WorldWideScience

Sample records for adaptive mutations implications

  1. 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

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

    Science.gov (United States)

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

  3. Is The Ribosome Targeted By Adaptive Mutations

    DEFF Research Database (Denmark)

    Jimenez Fernandez, Alicia; Molin, Søren; Johansen, Helle Krogh

    2015-01-01

    degree of evolutionary conservation of the cellular MMSM tend to support this view. However, under certain selective conditions the machinery itself may be targeted by adaptive mutations, which result in fitness-increasing phenotypic changes. Here we investigate and characterize the role of ribosomal...... mutations in adaptive evolution. Methods: Several mutations in ribosomal genes have been identified in the genome analysis of nearly 700 Pseudomonas aeruginosa isolates from infected cystic fibrosis patients. Among these mutations we have repeatedly identified insertions, deletions and substitutions...... in specific ribosomal genes. The bacterial phenotypes of the mutated strains will be investigated. Results: Preliminary assays show that mutant strains have reduced growth rate and an altered antibiotic resistance pattern. The selection for mutations in ribosomal protein genes is partly explainable...

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

    African Journals Online (AJOL)

    Reem Mebed

    2015-04-23

    Apr 23, 2015 ... Rhodopsin mutations are scarcely implicated in autosomal recessive retinitis pigmentosa: A preliminary study of Egyptian retinitis pigmentosa patients. Reem Mebed a,. *, Yasser B.M. Ali b. , Nahed Solouma c. , Amr Eldib d. ,. Mahmoud Amer e. , Ahmed Osman e,f a National Organization for Research and ...

  5. 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...... 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...... can drive adaptive evolution and suggest that this class of mutation may be underappreciated as a cause of adaptation and evolutionary dynamics....

  6. Experimental Design to Evaluate Directed Adaptive Mutation in Mammalian Cells

    Science.gov (United States)

    Chiaro, Christopher R; May, Tobias

    2014-01-01

    Background We describe the experimental design for a methodological approach to determine whether directed adaptive mutation occurs in mammalian cells. Identification of directed adaptive mutation would have profound practical significance for a wide variety of biomedical problems, including disease development and resistance to treatment. In adaptive mutation, the genetic or epigenetic change is not random; instead, the presence and type of selection influences the frequency and character of the mutation event. Adaptive mutation can contribute to the evolution of microbial pathogenesis, cancer, and drug resistance, and may become a focus of novel therapeutic interventions. Objective Our experimental approach was designed to distinguish between 3 types of mutation: (1) random mutations that are independent of selective pressure, (2) undirected adaptive mutations that arise when selective pressure induces a general increase in the mutation rate, and (3) directed adaptive mutations that arise when selective pressure induces targeted mutations that specifically influence the adaptive response. The purpose of this report is to introduce an experimental design and describe limited pilot experiment data (not to describe a complete set of experiments); hence, it is an early report. Methods An experimental design based on immortalization of mouse embryonic fibroblast cells is presented that links clonal cell growth to reversal of an inactivating polyadenylation site mutation. Thus, cells exhibit growth only in the presence of both the countermutation and an inducing agent (doxycycline). The type and frequency of mutation in the presence or absence of doxycycline will be evaluated. Additional experimental approaches would determine whether the cells exhibit a generalized increase in mutation rate and/or whether the cells show altered expression of error-prone DNA polymerases or of mismatch repair proteins. Results We performed the initial stages of characterizing our system

  7. Experimental design to evaluate directed adaptive mutation in Mammalian cells.

    Science.gov (United States)

    Bordonaro, Michael; Chiaro, Christopher R; May, Tobias

    2014-12-09

    We describe the experimental design for a methodological approach to determine whether directed adaptive mutation occurs in mammalian cells. Identification of directed adaptive mutation would have profound practical significance for a wide variety of biomedical problems, including disease development and resistance to treatment. In adaptive mutation, the genetic or epigenetic change is not random; instead, the presence and type of selection influences the frequency and character of the mutation event. Adaptive mutation can contribute to the evolution of microbial pathogenesis, cancer, and drug resistance, and may become a focus of novel therapeutic interventions. Our experimental approach was designed to distinguish between 3 types of mutation: (1) random mutations that are independent of selective pressure, (2) undirected adaptive mutations that arise when selective pressure induces a general increase in the mutation rate, and (3) directed adaptive mutations that arise when selective pressure induces targeted mutations that specifically influence the adaptive response. The purpose of this report is to introduce an experimental design and describe limited pilot experiment data (not to describe a complete set of experiments); hence, it is an early report. An experimental design based on immortalization of mouse embryonic fibroblast cells is presented that links clonal cell growth to reversal of an inactivating polyadenylation site mutation. Thus, cells exhibit growth only in the presence of both the countermutation and an inducing agent (doxycycline). The type and frequency of mutation in the presence or absence of doxycycline will be evaluated. Additional experimental approaches would determine whether the cells exhibit a generalized increase in mutation rate and/or whether the cells show altered expression of error-prone DNA polymerases or of mismatch repair proteins. We performed the initial stages of characterizing our system and have limited preliminary data

  8. Clonal Heterogeneity Influences the Fate of New Adaptive Mutations

    Directory of Open Access Journals (Sweden)

    Ignacio Vázquez-García

    2017-10-01

    Full Text Available The joint contribution of pre-existing and de novo genetic variation to clonal adaptation is poorly understood but essential to designing successful antimicrobial or cancer therapies. To address this, we evolve genetically diverse populations of budding yeast, S. cerevisiae, consisting of diploid cells with unique haplotype combinations. We study the asexual evolution of these populations under selective inhibition with chemotherapeutic drugs by time-resolved whole-genome sequencing and phenotyping. All populations undergo clonal expansions driven by de novo mutations but remain genetically and phenotypically diverse. The clones exhibit widespread genomic instability, rendering recessive de novo mutations homozygous and refining pre-existing variation. Finally, we decompose the fitness contributions of pre-existing and de novo mutations by creating a large recombinant library of adaptive mutations in an ensemble of genetic backgrounds. Both pre-existing and de novo mutations substantially contribute to fitness, and the relative fitness of pre-existing variants sets a selective threshold for new adaptive mutations.

  9. Adaptive mutations alter antibody structure and dynamics during affinity maturation.

    Science.gov (United States)

    Adhikary, Ramkrishna; Yu, Wayne; Oda, Masayuki; Walker, Ross C; Chen, Tingjian; Stanfield, Robyn L; Wilson, Ian A; Zimmermann, Jörg; Romesberg, Floyd E

    2015-03-24

    While adaptive mutations can bestow new functions on proteins via the introduction or optimization of reactive centers, or other structural changes, a role for the optimization of protein dynamics also seems likely but has been more difficult to evaluate. Antibody (Ab) affinity maturation is an example of adaptive evolution wherein the adaptive mutations may be identified and Abs may be raised to specific targets that facilitate the characterization of protein dynamics. Here, we report the characterization of three affinity matured Abs that evolved from a common germline precursor to bind the chromophoric antigen (Ag), 8-methoxypyrene-1,3,6-trisulfonate (MPTS). In addition to characterizing the sequence, molecular recognition, and structure of each Ab, we characterized the dynamics of each complex by determining their mechanical response to an applied force via three-pulse photon echo peak shift (3PEPS) spectroscopy and deconvoluting the response into elastic, anelastic, and plastic components. We find that for one Ab, affinity maturation was accomplished via the introduction of a single functional group that mediates a direct contact with MPTS and results in a complex with little anelasticity or plasticity. In the other two cases, more mutations were introduced but none directly contact MPTS, and while their effects on structure are subtle, their effects on anelasticity and plasticity are significant, with the level of plasticity correlated with specificity, suggesting that the optimization of protein dynamics may have contributed to affinity maturation. A similar optimization of structure and dynamics may contribute to the evolution of other proteins.

  10. Clinical and biological implications of driver mutations in myelodysplastic syndromes.

    Science.gov (United States)

    Papaemmanuil, Elli; Gerstung, Moritz; Malcovati, Luca; Tauro, Sudhir; Gundem, Gunes; Van Loo, Peter; Yoon, Chris J; Ellis, Peter; Wedge, David C; Pellagatti, Andrea; Shlien, Adam; Groves, Michael John; Forbes, Simon A; Raine, Keiran; Hinton, Jon; Mudie, Laura J; McLaren, Stuart; Hardy, Claire; Latimer, Calli; Della Porta, Matteo G; O'Meara, Sarah; Ambaglio, Ilaria; Galli, Anna; Butler, Adam P; Walldin, Gunilla; Teague, Jon W; Quek, Lynn; Sternberg, Alex; Gambacorti-Passerini, Carlo; Cross, Nicholas C P; Green, Anthony R; Boultwood, Jacqueline; Vyas, Paresh; Hellstrom-Lindberg, Eva; Bowen, David; Cazzola, Mario; Stratton, Michael R; Campbell, Peter J

    2013-11-21

    Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic hematological malignancies characterized by dysplasia, ineffective hematopoiesis and a variable risk of progression to acute myeloid leukemia. Sequencing of MDS genomes has identified mutations in genes implicated in RNA splicing, DNA modification, chromatin regulation, and cell signaling. We sequenced 111 genes across 738 patients with MDS or closely related neoplasms (including chronic myelomonocytic leukemia and MDS-myeloproliferative neoplasms) to explore the role of acquired mutations in MDS biology and clinical phenotype. Seventy-eight percent of patients had 1 or more oncogenic mutations. We identify complex patterns of pairwise association between genes, indicative of epistatic interactions involving components of the spliceosome machinery and epigenetic modifiers. Coupled with inferences on subclonal mutations, these data suggest a hypothesis of genetic "predestination," in which early driver mutations, typically affecting genes involved in RNA splicing, dictate future trajectories of disease evolution with distinct clinical phenotypes. Driver mutations had equivalent prognostic significance, whether clonal or subclonal, and leukemia-free survival deteriorated steadily as numbers of driver mutations increased. Thus, analysis of oncogenic mutations in large, well-characterized cohorts of patients illustrates the interconnections between the cancer genome and disease biology, with considerable potential for clinical application.

  11. 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

    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...

  12. 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

  13. Electron holes appear to trigger cancer-implicated mutations

    Science.gov (United States)

    Miller, John; Villagran, Martha

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

  14. Clinical implications of hepatitis B virus mutations: recent advances.

    Science.gov (United States)

    Lazarevic, Ivana

    2014-06-28

    Hepatitis B virus (HBV) infection is a major cause of acute and chronic hepatitis, and of its long-term complications. It is the most variable among DNA viruses, mostly because of its unique life cycle which includes the activity of error-prone enzyme, reverse transcriptase, and the very high virion production per day. In last two decades, numerous research studies have shown that the speed of disease progression, reliability of diagnostic methods and the success of antiviral therapy and immunization are all influenced by genetic variability of this virus. It was shown that mutations in specific regions of HBV genome could be responsible for unwanted clinical outcomes or evasion of detection by diagnostic tools, thus making the monitoring for these mutations a necessity in proper evaluation of patients. The success of the vaccination programs has now been challenged by the discovery of mutant viruses showing amino acid substitutions in hepatitis B surface antigen (HBsAg), which may lead to evasion of vaccine-induced immunity. However, the emergence of these mutations has not yet raised concern since it was shown that they develop slowly. Investigations of HBV genetic variability and clinical implications of specific mutations have resulted in significant advances over the past decade, particularly in regard to management of resistance to antiviral drugs. In the era of drugs with high genetic barrier for resistance, on-going monitoring for possible resistance is still essential since prolonged therapy is often necessary. Understanding the frequencies and clinical implications of viral mutations may contribute to improvement of diagnostic procedures, more proper planning of immunization programs and creating the most efficient therapeutic protocols.

  15. 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…

  16. Development of a comprehensive genotype-to-fitness map of adaptation-driving mutations in yeast

    Science.gov (United States)

    Venkataram, Sandeep; Dunn, Barbara; Li, Yuping; Agarwala, Atish; Chang, Jessica; Ebel, Emily; Geiler-Samerotte, Kerry; Herissant, Lucas; Blundell, Jamie; Levy, Sasha F.; Fisher, Daniel S.; Sherlock, Gavin; Petrov, Dmitri A.

    2016-01-01

    Summary Adaptive evolution plays a large role in generating the phenotypic diversity observed in nature, yet current methods are impractical for characterizing the molecular basis and fitness effects of large numbers of individual adaptive mutations. Here we used a DNA barcoding approach to generate the genotype-to-fitness map for adaptation-driving mutations from a Saccharomyces cerevisiae population experimentally evolved by serial transfer under limiting glucose. We isolated and measured the fitness of thousands of independent adaptive clones, and sequenced the genomes of hundreds of clones. We found only two major classes of adaptive mutations: self-diploidization, and mutations in the nutrient-responsive Ras/PKA and TOR/Sch9 pathways. Our large sample size and precision of measurement allowed us to determine that there are significant differences in fitness between mutations in different genes, between different paralogs, and even between different classes of mutations within the same gene. PMID:27594428

  17. Expected Effect of Deleterious Mutations on Within-Host Adaptation of Pathogens

    Science.gov (United States)

    2015-01-01

    ABSTRACT Adaptation is a common theme in both pathogen emergence, for example, in zoonotic cross-species transmission, and pathogen control, where adaptation might limit the effect of the immune response and antiviral treatment. When such evolution requires deleterious intermediate mutations, fitness ridges and valleys arise in the pathogen's fitness landscape. The effect of deleterious intermediate mutations on within-host pathogen adaptation is examined with deterministic calculations, appropriate for pathogens replicating in large populations with high error rates. The effect of deleterious intermediate mutations on pathogen adaptation is smaller than their name might suggest: when two mutations are required and each individual single mutation is fully deleterious, the pathogen can jump across the fitness valley by obtaining two mutations at once, leading to a proportion of adapted mutants that is 20-fold lower than that in the situation where the fitness of all mutants is neutral. The negative effects of deleterious intermediates are typically substantially smaller and outweighed by the fitness advantages of the adapted mutant. Moreover, requiring a specific mutation order has a substantially smaller effect on pathogen adaptation than the effect of all intermediates being deleterious. These results can be rationalized when the number of routes of mutation available to the pathogen is calculated, providing a simple approach to estimate the effect of deleterious mutations. The calculations discussed here are applicable when the effect of deleterious mutations on the within-host adaptation of pathogens is assessed, for example, in the context of zoonotic emergence, antigenic escape, and drug resistance. IMPORTANCE Adaptation is critical for pathogens after zoonotic transmission into a new host species or to achieve antigenic immune escape and drug resistance. Using a deterministic approach, the effects of deleterious intermediate mutations on pathogen adaptation

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

    Directory of Open Access Journals (Sweden)

    Talia Karasov

    2010-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Daniel J Kvitek

    2011-04-01

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

  20. 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

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

    Directory of Open Access Journals (Sweden)

    Chaitanya R Churi

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

  2. First-step mutations for adaptation at elevated temperature increase capsid stability in a virus.

    Directory of Open Access Journals (Sweden)

    Kuo Hao Lee

    Full Text Available The relationship between mutation, protein stability and protein function plays a central role in molecular evolution. Mutations tend to be destabilizing, including those that would confer novel functions such as host-switching or antibiotic resistance. Elevated temperature may play an important role in preadapting a protein for such novel functions by selecting for stabilizing mutations. In this study, we test the stability change conferred by single mutations that arise in a G4-like bacteriophage adapting to elevated temperature. The vast majority of these mutations map to interfaces between viral coat proteins, suggesting they affect protein-protein interactions. We assess their effects by estimating thermodynamic stability using molecular dynamic simulations and measuring kinetic stability using experimental decay assays. The results indicate that most, though not all, of the observed mutations are stabilizing.

  3. First-step mutations for adaptation at elevated temperature increase capsid stability in a virus.

    Science.gov (United States)

    Lee, Kuo Hao; Miller, Craig R; Nagel, Anna C; Wichman, Holly A; Joyce, Paul; Ytreberg, F Marty

    2011-01-01

    The relationship between mutation, protein stability and protein function plays a central role in molecular evolution. Mutations tend to be destabilizing, including those that would confer novel functions such as host-switching or antibiotic resistance. Elevated temperature may play an important role in preadapting a protein for such novel functions by selecting for stabilizing mutations. In this study, we test the stability change conferred by single mutations that arise in a G4-like bacteriophage adapting to elevated temperature. The vast majority of these mutations map to interfaces between viral coat proteins, suggesting they affect protein-protein interactions. We assess their effects by estimating thermodynamic stability using molecular dynamic simulations and measuring kinetic stability using experimental decay assays. The results indicate that most, though not all, of the observed mutations are stabilizing.

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

    Directory of Open Access Journals (Sweden)

    Adela M Luján

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

  5. 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.

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

    Science.gov (United States)

    Tomar, Swati; Sethi, Raman; Sundar, Gangadhara; Quah, Thuan Chong; Quah, Boon Long; Lai, Poh San

    2017-01-01

    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 asymptomatic

  8. Contribution of a mutational hot spot to hemoglobin adaptation in high-altitude Andean house wrens.

    Science.gov (United States)

    Galen, Spencer C; Natarajan, Chandrasekhar; Moriyama, Hideaki; Weber, Roy E; Fago, Angela; Benham, Phred M; Chavez, Andrea N; Cheviron, Zachary A; Storz, Jay F; Witt, Christopher C

    2015-11-10

    A key question in evolutionary genetics is why certain mutations or certain types of mutation make disproportionate contributions to adaptive phenotypic evolution. In principle, the preferential fixation of particular mutations could stem directly from variation in the underlying rate of mutation to function-altering alleles. However, the influence of mutation bias on the genetic architecture of phenotypic evolution is difficult to evaluate because data on rates of mutation to function-altering alleles are seldom available. Here, we report the discovery that a single point mutation at a highly mutable site in the β(A)-globin gene has contributed to an evolutionary change in hemoglobin (Hb) function in high-altitude Andean house wrens (Troglodytes aedon). Results of experiments on native Hb variants and engineered, recombinant Hb mutants demonstrate that a nonsynonymous mutation at a CpG dinucleotide in the β(A)-globin gene is responsible for an evolved difference in Hb-O2 affinity between high- and low-altitude house wren populations. Moreover, patterns of genomic differentiation between high- and low-altitude populations suggest that altitudinal differentiation in allele frequencies at the causal amino acid polymorphism reflects a history of spatially varying selection. The experimental results highlight the influence of mutation rate on the genetic basis of phenotypic evolution by demonstrating that a large-effect allele at a highly mutable CpG site has promoted physiological differentiation in blood O2 transport capacity between house wren populations that are native to different elevations.

  9. 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.

  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. Second-order selection in bacterial evolution: selection acting on mutation and recombination rates in the course of adaptation.

    Science.gov (United States)

    Tenaillon, O; Taddei, F; Radmian, M; Matic, I

    2001-01-01

    The increase in genetic variability of a population can be selected during adaptation, as demonstrated by the selection of mutator alleles. The dynamics of this phenomenon, named second-order selection, can result in an improved adaptability of bacteria through regulation of all facets of mutation and recombination processes.

  12. Clinical implications of mutation analysis in primary hyperoxaluria type 1

    NARCIS (Netherlands)

    van Woerden, Christiaan S.; Groothoff, Jaap W.; Wijburg, Frits A.; Annink, Carla; Wanders, Ronald J. A.; Waterham, Hans R.

    2004-01-01

    BACKGROUND: Primary hyperoxaluria type 1 (PH1) is an inborn error of glyoxylate metabolism with an extensive clinical and genetic heterogeneity. Although over 50 disease-causing mutations have been identified, the relationship between genotype and clinical outcome remains unclear. The aim of this

  13. Oncological implications of RET gene mutations in Hirschsprung's disease

    NARCIS (Netherlands)

    Sijmons, RH; Hofstra, RMW; Wijburg, FA; Links, TP; Zwierstra, RP; Vermey, A; Aronson, DC; Tan-Sindhunata, G; Brouwers-Smalbraak, GJ; Maas, SM; Buys, CHCM

    1998-01-01

    Background-Germline mutations of the RET proto-oncogene identical to those found in the tumour predisposition syndrome multiple endocrine neoplasia type 2A (MEN2A), were detected in 2.5-5% of sporadic and familial cases of Hirschsprung's disease. Some patients with Hirschsprung's disease may

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

    Directory of Open Access Journals (Sweden)

    Emily J. Howells

    2011-08-01

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

  15. Implications of plan-based generalization in sensorimotor adaptation.

    Science.gov (United States)

    McDougle, Samuel D; Bond, Krista M; Taylor, Jordan A

    2017-07-01

    Generalization is a fundamental aspect of behavior, allowing for the transfer of knowledge from one context to another. The details of this transfer are thought to reveal how the brain represents what it learns. Generalization has been a central focus in studies of sensorimotor adaptation, and its pattern has been well characterized: Learning of new dynamic and kinematic transformations in one region of space tapers off in a Gaussian-like fashion to neighboring untrained regions, echoing tuned population codes in the brain. In contrast to common allusions to generalization in cognitive science, generalization in visually guided reaching is usually framed as a passive consequence of neural tuning functions rather than a cognitive feature of learning. While previous research has presumed that maximum generalization occurs at the instructed task goal or the actual movement direction, recent work suggests that maximum generalization may occur at the location of an explicitly accessible movement plan. Here we provide further support for plan-based generalization, formalize this theory in an updated model of adaptation, and test several unexpected implications of the model. First, we employ a generalization paradigm to parameterize the generalization function and ascertain its maximum point. We then apply the derived generalization function to our model and successfully simulate and fit the time course of implicit adaptation across three behavioral experiments. We find that dynamics predicted by plan-based generalization are borne out in the data, are contrary to what traditional models predict, and lead to surprising implications for the behavioral, computational, and neural characteristics of sensorimotor adaptation.NEW & NOTEWORTHY The pattern of generalization is thought to reveal how the motor system represents learned actions. Recent work has made the intriguing suggestion that maximum generalization in sensorimotor adaptation tasks occurs at the location of the

  16. 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.

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

    Science.gov (United States)

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

    2014-04-01

    Mutations in PARK2, PINK1, and DJ-1 have been associated with autosomal recessive early-onset Parkinson's disease. Here, we report the prevalence of sequence and structural mutations in these three main recessive genes in Mexican Mestizo patients. The complete sequences of these three genes were analyzed by homo/heteroduplex DNA formation and direct sequencing; exon dosage was determined by multiplex ligation-dependent probe amplification and real-time PCR in 127 patients belonging to 122 families and 120 healthy Mexican Mestizo controls. All individuals had been previously screened for the three most common LRRK2 mutations. The presence of two mutations in compound heterozygous or homozygous genotypes was found in 16 unrelated patients, 10 had mutations in PARK2, six in PINK1, and none in DJ-1. Two PARK2-PINK1 and one PARK2-LRRK2 digenic cases were observed. Novel mutations were identified in PARK2 and PINK1 genes, including PINK1 duplication for the first time. Exon dosage deletions were the most frequent mutations in PARK2 (mainly in exons 9 and 12), followed by those in PINK1. The high prevalence of heterozygous mutations in PARK2 (12.3%) and the novel heterozygous and homozygous point mutations in PINK1 observed in familial and sporadic cases from various states of Mexico support the concept that single heterozygous mutations in recessive Parkinson's disease genes play a pathogenic role. These data have important implications for genetic counseling of Mexican Mestizo patients with early-onset Parkinson's disease. The presence of digenic inheritance underscores the importance of studying several genes in this disease. A step-ordered strategy for molecular diagnosis is proposed. © 2014 Wiley Periodicals, Inc.

  18. Cost of Adaptation and Fitness Effects of Beneficial Mutations in Pseudomonas fluorescens

    Science.gov (United States)

    Bataillon, Thomas; Zhang, Tianyi; Kassen, Rees

    2011-01-01

    Adaptations are constructed through the sequential substitution of beneficial mutations by natural selection. However, the rarity of beneficial mutations has precluded efforts to describe even their most basic properties. Do beneficial mutations typically confer small or large fitness gains? Are their fitness effects environment specific, or are they broadly beneficial across a range of environments? To answer these questions, we used two subsets (n = 18 and n = 63) of a large library of mutants carrying antibiotic resistance mutations in the bacterium Pseudomonas fluorescens whose fitness, along with the antibiotic sensitive ancestor, was assayed across 95 novel environments differing in the carbon source available for growth. We explore patterns of genotype-by-environment (G×E) interactions and ecological specialization among the 18 mutants initially found superior to the sensitive ancestor in one environment. We find that G×E is remarkably similar between the two sets of mutants and that beneficial mutants are not typically associated with large costs of adaptation. Fitness effects among beneficial mutants depart from a strict exponential distribution: they assume a variety of shapes that are often roughly L shaped but always right truncated. Distributions of (beneficial) fitness effects predicted by a landscape model assuming multiple traits underlying fitness and a single optimum often provide a good description of the empirical distributions in our data. Simulations of data sets containing a mixture of single and double mutants under this landscape show that inferences about the distribution of fitness effects of beneficial mutants is quite robust to contamination by second-site mutations. PMID:21868607

  19. Gene mutations in the Ras pathway and the prognostic implication in Korean patients with juvenile myelomonocytic leukemia.

    Science.gov (United States)

    Park, Hyung-Doo; Lee, Soo Hyun; Sung, Ki Woong; Koo, Hong Hoe; Jung, Nak Gyun; Cho, Bin; Kim, Hak Ki; Park, In-Ae; Lee, Ki-O; Ki, Chang-Seok; Kim, Sun-Hee; Yoo, Keon Hee; Kim, Hee-Jin

    2012-04-01

    Juvenile myelomonocytic leukemia (JMML) is a rare hematologic malignancy in children. Hyperactivation of the Ras pathway from gene mutations is known to be the key culprit in the development of JMML. In this study, we investigated Ras pathway mutations and prognostic implication in Korean patients with JMML. A total of 22 Korean patients with JMML were recruited from two institutions (19 boys and three girls; median age, 17 months; range, 1-74 months). Hematologic and cytogenetic findings were reviewed. Mutation analyses involved PTPN11, KRAS, NRAS, and CBL genes by direct sequencing analyses (selected exons except in CBL). Survival analysis was performed by the Kaplan-Meier method. Cytogenetic and/or gene mutations were detected in 18 patients out of 22 (82%). Four patients (18%) had chromosomal abnormalities, with monosomy 7 being the most common. Seventeen (77%) had gene mutations. PTPN11 mutations were detected in 13 patients (59%). The patient heterozygous for c.854T>C had Noonan syndrome. NRAS and KRAS mutations were detected in two patients (9%) and one patient (5%), respectively. A homozygous CBL mutation was detected in one patient (5%; c.1228-2A>G). All mutations detected were previously reported mutations. Survival analyses suggested an unfavorable prognostic implication of PTPN11 mutation, albeit without a statistical significance. Collectively, the results from molecular genetics study and survival analyses suggested a relatively higher frequency and unfavorable prognostic implication of PTPN11 mutations in Korean patients with JMML.

  20. 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...

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

    Directory of Open Access Journals (Sweden)

    Nicole E Forbes

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

  2. Differential Evolution with Novel Mutation and Adaptive Crossover Strategies for Solving Large Scale Global Optimization Problems

    Directory of Open Access Journals (Sweden)

    Ali Wagdy Mohamed

    2017-01-01

    Full Text Available This paper presents Differential Evolution algorithm for solving high-dimensional optimization problems over continuous space. The proposed algorithm, namely, ANDE, introduces a new triangular mutation rule based on the convex combination vector of the triplet defined by the three randomly chosen vectors and the difference vectors between the best, better, and the worst individuals among the three randomly selected vectors. The mutation rule is combined with the basic mutation strategy DE/rand/1/bin, where the new triangular mutation rule is applied with the probability of 2/3 since it has both exploration ability and exploitation tendency. Furthermore, we propose a novel self-adaptive scheme for gradual change of the values of the crossover rate that can excellently benefit from the past experience of the individuals in the search space during evolution process which in turn can considerably balance the common trade-off between the population diversity and convergence speed. The proposed algorithm has been evaluated on the 20 standard high-dimensional benchmark numerical optimization problems for the IEEE CEC-2010 Special Session and Competition on Large Scale Global Optimization. The comparison results between ANDE and its versions and the other seven state-of-the-art evolutionary algorithms that were all tested on this test suite indicate that the proposed algorithm and its two versions are highly competitive algorithms for solving large scale global optimization problems.

  3. 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

  4. 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

  5. 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.

  6. 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

    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......, and NS2 all increased virus production. A single-cycle replication assay in CD81-deficient cells was developed to study more precisely the effect of the adaptive mutations. The E2 mutation had minimal effect on the amount of infectious virus released but probably enhanced entry into cells. In contrast......, both the p7 and NS2 mutations independently increased the amount of virus released....

  7. 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.

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

    Science.gov (United States)

    Chou, Hsin-Hung; Delaney, Nigel F; Draghi, Jeremy A; Marx, Christopher J

    2014-02-01

    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.

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

    Directory of Open Access Journals (Sweden)

    Chun-Liang Lu

    2014-12-01

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

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

    Directory of Open Access Journals (Sweden)

    Shamil R Sunyaev

    2009-02-01

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

  11. 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.

  12. Population structure, stepwise mutations, heterozygote deficiency and their implications in DNA forensics.

    Science.gov (United States)

    Jin, L; Chakraborty, R

    1995-03-01

    In a substructured population the overall heterozygote deficiency can be predicted from the number of subpopulations (s), their time of divergence (t), and the nature of the mutations. At present the true mutational mechanisms at the hypervariable DNA loci are not known. However, the two existing mutation models (the infinite allele model (IAM) and the stepwise mutation model (SMM)) provide some guides to predictions from which the possible effect of population substructuring may be evaluated, assuming that the subpopulations do not exchange any genes among them during evolution. The theory predicts that the loci with larger mutation rate, and consequently showing greater heterozygosity within subpopulations, should exhibit a smaller proportional heterozygote deficiency (GST) and, hence, the effects of population substructuring should be minimal at the hypervariable DNA loci (an order of magnitude smaller than that at the blood group and protein loci). Applications of this theory to data on six Variable Number of Tandem Repeat (VNTR) loci and five short tandem repeat (STR) loci in the major cosmopolitan populations of the USA show that while the VNTR loci often exhibit a large significant heterozygote deficiency, the STR loci do not show a similar tendency. This discordant finding may be ascribed to the limitations, coalescence and nondetectability of alleles associated with the restriction fragment length polymorphism (RFLP) analysis through which the VNTR loci are scored. Such limitations do not apply to the polymerase chain reaction (PCR) method, through which the STR loci are scored. The implications of these results are discussed in the context of the forensic use of DNA typing data.

  13. Melorheostosis: Exome sequencing of an associated dermatosis implicates postzygotic mosaicism of mutated KRAS.

    Science.gov (United States)

    Whyte, Michael P; Griffith, Malachi; Trani, Lee; Mumm, Steven; Gottesman, Gary S; McAlister, William H; Krysiak, Kilannin; Lesurf, Robert; Skidmore, Zachary L; Campbell, Katie M; Rosman, Ilana S; Bayliss, Susan; Bijanki, Vinieth N; Nenninger, Angela; Van Tine, Brian A; Griffith, Obi L; Mardis, Elaine R

    2017-08-01

    Melorheostosis (MEL) is the rare sporadic dysostosis characterized by monostotic or polyostotic osteosclerosis and hyperostosis often distributed in a sclerotomal pattern. The prevailing hypothesis for MEL invokes postzygotic mosaicism. Sometimes scleroderma-like skin changes, considered a representation of the pathogenetic process of MEL, overlie the bony changes, and sometimes MEL becomes malignant. Osteopoikilosis (OPK) is the autosomal dominant skeletal dysplasia that features symmetrically distributed punctate osteosclerosis due to heterozygous loss-of-function mutation within LEMD3. Rarely, radiographic findings of MEL occur in OPK. However, germline mutation of LEMD3 does not explain sporadic MEL. To explore if mosaicism underlies MEL, we studied a boy with polyostotic MEL and characteristic overlying scleroderma-like skin, a few bony lesions consistent with OPK, and a large epidermal nevus known to usually harbor a HRAS, FGFR3, or PIK3CA gene mutation. Exome sequencing was performed to ~100× average read depth for his two dermatoses, two areas of normal skin, and peripheral blood leukocytes. As expected for non-malignant tissues, the patient's mutation burden in his normal skin and leukocytes was low. He, his mother, and his maternal grandfather carried a heterozygous, germline, in-frame, 24-base-pair deletion in LEMD3. Radiographs of the patient and his mother revealed bony foci consistent with OPK, but she showed no MEL. For the patient, somatic variant analysis, using four algorithms to compare all 20 possible pairwise combinations of his five DNA samples, identified only one high-confidence mutation, heterozygous KRAS Q61H (NM_033360.3:c.183A>C, NP_203524.1:p.Gln61His), in both his dermatoses but absent in his normal skin and blood. Thus, sparing our patient biopsy of his MEL bone, we identified a heterozygous somatic KRAS mutation in his scleroderma-like dermatosis considered a surrogate for MEL. This implicates postzygotic mosaicism of mutated KRAS

  14. 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...... reaffirmed the impact of the key mutations on the growth rate at 42 °C. Interestingly, most of the identified key gene targets differed significantly from those found in similar temperature adaptation studies, highlighting the sensitivity of genetic evolution to experimental conditions and ancestral genotype...

  15. Implications of Early Sociocultural Adaptation for Study Abroad Students

    Science.gov (United States)

    Savicki, Victor

    2010-01-01

    Helping students and others facing the task of adapting to a foreign culture is becoming ever more pressing. The current study delves into sociocultural adaptation in order to clarify that process and provide information useful for educators, trainers, coaches, and others guiding those facing a sojourn in a foreign culture. A question to be…

  16. 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…

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

    DEFF Research Database (Denmark)

    Zheng, Yuan

    . The thesis, carried out in three mountain villages in southwest China, seeks to advance the understanding of local adaptation process and its implications for vulnerability and policy designs. In particular, the research contributes to quantitative assessment of current and forward-looking adaptation...

  18. BRCA1 genetic mutation and its link to ovarian cancer: implications for advanced practice nurses.

    Science.gov (United States)

    Brunsvold, Amy N; Wung, Shu-Fen; Merkle, Carrie J

    2005-12-01

    The purpose of this paper is to review (a) the linkage between the BRCA1 gene and ovarian cancer and (b) BRCA1 testing and its related issues. This review is aimed for nurse practitioners (NPs), who may be in positions to identify those at risk for BRCA1-associated ovarian cancer and to assist patients with related issues. Data sources include reviews and original research from scholarly journals and Internet sites. Ovarian cancer is a deadly disease. Identification of those at risk because of BRCA1 mutation is possible through genetic testing. Testing for BRCA1 gene mutations has many implications whether results are positive or negative. Those with positive results will be faced with decisions regarding the best management strategies. Negative results do not completely eliminate ovarian cancer risk. Current management options for carriers of the BRCA1 mutation include taking no action, increasing surveillance for ovarian cancer, and chemoprevention with oral contraceptives or prophylactic oophorectomy for those who have completed childbearing. It is essential that NPs have knowledge underlying the issues and concerns of patients and their families at risk for BRCA1-associated ovarian cancer. NPs are in a unique position to help identify BRCA1 mutation carriers and to assist them and their families with the complex issues involving genetic testing and management options. Understanding these issues will allow NPs to give appropriate care that may include making appropriate referrals to certified genetic counselors and having balanced discussions on treatment options. Such measurements may improve early diagnosis of ovarian cancer and increase survival from this disease.

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

    Directory of Open Access Journals (Sweden)

    Cai Y

    2015-07-01

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

  20. 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

    In clinical genetic diagnostics, it is difficult to predict whether genetic mutations that do not greatly alter the primary sequence of the encoded protein causing unknown functional effects on cognate proteins lead to development of disease. Here, we report the clinical identification of c.2038 T......>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....

  1. 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

      Knowledge of local adaptation and adaptive potential of natural populations is becoming increasingly relevant due to anthropogenic changes in the environment, such as climate change. The concern is that populations will be negatively affected by increasing temperatures without the capacity...... and heritable variation in phenotypic plasticity suggest that although increasing temperatures are likely to affect some populations negatively, they may have the potential to adapt to changing temperature regimes.  ...... traits, indicating local adaptation. A temperature effect was observed for three traits. However, this effect varied among populations due to locally adapted reaction norms, corresponding to the temperature regimes experienced by the populations in their native environments. Additive genetic variance...

  2. Frequency of EGFR mutations in lung adenocarcinoma with malignant pleural effusion: Implication of cancer biological behaviour regulated by EGFR mutation.

    Science.gov (United States)

    Zou, JianYong; Bella, Amos Ela; Chen, ZhenGuang; Han, XiangQian; Su, ChunHua; Lei, YiYan; Luo, HongHe

    2014-10-01

    A retrospective single-centre study to compare the clinical features of patients with lung adenocarcinoma with and without epidermal growth factor receptor (EGFR) mutations. Pretreatment medical records of patients with lung adenocarcinoma were reviewed. DNA was extracted from paraffin wax-embedded tumour tissue for analysis of EGFR mutations. Malignant pleural effusion (MPE) was diagnosed by cytopathological testing of pleural fluid. EGFR mutations (19-Del and L858R) were recorded in 81/283 patients (28.6%). MPE was found in 42/283 patients (14.8%). In patients with stage IV disease, the frequency of EGFR mutations was higher in those with MPE than in those without MPE. EGFR mutations were independently associated with female sex, no history of smoking and presence of MPE. There was a positive association between EGFR mutation and the presence of MPE. EGFR mutations may play an important role in the formation of MPE. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

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

    Directory of Open Access Journals (Sweden)

    Yi Cai

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

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

    Directory of Open Access Journals (Sweden)

    Konstantin A Tsetsarkin

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

  5. Living with the BRCA1 and BRCA2 genetic mutation: learning how to adapt to a virtual chronic illness.

    Science.gov (United States)

    Samson, A; DiMillo, J; Thériault, A; Lowry, S; Corsini, L; Verma, S; Tomiak, E

    2014-01-01

    The objective of this study was to understand how women living with the BRCA1 and BRCA2 genetic mutation adapt to this life transition and to identify the main adaptive tasks. A qualitative inquiry inspired by grounded theory revealed that participants cognitively appraised their test result in the same manner as women who have been diagnosed with breast cancer. Consequently, participants had to adapt to a condition that they perceived as a chronic illness. The following three main tasks were identified: Physical Task: Attempting to Limit the Impact of the Test Result, Psychological Task: Living with Uncertainty, and Social Task: Finding Effective Support. In conclusion, although these women live with the possibility of developing breast cancer, their experiences mirror those of individuals living with a chronic illness, and they must therefore adapt accordingly in a physical, psychological, and social manner.

  6. The Implications of Complex Adaptive Systems Theory for C2

    Science.gov (United States)

    2006-06-01

    adaptive mechanisms operating in CAS that we wish to infuence , whether they are our own systems, benign or neutral systems that we need to interact with...logistic systems individual humans government and NGOs the media and public opinion adversaries/allies civil infrastructure What makes these systems

  7. 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...

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

    Directory of Open Access Journals (Sweden)

    Eun-Young Kim

    2014-07-01

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

  9. 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.

