electromyography. Runners were asked to run at a prescribed speed (3.1 m/s) and a self-selected speed. For the 3.1 m/s running speed, significant differences were found in the calculated mean lumbar posture (p = 0.001) during the stance phase, including a more extended lumbar posture after minimalist running training. A significant reduction in the contralateral lumbar paraspinal muscle activation was also observed (p = 0.039). For the preferred running speed, similar findings of a more extended lumbar posture (p = 0.002) and a reduction in contralateral lumbar paraspinal muscle activation (p = 0.047) were observed. A 4-week minimalist running training program produced significant changes in lumbar biomechanics during running. Specifically, runners adopted a more extended lumbar posture and reduced lumbar paraspinal muscle activation. These findings may have clinical implications for treating individuals with running-related lower back pain. Copyright © 2016 Elsevier Ltd. All rights reserved.

  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. 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.

  9. Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren’s syndrome

    Science.gov (United States)

    Lessard, Christopher J.; Li, He; Adrianto, Indra; Ice, John A.; Rasmussen, Astrid; Grundahl, Kiely M.; Kelly, Jennifer A.; Dozmorov, Mikhail G.; Miceli-Richard, Corinne; Bowman, Simon; Lester, Sue; Eriksson, Per; Eloranta, Maija-Leena; Brun, Johan G.; Gøransson, Lasse G.; Harboe, Erna; Guthridge, Joel M.; Kaufman, Kenneth M.; Kvarnström, Marika; Jazebi, Helmi; Graham, Deborah S. Cunninghame; Grandits, Martha E.; Nazmul-Hossain, Abu N. M.; Patel, Ketan; Adler, Adam J.; Maier-Moore, Jacen S.; Farris, A. Darise; Brennan, Michael T.; Lessard, James A.; Chodosh, James; Gopalakrishnan, Rajaram; Hefner, Kimberly S.; Houston, Glen D.; Huang, Andrew J.W.; Hughes, Pamela J.; Lewis, David M.; Radfar, Lida; Rohrer, Michael D.; Stone, Donald U.; Wren, Jonathan D.; Vyse, Timothy J.; Gaffney, Patrick M.; James, Judith A.; Omdal, Roald; Wahren-Herlenius, Marie; Illei, Gabor G.; Witte, Torsten; Jonsson, Roland; Rischmueller, Maureen; Rönnblom, Lars; Nordmark, Gunnel; Ng, Wan-Fai; Mariette, Xavier; Anaya, Juan-Manuel; Rhodus, Nelson L.; Segal, Barbara M.; Scofield, R. Hal; Montgomery, Courtney G.; Harley, John B.; Sivils, Kathy L. Moser

    2013-01-01

    Sjögren’s syndrome is a common autoimmune disease (~0.7% of European Americans) typically presenting as keratoconjunctivitis sicca and xerostomia. In addition to strong association within the HLA region at 6p21 (Pmeta=7.65×10−114), we establish associations with IRF5-TNPO3 (Pmeta=2.73×10−19), STAT4 (Pmeta=6.80×10−15), IL12A (Pmeta =1.17×10−10), FAM167A-BLK (Pmeta=4.97×10−10), DDX6-CXCR5 (Pmeta=1.10×10−8), and TNIP1 (Pmeta=3.30×10−8). Suggestive associations with Pmeta<5×10−5 were observed with 29 regions including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2, and PHIP amongst others. These results highlight the importance of genes involved in both innate and adaptive immunity in Sjögren’s syndrome. PMID:24097067

  10. Missense mutations in IHH impair Indian Hedgehog signaling in C3H10T1/2 cells: Implications for brachydactyly type A1, and new targets for Hedgehog signaling.

    Science.gov (United States)

    Guo, Shengzhen; Zhou, Jian; Gao, Bo; Hu, Jianxin; Wang, Hongsheng; Meng, Junwei; Zhao, Xinzhi; Ma, Gang; Lin, Chuwen; Xiao, Yue; Tang, Wei; Zhu, Xuming; Cheah, Kathryn S E; Feng, Guoying; Chan, Danny; He, Lin

    2010-01-01

    Heterozygous missense mutations in IHH result in Brachydactyly type A1 (BDA1; OMIM 112500), a condition characterized by the shortening of digits due to hypoplasia/aplasia of the middle phalanx. Indian Hedgehog signaling regulates the proliferation and differentiation of chondrocytes and is essential for endochondral bone formation. Analyses of activated IHH signaling in C3H10T1/2 cells showed that three BDA1-associated mutations (p.E95K, p.D100E and p.E131K) severely impaired the induction of targets such as Ptch1 and Gli1. However, this was not a complete loss of function, suggesting that these mutations may affect the interaction with the receptor PTCH1 or its partners, with an impact on the induction potency. From comparative microarray expression analyses and quantitative real-time PCR, we identified three additional targets, Sostdc1, Penk1 and Igfbp5, which were also severely affected. Penk1 and Igfbp5 were confirmed to be regulated by GLI1, while the induction of Sostdc1 by IHH is independent of GLI1. SOSTDC1 is a BMP antagonist, and altered BMP signaling is known to affect digit formation. The role of Penk1 and Igfbp5 in skeletogenesis is not known. However, we have shown that both Penk1 and Igfbp5 are expressed in the interzone region of the developing joint of mouse digits, providing another link for a role for IHH signaling in the formation of the distal digits.

  11. Mutation breeding of pearl millet and sorghum

    Energy Technology Data Exchange (ETDEWEB)

    Hanna, W W [United States Department of Agriculture, Agricultural Research Service, University of Georgia, College of Agricultural Experiment Stations, Coastal Plain Station, Agronomy Department, Tifton, GA (United States)

    1982-07-01

    Pearl millet and sorghum are important food and feed crops grown mostly in semi-arid regions of the world. Although there exists a large amount of genetic variability in both species, it does not always satisfy the needs of plant breeders in improving varieties with regard to yield, quality, resistance or environmental adaptation. Plant breeders interested in using induced mutations for variety improvement will find in this review information about the techniques used by others. (author)

  12. Mutation breeding of pearl millet and sorghum

    International Nuclear Information System (INIS)

    Hanna, W.W.

    1982-01-01

    Pearl millet and sorghum are important food and feed crops grown mostly in semi-arid regions of the world. Although there exists a large amount of genetic variability in both species, it does not always satisfy the needs of plant breeders in improving varieties with regard to yield, quality, resistance or environmental adaptation. Plant breeders interested in using induced mutations for variety improvement will find in this review information about the techniques used by others. (author)

  13. Mosaicism for the FMR1 gene influences adaptive skills development in fragile X-affected males

    Energy Technology Data Exchange (ETDEWEB)

    Cohen, I.L.; Sudhalter, V.; Nolin, S.L. [New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY (United States)

    1996-08-09

    Fragile X syndrome is one of the most common forms of inherited mental retardation, and the first of a new class of genetic disorders associated with expanded trinucleotide repeats. Previously, we found that about 41% of affected males are mosaic for this mutation in that some of their blood cells have an active fragile X gene and others do not. It has been hypothesized that these mosaic cases should show higher levels of functioning than those who have only the inactive full mutation gene, but previous studies have provided negative or equivocal results. In the present study, the cross-sectional development of communication, self-care, socialization, and motor skills was studied in 46 males with fragile X syndrome under age 20 years as a function of two variables: age and the presence or absence of mosaicism. The rate of adaptive skills development was 2-4 times as great in mosaic cases as in full mutation cases. There was also a trend for cases with autism to be more prevalent in the full-mutation group. These results have implications for prognosis, for the utility of gene or protein replacement therapies for this disorder, and for understanding the association between mental retardation, developmental disorders, and fragile X syndrome. 21 refs., 3 figs.

  14. Mutation and premating isolation

    Science.gov (United States)

    Woodruff, R. C.; Thompson, J. N. Jr

    2002-01-01

    While premating isolation might be traceable to different genetic mechanisms in different species, evidence supports the idea that as few as one or two genes may often be sufficient to initiate isolation. Thus, new mutation can theoretically play a key role in the process. But it has long been thought that a new isolation mutation would fail, because there would be no other individuals for the isolation-mutation-carrier to mate with. We now realize that premeiotic mutations are very common and will yield a cluster of progeny carrying the same new mutant allele. In this paper, we discuss the evidence for genetically simple premating isolation barriers and the role that clusters of an isolation mutation may play in initiating allopatric, and even sympatric, species divisions.

  15. Adaptive Education.

    Science.gov (United States)

    Anderson, Lorin W.

    1979-01-01

    Schools have devised several ways to adapt instruction to a wide variety of student abilities and needs. Judged by criteria for what adaptive education should be, most learning for mastery programs look good. (Author/JM)

  16. Fanconi anemia founder mutation in Macedonian patients.

    Science.gov (United States)

    Madjunkova, Svetlana; Kocheva, Svetlana A; Plaseska-Karanfilska, Dijana

    2014-01-01

    Fanconi anemia (FA) is a rare autosomal recessive disorder clinically characterized by developmental abnormalities, progressive bone marrow failure (BMF) and profound cancer predisposition. Approximately 65% of all affected individuals have mutation in the FANCA (Fanconi anemia complementation group A) gene. The mutation spectrum of the FANCA gene is highly heterogeneous. FA-A is usually associated with private FANCA mutations in individual families. We describe 3 unrelated patients with FA with a similar clinical presentation: BMF, renal anomalies and café-au-lait pigmentation without major skeletal abnormality. The molecular analysis of the FANCA gene using the FA MLPA kit P031-A2/P032 FANCA, showed homozygous deletion of exon 3 in all 3 patients. Molecular analysis of the flanking regions of exon 3 precisely defined unique deletion of 2,040 bp and duplication of C (1788_3828dupC). These are the first 3 patients homozygous for deletion of FANCA exon 3 described to date. Although not related, the patients originated from the same Gypsy-like ethnic population. We conclude that c.190-256_283 + 1680del2040 dupC mutation in the FANCA gene is a founder mutation in Macedonian FA patients of Gypsy-like ethnic origin. Our finding has very strong implications for these patients in formulating diagnostic and carrier-screening strategy for BMF and FA and to enable comprehensive genetic counseling. © 2013 S. Karger AG, Basel.

  17. Motivational and Adaptation Experiences of Returnees and Migrants to Cyprus: A Grounded Theory Study With Counselling Psychology Application and Practice Implications in Europe

    Directory of Open Access Journals (Sweden)

    Maria Luca

    2014-03-01

    Full Text Available This grounded theory study explored the existential lived experience of migrants and second-generation Greek-Cypriot returnees to Cyprus and implications for counselling psychology. It looked at their motivation to return/migrate, their encounter with the new world and desires to belong. Eight semi-structured interviews were conducted with four migrants and four returnees, recruited within the Cyprus Euroguidance employment service in three cities, Nicosia, Limassol and Larnaca in Cyprus, E.U. All participants were in the process of seeking employment. Migrants and returnees faced intense dilemmas following relocation. Returnees’ motivations to return were influenced by childhood memories of visiting the country, desires for an improved economic and familial lifestyle, and the need to find a true sense of belonging. Migrants’ motivations included being married to a Cypriot, hoping for better economic prospects and living in a sunny environment. People experienced a cultural transition after choosing to put their ethnic identity in a different ethnic environment to the one where it was formed and in their attempts to find work, develop friendships, be accepted and find a home they experienced an unsettling reality. In Counselling psychology terms, the findings support other literature (Ward, Bochner, & Furnham, 2001 highlighting that migrants go through phases of adjustment, with cultural contact and acceptance by the host society, as well as financial independence being key factors. They described their experience as an outsider in a system dominated by nepotism and in a society new to them, that appeared to be suspicious of them. This transition lived by them was psychologically de-stabilising, characterised by stress, frustration, depression and isolation. Their commitment to find a way to belong was shown through their resilience. These findings are discussed with the application and practice of Counselling Psychology in mind.

  18. Mobile phone sensors and supervised machine learning to identify alcohol use events in young adults: Implications for just-in-time adaptive interventions.