  10. Most Factor VIII B Domain Missense Mutations Are Unlikely to Be Causative Mutations for Severe Hemophilia A: Implications for Genotyping

    Science.gov (United States)

    Ogata, Kyoichi; Selvaraj, Sundar R; Miao, Hongzhi Z; Pipe, Steven W

    2011-01-01

    Summary Background & Objective The factor VIII (FVIII) B domain shares very little amino acid homology to other known proteins and is not directly necessary for procoagulant activity. Despite this, missense mutations within the B domain have been reported in patients with hemophilia A. Given that the B domain is dispensable for secretion and function of FVIII, we hypothesized that these mutations should not be causative of hemophilia A in these patients. Methods Plasmid vectors containing B domain missense mutations that were reported to be associated with moderate/severe hemophilia A (T751S, D826E, V993L, H1047Y, T1353A, N1441K, L1462P, E1579D, A1591S, P1641L and S1669L) were analyzed for their effect on synthesis and secretion compared to FVIII wild-type (WT) following transient transfection into COS-1 and CHO cells in vitro. Further, H1047Y, N1441K and E1579D mutants were expressed in vivo in a hemophilia A mouse model by hydrodynamic tail-vein injection. Results FVIII activity and antigen levels for all mutants expressed into the conditioned media of COS-1 and CHO cells were similar to FVIII WT. Also, plasma expression of these mutants was similar to FVIII WT in hemophilia A mice. An in vivo tail clip bleeding assay also demonstrated that blood loss from hemophilia A mice expressing FVIII WT, H1047Y, N1441K and E1579D were similar. Conclusion We conclude that most missense mutations within the FVIII B domain would be unlikely to lead to severe hemophilia A and that the majority of such missense mutations represent polymorphisms or non-pathologic mutations. PMID:21645226

  11. 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.

  12. 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.

  13. Novel mutations affecting the Na, K ATPase alpha model complex neurological diseases and implicate the sodium pump in increased longevity.

    Science.gov (United States)

    Ashmore, Lesley J; Hrizo, Stacy L; Paul, Sarah M; Van Voorhies, Wayne A; Beitel, Greg J; Palladino, Michael J

    2009-09-01

    Mutations affecting the Na(+), K(+) ATPase alpha subunit have been implicated in at least two distinct human diseases, rapid-onset dystonia Parkinsonism (RDP), and familial hemiplegic migraine (FHM). Over 40 mutations have been mapped to the human ATP1A2 and ATP1A3 genes and are known to result in RDP, FHM or a variant of FHM with neurological complications. To develop a genetically tractable model system for investigating the role of the Na(+), K(+) ATPase in neural pathologies we performed genetic screens in Drosophila melanogaster to isolate loss-of-function alleles affecting the Na(+), K(+) ATPase alpha subunit. Flies heterozygous for these mutations all exhibit reduced respiration, consistent with a loss-of-function in the major ATPase. However, these mutations do not affect all functions of the Na(+), K(+) ATPase alpha protein since embryos homozygous for these mutations have normal septate junction paracellular barrier function and tracheal morphology. Importantly, all of these mutations cause neurological phenotypes and, akin to the mutations that cause RDP and FHM, these new alleles are missense mutations. All of these alleles exhibit progressive stress-induced locomotor impairment suggesting neuromuscular dysfunction, yet neurodegeneration is observed in an allele-specific manner. Surprisingly, studies of longevity demonstrate that mild hypomorphic mutations in the sodium pump significantly improve longevity, which was verified using the Na(+), K(+) ATPase antagonist ouabain. The isolation and characterization of a series of new missense alleles of ATPalpha in Drosophila provides the foundation for further studies of these neurological diseases and the role of sodium pump impairment in animal longevity.

  14. 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.

  15. 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.

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

  17. 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.

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

    DEFF Research Database (Denmark)

    Zheng, Yuan

    As challenges and opportunities induced by climate change become increasingly manifested, adaptation strategies to these changes have received growing attention. While earlier studies focus on quantifying impacts of climate change or adaptation potential, empirical studies have been increasingly....... The thesis, carried out in three mountain villages in southwest China, seeks to advance the understanding of local adaptation process and its implications for vulnerability and policy designs. In particular, the research contributes to quantitative assessment of current and forward-looking adaptation...... changes in social-ecological systems. The PhD research demonstrates 1) the interwoven impacts of co-evolving socio-economic, political and environmental changes in shaping livelihood changes and households’ vulnerability; 2) the usefulness to accommodate key cognitive processes, such as risk perception...

  19. The prognostic implication of SRSF2 mutations in Chinese patients with acute myeloid leukemia.

    Science.gov (United States)

    Yang, Jing; Yao, Dong-Ming; Ma, Ji-Chun; Yang, Lei; Guo, Hong; Wen, Xiang-Mei; Xiao, Gao-Fei; Qian, Zhen; Lin, Jiang; Qian, Jun

    2016-08-01

    Recently, somatic mutations in SRSF2 gene have been discovered in a proportion of hematologic malignancies including acute myeloid leukemia (AML). This study was aimed to investigate SRSF2 mutations in Chinese AML patients. High-resolution melting analysis (HRMA) was developed to screen SRSF2 mutations in 249 cases with AML, and then direct DNA sequencing was used to verify the results of HRMA. In this study, 3.6 % (9/249) of Chinese AML patients were found with heterozygous SRSF2 mutations. Patients with SRSF2 mutations were older than those with wild-type SRSF2 (P = 0.014). No differences in the sex, blood parameters, French-American-British classification (FAB) subtypes, and karyotypes were observed between AML patients with and without SRSF2 mutations. Although the overall survival (OS) of SRSF2-mutated patients was inferior to those without mutations in both whole AML patients (median 4 vs. 11 months, respectively; P = 0.006) and cytogenetically normal patients (median 2 vs. 12 months, respectively; P = 0.008), multiple analysis disclosed that SRSF2 mutation was not an independent prognostic factor in AML patients. These results suggest that SRSF2 mutation occurs at a low frequency in aged AML patients and might not be associated with adverse prognosis in Chinese AML patients.

  20. The R403Q myosin mutation implicated in familial hypertrophic cardiomyopathy causes disorder at the actomyosin interface.

    Directory of Open Access Journals (Sweden)

    Niels Volkmann

    2007-11-01

    Full Text Available Mutations in virtually all of the proteins comprising the cardiac muscle sarcomere have been implicated in causing Familial Hypertrophic Cardiomyopathy (FHC. Mutations in the beta-myosin heavy chain (MHC remain among the most common causes of FHC, with the widely studied R403Q mutation resulting in an especially severe clinical prognosis. In vitro functional studies of cardiac myosin containing the R403Q mutation have revealed significant changes in enzymatic and mechanical properties compared to wild-type myosin. It has been proposed that these molecular changes must trigger events that ultimately lead to the clinical phenotype.Here we examine the structural consequences of the R403Q mutation in a recombinant smooth muscle myosin subfragment (S1, whose kinetic features have much in common with slow beta-MHC. We obtained three-dimensional reconstructions of wild-type and R403Q smooth muscle S1 bound to actin filaments in the presence (ADP and absence (apo of nucleotide by electron cryomicroscopy and image analysis. We observed that the mutant S1 was attached to actin at highly variable angles compared to wild-type reconstructions, suggesting a severe disruption of the actin-myosin interaction at the interface.These results provide structural evidence that disarray at the molecular level may be linked to the histopathological myocyte disarray characteristic of the diseased state.

  1. 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.

  2. Adaptive and pathogenic aspects of sex-role stereotypes: implications for parenting and psychotherapy.

    Science.gov (United States)

    Lerner, H E

    1978-01-01

    There has been considerable controversy concerning adaptive versus pathogenic effects of sex-role stereotypes on individual development. The author evaluates both the positive and negative consequences of sex-role stereotypes without regard for any particular sociocultural definition of masculinity or feminity. She hypothesizes that the degree to which sex-role stereotypes are adaptive and facilitative (as opposed to restrictive and pathogenic) is inversely related to the degree to which an individual has consolidated a comfortable and stable gender is identity. Implications for parenting and treatment are elaborated.

  3. BRAF Mutations in an Italian Regional Population: Implications for the Therapy of Thyroid Cancer

    Directory of Open Access Journals (Sweden)

    Eleonora Monti

    2015-01-01

    Full Text Available Background. Molecular diagnostics has offered new techniques for searching for mutations in thyroid indeterminate lesions. The study’s aim was to evaluate the BRAF mutations’ incidence in an Italian regional population. Subjects and Methods. 70 Caucasian patients born in Liguria with indeterminate or suspicious cytological diagnoses. Results. A BRAF gene mutation was successfully analyzed in 56/70 patients. The mutation was BRAF V600E in 12/56 cases (21% and BRAF K601E in 2/56 (4%. Of the BRAF mutated samples on cytological diagnosis (14/56 cases, 2/14 cases (14% were benign on final histology and 12/14 (86% were malignant. All BRAF-mutated cases on cytology that were found to be benign on histological examination carried the K601E mutation. Of the nonmutated BRAF cases (42/56, 75% which were later found to be malignant on definitive histology, 5 cases were follicular carcinomas (36%, 3 cases were incidentally found to be papillary microcarcinomas (22%, 2 were cases papillary carcinomas (14%, 1 was case follicular variant of papillary carcinoma (7%, 1 was case medullary carcinoma (7%, 1 case was Hurtle cell tumor (7%, and 1 case was combined cell carcinoma and papillary oncocytic carcinoma (7%. Conclusions. The presence of the BRAF V600E mutation may suggest a more aggressive surgical approach. BRAF K601E mutation did not correlate with malignancy indexes.

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

    Science.gov (United States)

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

    2015-02-01

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

  5. Gene expression noise facilitates adaptation and drug resistance independently of mutation.

    Science.gov (United States)

    Charlebois, Daniel A; Abdennur, Nezar; Kaern, Mads

    2011-11-18

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

  6. A comprehensive functional analysis of PTEN mutations: implications in tumor- and autism-related syndromes.

    Science.gov (United States)

    Rodríguez-Escudero, Isabel; Oliver, María D; Andrés-Pons, Amparo; Molina, María; Cid, Víctor J; Pulido, Rafael

    2011-11-01

    The PTEN (phosphatase and tensin homolog) phosphatase is unique in mammals in terms of its tumor suppressor activity, exerted by dephosphorylation of the lipid second messenger PIP(3) (phosphatidylinositol 3,4,5-trisphosphate), which activates the phosphoinositide 3-kinase/Akt/mTOR (mammalian target of rapamycin) oncogenic pathway. Loss-of-function mutations in the PTEN gene are frequent in human cancer and in the germline of patients with PTEN hamartoma tumor-related syndromes (PHTSs). In addition, PTEN is mutated in patients with autism spectrum disorders (ASDs), although no functional information on these mutations is available. Here, we report a comprehensive in vivo functional analysis of human PTEN using a heterologous yeast reconstitution system. Ala-scanning mutagenesis at the catalytic loops of PTEN outlined the critical role of residues within the P-catalytic loop for PIP(3) phosphatase activity in vivo. PTEN mutations that mimic the P-catalytic loop of mammalian PTEN-like proteins (TPTE, TPIP, tensins and auxilins) affected PTEN function variably, whereas tumor- or PHTS-associated mutations targeting the PTEN P-loop produced complete loss of function. Conversely, Ala-substitutions, as well as tumor-related mutations at the WPD- and TI-catalytic loops, displayed partial activity in many cases. Interestingly, a tumor-related D92N mutation was partially active, supporting the notion that the PTEN Asp92 residue might not function as the catalytic general acid. The analysis of a panel of ASD-associated hereditary PTEN mutations revealed that most of them did not substantially abrogate PTEN activity in vivo, whereas most of PHTS-associated mutations did. Our findings reveal distinctive functional patterns among PTEN mutations found in tumors and in the germline of PHTS and ASD patients, which could be relevant for therapy.

  7. Clinical implications of cancer gene mutations in patients with chronic lymphocytic leukemia treated with lenalidomide.

    Science.gov (United States)

    Takahashi, Koichi; Hu, Boyu; Wang, Feng; Yan, Yuanqing; Kim, Ekaterina; Vitale, Candida; Patel, Keyur P; Strati, Paolo; Gumbs, Curtis; Little, Latasha; Tippen, Samantha; Song, Xingzhi; Zhang, Jianhua; Jain, Nitin; Thompson, Philip; Garcia-Manero, Guillermo; Kantarjian, Hagop; Estrov, Zeev; Do, Kim-Anh; Keating, Michael; Burger, Jan A; Ferrajoli, Alessandra; Futreal, P Andrew; Wierda, William G

    2018-01-22

    Lenalidomide is clinically active in chronic lymphocytic leukemia (CLL), but its effectiveness in the context of the CLL mutational landscape is unknown. We performed targeted capture sequencing of 295 cancer genes in specimens from 102 CLL patients with treatment-naïve disease (TN patients) and 186 CLL patients with relapsed/refractory disease (R/R patients) who received lenalidomide-based therapy at our institution. The most frequently mutated gene was SF3B1 (15%), followed by NOTCH1 (14%) and TP53 (14%), with R/R patients having significantly more TP53 mutations than TN patients. Mutated IGHV was associated with an increased prevalence of MYD88 mutations (p=0.005) and del(13q) (p=0.028), whereas unmutated IGHV was associated with an increased prevalence of NOTCH1 (p=0.035) and XPO1 (p=0.047). Among all lenalidomide-treated patients, del(17p) (p≤0.001), del(11q) (p=0.032), and complex karyotype (p=0.022), along with mutations in TP53 (p≤0.001), KRAS (p=0.034), and DDX3X (p≤0.001), were associated with worse overall response (OR). R/R patients with SF3B1 and MGA mutations had significantly worse OR (p=0.025 and 0.035, respectively). TN and R/R patients with del(17p) and TP53 mutations had worse overall survival (OS) and progression-free survival (PFS). In R/R patients, complex karyotype and SF3B1 mutations were associated with worse OS and PFS; DDX3X mutations were associated with worse PFS only. Weibull regression multivariate analysis revealed that TP53 aberrations-del(17p) and/or TP53 mutation-along with complex karyotype and SF3B1 mutations, were associated with worse OS in the R/R cohort. Taken together, cancer gene mutations in CLL contribute to the already comprehensive risk stratification and add to prognosis and response to treatment. The related trials were registered to https://clinicaltrials.gov as NCT00267059, NCT00535873, NCT00759603, NCT01446133, and NCT01002755. Copyright © 2018 American Society of Hematology.

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

    DEFF Research Database (Denmark)

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

    2017-01-01

    at several time-points during adaptive evolution experiments involving five different antibiotic conditions. We monitor the mutational spectra in lineages evolved to be resistant to single antibiotics [amikacin (AMK), chloramphenicol (CHL), and ciprofloxacin (CIP)], as well as antibiotic combinations (AMK...... and fixation allele dynamics. To further understand the selective forces driving specific allele dynamics, a subset of mutations were introduced into the ancestral wild type enabling differentiation between clonal interference and negative epistasis....

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

    Directory of Open Access Journals (Sweden)

    Lucena Evandro

    2009-07-01

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

  10. 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

  11. 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

  12. 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

  13. Comparison of QT peak and QT end interval responses to autonomic adaptation in asymptomatic LQT1 mutation carriers

    Science.gov (United States)

    Haapalahti, Petri; Viitasalo, Matti; Perhonen, Merja; Väänänen, Heikki; Mäkijärvi, Markku; Swan, Heikki; Toivonen, Lauri

    2011-01-01

    Background LQT1 subtype of long QT syndrome is characterized by defective IKs, which is intrinsically stronger in the epicardium than in the midmyocardial region. Electrocardiographic QT peak and QT end intervals may reflect complete repolarization of epicardium and midmyocardial region of the ventricular wall, respectively. Repolarization abnormalities in LQT1 carriers may therefore be more easily detected in the QT peak intervals. Methods Asymptomatic KCNQ1 mutation carriers (LQT1, n = 9) and unaffected healthy controls (n = 8) were studied during Valsalva manoeuvre, mental stress, handgrip and supine exercise. Global QT peak and QT end intervals derived from 25 simultaneous electrocardiographic leads were measured beat to beat with an automated method. Results In unaffected subjects, the percentage shortening of QT peak was greater than that of QT end during mental stress and during the recovery phases of Valsalva and supine exercise. In LQT1 carriers, the percentage shortening of the intervals was similar. At the beginning of Valsalva strain under abrupt endogenous sympathetic activation, QT peak shortened in LQT1 but not in control patients yielding increased electrocardiographic transmural dispersion of repolarization in LQT1. Conclusions In asymptomatic KCNQ1 mutation carriers, repolarization abnormalities are more evident in the QT peak than in the QT end interval during adrenergic adaptation, possibly related to transmural differences in the degree of IKs block. PMID:21138517

  14. Founder mutations in Tunisia: implications for diagnosis in North Africa and Middle East

    Directory of Open Access Journals (Sweden)

    Romdhane Lilia

    2012-08-01

    Full Text Available Abstract Background Tunisia is a North African country of 10 million inhabitants. The native background population is Berber. However, throughout its history, Tunisia has been the site of invasions and migratory waves of allogenic populations and ethnic groups such as Phoenicians, Romans, Vandals, Arabs, Ottomans and French. Like neighbouring and Middle Eastern countries, the Tunisian population shows a relatively high rate of consanguinity and endogamy that favor expression of recessive genetic disorders at relatively high rates. Many factors could contribute to the recurrence of monogenic morbid trait expression. Among them, founder mutations that arise in one ancestral individual and diffuse through generations in isolated communities. Method We report here on founder mutations in the Tunisian population by a systematic review of all available data from PubMed, other sources of the scientific literature as well as unpublished data from our research laboratory. Results We identified two different classes of founder mutations. The first includes founder mutations so far reported only among Tunisians that are responsible for 30 genetic diseases. The second group represents founder haplotypes described in 51 inherited conditions that occur among Tunisians and are also shared with other North African and Middle Eastern countries. Several heavily disabilitating diseases are caused by recessive founder mutations. They include, among others, neuromuscular diseases such as congenital muscular dystrophy and spastic paraglegia and also severe genodermatoses such as dystrophic epidermolysis bullosa and xeroderma pigmentosa. Conclusion This report provides informations on founder mutations for 73 genetic diseases either specific to Tunisians or shared by other populations. Taking into account the relatively high number and frequency of genetic diseases in the region and the limited resources, screening for these founder mutations should provide a rapid

  15. Founder mutations in Tunisia: implications for diagnosis in North Africa and Middle East.

    Science.gov (United States)

    Romdhane, Lilia; Kefi, Rym; Azaiez, Hela; Ben Halim, Nizar; Dellagi, Koussay; Abdelhak, Sonia

    2012-08-21

    Tunisia is a North African country of 10 million inhabitants. The native background population is Berber. However, throughout its history, Tunisia has been the site of invasions and migratory waves of allogenic populations and ethnic groups such as Phoenicians, Romans, Vandals, Arabs, Ottomans and French. Like neighbouring and Middle Eastern countries, the Tunisian population shows a relatively high rate of consanguinity and endogamy that favor expression of recessive genetic disorders at relatively high rates. Many factors could contribute to the recurrence of monogenic morbid trait expression. Among them, founder mutations that arise in one ancestral individual and diffuse through generations in isolated communities. We report here on founder mutations in the Tunisian population by a systematic review of all available data from PubMed, other sources of the scientific literature as well as unpublished data from our research laboratory. We identified two different classes of founder mutations. The first includes founder mutations so far reported only among Tunisians that are responsible for 30 genetic diseases. The second group represents founder haplotypes described in 51 inherited conditions that occur among Tunisians and are also shared with other North African and Middle Eastern countries. Several heavily disabilitating diseases are caused by recessive founder mutations. They include, among others, neuromuscular diseases such as congenital muscular dystrophy and spastic paraglegia and also severe genodermatoses such as dystrophic epidermolysis bullosa and xeroderma pigmentosa. This report provides informations on founder mutations for 73 genetic diseases either specific to Tunisians or shared by other populations. Taking into account the relatively high number and frequency of genetic diseases in the region and the limited resources, screening for these founder mutations should provide a rapid and cost effective tool for molecular diagnosis. Indeed, our report

  16. 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.

  17. Rates, Distribution, and Implications of Post-zygotic Mosaic Mutations in Autism Spectrum Disorder

    Science.gov (United States)

    Lim, Elaine T.; Uddin, Mohammed; De Rubeis, Silvia; Chan, Yingleong; Kamumbu, Anne S.; Zhang, Xiaochang; D'Gama, Alissa; Kim, Sonia N.; Hill, Robert Sean; Goldberg, Arthur P.; Poultney, Christopher; Minshew, Nancy J.; Kushima, Itaru; Aleksic, Branko; Ozaki, Norio; Parellada, Mara; Arango, Celso; Penzol, Maria J.; Carracedo, Angel; Kolevzon, Alexander; Hultman, Christina M.; Weiss, Lauren A.; Fromer, Menachem; Chiocchetti, Andreas G.; Freitag, Christine M.; Church, George M.; Scherer, Stephen W.; Buxbaum, Joseph D.; Walsh, Christopher A.

    2017-01-01

    We systematically analyzed post-zygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed re-sequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, with 83.3% of these PZMs not discovered in previous studies. Damaging, non-synonymous PZMs within critical exons of prenatally-expressed genes were more common in ASD probands than controls (P<1×10-6), and genes carrying these PZMs were enriched for expression in the amygdala (P=5.4×10-3). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU, SMARCA4) known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk. PMID:28714951

  18. 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.

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

    Science.gov (United States)

    Choi, Sarah M; Goldenson, Ben; Peterson, Lo Ann; Dinner, Shira; Stein, Brady L; Behdad, Amir

    2017-01-01

    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.

  20. 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.

  1. 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.

  2. Adaptive mutations in the nuclear export protein of human-derived H5N1 strains facilitate a polymerase activity-enhancing conformation

    NARCIS (Netherlands)

    P. Reuther (Peter); S. Giese (Sebastian); H.M. Götz (Hannelore); N. Kilb (Normann); B. Mänz (Benjamin); L. Brunotte (Linda); M. Schwemmle (Martin)

    2014-01-01

    textabstractThe nuclear export protein (NEP) (NS2) of the highly pathogenic human-derived H5N1 strain A/Thailand/1(KAN-1)/2004 with the adaptive mutation M16I greatly enhances the polymerase activity in human cells in a concentration-dependent manner. While low NEP levels enhance the polymerase

  3. Adaptation of yellow fever virus 17D to Vero cells is associated with mutations in structural and non-structural protein genes.

    Science.gov (United States)

    Beasley, David W C; Morin, Merribeth; Lamb, Ashley R; Hayman, Edward; Watts, Douglas M; Lee, Cynthia K; Trent, Dennis W; Monath, Thomas P

    2013-09-01

    Serial passaging of yellow fever virus 17D in Vero cells was employed to derive seed material for a novel inactivated vaccine, XRX-001. Two independent passaging series identified a novel lysine to arginine mutation at amino acid 160 of the envelope protein, a surface-exposed residue in structural domain I. A third passage series resulted in an isoleucine to methionine mutation at residue 113 of the NS4B protein, a central membrane spanning region of the protein which has previously been associated with Vero cell adaptation of other mosquito-borne flaviviruses. These studies confirm that flavivirus adaptation to growth in Vero cells can be mediated by structural or non-structural protein mutations. Copyright © 2013 Elsevier B.V. All rights reserved.

  4. 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.

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

    DEFF Research Database (Denmark)

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

    2012-01-01

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

  6. 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...... carbon source, and requires supplementation of C2 compounds to the medium in order to meet the requirement for cytosolic acetyl-CoA for biosynthesis of fatty acids and ergosterol. Results: In this study, a Pdc negative strain was adaptively evolved for improved growth in glucose medium via serial...... transfer, resulting in three independently evolved strains, which were able to grow in minimal medium containing glucose as the sole carbon source at the maximum specific rates of 0.138, 0.148, 0.141 h-1, respectively. Several genetic changes were identified in the evolved Pdc negative strains by genomic...

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

    Science.gov (United States)

    Flegr, Jaroslav

    2013-01-16

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

  8. Adaptive Immunity in Schizophrenia: Functional Implications of T Cells in the Etiology, Course and Treatment.

    Science.gov (United States)

    Debnath, Monojit

    2015-12-01

    Schizophrenia is a severe and highly complex neurodevelopmental disorder with an unknown etiopathology. Recently, immunopathogenesis has emerged as one of the most compelling etiological models of schizophrenia. Over the past few years considerable research has been devoted to the role of innate immune responses in schizophrenia. The findings of such studies have helped to conceptualize schizophrenia as a chronic low-grade inflammatory disorder. Although the contribution of adaptive immune responses has also been emphasized, however, the precise role of T cells in the underlying neurobiological pathways of schizophrenia is yet to be ascertained comprehensively. T cells have the ability to infiltrate brain and mediate neuro-immune cross-talk. Conversely, the central nervous system and the neurotransmitters are capable of regulating the immune system. Neurotransmitter like dopamine, implicated widely in schizophrenia risk and progression can modulate the proliferation, trafficking and functions of T cells. Within brain, T cells activate microglia, induce production of pro-inflammatory cytokines as well as reactive oxygen species and subsequently lead to neuroinflammation. Importantly, such processes contribute to neuronal injury/death and are gradually being implicated as mediators of neuroprogressive changes in schizophrenia. Antipsychotic drugs, commonly used to treat schizophrenia are also known to affect adaptive immune system; interfere with the differentiation and functions of T cells. This understanding suggests a pivotal role of T cells in the etiology, course and treatment of schizophrenia and forms the basis of this review.

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

    Directory of Open Access Journals (Sweden)

    Tiantian Liu

    2016-07-01

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

  10. 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.

  11. Implications of fALS Mutations on Sod1 Function and Oligomerization in Cell Models.

    Science.gov (United States)

    Brasil, Aline A; Magalhães, Rayne S S; De Carvalho, Mariana D C; Paiva, Isabel; Gerhardt, Ellen; Pereira, Marcos D; Outeiro, Tiago F; Eleutherio, Elis C A

    2017-09-07

    Among the familial forms of amyotrophic lateral sclerosis (fALS), 20% are associated with the Cu,Zn-superoxide dismutase (Sod1). fALS is characterized by the accumulation of aggregated proteins and the increase in oxidative stress markers. Here, we used the non-invasive bimolecular fluorescence complementation (BiFC) assay in human H4 cells to investigate the kinetics of aggregation and subcellular localization of Sod1 mutants. We also studied the effect of the different Sod1 mutants to respond against oxidative stress by following the levels of reactive oxygen species (ROS) after treatment with hydrogen peroxide. Our results showed that only 30% of cells transfected with A4VSod1 showed no inclusions while for the other Sod1 mutants tested (L38V, G93A and G93C), this percentage was at least 70%. In addition, we found that 10% of cells transfected with A4VSod1 displayed more than five inclusions per cell and that A4V and G93A Sod1 formed inclusions more rapidly than L38V and G93C Sod1. Expression of WTSod1 significantly decreased the intracellular oxidation levels in comparison with expression of fALS Sod1 mutants, suggesting the mutations induce a functional impairment. All fALS mutations impaired nuclear localization of Sod1, which is important for maintaining genomic stability. Consistently, expression of WTSod1, but not of fALS Sod1 mutants, reduced DNA damage, as measured by the comet assay. Altogether, our study sheds light into the effects of fALS Sod1 mutations on inclusion formation, dynamics, and localization as well as on antioxidant response, opening novel avenues for investigating the role of fALS Sod1 mutations in pathogenesis.

  12. IDH-1R132H mutation status in diffuse glioma patients: implications for classification.

    Science.gov (United States)

    Wang, Peng-Fei; Liu, Ning; Song, Hong-Wang; Yao, Kun; Jiang, Tao; Li, Shou-Wei; Yan, Chang-Xiang

    2016-05-24

    WHO2007 grading of diffuse gliomas in adults is well-established. However, IDH mutations make classification of gliomas according to the WHO2007 edition controversial. Here, we characterized IDH-1R132H mut status in a cohort of 670 adult patients with different WHO2007 grades of diffuse glioma. Patient characteristics, clinical data and prognoses were obtained from medical records. Patients with IDH-1R132H mut were younger and had better clinical outcomes than those without mutations. Differences in age among patients with astrocytomas of different WHO2007 grades were eliminated after patients were grouped based on IDH-1R132H status. IDH-1R132H mut was present more often in patients with lower Ki-67 and MGMT protein levels and higher mutant p53 levels. Ki-67 was also strongly associated with WHO2007 grade independently of IDH-1R132H mut status. Moreover, patients with Ki-67IDH-1R132H mut status. Patients in the IDH-1R132H mut group with lower MGMT protein levels also had better clinical outcomes than those in other groups. Our results indicate that to better treat gliomas, IDH mutation status should be included when determining WHO2007 grade in glioma patients.

  13. Health risks of climate change: an assessment of uncertainties and its implications for adaptation policies.

    Science.gov (United States)

    Wardekker, J Arjan; de Jong, Arie; van Bree, Leendert; Turkenburg, Wim C; van der Sluijs, Jeroen P

    2012-09-19

    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. 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. 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. 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 most appropriate. For climate related health

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

    Directory of Open Access Journals (Sweden)

    Wardekker J

    2012-09-01

    Full Text Available Abstract 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

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

    NARCIS (Netherlands)

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

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

  16. 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.

  17. 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.

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

    Directory of Open Access Journals (Sweden)

    Flegr Jaroslav

    2013-01-01

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

  19. 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.

  20. Nucleoside reverse transcriptase inhibitor resistance mutations associated with first-line stavudine-containing antiretroviral therapy: programmatic implications for countries phasing out stavudine

    NARCIS (Netherlands)

    Tang, Michele W.; Rhee, Soo-Yon; Bertagnolio, Silvia; Ford, Nathan; Holmes, Susan; Sigaloff, Kim C.; Hamers, Raph L.; Rinke de Wit, Tobias F.; Fleury, Herve J.; Kanki, Phyllis J.; Ruxrungtham, Kiat; Hawkins, Claudia A.; Wallis, Carole L.; Stevens, Wendy; van Zyl, Gert U.; Manosuthi, Weerawat; Hosseinipour, Mina C.; Ngo-Giang-Huong, Nicole; Belec, Laurent; Peeters, Martine; Aghokeng, Avelin; Bunupuradah, Torsak; Burda, Sherri; Cane, Patricia; Cappelli, Giulia; Charpentier, Charlotte; Dagnra, Anoumou Y.; Deshpande, Alaka K.; El-Katib, Ziad; Eshleman, Susan H.; Fokam, Joseph; Gody, Jean-Chrysostome; Katzenstein, David; Koyalta, Donato D.; Kumwenda, Johnstone J.; Lallemant, Marc; Lynen, Lutgarde; Marconi, Vincent C.; Margot, Nicolas A.; Moussa, Sandrine; Ndung'u, Thumbi; Nyambi, Phillipe N.; Orrell, Catherine; Schapiro, Jonathan M.; Schuurman, Rob; Sirivichayakul, Sunee; Smith, Davey; Zolfo, Maria; Jordan, Michael R.; Shafer, Robert W.

    2013-01-01

    The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for

  1. Evaluation of an MMPI--a short form: implications for adaptive testing.

    Science.gov (United States)

    Archer, R P; Tirrell, C A; Elkins, D E

    2001-02-01

    Efforts to develop a viable short form of the MMPI (Hathaway & McKinley, 1943) span more than 50 years, with more recent attempts to significantly shorten the item pool focused on the use of adaptive computerized test administration. In this article, we report some psychometric properties of an MMPI-Adolescent version (MMPI-A; Butcher et al., 1992) short form based on administration of the first 150 items of this test instrument. We report results for both the MMPI-A normative sample of 1,620 adolescents and a clinical sample of 565 adolescents in a variety of treatment settings. We summarize results for the MMPI-A basic scales in terms of Pearson product-moment correlations generated between full administration and short-form administration formats and mean Tscore elevations for the basic scales generated by each approach. In this investigation, we also examined single-scale and 2-point congruences found for the MMPI-A basic clinical scales as derived from standard and short-form administrations. We present the relative strengths and weaknesses of the MMPI-A short form and discuss the findings in terms of implications for attempts to shorten the item pool through the use of computerized adaptive assessment approaches.

  2. 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.

  3. Implications of movement-related cortical potential for understanding neural adaptations in muscle strength tasks

    Science.gov (United States)

    2014-01-01

    This systematic review aims to provide information about the implications of the movement-related cortical potential (MRCP) in acute and chronic responses to the counter resistance training. The structuring of the methods of this study followed the proposals of the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses). It was performed an electronically search in Pubmed/Medline and ISI Web of Knowledge data bases, from 1987 to 2013, besides the manual search in the selected references. The following terms were used: Bereitschaftspotential, MRCP, strength and force. The logical operator “AND” was used to combine descriptors and terms used to search publications. At the end, 11 studies attended all the eligibility criteria and the results demonstrated that the behavior of MRCP is altered because of different factors such as: force level, rate of force development, fatigue induced by exercise, and the specific phase of muscular action, leading to an increase in the amplitude in eccentric actions compared to concentric actions, in acute effects. The long-term adaptations demonstrated that the counter resistance training provokes an attenuation in the amplitude in areas related to the movement, which may be caused by neural adaptation occurred in the motor cortex. PMID:24602228

  4. Biosynthesis and trafficking of the bile salt export pump, BSEP: therapeutic implications of BSEP mutations.

    Science.gov (United States)

    Soroka, Carol J; Boyer, James L

    2014-06-01

    The bile salt export pump (BSEP, ABCB11) is the primary transporter of bile acids from the hepatocyte to the biliary system. This rate-limiting step in bile formation is essential to the formation of bile salt dependent bile flow, the enterohepatic circulation of bile acids, and the digestion of dietary fats. Mutations in BSEP are associated with cholestatic diseases such as progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis type 2 (BRIC2), drug-induced cholestasis, and intrahepatic cholestasis of pregnancy. Development of clinical therapies for these conditions necessitates a clear understanding of the cell biology of biosynthesis, trafficking, and transcriptional and translational regulation of BSEP. This chapter will focus on the molecular and cell biological aspects of this critical hepatic membrane transporter. Copyright © 2013 Elsevier Ltd. All rights reserved.

  5. 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.

  6. Tumor Protein 53 Gene Mutations Without 17p13 Deletion Have No Significant Clinical Implications in Chronic Lymphocytic Leukemia. Detection of a New Mutation.

    Science.gov (United States)

    Diamantopoulos, Panagiotis T; Samara, Stavroula; Kollia, Panagoula; Giannakopoulou, Nefeli; Sofotasiou, Maria; Kalala, Fani; Kodandreopoulou, Elina; Zervakis, Panagiotis; Vassilakopoulos, Theodoros; Siakantaris, Marina; Mantzourani, Marina; Angelopoulou, Maria; Kyrtshonis, Marie-Christine; Korkolopoulou, Penelope; Patsouris, Efstathios; Viniou, Nora-Athina

    2017-05-01

    The tumor protein p53 (TP53) gene may be inactivated through 17p13 deletion, somatic mutations, or both. In chronic lymphocytic leukemia (CLL) although 17p13 deletion is correlated with poor prognosis, the role of sole TP53 mutations remains controversial. We carried out a mutation analysis of TP53 gene in 72 patients with CLL. Seventy-one (98.6%) patients carried the polymorphic site c.215C>G, p.Pro72Arg, but its presence was not correlated with overall survival (OS). Moreover, 19 (26.4%) patients carried a mutation of TP53. Among the eight detected mutations, to our knowledge, one (c.587G>A) has never been reported in the past. There was a correlation of the mutation burden with the stage of the disease (p=0.022), but not with OS. None of the detected mutations was individually correlated with OS. The clinical significance of TP53 mutations is still a matter of debate and larger studies and meta-analyses are required to reach an unequivocal conclusion. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  7. Adaptive mutations and replacements of virulence traits in the Escherichia coli O104:H4 outbreak population.

    Directory of Open Access Journals (Sweden)

    Lionel Guy

    Full Text Available The sequencing of highly virulent Escherichia coli O104:H4 strains isolated during the outbreak of bloody diarrhea and hemolytic uremic syndrome in Europe in 2011 revealed a genome that contained a Shiga toxin encoding prophage and a plasmid encoding enteroaggregative fimbriae. Here, we present the draft genome sequence of a strain isolated in Sweden from a patient who had travelled to Tunisia in 2010 (E112/10 and was found to differ from the outbreak strains by only 38 SNPs in non-repetitive regions, 16 of which were mapped to the branch to the outbreak strain. We identified putatively adaptive mutations in genes for transporters, outer surface proteins and enzymes involved in the metabolism of carbohydrates. A comparative analysis with other historical strains showed that E112/10 contained Shiga toxin prophage genes of the same genotype as the outbreak strain, while these genes have been replaced by a different genotype in two otherwise very closely related strains isolated in the Republic of Georgia in 2009. We also present the genome sequences of two enteroaggregative E. coli strains affiliated with phylogroup A (C43/90 and C48/93 that contain the agg genes for the AAF/I-type fimbriae characteristic of the outbreak population. Interestingly, C43/90 also contained a tet/mer antibiotic resistance island that was nearly identical in sequence to that of the outbreak strain, while the corresponding island in the Georgian strains was most similar to E. coli strains of other serotypes. We conclude that the pan-genome of the outbreak population is shared with strains of the A phylogroup and that its evolutionary history is littered with gene replacement events, including most recently independent acquisitions of antibiotic resistance genes in the outbreak strains and its nearest neighbors. The results are summarized in a refined evolutionary model for the emergence of the O104:H4 outbreak population.

  8. 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

  9. Detection of five rare cystic fibrosis mutations peculiar to Southern Italy: implications in screening for the disease and phenotype characterization for patients with homozygote mutations.

    Science.gov (United States)

    Castaldo, G; Fuccio, A; Cazeneuve, C; Picci, L; Salvatore, D; Raia, V; Scarpa, M; Goossens, M; Salvatore, F

    1999-07-01

    The search for the eight most frequent mutations (i.e., DeltaF508, G542X, W1282X, N1303K, 1717-1G-->A, R553X, 2183AA-->G, and I148T) by allele-specific oligonucleotide dot-blot analysis revealed 78% of 396 cystic fibrosis alleles in Southern Italy. The observation of frequent haplotypes on the unidentified cystic fibrosis alleles suggested that a few mutations could account for a large number of unidentified alleles. We screened most of the coding sequence of the cystic fibrosis transmembrane regulator gene by denaturing gradient gel electrophoresis to determine the spectrum of these mutations in 68 unrelated cystic fibrosis patients bearing one or both unidentified mutations. The screening revealed five mutations, R1158X, 711+1G-->T, 4016insT, L1065P, and G1244E, each of which had a frequency of 1.3-1.8% (7% collectively). The 7% increase in the detection rate (85% vs 78%) reduces by >50% the residual risk of being cystic fibrosis carriers for couples who had tested negative by molecular analysis. We therefore designed a second allele-specific oligonucleotide set to analyze the five mutations. Among the patients analyzed, one patient homozygous for the L1065P mutation expressed a mild pulmonary and intestinal form of the disease with pancreatic insufficiency. Two other patients, homozygous for mutations R1158X and 4016insT, both expressed a severe cystic fibrosis phenotype. Five cystic fibrosis mutations are peculiar to patients from Southern Italy. The method described for their analysis is efficient, inexpensive, and can be semi-automated by use of a robotic workstation. The results obtained in patients from Southern Italy may have an impact on laboratories in other countries, given the large migrations of populations from Southern Italy to other countries in the last two centuries.

  10. 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.

  11. 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

  12. Implications of complex adaptive systems theory for the design of research on health care organizations.

    Science.gov (United States)

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

    2009-01-01

    Because health care organizations (HCOs) are complex adaptive systems (CASs), phenomena of interest often are dynamic and unfold in unpredictable ways, and unfolding events are often unique. Researchers of HCOs may recognize that the subject of their research is dynamic; however, their research designs may not take this into account. Researchers may also know that unfolding events are often unique, but their design may not have the capacity to obtain information from meager evidence. These two concerns led us to examine two ideas from organizational theory: (a) the ideas of K. E. Weick (1993) on organizational design as a verb and (b) the ideas of J. G. March, L. S. Sproull, and M. Tamuz (1991) on learning from samples of one or fewer. In this article, we applied these ideas to develop an enriched perspective of research design for studying CASs. We conducted a theoretical analysis of organizations as CASs, identifying relevant characteristics for research designs. We then explored two ideas from organizational theory and discussed the implications for research designs. Weick's idea of "design as a verb" helps in understanding dynamic and process-oriented research design. The idea of "learning from samples of one or fewer" of March, Sproull, and Tamuz provides strategies for research design that enables learning from meager evidence. When studying HCOs, research designs are likely to be more effective when they (a) anticipate change, (b) include tension, (c) capitalize on serendipity, and (d) use an "act-then-look" mind set. Implications for practice are discussed. Practitioners who understand HCOs as CASs will be cautious in accepting findings from studies that treat HCOs mechanistically. They will consider the characteristics of CAS when evaluating the evidence base for practice. Practitioners can use the strategies proposed in this article to stimulate discussion with researchers seeking to conduct research in their HCO.