    Science.gov (United States)

    Bae, Sangwon; Chung, Tammy; Ferreira, Denzil; Dey, Anind K; Suffoletto, Brian

    2017-11-27

    Real-time detection of drinking could improve timely delivery of interventions aimed at reducing alcohol consumption and alcohol-related injury, but existing detection methods are burdensome or impractical. To evaluate whether phone sensor data and machine learning models are useful to detect alcohol use events, and to discuss implications of these results for just-in-time mobile interventions. 38 non-treatment seeking young adult heavy drinkers downloaded AWARE app (which continuously collected mobile phone sensor data), and reported alcohol consumption (number of drinks, start/end time of prior day's drinking) for 28days. We tested various machine learning models using the 20 most informative sensor features to classify time periods as non-drinking, low-risk (1 to 3/4 drinks per occasion for women/men), and high-risk drinking (>4/5 drinks per occasion for women/men). Among 30 participants in the analyses, 207 non-drinking, 41 low-risk, and 45 high-risk drinking episodes were reported. A Random Forest model using 30-min windows with 1day of historical data performed best for detecting high-risk drinking, correctly classifying high-risk drinking windows 90.9% of the time. The most informative sensor features were related to time (i.e., day of week, time of day), movement (e.g., change in activities), device usage (e.g., screen duration), and communication (e.g., call duration, typing speed). Preliminary evidence suggests that sensor data captured from mobile phones of young adults is useful in building accurate models to detect periods of high-risk drinking. Interventions using mobile phone sensor features could trigger delivery of a range of interventions to potentially improve effectiveness. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. [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.

  20. Numb endocytic adapter proteins regulate the transport and processing of the amyloid precursor protein in an isoform-dependent manner: implications for Alzheimer disease pathogenesis.

    Science.gov (United States)

    Kyriazis, George A; Wei, Zelan; Vandermey, Miriam; Jo, Dong-Gyu; Xin, Ouyang; Mattson, Mark P; Chan, Sic L

    2008-09-12

    Central to the pathogenesis of Alzheimer disease is the aberrant processing of the amyloid precursor protein (APP) to generate amyloid beta-peptide (Abeta), the principle component of amyloid plaques. The cell fate determinant Numb is a phosphotyrosine binding domain (PTB)-containing endocytic adapter protein that interacts with the carboxyl-terminal domain of APP. The physiological relevance of this interaction is unknown. Mammals produce four alternatively spliced variants of Numb that differ in the length of their PTB and proline-rich region. In the current study, we determined the influence of the four human Numb isoforms on the intracellular trafficking and processing of APP. Stable expression of Numb isoforms that differ in the PTB but not in the proline-rich region results in marked differences in the sorting of APP to the recycling and degradative pathways. Neural cells expressing Numb isoforms that lack the insert in the PTB (short PTB (SPTB)) exhibited marked accumulation of APP in Rab5A-labeled early endosomal and recycling compartments, whereas those expressing isoforms with the insertion in the PTB (long PTB (LPTB)) exhibited reduced amounts of cellular APP and its proteolytic derivatives relative to parental control cells. Neither the activities of the beta- and gamma-secretases nor the expression of APP mRNA were significantly different in the stably transfected cells, suggesting that the differential effects of the Numb proteins on APP metabolism is likely to be secondary to altered APP trafficking. In addition, the expression of SPTB-Numb increases at the expense of LPTB-Numb in neuronal cultures subjected to stress, suggesting a role for Numb in stress-induced Abeta production. Taken together, these results suggest distinct roles for the human Numb isoforms in APP metabolism and may provide a novel potential link between altered Numb isoform expression and increased Abeta generation.

  1. Behavioral response to a just-in-time adaptive intervention (JITAI) to reduce sedentary behavior in obese adults: Implications for JITAI optimization.

    Science.gov (United States)

    Thomas, J Graham; Bond, Dale S

    2015-12-01

    Just-in-time adaptive interventions (JITAIs) use mobile computers, sensors, and software analytics to automatically detect behavior and deliver tailored treatment. However, little is known about how JITAIs influence patterns of behavior or how best to design JITAIs for maximum effect. This study examined prompts and behavioral response to the B-MOBILE JITAI for reducing sedentary behavior (SB) in overweight/obese individuals. Thirty participants (83% women; 67% White, mean ± SD body mass index = 36.2 kg/m2) tested 3 conditions presented in a randomized counterbalanced order involving smartphone-based prompts for walking breaks of (a) 3 min after 30 SB min, (b) 6 min after 60 SB min, and (c) 12 min after 120 SB min. Participants carried the smartphone an average of 6.90 days during each 7-day condition, for an average of 14.94 hr per day. The 3- and 6-min conditions resulted in the greatest number of prompts, walking breaks, the best adherence to prompts, the greatest amount of daily time spent in walking breaks, and fastest adherence to prompts (ps < .01). Small but statistically significant decreases in the number of daily walking breaks, adherence to prompts, and minutes per day spent in walking breaks were observed as a function of the number of days spent in a condition (ps < .05). The B-MOBILE JITAI was effective in prompting breaks in sedentary behavior when it was most clinically relevant. Frequent prompts for small change may be an optimal strategy for shaping sedentary behavior, although more research is needed to determine how best to promote long-term adherence. (PsycINFO Database Record (c) 2015 APA, all rights reserved).

  2. Adaptive capture of expert knowledge

    Energy Technology Data Exchange (ETDEWEB)

    Barrett, C.L.; Jones, R.D. [Los Alamos National Lab., NM (United States); Hand, Un Kyong [Los Alamos National Lab., NM (United States)]|[US Navy (United States)

    1995-05-01

    A method is introduced that can directly acquire knowledge-engineered, rule-based logic in an adaptive network. This adaptive representation of the rule system can then replace the rule system in simulated intelligent agents and thereby permit further performance-based adaptation of the rule system. The approach described provides both weight-fitting network adaptation and potentially powerful rule mutation and selection mechanisms. Nonlinear terms are generated implicitly in the mutation process through the emergent interaction of multiple linear terms. By this method it is possible to acquire nonlinear relations that exist in the training data without addition of hidden layers or imposition of explicit nonlinear terms in the network. We smoothed and captured a set of expert rules with an adaptive network. The motivation for this was to (1) realize a speed advantage over traditional rule-based simulations; (2) have variability in the intelligent objects not possible by rule-based systems but provided by adaptive systems: and (3) maintain the understandability of rule-based simulations. A set of binary rules was smoothed and converted into a simple set of arithmetic statements, where continuous, non-binary rules are permitted. A neural network, called the expert network, was developed to capture this rule set, which it was able to do with zero error. The expert network is also capable of learning a nonmonotonic term without a hidden layer. The trained network in feedforward operation is fast running, compact, and traceable to the rule base.

  3. Genetic improvement of Sesamun indicum through induced mutations

    International Nuclear Information System (INIS)

    Rajput, M.A.; Khan, Z.H.; Jafri, K.A.; Fazal Ali, J.A.

    2001-01-01

    Pakistan is chronically deficient in the production of edible oils. To enhance local production of edible oils, a mutation breeding project entitled ''Genetic improvement of Sesamum indicum through induced mutations'' was initiated for developing high yielding and widely adapted varieties of sesame. Quite a few mutants having earliness, short stature, semi-indehiscence, compact plant type, heavy bearing and high seed yield have been developed. The true breeding mutant lines developed have exhibited impressive yield potential. (author)

  4. Rates of Mutation and Host Transmission for an Escherichia coli Clone over 3 Years

    Science.gov (United States)

    Reeves, Peter R.; Liu, Bin; Zhou, Zhemin; Li, Dan; Guo, Dan; Ren, Yan; Clabots, Connie; Lan, Ruiting; Johnson, James R.; Wang, Lei

    2011-01-01

    Although over 50 complete Escherichia coli/Shigella genome sequences are available, it is only for closely related strains, for example the O55:H7 and O157:H7 clones of E. coli, that we can assign differences to individual evolutionary events along specific lineages. Here we sequence the genomes of 14 isolates of a uropathogenic E. coli clone that persisted for 3 years within a household, including a dog, causing a urinary tract infection (UTI) in the dog after 2 years. The 20 mutations observed fit a single tree that allows us to estimate the mutation rate to be about 1.1 per genome per year, with minimal evidence for adaptive change, including in relation to the UTI episode. The host data also imply at least 6 host transfer events over the 3 years, with 2 lineages present over much of that period. To our knowledge, these are the first direct measurements for a clone in a well-defined host community that includes rates of mutation and host transmission. There is a concentration of non-synonymous mutations associated with 2 transfers to the dog, suggesting some selection pressure from the change of host. However, there are no changes to which we can attribute the UTI event in the dog, which suggests that this occurrence after 2 years of the clone being in the household may have been due to chance, or some unknown change in the host or environment. The ability of a UTI strain to persist for 2 years and also to transfer readily within a household has implications for epidemiology, diagnosis, and clinical intervention. PMID:22046404

  5. Mutation breeding in vegetable crops

    Energy Technology Data Exchange (ETDEWEB)

    Yamaguchi, Takashi

    1984-03-01

    Vegetables breed by seeds and vegetative organs. In main vegetables, the differentiation of clopping types, the adoption of monoculture and year-round production and shipment are carried out, adapting to various socio-economic and cultivation conditions. Protected agriculture has advanced mainly for fruit vegetables, and the seeds for sale have become almost hybrid varieties. Reflecting this situation, the demand for breeding is diversified and characteristic. The present status of mutation breeding of vegetables is not yet well under way, but reports of about 40 raised varieties have been published in the world. The characters introduced by induced mutation and irradiation are compact form, harvesting aptitude, the forms and properties of stems and leaves, anti-lodging property, the size, form and uniformity of fruits, male sterility and so on. The radiation sources used were mostly gamma ray or X-ray, but sometimes, combined irradiation was used. Results obtained in Japan include: burdocks as an example to gamma ray irradiation of seeds; tomatoes as an example of inducing compound resistance against disease injury; and lettuce as an example of internal beta irradiation. (Kako, I.).

  6. 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...

  7. Correction for ‘artificial’ electron disequilibrium due to cone-beam CT density errors: implications for on-line adaptive stereotactic body radiation therapy of lung

    International Nuclear Information System (INIS)

    Disher, Brandon; Hajdok, George; Craig, Jeff; Gaede, Stewart; Battista, Jerry J; Wang, An

    2013-01-01

    Cone-beam computed tomography (CBCT) has rapidly become a clinically useful imaging modality for image-guided radiation therapy. Unfortunately, CBCT images of the thorax are susceptible to artefacts due to scattered photons, beam hardening, lag in data acquisition, and respiratory motion during a slow scan. These limitations cause dose errors when CBCT image data are used directly in dose computations for on-line, dose adaptive radiation therapy (DART). The purpose of this work is to assess the magnitude of errors in CBCT numbers (HU), and determine the resultant effects on derived tissue density and computed dose accuracy for stereotactic body radiation therapy (SBRT) of lung cancer. Planning CT (PCT) images of three lung patients were acquired using a Philips multi-slice helical CT simulator, while CBCT images were obtained with a Varian On-Board Imaging system. To account for erroneous CBCT data, three practical correction techniques were tested: (1) conversion of CBCT numbers to electron density using phantoms, (2) replacement of individual CBCT pixel values with bulk CT numbers, averaged from PCT images for tissue regions, and (3) limited replacement of CBCT lung pixels values (LCT) likely to produce artificial lateral electron disequilibrium. For each corrected CBCT data set, lung SBRT dose distributions were computed for a 6 MV volume modulated arc therapy (VMAT) technique within the Philips Pinnacle treatment planning system. The reference prescription dose was set such that 95% of the planning target volume (PTV) received at least 54 Gy (i.e. D95). Further, we used the relative depth dose factor as an a priori index to predict the effects of incorrect low tissue density on computed lung dose in regions of severe electron disequilibrium. CT number profiles from co-registered CBCT and PCT patient lung images revealed many reduced lung pixel values in CBCT data, with some pixels corresponding to vacuum (−1000 HU). Similarly, CBCT data in a plastic lung

  8. Genetic Mutations in Cancer

    Science.gov (United States)

    Many different types of genetic mutations are found in cancer cells. This infographic outlines certain types of alterations that are present in cancer, such as missense, nonsense, frameshift, and chromosome rearrangements.

  9. AIP mutations and gigantism.

    Science.gov (United States)

    Rostomyan, Liliya; Potorac, Iulia; Beckers, Pablo; Daly, Adrian F; Beckers, Albert

    2017-06-01

    AIP mutations are rare in sporadic acromegaly but they are seen at a higher frequency among certain specific populations of pituitary adenoma patients (pituitary gigantism cases, familial isolated pituitary adenoma (FIPA) kindreds, and patients with macroadenomas who are diagnosed ≤30 years). AIP mutations are most prevalent in patients with pituitary gigantism (29% of this group were found to have mutations in AIP gene). These data support targeted genetic screening for AIP mutations/deletions in these groups of pituitary adenoma patients. Earlier diagnosis of AIP-related acromegaly-gigantism cases enables timely clinical evaluation and treatment, thereby improving outcomes in terms of excessive linear growth and acromegaly comorbidities. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  10. Rate of accumulation of thymidine analogue mutations in patients continuing to receive virologically failing regimens containing zidovudine or stavudine: implications for antiretroviral therapy programs in resource-limited settings

    DEFF Research Database (Denmark)

    Cozzi-Lepri, Alessandro; Phillips, Andrew N; Martinez-Picado, Javier

    2009-01-01

    BACKGROUND: Because changes in antiretroviral therapy in resource-limited settings (RLSs) are delayed until patients experience immunological or clinical failure, it is important to be able to estimate the consequences in terms of accumulation of thymidine analogue (TA) mutations (TAMs). METHODS...... until the second GRT. RESULTS: At the time of the first GRT in a pair (t0), 1 year after virological failure, a median of 3 TAMs were detected, mutations 41L and 215Y in 65% of pairs and 67N in 52%. Overall, 126 TAMs were accumulated during 548 person-years of follow-up (PYFUs) (1/4.3 years; 95......% confidence interval, 3.7-5.0 years). Greater predicted activity of the TA at t0, TAM profile 2 (TAM2; vs TAM profile 1 [TAM1]) profiles at t0, use of a nonnucleoside reverse-transcriptase inhibitor (NNRTI) at t0 (vs combined NNRTI and protease inhibitor), and acquisition of HIV infection through heterosexual...

  11. Combined mutation and rearrangement screening by quantitative PCR high-resolution melting: is it relevant for hereditary recurrent Fever genes?

    Directory of Open Access Journals (Sweden)

    Nathalie Pallares-Ruiz

    2010-11-01

    Full Text Available The recent identification of genes implicated in hereditary recurrent fevers has allowed their specific diagnosis. So far however, only punctual mutations have been identified and a significant number of patients remain with no genetic confirmation of their disease after routine molecular approaches such as sequencing. The possible involvement of sequence rearrangements in these patients has only been examined in familial Mediterranean fever and was found to be unlikely. To assess the existence of larger genetic alterations in 3 other concerned genes, MVK (Mevalonate kinase, NLRP3 (Nod like receptor family, pyrin domain containing 3 and TNFRSF1A (TNF receptor superfamily 1A, we adapted the qPCR-HRM method to study possible intragenic deletions and duplications. This single-tube approach, combining both qualitative (mutations and quantitative (rearrangement screening, has proven effective in Lynch syndrome diagnosis. Using this approach, we studied 113 unselected (prospective group and 88 selected (retrospective group patients and identified no intragenic rearrangements in the 3 genes. Only qualitative alterations were found with a sensitivity similar to that obtained using classical molecular techniques for screening punctual mutations. Our results support that deleterious copy number alterations in MVK, NLRP3 and TNFRSF1A are rare or absent from the mutational spectrum of hereditary recurrent fevers, and demonstrate that a routine combined method such as qPCR-HRM provides no further help in genetic diagnosis. However, quantitative approaches such as qPCR or SQF-PCR did prove to be quick and effective and could still be useful after non contributory punctual mutation screening in the presence of clinically evocative signs.

  12. Mutation breeding in peas

    Energy Technology Data Exchange (ETDEWEB)

    Jaranowski, J [Institute of Genetics and Plant Breeding, Academy of Agriculture, Poznan (Poland); Micke, A [Joint FAO/IAEA Division of Isotope and Radiation Applications of Atomic Energy for Food and Agricultural Development, International Atomic Energy Agency, Vienna (Austria)

    1985-02-01

    The pea as an ancient crop plant still today has wide uses and is an import source of food protein. It is also an important object for genetic studies and as such has been widely used in mutation induction experiments. However, in comparison with cereals this ancient crop plant (like several other grain legumes) has gained relatively little from advances in breeding. The review focuses on the prospects of genetic improvement of pea by induced mutations, discusses principles and gives methodological information. (author)

  13. Mutation breeding in peas

    International Nuclear Information System (INIS)

    Jaranowski, J.; Micke, A.

    1985-01-01

    The pea as an ancient crop plant still today has wide uses and is an import source of food protein. It is also an important object for genetic studies and as such has been widely used in mutation induction experiments. However, in comparison with cereals this ancient crop plant (like several other grain legumes) has gained relatively little from advances in breeding. The review focuses on the prospects of genetic improvement of pea by induced mutations, discusses principles and gives methodological information. (author)

  14. ADAPT Dataset

    Data.gov (United States)

    National Aeronautics and Space Administration — Advanced Diagnostics and Prognostics Testbed (ADAPT) Project Lead: Scott Poll Subject Fault diagnosis in electrical power systems Description The Advanced...

  15. Mutations in HPSE2 Cause Urofacial Syndrome

    Science.gov (United States)

    Daly, Sarah B.; Urquhart, Jill E.; Hilton, Emma; McKenzie, Edward A.; Kammerer, Richard A.; Lewis, Malcolm; Kerr, Bronwyn; Stuart, Helen; Donnai, Dian; Long, David A.; Burgu, Berk; Aydogdu, Ozgu; Derbent, Murat; Garcia-Minaur, Sixto; Reardon, Willie; Gener, Blanca; Shalev, Stavit; Smith, Rupert; Woolf, Adrian S.; Black, Graeme C.; Newman, William G.

    2010-01-01

    Urinary voiding dysfunction in childhood, manifesting as incontinence, dysuria, and urinary frequency, is a common condition. Urofacial syndrome (UFS) is a rare autosomal recessive disease characterized by facial grimacing when attempting to smile and failure of the urinary bladder to void completely despite a lack of anatomical bladder outflow obstruction or overt neurological damage. UFS individuals often have reflux of infected urine from the bladder to the upper renal tract, with a risk of kidney damage and renal failure. Whole-genome SNP mapping in one affected individual defined an autozygous region of 16 Mb on chromosome 10q23-q24, within which a 10 kb deletion encompassing exons 8 and 9 of HPSE2 was identified. Homozygous exonic deletions, nonsense mutations, and frameshift mutations in five further unrelated families confirmed HPSE2 as the causative gene for UFS. Mutations were not identified in four additional UFS patients, indicating genetic heterogeneity. We show that HPSE2 is expressed in the fetal and adult central nervous system, where it might be implicated in controlling facial expression and urinary voiding, and also in bladder smooth muscle, consistent with a role in renal tract morphology and function. Our findings have broader implications for understanding the genetic basis of lower renal tract malformations and voiding dysfunction. PMID:20560210

  16. Mutations in HPSE2 cause urofacial syndrome.

    Science.gov (United States)

    Daly, Sarah B; Urquhart, Jill E; Hilton, Emma; McKenzie, Edward A; Kammerer, Richard A; Lewis, Malcolm; Kerr, Bronwyn; Stuart, Helen; Donnai, Dian; Long, David A; Burgu, Berk; Aydogdu, Ozgu; Derbent, Murat; Garcia-Minaur, Sixto; Reardon, Willie; Gener, Blanca; Shalev, Stavit; Smith, Rupert; Woolf, Adrian S; Black, Graeme C; Newman, William G

    2010-06-11

    Urinary voiding dysfunction in childhood, manifesting as incontinence, dysuria, and urinary frequency, is a common condition. Urofacial syndrome (UFS) is a rare autosomal recessive disease characterized by facial grimacing when attempting to smile and failure of the urinary bladder to void completely despite a lack of anatomical bladder outflow obstruction or overt neurological damage. UFS individuals often have reflux of infected urine from the bladder to the upper renal tract, with a risk of kidney damage and renal failure. Whole-genome SNP mapping in one affected individual defined an autozygous region of 16 Mb on chromosome 10q23-q24, within which a 10 kb deletion encompassing exons 8 and 9 of HPSE2 was identified. Homozygous exonic deletions, nonsense mutations, and frameshift mutations in five further unrelated families confirmed HPSE2 as the causative gene for UFS. Mutations were not identified in four additional UFS patients, indicating genetic heterogeneity. We show that HPSE2 is expressed in the fetal and adult central nervous system, where it might be implicated in controlling facial expression and urinary voiding, and also in bladder smooth muscle, consistent with a role in renal tract morphology and function. Our findings have broader implications for understanding the genetic basis of lower renal tract malformations and voiding dysfunction.

  17. Mutator activity in Schizophyllum commune

    Energy Technology Data Exchange (ETDEWEB)

    Shneyour, Y.; Koltin, Y. (Tel Aviv Univ. (Israel). Dept. of Microbiology)

    1983-01-01

    A strain with an elevated level of spontaneous mutations and an especially high rate of reversion at a specific locus (pab/sup -/) was identified. The mutator trait is recessive. UV sensitivity and the absence of a UV-specific endonucleolytic activity were associated with the enhancement of the mutation rate in mutator strains. The endonuclease associated with the regulation of the mutation rate also acted on single-stranded DNA. The molecular weight of this enzyme is about 38,000 daltons.

  18. Lethal mutagenesis: targeting the mutator phenotype in cancer.

    Science.gov (United States)

    Fox, Edward J; Loeb, Lawrence A

    2010-10-01

    The evolution of cancer and RNA viruses share many similarities. Both exploit high levels of genotypic diversity to enable extensive phenotypic plasticity and thereby facilitate rapid adaptation. In order to accumulate large numbers of mutations, we have proposed that cancers express a mutator phenotype. Similar to cancer cells, many viral populations, by replicating their genomes with low fidelity, carry a substantial mutational load. As high levels of mutation are potentially deleterious, the viral mutation frequency is thresholded at a level below which viral populations equilibrate in a traditional mutation-selection balance, and above which the population is no longer viable, i.e., the population undergoes an error catastrophe. Because their mutation frequencies are fine-tuned just below this error threshold, viral populations are susceptible to further increases in mutational load and, recently this phenomenon has been exploited therapeutically by a concept that has been termed lethal mutagenesis. Here we review the application of lethal mutagenesis to the treatment of HIV and discuss how lethal mutagenesis may represent a novel therapeutic approach for the treatment of solid cancers. Copyright © 2010 Elsevier Ltd. All rights reserved.

  19. Ambiguous Adaptation

    DEFF Research Database (Denmark)

    Møller Larsen, Marcus; Lyngsie, Jacob

    2017-01-01

    We investigate the connection between contract duration, relational mechanisms, and premature relationship termination. Based on an analysis of a large sample of exchange relationships in the global service-provider industry, we argue that investments in either longer contract duration or more in...... ambiguous reference points for adaption and thus increase the likelihood of premature termination by restricting the parties' set of adaptive actions....

  20. Climate adaptation

    Science.gov (United States)

    Kinzig, Ann P.

    2015-03-01

    This paper is intended as a brief introduction to climate adaptation in a conference devoted otherwise to the physics of sustainable energy. Whereas mitigation involves measures to reduce the probability of a potential event, such as climate change, adaptation refers to actions that lessen the impact of climate change. Mitigation and adaptation differ in other ways as well. Adaptation does not necessarily have to be implemented immediately to be effective; it only needs to be in place before the threat arrives. Also, adaptation does not necessarily require global, coordinated action; many effective adaptation actions can be local. Some urban communities, because of land-use change and the urban heat-island effect, currently face changes similar to some expected under climate change, such as changes in water availability, heat-related morbidity, or changes in disease patterns. Concern over those impacts might motivate the implementation of measures that would also help in climate adaptation, despite skepticism among some policy makers about anthropogenic global warming. Studies of ancient civilizations in the southwestern US lends some insight into factors that may or may not be important to successful adaptation.

  1. Modulation of allele leakiness and adaptive mutability in Escherichia ...

    Indian Academy of Sciences (India)

    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.

  2. Adaptive steganography

    Science.gov (United States)

    Chandramouli, Rajarathnam; Li, Grace; Memon, Nasir D.

    2002-04-01

    Steganalysis techniques attempt to differentiate between stego-objects and cover-objects. In recent work we developed an explicit analytic upper bound for the steganographic capacity of LSB based steganographic techniques for a given false probability of detection. In this paper we look at adaptive steganographic techniques. Adaptive steganographic techniques take explicit steps to escape detection. We explore different techniques that can be used to adapt message embedding to the image content or to a known steganalysis technique. We investigate the advantages of adaptive steganography within an analytical framework. We also give experimental results with a state-of-the-art steganalysis technique demonstrating that adaptive embedding results in a significant number of bits embedded without detection.

  3. Adaptive Lighting

    DEFF Research Database (Denmark)

    Petersen, Kjell Yngve; Søndergaard, Karin; Kongshaug, Jesper

    2015-01-01

    the investigations of lighting scenarios carried out in two test installations: White Cube and White Box. The test installations are discussed as large-scale experiential instruments. In these test installations we examine what could potentially occur when light using LED technology is integrated and distributed......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...... 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...