  13. Frequency and phenotypic implications of mitochondrial DNA mutations in human squamous cell cancers of the head and neck.

    Science.gov (United States)

    Zhou, Shaoyu; Kachhap, Sushant; Sun, Wenyue; Wu, Guojun; Chuang, Alice; Poeta, Luana; Grumbine, Lawson; Mithani, Suhail K; Chatterjee, Aditi; Koch, Wayne; Westra, William H; Maitra, Anirban; Glazer, Chad; Carducci, Michael; Sidransky, David; McFate, Thomas; Verma, Ajay; Califano, Joseph A

    2007-05-01

    Mitochondrial genomic mutations are found in a variety of human cancers; however, the frequency of mitochondrial DNA (mtDNA) mutations in coding regions remains poorly defined, and the functional effects of mitochondrial mutations found in primary human cancers are not well described. Using MitoChip, we sequenced the whole mitochondrial genome in 83 head and neck squamous cell carcinomas. Forty-one of 83 (49%) tumors contained mtDNA mutations. Mutations occurred within noncoding (D-loop) and coding regions. A nonrandom distribution of mutations was found throughout the mitochondrial enzyme complex components. Sequencing of margins with dysplasia demonstrated an identical nonconservative mitochondrial mutation (A76T in ND4L) as the tumor, suggesting a role of mtDNA mutation in tumor progression. Analysis of p53 status showed that mtDNA mutations correlated positively with p53 mutations (P < 0.002). To characterize biological function of the mtDNA mutations, we cloned NADH dehydrogenase subunit 2 (ND2) mutants based on primary tumor mutations. Expression of the nuclear-transcribed, mitochondrial-targeted ND2 mutants resulted in increased anchorage-dependent and -independent growth, which was accompanied by increased reactive oxygen species production and an aerobic glycolytic metabolic phenotype with hypoxia-inducible factor (HIF)-1alpha induction that is reversible by ascorbate. Cancer-specific mitochondrial mutations may contribute to development of a malignant phenotype by direct genotoxic effects from increased reactive oxygen species production as well as induction of aerobic glycolysis and growth promotion.

  14. 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

  15. 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

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

    Science.gov (United States)

    Pratt, Jessica D; Mooney, Kailen A

    2013-08-01

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

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

    Science.gov (United States)

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

    2016-12-01

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

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

    Science.gov (United States)

    Sinclair, Frazer H; Stone, Graham N; Nicholls, James A; Cavers, Stephen; Gibbs, Melanie; Butterill, Philip; Wagner, Stefanie; Ducousso, Alexis; Gerber, Sophie; Petit, Rémy J; Kremer, Antoine; Schönrogge, Karsten

    2015-12-01

    Disruption of species interactions is a key issue in climate change biology. Interactions involving forest trees may be particularly vulnerable due to evolutionary rate limitations imposed by long generation times. One mitigation strategy for such impacts is Climate matching - the augmentation of local native tree populations by input from nonlocal populations currently experiencing predicted future climates. This strategy is controversial because of potential cascading impacts on locally adapted animal communities. We explored these impacts using abundance data for local native gallwasp herbivores sampled from 20 provenances of sessile oak (Quercus petraea) planted in a common garden trial. We hypothesized that non-native provenances would show (i) declining growth performance with increasing distance between provenance origin and trial site, and (ii) phenological differences to local oaks that increased with latitudinal differences between origin and trial site. Under a local adaptation hypothesis, we predicted declining gallwasp abundance with increasing phenological mismatch between native and climate-matched trees. Both hypotheses for oaks were supported. Provenance explained significant variation in gallwasp abundance, but no gall type showed the relationship between abundance and phenological mismatch predicted by a local adaptation hypothesis. Our results show that climate matching would have complex and variable impacts on oak gall communities.

  19. Prevalence and implications of TERT promoter mutation in uveal and conjunctival melanoma and in benign and premalignant conjunctival melanocytic lesions.

    Science.gov (United States)

    Koopmans, Anna E; Ober, Kimberley; Dubbink, Hendrikus J; Paridaens, Dion; Naus, Nicole C; Belunek, Stephan; Krist, Bart; Post, Edward; Zwarthoff, Ellen C; de Klein, Annelies; Verdijk, Robert M

    2014-08-26

    Hot-spot mutations in the promoter region of telomerase reverse transcriptase (TERT promoter mutations) occur frequently in cutaneous and conjunctival melanoma and are exceedingly rare in uveal melanoma. No information is available on the presence of these mutations in the conjunctival melanocytic precursor lesion primary acquired melanosis (PAM). We tested a cohort of uveal and conjunctival melanomas as well as conjunctival benign and premalignant melanocytic lesions for TERT promoter mutations in order to elucidate the role of these mutations in tumor progression. TERT promoter mutation analysis on fresh tumor DNA and DNA from formalin-fixed, paraffin-embedded specimens was performed by SNaPshot analysis in 102 uveal melanomas, 39 conjunctival melanomas, 26 PAM with atypia, 14 PAM without atypia, and 56 conjunctival nevi. Mutations of the TERT promoter were not identified in conjunctival nevi or PAM without atypia, but were detected in 2/25 (8%) of PAM with atypia and 16/39 (41%) of conjunctival melanomas. A single TERT promoter mutation was detected in 102 uveal melanomas (1%). We present the second documented case of TERT promoter mutation in uveal melanoma. In comparison with other types of melanoma, TERT promoter mutations occur at extremely low frequency in uveal melanoma. TERT promoter mutations are frequent in conjunctival melanoma and occur at lower frequency in PAM with atypia but were not detected in benign conjunctival melanocytic lesions. These findings favor a pathogenetic tumor progression role for TERT promoter mutations in conjunctival melanocytic lesions. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

  20. Substrate Compositional Variation with Tissue/Region and Gba1 Mutations in Mouse Models?Implications for Gaucher Disease

    OpenAIRE

    Sun, Ying; Zhang, Wujuan; Xu, You-Hai; Quinn, Brian; Dasgupta, Nupur; Liou, Benjamin; Setchell, Kenneth D. R.; Grabowski, Gregory A.

    2013-01-01

    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 excess...

  1. Piebald trait: implication of kit mutation on in vitro melanocyte survival and on the clinical application of cultured epidermal autografts.

    Science.gov (United States)

    Bondanza, Sergio; Bellini, Melissa; Roversi, Gaia; Raskovic, Desanka; Maurelli, Riccardo; Paionni, Emanuel; Paterna, Patrizia; Dellambra, Elena; Larizza, Lidia; Guerra, Liliana

    2007-03-01

    Piebald trait leukoderma results from "loss-of-function" mutations in the kit gene. Correlations between mutation type and clinical phenotype have been reported. However, mutation classification has been mainly based on the clinical features of patients. The aim of this study was to get a better understanding of the pathogenesis of human piebaldism by establishing whether the kit mutation type may affect the in vitro survival/proliferation of patient melanocytes. Overall, the research was finalized to implement the clinical application of the autologous cultured epidermis in the treatment of piebald patients. Seven patients, who were transplanted with autologous in vitro reconstituted epidermis, showed an average percentage of repigmentation of 90.7. Six novel and one previously reported mutations were found and their postulated effects discussed in relation to the clinical phenotype and in vitro behavior of epidermal cells. Although mutation type did not impair repigmentation given by autotransplantation, it was shown to influence the survival/proliferation of co-cultured melanocytes and keratinocytes. In particular, tyrosine kinase domain mutations were found with melanocyte loss and keratinocyte senescence during expansion of epidermal cultures. Results indicate that the clinical application of cultured epidermis in piebald patients may be optimized by investigating mutation functional effects before planning surgical operations.

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

    Science.gov (United States)

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

  3. Leber's hereditary optic neuropathy: implications of the sex ratio for linkage studies in families with the 3460 ND1 mutation

    NARCIS (Netherlands)

    Black, G. C.; Craig, I. W.; Oostra, R. J.; Norby, S.; Rosenberg, T.; Morten, K.; Laborde, A.; Poulton, J.

    1995-01-01

    Leber's hereditary optic neuropathy (LHON), which is associated with mutations in mitochondrial DNA (mtDNA), is commoner in males than females. A study of over 30 LHON families with a mutation at position 3460 of mtDNA demonstrates a significantly decreased male excess from that generally quoted,

  4. 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

  5. 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

    BACKGROUND: The Plasmodium falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) are enzymes of central importance in parasite metabolism. The dhfr and dhps gene mutations are known to be associated with sulphadoxine/pyrimethamine (SP) resistance. OBJECTIVE: To investigate...... 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......-ELISA. RESULTS & CONCLUSION: Mutations were detected in dhfr at N51I, S108N and C59R, and in at dhps at A/S436F, A437G, K540E and A581G, the maximum number of mutations per infection were five. Based on number of mutant codons per infection (multiplicity of mutation, MOM), the infections were organized into six...

  6. 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.

  7. Implications of Untreated Cleft Palate in the Developing World: Adaptation of an Outcome Measure

    OpenAIRE

    Rees, J.; Muskett, TA; Enderby, P.; Stackhouse, J.

    2016-01-01

    Objectives: To identify the implications of living with untreated cleft palate and develop an outcome measure which reflects the broad impact of surgery but is sensitive to the physical impact, speech changes, and psychosocial implications of late intervention. Design, Participants, Setting: Focus groups and individual interviews were used to gather information on the implications of living with untreated cleft palate and the impact of subsequent surgery. Participants included 11 individuals ...

  8. Activating K-Ras mutations outwith ‘hotspot' codons in sporadic colorectal tumours – implications for personalised cancer medicine

    Science.gov (United States)

    Smith, G; Bounds, R; Wolf, H; Steele, R J C; Carey, F A; Wolf, C R

    2010-01-01

    Background: Response to EGFR-targeted therapies in colorectal cancer patients has been convincingly associated with Kirsten-Ras (K-Ras) mutation status. Current mandatory mutation testing for patient selection is limited to the K-Ras ‘hotspot' codons 12 and 13. Methods: Colorectal tumours (n=106) were screened for additional K-Ras mutations, phenotypes compared in transformation and Ras GTPase activating assays and gene and pathway changes induced by individual K-Ras mutants identified by microarray analysis. Taqman-based gene copy number and FISH analyses were used to investigate K-Ras gene amplification. Results: Four additional K-Ras mutations (Leu19Phe (1 out of 106 tumours), Lys117Asn (1 out of 106), Ala146Thr (7 out of 106) and Arg164Gln (1 out of 106)) were identified. Lys117Asn and Ala146Thr had phenotypes similar to the hotspot mutations, whereas Leu19Phe had an attenuated phenotype and the Arg164Gln mutation was phenotypically equivalent to wt K-Ras. We additionally identified a new K-Ras gene amplification event, present in approximately 2% of tumours. Conclusions: The identification of mutations outwith previously described hotspot codons increases the K-Ras mutation burden in colorectal tumours by one-third. Future mutation screening to facilitate optimal patient selection for treatment with EGFR-targeted therapies should therefore be extended to codon 146, and in addition should consider the unique molecular signatures associated with individual K-Ras mutations. PMID:20147967

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

    Directory of Open Access Journals (Sweden)

    Danuta M Skowronski

    Full Text Available Influenza vaccine effectiveness (VE is generally interpreted in the context of vaccine match/mismatch to circulating strains with evolutionary drift in the latter invoked to explain reduced protection. During the 2012-13 season, however, detailed genotypic and phenotypic characterization shows that low VE was instead related to mutations in the egg-adapted H3N2 vaccine strain rather than antigenic drift in circulating viruses.Component-specific VE against medically-attended, PCR-confirmed influenza was estimated in Canada by test-negative case-control design. Influenza A viruses were characterized genotypically by amino acid (AA sequencing of established haemagglutinin (HA antigenic sites and phenotypically through haemagglutination inhibition (HI assay. H3N2 viruses were characterized in relation to the WHO-recommended, cell-passaged vaccine prototype (A/Victoria/361/2011 as well as the egg-adapted strain as per actually used in vaccine production. Among the total of 1501 participants, influenza virus was detected in 652 (43%. Nearly two-thirds of viruses typed/subtyped were A(H3N2 (394/626; 63%; the remainder were A(H1N1pdm09 (79/626; 13%, B/Yamagata (98/626; 16% or B/Victoria (54/626; 9%. Suboptimal VE of 50% (95%CI: 33-63% overall was driven by predominant H3N2 activity for which VE was 41% (95%CI: 17-59%. All H3N2 field isolates were HI-characterized as well-matched to the WHO-recommended A/Victoria/361/2011 prototype whereas all but one were antigenically distinct from the egg-adapted strain as per actually used in vaccine production. The egg-adapted strain was itself antigenically distinct from the WHO-recommended prototype, and bore three AA mutations at antigenic sites B [H156Q, G186V] and D [S219Y]. Conversely, circulating viruses were identical to the WHO-recommended prototype at these positions with other genetic variation that did not affect antigenicity. VE was 59% (95%CI:16-80% against A(H1N1pdm09, 67% (95%CI: 30-85% against B

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

    Directory of Open Access Journals (Sweden)

    Melanie Boeckmann

    2016-09-01

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

  11. Altered Visual Adaptation to Body Shape in Eating Disorders: Implications for Body Image Distortion.

    Science.gov (United States)

    Mohr, Harald M; Rickmeyer, Constanze; Hummel, Dennis; Ernst, Mareike; Grabhorn, Ralph

    2016-07-01

    Previous research has shown that after adapting to a thin body, healthy participants (HP) perceive pictures of their own bodies as being fatter and vice versa. This aftereffect might contribute to the development of perceptual body image disturbances in eating disorders (ED).In the present study, HP and ED completed a behavioral experiment to rate manipulated pictures of their own bodies after adaptation to thin or fat body pictures. After adapting to a thin body, HP judged a thinner than actual body picture to be the most realistic and vice versa, resembling a typical aftereffect. ED only showed such an adaptation effect when they adapted to fat body pictures.The reported results indicate a relationship between body image distortion in ED and visual body image adaptation. It can be suspected that due to a pre-existing, long-lasting adaptation to thin body shapes in ED, an additional visual adaption to thin body shapes cannot be induced. Hence this pre-existing adaptation to thin body shapes could induce perceptual body image distortions in ED. © The Author(s) 2016.

  12. Adaptation of lettuce mosaic virus to Catharanthus roseus involves mutations in the central domain of the VPg.

    Science.gov (United States)

    Svanella-Dumas, Laurence; Verdin, Eric; Faure, Chantal; German-Retana, Sylvie; Gognalons, Patrick; Danet, Jean Luc; Marais, Armelle; Candresse, Thierry

    2014-05-01

    An isolate of Lettuce mosaic virus (LMV, a Potyvirus) infecting Madagascar periwinckle (Catharanthus roseus) was identified and characterized by Illumina deep sequencing. LMV-Cr has no close affinities to previously sequenced LMV isolates and represents a novel, divergent LMV clade. Inoculation experiments with other representative LMV isolates showed that they are unable to infect C. roseus, which was not known to be a host for LMV. However, three C. roseus variants of one of these isolates, LMV-AF199, could be selected and partially or completely sequenced. These variants are characterized by the accumulation of mutations affecting the C-terminal part of the cylindrical inclusion (CI) helicase and the central part of the VPg. In particular, a serine to proline mutation at amino acid 143 of the VPg was observed in all three independently selected variants and is also present in the LMV-Cr isolate, making it a prime candidate as a host-range determinant. Other mutations at VPg positions 65 and 144 could also contribute to the ability to infect C. roseus. Inoculation experiments involving a recombinant LMV expressing a permissive lettuce eukaryotic translation initiation factor 4E (eIF4E) suggest that eIF4E does not contribute to the interaction of most LMV isolates with C. roseus.

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

    Science.gov (United States)

    Hiona, Asimina; Leeuwenburgh, Christiaan

    2008-01-01

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

  14. 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

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

    DEFF Research Database (Denmark)

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

    2010-01-01

    are considered hallmarks of chronic virulence. The aims of our study were to investigate (1) the genetic background of the P. aeruginosa subpopulations with non-mutator, weak or strong mutator phenotype and their dynamics during the chronic lung infection, and (2) the time sequence in which the hypermutable...... CF patients (one to three isolates per time point). Analysis of the genetic background of the mutator phenotype showed that mutS was the most commonly affected gene followed by mutL in isolates with strong mutator phenotype. The mutT, mutY, mutM genes were affected in isolates with low fold......During the chronic lung infection of patients with cystic fibrosis (CF), Pseudomonas aeruginosa can survive for long periods due to adaptive evolution mediated by genetic variation. Hypermutability is considered to play an important role in this adaptive evolution and it has been demonstrated...

  16. Is the rapid adaptation paradigm too rapid? Implications for face and object processing.

    Science.gov (United States)

    Nemrodov, Dan; Itier, Roxane J

    2012-07-16

    Rapid adaptation is an adaptation procedure in which adaptors and test stimuli are presented in rapid succession. The current study tested the validity of this method for early ERP components by investigating the specificity of the adaptation effect on the face-sensitive N170 ERP component across multiple test stimuli. Experiments 1 and 2 showed identical response patterns for house and upright face test stimuli using the same adaptor stimuli. The results were also identical to those reported in a previous study using inverted face test stimuli (Nemrodov and Itier, 2011). In Experiment 3 all possible adaptor-test combinations between upright face, house, chair and car stimuli were used and no interaction between adaptor and test category, expected in the case of test-specific adaptation, was found. These results demonstrate that the rapid adaptation paradigm does not produce category-specific adaptation effects around 170-200 ms following test stimulus onset, a necessary condition for the interpretation of adaptation results. These results suggest the rapid categorical adaptation paradigm does not work. Copyright © 2012 Elsevier Inc. All rights reserved.

  17. Leisure Activities in Prader-Wlli Syndrome: Implications for Health, Cognition and Adaptive Functioning

    Science.gov (United States)

    Dykens, Elisabeth M.

    2014-01-01

    Although hyperphagia and compulsivity in Prader-Willi syndrome (PWS) are well described, recreation and adaptive skills are relatively unexplored. Parents of 123 participants with PWS (4--48 years) completed measures of their child's adaptive, recreation, and problem behaviors. Offspring received cognitive testing. Watching TV was the most…

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

    OpenAIRE

    Hiona, Asimina; Leeuwenburgh, Christiaan

    2007-01-01

    Aging is associated with a progressive loss of skeletal muscle mass and strength and the mechanisms mediating these effects likely involve mitochondrial DNA (mtDNA) mutations, mitochondrial dysfunction and the activation of mitochondrial mediated apoptosis. Because the mitochondrial genome is densely packed and close to the main generator of reactive oxygen species (ROS) in the cell, the electron transport chain (ETC), an important role for mtDNA mutations in aging has been proposed. Point mu...

  19. A review of adaptive change in musculoskeletal impedance during space flight and associated implications for postflight head movement control

    Science.gov (United States)

    McDonald, P. V.; Bloomberg, J. J.; Layne, C. S.

    1997-01-01

    We present a review of converging sources of evidence which suggest that the differences between loading histories experienced in 1-g and weightlessness are sufficient to stimulate adaptation in mechanical impedance of the musculoskeletal system. As a consequence of this adaptive change we argue that we should observe changes in the ability to attenuate force transmission through the musculoskeletal system both during and after space flight. By focusing attention on the relation between human sensorimotor activity and support surfaces, the importance of controlling mechanical energy flow through the musculoskeletal system is demonstrated. The implications of such control are discussed in light of visual-vestibular function in the specific context of head and gaze control during postflight locomotion. Evidence from locomotory biomechanics, visual-vestibular function, ergonomic evaluations of human vibration, and specific investigations of locomotion and head and gaze control after space flight, is considered.

  20. Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features

    Science.gov (United States)

    Pardi, Elena; Borsari, Simona; Saponaro, Federica; Bogazzi, Fausto; Urbani, Claudio; Mariotti, Stefano; Pigliaru, Francesca; Satta, Chiara; Pani, Fabiana; Materazzi, Gabriele; Miccoli, Paolo; Grantaliano, Lorena; Marcocci, Claudio

    2017-01-01

    The aim of this study was to carry out genetic screening of the MEN1, CDKN1B and AIP genes, both by direct sequencing of the coding region and multiplex ligation-dependent probe amplification (MLPA) assay in the largest monocentric series of Italian patients with Multiple Endocrine Neoplasia type 1 syndrome (MEN1) and Familial Isolated Hyperparathyroidism (FIHP). The study also aimed to describe and compare the clinical features of MEN1 mutation-negative and mutation-positive patients during long-term follow-up and to correlate the specific types and locations of MEN1 gene mutations with onset and aggressiveness of the main MEN1 manifestations. A total of 69 index cases followed at the Endocrinology Unit in Pisa over a period of 19 years, including 54 MEN1 and 15 FIHP kindreds were enrolled. Seven index cases with MEN1 but MEN1 mutation-negative, followed at the University Hospital of Cagliari, were also investigated. FIHP were also tested for CDC73 and CaSR gene alterations. MEN1 germline mutations were identified in 90% of the index cases of familial MEN1 (F-MEN1) and in 23% of sporadic cases (S-MEN1). MEN1 and CDC73 mutations accounted for 13% and 7% of the FIHP cohort, respectively. A CDKN1B mutation was identified in one F-MEN1. Two AIP variants of unknown significance were detected in two MEN1-negative S-MEN1. A MEN1 positive test best predicted the onset of all three major MEN1-related manifestations or parathyroid and gastro-entero-pancreatic tumors during follow-up. A comparison between the clinical characteristics of F and S-MEN1 showed a higher prevalence of a single parathyroid disease and pituitary tumors in sporadic compared to familial MEN1 patients. No significant correlation was found between the type and location of MEN1 mutations and the clinical phenotype. Since all MEN1 mutation-positive sporadic patients had a phenotype resembling that of familial MEN1 (multiglandular parathyroid hyperplasia, a prevalence of gastro-entero-pancreatic tumors and

  1. Saccade adaptation abnormalities implicate dysfunction of cerebellar-dependent learning mechanisms in Autism Spectrum Disorders (ASD)

    National Research Council Canada - National Science Library

    Mosconi, Matthew W; Luna, Beatriz; Kay-Stacey, Margaret; Nowinski, Caralynn V; Rubin, Leah H; Scudder, Charles; Minshew, Nancy; Sweeney, John A

    2013-01-01

    ...). This region maintains the consistent accuracy of saccadic eye movements and plays an especially important role in correcting systematic errors in saccade amplitudes such as those induced by adaptation paradigms...

  2. 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.

  3. 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

  4. 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.

  5. 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

  6. 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.

  7. High prevalence of BRCA1 stop mutation c.4183C>T in the Tyrolean population: implications for genetic testing.

    Science.gov (United States)

    Pölsler, Laura; Fiegl, Heidi; Wimmer, Katharina; Oberaigner, Willi; Amberger, Albert; Traunfellner, Pia; Morscher, Raphael J; Weber, Ingrid; Fauth, Christine; Wernstedt, Annekatrin; Sperner-Unterweger, Barbara; Oberguggenberger, Anne; Hubalek, Michael; Marth, Christian; Zschocke, Johannes

    2016-02-01

    Screening for founder mutations in BRCA1 and BRCA2 has been discussed as a cost-effective testing strategy in certain populations. In this study, comprehensive BRCA1 and BRCA2 testing was performed in a routine diagnostic setting. The prevalence of the BRCA1 stop mutation c.4183C>T, p.(Gln1395Ter), was determined in unselected breast and ovarian cancer patients from different regions in the Tyrol. Cancer registry data were used to evaluate the impact of this mutation on regional cancer incidence. The mutation c.4183C>T was detected in 30.4% of hereditary BRCA1-associated breast and ovarian cancer patients in our cohort. It was also identified in 4.1% of unselected (26% of unselected triple negative) Tyrolean breast cancer patients and 6.8% of unselected ovarian cancer patients from the Lower Inn Valley (LIV) region. Cancer incidences showed a region-specific increase in age-stratified breast and ovarian cancer risk with standardized incidence ratios of 1.23 and 2.13, respectively. We, thus, report a Tyrolean BRCA1 founder mutation that correlates to a local increase in the breast and ovarian cancer risks. On the basis of its high prevalence, we suggest that targeted genetic analysis should be offered to all women with breast or ovarian cancer and ancestry from the LIV region.

  8. Whole exome sequencing implicates an INO80D mutation in a syndrome of aortic hypoplasia, premature atherosclerosis, and arterial stiffness.

    Science.gov (United States)

    Shameer, Khader; Klee, Eric W; Dalenberg, Angela K; Kullo, Iftikhar J

    2014-10-01

    Massively parallel, high-throughput sequencing technology is helping to generate new insights into the genetic basis of human diseases. We used whole exome sequencing to identify the mutation underlying a syndrome affecting 2 siblings with aortic hypoplasia, calcific atherosclerosis, systolic hypertension, and premature cataract. Exonic regions were captured and sequenced using a next-generation sequencing platform to generate 100 bases paired-end reads. A computational genomic data analysis pipeline was used to perform quality control, align reads to a reference genome, and identify genetic variants; findings were confirmed using a different exome analyses pipeline. The 2 siblings were homozygous for a rare missense mutation (Ser818Cys) in INO80D, a subunit of the human INO80 chromatin remodeling complex. Homozygosity mapping and Sanger sequencing confirmed that the mutation is located in one of the runs of homozygosity on chromosome 2. INO80D encodes a key subunit of the human IN080 complex, a multiprotein complex involved in DNA binding, chromatin modification, organization of chromosome structure, and ATP-dependent nucleosome sliding. By introducing a new disulphide-bond in the protein product and also disrupting the composition of low-complexity regions, the Ser818Cys mutation may affect INO80D function, protein-protein interactions, and chromatin remodeling. Our findings suggest a link between the Ser818Cys mutation in INO80D, a subunit of the human INO80 chromatin remodeling complex, and accelerated arterial aging. © 2014 American Heart Association, Inc.

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

  10. 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 situ...... activation of the receptor kinase in skeletal muscle was reduced about 70%. Selection of only those receptors that bound to anti-phosphotyrosine antibody showed that these receptors had normal kinase activity and that the reduction in overall kinase activity was due to the inability of about 70......% of the receptors to become insulin-dependently activated. The mother carries a point mutation at the last base pair in exon 17 which, due to abnormal alternative splicing, could lead to normally transcribed receptor or truncated receptor lacking the kinase region. Kinase activation was normal in the mother...

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

    Science.gov (United States)

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

    2017-08-02

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

  12. 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.

  13. 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.

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

    Science.gov (United States)

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

    2012-03-01

    Current vision science adaptive optics systems use near infrared wavefront sensor 'beacons' that appear as red spots in the visual field. Colored fixation targets are known to influence the perceived color of macroscopic visual stimuli (Jameson, D., & Hurvich, L. M. (1967). Fixation-light bias: An unwanted by-product of fixation control. Vision Research, 7, 805-809.), suggesting that the wavefront sensor beacon may also influence perceived color for stimuli displayed with adaptive optics. Despite its importance for proper interpretation of adaptive optics experiments on the fine scale interaction of the retinal mosaic and spatial and color vision, this potential bias has not yet been quantified or addressed. Here we measure the impact of the wavefront sensor beacon on color appearance for dim, monochromatic point sources in five subjects. The presence of the beacon altered color reports both when used as a fixation target as well as when displaced in the visual field with a chromatically neutral fixation target. This influence must be taken into account when interpreting previous experiments and new methods of adaptive correction should be used in future experiments using adaptive optics to study color. Copyright © 2012 Elsevier Ltd. All rights reserved.

  15. Obsessive-compulsive disorder: The process of parental adaptation and implications for genetic counseling

    Science.gov (United States)

    Andrighetti, Heather; Semaka, Alicia; Stewart, S. Evelyn; Shuman, Cheryl; Hayeems, Robin; Austin, Jehannine

    2016-01-01

    Obsessive-compulsive disorder (OCD) has primarily pediatric onset and well-documented unique impacts on family functioning. Limited research has assessed the understanding that parents of children with OCD have of the etiology of the condition, and there are no data regarding potential applications of genetic counseling for this population. We recruited 13 parents of 13 children diagnosed with OCD from the OCD Registry at British Columbia Children’s Hospital, and conducted qualitative semi-structured telephone interviews to explore participants’ experiences with their child’s OCD, causal attributions of OCD, and perceptions of two genetic counseling vignettes. Interviews were audio-recorded, transcribed, and analyzed using elements of grounded theory qualitative methodology. Analysis revealed key components and contextual elements of the process through which parents adapt to their child’s OCD. This adaptation process involved conceptualizing the meaning of OCD, navigating its impact on family dynamics, and developing effective illness management strategies. Adaptation took place against a backdrop of stigmatization and was shaped by participants’ family history of mental illness and their child’s specific manifestations of OCD. Parents perceived genetic counseling, as described in the vignettes, as being empowering, alleviating guilt and blame, and positively impacting treatment orientation. These data provide insight into the process of parental adaptation to pediatric OCD, and suggest that genetic counseling services for families affected by OCD may help facilitate adaptation to this illness. PMID:26639756

  16. 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

    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...... 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....

  17. 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.

  18. 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

  19. 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

  20. 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.

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

    Science.gov (United States)

    Sun, Ying; Zhang, Wujuan; Xu, You-Hai; Quinn, Brian; Dasgupta, Nupur; Liou, Benjamin; Setchell, Kenneth D R; Grabowski, Gregory A

    2013-01-01

    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.

  2. Substrate Compositional Variation with Tissue/Region and Gba1 Mutations in Mouse Models–Implications for Gaucher Disease

    Science.gov (United States)

    Sun, Ying; Zhang, Wujuan; Xu, You-Hai; Quinn, Brian; Dasgupta, Nupur; Liou, Benjamin; Setchell, Kenneth D. R.; Grabowski, Gregory A.

    2013-01-01

    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. PMID:23520473

  3. 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 Pisum sativum SYM8 gene plays an essential part in both rhizobial and mycorrhizal symbioses. Mutation of sym8 in the original type line R25 blocks nodulation, mycorrhization, and Nod-factor-induced calcium spiking, an early component of the nodulation signaling pathway. We describe four new s...

  4. 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

  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. ADAPTIVE WATER SENSOR SIGNAL PROCESSING: EXPERIMENTAL RESULTS AND IMPLICATIONS FOR ONLINE CONTAMINANT WARNING SYSTEMS

    Science.gov (United States)

    A contaminant detection technique and its optimization algorithms have two principal functions. One is the adaptive signal treatment that suppresses background noise and enhances contaminant signals, leading to a promising detection of water quality changes at a false rate as low...

  7. 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

    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...

  8. 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…

  9. 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.

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

    Science.gov (United States)

    Wang, Mian; Lam, Yeana

    2017-01-01

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

  11. 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…

  12. The Role of Adaptive Behavior in Autism Spectrum Disorders: Implications for Functional Outcome

    Science.gov (United States)

    Kanne, Stephen M.; Gerber, Andrew J.; Quirmbach, Linda M.; Sparrow, Sara S.; Cicchetti, Domenic V.; Saulnier, Celine A.

    2011-01-01

    The relationship between adaptive functioning and autism symptomatology was examined in 1,089 verbal youths with ASD examining results on Vineland-II, IQ, and measures of ASD severity. Strong positive relationships were found between Vineland subscales and IQ. Vineland Composite was negatively associated with age. IQ accounted a significant amount…

  13. 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…

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

    Directory of Open Access Journals (Sweden)

    Sachin Rustgi

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

  15. General implications for CpG hot spot mutations: methylation patterns of the human iduronate-2-sulfatase gene locus.

    Science.gov (United States)

    Tomatsu, Shunji; Orii, Koji O; Bi, Y; Gutierrez, Monica A; Nishioka, Tatsuo; Yamaguchi, Seiji; Kondo, Naomi; Orii, Tadao; Noguchi, Akihiko; Sly, William S

    2004-06-01

    The methylation pattern at CpG sites of a housekeeping gene correlates with the likelihood of mutation. Mucopolysaccharidosis (MPS) type II, an X-linked disorder, results from the deficiency of iduronate-2-sulfatase (IDS). In these patients, over 35% of independent point mutations at the IDS gene locus were found at CpG sites as transitional events. To gain insight into the relationship between methylation status and CpG hot spot mutations, we investigated patterns of cytosine methylation in the entire IDS gene, except for introns 4-8. Bisulfite genomic sequencing was performed on the normal leukocyte DNA. Our data show that: 1) cytosine methylation at the CpG sites was extensive, except for those present from the promoter region to a portion of intron 3; 2) a sharp boundary of methylated-nonmethylated regions was observed at the 5'-flanking region, whereas a gradual change in methylation was observed in the 2.0-kb segment in the 3'-flanking region; 3) the boundary of the 5'-flanking region contained multiple Sp1 sites and the TATA box; 4) the CpG sites in exons 1 and 2 were hypomethylated and were associated only with rare transitional mutations, while the CpG sites in exon 3 were also hypomethylated, yet were associated with a high rate of transitional mutations; 5) there was no striking sex difference in the methylation patterns in active alleles; and, 6) the methylation in both strands was symmetrical, except at the boundary of methylated-unmethylated regions. Copyright 2004 Wiley-Liss, Inc.

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

    Science.gov (United States)

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

    2016-04-01

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

  17. IL-17A in Human Respiratory Diseases: Innate or Adaptive Immunity? Clinical Implications

    Directory of Open Access Journals (Sweden)

    Dominique M. A. Bullens

    2013-01-01

    Full Text Available Since the discovery of IL-17 in 1995 as a T-cell cytokine, inducing IL-6 and IL-8 production by fibroblasts, and the report of a separate T-cell lineage producing IL-17(A, called Th17 cells, in 2005, the role of IL-17 has been studied in several inflammatory diseases. By inducing IL-8 production and subsequent neutrophil attraction towards the site of inflammation, IL-17A can link adaptive and innate immune responses. More specifically, its role in respiratory diseases has intensively been investigated. We here review its role in human respiratory diseases and try to unravel the question whether IL-17A only provides a link between the adaptive and innate respiratory immunity or whether this cytokine might also be locally produced by innate immune cells. We furthermore briefly discuss the possibility to reduce local IL-17A production as a treatment option for respiratory diseases.

  18. High temporal resolution aberrometry in a 50-eye population and implications for adaptive optics error budget.

    Science.gov (United States)

    Jarosz, Jessica; Mecê, Pedro; Conan, Jean-Marc; Petit, Cyril; Paques, Michel; Meimon, Serge

    2017-04-01

    We formed a database gathering the wavefront aberrations of 50 healthy eyes measured with an original custom-built Shack-Hartmann aberrometer at a temporal frequency of 236 Hz, with 22 lenslets across a 7-mm diameter pupil, for a duration of 20 s. With this database, we draw statistics on the spatial and temporal behavior of the dynamic aberrations of the eye. Dynamic aberrations were studied on a 5-mm diameter pupil and on a 3.4 s sequence between blinks. We noted that, on average, temporal wavefront variance exhibits a n -2 power-law with radial order n and temporal spectra follow a f -1.5 power-law with temporal frequency f . From these statistics, we then extract guidelines for designing an adaptive optics system. For instance, we show the residual wavefront error evolution as a function of the number of corrected modes and of the adaptive optics loop frame rate. In particular, we infer that adaptive optics performance rapidly increases with the loop frequency up to 50 Hz, with gain being more limited at higher rates.

  19. Analysis of GTV reduction during radiotherapy for oropharyngeal cancer: Implications for adaptive radiotherapy.

    Science.gov (United States)

    Hamming-Vrieze, Olga; van Kranen, Simon R; Heemsbergen, Wilma D; Lange, Charlotte A H; van den Brekel, Michiel W M; Verheij, Marcel; Rasch, Coen R N; Sonke, Jan Jakob

    2017-02-01

    Adaptive field size reduction based on gross tumor volume (GTV) shrinkage imposes risk on coverage. Fiducial markers were used as surrogate for behavior of tissue surrounding the GTV edge to assess this risk by evaluating if GTVs during treatment are dissolving or actually shrinking. Eight patients with oropharyngeal tumors treated with chemo-radiation were included. Before treatment, fiducial markers (0.035×0.2cm(2), n=40) were implanted at the edge of the primary tumor. All patients underwent planning-CT, daily cone beam CT (CBCT) and MRIs (pre-treatment, weeks 3 and 6). Marker displacement on CBCT was compared to local GTV surface displacement on MRIs. Additionally, marker displacement relative to the GTV surfaces during treatment was measured. GTV surface displacement derived from MRI was larger than derived from fiducial markers (average difference: 0.1cm in week 3). During treatment, the distance between markers and GTV surface on MRI in week 3 increased in 33%>0.3cm and in 10%>0.5cm. The MRI-GTV shrank faster than the surrounding tissue represented by the markers, i.e. adapting to GTV shrinkage may cause under-dosage of microscopic disease. We showed that adapting to primary tumor GTV shrinkage on MRI mid-treatment is potentially not safe since at least part of the GTV is likely to be dissolving. Adjustment to clear anatomical boundaries, however, may be done safely. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  20. 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. PMID:22639624

  1. 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.

  2. 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.

  3. Network-Based Identification of Adaptive Pathways in Evolved Ethanol-Tolerant Bacterial Populations.

    Science.gov (United States)

    Swings, Toon; Weytjens, Bram; Schalck, Thomas; Bonte, Camille; Verstraeten, Natalie; Michiels, Jan; Marchal, Kathleen

    2017-11-01

    Efficient production of ethanol for use as a renewable fuel requires organisms with a high level of ethanol tolerance. However, this trait is complex and increased tolerance therefore requires mutations in multiple genes and pathways. Here, we use experimental evolution for a system-level analysis of adaptation of Escherichia coli to high ethanol stress. As adaptation to extreme stress often results in complex mutational data sets consisting of both causal and noncausal passenger mutations, identifying the true adaptive mutations in these settings is not trivial. Therefore, we developed a novel method named IAMBEE (Identification of Adaptive Mutations in Bacterial Evolution Experiments). IAMBEE exploits the temporal profile of the acquisition of mutations during evolution in combination with the functional implications of each mutation at the protein level. These data are mapped to a genome-wide interaction network to search for adaptive mutations at the level of pathways. The 16 evolved populations in our data set together harbored 2,286 mutated genes with 4,470 unique mutations. Analysis by IAMBEE significantly reduced this number and resulted in identification of 90 mutated genes and 345 unique mutations that are most likely to be adaptive. Moreover, IAMBEE not only enabled the identification of previously known pathways involved in ethanol tolerance, but also identified novel systems such as the AcrAB-TolC efflux pump and fatty acids biosynthesis and even allowed to gain insight into the temporal profile of adaptation to ethanol stress. Furthermore, this method offers a solid framework for identifying the molecular underpinnings of other complex traits as well. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  4. 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

  5. Efficacy of BRAF Inhibitors in Asian Metastatic Melanoma Patients: Potential Implications of Genomic Sequencing in BRAF-Mutated Melanoma

    Directory of Open Access Journals (Sweden)

    Hee Kyung Kim

    2016-12-01

    Full Text Available BACKGROUND: The BRAF inhibitors vemurafenib and dabrafenib are currently the standard treatment for metastatic melanoma with BRAF V600 mutations. However, given the rarity of noncutaneous melanoma, including acral and mucosal subtypes, the efficacy of BRAF inhibitors for this subset of patients has not been extensively investigated. Acquired resistance generally appears 6 to 8 months after treatment with a BRAF inhibitor, and the mechanism of resistance is not well established. METHODS: We examined treatment outcomes for patients diagnosed with metastatic melanoma and treated with BRAF inhibitors at Samsung Medical Center between April 2013 and December 2015. We analyzed genomic alterations in selected patients using targeted sequencing. RESULTS: Twenty-seven patients with a median age of 49 years (range 23-82 years with metastatic melanoma and treated with a BRAF inhibitor were identified. Of these patients, 19 (70.3% had noncutaneous melanoma, including acral and mucosal melanoma. All patients had BRAFV600E mutations. The median progression-free survival of all patients was 9.2 months (95% confidence interval, 1.6-16.7, and the objective response rate was 78.9% in the mucosal/acral melanoma group and 75.0% in the cutaneous melanoma group. Three (11.1% patients achieved complete response, and 19 (70.4% showed a partial response. Targeted sequencing in five patients demonstrated NF1 mutations in three patients who did not respond to BRAF inhibitors. CONCLUSION: BRAF inhibitors were an effective therapeutic option for Korean patients with metastatic melanoma harboring a BRAF V600 mutation regardless of melanoma subtype (acral/mucosa versus cutaneous.