  4. Decrease in specific micronutrient intake in colorectal cancer patients with tumors presenting Ki-ras mutation

    OpenAIRE

    JORDI SALAS; NURIA LASO; SERGI MAS; M. JOSE LAFUENTE; XAVIER CASTERAD; MANUEL TRIAS; ANTONIO BALLESTA; RAFAEL MOLINA; CARLOS ASCASO; SHICHUN ZHENG; JOHN K. WIENCKE; AMALIA LAFUENTE

    2004-01-01

    Decrease in specific micronutrient intake in colorectal cancer patients with tumors presenting Ki-ras mutation BACKGROUND: The diversity of the Mediterranean diet and the heterogeneity of acquired genetic alterations in colorectal cancer (CRC) led us to examine the possible association between dietary factors and mutations, such as Ki-ras mutations, in genes implicated in the pathogenesis of these neoplasms. PATIENTS AND METHODS: The study was based on 246 cases and 296 controls. For th...

  5. A Novel Mutation in the Transglutaminase-1 Gene in an Autosomal Recessive Congenital Ichthyosis Patient

    Directory of Open Access Journals (Sweden)

    D. Vaigundan

    2014-01-01

    Full Text Available Structure-function implication on a novel homozygous Trp250/Gly mutation of transglutaminase-1 (TGM1 observed in a patient of autosomal recessive congenital ichthyosis is invoked from a bioinformatics analysis. Structural consequences of this mutation are hypothesized in comparison to homologous enzyme human factor XIIIA accepted as valid in similar structural analysis and are projected as guidelines for future studies at an experimental level on TGM1 thus mutated.

  6. Pitfalls in genetic testing: the story of missed SCN1A mutations

    OpenAIRE

    Djémié, T.; Weckhuysen, S.; von Spiczak, S.; Carvill, G. L.; Jaehn, J.; Anttonen, A-K; Brilstra, E.; Caglayan, H. S.; de Kovel, C. G.; Depienne, C.; Gaily, E.; Gennaro, E.; Giraldez, B. G.; Gormley, P.; Guerrero-López, R.

    2016-01-01

    BACKGROUND: Sanger sequencing, still the standard technique for genetic testing in most diagnostic laboratories and until recently widely used in research, is gradually being complemented by next-generation sequencing (NGS). No single mutation detection technique is however perfect in identifying all mutations. Therefore, we wondered to what extent inconsistencies between Sanger sequencing and NGS affect the molecular diagnosis of patients. Since mutations in SCN1A, the major gene implicated ...

  7. Pitfalls in genetic testing : the story of missed SCN1A mutations

    OpenAIRE

    Djémié, Tania; Weckhuysen, Sarah; von Spiczak, Sarah; Carvill, Gemma L; Jaehn, Johanna; Anttonen, Anna-Kaisa; Brilstra, Eva; Caglayan, Hande S; de Kovel, Carolien G; Depienne, Christel; Gaily, Eija; Gennaro, Elena; Giraldez, Beatriz G; Gormley, Padhraig; Guerrero-López, Rosa

    2016-01-01

    BACKGROUND: Sanger sequencing, still the standard technique for genetic testing in most diagnostic laboratories and until recently widely used in research, is gradually being complemented by next-generation sequencing (NGS). No single mutation detection technique is however perfect in identifying all mutations. Therefore, we wondered to what extent inconsistencies between Sanger sequencing and NGS affect the molecular diagnosis of patients. Since mutations in SCN1A, the major gene implicated ...

  8. Whole genome sequencing of mutation accumulation lines reveals a low mutation rate in the social amoeba Dictyostelium discoideum.

    Directory of Open Access Journals (Sweden)

    Gerda Saxer

    Full Text Available Spontaneous mutations play a central role in evolution. Despite their importance, mutation rates are some of the most elusive parameters to measure in evolutionary biology. The combination of mutation accumulation (MA experiments and whole-genome sequencing now makes it possible to estimate mutation rates by directly observing new mutations at the molecular level across the whole genome. We performed an MA experiment with the social amoeba Dictyostelium discoideum and sequenced the genomes of three randomly chosen lines using high-throughput sequencing to estimate the spontaneous mutation rate in this model organism. The mitochondrial mutation rate of 6.76×10(-9, with a Poisson confidence interval of 4.1×10(-9 - 9.5×10(-9, per nucleotide per generation is slightly lower than estimates for other taxa. The mutation rate estimate for the nuclear DNA of 2.9×10(-11, with a Poisson confidence interval ranging from 7.4×10(-13 to 1.6×10(-10, is the lowest reported for any eukaryote. These results are consistent with low microsatellite mutation rates previously observed in D. discoideum and low levels of genetic variation observed in wild D. discoideum populations. In addition, D. discoideum has been shown to be quite resistant to DNA damage, which suggests an efficient DNA-repair mechanism that could be an adaptation to life in soil and frequent exposure to intracellular and extracellular mutagenic compounds. The social aspect of the life cycle of D. discoideum and a large portion of the genome under relaxed selection during vegetative growth could also select for a low mutation rate. This hypothesis is supported by a significantly lower mutation rate per cell division in multicellular eukaryotes compared with unicellular eukaryotes.

  9. Fate of a mutation in a fluctuating environment

    Science.gov (United States)

    Cvijović, Ivana; Good, Benjamin H.; Jerison, Elizabeth R.; Desai, Michael M.

    2015-01-01

    Natural environments are never truly constant, but the evolutionary implications of temporally varying selection pressures remain poorly understood. Here we investigate how the fate of a new mutation in a fluctuating environment depends on the dynamics of environmental variation and on the selective pressures in each condition. We find that even when a mutation experiences many environmental epochs before fixing or going extinct, its fate is not necessarily determined by its time-averaged selective effect. Instead, environmental variability reduces the efficiency of selection across a broad parameter regime, rendering selection unable to distinguish between mutations that are substantially beneficial and substantially deleterious on average. Temporal fluctuations can also dramatically increase fixation probabilities, often making the details of these fluctuations more important than the average selection pressures acting on each new mutation. For example, mutations that result in a trade-off between conditions but are strongly deleterious on average can nevertheless be more likely to fix than mutations that are always neutral or beneficial. These effects can have important implications for patterns of molecular evolution in variable environments, and they suggest that it may often be difficult for populations to maintain specialist traits, even when their loss leads to a decline in time-averaged fitness. PMID:26305937

  10. Stochastic dynamics of adaptive trait and neutral marker driven by eco-evolutionary feedbacks.

    Science.gov (United States)

    Billiard, Sylvain; Ferrière, Régis; Méléard, Sylvie; Tran, Viet Chi

    2015-11-01

    How the neutral diversity is affected by selection and adaptation is investigated in an eco-evolutionary framework. In our model, we study a finite population in continuous time, where each individual is characterized by a trait under selection and a completely linked neutral marker. Population dynamics are driven by births and deaths, mutations at birth, and competition between individuals. Trait values influence ecological processes (demographic events, competition), and competition generates selection on trait variation, thus closing the eco-evolutionary feedback loop. The demographic effects of the trait are also expected to influence the generation and maintenance of neutral variation. We consider a large population limit with rare mutation, under the assumption that the neutral marker mutates faster than the trait under selection. We prove the convergence of the stochastic individual-based process to a new measure-valued diffusive process with jumps that we call Substitution Fleming-Viot Process (SFVP). When restricted to the trait space this process is the Trait Substitution Sequence first introduced by Metz et al. (1996). During the invasion of a favorable mutation, a genetical bottleneck occurs and the marker associated with this favorable mutant is hitchhiked. By rigorously analysing the hitchhiking effect and how the neutral diversity is restored afterwards, we obtain the condition for a time-scale separation; under this condition, we show that the marker distribution is approximated by a Fleming-Viot distribution between two trait substitutions. We discuss the implications of the SFVP for our understanding of the dynamics of neutral variation under eco-evolutionary feedbacks and illustrate the main phenomena with simulations. Our results highlight the joint importance of mutations, ecological parameters, and trait values in the restoration of neutral diversity after a selective sweep.

  11. Induced mutation in tropical fruit trees

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2009-05-15

    This publication is based on an FAO/IAEA coordinated research project (CRP) and provides insight into the application of induced mutation and in vitro techniques for the improvement of well known fruit trees such as citrus, mango, avocado and papaya, as well as more exotic fruit trees such as litchi, annona, jujube, carambola, pitanga and jaboticaba. The latter are of particular importance due to their adaptation to harsh environments and their high potential as basic food and micronutrient providers for populations in poorer and more remote regions. The findings of the CRP show that application of radiation induced mutation techniques in tropical and subtropical fruit trees can contribute to improving nutritional balance food security, and to enhancing the economic status of growers.

  12. Induced mutation in tropical fruit trees

    International Nuclear Information System (INIS)

    2009-05-01

    This publication is based on an FAO/IAEA coordinated research project (CRP) and provides insight into the application of induced mutation and in vitro techniques for the improvement of well known fruit trees such as citrus, mango, avocado and papaya, as well as more exotic fruit trees such as litchi, annona, jujube, carambola, pitanga and jaboticaba. The latter are of particular importance due to their adaptation to harsh environments and their high potential as basic food and micronutrient providers for populations in poorer and more remote regions. The findings of the CRP show that application of radiation induced mutation techniques in tropical and subtropical fruit trees can contribute to improving nutritional balance food security, and to enhancing the economic status of growers

  13. Are There Mutator Polymerases?

    Directory of Open Access Journals (Sweden)

    Miguel Garcia-Diaz

    2003-01-01

    Full Text Available DNA polymerases are involved in different cellular events, including genome replication and DNA repair. In the last few years, a large number of novel DNA polymerases have been discovered, and the biochemical analysis of their properties has revealed a long list of intriguing features. Some of these polymerases have a very low fidelity and have been suggested to play mutator roles in different processes, like translesion synthesis or somatic hypermutation. The current view of these processes is reviewed, and the current understanding of DNA polymerases and their role as mutator enzymes is discussed.

  14. MUTATIONS IN CALMODULIN GENES

    DEFF Research Database (Denmark)

    2013-01-01

    The present invention relates to an isolated polynucleotide encoding at least a part of calmodulin and an isolated polypeptide comprising at least a part of a calmodulin protein, wherein the polynucleotide and the polypeptide comprise at least one mutation associated with a cardiac disorder. The ...... the binding of calmodulin to ryanodine receptor 2 and use of such compound in a treatment of an individual having a cardiac disorder. The invention further provides a kit that can be used to detect specific mutations in calmodulin encoding genes....

  15. Adaptation improves face trustworthiness discrimination

    Directory of Open Access Journals (Sweden)

    Bruce D Keefe

    2013-06-01

    Full Text Available Adaptation to facial characteristics, such as gender and viewpoint, has been shown to both bias our perception of faces and improve facial discrimination. In this study, we examined whether adapting to two levels of face trustworthiness improved sensitivity around the adapted level. Facial trustworthiness was manipulated by morphing between trustworthy and untrustworthy prototypes, each generated by morphing eight trustworthy and eight untrustworthy faces respectively. In the first experiment, just-noticeable differences (JNDs were calculated for an untrustworthy face after participants adapted to an untrustworthy face, a trustworthy face, or did not adapt. In the second experiment, the three conditions were identical, except that JNDs were calculated for a trustworthy face. In the third experiment we examined whether adapting to an untrustworthy male face improved discrimination to an untrustworthy female face. In all experiments, participants completed a two-interval forced-choice adaptive staircase procedure, in which they judged which face was more untrustworthy. JNDs were derived from a psychometric function fitted to the data. Adaptation improved sensitivity to faces conveying the same level of trustworthiness when compared to no adaptation. When adapting to and discriminating around a different level of face trustworthiness there was no improvement in sensitivity and JNDs were equivalent to those in the no adaptation condition. The improvement in sensitivity was found to occur even when adapting to a face with different gender and identity. These results suggest that adaptation to facial trustworthiness can selectively enhance mechanisms underlying the coding of facial trustworthiness to improve perceptual sensitivity. These findings have implications for the role of our visual experience in the decisions we make about the trustworthiness of other individuals.

  16. Pitfalls in genetic testing: the story of missed SCN1A mutations.

    Science.gov (United States)

    Djémié, Tania; Weckhuysen, Sarah; von Spiczak, Sarah; Carvill, Gemma L; Jaehn, Johanna; Anttonen, Anna-Kaisa; Brilstra, Eva; Caglayan, Hande S; de Kovel, Carolien G; Depienne, Christel; Gaily, Eija; Gennaro, Elena; Giraldez, Beatriz G; Gormley, Padhraig; Guerrero-López, Rosa; Guerrini, Renzo; Hämäläinen, Eija; Hartmann, Corinna; Hernandez-Hernandez, Laura; Hjalgrim, Helle; Koeleman, Bobby P C; Leguern, Eric; Lehesjoki, Anna-Elina; Lemke, Johannes R; Leu, Costin; Marini, Carla; McMahon, Jacinta M; Mei, Davide; Møller, Rikke S; Muhle, Hiltrud; Myers, Candace T; Nava, Caroline; Serratosa, Jose M; Sisodiya, Sanjay M; Stephani, Ulrich; Striano, Pasquale; van Kempen, Marjan J A; Verbeek, Nienke E; Usluer, Sunay; Zara, Federico; Palotie, Aarno; Mefford, Heather C; Scheffer, Ingrid E; De Jonghe, Peter; Helbig, Ingo; Suls, Arvid

    2016-07-01

    Sanger sequencing, still the standard technique for genetic testing in most diagnostic laboratories and until recently widely used in research, is gradually being complemented by next-generation sequencing (NGS). No single mutation detection technique is however perfect in identifying all mutations. Therefore, we wondered to what extent inconsistencies between Sanger sequencing and NGS affect the molecular diagnosis of patients. Since mutations in SCN1A, the major gene implicated in epilepsy, are found in the majority of Dravet syndrome (DS) patients, we focused on missed SCN1A mutations. We sent out a survey to 16 genetic centers performing SCN1A testing. We collected data on 28 mutations initially missed using Sanger sequencing. All patients were falsely reported as SCN1A mutation-negative, both due to technical limitations and human errors. We illustrate the pitfalls of Sanger sequencing and most importantly provide evidence that SCN1A mutations are an even more frequent cause of DS than already anticipated.

  17. Convergent evolution and adaptation of Pseudomonas aeruginosa within patients with cystic fibrosis

    DEFF Research Database (Denmark)

    Marvig, Rasmus Lykke; Madsen Sommer, Lea Mette; Molin, Søren

    2015-01-01

    fibrosis. Our analysis of 36 P. aeruginosa lineages identified convergent molecular evolution in 52 genes. This list of genes suggests a role in host adaptation for remodeling of regulatory networks and central metabolism, acquisition of antibiotic resistance and loss of extracellular virulence factors....... Furthermore, we find an ordered succession of mutations in key regulatory networks. Accordingly, mutations in downstream transcriptional regulators were contingent upon mutations in upstream regulators, suggesting that remodeling of regulatory networks might be important in adaptation. The characterization...

  18. Adaptation Insights

    International Development Research Centre (IDRC) Digital Library (Canada)

    Addressing Climate Change Adaptation in Africa through Participatory Action Research. A Regional Observatory ... while the average annual rainfall recorded between. 1968 and 1999 was .... the region of Thies. For sustainability reasons, the.

  19. Adaptation Stories

    International Development Research Centre (IDRC) Digital Library (Canada)

    By Reg'

    adaptation to climate change from various regions of the Sahel. Their .... This simple system, whose cost and maintenance were financially sustainable, brought ... method that enables him to learn from experience and save time, which he ...

  20. Preleukemic and second-hit mutational events in an acute myeloid leukemia patient with a novel germline RUNX1 mutation.

    Science.gov (United States)

    Ng, Isaac Ks; Lee, Joanne; Ng, Christopher; Kosmo, Bustamin; Chiu, Lily; Seah, Elaine; Mok, Michelle Meng Huang; Tan, Karen; Osato, Motomi; Chng, Wee-Joo; Yan, Benedict; Tan, Lip Kun

    2018-01-01

    Germline mutations in the RUNX1 transcription factor give rise to a rare autosomal dominant genetic condition classified under the entity: Familial Platelet Disorders with predisposition to Acute Myeloid Leukaemia (FPD/AML). While several studies have identified a myriad of germline RUNX1 mutations implicated in this disorder, second-hit mutational events are necessary for patients with hereditary thrombocytopenia to develop full-blown AML. The molecular picture behind this process remains unclear. We describe a patient of Malay descent with an unreported 7-bp germline RUNX1 frameshift deletion, who developed second-hit mutations that could have brought about the leukaemic transformation from a pre-leukaemic state. These mutations were charted through the course of the treatment and stem cell transplant, showing a clear correlation between her clinical presentation and the mutations present. The patient was a 27-year-old Malay woman who presented with AML on the background of hereditary thrombocytopenia affecting her father and 3 brothers. Initial molecular testing revealed the same novel RUNX1 mutation in all 5 individuals. The patient received standard induction, consolidation chemotherapy, and a haploidentical stem cell transplant from her mother with normal RUNX1 profile. Comprehensive genomic analyses were performed at diagnosis, post-chemotherapy and post-transplant. A total of 8 mutations ( RUNX1 , GATA2 , DNMT3A , BCORL1 , BCOR , 2 PHF6 and CDKN2A ) were identified in the pre-induction sample, of which 5 remained ( RUNX1 , DNMT3A , BCORL1 , BCOR and 1 out of 2 PHF6 ) in the post-treatment sample and none were present post-transplant. In brief, the 3 mutations which were lost along with the leukemic cells at complete morphological remission were most likely acquired leukemic driver mutations that were responsible for the AML transformation from a pre-leukemic germline RUNX1 -mutated state. On the contrary, the 5 mutations that persisted post

  1. Mutation directional selection sheds light on prion pathogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Shen, Liang [Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Shandong University of Technology, Zibo 255049 (China); Ji, Hong-Fang, E-mail: jhf@sdut.edu.cn [Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Shandong University of Technology, Zibo 255049 (China)

    2011-07-01

    Highlights: {yields} Most pathogenic mutations possess strong directional selection, i.e., enhancing hydrophobicity or decreasing negative and increasing positive charge. {yields} Mutation-induced changes may strengthen the interactions between PrP and facilitating factors. {yields} The findings also have significant implications for exploring potential regions involved in the conformational transition from PrP{sup C} to PrP{sup Sc}. -- Abstract: As mutations in the PRNP gene account for human hereditary prion diseases (PrDs), it is crucial to elucidating how these mutations affect the central pathogenic conformational transition of normal cellular prion protein (PrP{sup C}) to abnormal scrapie isoform (PrP{sup Sc}). Many studies proposed that these pathogenic mutations may make PrP more susceptible to conformational change through altering its structure stability. By evaluating the most recent observations regarding pathogenic mutations, it was found that the pathogenic mutations do not exert a uniform effect on the thermodynamic stability of the human PrP's structure. Through analyzing the reported PrDs-related mutations, we found that 25 out of 27 mutations possess strong directional selection, i.e., enhancing hydrophobicity or decreasing negative and increasing positive charge. Based on the triggering role reported by previous studies of facilitating factors in PrP{sup C} conversion, e.g., lipid and polyanion, we proposed that the mutation-induced changes may strengthen the interaction between PrP and facilitating factors, which will accelerate PrP conversion and cause PrDs.

  2. Mutation, somatic mutation and diseases of man

    International Nuclear Information System (INIS)

    Burnet, F.M.

    1976-01-01

    The relevance of the intrinsic mutagenesis for the evolution process, genetic diseases and the process of aging is exemplified. The fundamental reaction is the function of the DNA and the DNA-enzymes like the DNA-polymerases in replication, repair, and transcription. These defects are responsible for the mutation frequency and the genetic drift in the evolution process. They cause genetic diseases like Xeroderma pigmentosum which is described here in detail. The accumulation of structural and functional mistakes leads to diseases of old age, for example to autoimmune diseases and immune suppression. There is a proportionality between the duration of life and the frequency of mistakes in the enzymatic repair system. No possibility of prophylaxis or therapy is seen. Methods for prognosis could be developed. (AJ) [de

  3. The role of mutation in the new cancer paradigm

    Directory of Open Access Journals (Sweden)

    Prehn Richmond T

    2005-04-01

    Full Text Available Abstract The almost universal belief that cancer is caused by mutation may gradually be giving way to the belief that cancer begins as a cellular adaptation that involves the local epigenetic silencing of various genes. In my own interpretation of the new epigenetic paradigm, the genes epigenetically suppressed are genes that normally serve in post-embryonic life to suppress and keep suppressed those other genes upon which embryonic development depends. Those other genes, if not silenced or suppressed in the post-embryonic animal, become, I suggest, the oncogenes that are the basis of neoplasia. Mutations that occur in silenced genes supposedly go unrepaired and are, therefore, postulated to accumulate, but such mutations probably play little or no causative role in neoplasia because they occur in already epigenetically silenced genes. These mutations probably often serve to make the silencing, and therefore the cancer, epigenetically irreversible.

  4. Mutations and chromosomal aberrations

    International Nuclear Information System (INIS)

    Kihlman, B.A.

    1977-01-01

    The genetic changes of mutations and chromosomal aberrations are discussed. The consequences of both depend not only on the type of genetic change produced but also on the type of cell that is affected and on the development stage of the organism. (C.F.)

  5. Mutations in GABRB3

    DEFF Research Database (Denmark)

    Møller, Rikke S; Wuttke, Thomas V; Helbig, Ingo

    2017-01-01

    OBJECTIVE: To examine the role of mutations in GABRB3 encoding the β3 subunit of the GABAA receptor in individual patients with epilepsy with regard to causality, the spectrum of genetic variants, their pathophysiology, and associated phenotypes. METHODS: We performed massive parallel sequencing ...

  6. Kin Selection - Mutation Balance

    DEFF Research Database (Denmark)

    Dyken, J. David Van; Linksvayer, Timothy Arnold; Wade, Michael J.

    2011-01-01

    selection-mutation balance, which provides an evolutionary null hypothesis for the statics and dynamics of cheating. When social interactions have linear fitness effects and Hamilton´s rule is satisfied, selection is never strong enough to eliminate recurrent cheater mutants from a population, but cheater...

  7. Frequent beneficial mutations during single-colony serial transfer of Streptococcus pneumoniae.

    Directory of Open Access Journals (Sweden)

    Kathleen E Stevens

    2011-08-01

    Full Text Available The appearance of new mutations within a population provides the raw material for evolution. The consistent decline in fitness observed in classical mutation accumulation studies has provided support for the long-held view that deleterious mutations are more common than beneficial mutations. Here we present results of a study using a mutation accumulation design with the bacterium Streptococcus pneumoniae in which the fitness of the derived populations increased. This rise in fitness was associated specifically with adaptation to survival during brief stationary phase periods between single-colony population bottlenecks. To understand better the population dynamics behind this unanticipated adaptation, we developed a maximum likelihood model describing the processes of mutation and stationary-phase selection in the context of frequent population bottlenecks. Using this model, we estimate that the rate of beneficial mutations may be as high as 4.8×10(-4 events per genome for each time interval corresponding to the pneumococcal generation time. This rate is several orders of magnitude higher than earlier estimates of beneficial mutation rates in bacteria but supports recent results obtained through the propagation of small populations of Escherichia coli. Our findings indicate that beneficial mutations may be relatively frequent in bacteria and suggest that in S. pneumoniae, which develops natural competence for transformation, a steady supply of such mutations may be available for sampling by recombination.

  8. Ethical Considerations in Designing Adaptive Persuasive Games

    DEFF Research Database (Denmark)

    Pedersen, Christoffer Holmgård; Khaled, Rilla; Yannakakis, Georgios N.

    In this poster, we describe an ongoing project concerning the development of an Adaptive Treatment Game (ATG) for treating Post Traumatic Stress Disorder. The ATG uses biofeedback and computer game technology to enable multiple treatment techniques and goals. We examine how a multidisciplinary ap...... approach shaped the prototype and we discuss the ethical implications of creating a self-adaptive, semiautonomous treatment game....