  6. Conformational heterogeneity of the Roc domains in C. tepidum Roc–COR and implications for human LRRK2 Parkinson mutations

    Science.gov (United States)

    Rudi, Katharina; Ho, Franz Y.; Gilsbach, Bernd K.; Pots, Henderikus; Wittinghofer, Alfred; Kortholt, Arjan; Klare, Johann P.

    2015-01-01

    Ras of complex proteins (Roc) is a Ras-like GTP-binding domain that always occurs in tandem with the C-terminal of Roc (COR) domain and is found in bacteria, plants and animals. Recently, it has been shown that Roco proteins belong to the family of G-proteins activated by nucleotide (nt)-dependent dimerization (GADs). We investigated the RocCOR tandem from the bacteria Chlorobium tepidum with site-directed spin labelling and pulse EPR distance measurements to follow conformational changes during the Roco G-protein cycle. Our results confirm that the COR domains are a stable dimerization device serving as a scaffold for the Roc domains that, in contrast, are structurally heterogeneous and dynamic entities. Contrary to other GAD proteins, we observed only minor structural alterations upon binding and hydrolysis of GTP, indicating significant mechanistic variations within this protein class. Mutations in the most prominent member of the Roco family of proteins, leucine-rich repeat (LRR) kinase 2 (LRRK2), are the most frequent cause of late-onset Parkinson's disease (PD). Using a stable recombinant LRRK2 Roc-COR-kinase fragment we obtained detailed kinetic data for the G-protein cycle. Our data confirmed that dimerization is essential for efficient GTP hydrolysis and PD mutations in the Roc domain result in decreased GTPase activity. Previous data have shown that these LRRK2 PD-mutations are located in the interface between Roc and COR. Importantly, analogous mutations in the conserved C. tepidum Roc/COR interface significantly influence the structure and nt-induced conformational changes of the Roc domains. PMID:26310572

  7. An Emerging Entity: Pancreatic Adenocarcinoma Associated with a Known BRCA Mutation: Clinical Descriptors, Treatment Implications, and Future Directions

    Science.gov (United States)

    Lowery, Maeve A.; Kelsen, David P.; Stadler, Zsofia K.; Yu, Kenneth H.; Janjigian, Yelena Y.; Ludwig, Emmy; D'Adamo, David R.; Salo-Mullen, Erin; Robson, Mark E.; Allen, Peter J.; Kurtz, Robert C.

    2011-01-01

    Background. BRCA1 and BRCA2 germline mutations are associated with an elevated risk for pancreas adenocarcinoma (PAC). Other BRCA-associated cancers have been shown to have greater sensitivity to platinum and poly(ADP-ribose) polymerase (PARP) inhibitors with better clinical outcomes than in sporadic cases; however, outcomes in BRCA-associated PAC have not been reported. Methods. Patients with a known BRCA1 or BRCA2 mutation and a diagnosis of PAC were identified from the Gastrointestinal Oncology Service, Familial Pancreas Cancer Registry, and Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center. Results. Fifteen patients, five male, with a BRCA1 (n = 4) or BRCA2 (n = 11) mutation and PAC and one patient with a BRCA1 mutation and acinar cell carcinoma of the pancreas were identified. Seven female patients (70%) had a prior history of breast cancer. Four patients received a PARP inhibitor alone or in combination with chemotherapy; three demonstrated an initial radiographic partial response by Response Evaluation Criteria in Solid Tumors whereas one patient had stable disease for 6 months. Six patients received platinum-based chemotherapy first line for metastatic disease; five of those patients had a radiographic partial response. Conclusion. BRCA mutation–associated PAC represents an underidentified, but clinically important, subgroup of patients. This is of particular relevance given the ongoing development of therapeutic agents targeting DNA repair, which may potentially offer a significant benefit to a genetically selected population. We anticipate that further study and understanding of the clinical and biologic features of BRCA-mutant PAC will aid in the identification of tissue biomarkers indicating defective tumor DNA repair pathways in sporadic PAC. PMID:21934105

  8. Adaptive Mutations That Occurred during Circulation in Humans of H1N1 Influenza Virus in the 2009 Pandemic Enhance Virulence in Mice.

    Science.gov (United States)

    Otte, A; Sauter, M; Daxer, M A; McHardy, A C; Klingel, K; Gabriel, G

    2015-07-01

    During the 2009 H1N1 influenza pandemic, infection attack rates were particularly high among young individuals who suffered from pneumonia with occasional death. Moreover, previously reported determinants of mammalian adaptation and pathogenicity were not present in 2009 pandemic H1N1 influenza A viruses. Thus, it was proposed that unknown viral factors might have contributed to disease severity in humans. In this study, we performed a comparative analysis of two clinical 2009 pandemic H1N1 strains that belong to the very early and later phases of the pandemic. We identified mutations in the viral hemagglutinin (HA) and the nucleoprotein (NP) that occurred during pandemic progression and mediate increased virulence in mice. Lethal disease outcome correlated with elevated viral replication in the alveolar epithelium, increased proinflammatory cytokine and chemokine responses, pneumonia, and lymphopenia in mice. These findings show that viral mutations that have occurred during pandemic circulation among humans are associated with severe disease in mice. In this study, novel determinants of 2009 pandemic H1N1 influenza pathogenicity were identified in the viral hemagglutinin (HA) and the nucleoprotein (NP) genes. In contrast to highly pathogenic avian influenza viruses, increased virulence in mice did not correlate with enhanced polymerase activity but with reduced activity. Lethal 2009 pandemic H1N1 infection in mice correlated with lymphopenia and severe pneumonia. These studies suggest that molecular mechanisms that mediate 2009 pandemic H1N1 influenza pathogenicity are distinct from those that mediate avian influenza virus pathogenicity in mice. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

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

    Directory of Open Access Journals (Sweden)

    Luz Berenice López-Hernández

    2015-03-01

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

  10. A common mutational pattern in Cockayne syndrome patients from xeroderma pigmentosum group G: implications for a second XPG function.

    Science.gov (United States)

    Nouspikel, T; Lalle, P; Leadon, S A; Cooper, P K; Clarkson, S G

    1997-04-01

    Xeroderma pigmentosum (XP) patients have defects in nucleotide excision repair (NER), the versatile repair pathway that removes UV-induced damage and other bulky DNA adducts. Patients with Cockayne syndrome (CS), another rare sun-sensitive disorder, are specifically defective in the preferential removal of damage from the transcribed strand of active genes, a process known as transcription-coupled repair. These two disorders are usually clinically and genetically distinct, but complementation analyses have assigned a few CS patients to the rare XP groups B, D, or G. The XPG gene encodes a structure-specific endonuclease that nicks damaged DNA 3' to the lesion during NER. Here we show that three XPG/CS patients had mutations that would produce severely truncated XPG proteins. In contrast, two sibling XPG patients without CS are able to make full-length XPG, but with a missense mutation that inactivates its function in NER. These results suggest that XPG/CS mutations abolish interactions required for a second important XPG function and that it is the loss of this second function that leads to the CS clinical phenotype.

  11. 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.

  12. TSC1 and TSC2 gene mutations and their implications for treatment in Tuberous Sclerosis Complex: a review

    Directory of Open Access Journals (Sweden)

    Clévia Rosset

    Full Text Available Abstract Tuberous sclerosis complex is an autosomal dominant disorder characterized by skin manifestations and formation of multiple tumors in different organs, mainly in the central nervous system. Tuberous sclerosis is caused by the mutation of one of two tumor suppressor genes, TSC1 or TSC2. Currently, the development of novel techniques and great advances in high-throughput genetic analysis made mutation screening of the TSC1 and TSC2 genes more widely available. Extensive studies of the TSC1 and TSC2 genes in patients with TSC worldwide have revealed a wide spectrum of mutations. Consequently, the discovery of the underlying genetic defects in TSC has furthered our understanding of this complex genetic disorder, and genotype-phenotype correlations are becoming possible, although there are still only a few clearly established correlations. This review focuses on the main symptoms and genetic alterations described in TSC patients from 13 countries in three continents, as well as on genotype-phenotype correlations established to date. The determination of genotype-phenotype correlations may contribute to the establishment of successful personalized treatment for TSC.

  13. Integrity of the osteocyte bone cell network in osteoporotic fracture: Implications for mechanical load adaptation

    Science.gov (United States)

    Kuliwaba, J. S.; Truong, L.; Codrington, J. D.; Fazzalari, N. L.

    2010-06-01

    The human skeleton has the ability to modify its material composition and structure to accommodate loads through adaptive modelling and remodelling. The osteocyte cell network is now considered to be central to the regulation of skeletal homeostasis; however, very little is known of the integrity of the osteocyte cell network in osteoporotic fragility fracture. This study was designed to characterise osteocyte morphology, the extent of osteocyte cell apoptosis and expression of sclerostin protein (a negative regulator of bone formation) in trabecular bone from the intertrochanteric region of the proximal femur, for postmenopausal women with fragility hip fracture compared to age-matched women who had not sustained fragility fracture. Osteocyte morphology (osteocyte, empty lacunar, and total lacunar densities) and the degree of osteocyte apoptosis (percent caspase-3 positive osteocyte lacunae) were similar between the fracture patients and non-fracture women. The fragility hip fracture patients had a lower proportion of sclerostin-positive osteocyte lacunae in comparison to sclerostin-negative osteocyte lacunae, in contrast to similar percent sclerostin-positive/sclerostin-negative lacunae for non-fracture women. The unexpected finding of decreased sclerostin expression in trabecular bone osteocytes from fracture cases may be indicative of elevated bone turnover and under-mineralisation, characteristic of postmenopausal osteoporosis. Further, altered osteocytic expression of sclerostin may be involved in the mechano-responsiveness of bone. Optimal function of the osteocyte cell network is likely to be a critical determinant of bone strength, acting via mechanical load adaptation, and thus contributing to osteoporotic fracture risk.

  14. Socio-cultural reflections on heat in Australia with implications for health and climate change adaptation.

    Science.gov (United States)

    Banwell, Cathy; Dixon, Jane; Bambrick, Hilary; Edwards, Ferne; Kjellström, Tord

    2012-10-16

    Australia has a hot climate with maximum summer temperatures in its major cities frequently exceeding 35°C. Although 'heat waves' are an annual occurrence, the associated heat-related deaths among vulnerable groups, such as older people, suggest that Australians could be better prepared to deal with extreme heat. To understand ways in which a vulnerable sub-population adapt their personal behaviour to cope with heat within the context of Australians' relationship with heat. We draw upon scientific, historical and literary sources and on a set of repeat interviews in the suburbs of Western Sydney with eight older participants and two focus group discussions. We discuss ways in which this group of older people modifies their behaviour to adapt to heat, and reflect on manifestations of Australians' ambivalence towards heat. Participants reported a number of methods for coping with extreme heat, including a number of methods of personal cooling, changing patterns of daily activity and altering dietary habits. The use of air-conditioning was near universal, but with recognition that increasing energy costs may become more prohibitive over time. While a number of methods are employed by older people to stay cool, these may become limited in the future. Australians' attitudes may contribute to the ill-health and mortality associated with excessive heat.

  15. Socio-cultural reflections on heat in Australia with implications for health and climate change adaptation

    Directory of Open Access Journals (Sweden)

    Cathy Banwell

    2012-10-01

    Full Text Available Background : Australia has a hot climate with maximum summer temperatures in its major cities frequently exceeding 35°C. Although ‘heat waves’ are an annual occurrence, the associated heat-related deaths among vulnerable groups, such as older people, suggest that Australians could be better prepared to deal with extreme heat. Objective : To understand ways in which a vulnerable sub-population adapt their personal behaviour to cope with heat within the context of Australians’ relationship with heat. Design : We draw upon scientific, historical and literary sources and on a set of repeat interviews in the suburbs of Western Sydney with eight older participants and two focus group discussions. We discuss ways in which this group of older people modifies their behaviour to adapt to heat, and reflect on manifestations of Australians’ ambivalence towards heat. Results : Participants reported a number of methods for coping with extreme heat, including a number of methods of personal cooling, changing patterns of daily activity and altering dietary habits. The use of air-conditioning was near universal, but with recognition that increasing energy costs may become more prohibitive over time. Conclusions : While a number of methods are employed by older people to stay cool, these may become limited in the future. Australians’ attitudes may contribute to the ill-health and mortality associated with excessive heat.

  16. The Implications of Alternative Allocation Criteria in Adaptive Design for Panel Surveys

    Directory of Open Access Journals (Sweden)

    Kaminska Olena

    2017-09-01

    Full Text Available Adaptive survey designs can be used to allocate sample elements to alternative data collection protocols in order to achieve a desired balance between some quality measure and survey costs. We compare four alternative methods for allocating sample elements to one of two data collection protocols. The methods differ in terms of the quality measure that they aim to optimize: response rate, R-indicator, coefficient of variation of the participation propensities, or effective sample size. Costs are also compared for a range of sample sizes. The data collection protocols considered are CAPI single-mode and web-CAPI sequential mixed-mode. We use data from a large experiment with random allocation to one of these two protocols. For each allocation method we predict outcomes in terms of several quality measures and costs. Although allocating the whole sample to single-mode CAPI produces a higher response rate than allocating the whole sample to the mixed-mode protocol, we find that two of the targeted allocations achieve a better response rate than single-mode CAPI at a lower cost. We also find that all four of the targeted designs out-perform both single-protocol designs in terms of representativity and effective sample size. For all but the smallest sample sizes, the adaptive designs bring cost savings relative to CAPI-only, though these are fairly modest in magnitude.

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

    Directory of Open Access Journals (Sweden)

    Klempel Monica C

    2010-09-01

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

  18. 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.

  19. A Common Methodology for Risk Assessment and Mapping of Climate Change Related Hazards—Implications for Climate Change Adaptation Policies

    Directory of Open Access Journals (Sweden)

    Maria Papathoma-Köhle

    2016-02-01

    Full Text Available The Intergovernmental Panel on Climate Change (IPCC, 2014, suggests that an important increase in frequency and magnitude of hazardous processes related to climate change is to be expected at the global scale. Consequently, it is necessary to improve the level of preparedness and the level of public awareness, to fill institutional gaps, and to improve territorial planning in order to reduce the potentially disastrous impact of natural hazards related to climate change. This paper mainly presents a new framework for risk assessment and mapping which enables countries with limited data sources to assess their risk to climate change related hazards at the local level, in order to reduce potential costs, to develop risk reduction strategies, to harmonize their preparedness efforts with neighboring countries and to deal with trans-boundary risk. The methodology is based on the European Commission’s “Risk Assessment and Mapping Guidelines for Disaster Management” (2010 and considers local restrictions, such as a lack of documentation of historic disastrous events, spatial and other relevant data, offering alternative options for risk assessment, and the production of risk maps. The methodology is based on event tree analysis. It was developed within the European project SEERISK and adapted for a number of climate change-related hazards including floods, heat waves, wildfires, and storms. Additionally, the framework offers the possibility for risk assessment under different future scenarios. The implications for climate change adaptation policy are discussed.

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

    Science.gov (United States)

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

    2015-11-20

    Bacteria are constantly faced to stress situations in their ecological niches, the food and the host gastrointestinal tract. The capacity to detect and respond to surrounding changes is crucial for bacterial pathogens to survive or grow in changing environments. To this purpose, cells have evolved various sophisticated networks designed to protect against stressors or repair damage caused by them. Challenges can occur during production of foods when subjected to processing, and after food ingestion when confronted with host defensive barriers. Some pathogenic bacteria have shown the capacity to develop stable resistance against extreme conditions within a defined genomic context and a limited number of generations. On the other hand, bacteria can also respond to adverse conditions in a transient manner, through the so-called stress tolerance responses. Bacterial stress tolerance responses include both structural and physiological modifications in the cell and are mediated by complex genetic regulatory machinery. Major aspects in the adaptive response are the sensing mechanisms, the characterization of cell defensive systems, such as the operation of regulatory proteins (e.g. RpoS), the induction of homeostatic and repair systems, the synthesis of shock response proteins, and the modifications of cell membranes, particularly in their fatty acid composition and physical properties. This article reviews certain strategies used by food-borne bacteria to respond to particular stresses (acid, cold stress, extreme pressure) in a permanent or transient manner and discusses the implications that such adaptive responses pose for food safety. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. 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

  2. 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

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

    Science.gov (United States)

    Burman, Chris J; Aphane, Marota A

    2016-05-16

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

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. The estimated mechanical advantage of the prosimian ankle joint musculature, and implications for locomotor adaptation

    Science.gov (United States)

    Goto, Ryosuke; Kumakura, Hiroo

    2013-01-01

    In this study we compared the power arm lengths and mechanical advantages attributed to 12 lower leg muscles across three prosimian species. The origins and insertions of the lower leg muscles in Garnett's galago, the ring-tailed lemur, and the slow loris were quantified and correlated with positional behaviour. The ankle joint of the galago has a speed-oriented mechanical system, in contrast to that of the slow loris, which exhibits more power-oriented mechanics. The lemur ankle joint exhibited intermediate power arm lengths and an intermediate mechanical advantage relative to the other primates. This result suggests that the mechanical differences in the ankle between the galago and the lemur, taxa that exhibit similar locomotory repertoires, reflect a difference in the kinematics and kinetics of leaping (i.e. generalised vs. specialised leapers). In contrast to leaping primates, lorises have developed a more power-oriented mechanical system as a foot adaptation for positional behaviours such as bridging or cantilevering in their arboreal habitat. PMID:23489408

  9. Atmospheric Feedback of Urban Boundary Layer with Implications for Climate Adaptation.

    Science.gov (United States)

    Liang, Marissa S; Keener, Timothy C

    2015-09-01

    Atmospheric structure changes in response to the urban form, land use, and the type of land cover (LULC). This interaction controls thermal and air pollutant transport and distribution. The interrelationships among LULC, ambient temperature, and air quality were analyzed and found to be significant in a case study in Cincinnati, Ohio, U.S.A. Within the urban canopy layer (UCL), traffic-origin PM2.5 and black carbon followed Gaussian dispersion in the near road area in the daytime, while higher concentrations, over 1 order of magnitude, were correlated to the lapse rate under nocturnal inversions. In the overlying urban boundary layer (UBL), ambient temperature and PM2.5 variations were correlated among urban-wide locations indicating effective thermal and mass communications. Beyond the spatial correlation, LULC-related local urban heat island effects are noteworthy. The high-density urbanized zone along a narrow highway-following corridor is marked by higher nighttime temperature by ∼1.6 °C with a long-term increase by 2.0 °C/decade, and by a higher PM2.5 concentration, than in the low-density residential LULC. These results indicate that the urban LULC may have contributed to the nocturnal thermal inversion affecting urban air circulation and air quality in UCL and UBL. Such relationships point to the potentials of climate adaptation through urban planning.

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

    Science.gov (United States)

    2016-01-01

    Across the last three decades, the application of noninvasive brain stimulation (NIBS) has substantially increased the current knowledge of the brain's potential to undergo rapid short-term reorganization on the systems level. A large number of studies applied transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) in the healthy brain to probe the functional relevance and interaction of specific areas for different cognitive processes. NIBS is also increasingly being used to induce adaptive plasticity in motor and cognitive networks and shape cognitive functions. Recently, NIBS has been combined with electrophysiological techniques to modulate neural oscillations of specific cortical networks. In this review, we will discuss recent advances in the use of NIBS to modulate neural activity and effective connectivity in the healthy language network, with a special focus on the combination of NIBS and neuroimaging or electrophysiological approaches. Moreover, we outline how these results can be transferred to the lesioned brain to unravel the dynamics of reorganization processes in poststroke aphasia. We conclude with a critical discussion on the potential of NIBS to facilitate language recovery after stroke and propose a phase-specific model for the application of NIBS in language rehabilitation. PMID:27830094

  11. 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.

  12. 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.

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

    Directory of Open Access Journals (Sweden)

    John Parkinson

    Full Text Available 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.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.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 and for further genomic and proteomic analyses focused on

  14. 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.

  15. A Proposed Model With Possible Implications for Safety and Technique Adaptations for Chiropractic Spinal Manipulative Therapy for Infants and Children.

    Science.gov (United States)

    Marchand, Aurélie M

    2015-01-01

    A literature review of tensile strength of adults and pediatric human spine specimens was performed to gather information about biomechanical forces and spinal differences of adults and children and to synthesize these findings into a scaling model to guide safety and clinical decisions for spinal manipulative therapy (SMT) for children and infants. The literature search was performed using PubMed from inception to November 2012 with no filters or language restrictions. The search included terms related to pediatric spine biomechanics and tensile strength. Studies included those in which human tensile strengths necessary to create anatomical damage in the cervical, thoracic, or lumbar spine of pediatric human subjects were recorded. The pediatric population was defined as human subjects from birth to 18 years old. Biomechanical findings were used to propose a scaling model based on specimen age and differences in tensile strengths. A model of care was proposed using the scaling model and the existing literature on pediatric technique adaptations. Nine experimental studies were selected, 5 in the pediatric population (46 specimens) and 4 in the adult population (47 specimens). Mean tensile strengths were estimated, and ratios were used to describe differences between 4 age groups. The preliminary model of care proposed includes maximum loading forces by age group. From these studies, a model showed a nonlinear increase in the cervical spine tensile strengths based on specimen age. The literature showed that tensile strength differences have been observed between pediatric and adult specimens. A preliminary model of care including pediatric SMT technique adaptation based on patient age is proposed, which may possibly contribute to further knowledge of safety and clinical implications for SMT for children and infants. Copyright © 2015 National University of Health Sciences. Published by Elsevier Inc. All rights reserved.

  16. 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

  17. Crystallographic and Mutational Analysis of the CD40-CD154 Complex and Its Implications for Receptor Activation*

    Science.gov (United States)

    An, Hyun-Jung; Kim, Young Jin; Song, Dong Hyun; Park, Beom Suk; Kim, Ho Min; Lee, Ju Dong; Paik, Sang-Gi; Lee, Jie-Oh; Lee, Hayyoung

    2011-01-01

    CD40 is a tumor necrosis factor receptor (TNFR) family protein that plays an important role in B cell development. CD154/CD40L is the physiological ligand of CD40. We have determined the crystal structure of the CD40-CD154 complex at 3.5 Å resolution. The binding site of CD40 is located in a crevice formed between two CD154 subunits. Charge complementarity plays a critical role in the CD40-CD154 interaction. Some of the missense mutations found in hereditary hyper-IgM syndrome can be mapped to the CD40-CD154 interface. The CD40 interaction area of one of the CD154 subunits is twice as large as that of the other subunit forming the binding crevice. This is because cysteine-rich domain 3 (CRD3) of CD40 has a disulfide bridge in an unusual position that alters the direction of the ladder-like structure of CD40. The Ser132 loop of CD154 is not involved in CD40 binding but its substitution significantly reduces p38- and ERK-dependent signaling by CD40, whereas JNK-dependent signaling is not affected. These findings suggest that ligand-induced di- or trimerization is necessary but not sufficient for complete activation of CD40. PMID:21285457

  18. Crystallographic and mutational analysis of the CD40-CD154 complex and its implications for receptor activation.

    Science.gov (United States)

    An, Hyun-Jung; Kim, Young Jin; Song, Dong Hyun; Park, Beom Suk; Kim, Ho Min; Lee, Ju Dong; Paik, Sang-Gi; Lee, Jie-Oh; Lee, Hayyoung

    2011-04-01

    CD40 is a tumor necrosis factor receptor (TNFR) family protein that plays an important role in B cell development. CD154/CD40L is the physiological ligand of CD40. We have determined the crystal structure of the CD40-CD154 complex at 3.5 Å resolution. The binding site of CD40 is located in a crevice formed between two CD154 subunits. Charge complementarity plays a critical role in the CD40-CD154 interaction. Some of the missense mutations found in hereditary hyper-IgM syndrome can be mapped to the CD40-CD154 interface. The CD40 interaction area of one of the CD154 subunits is twice as large as that of the other subunit forming the binding crevice. This is because cysteine-rich domain 3 (CRD3) of CD40 has a disulfide bridge in an unusual position that alters the direction of the ladder-like structure of CD40. The Ser(132) loop of CD154 is not involved in CD40 binding but its substitution significantly reduces p38- and ERK-dependent signaling by CD40, whereas JNK-dependent signaling is not affected. These findings suggest that ligand-induced di- or trimerization is necessary but not sufficient for complete activation of CD40.

  19. 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

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

    Science.gov (United States)

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

    2015-07-01

    Somatic mutations in exon 2 of MED12 have been described in benign and malignant smooth muscle cell tumors suggesting a functional role in these neoplasms. Recently fibroadenomas of the breast were also reported to harbor MED12 mutations. Hence, we explored MED12 mutations in fibroepithelial tumors of the breast, histological subtypes of fibroadenomas and phyllodes tumors, to validate and extend previous efforts. Using conventional Sanger sequencing, we profiled 39 cases of fibroepithelial breast tumors comprising classic histological subtypes of fibroadenomas as well as benign and malignant phyllodes tumors for mutations in exon 2 of MED12. MED12 mutations were detected in 60% of all tumor samples with the majority being missense mutations affecting codon 44. Additionally, we report novel in-frame deletions that have not been described previously. Sixty-two percent of the fibroadenomas harbored mutated MED12 with intracanalicular fibroadenomas being the most frequently mutated histological subtype (82%). Of note, 8/11 of benign phyllodes tumors had MED12 mutations while only 1/5 of malignant phyllodes tumors showed mutations in exon 2 of MED12. In conclusion, we confirm the frequent occurrence of MED12 mutations in fibroadenomas, provide evidence that most intracanalicular fibroadenomas closely resembling benign phyllodes as well as benign phyllodes tumors harbor MED12 mutations, and conclude that MED12 mutations in malignant phyllodes tumors appear to be relatively rare. © 2015 Wiley Periodicals, Inc.

  1. Two novel mutations in the glycine-rich region of human PAX6 gene: Implications for an association of cataracts and anosmia with aniridia

    Energy Technology Data Exchange (ETDEWEB)

    Martha, A.; Ferrel, R.E.; Hittner, H.M.; Saunders, G.F. [Univ. of Texas M.D. Anderson Cancer Center, Houston, TX (United States)

    1994-09-01

    Aniridia (iris hyplasia) is a autosomal dominant congenital disorder of the eye. Mutations in the human aniridia (PAX6) gene have now been identified in many patients from various ethnic groups. In the present study we describe new mutations in this gene. Out of four mutations found, three were novel mutations; the fourth one is identical to the previously reported mutations (C{yields}T transition at nt 240). The three novel mutations analyzed were in the glycine-rich region (two) and in the proline/serine/threonine-rich (PST) region (one). Previously no mutations were reported for the glycine-rich region in humans. One of the mutations found in this region is associated with cataracts in an aniridia family. The other splice mutation found in the PST domain is associated with anosmia (lack of sensation to smell) in a sporadic aniridia case. Two of the mutations presented here, one in the glycine-rich region and the other in the PST domain, were not detected by SSCR. These mutations could be detected by using MDE gel and heteroduplex information. All mutations found in the present study are similar in that 32 of 33 PAX6 mutations result in protein truncation and haploinsufficiency.

  2. Mitochondrial mutations in cancer.

    Science.gov (United States)

    Brandon, M; Baldi, P; Wallace, D C

    2006-08-07

    The metabolism of solid tumors is associated with high lactate production while growing in oxygen (aerobic glycolysis) suggesting that tumors may have defects in mitochondrial function. The mitochondria produce cellular energy by oxidative phosphorylation (OXPHOS), generate reactive oxygen species (ROS) as a by-product, and regulate apoptosis via the mitochondrial permeability transition pore (mtPTP). The mitochondria are assembled from both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) genes. The mtDNA codes for 37 genes essential of OXPHOS, is present in thousands of copies per cell, and has a very high mutations rate. In humans, severe mtDNA mutations result in multisystem disease, while some functional population-specific polymorphisms appear to have permitted humans to adapt to new environments. Mutations in the nDNA-encoded mitochondrial genes for fumarate hydratase and succinate dehydrogenase have been linked to uterine leiomyomas and paragangliomas, and cancer cells have been shown to induce hexokinase II which harnesses OXPHOS adenosine triphosphate (ATP) production to drive glycolysis. Germline mtDNA mutations at nucleotides 10398 and 16189 have been associated with breast cancer and endometrial cancer. Tumor mtDNA somatic mutations range from severe insertion-deletion and chain termination mutations to mild missense mutations. Surprisingly, of the 190 tumor-specific somatic mtDNA mutations reported, 72% are also mtDNA sequence variants found in the general population. These include 52% of the tumor somatic mRNA missense mutations, 83% of the tRNA mutations, 38% of the rRNA mutations, and 85% of the control region mutations. Some associations might reflect mtDNA sequencing errors, but analysis of several of the tumor-specific somatic missense mutations with population counterparts appear legitimate. Therefore, mtDNA mutations in tumors may fall into two main classes: (1) severe mutations that inhibit OXPHOS, increase ROS production and promote tumor

  3. Germline and somatic mosaicism for FGFR2 mutation in the mother of a child with Crouzon syndrome: Implications for genetic testing in ?paternal age-effect? syndromes

    OpenAIRE

    Goriely, Anne; Lord, Helen; Lim, Jasmine; Johnson, David; Lester, Tracy; Firth, Helen V.; Wilkie, Andrew OM

    2010-01-01

    Crouzon syndrome is a dominantly inherited disorder characterized by craniosynostosis and facial dysostosis, caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene; it belongs to a class of disorders that mostly arise as de novo mutations and exhibit a near-exclusive paternal origin of mutation and elevated paternal age (?paternal age effect?). However, even if this is the major mode of origin of mutations in paternal age-effect disorders, germline mosaicism may also occu...

  4. The cys-loop ligand-gated ion channel gene family of Tetranychus urticae: implications for acaricide toxicology and a novel mutation associated with abamectin resistance.

    Science.gov (United States)

    Dermauw, W; Ilias, A; Riga, M; Tsagkarakou, A; Grbić, M; Tirry, L; Van Leeuwen, T; Vontas, J

    2012-07-01

    The cys-loop ligand-gated ion channel (cysLGIC) super family of Tetranychus urticae, the two-spotted spider mite, represents the largest arthropod cysLGIC super family described to date and the first characterised one within the group of chelicerates. Genome annotation, phylogenetic analysis and comparison of the cysLGIC subunits with their counterparts in insects reveals that the T. urticae genome encodes for a high number of glutamate- and histamine-gated chloride channel genes (GluCl and HisCl) compared to insects. Three orthologues of the insect γ-aminobutyric acid (GABA)-gated chloride channel gene Rdl were detected. Other cysLGIC groups, such as the nAChR subunits, are more conserved and have clear insect orthologues. Members of cysLGIC family mediate endogenous chemical neurotransmission and they are prime targets of insecticides. Implications for toxicology associated with the identity and specific features of T. urticae family members are discussed. We further reveal the accumulation of known and novel mutations in different GluCl channel subunits (Tu_GluCl1 and Tu_GluCl3) associated with abamectin resistance in T. urticae, and provide genetic evidence for their causality. Our study provides useful toxicological insights for the exploration of the T. urticae cysLGIC subunits as putative molecular targets for current and future chemical control strategies. Copyright © 2012 Elsevier Ltd. All rights reserved.

  5. Prevalence of BRCA1/2 mutations in sporadic breast/ovarian cancer patients and identification of a novel de novo BRCA1 mutation in a patient diagnosed with late onset breast and ovarian cancer: implications for genetic testing.

    Science.gov (United States)

    De Leeneer, Kim; Coene, Ilse; Crombez, Brecht; Simkens, Justine; Van den Broecke, Rudy; Bols, Alain; Stragier, Barbara; Vanhoutte, Ilse; De Paepe, Anne; Poppe, Bruce; Claes, Kathleen

    2012-02-01

    In order to adequately evaluate the clinical relevance of genetic testing in sporadic breast and ovarian cancer patients, we offered comprehensive BRCA1/2 mutation analysis in patients without a family history for the disease. We evaluated the complete coding and splice site regions of BRCA1/2 in 193 sporadic patients. In addition, a de novo mutation was further investigated with ultra deep sequencing and microsatellite marker analysis. In 17 patients (8.8%), a deleterious germline BRCA1/2 mutation was identified. The highest mutation detection ratio (3/7 = 42.9%) was obtained in sporadic patients diagnosed with breast and ovarian cancer after the age of 40. In 21 bilateral breast cancer patients, two mutations were identified (9.5%). Furthermore, 140 sporadic patients with unilateral breast cancer were investigated. Mutations were only identified in patients diagnosed with breast cancer before the age of 40 (12/128 = 9.4% vs. 0/12 with Dx > 40). No mutations were detected in 17 sporadic male breast cancer and 6 ovarian cancer patients. BRCA1 c.3494_3495delTT was identified in a patient diagnosed with breast and ovarian cancer at the age of 52 and 53, respectively, and was proven to have occurred de novo at the paternal allele. Our study shows that the mutation detection probability in specific patient subsets can be significant, therefore mutation analysis should be considered in sporadic patients. As a consequence, a family history for the disease and an early age of onset should not be used as the only criteria for mutation analysis of BRCA1/2. The relatively high mutation detection ratio suggests that the prevalence of BRCA1/2 may be underestimated, especially in sporadic patients who developed breast and ovarian cancer. In addition, although rare, the possibility of a de novo occurrence in a sporadic patient should be considered.

  6. Potential Effects of Drought on Tree Dieback in Great Britain and Implications for Forest Management in Adaptation to Climate Change

    Science.gov (United States)

    Yu, Jianjun; Berry, Pam

    2017-04-01

    The drought and heat stress has alerted the composition, structure and biogeography of forests globally, whilst the projected severe and widespread droughts are potentially increasing. This challenges the sustainable forest management to better cope with future climate and maintain the forest ecosystem functions and services. Many studies have investigated the climate change impacts on forest ecosystem but less considered the climate extremes like drought. In this study, we implement a dynamic ecosystem model based on a version of LPJ-GUESS parameterized with European tree species and apply to Great Britain at a finer spatial resolution of 5*5 km. The model runs for the baseline from 1961 to 2011 and projects to the latter 21st century using 100 climate scenarios generated from MaRIUS project to tackle the climate model uncertainty. We will show the potential impacts of climate change on forest ecosystem and vegetation transition in Great Britain by comparing the modelled conditions in the 2030s and the 2080s relative to the baseline. In particular, by analyzing the modelled tree mortality, we will show the tree dieback patterns in response to drought for various species, and assess their drought vulnerability across Great Britain. We also use species distribution modelling to project the suitable climate space for selected tree species using the same climate scenarios. Aided by these two modelling approaches and based on the corresponding modelling results, we will discuss the implications for adaptation strategy for forest management, especially in extreme drought conditions. The gained knowledge and lessons for Great Britain are considered to be transferable in many other regions.

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

    Science.gov (United States)

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

    2012-12-24

    Classical Galactosemia is an autosomal recessive disorder of galactose metabolism caused by severe reduction or absence of the galactose-1-phosphate uridyl transferase (GALT) enzyme. Till date, no reports are available on clinical and molecular spectrum of galactosemia from Indian population. The characterization of underlying GALT gene lesions was performed in 55 unrelated galactosemia patients. The GALT mutational spectrum comprised 16 distinct mutations including 10 previously unreported mutations. N314D was the most common mutation with a frequency of 40% followed by Q188R at 2.7%. The novel GALT gene mutations included 6 missense mutations viz. Y89H, Q103R, P166A, S181F, K285R, R333L; one nonsense mutation, S307X and 3 silent mutations--Q103Q, K210K and H319H. The functional significance of the novel GALT missense mutations was investigated using SNPs&GO and SIFT tools. Further, modeling studies using 3D models of mutant and wild type GALT proteins revealed mutations to exert their effects at the molecular level by altering H-bonds, salt bridges, secondary structure or surface features. The study highlighted the heterogeneity of classical galactosemia in the Indian population and also emphasizes the importance of GALT gene analysis in diagnosis of galactosemia. It also revealed that the Indian GALT mutational profile differs significantly from other populations studied. Copyright © 2012 Elsevier B.V. All rights reserved.

  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. 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

  10. Monogonont rotifers as model systems for the study of micro-evolutionary adaptation and its eco-evolutionary implications

    NARCIS (Netherlands)

    Declerck, S.A.J.; Papakostas, S.

    2017-01-01

    A better understanding of the ability of organisms to adapt to local selection conditions is essential for a better insight in their ecological dynamics. The study of micro-evolutionary adaptation and its eco-evolutionary consequences is challenging for many reasons and the choice of a suitable

  11. Novel and de novo glycine substitution mutations in the type VII collagen gene (COL7A1) in dystrophic epidermolysis bullosa : Implications for genetic counseling

    NARCIS (Netherlands)

    Rouan, F; Pulkkinen, L; Jonkman, MF; Cserhalmi-Friedman, PB; Christiano, AM; Uitto, J

    1998-01-01

    The dystrophic forms of epidermolysis bullosa (DEB) are due to mutations in the type VII collagen gene (COL7A1). In dominant DEB, a characteristic genetic lesion is a glycine substitution mutation within the collagenous domain of the protein. In this study, we have examined the molecular basis of

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1996-07-01

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

  13. 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

    often mutated: the global transcription gene rpoB, an 82-bp deletion between the metabolic pyrE gene and rph, and an IS element between the DNA structural gene hns and tdk. Model-derived classification of gene expression revealed a number of processes important for increased growth that were missed...

  14. 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.

  15. Identification of fragile X pre-mutation carriers in the Chinese obstetric population using a robust FMR1 polymerase chain reaction assay: implications for screening and prenatal diagnosis.

    Science.gov (United States)

    Cheng, Y Ky; Lin, C Sw; Kwok, Y Ky; Chan, Y M; Lau, T K; Leung, T Y; Choy, K W

    2017-04-01

    There is significant morbidity associated with fragile X syndrome. Unfortunately, most maternal carriers are clinically silent during their reproductive years. Because of this, many experts have put forward the notion of preconception or prenatal fragile X carrier screening for females. This study aimed to determine the prevalence of fragile X syndrome pre-mutation and asymptomatic full-mutation carriers in a Chinese pregnant population, and the distribution of cytosine-guanine-guanine (CGG) repeat numbers using a robust fragile X mental retardation 1 (FMR1) polymerase chain reaction assay. This was a cross-sectional survey in prospectively recruited pregnant women from a university hospital in Hong Kong. Chinese pregnant women without a family history of fragile X syndrome were recruited between April 2013 and May 2015. A specific FMR1 polymerase chain reaction assay was performed on peripheral blood to determine the CGG repeat number of the FMR1 gene. Prenatal counselling was offered to full-mutation and pre-mutation carriers. In 2650 Chinese pregnant women, two individuals with pre-mutation alleles (0.08%, one in 1325) and one asymptomatic woman with full-mutation (0.04%, one in 2650) alleles were identified. The overall prevalence of pre-mutation and full-mutation alleles was 0.11% (1 in 883). Furthermore, 30 (1.1%) individuals with intermediate alleles were detected. In the 2617 women with normal CGG repeats, the most common CGG repeat allele was 30. The overall prevalence of pre-mutation and asymptomatic full-mutation carriers in the Chinese pregnant population was one in 883, detected by a new FMR1 polymerase chain reaction assay.