  9. Is adaptation. Truly an adaptation? Is adaptation. Truly an adaptation?

    Directory of Open Access Journals (Sweden)

    Thais Flores Nogueira Diniz

    2008-04-01

    Full Text Available The article begins by historicizing film adaptation from the arrival of cinema, pointing out the many theoretical approaches under which the process has been seen: from the concept of “the same story told in a different medium” to a comprehensible definition such as “the process through which works can be transformed, forming an intersection of textual surfaces, quotations, conflations and inversions of other texts”. To illustrate this new concept, the article discusses Spike Jonze’s film Adaptation. according to James Naremore’s proposal which considers the study of adaptation as part of a general theory of repetition, joined with the study of recycling, remaking, and every form of retelling. The film deals with the attempt by the scriptwriter Charles Kaufman, cast by Nicholas Cage, to adapt/translate a non-fictional book to the cinema, but ends up with a kind of film which is by no means what it intended to be: a film of action in the model of Hollywood productions. During the process of creation, Charles and his twin brother, Donald, undergo a series of adventures involving some real persons from the world of film, the author and the protagonist of the book, all of them turning into fictional characters in the film. In the film, adaptation then signifies something different from itstraditional meaning. The article begins by historicizing film adaptation from the arrival of cinema, pointing out the many theoretical approaches under which the process has been seen: from the concept of “the same story told in a different medium” to a comprehensible definition such as “the process through which works can be transformed, forming an intersection of textual surfaces, quotations, conflations and inversions of other texts”. To illustrate this new concept, the article discusses Spike Jonze’s film Adaptation. according to James Naremore’s proposal which considers the study of adaptation as part of a general theory of repetition

  10. Mutations in galactosemia

    Energy Technology Data Exchange (ETDEWEB)

    Reichardt, J.K.V. [Univ. of Southern California School of Medicine, Los Angeles, CA (United States)

    1995-10-01

    This Letter raises four issues concerning two papers on galactosemia published in the March 1995 of the Journal. First, table 2 in the paper by Elsas et al. incorrectly attributes seven galactose-l-phosphate uridyl transferase (GALT) mutations (S135L, L195P, K285N, N314D, R333W, R333G, and K334R). The table also fails to mention that others have reported the same two findings attributed to {open_quotes}Leslie et al.; Elsas et al. and in press{close_quotes} and {open_quotes}Leslie et al.; Elsas et al.{close_quotes} The first finding on the prevalence of the Q188R galactosemia mutation in the G/G Caucasian population has also been described by Ng et al., and the second finding on the correlation of the N314D GALT mutation with the Duarte variant was reported by Lin et al. Second, Elsas et al. suggest that the E203K and N314D mutations may {open_quotes}produce intra-allelic complementation when in cis{close_quotes}. This speculation is supported by the activity data of individual III-2 but is inconsistent with the activities of three other individuals I-1, II-1, and III-1 of the same pedigree. The GALT activity measured in these three individuals suggests a dominant negative effect of E203K in E203K-N314D chromosomes, since they all have less than normal activity. Thus, the preponderance of the data in this paper is at odds with the authors speculation. It is worth recalling that Lin et al. also identified four N314D GALT mutations on 95 galactosemic chromosomes examined. A similar situation also appears to be the case in proband III-1 (with genotype E203K-N314D/IVSC) in the Elsas et al. paper. 9 refs.

  11. Mutation breeding newsletter. No. 45

    International Nuclear Information System (INIS)

    2001-07-01

    This issue of the Mutation Breeding newsletter contains 39 articles dealing with radiation induced mutations and chemical mutagenesis techniques in plant breeding programs with the aims of improving crop productivity and disease resistance as well as exploring genetic variabilities

  12. Mutation breeding newsletter. No. 33

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1989-01-01

    This issue of the newsletter reports a number of research news and research abstracts on application of radiation induced mutation techniques to increase mutagenesis and mutation frequency in plant breeding projects.

  13. Mutation breeding newsletter. No. 33

    International Nuclear Information System (INIS)

    1989-01-01

    This issue of the newsletter reports a number of research news and research abstracts on application of radiation induced mutation techniques to increase mutagenesis and mutation frequency in plant breeding projects

  14. Mutations and binding sites of human transcription factors

    KAUST Repository

    Kamanu, Frederick Kinyua

    2012-06-01

    Mutations in any genome may lead to phenotype characteristics that determine ability of an individual to cope with adaptation to environmental challenges. In studies of human biology, among the most interesting ones are phenotype characteristics that determine responses to drug treatments, response to infections, or predisposition to specific inherited diseases. Most of the research in this field has been focused on the studies of mutation effects on the final gene products, peptides, and their alterations. Considerably less attention was given to the mutations that may affect regulatory mechanism(s) of gene expression, although these may also affect the phenotype characteristics. In this study we make a pilot analysis of mutations observed in the regulatory regions of 24,667 human RefSeq genes. Our study reveals that out of eight studied mutation types, insertions are the only one that in a statistically significant manner alters predicted transcription factor binding sites (TFBSs). We also find that 25 families of TFBSs have been altered by mutations in a statistically significant manner in the promoter regions we considered. Moreover, we find that the related transcription factors are, for example, prominent in processes related to intracellular signaling; cell fate; morphogenesis of organs and epithelium; development of urogenital system, epithelium, and tube; neuron fate commitment. Our study highlights the significance of studying mutations within the genes regulatory regions and opens way for further detailed investigations on this topic, particularly on the downstream affected pathways. 2012 Kamanu, Medvedeva, Schaefer, Jankovic, Archer and Bajic.

  15. Interfering Waves of Adaptation Promote Spatial Mixing

    DEFF Research Database (Denmark)

    Martens, Erik Andreas; Hallatschek, Oskar

    2011-01-01

    A fundamental problem of asexual adaptation is that beneficial substitutions are not efficiently accumulated in large populations: Beneficial mutations often go extinct because they compete with one another in going to fixation. It has been argued that such clonal interference may have led...... to the evolution of sex and recombination in well-mixed populations. Here, we study clonal interference, and mechanisms of its mitigation, in an evolutionary model of spatially structured populations with uniform selection pressure. Clonal interference is much more prevalent with spatial structure than without......, due to the slow wave-like spread of beneficial mutations through space. We find that the adaptation speed of asexuals saturates when the linear habitat size exceeds a characteristic interference length, which becomes shorter with smaller migration and larger mutation rate. The limiting speed...

  16. Adaptation dynamics of the quasispecies model

    Indian Academy of Sciences (India)

    We study the adaptation dynamics of an initially maladapted population evolving via the elementary processes of mutation and selection. The evolution occurs on rugged fitness landscapes which are defined on the multi-dimensional genotypic space and have many local peaks separated by low fitness valleys. We mainly ...

  17. Disease-associated mutations disrupt functionally important regions of intrinsic protein disorder.

    Directory of Open Access Journals (Sweden)

    Vladimir Vacic

    offer a new perspective on the role of mutations in disease, with implications for improving predictors of the functional impact of missense mutations.

  18. Adaptive Markets and the New World Order

    OpenAIRE

    Lo, Andrew W.

    2012-01-01

    In the adaptive markets hypothesis (AMH) intelligent but fallible investors learn from and adapt to changing economic environments. This implies that markets are not always efficient but are usually competitive and adaptive, varying in their degree of efficiency as the environment and investor population change over time. The AMH has several implications, including the possibility of negative risk premiums, alpha converging to beta, and the importance of macro factors and risk budgeting in as...

  19. Understanding the adaptive approach to thermal comfort

    Energy Technology Data Exchange (ETDEWEB)

    Humphreys, M.A. [Oxford Univ. (United Kingdom). Centre for the Study of Christianity and Culture; Nicol, J.F. [Oxford Brookes Univ. (United Kingdom). School of Architecture

    1998-10-01

    This paper explains the adaptive approach to thermal comfort, and an adaptive model for thermal comfort is presented. The model is an example of a complex adaptive system (Casti 1996) whose equilibria are determined by the restrictions acting upon it. People`s adaptive actions are generally effective in securing comfort, which occurs at a wide variety of indoor temperatures. These comfort temperatures depend upon the circumstances in which people live, such as the climate and the heating or cooling regime. The temperatures may be estimated from the mean outdoor temperature and the availability of a heating or cooling plant. The evaluation of the parameters of the adaptive model requires cross-sectional surveys to establish current norms and sequential surveys (with and without intervention) to evaluate the rapidity of people`s adaptive actions. Standards for thermal comfort will need revision in the light of the adaptive approach. Implications of the adaptive model for the HVAC industry are noted.

  20. Genetic mutations associated with status epilepticus.

    Science.gov (United States)

    Bhatnagar, M; Shorvon, S

    2015-08-01

    -onset status epilepticus cases remains obscure. It has been suggested that idiopathic adult-onset status epilepticus might often have an immunological cause but no gene mutations which relate to immunological mechanisms were identified. Overall, the clinical utility of what is currently known about the genetics of status epilepticus is slight and the findings have had little impact on clinical treatment despite what has been a very large investment in money and time. New genetic technologies may result in the identification of further genes, but if the identified genetic defects confer only minor susceptibility, this is unlikely to influence therapy. It is also important to recognize that genetics has social implications in a way that other areas of science do not. This article is part of a Special Issue entitled "Status Epilepticus". Copyright © 2015. Published by Elsevier Inc.

  1. Sustainable groundwater use, the capture principle, and adaptive ...

    African Journals Online (AJOL)

    Implications for using the capture principle in the implementation of the NWA are discussed, and adaptive management is proposed as an appropriate management approach. Implications for groundwater monitoring are also discussed. Case studies are described that support the need for adaptive management and the ...

  2. Implicative Algebras

    African Journals Online (AJOL)

    Tadesse

    In this paper we introduce the concept of implicative algebras which is an equivalent definition of lattice implication algebra of Xu (1993) and further we prove that it is a regular Autometrized. Algebra. Further we remark that the binary operation → on lattice implicative algebra can never be associative. Key words: Implicative ...

  3. A phenotype of atypical apraxia of speech in a family carrying SQSTM1 mutation.

    Science.gov (United States)

    Boutoleau-Bretonnière, Claire; Camuzat, Agnès; Le Ber, Isabelle; Bouya-Ahmed, Kawtar; Guerreiro, Rita; Deruet, Anne-Laure; Evrard, Christelle; Bras, José; Lamy, Estelle; Auffray-Calvier, Elisabeth; Pallardy, Amandine; Hardy, John; Brice, Alexis; Derkinderen, Pascal; Vercelletto, Martine

    2015-01-01

    SQSTM1 mutations, coding for the p62 protein, were identified as a monogenic cause of Paget disease of bone and of amyotrophic lateral sclerosis. More recently, SQSTM1 mutations were identified in few families with frontotemporal dementia. We report a new family carrying SQSTM1 mutation and presenting with a clinical phenotype of speech apraxia or atypical behavioral disorders, associated with early visuo-contructional deficits. This study further supports the implication of SQSTM1 in frontotemporal dementia, and enlarges the phenotypic spectrum associated with SQSTM1 mutations.

  4. Neurogenomics and the role of a large mutational target on rapid behavioral change.

    Science.gov (United States)

    Stanley, Craig E; Kulathinal, Rob J

    2016-11-08

    , the large mutational target hypothesis places genomic architecture and a larger allelic pool at the forefront of rapid evolutionary change, particularly in genetic systems that are polygenic and regulatory in nature. Genomic data from brain and neural tissues in mammals as well as a preliminary survey of neurogenic genes from comparative genomic data support this hypothesis while rejecting both positive and relaxed selection on proteins or higher mutation rates. In mammals and invertebrates, neurogenic genes harbor larger protein-coding regions and possess a richer regulatory repertoire of miRNA targets and transcription factor binding sites. Overall, neurogenic genes cover a disproportionately large genomic fraction, providing a sizeable substrate for evolutionary, genetic, and molecular mechanisms to act upon. Readily available comparative and functional genomic data provide unexplored opportunities to test whether a distinct neurogenomic architecture can promote rapid behavioral change via several mechanisms unique to large genes, and which components of this large footprint are uniquely metazoan. The large mutational target hypothesis highlights the eminent roles of mutation and functional genomic architecture in generating rapid developmental and evolutionary change. It has broad implications on our understanding of the genetics of complex adaptive traits such as behavior by focusing on the importance of mutational input, from SNPs to alternative transcripts to transposable elements, on driving evolutionary rates of functional systems. Such functional divergence has important implications in promoting behavioral isolation across short- and long-term timescales. Due to genome-scaled polygenic adaptation, the large target effect also contributes to our inability to identify adapted behavioral candidate genes. The presence of large neurogenic genes, particularly in the mammalian brain and other neural tissues, further offers emerging insight into the etiology of

  5. Strategic Adaptation

    DEFF Research Database (Denmark)

    Andersen, Torben Juul

    2015-01-01

    This article provides an overview of theoretical contributions that have influenced the discourse around strategic adaptation including contingency perspectives, strategic fit reasoning, decision structure, information processing, corporate entrepreneurship, and strategy process. The related...... concepts of strategic renewal, dynamic managerial capabilities, dynamic capabilities, and strategic response capabilities are discussed and contextualized against strategic responsiveness. The insights derived from this article are used to outline the contours of a dynamic process of strategic adaptation....... This model incorporates elements of central strategizing, autonomous entrepreneurial behavior, interactive information processing, and open communication systems that enhance the organization's ability to observe exogenous changes and respond effectively to them....