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

    Science.gov (United States)

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

    2006-01-01

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

  17. Evaluation of molecular diagnostic approaches for the detection of BRAF p.V600E mutations in papillary thyroid cancer: Clinical implications.

    Directory of Open Access Journals (Sweden)

    Artur Kowalik

    Full Text Available Differentiated papillary thyroid cancer (PTC is the most common cancer of the endocrine system. PTC has a very good prognosis and a high 5 year survival rate; however, some patients are unresponsive to treatment, and their diagnosis eventually results in death. Recent efforts have focused on searching for prognostic and predictive factors that may enable treatment personalization and monitoring across the course of the disease. The presence of the BRAF mutation is considered to contribute to the risk of poor clinical course, according to American Thyroid Association (ATA recommendations. The method used for genotyping can impact the predicted mutation frequency; however, ATA recommendations do not address this issue. We evaluated the molecular diagnostic (BRAF p.V600E mutation results of 410 patients treated for PTC. We thoroughly analyzed the impact of three different BRAF mutation detection methods, Sanger Sequencing (Seq, allele-specific amplification PCR (ASA-PCR, and quantitative PCR (qPCR, on the frequency of mutation detection in 399 patients. Using Seq, we detected the BRAF mutation in 37% of patients; however, we were able to detect BRAF mutations in 57% and 60% of patients using the more sensitive ASA-PCR and qPCR technologies, respectively. Differences between methods were particularly marked in the thyroid papillary microcarcinoma group; BRAF p.V600E mutations were found in 37% of patients using Seq and 63% and 66% of patients using ASA-PCR and qPCR, respectively. We also evaluated how these different diagnostic methods were impacted by DNA quality. Applying methods with different sensitivities to the detection of BRAF p.V600E mutations may result in different results for the same patient; such data can influence stratification of patients into different risk groups, leading to alteration of treatment and follow-up schemes.

  18. Survival and growth patterns of white spruce (Picea glauca [Moench] Voss) rangewide provenances and their implications for climate change adaptation

    OpenAIRE

    Lu, Pengxin; Parker, William H; Cherry, Marilyn; Colombo, Steve; William C. Parker; Man, Rongzhou; Roubal, Ngaire

    2014-01-01

    Intraspecific assisted migration (ISAM) through seed transfer during artificial forest regeneration has been suggested as an adaptation strategy to enhance forest resilience and productivity under future climate. In this study, we assessed the risks and benefits of ISAM in white spruce based on long-term and multilocation, rangewide provenance test data. Our results indicate that the adaptive capacity and growth potential of white spruce varied considerably among 245 range-wide provenances sa...

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

    Science.gov (United States)

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

    2016-03-09

    The auditory system is able to detect movement down to atomic dimensions. This sensitivity comes in part from mechanisms associated with gating of hair cell mechanoelectric transduction (MET) channels. MET channels, located at the tops of stereocilia, are poised to detect tension induced by hair bundle deflection. Hair bundle deflection generates a force by pulling on tip-link proteins connecting adjacent stereocilia. The resting open probability (P(open)) of MET channels determines the linearity and sensitivity to mechanical stimulation. Classically, P(open) is regulated by a calcium-sensitive adaptation mechanism in which lowering extracellular calcium or depolarization increases P(open). Recent data demonstrated that the fast component of adaptation is independent of both calcium and voltage, thus requiring an alternative explanation for the sensitivity of P(open) to calcium and voltage. Using rat auditory hair cells, we characterize a mechanism, separate from fast adaptation, whereby divalent ions interacting with the local lipid environment modulate resting P(open). The specificity of this effect for different divalent ions suggests binding sites that are not an EF-hand or calmodulin model. GsMTx4, a lipid-mediated modifier of cationic stretch-activated channels, eliminated the voltage and divalent sensitivity with minimal effects on adaptation. We hypothesize that the dual mechanisms (lipid modulation and adaptation) extend the dynamic range of the system while maintaining adaptation kinetics at their maximal rates. Copyright © 2016 the authors 0270-6474/16/362945-12$15.00/0.

  20. Can random mutation mimic design?: a guided inquiry laboratory for undergraduate students.

    Science.gov (United States)

    Kalinowski, Steven T; Taper, Mark L; Metz, Anneke M

    2006-11-01

    Complex biological structures, such as the human eye, have been interpreted as evidence for a creator for over three centuries. This raises the question of whether random mutation can create such adaptations. In this article, we present an inquiry-based laboratory experiment that explores this question using paper airplanes as a model organism. The main task for students in this investigation is to figure out how to simulate paper airplane evolution (including reproduction, inheritance, mutation, and selection). In addition, the lab requires students to practice analytic thinking and to carefully delineate the implications of their results.

  1. Familial Mediterranean fever gene (MEFV) mutations and disease severity in systemic lupus erythematosus (SLE): implications for the role of the E148Q MEFV allele in inflammation.

    Science.gov (United States)

    Deniz, R; Ozen, G; Yilmaz-Oner, S; Alibaz-Oner, F; Erzik, C; Aydin, S Z; Inanc, N; Eren, F; Bayalan, F; Direskeneli, H; Atagunduz, P

    2015-06-01

    Observed low prevalence of SLE among familial Mediterranean fever (FMF) patients in several large cohorts suggests a possible protective effect of the MEFV mutations from SLE. In contrast, SLE patient carriers for the common MEFV mutations had rather complex disease expression with an increased frequency of febrile episodes and pleurisy and a decreased renal complication rate. Our aim was to investigate the prevalence of MEFV gene mutations in patients with SLE and their effect on organ involvement in a well-defined group of biopsy-proven SLE nephritis patients. The prevalence of four MEFV gene mutations (M694V, M680I, V726A and E148Q) was investigated in 114 SLE patients and effect on disease severity was analyzed in patients with biopsy-proven SLE nephritis. None of the SLE patients fulfilled the revised Tel-Hashomer criteria. Fourteen of 114 SLE patients (12.2%) were found to carry at least one MEFV mutation. A single patient in the SLE-Nephritis group was compound heterozygous for M694V/M680I mutations and only one patient in the SLE-Mild group was homozygous for E148Q mutation. Carrier frequency was similar to controls in SLE patients (12.2 vs 18.8%, p = 0.34). After the exclusion of the less penetrant E148Q mutation, re-analysis revealed an association between exon 10 mutations and SLE nephritis (p = 0.050, odds ratio (OR) = 4.16, 95% confidence interval (CI) = 1.04-16.6). Carrier rate for the E148Q mutation decreased in the SLE group (controls vs. SLE = 20/186 vs. 3/114, p = 0.08) and E148Q mutation was absent in SLE nephritis (controls vs. SLE nephritis = 20/186 vs. 0/47, p = 0.016, OR = 11.69, 95% CI = 0.69-197.13). Carrier rate for the studied MEFV mutations was slightly lower in the SLE group, which is in agreement with previous observations that FMF may confer some protection from SLE. Exon 10 mutations were associated with SLE nephritis after the exclusion of the E148Q mutation. The significance of the E148Q as a

  2. Increased prevalence of lung, breast and pancreatic cancers in addition to melanoma risk in families bearing the CDKN2A mutation: Implications for genetic counseling

    Science.gov (United States)

    Potrony, Miriam; Puig-Butillé, Joan Anton; Aguilera, Paula; Badenas, Celia; Carrera, Cristina; Malvehy, Josep; Puig, Susana

    2014-01-01

    BACKGROUND CDKN2A is the major high-risk susceptibility gene for melanoma. OBJECTIVE To evaluate the effect of CDKN2A mutations in high-risk Spanish melanoma patients and the association with clinical and family history features. METHODS A cross-sectional study design was used to analyze the CDKN2A impact in 702 Spanish patients with a high-risk of developing melanoma. RESULTS The CDKN2A mutation prevalence was 8.5% in sporadic multiple primary melanoma patients and 14.1% in familial melanoma. Number of cases in the family, number of primary melanomas and age of onset were associated with the presence of CDKN2A mutation. Having a CDKN2A mutation in the family increased the prevalence of other cancers (PR=2.99, p=0.012), pancreatic (PR=2.97, p=0.006), lung (PR=3.04, pMelanoma-prone families with mutations in CDKN2A have an increased prevalence of a broad spectrum of cancers including lung, pancreatic and breast cancer. This information should be included in genetic counseling and cancer prevention programs for CDKN2A mutation carriers. PMID:25064638

  3.  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.

  4. Cosegregation of intragenic markers with a novel mutation that causes Crigler-Najjar syndrome type I: Implication in carrier detection and prenatal diagnosis

    Energy Technology Data Exchange (ETDEWEB)

    Moghrabi, N.; Clarke, D.J.; Burchell, B.; Boxer, M. (Univ. of Dundee (United Kingdom))

    1993-09-01

    Crigler-Najjar syndrome type I (CN-1) is a familial disorder characterized by severe unconjugated hyperbilirubinemia and jaundice and leads to kernicterus, neurological damage, and eventual death unless treated with liver transplantation. Previous reports identified mutations in the UGT1 gene complex to be the cause of the disease. The total absence of all phenol/bilirubin UGT (UDP-glucuronosyl transferase) proteins and their activities in liver homogenate of a CN-1 patient was determined by enzymological and immunochemical analysis. A novel homozygous nonsense mutation (CGA [yields] TGA) was identified in the patient by the combined techniques of PCR and direct sequenching. This mutation was located in exon 3 of the constant region in the gene complex which is common to all phenol and bilirubin UGTs. The segregation of the mutation in the patient's family was analyzed and confirmed the recessive nature of the disease. Newly developed intragenic polymorphic probes (UGT1[sup *]4 and UGT-Const) were used on Southern blots of MspI-digested genomic DNA of the patient and his family. The segregation of haplotypes with the mutation for the patient and his family revealed the allele identified by the A1-B1-C2 haplotype to be carrying the mutation. The risk of recombination occurring is negligible, because of the intragenic nature of the probes. This study demonstrates the potential usefulness of these probes in carrier detection and prenatal/presymptomatic diagnosis. 36 refs., 5 figs., 1 tab.

  5. Germline and somatic mosaicism for FGFR2 mutation in the mother of a child with Crouzon syndrome: Implications for genetic testing in "paternal age-effect" syndromes.

    Science.gov (United States)

    Goriely, Anne; Lord, Helen; Lim, Jasmine; Johnson, David; Lester, Tracy; Firth, Helen V; Wilkie, Andrew O M

    2010-08-01

    Crouzon syndrome is a dominantly inherited disorder characterized by craniosynostosis and facial dysostosis, caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene; it belongs to a class of disorders that mostly arise as de novo mutations and exhibit a near-exclusive paternal origin of mutation and elevated paternal age ("paternal age effect"). However, even if this is the major mode of origin of mutations in paternal age-effect disorders, germline mosaicism may also occur. Here we describe the first molecularly documented evidence of germline and somatic mosaicism for FGFR2 mutation, identified in the mother of a child with Crouzon syndrome caused by a heterozygous c.1007A>G (p.Asp336Gly) substitution. Levels of maternal somatic mosaicism for this mutation, estimated by pyrosequencing, ranged from 3.3% in hair roots to 14.1% in blood. Our observation underlines the importance of parental molecular testing for accurate genetic counseling of the risk of recurrence for Crouzon, and other paternal age-effect syndromes.

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

    Science.gov (United States)

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

    2017-04-01

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

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

    Science.gov (United States)

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

    2013-01-01

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

  8. 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

  9. Gefitinib as first-line treatment for patients with advanced non-small-cell lung cancer with activating Epidermal Growth Factor Receptor mutation: implications for clinical practice and open issues.

    Science.gov (United States)

    Gridelli, C; De Marinis, F; Di Maio, M; Cortinovis, D; Cappuzzo, F; Mok, T

    2011-04-01

    Randomized trials comparing gefitinib with chemotherapy as first-line treatment in patients with EGFR mutated advanced NSCLC support gefitinib as a new, highly effective treatment option in this setting. However, its use in clinical practice has several relevant implications and open issues. In order to choose the best treatment, a molecular characterization is now mandatory, as part of baseline diagnostic procedures. Every effort should be made in order to obtain sufficient tissue. If a clinical enrichment has to be performed for selecting patients to test for EGFR mutation, a reasonable proposal is to test all non-squamous tumors, and patients with squamous tumors only if never smokers. In patients with EGFR mutated tumor, one major issue is the decision about immediate use of gefitinib as first-line, or after failure of standard chemotherapy. First-line gefitinib, compared to chemotherapy, is associated with longer progression-free survival, higher response rate, better toxicity profile and quality of life, and its administration as first-line warrants that all patients have the chance of receiving an EGFR inhibitor. Evidence about the efficacy of erlotinib in the same setting will be soon available, however, at the moment, there are no direct comparisons between gefitinib and erlotinib in EGFR mutated patients. Treatment with gefitinib is usually well tolerated. Typical side effects in most cases are of mild to moderate intensity, and usually manageable with temporary interruption of treatment. When indicated gefitinib appears feasible also in special populations, like elderly or unfit patients, characterized by a significantly poorer risk/benefit ratio with standard chemotherapy. Personalized medicine for patients with lung cancer is now a reality, and patients with EGFR mutation should be treated with first-line EGFR tyrosine kinase inhibitor. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  10. The Frequency and Clinical Implications of the BRAF Mutation in Papillary Thyroid Cancer Patients in Korea Over the Past Two Decades

    Directory of Open Access Journals (Sweden)

    A Ram Hong

    2014-12-01

    Full Text Available BackgroundOver the past several decades, there has been a rapid worldwide increase in the prevalence of papillary thyroid cancer (PTC as well as a number of changes in the clinicopathological characteristics of this disease. BRAFV600E, which is a mutation of the proto-oncogene BRAF, has become the most frequent genetic mutation associated with PTC, particularly in Korea. Thus, the present study investigated whether the prevalence of the BRAFV600E mutation has increased over the past two decades in the Korean population and whether various PTC-related clinicopathological characteristics have changed.MethodsThe present study included 2,624 patients who underwent a thyroidectomy for PTC during two preselected periods; 1995 to 2003 and 2009 to 2012. The BRAFV600E mutation status of each patient was confirmed using the polymerase chain reaction-restriction fragment length polymorphism method or by the direct sequencing of DNA.ResultsThe prevalence of the BRAFV600E mutation in Korean PTC patients increased from 62.2% to 73.7% (P=0.001 over the last two decades. Additionally, there was a greater degree of extrathyroidal extension (ETE and lymph node metastasis in 2009 to 2012 patients with the BRAFV600E mutation and a higher frequency of thyroiditis and follicular variant-PTC in 2009 to 2012 patients with wild-type BRAF. However, only the frequency of ETE was significantly higher in 1995 to 2003 patients with the BRAFV600E mutation (P=0.047. Long-term recurrence rates during a 10-year median follow-up did not differ based on BRAFV600E mutation status.ConclusionThe BRAFV600E mutation rate in Korean PTC patients has been persistently high (approximately 70% over the past two decades and continues to increase. The present findings demonstrate that BRAFV600E-positive PTC was associated with more aggressive clinicopathological features, especially in patients who were recently diagnosed, suggesting that BRAFV600E mutation status may be a useful prognostic

  11. On slowly varying systems - l-infinity to l-infinity performance and implications to robust adaptive control

    Science.gov (United States)

    Voulgaris, Petros G.; Dahleh, Munther A.; Valavani, Lena S.

    1992-01-01

    The authors present a result on the l-infinity to l-infinity performance of slowly time varying systems. In particular, it is shown that the performance of such systems cannot be much worse than that of the frozen-time systems which are time invariant. This result is used to characterize a class of indirect adaptive controllers that can stabilize a time-invariant system subjected to both parametric and l-infinity to l-infinity bounded unstructured uncertainty. Pertaining to this class of controllers, a particular indirect adaptive scheme is proposed that provides the greatest upper bound on the size of the unstructured uncertainty for which stability is ensured.

  12. Long-term metabolic and skeletal muscle adaptations to short-sprint training: implications for sprint training and tapering.

    Science.gov (United States)

    Ross, A; Leveritt, M

    2001-01-01

    The adaptations of muscle to sprint training can be separated into metabolic and morphological changes. Enzyme adaptations represent a major metabolic adaptation to sprint training, with the enzymes of all three energy systems showing signs of adaptation to training and some evidence of a return to baseline levels with detraining. Myokinase and creatine phosphokinase have shown small increases as a result of short-sprint training in some studies and elite sprinters appear better able to rapidly breakdown phosphocreatine (PCr) than the sub-elite. No changes in these enzyme levels have been reported as a result of detraining. Similarly, glycolytic enzyme activity (notably lactate dehydrogenase, phosphofructokinase and glycogen phosphorylase) has been shown to increase after training consisting of either long (>10-second) or short (training levels after somewhere between 7 weeks and 6 months of detraining. Mitochondrial enzyme activity also increases after sprint training, particularly when long sprints or short recovery between short sprints are used as the training stimulus. Morphological adaptations to sprint training include changes in muscle fibre type, sarcoplasmic reticulum, and fibre cross-sectional area. An appropriate sprint training programme could be expected to induce a shift toward type IIa muscle, increase muscle cross-sectional area and increase the sarcoplasmic reticulum volume to aid release of Ca(2+). Training volume and/or frequency of sprint training in excess of what is optimal for an individual, however, will induce a shift toward slower muscle contractile characteristics. In contrast, detraining appears to shift the contractile characteristics towards type IIb, although muscle atrophy is also likely to occur. Muscle conduction velocity appears to be a potential non-invasive method of monitoring contractile changes in response to sprint training and detraining. In summary, adaptation to sprint training is clearly dependent on the duration of

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

    Science.gov (United States)

    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, Wie-Yen; Guan, Min-Xin

    2006-02-03

    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.

  14. 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 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.

  15. Sources of error inherent in species-tree estimation: impact of mutational and coalescent effects on accuracy and implications for choosing among different methods.

    Science.gov (United States)

    Huang, Huateng; He, Qixin; Kubatko, Laura S; Knowles, L Lacey

    2010-10-01

    Discord in the estimated gene trees among loci can be attributed to both the process of mutation and incomplete lineage sorting. Effectively modeling these two sources of variation--mutational and coalescent variance--provides two distinct challenges for phylogenetic studies. Despite extensive investigation on mutational models for gene-tree estimation over the past two decades and recent attention to modeling of the coalescent process for phylogenetic estimation, the effects of these two variances have yet to be evaluated simultaneously. Here, we partition the effects of mutational and coalescent processes on phylogenetic accuracy by comparing the accuracy of species trees estimated from gene trees (i.e., the actual coalescent genealogies) with that of species trees estimated from estimated gene trees (i.e., trees estimated from nucleotide sequences, which contain both coalescent and mutational variance). Not only is there a significant contribution of both mutational and coalescent variance to errors in species-tree estimates, but the relative magnitude of the effects on the accuracy of species-tree estimation also differs systematically depending on 1) the timing of divergence, 2) the sampling design, and 3) the method used for species-tree estimation. These findings explain why using more information contained in gene trees (e.g., topology and branch lengths as opposed to just topology) does not necessarily translate into pronounced gains in accuracy, highlighting the strengths and limits of different methods for species-tree estimation. Differences in accuracy scores between methods for different sampling regimes also emphasize that it would be a mistake to assume more computationally intensive species-tree estimation procedures that will always provide better estimates of species trees. To the contrary, the performance of a method depends not only on the method per se but also on the compatibilities between the input genetic data and the method as determined

  16. Reduced Mitochondrial Membrane Potential Is a Late Adaptation of Trypanosoma brucei brucei to Isometamidium Preceded by Mutations in the γ Subunit of the F1Fo-ATPase.

    Directory of Open Access Journals (Sweden)

    Anthonius A Eze

    2016-08-01

    Full Text Available Isometamidium is the main prophylactic drug used to prevent the infection of livestock with trypanosomes that cause Animal African Trypanosomiasis. As well as the animal infective trypanosome species, livestock can also harbor the closely related human infective subspecies T. b. gambiense and T. b. rhodesiense. Resistance to isometamidium is a growing concern, as is cross-resistance to the diamidine drugs diminazene and pentamidine.Two isometamidium resistant Trypanosoma brucei clones were generated (ISMR1 and ISMR15, being 7270- and 16,000-fold resistant to isometamidium, respectively, which retained their ability to grow in vitro and establish an infection in mice. Considerable cross-resistance was shown to ethidium bromide and diminazene, with minor cross-resistance to pentamidine. The mitochondrial membrane potentials of both resistant cell lines were significantly reduced compared to the wild type. The net uptake rate of isometamidium was reduced 2-3-fold but isometamidium efflux was similar in wild-type and resistant lines. Fluorescence microscopy and PCR analysis revealed that ISMR1 and ISMR15 had completely lost their kinetoplast DNA (kDNA and both lines carried a mutation in the nuclearly encoded γ subunit gene of F1 ATPase, truncating the protein by 22 amino acids. The mutation compensated for the loss of the kinetoplast in bloodstream forms, allowing near-normal growth, and conferred considerable resistance to isometamidium and ethidium as well as significant resistance to diminazene and pentamidine, when expressed in wild type trypanosomes. Subsequent exposure to either isometamidium or ethidium led to rapid loss of kDNA and a further increase in isometamidium resistance.Sub-lethal exposure to isometamidium gives rise to viable but highly resistant trypanosomes that, depending on sub-species, are infective to humans and cross-resistant to at least some diamidine drugs. The crucial mutation is in the F1 ATPase γ subunit, which

  17. 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.

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

    Science.gov (United States)

    Mbajiorgu, Ngozika; Anidu, Innocent

    2017-01-01

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

  19. 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

  20. 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.

  1. 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…

  2. Revised Robert's cytoprotection and adaptive cytoprotection and stable gastric pentadecapeptide BPC 157. Possible significance and implications for novel mediator.

    Science.gov (United States)

    Sikiric, Predrag; Seiwerth, Sven; Brcic, Luka; Sever, Marko; Klicek, Robert; Radic, Bozo; Drmic, Domagoj; Ilic, Spomenko; Kolenc, Danijela

    2010-01-01

    The significance of cytoprotection and adaptive cytoprotection and the peptides importance remained to be not completely determined. BPC 157 is an anti-ulcer peptidergic agent, proven in clinical trials to be both safe in inflammatory bowel disease (PL-10, PLD-116, PL 14736) and wound healing, and stable in human gastric juice, with no toxicity being reported. It has a prominent effect on alcohol- lesions (i.e., induced acutely and chronically) and non-steroidal anti-inflammatory drugs-lesions (while interestingly BPC 157 may both prevent and reverse adjuvant arthritis). To review the importance of BPC 157, this review focused on Robert's cytoprotection concept described in rat stomach, reviewing our evidence that may resolve whether the cytoprotection and adaptive cytoprotection is an uniform phenomenon or not; whether the phenomenon or phenomena are endogenous or not, depending on nature of the irritants (mild or strong); whether this may contribute to stomach mucosa defense either when threaten by various ulcerogens or afforded by various antiulcer agents; whether these phenomena are uniform in whole gastrointestinal tract or not; whether they are interrelated or not. Finally, the importance of the cytoprotection phenomena and cytoprotection activity for skin wound healing, and wound healing in general was challenged. Thereby, this review focused on BPC 157 role in cytoprotection and adaptative cytoprotection suggesting that it may be the essential endogenous mediator able to mediate both cytoprotective and adaptive cytoprotective response in stomach and the whole gastrointestinal tract with significant importance in wound healing as well.

  3. Fitness effects of fixed beneficial mutations in microbial populations

    NARCIS (Netherlands)

    Rozen, D.; Visser, de J.A.G.M.; Gerrish, P.J.

    2002-01-01

    Beneficial mutations are intuitively relevant to understanding adaptation [1-3], yet not all beneficial mutations are of consequence to the long-term evolutionary outcome of adaptation. Many beneficial mutations - mostly those of small effect - are lost due either to (1) genetic drift [4, 5] or to

  4. Towards improvements in the estimation of the coalescent: implications for the most effective use of Y chromosome short tandem repeat mutation rates.

    Directory of Open Access Journals (Sweden)

    Steven C Bird

    Full Text Available Over the past two decades, many short tandem repeat (STR microsatellite loci on the human Y chromosome have been identified together with mutation rate estimates for the individual loci. These have been used to estimate the coalescent age, or the time to the most recent common ancestor (TMRCA expressed in generations, in conjunction with the average square difference measure (ASD, an unbiased point estimator of TMRCA based upon the average within-locus allele variance between haplotypes. The ASD estimator, in turn, depends on accurate mutation rate estimates to be able to produce good approximations of the coalescent age of a sample. Here, a comparison is made between three published sets of per locus mutation rate estimates as they are applied to the calculation of the coalescent age for real and simulated population samples. A novel evaluation method is developed for estimating the degree of conformity of any Y chromosome STR locus of interest to the strict stepwise mutation model and specific recommendations are made regarding the suitability of thirty-two commonly used Y-STR loci for the purpose of estimating the coalescent. The use of the geometric mean for averaging ASD and û across loci is shown to improve the consistency of the resulting estimates, with decreased sensitivity to outliers and to the number of STR loci compared or the particular set of mutation rates selected.

  5. Revealing very small FLT3 ITD mutated clones by ultra-deep sequencing analysis has important clinical implications in AML patients.

    Science.gov (United States)

    Zuffa, Elisa; Franchini, Eugenia; Papayannidis, Cristina; Baldazzi, Carmen; Simonetti, Giorgia; Testoni, Nicoletta; Abbenante, Maria Chiara; Paolini, Stefania; Sartor, Chiara; Parisi, Sarah; Marconi, Giovanni; Cattina, Federica; Bochicchio, Maria Teresa; Venturi, Claudia; Ottaviani, Emanuela; Cavo, Michele; Martinelli, Giovanni

    2015-10-13

    FLT3 internal tandem duplication (ITD), one of the most frequent mutations in Acute Myeloid Leukemia (AML), is reported to be an unstable marker, as it can evolve from FLT3 ITD- to ITD+ during the disease course. A single-gene sensitive mutational screening approach may be helpful for better clarifying the exact timing of mutation occurrence, especially when FLT3 ITD appears to occur late, at disease progression. We developed an amplicon-based ultra-deep-sequencing (UDS) approach for FLT3 mutational screening. We exploited this highly sensitive technology for the retrospective screening of diagnosis, relapse and follow-up samples of 5 out of 256 cytogenetically normal (CN-) AML who were FLT3 wild-type at presentation, but tested ITD+ at relapse or disease progression. Our study revealed that all patients carried a small ITD+ clone at diagnosis, which was undetectable by routine analysis (0,2-2% abundance). The dynamics of ITD+ clones from diagnosis to disease progression, assessed by UDS, reflected clonal evolution under treatment pressure. UDS appears as a valuable tool for FLT3 mutational screening and for the assessment of minimal residual disease (MRD) during follow-up, by detecting small ITD+ clones that may survive chemotherapy, evolve over time and definitely worsen the prognosis of CN-AML patients.

  6. Endometrial cancers in mutation carriers from hereditary breast ovarian cancer syndrome kindreds: report from the Creighton University Hereditary Cancer Registry with review of the implications.

    Science.gov (United States)

    Casey, Murray Joseph; Bewtra, Chhanda; Lynch, Henry T; Snyder, Carrie L; Stacey, Mark

    2015-05-01

    The aim of this study was to categorize and report endometrial cancers in mutation carriers from hereditary breast ovarian cancer families. Our Hereditary Cancer Registry was searched for gynecologic and peritoneal cancers linked to mutations in BRCA1 or BRCA2. Invasive cancers were registered in 101 mutation carriers with complete pathology reports. Efforts were made to secure diagnostic surgical pathology tissues for review. All records and available diagnostic slides were meticulously studied, and primary cancers were classified. Eight malignancies were classified as primary endometrial cancers. Five of these were low- or intermediate-grade endometrioid carcinomas, and 3 were pure serous carcinomas or contained serous carcinoma elements mixed with high-grade endometrioid carcinoma. Breast cancers were diagnosed in 5 patients before and in 1 patient after endometrial carcinoma. Three endometrioid carcinomas were preceded by estrogen treatment, 2 for many years and the other for only 2 months, and 2 of the patients with serous carcinoma had been treated with tamoxifen. The finding that 8 of gynecologic and peritoneal cancers in 101 mutation carriers were endometrial cancers with a smaller proportion of endometrioid carcinomas than reported in general populations is added to the current controversial literature on endometrial cancer, particularly regarding serous carcinomas, in hereditary breast ovarian cancer syndrome. Well-designed prospective programs for standardized surgical and pathologic handling, processing, and reporting are essential for working out the pathogenesis, true risks, and best management of this disease in carriers of deleterious BRCA1 and BRCA2 germline mutations.

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

    Directory of Open Access Journals (Sweden)

    Naoki Morimoto

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

  8. 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

  9. Default-mode and task-positive network activity in major depressive disorder: implications for adaptive and maladaptive rumination.

    Science.gov (United States)

    Hamilton, J Paul; Furman, Daniella J; Chang, Catie; Thomason, Moriah E; Dennis, Emily; Gotlib, Ian H

    2011-08-15

    Major depressive disorder (MDD) has been associated reliably with ruminative responding; this kind of responding is composed of both maladaptive and adaptive components. Levels of activity in the default-mode network (DMN) relative to the task-positive network (TPN), as well as activity in structures that influence DMN and TPN functioning, may represent important neural substrates of maladaptive and adaptive rumination in MDD. We used a unique metric to estimate DMN dominance over TPN from blood oxygenation level-dependent data collected during eyes-closed rest in 17 currently depressed and 17 never-disordered adults. We calculated correlations between this metric of DMN dominance over TPN and the depressive, brooding, and reflective subscales of the Ruminative Responses Scale, correcting for associations between these measures both with one another and with severity of depression. Finally, we estimated and compared across groups right fronto-insular cortex (RFIC) response during initiations of ascent in DMN and in TPN activity. In the MDD participants, increasing levels of DMN dominance were associated with higher levels of maladaptive, depressive rumination and lower levels of adaptive, reflective rumination. Moreover, our RFIC state-change analysis showed increased RFIC activation in the MDD participants at the onset of increases in TPN activity; conversely, healthy control participants exhibited increased RFIC response at the onset of increases in DMN activity. These findings support a formulation in which the DMN undergirds representation of negative, self-referential information in depression, and the RFIC, when prompted by increased levels of DMN activity, initiates an adaptive engagement of the TPN. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  10. Rapid Evolution of piRNA Pathway in the Teleost Fish: Implication for an Adaptation to Transposon Diversity

    Science.gov (United States)

    Yi, Minhan; Chen, Feng; Luo, Majing; Cheng, Yibin; Zhao, Huabin; Cheng, Hanhua; Zhou, Rongjia

    2014-01-01

    The Piwi-interacting RNA (piRNA) pathway is responsible for germline specification, gametogenesis, transposon silencing, and genome integrity. Transposable elements can disrupt genome and its functions. However, piRNA pathway evolution and its adaptation to transposon diversity in the teleost fish remain unknown. This article unveils evolutionary scene of piRNA pathway and its association with diverse transposons by systematically comparative analysis on diverse teleost fish genomes. Selective pressure analysis on piRNA pathway and miRNA/siRNA (microRNA/small interfering RNA) pathway genes between teleosts and mammals showed an accelerated evolution of piRNA pathway genes in the teleost lineages, and positive selection on functional PAZ (Piwi/Ago/Zwille) and Tudor domains involved in the Piwi–piRNA/Tudor interaction, suggesting that the amino acid substitutions are adaptive to their functions in piRNA pathway in the teleost fish species. Notably five piRNA pathway genes evolved faster in the swamp eel, a kind of protogynous hermaphrodite fish, than the other teleosts, indicating a differential evolution of piRNA pathway between the swamp eel and other gonochoristic fishes. In addition, genome-wide analysis showed higher diversity of transposons in the teleost fish species compared with mammals. Our results suggest that rapidly evolved piRNA pathway in the teleost fish is likely to be involved in the adaption to transposon diversity. PMID:24846630

  11. Dengue type four viruses with E-Glu345Lys adaptive mutation from MRC-5 cells induce low viremia but elicit potent neutralizing antibodies in rhesus monkeys.

    Directory of Open Access Journals (Sweden)

    Hsiao-Han Lin

    Full Text Available Knowledge of virulence and immunogenicity is important for development of live-attenuated dengue vaccines. We previously reported that an infectious clone-derived dengue type 4 virus (DENV-4 passaged in MRC-5 cells acquired a Glu345Lys (E-E345K substitution in the E protein domain III (E-DIII. The same cloned DENV-4 was found to yield a single E-Glu327Gly (E-E327G mutation after passage in FRhL cells and cause the loss of immunogenicity in rhesus monkeys. Here, we used site-directed mutagenesis to generate the E-E345K and E-E327G mutants from DENV-4 and DENV-4Δ30 infectious clones and propagated in Vero or MRC-5 cells. The E-E345K mutations were consistently presented in viruses recovered from MRC-5 cells, but not Vero cells. Recombinant E-DIII proteins of E345K and E327G increased heparin binding correlated with the reduced infectivity by heparin treatment in cell cultures. Different from the E-E327G mutant viruses to lose the immunogencity in rhesus monkeys, the E-E345K mutant viruses were able to induce neutralizing antibodies in rhesus monkeys with an almost a 10-fold lower level of viremia as compared to the wild type virus. Monkeys immunized with the E-E345K mutant virus were completely protected with no detectable viremia after live virus challenges with the wild type DENV-4. These results suggest that the E-E345K mutant virus propagated in MRC-5 cells may have potential for the use in live-attenuated DENV vaccine development.

  12. An Adaptive Mutation in Enterococcus faecium LiaR Associated with Antimicrobial Peptide Resistance Mimics Phosphorylation and Stabilizes LiaR in an Activated State.

    Science.gov (United States)

    Davlieva, Milya; Tovar-Yanez, Angel; DeBruler, Kimberly; Leonard, Paul G; Zianni, Michael R; Arias, Cesar A; Shamoo, Yousif

    2016-11-06

    The cyclic antimicrobial lipopeptide daptomycin (DAP) triggers the LiaFSR membrane stress response pathway in enterococci and many other Gram-positive organisms. LiaR is the response regulator that, upon phosphorylation, binds in a sequence-specific manner to DNA to regulate transcription in response to membrane stress. In clinical settings, non-susceptibility to DAP by Enterococcus faecium is correlated frequently with a mutation in LiaR of Trp73 to Cys (LiaR W73C ). We have determined the structure of the activated E. faecium LiaR protein at 3.2Å resolution and, in combination with solution studies, show that the activation of LiaR induces the formation of a LiaR dimer that increases LiaR affinity at least 40-fold for the extended regulatory regions upstream of the liaFSR and liaXYZ operons. In vitro, LiaR W73C induces phosphorylation-independent dimerization of LiaR and provides a biochemical basis for non-susceptibility to DAP by the upregulation of the LiaFSR regulon. A comparison of the E. faecalis LiaR, E. faecium LiaR, and the LiaR homolog from Staphylococcus aureus (VraR) and the mutations associated with DAP resistance suggests that physicochemical properties such as oligomerization state and DNA specificity, although tuned to the biology of each organism, share some features that could be targeted for new antimicrobials. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Rapid and inexpensive detection of common HBB gene mutations in Tunisian population by high-resolution melting analysis: implication for molecular diagnosis.

    Science.gov (United States)

    Ouragini, Houyem; Haddad, Faten; Darragi, Imen; Abbes, Salem

    2014-03-01

    In Tunisia, β-thalassemia is a common hereditary disease with a carrying rate of 2.21%. Up to now, detection of responsible mutations was made by laborious, expensive, and/or time consuming methods. The aim of this study is to develop and validate a specific assay for detection of the two most frequent mutations in Tunisian population, the IVS-I-110 (G → A) and Cd39 (C → T) mutations. In this study, we optimize high resolution melting analysis (HRMA) conditions for these mutations, using control DNAs. Then, we evaluate the strength of this methodology by screening a cohort of patients with β-thalassemia. All examined reference DNA samples were unambiguously distinguished from each other. For the blinded test, the results were completely compatible with direct sequencing, performed after the HRMA. As HRMA represents a highly sensitive and high-throughput gene scanning method, it can provide timely diagnosis at low cost for effective clinical management of β-thalassemia.

  14. Unexpected gynecologic neoplasms in patients with proven or suspected BRCA-1 or -2 mutations: implications for gross examination, cytology, and clinical follow-up.

    Science.gov (United States)

    Agoff, S Nicholas; Mendelin, Joel E; Grieco, Verena S; Garcia, Rochelle L

    2002-02-01

    Identification of inheritable mutations associated with the development of malignancy has led to prophylactic surgeries to remove tissues at risk. We report seven unrelated patients with family histories of breast and/or ovarian cancer, five of whom underwent prophylactic salpingo-oophorectomy with hysterectomy. Four had proven BRCA-1 or -2 mutations. Malignant cells were found unexpectedly in the peritoneal washings of two patients, leading to the discovery of early-stage fallopian tube carcinoma. After changing the sampling technique at our institution, two more cases of unexpected fallopian tube carcinoma in situ were discovered. Another patient had a significant family history and underwent hysterectomy for uterine fibroids, leading to the discovery of fallopian tube carcinoma. Another patient with BRCA-1 mutation had unexpected widespread primary peritoneal papillary serous adenocarcinoma. The final patient had a borderline malignant clear cell adenofibroma. These cases underscore the importance of peritoneal cytology and thorough sampling in the management of patients undergoing hysterectomy with a family history of breast/ovarian cancer and/or known BRCA-1/BRCA-2 mutations. As prophylactic surgeries are becoming more common secondary to advances in molecular diagnostics, pathologists need to be aware that surgical specimens from these patients may require more rigorous examination to uncover early neoplastic changes.

  15. 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

    Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS) is a rare clinically distinct syndrome caused by a single dominant missense mutation, c.2452G>A, p.Glu818Lys, in ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase α3. Allelic ...

  16. 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...

  17. Rapid evolution of piRNA pathway in the teleost fish: implication for an adaptation to transposon diversity.

    Science.gov (United States)

    Yi, Minhan; Chen, Feng; Luo, Majing; Cheng, Yibin; Zhao, Huabin; Cheng, Hanhua; Zhou, Rongjia

    2014-05-19

    The Piwi-interacting RNA (piRNA) pathway is responsible for germline specification, gametogenesis, transposon silencing, and genome integrity. Transposable elements can disrupt genome and its functions. However, piRNA pathway evolution and its adaptation to transposon diversity in the teleost fish remain unknown. This article unveils evolutionary scene of piRNA pathway and its association with diverse transposons by systematically comparative analysis on diverse teleost fish genomes. Selective pressure analysis on piRNA pathway and miRNA/siRNA (microRNA/small interfering RNA) pathway genes between teleosts and mammals showed an accelerated evolution of piRNA pathway genes in the teleost lineages, and positive selection on functional PAZ (Piwi/Ago/Zwille) and Tudor domains involved in the Piwi-piRNA/Tudor interaction, suggesting that the amino acid substitutions are adaptive to their functions in piRNA pathway in the teleost fish species. Notably five piRNA pathway genes evolved faster in the swamp eel, a kind of protogynous hermaphrodite fish, than the other teleosts, indicating a differential evolution of piRNA pathway between the swamp eel and other gonochoristic fishes. In addition, genome-wide analysis showed higher diversity of transposons in the teleost fish species compared with mammals. Our results suggest that rapidly evolved piRNA pathway in the teleost fish is likely to be involved in the adaption to transposon diversity. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

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

    Directory of Open Access Journals (Sweden)

    Maria eMooshammer

    2014-02-01

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

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

    Science.gov (United States)

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

    2016-12-01

    One of the key advantages of adaptive licensing (AL) is to align the licensing of new medicines more closely with patient needs for earlier access to beneficial treatments. From an innovators perspective, "earlier" market access may seem an obvious incentive to gain earlier revenue generation. However, this is offset with an "earlier" start to patent and regulatory protection periods, which, depending on the technology, disease, population, and timing of subsequent asset protection periods, can present a conflict. © 2016 American Society for Clinical Pharmacology and Therapeutics.

  20. 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

  1. Implications of New Technological Adaptions on Switching Barriers: An Empirical Study of Mobile Telecommunication Subscribers in Sri Lanka

    Directory of Open Access Journals (Sweden)

    EACP Karunarathne

    2017-02-01

    Full Text Available With the technological advancements in the past few years in the mobile telecommunication industry, customer requirements and their behavioral patterns changed a lot. Implications of two of most popular such technological approaches which are independent from the service provider were discussed in this paper. Usually, firms have identified the value of maintaining a higher level of switching barriers since it is one kind of successful strategic aspects in mobile telecommunication. But, the importance of these strategies was challenged with the adoptions of new technologies. Therefore, to study its’ implication, data set was obtained by conducting a survey from randomly select mobile subscribers in Sri Lanka. Descriptive statistics, correlation analysis, t-test and factorial ANOVA test were used for the data analysis purpose. According to the analysis, it is revealed that these two technological advancements are weakened the level of switching barriers significantly. It may allow subscribers to switch service providers easily. On the other hand, subscribers with higher relationship age are having the highest switching barrier level even though they are users of those new technologies. But a significant difference among users and non-users has been identified through the study. Thus, policy makers are required to come up with new strategies to retain those subscribers within the network.

  2. 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.

  3. 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.

  4. Cell size variations of large granular lymphocyte leukemia: Implication of a small cell subtype of granular lymphocyte leukemia with STAT3 mutations.

    Science.gov (United States)

    Tanahashi, Takahiro; Sekiguchi, Nodoka; Matsuda, Kazuyuki; Takezawa, Yuka; Ito, Toshiro; Kobayashi, Hikaru; Ichikawa, Naoaki; Nishina, Sayaka; Senoo, Noriko; Sakai, Hitoshi; Nakazawa, Hideyuki; Ishida, Fumihiro

    2016-06-01

    Large granular lymphocyte leukemia (LGL-L) has been morphologically defined as a group of lymphoproliferative disorders, including T-cell large granular lymphocytic leukemia (T-LGL-L), chronic lymphoproliferative disorders of NK cells (CLPD-NK) and aggressive NK cell leukemia. We investigated the morphological features of LGL leukemic cells in 26 LGL-L patients in order to elucidate relationships with current classifications and molecular backgrounds. LGL-L cells were mostly indistinguishable from normal LGL. Patients with STAT3 SH2 domain mutations showed significantly smaller cells compared with patients without STAT3 mutations. Four patients with T-LGL-L showed smaller granular lymphocytes with a median diameter of less than 13μm, which were rarely seen in normal subjects. This small subtype of T-LGL-L was recognized among rather young patients and was associated with D661Y mutations in the STAT3 gene SH2 domain. In addition, all of them showed anemia including two cases with pure red cell aplasia. These results suggest the heterogeneity of T-LGL-L and a specific subtype with small variants of T-LGL-L. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Survival and growth patterns of white spruce (Picea glauca [Moench] Voss) rangewide provenances and their implications for climate change adaptation.

    Science.gov (United States)

    Lu, Pengxin; Parker, William H; Cherry, Marilyn; Colombo, Steve; Parker, William C; Man, Rongzhou; Roubal, Ngaire

    2014-06-01

    Intraspecific assisted migration (ISAM) through seed transfer during artificial forest regeneration has been suggested as an adaptation strategy to enhance forest resilience and productivity under future climate. In this study, we assessed the risks and benefits of ISAM in white spruce based on long-term and multilocation, rangewide provenance test data. Our results indicate that the adaptive capacity and growth potential of white spruce varied considerably among 245 range-wide provenances sampled across North America; however, the results revealed that local populations could be outperformed by nonlocal ones. Provenances originating from south-central Ontario and southwestern Québec, Canada, close to the southern edge of the species' natural distribution, demonstrated superior growth in more northerly environments compared with local populations and performed much better than populations from western Canada and Alaska, United States. During the 19-28 years between planting and measurement, the southern provenances have not been more susceptible to freezing damage compared with local populations, indicating they have the potential to be used now for the reforestation of more northerly planting sites; based on changing temperature, these seed sources potentially could maintain or increase white spruce productivity at or above historical levels at northern sites. A universal response function (URF), which uses climatic variables to predict provenance performance across field trials, indicated a relatively weak relationship between provenance performance and the climate at provenance origin. Consequently, the URF from this study did not provide information useful to ISAM. The ecological and economic importance of conserving white spruce genetic resources in south-central Ontario and southwestern Québec for use in ISAM is discussed.

  6. 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.

  7. Modeled Sea Level Rise Impacts on Coastal Ecosystems at Six Major Estuaries on Florida's Gulf Coast: Implications for Adaptation Planning.

    Directory of Open Access Journals (Sweden)

    Laura L Geselbracht

    Full Text Available The Sea Level Affecting Marshes Model (SLAMM was applied at six major estuaries along Florida's Gulf Coast (Pensacola Bay, St. Andrews/Choctawhatchee Bays, Apalachicola Bay, Southern Big Bend, Tampa Bay and Charlotte Harbor to provide quantitative and spatial information on how coastal ecosystems may change with sea level rise (SLR and to identify how this information can be used to inform adaption planning. High resolution LiDAR-derived elevation data was utilized under three SLR scenarios: 0.7 m, 1 m and 2 m through the year 2100 and uncertainty analyses were conducted on selected input parameters at three sites. Results indicate that the extent, spatial orientation and relative composition of coastal ecosystems at the study areas may substantially change with SLR. Under the 1 m SLR scenario, total predicted impacts for all study areas indicate that coastal forest (-69,308 ha; -18%, undeveloped dry land (-28,444 ha; -2% and tidal flat (-25,556 ha; -47% will likely face the greatest loss in cover by the year 2100. The largest potential gains in cover were predicted for saltmarsh (+32,922 ha; +88%, transitional saltmarsh (+23,645 ha; na and mangrove forest (+12,583 ha; +40%. The Charlotte Harbor and Tampa Bay study areas were predicted to experience the greatest net loss in coastal wetlands The uncertainty analyses revealed low to moderate changes in results when some numerical SLAMM input parameters were varied highlighting the value of collecting long-term sedimentation, accretion and erosion data to improve SLAMM precision. The changes predicted by SLAMM will affect exposure of adjacent human communities to coastal hazards and ecosystem functions potentially resulting in impacts to property values, infrastructure investment and insurance rates. The results and process presented here can be used as a guide for communities vulnerable to SLR to identify and prioritize adaptation strategies that slow and/or accommodate the changes underway.

  8. 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.

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

    Directory of Open Access Journals (Sweden)

    Luis Cisneros

    response to 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.

  10. Human migration to space: Alternative technological approaches for long-term adaptation to extraterrestrial environments and the implications for human evolution

    Science.gov (United States)

    Lockard, Elizabeth Song

    As humans embark upon the next phase of Space exploration---establishing human outposts in low-Earth orbit, on the Moon, and on Mars---the scope of human factors must expand beyond the meager requirements for short-term missions to Space to include issues of comfort and well-being necessary for long-term durations. However, to habitate---to dwell in a place---implies more than creature comforts in order to adapt. Human factors research must also include a phenomenological perspective---an understanding of how we experience the places we live in---in order for a community to be robust and to thrive. The first phase of migration will be an especially tenuous one requiring intensive technological intervention. The modes by which those technologies are implemented will have significant bearing on the process of human adaptation: the nature of the mediation can be either one of domination, subordination, avoidance, or integration. Ultimately, adaptation is best ensured if symbiotic processes of negotiation and cooperation between subject and environment are espoused over acts of conquest or acquiescence. The adaptive mechanisms we choose to develop and employ will have wider implications for long-range human evolution. The transformations we will undergo will be influenced by both the initial decision to migrate to Space (technological), as well as the actual conditions of Space (environmental). Migration to extraterrestrial environments will be unequivocally the most profound catalyst for evolution in the history of humankind---not only for the human species itself but also for the new environments we will eventually inhabit. At the same time, we also find ourselves---via a new generation of bio-, nano-, and digital technologies---in the position to consciously and willfully direct our own evolution. Technology has always been transformative, but in the not-so-distant future, we will soon possess the capacity to radically re-invent ourselves in almost any way

  11. Adaptation of High-Growth Influenza H5N1 Vaccine Virus in Vero Cells: Implications for Pandemic Preparedness

    Science.gov (United States)

    Huang, Mei-Liang; Yeh, Wei-Zhou; Weng, Tsai-Chuan; Chen, Yu-Shuan; Chong, Pele; Lee, Min-Shi

    2011-01-01

    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 108 TCID50/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. PMID:22022351

  12. 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.

  13. Sheep grazing causes shift in sex ratio and cohort structure of Brandt's vole: Implication of their adaptation to food shortage.

    Science.gov (United States)

    Li, Guoliang; Hou, Xianglei; Wan, Xinrong; Zhang, Zhibin

    2016-01-01

    Livestock grazing has been demonstrated to affect the population abundance of small rodents in grasslands, but the causative mechanism of grazing on demographic parameters, particularly the age structure and sex ratio, is rarely investigated. In this study, we examined the effects of sheep grazing on the cohort structure and sex ratio of Brandt's vole (Lasiopodomys brandtii) in Inner Mongolia of China by using large manipulative experimental enclosures during 2010-2013. Our results indicated that sheep grazing significantly decreased the proportion of the spring-born cohort, but increased the proportion of the summer-born cohort. Grazing increased the proportion of males in both spring and summer cohorts. In addition, we found a negative relation between population density and the proportion of the overwinter cohort. Our results suggest that a shift in the cohort structure and the sex ratio may be an important strategy for small rodents to adapt to changes in food resources resulting from livestock grazing. © 2015 International Society of Zoological Sciences, Institute of Zoology/Chinese Academy of Sciences and John Wiley & Sons Australia, Ltd.

  14. Histology of selected tissues of the leopard seal and implications for functional adaptations to an aquatic lifestyle.

    Science.gov (United States)

    Gray, Rachael; Canfield, Paul; Rogers, Tracey

    2006-08-01

    The microscopic anatomy of the cardio-respiratory system, digestive system, kidney, lymphatic system and integument was investigated in the leopard seal, Hydrurga leptonyx, by examining histological sections of tissues collected from leopard seals in Antarctica and New South Wales, Australia. The majority of the tissues had similar histological features to those described in terrestrial mammals and other pinniped species, particularly phocid seals. Differences noted included readily identifiable Purkinje cells within the endocardium, muscular rather than cartilaginous reinforcement of the smaller airways, a single capillary layer within the alveolar septa, limited and variable keratinization of the oesophageal epithelium, few lymphoid follicles within the lamina propria of the gastrointestinal tract, and an absence of a sporta perimedullaris musculosa described in the kidney of cetaceans and some pinniped species. Adaptations of the lung, spleen and integument, similar to those described in other pinnipeds, including reinforcement of the pulmonary terminal airways, prominent pulmonary interlobular septa, ample smooth muscle in the capsule and trabeculae of the spleen, increased thickness of the epidermis, well-developed dermal sebaceous glands, and a thick blubber layer, appear to confer upon the leopard seal advantages related to its aquatic lifestyle.

  15. 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

  16. 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.

  17. Different adaptations of IgG effector function in human and nonhuman primates and implications for therapeutic antibody treatment.

    Science.gov (United States)

    Warncke, Max; Calzascia, Thomas; Coulot, Michele; Balke, Nicole; Touil, Ratiba; Kolbinger, Frank; Heusser, Christoph

    2012-05-01

    Safety of human therapeutic Abs is generally assessed in nonhuman primates. Whereas IgG1 shows identical FcγR interaction and effector function profile in both species, fundamental differences in the IgG2 and IgG4 Ab subclasses were found between the two species. Granulocytes, the main effector cells against IgG2- and IgG4-opsonized bacteria and parasites, do not express FcγRIIIb, but show higher levels of FcγRII in cynomolgus monkey. In humans, IgG2 and IgG4 adapted a silent Fc region with weak binding to FcγR and effector functions, whereas, in contrast, cynomolgus monkey IgG2 and IgG4 display strong effector function as well as differences in IgG4 Fab arm exchange. To balance this shift toward activation, the cynomolgus inhibitory FcγRIIb shows strongly increased affinity for IgG2. In view of these findings, in vitro and in vivo results for human IgG2 and IgG4 obtained in the cynomolgus monkey have to be cautiously interpreted, whereas effector function-related effects of human IgG1 Abs are expected to be predictable for humans.

  18. Mitigation/adaptation and health: health policymaking in the global response to climate change and implications for other upstream determinants.

    Science.gov (United States)

    Wiley, Lindsay F

    2010-01-01

    The time is ripe for innovation in global health governance if we are to achieve global health and development objectives in the face of formidable challenges. Integration of global health concerns into the law and governance of other, related disciplines should be given high priority. This article explores opportunities for health policymaking in the global response to climate change. Climate change and environmental degradation will affect weather disasters, food and water security, infectious disease patterns, and air pollution. Although scientific research has pointed to the interdependence of the global environment and human health, policymakers have been slow to integrate their approaches to environmental and health concerns. A robust response to climate change will require improved integration on two fronts: health concerns must be given higher priority in the response to climate change and threats associated with climate change and environmental degradation must be more adequately addressed by global health law and governance. The mitigation/adaptation response paradigm developing within and beyond the United Nations Framework Convention on Climate Change provides a useful framework for thinking about global health law and governance with respect to climate change, environmental degradation, and possibly other upstream determinants of health as well. © 2010 American Society of Law, Medicine & Ethics, Inc.

  19. Natural colonization and adaptation of a mosquito species in Galapagos and its implications for disease threats to endemic wildlife.

    Science.gov (United States)

    Bataille, Arnaud; Cunningham, Andrew A; Cedeño, Virna; Patiño, Leandro; Constantinou, Andreas; Kramer, Laura D; Goodman, Simon J

    2009-06-23

    Emerging infectious diseases of wildlife have been recognized as a major threat to global biodiversity. Endemic species on isolated oceanic islands, such as the Galápagos, are particularly at risk in the face of introduced pathogens and disease vectors. The black salt-marsh mosquito (Aedes taeniorhynchus) is the only mosquito widely distributed across the Galápagos Archipelago. Here we show that this mosquito naturally colonized the Galápagos before the arrival of man, and since then it has evolved to represent a distinct evolutionary unit and has adapted to habitats unusual for its coastal progenitor. We also present evidence that A. taeniorhynchus feeds on reptiles in Galápagos in addition to previously reported mammal and bird hosts, highlighting the important role this mosquito might play as a bridge-vector in the transmission and spread of extant and newly introduced diseases in the Galápagos Islands. These findings are particularly pertinent for West Nile virus, which can cause significant morbidity and mortality in mammals (including humans), birds, and reptiles, and which recently has spread from an introductory focus in New York to much of the North and South American mainland and could soon reach the Galápagos Islands. Unlike Hawaii, there are likely to be no highland refugia free from invading mosquito-borne diseases in Galápagos, suggesting bleak outcomes to possible future pathogen introduction events.

  20. Mutational analysis of the flagellar protein FliG: sites of interaction with FliM and implications for organization of the switch complex.

    Science.gov (United States)

    Brown, Perry N; Terrazas, Moises; Paul, Koushik; Blair, David F

    2007-01-01

    The switch complex at the base of the bacterial flagellum is essential for flagellar assembly, rotation, and switching. In Escherichia coli and Salmonella, the complex contains about 26 copies of FliG, 34 copies of FliM, and more then 100 copies of FliN, together forming the basal body C ring. FliG is involved most directly in motor rotation and is located in the upper (membrane-proximal) part of the C ring. A crystal structure of the middle and C-terminal parts of FliG shows two globular domains connected by an alpha-helix and a short extended segment. The middle domain of FliG has a conserved surface patch formed by the residues EHPQ(125-128) and R(160) (the EHPQR motif), and the C-terminal domain has a conserved surface hydrophobic patch. To examine the functional importance of these and other surface features of FliG, we made mutations in residues distributed over the protein surface and measured the effects on flagellar assembly and function. Mutations preventing flagellar assembly occurred mainly in the vicinity of the EHPQR motif and the hydrophobic patch. Mutations causing aberrant clockwise or counterclockwise motor bias occurred in these same regions and in the waist between the upper and lower parts of the C-terminal domain. Pull-down assays with glutathione S-transferase-FliM showed that FliG interacts with FliM through both the EHPQR motif and the hydrophobic patch. We propose a model for the organization of FliG and FliM subunits that accounts for the FliG-FliM interactions identified here and for the different copy numbers of FliG and FliM in the flagellum.

  1. Projecting Future Land Use Changes in West Africa Driven by Climate and Socioeconomic Factors: Uncertainties and Implications for Adaptation

    Science.gov (United States)

    Wang, G.; Ahmed, K. F.; You, L.

    2015-12-01

    Land use changes constitute an important regional climate change forcing in West Africa, a region of strong land-atmosphere coupling. At the same time, climate change can be an important driver for land use, although its importance relative to the impact of socio-economic factors may vary significant from region to region. This study compares the contributions of climate change and socioeconomic development to potential future changes of agricultural land use in West Africa and examines various sources of uncertainty using a land use projection model (LandPro) that accounts for the impact of socioeconomic drivers on the demand side and the impact of climate-induced crop yield changes on the supply side. Future crop yield changes were simulated by a process-based crop model driven with future climate projections from a regional climate model, and future changes of food demand is projected using a model for policy analysis of agricultural commodities and trade. The impact of human decision-making on land use was explicitly considered through multiple "what-if" scenarios to examine the range of uncertainties in projecting future land use. Without agricultural intensification, the climate-induced decrease of crop yield together with increase of food demand are found to cause a significant increase in agricultural land use at the expense of forest and grassland by the mid-century, and the resulting land use land cover changes are found to feed back to the regional climate in a way that exacerbates the negative impact of climate on crop yield. Analysis of results from multiple decision-making scenarios suggests that human adaptation characterized by science-informed decision making to minimize land use could be very effective in many parts of the region.

  2. The structural rigidity of the cranium of Australopithecus africanus: implications for diet, dietary adaptations, and the allometry of feeding biomechanics.

    Science.gov (United States)

    Strait, David S; Grosse, Ian R; Dechow, Paul C; Smith, Amanda L; Wang, Qian; Weber, Gerhard W; Neubauer, Simon; Slice, Dennis E; Chalk, Janine; Richmond, Brian G; Lucas, Peter W; Spencer, Mark A; Schrein, Caitlin; Wright, Barth W; Byron, Craig; Ross, Callum F

    2010-04-01

    Australopithecus africanus is an early hominin (i.e., human relative) believed to exhibit stress-reducing adaptations in its craniofacial skeleton that may be related to the consumption of resistant food items using its premolar teeth. Finite element analyses simulating molar and premolar biting were used to test the hypothesis that the cranium of A. africanus is structurally more rigid than that of Macaca fascicularis, an Old World monkey that lacks derived australopith facial features. Previously generated finite element models of crania of these species were subjected to isometrically scaled loads, permitting a direct comparison of strain magnitudes. Moreover, strain energy (SE) in the models was compared after results were scaled to account for differences in bone volume and muscle forces. Results indicate that strains in certain skeletal regions below the orbits are higher in M. fascicularis than in A. africanus. Moreover, although premolar bites produce von Mises strains in the rostrum that are elevated relative to those produced by molar biting in both species, rostral strains are much higher in the macaque than in the australopith. These data suggest that at least the midface of A. africanus is more rigid than that of M. fascicularis. Comparisons of SE reveal that the A. africanus cranium is, overall, more rigid than that of M. fascicularis during premolar biting. This is consistent with the hypothesis that this hominin may have periodically consumed large, hard food items. However, the SE data suggest that the A. africanus cranium is marginally less rigid than that of the macaque during molar biting. It is hypothesized that the SE results are being influenced by the allometric scaling of cranial cortical bone thickness. (c) 2010 Wiley-Liss, Inc.

  3. 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

  4. Restoration of correct splicing in IVSI-110 mutation of β-globin gene with antisense oligonucleotides: implications and applications in functional assay development

    Directory of Open Access Journals (Sweden)

    Sima Mansoori Derakhshan

    2017-06-01

    Full Text Available Objective(s: The use of antisense oligonucleotides (AOs to restore normal splicing by blocking the recognition of aberrant splice sites by the spliceosome represents an innovative means of potentially controlling certain inherited disorders affected by aberrant splicing. Selection of the appropriate target site is essential in the success of an AO therapy. In this study, in search for a splice model system to facilitate the evaluation of AOs to redirect defective splicing of IVSI-110 β-globin intron, an EGFP-based IVSI-110 specific cellular reporter assay system has been developed and a number of AOs were tested in this cellular splicing assay. Materials and Methods: A recombinant plasmid (pEGFP/I-110 carrying the EGFP gene interrupted by a mutated human β-globin intron 1 (IVSI-110 was developed and transfected into K562 cells. A number of AOs with a 2’-O-methyl oligoribonucleotide (2’-O-Me backbone system were systematically tested in this cellular splicing assay. Results: The mutation in the intron causes aberrant splicing of EGFP pre-mRNA, preventing translation of EGFP; however, treatment of the cells with specific concentration of a sequence specific 2’-O-Me AO targeted to the aberrant splice site induced correct splicing and resulted in restoring of EGFP activity. Conclusion: This cellular splicing assay provides a novel functional assay system in assessing the cellular delivery efficiency of AOs and therapeutic effect of AOs in restoration of aberrant splicing.

  5. 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

  6. 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......) entry. We investigated receptor usage by antibody blocking and receptor silencing in Huh7.5 cells, followed by inoculation of parental and HVR1-deleted HCV recombinants. Compared to parental viruses, scavenger receptor class B type I (SR-BI) dependency was decreased for H77(ΔHVR1/N476D/S733F), H77(N476D....../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...

  7. Markov models for accumulating mutations

    CERN Document Server

    Beerenwinkel, Niko

    2007-01-01

    We introduce and analyze a waiting time model for the accumulation of genetic changes. The continuous time conjunctive Bayesian network is defined by a partially ordered set of mutations and by the rate of fixation of each mutation. The partial order encodes constraints on the order in which mutations can fixate in the population, shedding light on the mutational pathways underlying the evolutionary process. We study a censored version of the model and derive equations for an EM algorithm to perform maximum likelihood estimation of the model parameters. We also show how to select the maximum likelihood poset. The model is applied to genetic data from different cancers and from drug resistant HIV samples, indicating implications for diagnosis and treatment.

  8. Diverse Drought Spatiotemporal Trends, Diverse Etic-Emic Perceptions and Knowledge: Implications for Adaptive Capacity and Resource Management for Indigenous Maasai-Pastoralism in the Rangelands of Kenya

    Directory of Open Access Journals (Sweden)

    Margaret Mwangi

    2016-04-01

    Full Text Available The study examined the spatiotemporal distribution of drought in the Maasai rangelands of Kenya. The implications of this distribution, in concert with the documented existing and/or projected social and biophysical factors, on critical rangeland resources in Maasai-pastoralism are discussed using an integrated approach. Participatory interviews with the Maasai, retrieval from archives, and acquisition from instrument measurements provided data for the study. Empirical evidence of the current study reveals that drought occurrences in this rangeland have been recurrent, widespread, cyclic, sometimes temporally clustered, and have manifested with varying intensities across spatial, temporal, and, occasionally, social scales; and they have more intensity in lower than higher agroecological areas. An estimated 86% of drought occurrences in this rangeland, over the last three decades alone, were of major drought category. The 2000s, with four major drought events including two extreme droughts, are an important drought period. A strong consensus exists among the Maasai regarding observed drought events. In Maasai-pastoralism, the phenomenon called drought, pastoralist drought, is simultaneously multivariate and multiscalar: its perception comprises the simultaneous manifestation of cross-scale meteorological, socioeconomic, and environmental factors and processes, and their various combinations. The inherent simultaneous multivariate and scalar nature of the pastoralist drought distinguishes it from the conventional drought types, particularly the meteorological drought that predominantly guides drought and resource management in the rangelands of Kenya. In Maasai-pastoralism, the scarcely used (33% meteorological drought is construed as rainfall delay/failure across spatial and/or temporal scale, and never its reduced amount. Collectively, the current findings reveal that knowledge about drought affects the way the manifestation of this climatic

  9. The spectrum of KIAA0196 variants, and characterization of a murine knockout: implications for the mutational mechanism in hereditary spastic paraplegia type SPG8.

    Science.gov (United States)

    Jahic, Amir; Khundadze, Mukhran; Jaenisch, Nadine; Schüle, Rebecca; Klimpe, Sven; Klebe, Stephan; Frahm, Christiane; Kassubek, Jan; Stevanin, Giovanni; Schöls, Ludger; Brice, Alexis; Hübner, Christian A; Beetz, Christian

    2015-11-16

    The hereditary spastic paraplegias (HSPs) are rare neurodegenerative gait disorders which are genetically highly heterogeneous. For each single form, eventual consideration of therapeutic strategies requires an understanding of the mechanism by which mutations confer pathogenicity. SPG8 is a dominantly inherited HSP, and associated with rather early onset and rapid progression. A total of nine mutations in KIAA0196, which encodes the WASH regulatory complex (SHRC) member strumpellin, have been reported in SPG8 patients so far. Based on biochemical and cell biological approaches, they have been suggested to act via loss of function-mediated haploinsufficiency. We generated a deletion-based knockout allele for E430025E21Rik, i.e. the murine homologue of KIAA0196. The consequences on mRNA and protein levels were analyzed by qPCR and Western-blotting, respectively. Motor performance was evaluated by the foot-base angle paradigm. Axon outgrowth and relevant organelle compartments were investigated in primary neuron cultures and primary fibroblast cultures, respectively. A homemade multiplex ligation-dependent probe amplification assay enabling identification of large inactivating KIAA0196 deletion alleles was applied to DNA from 240 HSP index patients. Homozygous but not heterozygous mice showed early embryonic lethality. No transcripts from the knockout allele were detected, and the previously suggested compensation by the wild-type allele upon heterozygosity was disproven. mRNA expression of genes encoding other SHRC members was unaltered, while there was evidence for reduced SHRC abundance at protein level. We did, however, neither observe HSP-related in vivo and ex vivo phenotypes, nor alterations affecting endosomal, lysosomal, or autophagic compartments. KIAA0196 copy number screening excluded large inactivating deletion mutations in HSP patients. The consequences of monoallelic KIAA0196/E430025E21Rik activation thus differ from those observed for dominant HSP

  10. 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

  11. Evolutionary Accessibility of Mutational Pathways

    Science.gov (United States)

    Franke, Jasper; Klözer, Alexander; de Visser, J. Arjan G. M.; Krug, Joachim

    2011-01-01

    Functional effects of different mutations are known to combine to the total effect in highly nontrivial ways. For the trait under evolutionary selection (‘fitness’), measured values over all possible combinations of a set of mutations yield a fitness landscape that determines which mutational states can be reached from a given initial genotype. Understanding the accessibility properties of fitness landscapes is conceptually important in answering questions about the predictability and repeatability of evolutionary adaptation. Here we theoretically investigate accessibility of the globally optimal state on a wide variety of model landscapes, including landscapes with tunable ruggedness as well as neutral ‘holey’ landscapes. We define a mutational pathway to be accessible if it contains the minimal number of mutations required to reach the target genotype, and if fitness increases in each mutational step. Under this definition accessibility is high, in the sense that at least one accessible pathway exists with a substantial probability that approaches unity as the dimensionality of the fitness landscape (set by the number of mutational loci) becomes large. At the same time the number of alternative accessible pathways grows without bounds. We test the model predictions against an empirical 8-locus fitness landscape obtained for the filamentous fungus Aspergillus niger. By analyzing subgraphs of the full landscape containing different subsets of mutations, we are able to probe the mutational distance scale in the empirical data. The predicted effect of high accessibility is supported by the empirical data and is very robust, which we argue reflects the generic topology of sequence spaces. Together with the restrictive assumptions that lie in our definition of accessibility, this implies that the globally optimal configuration should be accessible to genome wide evolution, but the repeatability of evolutionary trajectories is limited owing to the presence of a

  12. A P-loop mutation in Gα subunits prevents transition to the active state: implications for G-protein signaling in fungal pathogenesis.

    Directory of Open Access Journals (Sweden)

    Dustin E Bosch

    2012-02-01

    Full Text Available Heterotrimeric G-proteins are molecular switches integral to a panoply of different physiological responses that many organisms make to environmental cues. The switch from inactive to active Gαβγ heterotrimer relies on nucleotide cycling by the Gα subunit: exchange of GTP for GDP activates Gα, whereas its intrinsic enzymatic activity catalyzes GTP hydrolysis to GDP and inorganic phosphate, thereby reverting Gα to its inactive state. In several genetic studies of filamentous fungi, such as the rice blast fungus Magnaporthe oryzae, a G42R mutation in the phosphate-binding loop of Gα subunits is assumed to be GTPase-deficient and thus constitutively active. Here, we demonstrate that Gα(G42R mutants are not GTPase deficient, but rather incapable of achieving the activated conformation. Two crystal structure models suggest that Arg-42 prevents a typical switch region conformational change upon Gα(i1(G42R binding to GDP·AlF(4(- or GTP, but rotameric flexibility at this locus allows for unperturbed GTP hydrolysis. Gα(G42R mutants do not engage the active state-selective peptide KB-1753 nor RGS domains with high affinity, but instead favor interaction with Gβγ and GoLoco motifs in any nucleotide state. The corresponding Gα(q(G48R mutant is not constitutively active in cells and responds poorly to aluminum tetrafluoride activation. Comparative analyses of M. oryzae strains harboring either G42R or GTPase-deficient Q/L mutations in the Gα subunits MagA or MagB illustrate functional differences in environmental cue processing and intracellular signaling outcomes between these two Gα mutants, thus demonstrating the in vivo functional divergence of G42R and activating G-protein mutants.

  13. A P-loop Mutation in G[alpha] Subunits Prevents Transition to the Active State: Implications for G-protein Signaling in Fungal Pathogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Bosch, Dustin E.; Willard, Francis S.; Ramanujam, Ravikrishna; Kimple, Adam J.; Willard, Melinda D.; Naqvi, Naweed I.; Siderovski, David P. (UNC); (Singapore)

    2012-10-23

    Heterotrimeric G-proteins are molecular switches integral to a panoply of different physiological responses that many organisms make to environmental cues. The switch from inactive to active G{alpha}{beta}{gamma} heterotrimer relies on nucleotide cycling by the G{alpha} subunit: exchange of GTP for GDP activates G{alpha}, whereas its intrinsic enzymatic activity catalyzes GTP hydrolysis to GDP and inorganic phosphate, thereby reverting G{alpha} to its inactive state. In several genetic studies of filamentous fungi, such as the rice blast fungus Magnaporthe oryzae, a G42R mutation in the phosphate-binding loop of G{alpha} subunits is assumed to be GTPase-deficient and thus constitutively active. Here, we demonstrate that G{alpha}(G42R) mutants are not GTPase deficient, but rather incapable of achieving the activated conformation. Two crystal structure models suggest that Arg-42 prevents a typical switch region conformational change upon G{alpha}{sub i1}(G42R) binding to GDP {center_dot} AlF{sub 4}{sup -} or GTP, but rotameric flexibility at this locus allows for unperturbed GTP hydrolysis. G{alpha}(G42R) mutants do not engage the active state-selective peptide KB-1753 nor RGS domains with high affinity, but instead favor interaction with G{beta}{gamma} and GoLoco motifs in any nucleotide state. The corresponding G{alpha}{sub q}(G48R) mutant is not constitutively active in cells and responds poorly to aluminum tetrafluoride activation. Comparative analyses of M. oryzae strains harboring either G42R or GTPase-deficient Q/L mutations in the G{alpha} subunits MagA or MagB illustrate functional differences in environmental cue processing and intracellular signaling outcomes between these two G{alpha} mutants, thus demonstrating the in vivo functional divergence of G42R and activating G-protein mutants.

  14. Kinetic analysis of a Saccharomyces cerevisiae strain adapted for improved growth on glycerol: Implications for the development of yeast bioprocesses on glycerol.

    Science.gov (United States)

    Ochoa-Estopier, A; Lesage, J; Gorret, N; Guillouet, S E

    2011-01-01

    Glycerol is an agro-industrial residue generated in high amounts during the biodiesel production. The growing production of biodiesel is creating a worldwide glycerol surplus. Therefore, replacing sugar-based feedstock in bioprocesses by glycerol could be potentially attractive. Saccharomyces cerevisiae is one of the most commonly used microorganisms in the agri-food industry and therefore currently produced in large quantities from sugar-based feedstock. Unfortunately, growth of S. cerevisiae strains on glycerol is very low with reported μmax around 0.01 h(-1). This study demonstrates that successive growth of the S. cerevisiae CBS 8066, CEN.PK 113-7 D and Ethanol Red on glycerol as sole carbon source considerably improved the μmax from 0.01 up to 0.2 h(-1). The "adapted strain" CBS 8066-FL20 was kinetically characterized during aerobic and oxygen-limited cultivation in bioreactor and the results discussed in terms of their implication for developing glycerol-based S. cerevisiae bioprocesses. Copyright © 2010 Elsevier Ltd. All rights reserved.

  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. Molecular evolution of rbcL in three gymnosperm families: identifying adaptive and coevolutionary patterns.

    Science.gov (United States)

    Sen, Lin; Fares, Mario A; Liang, Bo; Gao, Lei; Wang, Bo; Wang, Ting; Su, Ying-Juan

    2011-06-03

    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. 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. 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 mutations put forward the conclusion that

  17. Molecular evolution of rbcL in three gymnosperm families: identifying adaptive and coevolutionary patterns

    Directory of Open Access Journals (Sweden)

    Gao Lei

    2011-06-01

    implications of such mutations put forward the conclusion that this evolutionary scenario has been possible through a complex interplay between adaptive mutations, often structurally destabilizing, and compensatory mutations. Our results unearth patterns of evolution that have likely optimized the Rubisco activity and uncover mutational dynamics useful in the molecular engineering of enzymatic activities. Reviewers This article was reviewed by Prof. Christian Blouin (nominated by Dr W Ford Doolittle, Dr Endre Barta (nominated by Dr Sandor Pongor, and Dr Nicolas Galtier.

  18. 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...... mutations during ageing....

  19. Fitness seascapes and adaptive evolution of the influenza virus

    Science.gov (United States)

    Lassig, Michael

    2014-03-01

    The seasonal human influenza A virus undergoes rapid genome evolution. This process is triggered by interactions with the host immune system and produces significant year-to-year sequence turnover in the population of circulating viral strains. We develop a dynamical fitness model that predicts the evolution of the viral population from one year to the next. Two factors are shown to determine the fitness of a viral strain: adaptive changes, which are under positive selection, and deleterious mutations, which affect conserved viral functions such as protein stability. Combined with the influenza strain tree, this fitness model maps the adaptive history of influenza A. We discuss the implications of our results for the statistical theory of adaptive evolution in asexual populations. Based on this and related systems, we touch upon the fundamental question of when evolution can be predicted. Joint work with Marta Luksza, Columbia University.

  20. Mutations in the capsid protein of Brome mosaic virus affecting encapsidation eliminate vesicle induction in planta: implications for virus cell-to-cell spread.

    Science.gov (United States)

    Bamunusinghe, Devinka; Chaturvedi, Sonali; Seo, Jang-Kyun; Rao, A L N

    2013-08-01

    Positive-strand RNA viruses are known to rearrange the endomembrane network to make it more conducive for replication, maturation, or egress. Our previous transmission electron microscopic (TEM) analysis showed that ectopic expression of wild-type (wt) capsid protein (CP) of Brome mosaic virus (BMV) has an intrinsic property of modifying the endoplasmic reticulum (ER) to induce vesicles similar to those present in wt BMV infection. In this study, we evaluated the functional significance of CP-mediated vesicle induction to the BMV infection cycle in planta. Consequently, the cytopathologic changes induced by wt CP or its mutants defective in virion assembly due to mutations engineered in either N- or C-proximal domains were comparatively analyzed by TEM in two susceptible (Nicotiana benthamiana and Chenopodium quinoa) and one nonhost (N. clevelandii) plant species. The results showed that in susceptible hosts, CP-mediated ER-derived vesicle induction is contingent on the expression of encapsidation-competent CP. In contrast, unlike in N. benthamiana and C. quinoa, transient expression of wt CP in nonhost N. clevelandii plants eliminated vesicle induction. Additionally, comparative source-to-sink analysis of virus spread in leaves of N. benthamiana and N. clevelandii coexpressing wt BMV and Cucumber mosaic virus (CMV) showed that despite trans-encapsidation, CMV failed to complement the defective cell-to-cell movement of BMV. The significance and relation of CP-mediated vesicle induction to virus cell-to-cell movement are discussed.

  1. Mutational profiling reveals PIK3CA mutations in gallbladder carcinoma

    Directory of Open Access Journals (Sweden)

    Bardeesy Nabeel

    2011-02-01

    Full Text Available Abstract Background The genetics of advanced biliary tract cancers (BTC, which encompass intra- and extra-hepatic cholangiocarcinomas as well as gallbladder carcinomas, are heterogeneous and remain to be fully defined. Methods To better characterize mutations in established known oncogenes and tumor suppressor genes we tested a mass spectrometric based platform to interrogate common cancer associated mutations across a panel of 77 formalin fixed paraffin embedded archived BTC cases. Results Mutations among three genes, KRAS, NRAS and PIK3CA were confirmed in this cohort. Activating mutations in PIK3CA were identified exclusively in GBC (4/32, 12.5%. KRAS mutations were identified in 3 (13% intra-hepatic cholangiocarcinomas and 1 (33% perihillar cholangiocarcinoma but were not identified in gallbladder carcinomas and extra-hepatic cholangiocarcinoma. Conclusions The presence of activating mutations in PIK3CA specifically in GBC has clinical implications in both the diagnosis of this cancer type, as well as the potential utility of targeted therapies such as PI3 kinase inhibitors.

  2. 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.

  3. Adaptive Genetic Algorithm

    OpenAIRE

    Jakobović, Domagoj; Golub, Marin

    1999-01-01

    In this paper we introduce an adaptive, 'self-contained' genetic algorithm (GA) with steady-state selection. This variant of GA utilizes empirically based methods for calculating its control parameters. The adaptive algorithm estimates the percentage of the population to be replaced with new individuals (generation gap). It chooses the solutions for crossover and varies the number of mutations, ail regarding the current population state. The state of the population is evaluated by observing s...

  4. Crystal structure and mutational analysis of the Saccharomyces cerevisiae cell cycle regulatory protein Cks1: implications for domain swapping, anion binding and protein interactions.

    Science.gov (United States)

    Bourne, Y; Watson, M H; Arvai, A S; Bernstein, S L; Reed, S I; Tainer, J A

    2000-08-15

    The Saccharomyces cerevisiae protein Cks1 (cyclin-dependent kinase subunit 1) is essential for cell-cycle progression. The biological function of Cks1 can be modulated by a switch between two distinct molecular assemblies: the single domain fold, which results from the closing of a beta-hinge motif, and the intersubunit beta-strand interchanged dimer, which arises from the opening of the beta-hinge motif. The crystal structure of a cyclin-dependent kinase (Cdk) in complex with the human Cks homolog CksHs1 single-domain fold revealed the importance of conserved hydrophobic residues and charged residues within the beta-hinge motif. The 3.0 A resolution Cks1 structure reveals the strict structural conservation of the Cks alpha/beta-core fold and the beta-hinge motif. The beta hinge identified in the Cks1 structure includes a novel pivot and exposes a cluster of conserved tyrosine residues that are involved in Cdk binding but are sequestered in the beta-interchanged Cks homolog suc1 dimer structure. This Cks1 structure confirms the conservation of the Cks anion-binding site, which interacts with sidechain residues from the C-terminal alpha helix of another subunit in the crystal. The Cks1 structure exemplifies the conservation of the beta-interchanged dimer and the anion-binding site in evolutionarily distant yeast and human Cks homologs. Mutational analyses including in vivo rescue of CKS1 disruption support the dual functional roles of the beta-hinge residue Glu94, which participates in Cdk binding, and of the anion-binding pocket that is located 22 A away and on an opposite face to Glu94. The Cks1 structure suggests a biological role for the beta-interchanged dimer and the anion-binding site in targeting Cdks to specific phosphoproteins during cell-cycle progression.