  6. Adaptive Lighting

    DEFF Research Database (Denmark)

    Petersen, Kjell Yngve; Kongshaug, Jesper; Søndergaard, Karin

    2015-01-01

    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...... to be static, and no longer acts as a kind of spatial constancy maintaining stability and order? Moreover, what new potentials open in lighting design? This book is one of four books that is published in connection with the research project entitled LED Lighting; Interdisciplinary LED Lighting Research...

  7. Adaptive test

    DEFF Research Database (Denmark)

    Kjeldsen, Lars Peter; Eriksen, Mette Rose

    2010-01-01

    Artikelen er en evaluering af de adaptive tests, som blev indført i folkeskolen. Artiklen sætter særligt fokus på evaluering i folkeskolen, herunder bidrager den med vejledning til evaluering, evalueringsværktøjer og fagspecifkt evalueringsmateriale.......Artikelen er en evaluering af de adaptive tests, som blev indført i folkeskolen. Artiklen sætter særligt fokus på evaluering i folkeskolen, herunder bidrager den med vejledning til evaluering, evalueringsværktøjer og fagspecifkt evalueringsmateriale....

  8. Mutation breeding in pepper

    Energy Technology Data Exchange (ETDEWEB)

    Daskalov, S [Plant Breeding Unit, Joint FAO/IAEA Division of Isotope and Radiation Applications of Atomic Energy for Food and Agricultural Development, Seibersdorf Laboratory, International Atomic Energy Agency, Vienna (Austria)

    1986-03-01

    Pepper (Capsicum sp.) is an important vegetable and spice crop widely grown in tropical as well as in temperate regions. Until recently the improvement programmes were based mainly on using natural sources of germ plasma, crossbreeding and exploiting the heterosis of F{sub 1} hybrids. However, interest in using induced mutations is growing. A great number of agronomically useful mutants as well as mutants valuable for genetic, cytological and physiological studies have been induced and described. In this review information is presented about suitable mutagen treatment procedures with radiation as well as chemicals, M{sub 1} effects, handling the treated material in M{sub 1}, M{sub 2} and subsequent generations, and mutant screening procedures. This is supplemented by a description of reported useful mutants and released cultivars. Finally, general advice is given on when and how to incorporate mutation induction in Capsicum improvement programmes. (author)

  9. Mutation breeding in pepper

    International Nuclear Information System (INIS)

    Daskalov, S.

    1986-01-01

    Pepper (Capsicum sp.) is an important vegetable and spice crop widely grown in tropical as well as in temperate regions. Until recently the improvement programmes were based mainly on using natural sources of germ plasma, crossbreeding and exploiting the heterosis of F 1 hybrids. However, interest in using induced mutations is growing. A great number of agronomically useful mutants as well as mutants valuable for genetic, cytological and physiological studies have been induced and described. In this review information is presented about suitable mutagen treatment procedures with radiation as well as chemicals, M 1 effects, handling the treated material in M 1 , M 2 and subsequent generations, and mutant screening procedures. This is supplemented by a description of reported useful mutants and released cultivars. Finally, general advice is given on when and how to incorporate mutation induction in Capsicum improvement programmes. (author)

  10. Lack of MEF2A mutations in coronary artery disease

    Energy Technology Data Exchange (ETDEWEB)

    Weng, Li; Kavaslar, Nihan; Ustaszewska, Anna; Doelle, Heather; Schackwitz, Wendy; Hebert, Sybil; Cohen, Jonathan; McPherson, Ruth; Pennacchio, Len A.

    2004-12-01

    Mutations in MEF2A have been implicated in an autosomal dominant form of coronary artery disease (adCAD1). In this study we sought to determine whether severe mutations in MEF2A might also explain sporadic cases of coronary artery disease (CAD). To do this, we resequenced the coding sequence and splice sites of MEF2A in {approx}300 patients with premature CAD and failed to find causative mutations in the CAD cohort. However, we did identify the 21 base pair (bp) MEF2A coding sequence deletion originally implicated in adCAD1 in one of 300 elderly control subjects without CAD. Further screening of an additional {approx}1,500 non-CAD patients revealed two more subjects with the MEF2A 21 bp deletion. Genotyping of 19 family members of the three probands with the 21 bp deletion in MEF2A revealed that the mutation did not co-segregate with early CAD. These studies demonstrate that MEF2A mutations are not a common cause of CAD and cast serious doubt on the role of the MEF2A 21 bp deletion in adCAD1.

  11. Is adaptation. Truly an adaptation?

    Directory of Open Access Journals (Sweden)

    Thais Flores Nogueira Diniz

    2006-04-01

    Full Text Available The article begins by historicizing film adaptation from the arrival of cinema, pointing out the many theoretical approaches under which the process has been seen: from the concept of “the same story told in a different medium” to a comprehensible definition such as “the process through which works can be transformed, forming an intersection of textual surfaces, quotations, conflations and inversions of other texts”. To illustrate this new concept, the article discusses Spike Jonze’s film Adaptation. according to James Naremore’s proposal which considers the study of adaptation as part of a general theory of repetition, joined with the study of recycling, remaking, and every form of retelling. The film deals with the attempt by the scriptwriter Charles Kaufman, cast by Nicholas Cage, to adapt/translate a non-fictional book to the cinema, but ends up with a kind of film which is by no means what it intended to be: a film of action in the model of Hollywood productions. During the process of creation, Charles and his twin brother, Donald, undergo a series of adventures involving some real persons from the world of film, the author and the protagonist of the book, all of them turning into fictional characters in the film. In the film, adaptation then signifies something different from itstraditional meaning.

  12. A pathway-centric survey of somatic mutations in Chinese patients with colorectal carcinomas.

    Directory of Open Access Journals (Sweden)

    Chao Ling

    Full Text Available Previous genetic studies on colorectal carcinomas (CRC have identified multiple somatic mutations in four candidate pathways (TGF-β, Wnt, P53 and RTK-RAS pathways on populations of European ancestry. However, it is under-studied whether other populations harbor different sets of hot-spot somatic mutations in these pathways and other oncogenes. In this study, to evaluate the mutational spectrum of novel somatic mutations, we assessed 41 pairs of tumor-stroma tissues from Chinese patients with CRC, including 29 colon carcinomas and 12 rectal carcinomas. We designed Illumina Custom Amplicon panel to target 43 genes, including genes in the four candidate pathways, as well as several known oncogenes for other cancers. Candidate mutations were validated by Sanger sequencing, and we further used SIFT and PolyPhen-2 to assess potentially functional mutations. We discovered 3 new somatic mutations in gene APC, TCF7L2, and PIK3CA that had never been reported in the COSMIC or NCI-60 databases. Additionally, we confirmed 6 known somatic mutations in gene SMAD4, APC, FBXW7, BRAF and PTEN in Chinese CRC patients. While most were previously reported in CRC, one mutation in PTEN was reported only in malignant endometrium cancer. Our study confirmed the existence of known somatic mutations in the four candidate pathways for CRC in Chinese patients. We also discovered a number of novel somatic mutations in these pathways, which may have implications for the pathogenesis of CRC.

  13. Sex speeds adaptation by altering the dynamics of molecular evolution.

    Science.gov (United States)

    McDonald, Michael J; Rice, Daniel P; Desai, Michael M

    2016-03-10

    Sex and recombination are pervasive throughout nature despite their substantial costs. Understanding the evolutionary forces that maintain these phenomena is a central challenge in biology. One longstanding hypothesis argues that sex is beneficial because recombination speeds adaptation. Theory has proposed several distinct population genetic mechanisms that could underlie this advantage. For example, sex can promote the fixation of beneficial mutations either by alleviating interference competition (the Fisher-Muller effect) or by separating them from deleterious load (the ruby in the rubbish effect). Previous experiments confirm that sex can increase the rate of adaptation, but these studies did not observe the evolutionary dynamics that drive this effect at the genomic level. Here we present the first, to our knowledge, comparison between the sequence-level dynamics of adaptation in experimental sexual and asexual Saccharomyces cerevisiae populations, which allows us to identify the specific mechanisms by which sex speeds adaptation. We find that sex alters the molecular signatures of evolution by changing the spectrum of mutations that fix, and confirm theoretical predictions that it does so by alleviating clonal interference. We also show that substantially deleterious mutations hitchhike to fixation in adapting asexual populations. In contrast, recombination prevents such mutations from fixing. Our results demonstrate that sex both speeds adaptation and alters its molecular signature by allowing natural selection to more efficiently sort beneficial from deleterious mutations.

  14. Unveiling adaptation using high-resolution lineage tracking

    Science.gov (United States)

    Blundell, Jamie; Levy, Sasha; Fisher, Daniel; Petrov, Dmitri; Sherlock, Gavin

    2013-03-01

    Human diseases such as cancer and microbial infections are adaptive processes inside the human body with enormous population sizes: between 106 -1012 cells. In spite of this our understanding of adaptation in large populations is limited. The key problem is the difficulty in identifying anything more than a handful of rare, large-effect beneficial mutations. The development and use of molecular barcodes allows us to uniquely tag hundreds of thousands of cells and enable us to track tens of thousands of adaptive mutations in large yeast populations. We use this system to test some of the key theories on which our understanding of adaptation in large populations is based. We (i) measure the fitness distribution in an evolving population at different times, (ii) identify when an appreciable fraction of clones in the population have at most a single adaptive mutation and isolate a large number of clones with independent single adaptive mutations, and (iii) use this clone collection to determine the distribution of fitness effects of single beneficial mutations.

  15. Mutated hilltop inflation revisited

    Science.gov (United States)

    Pal, Barun Kumar

    2018-05-01

    In this work we re-investigate pros and cons of mutated hilltop inflation. Applying Hamilton-Jacobi formalism we solve inflationary dynamics and find that inflation goes on along the {W}_{-1} branch of the Lambert function. Depending on the model parameter mutated hilltop model renders two types of inflationary solutions: one corresponds to small inflaton excursion during observable inflation and the other describes large field inflation. The inflationary observables from curvature perturbation are in tune with the current data for a wide range of the model parameter. The small field branch predicts negligible amount of tensor to scalar ratio r˜ O(10^{-4}), while the large field sector is capable of generating high amplitude for tensor perturbations, r˜ O(10^{-1}). Also, the spectral index is almost independent of the model parameter along with a very small negative amount of scalar running. Finally we find that the mutated hilltop inflation closely resembles the α -attractor class of inflationary models in the limit of α φ ≫ 1.

  16. Mutation breeding in jute

    International Nuclear Information System (INIS)

    Joshua, D.C.

    1980-01-01

    Mutagenic studies in jute in general dealt with the morphological abnormalities of the M 1 generation in great detail. Of late, induction of a wide spectrum of viable mutations have been reported in different varieties of both the species. Mutations affecting several traits of agronomic importance such as, plant height, time of flowering, fibre yield and quality, resistance to pests and diseases are also available. Cytological analysis of a large collection of induced mutants resulted in the isolation of seven trisomics in an olitorius variety. Several anatomical parameters which are the components of fibre yield, have also received attention. Some mutants with completely altered morphology were used for interpreting the evolution of leaf shape in Tiliaceas and related families. A capsularis variety developed using mutation breeding technique has been released for cultivation. Several others, including derivatives of inter-mutant hybridization have been found to perform well at different locations in the All India Coordinated Trials. Presently, chemical mutagenesis and induction of mutants of physiological significance are receiving considerable attention. The induced variability is being used in genetic and linkage studies. (author)

  17. Adaptation is...

    International Development Research Centre (IDRC) Digital Library (Canada)

    IDRC

    vital sector is under threat. While it is far from the only development challenge facing local farmers, extreme variations in the climate of West Africa in the past several decades have dealt the region a bad hand. Drought and flood now follow each other in succession. Adaptation is... “The floods spoiled our harvests and we.

  18. Ambiguous Adaptation

    DEFF Research Database (Denmark)

    Møller Larsen, Marcus; Lyngsie, Jacob

    and reciprocal adaptation of informal governance structure create ambiguity in situations of contingencies, which, subsequently, increases the likelihood of premature relationship termination. Using a large sample of exchange relationships in the global service provider industry, we find support for a hypothesis...

  19. Mutational analysis of EGFR and related signaling pathway genes in lung adenocarcinomas identifies a novel somatic kinase domain mutation in FGFR4.