  5. Norm comparisons of the Spanish-language and English-language WAIS-III: Implications for clinical assessment and test adaptation.

    Science.gov (United States)

    Funes, Cynthia M; Rodriguez, Juventino Hernandez; Lopez, Steven Regeser

    2016-12-01

    This study provides a systematic comparison of the norms of 3 Spanish-language Wechsler Adult Intelligence Scales (WAIS-III) batteries from Mexico, Spain, and Puerto Rico, and the U.S. English-language WAIS-III battery. Specifically, we examined the performance of the 4 normative samples on 2 identical subtests (Digit Span and Digit Symbol-Coding) and 1 nearly identical subtest (Block Design). We found that across most age groups the means associated with the Spanish-language versions of the 3 subtests were lower than the means of the U.S. English-language version. In addition, we found that for most age ranges the Mexican subsamples scored lower than the Spanish subsamples. Lower educational levels of Mexicans and Spaniards compared to U.S. residents are consistent with the general pattern of findings. These results suggest that because of the different norms, applying any of the 3 Spanish-language versions of the WAIS-III generally risks underestimating deficits, and that applying the English-language WAIS-III norms risks overestimating deficits of Spanish-speaking adults. There were a few exceptions to these general patterns. For example, the Mexican subsample ages 70 years and above performed significantly better on the Digit Symbol and Block Design than did the U.S. and Spanish subsamples. Implications for the clinical assessment of U.S. Spanish-speaking Latinos and test adaptation are discussed with an eye toward improving the clinical care for this community. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  6. Disease consequences of human adaptation

    Directory of Open Access Journals (Sweden)

    Justin C. Fay

    2013-12-01

    Full Text Available Adaptive evolution has provided us with a unique set of characteristics that define us as humans, including morphological, physiological and cellular changes. Yet, natural selection provides no assurances that adaptation is without human health consequences; advantageous mutations will increase in frequency so long as there is a net gain in fitness. As such, the current incidence of human disease can depend on previous adaptations. Here, I review genome-wide and gene-specific studies in which adaptive evolution has played a role in shaping human genetic disease. In addition to the disease consequences of adaptive phenotypes, such as bipedal locomotion and resistance to certain pathogens, I review evidence that adaptive mutations have influenced the frequency of linked disease alleles through genetic hitchhiking. Taken together, the links between human adaptation and disease highlight the importance of their combined influence on functional variation within the human genome and offer opportunities to discover and characterize such variation.

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

    Science.gov (United States)

    Pinto, João; Lynd, Amy; Vicente, José L; Santolamazza, Federica; Randle, Nadine P; Gentile, Gabriele; Moreno, Marta; Simard, Frédéric; Charlwood, Jacques Derek; do Rosário, Virgílio E; Caccone, Adalgisa; Della Torre, Alessandra; Donnelly, Martin J

    2007-11-28

    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.

  8. 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.

  9. Impacts of mutation effects and population size on mutation rate in asexual populations: a simulation study

    Directory of Open Access Journals (Sweden)

    Huang Zhuoran

    2010-09-01

    Full Text Available Abstract Background In any natural population, mutation is the primary source of genetic variation required for evolutionary novelty and adaptation. Nevertheless, most mutations, especially those with phenotypic effects, are harmful and are consequently removed by natural selection. For this reason, under natural selection, an organism will evolve to a lower mutation rate. Overall, the action of natural selection on mutation rate is related to population size and mutation effects. Although theoretical work has intensively investigated the relationship between natural selection and mutation rate, most of these studies have focused on individual competition within a population, rather than on competition among populations. The aim of the present study was to use computer simulations to investigate how natural selection adjusts mutation rate among asexually reproducing subpopulations with different mutation rates. Results The competition results for the different subpopulations showed that a population could evolve to an "optimum" mutation rate during long-term evolution, and that this rate was modulated by both population size and mutation effects. A larger population could evolve to a higher optimum mutation rate than could a smaller population. The optimum mutation rate depended on both the fraction and the effects of beneficial mutations, rather than on the effects of deleterious ones. The optimum mutation rate increased with either the fraction or the effects of beneficial mutations. When strongly favored mutations appeared, the optimum mutation rate was elevated to a much higher level. The competition time among the subpopulations also substantially shortened. Conclusions Competition at the population level revealed that the evolution of the mutation rate in asexual populations was determined by both population size and mutation effects. The most striking finding was that beneficial mutations, rather than deleterious mutations, were the

  10. 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.

  11. Dynamics and Fate of Beneficial Mutations Under Lineage Contamination by Linked Deleterious Mutations

    Science.gov (United States)

    Pénisson, Sophie; Singh, Tanya; Sniegowski, Paul

    2017-01-01

    Beneficial mutations drive adaptive evolution, yet their selective advantage does not ensure their fixation. Haldane’s application of single-type branching process theory showed that genetic drift alone could cause the extinction of newly arising beneficial mutations with high probability. With linkage, deleterious mutations will affect the dynamics of beneficial mutations and might further increase their extinction probability. Here, we model the lineage dynamics of a newly arising beneficial mutation as a multitype branching process. Our approach accounts for the combined effects of drift and the stochastic accumulation of linked deleterious mutations, which we call lineage contamination. We first study the lineage-contamination phenomenon in isolation, deriving dynamics and survival probabilities (the complement of extinction probabilities) of beneficial lineages. We find that survival probability is zero when U≳sb, where U is deleterious mutation rate and sb is the selective advantage of the beneficial mutation in question, and is otherwise depressed below classical predictions by a factor bounded from below by ∼1−U/sb. We then put the lineage contamination phenomenon into the context of an evolving population by incorporating the effects of background selection. We find that, under the combined effects of lineage contamination and background selection, ensemble survival probability is never zero but is depressed below classical predictions by a factor bounded from below by e−εU/s¯b, where s¯b is mean selective advantage of beneficial mutations, and ε=1−e−1≈0.63. This factor, and other bounds derived from it, are independent of the fitness effects of deleterious mutations. At high enough mutation rates, lineage contamination can depress fixation probabilities to values that approach zero. This fact suggests that high mutation rates can, perhaps paradoxically, (1) alleviate competition among beneficial mutations, or (2) potentially even shut

  12. Short-time evolution in the adaptive immune system.

    Science.gov (United States)

    Guttenberg, Nicholas; Tabei, S M Ali; Dinner, Aaron R

    2011-09-01

    We exploit a simple model to numerically and analytically investigate the effect of enforcing a time constraint for achieving a system-wide goal during an evolutionary dynamics. This situation is relevant to finding antibody specificities in the adaptive immune response as well as to artificial situations in which an evolutionary dynamics is used to generate a desired capability in a limited number of generations. When the likelihood of finding the target phenotype is low, we find that the optimal mutation rate can exceed the error threshold, in contrast to conventional evolutionary dynamics. We also show how a logarithmic correction to the usual inverse scaling of population size with mutation rate arises. Implications for natural and artificial evolutionary situations are discussed.

  13. 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.

  14. Biogenic sediments from coastal ecosystems to beach-dune systems: implications for the adaptation of mixed and carbonate beaches to future sea level rise

    Science.gov (United States)

    De Falco, Giovanni; Molinaroli, Emanuela; Conforti, Alessandro; Simeone, Simone; Tonielli, Renato

    2017-07-01

    century-1, 28 % (15 % / 34 %) of which is transported to the beach-dune system, thus significantly contributing to the beach sediment budget. The contribution to the beach sediment budget represents a further ecosystem service, which our data can help quantify, provided by P. oceanica. The value of this sediment-supply service is in addition to the other important ecological services provided by seagrass meadows. The dependence of the beach sediment budget on carbonate production associated with coastal ecosystems has several implications for the adaptation of mixed and carbonate beaches to the loss of seagrass meadows due to local impacts and the changes expected to occur over the next few decades in coastal ecosystems following sea level rise.

  15. 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.

    Science.gov (United States)

    Iqbal, Zafar; Aleem, Aamer; Iqbal, Mudassar; Naqvi, Mubashar Iqbal; Gill, Ammara; Taj, Abid Sohail; Qayyum, Abdul; ur-Rehman, Najeeb; Khalid, Ahmad Mukhtar; Shah, Ijaz Hussain; Khalid, Muhammad; Haq, Riazul; Khan, Mahwish; Baig, Shahid Mahmood; Jamil, Abid; Abbas, Muhammad Naeem; Absar, Muhammad; Mahmood, Amer; Rasool, Mahmood; Akhtar, Tanveer

    2013-01-01

    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. 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. 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. 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 leukemia along with imatinib, all of which vary in their

  16. 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

    Science.gov (United States)

    Iqbal, Mudassar; Naqvi, Mubashar Iqbal; Gill, Ammara; Taj, Abid Sohail; Qayyum, Abdul; ur-Rehman, Najeeb; Khalid, Ahmad Mukhtar; Shah, Ijaz Hussain; Khalid, Muhammad; Haq, Riazul; Khan, Mahwish; Baig, Shahid Mahmood; Jamil, Abid; Abbas, Muhammad Naeem; Absar, Muhammad; Mahmood, Amer; Rasool, Mahmood; Akhtar, Tanveer

    2013-01-01

    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 leukemia along with

  17. 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

  18. Driven by Mutations: The Predictive Value of Mutation Subtype in EGFR-Mutated Non-Small Cell Lung Cancer.

    Science.gov (United States)

    Castellanos, Emily; Feld, Emily; Horn, Leora

    2017-04-01

    EGFR-mutated NSCLC is a genetically heterogeneous disease that includes more than 200 distinct mutations. The implications of mutational subtype for both prognostic and predictive value are being increasingly understood. Although the most common EGFR mutations-exon 19 deletions or L858R mutations-predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs), it is now being recognized that outcomes may be improved in patients with exon 19 deletions. Additionally, 10% of patients will have an uncommon EGFR mutation, and response to EGFR TKI therapy is highly variable depending on the mutation. Given the growing recognition of the genetic and clinical variation seen in this disease, the development of comprehensive bioinformatics-driven tools to both analyze response in uncommon mutation subtypes and inform clinical decision making will be increasingly important. Clinical trials of novel EGFR TKIs should prospectively account for the presence of uncommon mutation subtypes in study design. Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

  19. Differences in the relationship between sensory adaptation of antennae and concentration of aerial pheromone in the oriental fruit moth and obliquebanded leafroller (Lepidoptera: Tortricidae): implications for the role of adaptation in sex pheromone-mediated mating disruption of these species.

    Science.gov (United States)

    Trimble, R M; Marshall, D B

    2010-04-01

    The antennae of Grapholita molesta (Busck) are more susceptible to sex pheromone-induced sensory adaptation than the antennae of Choristoneura rosaceana (Harris). Adaptation is detectable in G. molesta at 1/1,000th the aerial concentration of pheromone (i.e., 5.0 x 10(-7) ng Z8-12:OAc/ml air) that is required to induce detectable adaptation in C. rosaceana (i.e., 5.0 x 10(-4) ng Z11-14:OAc/ml air). In addition, the predicted concentration of pheromone required to induce 50% adaptation in G. molesta (i.e., 1.2 x 10(-3) ng Z8-12:OAc/ml air) after 15 min of exposure is only one sixth the estimated aerial concentration required to induce the same level of adaptation in C. rosaceana (i.e., 7.5 x 10(-3) ng Z11-14:OAc/ml air) after 15 min of exposure. Sixteen percent and 28% adaptation of G. molesta antennae is predicted after 15 and 30 min of exposure to the equivalent of 1 ng Z8-12:OAc/m(3) air (i.e., 1 x 10(-6) ng Z8-12:OAc/ml air). The predicted level of adaptation in C. rosaceana antennae, however, is only 1.5 and 9.9% after 15 and 30 min of exposure, respectively, to the equivalent of 1 ng Z11-14:OAc/m(3) air (i.e., 1 x 10(-6) ng Z11-14:OAc/ml air). The approximately three-fold greater level of sensory adaptation in G. molesta antennae after 30 min of exposure to a pheromone concentration measured in pheromone-treated orchards (i.e., 1 ng/m(3)) may be one reason why this species is more readily controlled than C. rosaceana using mating disruption.

  20. Interfering Waves of Adaptation Promote Spatial Mixing

    DEFF Research Database (Denmark)

    Martens, Erik Andreas; Hallatschek, Oskar

    2011-01-01

    , 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...... is proportional to $(1/2) and $(1/3) in linear and planar habitats, respectively, where the mutational supply $ is the product of mutation rate and local population density. This scaling and the existence of a speed limit should be amenable to experimental tests as they fall far below predicted adaptation speeds...

  1. Biogenic sediments from coastal ecosystems to beach–dune systems: implications for the adaptation of mixed and carbonate beaches to future sea level rise

    Directory of Open Access Journals (Sweden)

    G. De Falco

    2017-07-01

    the total beach–dune sediment mass. Carbonate production from coastal ecosystems was estimated to be 132 000∕307 000 t century−1, 28 % (15 % ∕ 34 % of which is transported to the beach–dune system, thus significantly contributing to the beach sediment budget. The contribution to the beach sediment budget represents a further ecosystem service, which our data can help quantify, provided by P. oceanica. The value of this sediment-supply service is in addition to the other important ecological services provided by seagrass meadows. The dependence of the beach sediment budget on carbonate production associated with coastal ecosystems has several implications for the adaptation of mixed and carbonate beaches to the loss of seagrass meadows due to local impacts and the changes expected to occur over the next few decades in coastal ecosystems following sea level rise.

  2. Lack of adaptation to a new host in a generalist herbivore: implications for host plant resistance to twospotted spider mites in cotton.

    Science.gov (United States)

    Miyazaki, Junji; Wilson, Lewis J; Stiller, Warwick N

    2015-04-01

    The twospotted spider mite (Tetranychus urticae Koch) is an important pest of cotton. This pest has a broad host range, but when changing between hosts an initial decline in fitness often occurs. This is usually followed by an increase in fitness after rapid adaptation to the new host, usually within five generations. The generality of this adaptive response was tested by assessing elements of fitness when mites were reared on a host to which they were adapted (Gossypium hirsutum L. cv. Sicot 71) or on a new host, Gossypium arboreum L. (accession BM13H). In a first experiment, mites reared on the new host for ten generations showed declining immature survival compared with those reared on the adapted host. In a second experiment, the intrinsic capacity for increase of mites cultured on the new host for six generations was significantly lower than that of mites cultured on the adapted host for six generations and then transferred to the new host. Hence, exposure to the new host for six or ten generations resulted in declining fitness. This 'negative adaptation' indicates robust antibiosis traits in G. arboreum accession BM13H, which therefore have value in developing mite-resistant G. hirsutum cultivars. © 2014 Society of Chemical Industry.

  3. A nonsymbiotic root hair tip growth phenotype in NORK-mutated legumes: implications for nodulation factor-induced signaling and formation of a multifaceted root hair pocket for bacteria

    NARCIS (Netherlands)

    Esseling, J.J.; Lhuissier, F.G.P.; Emons, A.M.C.

    2004-01-01

    The Medicago truncatula Does not Make Infections (DMI2) mutant is mutated in the nodulation receptor-like kinase, NORK. Here, we report that NORK-mutated legumes of three species show an enhanced touch response to experimental handling, which results in a nonsymbiotic root hair phenotype. When care

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

    African Journals Online (AJOL)

    Background: Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of inherited retinal degenerations that is estimated to affect more than 1.5 million people worldwide. RP is characterized by retinal pigment deposits visible on fundus examination, abnormal electroretinogram and progressive retinal ...

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

    Science.gov (United States)

    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 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. PMID:26177190

  6. Mutations of the KISS1 Gene in Disorders of Puberty

    National Research Council Canada - National Science Library

    Silveira, L. G; Noel, S. D; Silveira-Neto, A. P; Abreu, A. P; Brito, V. N; Santos, M. G; Bianco, S. D. C; Kuohung, W; Xu, S; Gryngarten, M; Escobar, M. E; Arnhold, I. J. P; Mendonca, B. B; Kaiser, U. B; Latronico, A. C

    2010-01-01

    ... transmission with incomplete, sex-dependent penetrance (6).Kisspeptin, encoded by the KISS1 gene, is a key gatekeeper of human puberty (8). Loss-of-function mutations of the kisspeptin receptor (GPR54 or KISS1R) cause normosmic IHH (9, 10). Recently, an activating mutation of KISS1R was identified in a girl with CPP, implicating the kisspeptin sys...

  7. Splice site, frameshift, and chimeric GFAP mutations in Alexander disease

    NARCIS (Netherlands)

    Flint, D.; Li, R.; Webster, L.S.; Naidu, S.; Kolodny, E.; Percy, A.; van der Knaap, M.S.; Powers, J.M.; Mantovani, J.F.; Ekstein, J.; Goldman, J.E.; Messing, A.; Brenner, M.

    2012-01-01

    Alexander disease (AxD) is a usually fatal astrogliopathy primarily caused by mutations in the gene encoding glial fibrillary acidic protein (GFAP), an intermediate filament protein expressed in astrocytes. We describe three patients with unique characteristics, and whose mutations have implications

  8. Mistranslation can enhance fitness through purging of deleterious mutations.

    Science.gov (United States)

    Bratulic, Sinisa; Toll-Riera, Macarena; Wagner, Andreas

    2017-05-19

    Phenotypic mutations are amino acid changes caused by mistranslation. How phenotypic mutations affect the adaptive evolution of new protein functions is unknown. Here we evolve the antibiotic resistance protein TEM-1 towards resistance on the antibiotic cefotaxime in an Escherichia coli strain with a high mistranslation rate. TEM-1 populations evolved in such strains endow host cells with a general growth advantage, not only on cefotaxime but also on several other antibiotics that ancestral TEM-1 had been unable to deactivate. High-throughput sequencing of TEM-1 populations shows that this advantage is associated with a lower incidence of weakly deleterious genotypic mutations. Our observations show that mistranslation is not just a source of noise that delays adaptive evolution. It could even facilitate adaptive evolution by exacerbating the effects of deleterious mutations and leading to their more efficient purging. The ubiquity of mistranslation and its effects render mistranslation an important factor in adaptive protein evolution.

  9. Mutation Clusters from Cancer Exome.

    Science.gov (United States)

    Kakushadze, Zura; Yu, Willie

    2017-08-15

    We apply our statistically deterministic machine learning/clustering algorithm *K-means (recently developed in https://ssrn.com/abstract=2908286) to 10,656 published exome samples for 32 cancer types. A majority of cancer types exhibit a mutation clustering structure. Our results are in-sample stable. They are also out-of-sample stable when applied to 1389 published genome samples across 14 cancer types. In contrast, we find in- and out-of-sample instabilities in cancer signatures extracted from exome samples via nonnegative matrix factorization (NMF), a computationally-costly and non-deterministic method. Extracting stable mutation structures from exome data could have important implications for speed and cost, which are critical for early-stage cancer diagnostics, such as novel blood-test methods currently in development.

  10. 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.

  11. Spontaneous Mutation Rate of Measles Virus: Direct Estimation Based on Mutations Conferring Monoclonal Antibody Resistance

    Science.gov (United States)

    Schrag, Stephanie J.; Rota, Paul A.; Bellini, William J.

    1999-01-01

    High mutation rates typical of RNA viruses often generate a unique viral population structure consisting of a large number of genetic microvariants. In the case of viral pathogens, this can result in rapid evolution of antiviral resistance or vaccine-escape mutants. We determined a direct estimate of the mutation rate of measles virus, the next likely target for global elimination following poliovirus. In a laboratory tissue culture system, we used the fluctuation test method of estimating mutation rate, which involves screening a large number of independent populations initiated by a small number of viruses each for the presence or absence of a particular single point mutation. The mutation we focused on, which can be screened for phenotypically, confers resistance to a monoclonal antibody (MAb 80-III-B2). The entire H gene of a subset of mutants was sequenced to verify that the resistance phenotype was associated with single point mutations. The epitope conferring MAb resistance was further characterized by Western blot analysis. Based on this approach, measles virus was estimated to have a mutation rate of 9 × 10−5 per base per replication and a genomic mutation rate of 1.43 per replication. The mutation rates we estimated for measles virus are comparable to recent in vitro estimates for both poliovirus and vesicular stomatitis virus. In the field, however, measles virus shows marked genetic stability. We briefly discuss the evolutionary implications of these results. PMID:9847306

  12. Design of a Computer-Adaptive Test to Measure English Literacy and Numeracy in the Singapore Workforce: Considerations, Benefits, and Implications

    Science.gov (United States)

    Jacobsen, Jared; Ackermann, Richard; Eguez, Jane; Ganguli, Debalina; Rickard, Patricia; Taylor, Linda

    2011-01-01

    A computer adaptive test (CAT) is a delivery methodology that serves the larger goals of the assessment system in which it is embedded. A thorough analysis of the assessment system for which a CAT is being designed is critical to ensure that the delivery platform is appropriate and addresses all relevant complexities. As such, a CAT engine must be…

  13. Compound EGFR mutation is frequently detected with co-mutations of actionable genes and associated with poor clinical outcome in lung adenocarcinoma.

    Science.gov (United States)

    Kim, Eun Young; Cho, Eun Na; Park, Heae Surng; Hong, Ji Young; Lim, Seri; Youn, Jong Pil; Hwang, Seung Yong; Chang, Yoon Soo

    2016-01-01

    Compound EGFR mutations, defined as double or multiple mutations in the EGFR tyrosine kinase domain, are frequently detected with advances in sequencing technology but its clinical significance is unclear. This study analyzed 61 cases of EGFR mutation positive lung adenocarcinoma using next-generation sequencing (NGS) based repeated deep sequencing panel of 16 genes that contain actionable mutations and investigated clinical implication of compound EGFR mutations. Compound EGFR mutation was detected in 15 (24.6%) of 61 cases of EGFR mutation-positive lung adenocarcinoma. The majority (12/15) of compound mutations are combination of the atypical mutation and typical mutations such as exon19 deletion, L858R or G719X substitutions, or exon 20 insertion whereas 3 were combinations of rare atypical mutations. The patients with compound mutation showed shorter overall survival than those with simple mutations (83.7 vs. 72.8 mo; P = 0.020, Breslow test). Among the 115 missense mutations discovered in the tested genes, a few number of actionable mutations were detected irrelevant to the subtype of EGFR mutations, including ALK rearrangement, BCL2L11 intron 2 deletion, KRAS c.35G>A, PIK3CA c.1633G>A which are possible target of crizotinib, BH3 mimetics, MEK inhibitors, and PI3K-tyrosine kinase inhibitors, respectively. 31 missense mutations were detected in the cases with simple mutations whereas 84 in those with compound mutation, showing that the cases with compound missense mutation have higher burden of missense mutations (P = 0.001, independent sample t-test). Compound EGFR mutations are detected at a high frequency using NGS-based repeated deep sequencing. Because patients with compound EGFR mutations showed poor clinical outcomes, they should be closely monitored during follow-up.

  14. Hypermutation and stress adaptation in bacteria

    Indian Academy of Sciences (India)

    2011-08-19

    Aug 19, 2011 ... Abstract. Hypermutability is a phenotype characterized by a moderate to high elevation of spontaneous mutation rates and could result from DNA replication errors, defects in error correction mechanisms and many other causes. The elevated mutation rates are helpful to organisms to adapt to sudden and ...

  15. Normal mutation rate variants arise in a Mutator (Mut S Escherichia coli population.

    Directory of Open Access Journals (Sweden)

    María-Carmen Turrientes

    Full Text Available The rate at which mutations are generated is central to the pace of evolution. Although this rate is remarkably similar amongst all cellular organisms, bacterial strains with mutation rates 100 fold greater than the modal rates of their species are commonly isolated from natural sources and emerge in experimental populations. Theoretical studies postulate and empirical studies teort the hypotheses that these "mutator" strains evolved in response to selection for elevated rates of generation of inherited variation that enable bacteria to adapt to novel and/or rapidly changing environments. Less clear are the conditions under which selection will favor reductions in mutation rates. Declines in rates of mutation for established populations of mutator bacteria are not anticipated if such changes are attributed to the costs of augmented rates of generation of deleterious mutations. Here we report experimental evidence of evolution towards reduced mutation rates in a clinical isolate of Escherichia coli with an hyper-mutable phenotype due a deletion in a mismatch repair gene, (ΔmutS. The emergence in a ΔmutS background of variants with mutation rates approaching those of the normal rates of strains carrying wild-type MutS was associated with increase in fitness with respect to ancestral strain. We postulate that such an increase in fitness could be attributed to the emergence of mechanisms driving a permanent "aerobic style of life", the negative consequence of this behavior being regulated by the evolution of mechanisms protecting the cell against increased endogenous oxidative radicals involved in DNA damage, and thus reducing mutation rate. Gene expression assays and full sequencing of evolved mutator and normo-mutable variants supports the hypothesis. In conclusion, we postulate that the observed reductions in mutation rate are coincidental to, rather than, the selective force responsible for this evolution.

  16. 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.

  17. Mapping Mutations on Phylogenies

    DEFF Research Database (Denmark)

    Nielsen, Rasmus

    2005-01-01

    This chapter provides a short review of recent methodologies developed for mapping mutations on phylogenies. Mapping of mutations, or character changes in general, using the maximum parsimony principle has been one of the most powerful tools in phylogenetics, and it has been used in a variety...... uncertainty in the mapping. Recently developed probabilistic methods can incorporate statistical uncertainty in the character mappings. In these methods, focus is on a probability distribution of mutational mappings instead of a single estimate of the mutational mapping....

  18. Mutational landscape of yeast mutator strains.

    Science.gov (United States)

    Serero, Alexandre; Jubin, Claire; Loeillet, Sophie; Legoix-Né, Patricia; Nicolas, Alain G

    2014-02-04

    The acquisition of mutations is relevant to every aspect of genetics, including cancer and evolution of species on Darwinian selection. Genome variations arise from rare stochastic imperfections of cellular metabolism and deficiencies in maintenance genes. Here, we established the genome-wide spectrum of mutations that accumulate in a WT and in nine Saccharomyces cerevisiae mutator strains deficient for distinct genome maintenance processes: pol32Δ and rad27Δ (replication), msh2Δ (mismatch repair), tsa1Δ (oxidative stress), mre11Δ (recombination), mec1Δ tel1Δ (DNA damage/S-phase checkpoints), pif1Δ (maintenance of mitochondrial genome and telomere length), cac1Δ cac3Δ (nucleosome deposition), and clb5Δ (cell cycle progression). This study reveals the diversity, complexity, and ultimate unique nature of each mutational spectrum, composed of punctual mutations, chromosomal structural variations, and/or aneuploidies. The mutations produced in clb5Δ/CCNB1, mec1Δ/ATR, tel1Δ/ATM, and rad27Δ/FEN1 strains extensively reshape the genome, following a trajectory dependent on previous events. It comprises the transmission of unstable genomes that lead to colony mosaicisms. This comprehensive analytical approach of mutator defects provides a model to understand how genome variations might accumulate during clonal evolution of somatic cell populations, including tumor cells.

  19. Systemic epidermal nevus with involvement of the oral mucosa due to FGFR3 mutation

    DEFF Research Database (Denmark)

    Bygum, Anette; Fagerberg, Christina R; Clemmensen, Ole J

    2011-01-01

    Epidermal nevi (EN) represent benign congenital skin lesions following the lines of Blaschko. They result from genetic mosaicism, and activating FGFR3 and PIK3CA mutations have been implicated.......Epidermal nevi (EN) represent benign congenital skin lesions following the lines of Blaschko. They result from genetic mosaicism, and activating FGFR3 and PIK3CA mutations have been implicated....

  20. Salivary miRNA profiles identify children with autism spectrum disorder, correlate with adaptive behavior, and implicate ASD candidate genes involved in neurodevelopment.

    Science.gov (United States)

    Hicks, Steven D; Ignacio, Cherry; Gentile, Karen; Middleton, Frank A

    2016-04-22

    Autism spectrum disorder (ASD) is a common neurodevelopmental disorder that lacks adequate screening tools, often delaying diagnosis and therapeutic interventions. Despite a substantial genetic component, no single gene variant accounts for >1 % of ASD incidence. Epigenetic mechanisms that include microRNAs (miRNAs) may contribute to the ASD phenotype by altering networks of neurodevelopmental genes. The extracellular availability of miRNAs allows for painless, noninvasive collection from biofluids. In this study, we investigated the potential for saliva-based miRNAs to serve as diagnostic screening tools and evaluated their potential functional importance. Salivary miRNA was purified from 24 ASD subjects and 21 age- and gender-matched control subjects. The ASD group included individuals with mild ASD (DSM-5 criteria and Autism Diagnostic Observation Schedule) and no history of neurologic disorder, pre-term birth, or known chromosomal abnormality. All subjects completed a thorough neurodevelopmental assessment with the Vineland Adaptive Behavior Scales at the time of saliva collection. A total of 246 miRNAs were detected and quantified in at least half the samples by RNA-Seq and used to perform between-group comparisons with non-parametric testing, multivariate logistic regression and classification analyses, as well as Monte-Carlo Cross-Validation (MCCV). The top miRNAs were examined for correlations with measures of adaptive behavior. Functional enrichment analysis of the highest confidence mRNA targets of the top differentially expressed miRNAs was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID), as well as the Simons Foundation Autism Database (AutDB) of ASD candidate genes. Fourteen miRNAs were differentially expressed in ASD subjects compared to controls (p adaptive behavior. These miRNAs have high specificity and cross-validated utility as a potential screening tool for ASD.

  1. UV Signature Mutations

    Science.gov (United States)

    2014-01-01

    Sequencing complete tumor genomes and exomes has sparked the cancer field's interest in mutation signatures for identifying the tumor's carcinogen. This review and meta-analysis discusses signatures and their proper use. We first distinguish between a mutagen's canonical mutations – deviations from a random distribution of base changes to create a pattern typical of that mutagen – and the subset of signature mutations, which are unique to that mutagen and permit inference backward from mutations to mutagen. To verify UV signature mutations, we assembled literature datasets on cells exposed to UVC, UVB, UVA, or solar simulator light (SSL) and tested canonical UV mutation features as criteria for clustering datasets. A confirmed UV signature was: ≥60% of mutations are C→T at a dipyrimidine site, with ≥5% CC→TT. Other canonical features such as a bias for mutations on the non-transcribed strand or at the 3' pyrimidine had limited application. The most robust classifier combined these features with criteria for the rarity of non-UV canonical mutations. In addition, several signatures proposed for specific UV wavelengths were limited to specific genes or species; non-signature mutations induced by UV may cause melanoma BRAF mutations; and the mutagen for sunlight-related skin neoplasms may vary between continents. PMID:25354245

  2. Quantifying the Adaptive Potential of an Antibiotic Resistance Enzyme

    OpenAIRE

    Schenk, Martijn F; Szendro, Ivan G.; Joachim Krug; J Arjan G M de Visser

    2012-01-01

    For a quantitative understanding of the process of adaptation, we need to understand its "raw material," that is, the frequency and fitness effects of beneficial mutations. At present, most empirical evidence suggests an exponential distribution of fitness effects of beneficial mutations, as predicted for Gumbel-domain distributions by extreme value theory. Here, we study the distribution of mutation effects on cefotaxime (Ctx) resistance and fitness of 48 unique beneficial mutations in the b...

  3. Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype.

    Science.gov (United States)

    Tatton-Brown, Katrina; Murray, Anne; Hanks, Sandra; Douglas, Jenny; Armstrong, Ruth; Banka, Siddharth; Bird, Lynne M; Clericuzio, Carol L; Cormier-Daire, Valerie; Cushing, Tom; Flinter, Frances; Jacquemont, Marie-Line; Joss, Shelagh; Kinning, Esther; Lynch, Sally Ann; Magee, Alex; McConnell, Vivienne; Medeira, Ana; Ozono, Keiichi; Patton, Michael; Rankin, Julia; Shears, Debbie; Simon, Marleen; Splitt, Miranda; Strenger, Volker; Stuurman, Kyra; Taylor, Clare; Titheradge, Hannah; Van Maldergem, Lionel; Temple, I Karen; Cole, Trevor; Seal, Sheila; Rahman, Nazneen

    2013-12-01

    Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with EZH2 mutations. The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain. Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals. However, tall stature is very common, reported in >90% of affected individuals. Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild. Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. As mutation testing becomes increasingly accessible and larger numbers of EZH2 mutation-positive individuals are identified, knowledge of the clinical spectrum and prognostic implications of EZH2 mutations should improve. © 2013 Wiley Periodicals, Inc.

  4. 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.

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

    Science.gov (United States)

    Mithani, Suhail K; Shao, Chunbo; Tan, Marietta; Smith, Ian M; Califano, Joseph A; El-Naggar, Adel K; Ha, Patrick K

    2009-12-30

    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. 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. 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. 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.

  6. Short-Term Local Adaptation of Historical Common Bean (Phaseolus vulgaris L.) Varieties and Implications for In Situ Management of Bean Diversity.

    Science.gov (United States)

    Klaedtke, Stephanie M; Caproni, Leonardo; Klauck, Julia; de la Grandville, Paul; Dutartre, Martin; Stassart, Pierre M; Chable, Véronique; Negri, Valeria; Raggi, Lorenzo

    2017-02-28

    Recognizing both the stakes of traditional European common bean diversity and the role farmers' and gardeners' networks play in maintaining this diversity, the present study examines the role that local adaptation plays for the management of common bean diversity in situ. To the purpose, four historical bean varieties and one modern control were multiplied on two organic farms for three growing seasons. The fifteen resulting populations, the initial ones and two populations of each variety obtained after the three years of multiplication, were then grown in a common garden. Twenty-two Simple Sequence Repeat (SSR) markers and 13 phenotypic traits were assessed. In total, 68.2% of tested markers were polymorphic and a total of 66 different alleles were identified. FST analysis showed that the genetic composition of two varieties multiplied in different environments changed. At the phenotypic level, differences were observed in flowering date and leaf length. Results indicate that three years of multiplication suffice for local adaptation to occur. The spatial dynamics of genetic and phenotypic bean diversity imply that the maintenance of diversity should be considered at the scale of the network, rather than individual farms and gardens. The microevolution of bean populations within networks of gardens and farms emerges as a research perspective.

  7. 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.

  8. Loss-of-Function Mutations in the KCNJ8-Encoded Kir6.1 KATP Channel and Sudden Infant Death Syndrome

    Science.gov (United States)

    Tester, David J.; Tan, Bi-Hua; Medeiros-Domingo, Argelia; Song, Chunhua; Makielski, Jonathan C.; Ackerman, Michael J.

    2011-01-01

    Background Approximately 10% of sudden infant death syndrome (SIDS) may stem from cardiac channelopathies. The KCNJ8-encoded Kir6.1 (KATP) channel critically regulates vascular tone and cardiac adaptive response to systemic metabolic stressors, including sepsis. KCNJ8-deficient mice are prone to premature sudden death, particularly with infection. We determined the spectrum, prevalence, and function of KCNJ8 mutations in a large SIDS cohort. Methods and Results Using PCR, DHPLC, and DNA sequencing, comprehensive open reading frame/splice-site mutational analysis of KCNJ8 was performed on genomic DNA isolated from necropsy tissue on 292 unrelated SIDS cases (178 males, 204 white, age 2.9 ± 1.9 months). KCNJ8 mutations were co-expressed heterologously with SUR2A in COS-1 cells and characterized using whole cell patch-clamp. Two novel KCNJ8 mutations were identified. A 5-month-old white male had an in-frame deletion (E332del) and a 2-month-old black female had a missense mutation (V346I). Both mutations localized to Kir6.1's C-terminus, involved conserved residues, and were absent in 400 and 200 ethnic-matched reference alleles respectively. Both cases were negative for mutations in established channelopathic genes. Compared to WT, the pinacidil-activated KATP current was decreased 45% to 68% for Kir6.1-E322del and 40% to 57% for V346I between -20 mV to 40 mV. Conclusions Molecular and functional evidence implicated loss-of-function KCNJ8 mutations as a novel pathogenic mechanism in SIDS, possibly by predisposition of a maladaptive cardiac response to systemic metabolic stressors akin to the mouse models of KCNJ8 deficiency. PMID:21836131

  9. Phenotypic effect of mutations in evolving populations of RNA molecules

    Directory of Open Access Journals (Sweden)

    Manrubia Susanna C

    2010-02-01

    Full Text Available Abstract Background The secondary structure of folded RNA sequences is a good model to map phenotype onto genotype, as represented by the RNA sequence. Computational studies of the evolution of ensembles of RNA molecules towards target secondary structures yield valuable clues to the mechanisms behind adaptation of complex populations. The relationship between the space of sequences and structures, the organization of RNA ensembles at mutation-selection equilibrium, the time of adaptation as a function of the population parameters, the presence of collective effects in quasispecies, or the optimal mutation rates to promote adaptation all are issues that can be explored within this framework. Results We investigate the effect of microscopic mutations on the phenotype of RNA molecules during their in silico evolution and adaptation. We calculate the distribution of the effects of mutations on fitness, the relative fractions of beneficial and deleterious mutations and the corresponding selection coefficients for populations evolving under different mutation rates. Three different situations are explored: the mutation-selection equilibrium (optimized population in three different fitness landscapes, the dynamics during adaptation towards a goal structure (adapting population, and the behavior under periodic population bottlenecks (perturbed population. Conclusions The ratio between the number of beneficial and deleterious mutations experienced by a population of RNA sequences increases with the value of the mutation rate μ at which evolution proceeds. In contrast, the selective value of mutations remains almost constant, independent of μ, indicating that adaptation occurs through an increase in the amount of beneficial mutations, with little variations in the average effect they have on fitness. Statistical analyses of the distribution of fitness effects reveal that small effects, either beneficial or deleterious, are well described by a Pareto

  10. In-host adaptation and acquired triazole resistance in Aspergillus fumigatus: a dilemma for clinical management.

    Science.gov (United States)

    Verweij, Paul E; Zhang, Jianhua; Debets, Alfons J M; Meis, Jacques F; van de Veerdonk, Frank L; Schoustra, Sijmen E; Zwaan, Bas J; Melchers, Willem J G

    2016-11-01

    Aspergillus fumigatus causes a range of diseases in human beings, some of which are characterised by fungal persistence. A fumigatus can persist by adapting to the human lung environment through physiological and genomic changes. The physiological changes are based on the large biochemical versatility of the fungus, and the genomic changes are based on the capacity of the fungus to generate genetic diversity by spontaneous mutations or recombination and subsequent selection of the genotypes that are most adapted to the new environment. In this Review, we explore the adaptation strategies of A fumigatus in relation to azole resistance selection and the clinical implications thereof for management of diseases caused by Aspergillus spp. We hypothesise that the current diagnostic tools and treatment strategies do not take into account the biology of the fungus and might result in an increased likelihood of fungal persistence in patients. Stress factors, such as triazole exposure, cause mutations that render resistance. The process of reproduction-ie, sexual, parasexual, or asexual-is probably crucial for the adaptive potential of Aspergillus spp. As any change in the environment can provoke adaptation, switching between triazoles in patients with chronic pulmonary aspergillosis might result in a high-level pan-triazole-resistant phenotype through the accumulation of resistance mutations. Alternatively, when triazole therapy is stopped, an azole-free environment is created that could prompt selection for compensatory mutations that overcome any fitness costs that are expected to accompany resistance development. As a consequence, starting, switching, and stopping azole therapy has the risk of selecting for highly resistant strains with wildtype fitness. A similar adaptation is expected to occur in response to other stress factors, such as endogenous antimicrobial peptides; over time the fungus will become increasingly adapted to the lung environment, thereby limiting

  11. Mutation@A Glance : an integrative web application for analysing mutations from human genetic diseases

    NARCIS (Netherlands)

    Hijikata, A.; Raju, R.; Keerthikumar, S.; Ramabadran, S.; Balakrishnan, L.; Ramadoss, S.K.; Pandey, A.; Mohan, S.; Ohara, O.