    Directory of Open Access Journals (Sweden)

    Jenifer L Marks

    2007-05-01

    Full Text Available Fifty percent of lung adenocarcinomas harbor somatic mutations in six genes that encode proteins in the EGFR signaling pathway, i.e., EGFR, HER2/ERBB2, HER4/ERBB4, PIK3CA, BRAF, and KRAS. We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other potential somatic mutations in genes of this signaling pathway that could contribute to lung tumorigenesis.We analyzed genomic DNA from a total of 261 resected, clinically annotated non-small cell lung cancer (NSCLC specimens. The coding sequences of 39 genes were screened for somatic mutations via high-throughput dideoxynucleotide sequencing of PCR-amplified gene products. Mutations were considered to be somatic only if they were found in an independent tumor-derived PCR product but not in matched normal tissue. Sequencing of 9MB of tumor sequence identified 239 putative genetic variants. We further examined 22 variants found in RAS family genes and 135 variants localized to exons encoding the kinase domain of respective proteins. We identified a total of 37 non-synonymous somatic mutations; 36 were found collectively in EGFR, KRAS, BRAF, and PIK3CA. One somatic mutation was a previously unreported mutation in the kinase domain (exon 16 of FGFR4 (Glu681Lys, identified in 1 of 158 tumors. The FGFR4 mutation is analogous to a reported tumor-specific somatic mutation in ERBB2 and is located in the same exon as a previously reported kinase domain mutation in FGFR4 (Pro712Thr in a lung adenocarcinoma cell line.This study is one of the first comprehensive mutational analyses of major genes in a specific signaling pathway in a sizeable cohort of lung adenocarcinomas. Our results suggest the majority of gain-of-function mutations within kinase genes in the EGFR signaling pathway have already been identified. Our findings also implicate FGFR4 in the pathogenesis of a subset of lung adenocarcinomas.

  20. Mining TCGA data using Boolean implications.

    Directory of Open Access Journals (Sweden)

    Subarna Sinha

    Full Text Available Boolean implications (if-then rules provide a conceptually simple, uniform and highly scalable way to find associations between pairs of random variables. In this paper, we propose to use Boolean implications to find relationships between variables of different data types (mutation, copy number alteration, DNA methylation and gene expression from the glioblastoma (GBM and ovarian serous cystadenoma (OV data sets from The Cancer Genome Atlas (TCGA. We find hundreds of thousands of Boolean implications from these data sets. A direct comparison of the relationships found by Boolean implications and those found by commonly used methods for mining associations show that existing methods would miss relationships found by Boolean implications. Furthermore, many relationships exposed by Boolean implications reflect important aspects of cancer biology. Examples of our findings include cis relationships between copy number alteration, DNA methylation and expression of genes, a new hierarchy of mutations and recurrent copy number alterations, loss-of-heterozygosity of well-known tumor suppressors, and the hypermethylation phenotype associated with IDH1 mutations in GBM. The Boolean implication results used in the paper can be accessed at http://crookneck.stanford.edu/microarray/TCGANetworks/.

  1. Double-stranded-RNA-specific adenosine deaminase 1 (ADAR1) is proposed to contribute to the adaptation of equine infectious anemia virus from horses to donkeys.

    Science.gov (United States)

    Tang, Yan-Dong; Zhang, Xiang; Na, Lei; Wang, Xue-Feng; Fu, Li-Hua; Zhu, Chun-Hui; Wang, Xiaojun; Zhou, Jian-Hua

    2016-10-01

    Equine infectious anemia virus (EIAV) is a member of the genus Lentivirus of the family Retroviridae. Horses are the most susceptible equids to EIAV infection and are therefore the primary hosts of this virus. In contrast, infected donkeys do not develop clinically active equine infectious anemia (EIA). This phenomenon is similar to what has been observed with HIV-1, which fails to induce AIDS in non-human primates. Interestingly, Shen et al. developed a donkey-tropic pathogenic virus strain (EIAVDV117, DV117) by serially passaging a horse-tropic pathogenic strain, EIAVLN40 (LN40), in donkeys. LN40, which was generated by passaging a field isolate in horses, displayed enhanced virulence in horses but caused no clinical symptoms in donkeys. Infection with DV117 induced acute EIA in nearly 100 % of donkeys. Genomic analysis of DV117 revealed a significantly higher frequency of A-to-G substitutions when compared to LN40. Furthermore, detailed analysis of dinucleotide editing showed that A-to-G mutations had a preference for 5'TpA and 5'ApA. These results strongly implicated the activity of the adenosine deaminase, ADAR1, in this type of mutation. Further investigation demonstrated that overexpression of donkey ADAR1 increased A-to-G mutations within the genome of EIAV. Together with our previous finding that multiple mutations in multiple genes are generated in DV117 during its adaptation from horses to donkeys, the present study suggests that ADAR1-induced A-to-G mutations occur during virus adaption to related new hosts contributing to the alteration of EIAV host tropism.

  2. Systematic Analysis of Splice-Site-Creating Mutations in Cancer.

    Science.gov (United States)

    Jayasinghe, Reyka G; Cao, Song; Gao, Qingsong; Wendl, Michael C; Vo, Nam Sy; Reynolds, Sheila M; Zhao, Yanyan; Climente-González, Héctor; Chai, Shengjie; Wang, Fang; Varghese, Rajees; Huang, Mo; Liang, Wen-Wei; Wyczalkowski, Matthew A; Sengupta, Sohini; Li, Zhi; Payne, Samuel H; Fenyö, David; Miner, Jeffrey H; Walter, Matthew J; Vincent, Benjamin; Eyras, Eduardo; Chen, Ken; Shmulevich, Ilya; Chen, Feng; Ding, Li

    2018-04-03

    For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for the large-scale discovery of splice-site-creating mutations (SCMs) across 8,656 TCGA tumors. We report 1,964 originally mis-annotated mutations having clear evidence of creating alternative splice junctions. TP53 and GATA3 have 26 and 18 SCMs, respectively, and ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function. Notably, we found that neoantigens induced by SCMs are likely several folds more immunogenic compared to missense mutations, exemplified by the recurrent GATA3 SCM. Further, high expression of PD-1 and PD-L1 was observed in tumors with SCMs, suggesting candidates for immune blockade therapy. Our work highlights the importance of integrating DNA and RNA data for understanding the functional and the clinical implications of mutations in human diseases. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Heterozygous RTEL1 mutations are associated with familial pulmonary fibrosis.

    Science.gov (United States)

    Kannengiesser, Caroline; Borie, Raphael; Ménard, Christelle; Réocreux, Marion; Nitschké, Patrick; Gazal, Steven; Mal, Hervé; Taillé, Camille; Cadranel, Jacques; Nunes, Hilario; Valeyre, Dominique; Cordier, Jean François; Callebaut, Isabelle; Boileau, Catherine; Cottin, Vincent; Grandchamp, Bernard; Revy, Patrick; Crestani, Bruno

    2015-08-01

    Pulmonary fibrosis is a fatal disease with progressive loss of respiratory function. Defective telomere maintenance leading to telomere shortening is a cause of pulmonary fibrosis, as mutations in the telomerase component genes TERT (reverse transcriptase) and TERC (RNA component) are found in 15% of familial pulmonary fibrosis (FPF) cases. However, so far, about 85% of FPF remain genetically uncharacterised.Here, in order to identify new genetic causes of FPF, we performed whole-exome sequencing, with a candidate-gene approach, of 47 affected subjects from 35 families with FPF without TERT and TERC mutations.We identified heterozygous mutations in regulator of telomere elongation helicase 1 (RTEL1) in four families. RTEL1 is a DNA helicase with roles in DNA replication, genome stability, DNA repair and telomere maintenance. The heterozygous RTEL1 mutations segregated as an autosomal dominant trait in FPF, and were predicted by structural analyses to severely affect the function and/or stability of RTEL1. In agreement with this, RTEL1-mutated patients exhibited short telomeres in comparison with age-matched controls.Our results provide evidence that heterozygous RTEL1 mutations are responsible for FPF and, thereby, extend the clinical spectrum of RTEL1 deficiency. Thus, RTEL1 enlarges the number of telomere-associated genes implicated in FPF. Copyright ©ERS 2015.

  4. Cold-Adapted Enzymes

    Science.gov (United States)

    Georlette, D.; Bentahir, M.; Claverie, P.; Collins, T.; D'amico, S.; Delille, D.; Feller, G.; Gratia, E.; Hoyoux, A.; Lonhienne, T.; Meuwis, M.-a.; Zecchinon, L.; Gerday, Ch.

    In the last few years, increased attention has been focused on enzymes produced by cold-adapted micro-organisms. It has emerged that psychrophilic enzymes represent an extremely powerful tool in both protein folding investigations and for biotechnological purposes. Such enzymes are characterised by an increased thermosensitivity and, most of them, by a higher catalytic efficiency at low and moderate temperatures, when compared to their mesophilic counterparts. The high thermosensitivity probably originates from an increased flexibility of either a selected area of the molecular edifice or the overall protein structure, providing enhanced abilities to undergo conformational changes during catalysis at low temperatures. Structure modelling and recent crystallographic data have allowed to elucidate the structural parameters that could be involved in this higher resilience. It was demonstrated that each psychrophilic enzyme adopts its own adaptive strategy. It appears, moreover, that there is a continuum in the strategy of protein adaptation to temperature, as the previously mentioned structural parameters are implicated in the stability of thermophilic proteins. Additional 3D crystal structures, site-directed and random mutagenesis experiments should now be undertaken to further investigate the stability-flexibility-activity relationship.

  5. Adaptive evolution of molecular phenotypes

    International Nuclear Information System (INIS)

    Held, Torsten; Nourmohammad, Armita; Lässig, Michael

    2014-01-01

    Molecular phenotypes link genomic information with organismic functions, fitness, and evolution. Quantitative traits are complex phenotypes that depend on multiple genomic loci. In this paper, we study the adaptive evolution of a quantitative trait under time-dependent selection, which arises from environmental changes or through fitness interactions with other co-evolving phenotypes. We analyze a model of trait evolution under mutations and genetic drift in a single-peak fitness seascape. The fitness peak performs a constrained random walk in the trait amplitude, which determines the time-dependent trait optimum in a given population. We derive analytical expressions for the distribution of the time-dependent trait divergence between populations and of the trait diversity within populations. Based on this solution, we develop a method to infer adaptive evolution of quantitative traits. Specifically, we show that the ratio of the average trait divergence and the diversity is a universal function of evolutionary time, which predicts the stabilizing strength and the driving rate of the fitness seascape. From an information-theoretic point of view, this function measures the macro-evolutionary entropy in a population ensemble, which determines the predictability of the evolutionary process. Our solution also quantifies two key characteristics of adapting populations: the cumulative fitness flux, which measures the total amount of adaptation, and the adaptive load, which is the fitness cost due to a population's lag behind the fitness peak. (paper)

  6. Global impact of induced mutation in plant breeding

    International Nuclear Information System (INIS)

    Bhatia, R.

    2001-01-01

    Sudden, heritable changes in the genetic material, DNA, are known as mutations. Selection of naturally occurring mutations in wild, ancestral species helped humans in the domestication and further improvement of today's crop plants. Although Charles Darwin was unaware in 1859 of variation and mutations in living organisms, his theory of evolution by natural selection assumed variability. Much later, it was established that mutations are the source of biodiversity, and the driving force for evolution. Gregor Mendel in 1865 also used several mutants in his experiments with garden pea to formulate the laws of inheritance. The term mutation itself was used for the first time by Hugo de Vries in 1901 in his mutation theory. Plant breeding based on the science of genetics, as practiced over the past 100 years, exploited the available genetic variability in the primary gene pool of crop plants, and sometimes in related species. This approach enlarged the yield potential of crops several fold. It also a) improved the stability of yield by incorporating resistance to various biotic and abiotic stresses; b) improved quality of the produce; and c) altered the adaptability of crop species, providing opportunities to grow new crops for food security outside their traditional range. Genetically improved seed (or other planting material) is the most significant input for developing sustainable cropping systems for food security and economic growth. Half of the increased productivity of today's crop plants comes from genetic improvements. The other half is contributed by inputs and management practices

  7. The use of radiations to induce useful mutations in fruit trees

    International Nuclear Information System (INIS)

    Donini, B.

    1976-01-01

    The researches carried out at Casaccia in this field had covered the problems of technique of mutagenic treatment, mechanism of mutation induction and methodology of somatic mutation isolation. To enhance the efficiency of somatic mutation induction several conditions during and after the treatment have been studied. More experience has been gained with regard to the induction of somatic