    2010-01-01

    Although mutation analysis serves as a key part in making a definitive diagnosis about a genetic disease, it still remains a time-consuming step to interpret their biological implications through integration of various lines of archived information about genes in question. To expedite this

  12. Mutation accumulation may be a minor force in shaping life history traits

    DEFF Research Database (Denmark)

    Dańko, Maciej Jan; Kozłowski, Jan; Vaupel, James Walton

    2012-01-01

    -strings to capture different age-specific mutational patterns. Each pattern represents a genotype and for each genotype we find the life history strategy that maximizes fitness. Genotypes compete with each other and are subject to selection and to new mutations over generations until equilibrium in gene......-frequencies is reached. The mutation-selection equilibrium provides information about mutational load and the differential effects of mutations on a life history trait--the optimal age at maturity. We find that mutations accumulate only at ages with negligible impact on fitness and that mutation accumulation has very...... little effect on the optimal age at maturity. These results suggest that life histories are largely determined by adaptive processes. The non-adaptive process of mutation accumulation seems to be unimportant at evolutionarily relevant ages....

  13. A novel MERTK mutation causing retinitis pigmentosa.

    Science.gov (United States)

    Al-Khersan, Hasenin; Shah, Kaanan P; Jung, Segun C; Rodriguez, Alex; Madduri, Ravi K; Grassi, Michael A

    2017-08-01

    Retinitis pigmentosa (RP) is a genetically heterogeneous inherited retinal dystrophy. To date, over 80 genes have been implicated in RP. However, the disease demonstrates significant locus and allelic heterogeneity not entirely captured by current testing platforms. The purpose of the present study was to characterize the underlying mutation in a patient with RP without a molecular diagnosis after initial genetic testing. Whole-exome sequencing of the affected proband was performed. Candidate gene mutations were selected based on adherence to expected genetic inheritance pattern and predicted pathogenicity. Sanger sequencing of MERTK was completed on the patient's unaffected mother, affected brother, and unaffected sister to determine genetic phase. Eight sequence variants were identified in the proband in known RP-associated genes. Sequence analysis revealed that the proband was a compound heterozygote with two independent mutations in MERTK, a novel nonsense mutation (c.2179C > T) and a previously reported missense variant (c.2530C > T). The proband's affected brother also had both mutations. Predicted phase was confirmed in unaffected family members. Our study identifies a novel nonsense mutation in MERTK in a family with RP and no prior molecular diagnosis. The present study also demonstrates the clinical value of exome sequencing in determining the genetic basis of Mendelian diseases when standard genetic testing is unsuccessful.

  14. 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.

  15. 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...... 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......-meandering of channelised streams, which may all have a large impact on, not least, the N loading of lakes. In the arid zone, also restrictions on human use of water are urgently needed, not least on the quantity of water used for irrigation purposes....

  16. 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

  17. 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

  18. A Naturally Occurring hPMS2 Mutation Can Confer a Dominant Negative Mutator Phenotype

    Science.gov (United States)

    Nicolaides, Nicholas C.; Littman, Susan J.; Modrich, Paul; Kinzler, Kenneth W.; Vogelstein, Bert

    1998-01-01

    Defects in mismatch repair (MMR) genes result in a mutator phenotype by inducing microsatellite instability (MI), a characteristic of hereditary nonpolyposis colorectal cancers (HNPCC) and a subset of sporadic colon tumors. Present models describing the mechanism by which germ line mutations in MMR genes predispose kindreds to HNPCC suggest a “two-hit” inactivation of both alleles of a particular MMR gene. Here we present experimental evidence that a nonsense mutation at codon 134 of the hPMS2 gene is sufficient to reduce MMR and induce MI in cells containing a wild-type hPMS2 allele. These results have significant implications for understanding the relationship between mutagenesis and carcinogenesis and the ability to generate mammalian cells with mutator phenotypes. PMID:9488480

  19. 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...

  20. TET2 gene mutation is unfavorable prognostic factor in cytogenetically normal acute myeloid leukemia patients with NPM1+ and FLT3-ITD - mutations.

    Science.gov (United States)

    Tian, Xiaopeng; Xu, Yang; Yin, Jia; Tian, Hong; Chen, Suning; Wu, Depei; Sun, Aining

    2014-07-01

    Cytogenetically normal acute myeloid leukemia (cn-AML) is a group of heterogeneous diseases. Gene mutations are increasingly used to assess the prognosis of cn-AML patients and guide risk-adapted treatment. In the present study, we analyzed the molecular genetics characteristics of 373 adult cn-AML patients and explored the relationship between TET2 gene mutations or different genetic mutation patterns and prognosis. We found that 16.1 % of patients had TET2 mutations, 31.6 % had FLT3 internal tandem duplications (ITDs), 6.2 % had FLT3 tyrosine kinase domain mutations, 2.4 % had c-KIT mutations, 37.8 % had NPM1 mutations, 11.3 % had WT1 mutations, 5.9 % had RUNX1 mutations, 11.5 % had ASXL1 mutations, 3.8 % had MLL-PTDs, 7.8 % had IDH1 mutations, 7.8 % had NRAS mutations, 12.3 % had IDH2 mutations, 1.6 % had EZH2 mutations, and 14.7 % had DNMT3A mutations, while none had CBL mutations. Gene mutations were detected in 76.94 % (287/373) of all patients. In the NPM1m(+) patients, those with TET2 mutations were associated with a shorter median overall survival (OS) as compared to TET2 wild-type (wt) patients (9.9 vs. 27.0 months, respectively; P = 0.023); Interestingly, the TET2 mutation was identified as an unfavorable prognostic factor and was closely associated with a shorter median OS as compared to TET2-wt (9.5 vs. 32.2 months, respectively; P = 0.013) in the NPM1m(+)/FLT3-ITDm(-) patient group. Thus, identification of TET2 combined with classic NPM1 and FLT3-ITD mutations allowed us to stratify cn-AML into distinct subtypes.

  1. White-opaque switching in natural MTLa/α isolates of Candida albicans: evolutionary implications for roles in host adaptation, pathogenesis, and sex.

    Directory of Open Access Journals (Sweden)

    Jing Xie

    Full Text Available Phenotypic transitions play critical roles in host adaptation, virulence, and sexual reproduction in pathogenic fungi. A minority of natural isolates of Candida albicans, which are homozygous at the mating type locus (MTL, a/a or α/α, are known to be able to switch between two distinct cell types: white and opaque. It is puzzling that white-opaque switching has never been observed in the majority of natural C. albicans strains that have heterozygous MTL genotypes (a/α, given that they contain all of the opaque-specific genes essential for switching. Here we report the discovery of white-opaque switching in a number of natural a/α strains of C. albicans under a condition mimicking aspects of the host environment. The optimal condition for white-to-opaque switching in a/α strains of C. albicans is to use N-acetylglucosamine (GlcNAc as the sole carbon source and to incubate the cells in 5% CO2. Although the induction of white-to-opaque switching in a/α strains of C. albicans is not as robust as in MTL homozygotes in response to GlcNAc and CO2, opaque cells of a/α strains exhibit similar features of cellular and colony morphology to their MTL homozygous counterparts. Like MTL homozygotes, white and opaque cells of a/α strains differ in their behavior in different mouse infection models. We have further demonstrated that the transcriptional regulators Rfg1, Brg1, and Efg1 are involved in the regulation of white-to-opaque switching in a/α strains. We propose that the integration of multiple environmental cues and the activation and inactivation of a set of transcriptional regulators controls the expression of the master switching regulator WOR1, which determines the final fate of the cell type in C. albicans. Our discovery of white-opaque switching in the majority of natural a/α strains of C. albicans emphasizes its widespread nature and importance in host adaptation, pathogenesis, and parasexual reproduction.

  2. Evaluating the Photoprotective Effects of Ochre on Human Skin by In Vivo SPF Assessment: Implications for Human Evolution, Adaptation and Dispersal.

    Directory of Open Access Journals (Sweden)

    Riaan F Rifkin

    Full Text Available Archaeological indicators of cognitively modern behaviour become increasingly prevalent during the African Middle Stone Age (MSA. Although the exploitation of ochre is viewed as a key feature of the emergence of modern human behaviour, the uses to which ochre and ochre-based mixtures were put remain ambiguous. Here we present the results of an experimental study exploring the efficacy of ochre as a topical photoprotective compound. This is achieved through the in vivo calculation of the sun protection factor (SPF values of ochre samples obtained from Ovahimba women (Kunene Region, Northern Namibia and the Palaeozoic Bokkeveld Group deposits of the Cape Supergroup (Western Cape Province, South Africa. We employ visible spectroscopy, energy-dispersive X-ray fluorescence (ED-XRF, X-ray diffraction (XRD and granulometric analyses to characterise ochre samples. The capacity of ochre to inhibit the susceptibility of humans to the harmful effects of exposure to ultraviolet radiation (UVR is confirmed and the mechanisms implicated in the efficacy of ochre as a sunscreen identified. It is posited that the habitual application of ochre may have represented a crucial innovation for MSA humans by limiting the adverse effects of ultraviolet exposure. This may have facilitated the colonisation of geographic regions largely unfavourable to the constitutive skin colour of newly arriving populations.

  3. 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.

  4. 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.

  5. A New Deep-Sea Hydrothermal Vent Species of Ostracoda (Crustacea) from the Western Pacific: Implications for Adaptation, Endemism, and Dispersal of Ostracodes in Chemosynthetic Systems.

    Science.gov (United States)

    Tanaka, Hayato; Yasuhara, Moriaki

    2016-10-01

    Deep-sea hydrothermal vent fields are among the most extreme habitats on Earth. Major research interests in these ecosystems have focused on the anomalous macrofauna, which are nourished by chemoautotrophic bacterial endosymbionts. In contrast, the meiofauna is largely overlooked in this chemosynthetic environment. The present study describes a new species, Thomontocypris shimanagai sp. nov. (Crustacea: Ostracoda), which was collected from the surface of colonies of neoverrucid barnacles and paralvinellid worms on the chimneys at the Myojin-sho submarine caldera. This is the first discovery of an ostracode from deep-sea hydrothermal vent environments in the western Pacific region. In addition to the species description, we discuss three aspects: 1) adaptation, 2) endemism, and 3) dispersal strategy of the hydrothermal vent ostracodes. Regarding these aspects, we conclude the following: 1) the new species may feed on sloughed-off tissues, mucus secretions, or fecal pellets of sessile organisms, rather than depend on chemoautotrophic bacteria as symbionts for energy; 2) as has been pointed out by other studies, Thomontocypris does not likely represent a vent-specific genus; however, this new species is considered to be endemic at the species level, as it has not been found outside of the type locality; and 3) this new species may have migrated from adjacent deep-sea chemosynthesis-based habitats, such as hydrothermal vents, with wood falls potentially having acted as stepping stones.

  6. 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.

  7. Systematic analysis of somatic mutations impacting gene expression in 12 tumour types

    Science.gov (United States)

    Ding, Jiarui; McConechy, Melissa K.; Horlings, Hugo M.; Ha, Gavin; Chun Chan, Fong; Funnell, Tyler; Mullaly, Sarah C.; Reimand, Jüri; Bashashati, Ali; Bader, Gary D.; Huntsman, David; Aparicio, Samuel; Condon, Anne; Shah, Sohrab P.

    2015-01-01

    We present a novel hierarchical Bayes statistical model, xseq, to systematically quantify the impact of somatic mutations on expression profiles. We establish the theoretical framework and robust inference characteristics of the method using computational benchmarking. We then use xseq to analyse thousands of tumour data sets available through The Cancer Genome Atlas, to systematically quantify somatic mutations impacting expression profiles. We identify 30 novel cis-effect tumour suppressor gene candidates, enriched in loss-of-function mutations and biallelic inactivation. Analysis of trans-effects of mutations and copy number alterations with xseq identifies mutations in 150 genes impacting expression networks, with 89 novel predictions. We reveal two important novel characteristics of mutation impact on expression: (1) patients harbouring known driver mutations exhibit different downstream gene expression consequences; (2) expression patterns for some mutations are stable across tumour types. These results have critical implications for identification and interpretation of mutations with consequent impact on transcription in cancer. PMID:26436532

  8. Multiscale mutation clustering algorithm identifies pan-cancer mutational clusters associated with pathway-level changes in gene expression.

    Science.gov (United States)

    Poole, William; Leinonen, Kalle; Shmulevich, Ilya; Knijnenburg, Theo A; Bernard, Brady

    2017-02-01

    Cancer researchers have long recognized that somatic mutations are not uniformly distributed within genes. However, most approaches for identifying cancer mutations focus on either the entire-gene or single amino-acid level. We have bridged these two methodologies with a multiscale mutation clustering algorithm that identifies variable length mutation clusters in cancer genes. We ran our algorithm on 539 genes using the combined mutation data in 23 cancer types from The Cancer Genome Atlas (TCGA) and identified 1295 mutation clusters. The resulting mutation clusters cover a wide range of scales and often overlap with many kinds of protein features including structured domains, phosphorylation sites, and known single nucleotide variants. We statistically associated these multiscale clusters with gene expression and drug response data to illuminate the functional and clinical consequences of mutations in our clusters. Interestingly, we find multiple clusters within individual genes that have differential functional associations: these include PTEN, FUBP1, and CDH1. This methodology has potential implications in identifying protein regions for drug targets, understanding the biological underpinnings of cancer, and personalizing cancer treatments. Toward this end, we have made the mutation clusters and the clustering algorithm available to the public. Clusters and pathway associations can be interactively browsed at m2c.systemsbiology.net. The multiscale mutation clustering algorithm is available at https://github.com/IlyaLab/M2C.

  9. 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.

  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

    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...

  11. 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.

  12. 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.

  13. 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

    requiring high virus concentrations, such as studies of HCV particle composition and development of whole-virus vaccine antigens. IMPORTANCE: Hepatitis C virus (HCV) is a major global health care burden, affecting more than 150 million people worldwide. These individuals are at high risk of developing......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......, yielding a virus with greatly improved spread kinetics and an infectivity titer of 6.7 log10 focus-forming units (FFU)/ml. We identified several putative adaptive amino acid changes. In head-to-head infections at fixed multiplicities of infection, one SA13/JFH1orig mutant termed SA13/JFH1Core-NS5B...

  14. 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.

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

    Science.gov (United States)

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

    2013-06-21

    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

  16. Adaptive Lighting

    DEFF Research Database (Denmark)

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

    2015-01-01

    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......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...

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

    DEFF Research Database (Denmark)

    Khademi, Seyed Mohammad Hossein

    Most knowledge gained from evolutionary studies of bacteria in natural and experimental settings center around contribution of intragenic mutations on bacterial evolution. While cases of adaptive intergenic mutations have sometimes been reported or explored, none of these studies consider...... intergenic mutations in broader context as key players in evolutionary adaptation of bacteria. The focus of this thesis has been to provide novel insights on contributions of non-coding intergenic mutations in natural evolution of bacteria. The model system used for these investigations is adaptation...... of opportunistic pathogen Pseudomonas aeruginosa in long-term chronic airway infections of Cystic fibrosis (CF) patients. Using sequenced genomes of P. aeruginosa isolated from this setting, 88 intergenic regions under positive selection for adaptive mutations within and across isolates of different P. aeruginosa...

  18. Prevalent mutations in prostate cancer.

    Science.gov (United States)

    Dong, Jin-Tang

    2006-02-15

    Quantitative and structural genetic alterations cause the development and progression of prostate cancer. A number of genes have been implicated in prostate cancer by genetic alterations and functional consequences of the genetic alterations. These include the ELAC2 (HPC2), MSR1, and RNASEL (HPC1) genes that have germline mutations in familial prostate cancer; AR, ATBF1, EPHB2 (ERK), KLF6, mitochondria DNA, p53, PTEN, and RAS that have somatic mutations in sporadic prostate cancer; AR, BRCA1, BRCA2, CHEK2 (RAD53), CYP17, CYP1B1, CYP3A4, GSTM1, GSTP1, GSTT1, PON1, SRD5A2, and VDR that have germline genetic variants associated with either hereditary and/or sporadic prostate cancer; and ANXA7 (ANX7), KLF5, NKX3-1 (NKX3.1), CDKN1B (p27), and MYC that have genomic copy number changes affecting gene function. More genes relevant to prostate cancer remain to be identified in each of these gene groups. For the genes that have been identified, most need additional genetic, functional, and/or biochemical examination. Identification and characterization of these genes will be a key step for improving the detection and treatment of prostate cancer. (c) 2005 Wiley-Liss, Inc.

  19. Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors

    DEFF Research Database (Denmark)

    Goriely, Anne; Hansen, Ruth M S; Taylor, Indira B

    2009-01-01

    Genes mutated in congenital malformation syndromes are frequently implicated in oncogenesis, but the causative germline and somatic mutations occur in separate cells at different times of an organism's life. Here we unify these processes to a single cellular event for mutations arising in male germ...

  20. Minkowski Polynomials and Mutations

    Directory of Open Access Journals (Sweden)

    Mohammad Akhtar

    2012-12-01

    Full Text Available Given a Laurent polynomial f, one can form the period of f: this is a function of one complex variable that plays an important role in mirror symmetry for Fano manifolds. Mutations are a particular class of birational transformations acting on Laurent polynomials in two variables; they preserve the period and are closely connected with cluster algebras. We propose a higher-dimensional analog of mutation acting on Laurent polynomials f in n variables. In particular we give a combinatorial description of mutation acting on the Newton polytope P of f, and use this to establish many basic facts about mutations. Mutations can be understood combinatorially in terms of Minkowski rearrangements of slices of P, or in terms of piecewise-linear transformations acting on the dual polytope P* (much like cluster transformations. Mutations map Fano polytopes to Fano polytopes, preserve the Ehrhart series of the dual polytope, and preserve the period of f. Finally we use our results to show that Minkowski polynomials, which are a family of Laurent polynomials that give mirror partners to many three-dimensional Fano manifolds, are connected by a sequence of mutations if and only if they have the same period.

  1. SPOP mutation leads to genomic instability in prostate cancer

    Science.gov (United States)

    Boysen, Gunther; Barbieri, Christopher E; Prandi, Davide; Blattner, Mirjam; Chae, Sung-Suk; Dahija, Arun; Nataraj, Srilakshmi; Huang, Dennis; Marotz, Clarisse; Xu, Limei; Huang, Julie; Lecca, Paola; Chhangawala, Sagar; Liu, Deli; Zhou, Pengbo; Sboner, Andrea; de Bono, Johann S

    2015-01-01

    Genomic instability is a fundamental feature of human cancer often resulting from impaired genome maintenance. In prostate cancer, structural genomic rearrangements are a common mechanism driving tumorigenesis. However, somatic alterations predisposing to chromosomal rearrangements in prostate cancer remain largely undefined. Here, we show that SPOP, the most commonly mutated gene in primary prostate cancer modulates DNA double strand break (DSB) repair, and that SPOP mutation is associated with genomic instability. In vivo, SPOP mutation results in a transcriptional response consistent with BRCA1 inactivation resulting in impaired homology-directed repair (HDR) of DSB. Furthermore, we found that SPOP mutation sensitizes to DNA damaging therapeutic agents such as PARP inhibitors. These results implicate SPOP as a novel participant in DSB repair, suggest that SPOP mutation drives prostate tumorigenesis in part through genomic instability, and indicate that mutant SPOP may increase response to DNA-damaging therapeutics. DOI: http://dx.doi.org/10.7554/eLife.09207.001 PMID:26374986

  2. Neonatal Diabetes Caused by Activating Mutations in the Sulphonylurea Receptor

    Directory of Open Access Journals (Sweden)

    Peter Proks

    2013-06-01

    Full Text Available Adenosine triphosphate (ATP-sensitive potassium (KATP channels in pancreatic β-cells play a crucial role in insulin secretion and glucose homeostasis. These channels are composed of two subunits: a pore-forming subunit (Kir6.2 and a regulatory subunit (sulphonylurea receptor-1. Recent studies identified large number of gain of function mutations in the regulatory subunit of the channel which cause neonatal diabetes. Majority of mutations cause neonatal diabetes alone, however some lead to a severe form of neonatal diabetes with associated neurological complications. This review focuses on the functional effects of these mutations as well as the implications for treatment.

  3. 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...

  4. Adaptive skills

    Directory of Open Access Journals (Sweden)

    Staša Stropnik

    2013-02-01

    Full Text Available Adaptive skills are defined as a collection of conceptual, social and practical skills that are learned by people in order to function in their everyday lives. They include an individual's ability to adapt to and manage her or his surroundings to effectively function and meet social or community expectations. Good adaptive skills promote individual's independence in different environments, whereas poorly developed adaptive skills are connected to individual's dependency and with greater need for control and help with everyday tasks. Assessment of adaptive skills is often connected to assessment of intellectual disability, due to the reason that the diagnosis of intellectual disability includes lower levels of achievements on standardized tests of intellectual abilities as well as important deficits in adaptive skills. Assessment of adaptive behavior is a part of standard assessment battery with children and adults with different problems, disorders or disabilities that affect their everyday functioning. This contribution also presents psychometric tools most regularly used for assessment of adaptive skills and characteristics of adaptive skills with individual clinical groups.

  5. Adaptation of couples living with a high risk of breast/ovarian cancer and the association with risk-reducing surgery.

    Science.gov (United States)

    Shapira, Rachel; Turbitt, Erin; Erby, Lori H; Biesecker, Barbara B; Klein, William M P; Hooker, Gillian W

    2017-12-05

    Women who carry BRCA1/2 mutations have a significantly elevated risk for breast and ovarian cancer. The positive test result and subsequent decisions about risk reducing behaviors can evoke distress, anxiety and worry. Psychological adaptation, or the process of coming to terms with the implications of a health threat, is an understudied construct in BRCA1/2 carriers. Little is known about adaptation and how it relates to other aspects of living at high risk for cancer. Even less is understood about adaptation among partners of BRCA1/2 carriers, and its relationship to adaptation in high risk individuals. Women at increased risk of breast/ovarian cancer (N = 103) and a subset of partners (N = 39) completed questionnaires that assessed risk management decisions (e.g. screening, risk-reducing surgery), dyadic coping, and the outcome of psychological adaptation. Women who had undergone risk-reducing mastectomy (RRM) had significantly higher levels of adaptation than those who had not (t = 5.5, p adaptation than partners of women who had not undergone RRM (t = 3.7, p = 0.01, d = 0.96), though this association was not statistically significant when controlling for carriers' adaptation. Undergoing risk-reducing oophorectomy was not associated with adaptation for BRCA1/2 carriers or their partners. Risk-reducing mastectomy is a significant event in the process of adapting to life at risk for hereditary cancer. Further, adaptation among partners is highly related to adaptation in carriers. These results aid in the understanding of the experience of couples living with cancer risk and the medical decisions related to adaptation.

  6. 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...... of GABRB3 in 416 patients with a range of epileptic encephalopathies and childhood-onset epilepsies and recruited additional patients with epilepsy with GABRB3 mutations from other research and diagnostic programs. RESULTS: We identified 22 patients with heterozygous mutations in GABRB3, including 3...... probands from multiplex families. The phenotypic spectrum of the mutation carriers ranged from simple febrile seizures, genetic epilepsies with febrile seizures plus, and epilepsy with myoclonic-atonic seizures to West syndrome and other types of severe, early-onset epileptic encephalopathies...

  7. 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.

  8. PRRT2 gene mutations

    Science.gov (United States)

    Gardiner, Alice R.; Bhatia, Kailash P.; Stamelou, Maria; Dale, Russell C.; Kurian, Manju A.; Schneider, Susanne A.; Wali, G.M.; Counihan, Tim; Schapira, Anthony H.; Spacey, Sian D.; Valente, Enza-Maria; Silveira-Moriyama, Laura; Teive, Hélio A.G.; Raskin, Salmo; Sander, Josemir W.; Lees, Andrew; Warner, Tom; Kullmann, Dimitri M.; Wood, Nicholas W.; Hanna, Michael

    2012-01-01

    ABSTRACT Objective: The proline-rich transmembrane protein (PRRT2) gene was recently identified using exome sequencing as the cause of autosomal dominant paroxysmal kinesigenic dyskinesia (PKD) with or without infantile convulsions (IC) (PKD/IC syndrome). Episodic neurologic disorders, such as epilepsy, migraine, and paroxysmal movement disorders, often coexist and are thought to have a shared channel-related etiology. To investigate further the frequency, spectrum, and phenotype of PRRT2 mutations, we analyzed this gene in 3 large series of episodic neurologic disorders with PKD/IC, episodic ataxia (EA), and hemiplegic migraine (HM). Methods: The PRRT2 gene was sequenced in 58 family probands/sporadic individuals with PKD/IC, 182 with EA, 128 with HM, and 475 UK and 96 Asian controls. Results: PRRT2 genetic mutations were identified in 28 out of 58 individuals with PKD/IC (48%), 1/182 individuals with EA, and 1/128 individuals with HM. A number of loss-of-function and coding missense mutations were identified; the most common mutation found was the p.R217Pfs*8 insertion. Males were more frequently affected than females (ratio 52:32). There was a high proportion of PRRT2 mutations found in families and sporadic cases with PKD associated with migraine or HM (10 out of 28). One family had EA with HM and another large family had typical HM alone. Conclusions: This work expands the phenotype of mutations in the PRRT2 gene to include the frequent occurrence of migraine and HM with PKD/IC, and the association of mutations with EA and HM and with familial HM alone. We have also extended the PRRT2 mutation type and frequency in PKD and other episodic neurologic disorders. PMID:23077024

  9. Mutations in Lettuce Improvement

    OpenAIRE

    Mou, Beiquan

    2012-01-01

    Lettuce is a major vegetable in western countries. Mutations generated genetic variations and played an important role in the domestication of the crop. Many traits derived from natural and induced mutations, such as dwarfing, early flowering, male sterility, and chlorophyll deficiency, are useful in physiological and genetic studies. Mutants were also used to develop new lettuce products including miniature and herbicide-tolerant cultivars. Mutant analysis was critical in lettuce genomic stu...

  10. An ancient founder mutation in PROKR2 impairs human reproduction.

    Science.gov (United States)

    Avbelj Stefanija, Magdalena; Jeanpierre, Marc; Sykiotis, Gerasimos P; Young, Jacques; Quinton, Richard; Abreu, Ana Paula; Plummer, Lacey; Au, Margaret G; Balasubramanian, Ravikumar; Dwyer, Andrew A; Florez, Jose C; Cheetham, Timothy; Pearce, Simon H; Purushothaman, Radhika; Schinzel, Albert; Pugeat, Michel; Jacobson-Dickman, Elka E; Ten, Svetlana; Latronico, Ana Claudia; Gusella, James F; Dode, Catherine; Crowley, William F; Pitteloud, Nelly

    2012-10-01

    Congenital gonadotropin-releasing hormone (GnRH) deficiency manifests as absent or incomplete sexual maturation and infertility. Although the disease exhibits marked locus and allelic heterogeneity, with the causal mutations being both rare and private, one causal mutation in the prokineticin receptor, PROKR2 L173R, appears unusually prevalent among GnRH-deficient patients of diverse geographic and ethnic origins. To track the genetic ancestry of PROKR2 L173R, haplotype mapping was performed in 22 unrelated patients with GnRH deficiency carrying L173R and their 30 first-degree relatives. The mutation's age was estimated using a haplotype-decay model. Thirteen subjects were informative and in all of them the mutation was present on the same ~123 kb haplotype whose population frequency is ≤10%. Thus, PROKR2 L173R represents a founder mutation whose age is estimated at approximately 9000 years. Inheritance of PROKR2 L173R-associated GnRH deficiency was complex with highly variable penetrance among carriers, influenced by additional mutations in the other PROKR2 allele (recessive inheritance) or another gene (digenicity). The paradoxical identification of an ancient founder mutation that impairs reproduction has intriguing implications for the inheritance mechanisms of PROKR2 L173R-associated GnRH deficiency and for the relevant processes of evolutionary selection, including potential selective advantages of mutation carriers in genes affecting reproduction.

  11. Interpreting the Dependence of Mutation Rates on Age and Time.

    Directory of Open Access Journals (Sweden)

    Ziyue Gao

    2016-01-01

    Full Text Available Mutations can originate from the chance misincorporation of nucleotides during DNA replication or from DNA lesions that arise between replication cycles and are not repaired correctly. We introduce a model that relates the source of mutations to their accumulation with cell divisions, providing a framework for understanding how mutation rates depend on sex, age, and cell division rate. We show that the accrual of mutations should track cell divisions not only when mutations are replicative in origin but also when they are non-replicative and repaired efficiently. One implication is that observations from diverse fields that to date have been interpreted as pointing to a replicative origin of most mutations could instead reflect the accumulation of mutations arising from endogenous reactions or exogenous mutagens. We further find that only mutations that arise from inefficiently repaired lesions will accrue according to absolute time; thus, unless life history traits co-vary, the phylogenetic "molecular clock" should not be expected to run steadily across species.

  12. Interpreting the Dependence of Mutation Rates on Age and Time.

    Science.gov (United States)

    Gao, Ziyue; Wyman, Minyoung J; Sella, Guy; Przeworski, Molly

    2016-01-01

    Mutations can originate from the chance misincorporation of nucleotides during DNA replication or from DNA lesions that arise between replication cycles and are not repaired correctly. We introduce a model that relates the source of mutations to their accumulation with cell divisions, providing a framework for understanding how mutation rates depend on sex, age, and cell division rate. We show that the accrual of mutations should track cell divisions not only when mutations are replicative in origin but also when they are non-replicative and repaired efficiently. One implication is that observations from diverse fields that to date have been interpreted as pointing to a replicative origin of most mutations could instead reflect the accumulation of mutations arising from endogenous reactions or exogenous mutagens. We further find that only mutations that arise from inefficiently repaired lesions will accrue according to absolute time; thus, unless life history traits co-vary, the phylogenetic "molecular clock" should not be expected to run steadily across species.

  13. 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.

  14. The effect of spatial structure on adaptation in Escherichia coli

    OpenAIRE

    Perfeito, Lilia; Pereira, M. Inês; Campos, Paulo R. A.; Gordo, Isabel

    2007-01-01

    Populations of organisms are generally organized in a given spatial structure. However, the vast majority of population genetic studies are based on populations in which every individual competes globally. Here we use experimental evolution in Escherichia coli to directly test a recently made prediction that spatial structure slows down adaptation and that this cost increases with the mutation rate. This was studied by comparing populations of different mutation rates adapting to a liquid (un...

  15. Oxidative stress is not a major contributor to somatic mitochondrial DNA mutations.

    Directory of Open Access Journals (Sweden)

    Leslie S Itsara

    2014-02-01

    Full Text Available The accumulation of somatic mitochondrial DNA (mtDNA mutations is implicated in aging and common diseases of the elderly, including cancer and neurodegenerative disease. However, the mechanisms that influence the frequency of somatic mtDNA mutations are poorly understood. To develop a simple invertebrate model system to address this matter, we used the Random Mutation Capture (RMC assay to characterize the age-dependent frequency and distribution of mtDNA mutations in the fruit fly Drosophila melanogaster. Because oxidative stress is a major suspect in the age-dependent accumulation of somatic mtDNA mutations, we also used the RMC assay to explore the influence of oxidative stress on the somatic mtDNA mutation frequency. We found that many of the features associated with mtDNA mutations in vertebrates are conserved in Drosophila, including a comparable somatic mtDNA mutation frequency (∼10(-5, an increased frequency of mtDNA mutations with age, and a prevalence of transition mutations. Only a small fraction of the mtDNA mutations detected in young or old animals were G∶C to T∶A transversions, a signature of oxidative damage, and loss-of-function mutations in the mitochondrial superoxide dismutase, Sod2, had no detectable influence on the somatic mtDNA mutation frequency. Moreover, a loss-of-function mutation in Ogg1, which encodes a DNA repair enzyme that removes oxidatively damaged deoxyguanosine residues (8-hydroxy-2'-deoxyguanosine, did not significantly influence the somatic mtDNA mutation frequency of Sod2 mutants. Together, these findings indicate that oxidative stress is not a major cause of somatic mtDNA mutations. Our data instead suggests that somatic mtDNA mutations arise primarily from errors that occur during mtDNA replication. Further studies using Drosophila should aid in the identification of factors that influence the frequency of somatic mtDNA mutations.

  16. Oxidative Stress Is Not a Major Contributor to Somatic Mitochondrial DNA Mutations

    Science.gov (United States)

    Itsara, Leslie S.; Kennedy, Scott R.; Fox, Edward J.; Yu, Selina; Hewitt, Joshua J.; Sanchez-Contreras, Monica; Cardozo-Pelaez, Fernando; Pallanck, Leo J.

    2014-01-01

    The accumulation of somatic mitochondrial DNA (mtDNA) mutations is implicated in aging and common diseases of the elderly, including cancer and neurodegenerative disease. However, the mechanisms that influence the frequency of somatic mtDNA mutations are poorly understood. To develop a simple invertebrate model system to address this matter, we used the Random Mutation Capture (RMC) assay to characterize the age-dependent frequency and distribution of mtDNA mutations in the fruit fly Drosophila melanogaster. Because oxidative stress is a major suspect in the age-dependent accumulation of somatic mtDNA mutations, we also used the RMC assay to explore the influence of oxidative stress on the somatic mtDNA mutation frequency. We found that many of the features associated with mtDNA mutations in vertebrates are conserved in Drosophila, including a comparable somatic mtDNA mutation frequency (∼10−5), an increased frequency of mtDNA mutations with age, and a prevalence of transition mutations. Only a small fraction of the mtDNA mutations detected in young or old animals were G∶C to T∶A transversions, a signature of oxidative damage, and loss-of-function mutations in the mitochondrial superoxide dismutase, Sod2, had no detectable influence on the somatic mtDNA mutation frequency. Moreover, a loss-of-function mutation in Ogg1, which encodes a DNA repair enzyme that removes oxidatively damaged deoxyguanosine residues (8-hydroxy-2′-deoxyguanosine), did not significantly influence the somatic mtDNA mutation frequency of Sod2 mutants. Together, these findings indicate that oxidative stress is not a major cause of somatic mtDNA mutations. Our data instead suggests that somatic mtDNA mutations arise primarily from errors that occur during mtDNA replication. Further studies using Drosophila should aid in the identification of factors that influence the frequency of somatic mtDNA mutations. PMID:24516391

  17. Mutations in Exons 9 and 13 of KIT Gene Are Rare Events in Gastrointestinal Stromal Tumors

    Science.gov (United States)

    Lasota, Jerzy; Wozniak, Agnieszka; Sarlomo-Rikala, Maarit; Rys, Janusz; Kordek, Radzislaw; Nassar, Aziza; Sobin, Leslie H.; Miettinen, Markku

    2000-01-01

    Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, typically express the KIT protein. Activating mutations in the juxtamembrane domain (exon 11) of the c-kit gene have been shown in a subset of GISTs. These mutations lead into ligand-independent activation of the tyrosine kinase of c-kit, and have a transforming effect in vitro. Several groups have studied the clinical implication of the c-kit mutation status of exon 11 in GISTs and a possible relationship between c-kit mutations and malignant behavior has been established. Recently, a 1530ins6 mutation in exon 9 and missense mutations, 1945A>G in exon 13 of the c-kit gene were reported. The frequency and clinical importance of these findings are unknown. In this study we evaluated 200 GISTs for the presence of mutations in exons 9 and 13 of c-kit. Six cases revealed 1530ins6 mutation in exon 9 and two cases 1945A>G mutation in exon 13. All tumors with mutations in exon 9 and 13 lacked mutations in exon 11 of c-kit. None of the analyzed tumors had more than one type of c-kit mutation. All but one of the eight tumors with mutations in exon 9 or 13 of the c-kit gene were histologically and clinically malignant. All four of six cases with exon 9 mutation of which location of primary tumor was known, were small intestinal, suggesting that this type of mutation could preferentially occur in small intestinal tumors. Exon 9 and 13 mutations seem to be rare, and they cover only a small portion (8%) of the balance of GISTs that do not have mutations in exon 11 of c-kit. This finding indicates that other genetic alterations may activate c-kit in GISTs, or that KIT is not activated by mutations in all cases. PMID:11021812

  18. The Spontaneous Mutation Rate in the Fission Yeast Schizosaccharomyces pombe.

    Science.gov (United States)

    Farlow, Ashley; Long, Hongan; Arnoux, Stéphanie; Sung, Way; Doak, Thomas G; Nordborg, Magnus; Lynch, Michael

    2015-10-01

    The rate at which new mutations arise in the genome is a key factor in the evolution and adaptation of species. Here we describe the rate and spectrum of spontaneous mutations for the fission yeast Schizosaccharomyces pombe, a key model organism with many similarities to higher eukaryotes. We undertook an ∼1700-generation mutation accumulation (MA) experiment with a haploid S. pombe, generating 422 single-base substitutions and 119 insertion-deletion mutations (indels) across the 96 replicates. This equates to a base-substitution mutation rate of 2.00 × 10(-10) mutations per site per generation, similar to that reported for the distantly related budding yeast Saccharomyces cerevisiae. However, these two yeast species differ dramatically in their spectrum of base substitutions, the types of indels (S. pombe is more prone to insertions), and the pattern of selection required to counteract a strong AT-biased mutation rate. Overall, our results indicate that GC-biased gene conversion does not play a major role in shaping the nucleotide composition of the S. pombe genome and suggest that the mechanisms of DNA maintenance may have diverged significantly between fission and budding yeasts. Unexpectedly, CpG sites appear to be excessively liable to mutation in both species despite the likely absence of DNA methylation. Copyright © 2015 by the Genetics Society of America.

  19. Evolution of mutational robustness in an RNA virus.

    Directory of Open Access Journals (Sweden)

    Rebecca Montville

    2005-11-01

    Full Text Available Mutational (genetic robustness is phenotypic constancy in the face of mutational changes to the genome. Robustness is critical to the understanding of evolution because phenotypically expressed genetic variation is the fuel of natural selection. Nonetheless, the evidence for adaptive evolution of mutational robustness in biological populations is controversial. Robustness should be selectively favored when mutation rates are high, a common feature of RNA viruses. However, selection for robustness may be relaxed under virus co-infection because complementation between virus genotypes can buffer mutational effects. We therefore hypothesized that selection for genetic robustness in viruses will be weakened with increasing frequency of co-infection. To test this idea, we used populations of RNA phage phi6 that were experimentally evolved at low and high levels of co-infection and subjected lineages of these viruses to mutation accumulation through population bottlenecking. The data demonstrate that viruses evolved under high co-infection show relatively greater mean magnitude and variance in the fitness changes generated by addition of random mutations, confirming our hypothesis that they experience weakened selection for robustness. Our study further suggests that co-infection of host cells may be advantageous to RNA viruses only in the short term. In addition, we observed higher mutation frequencies in the more robust viruses, indicating that evolution of robustness might foster less-accurate genome replication in RNA viruses.

  20. Role of mutation in Pseudomonas aeruginosa biofilm development.

    Directory of Open Access Journals (Sweden)

    Tim C R Conibear

    2009-07-01

    Full Text Available The survival of bacteria in nature is greatly enhanced by their ability to grow within surface-associated communities called biofilms. Commonly, biofilms generate proliferations of bacterial cells, called microcolonies, which are highly recalcitrant, 3-dimensional foci of bacterial growth. Microcolony growth is initiated by only a subpopulation of bacteria within biofilms, but processes responsible for this differentiation remain poorly understood. Under conditions of crowding and intense competition between bacteria within biofilms, microevolutionary processes such as mutation selection may be important for growth; however their influence on microcolony-based biofilm growth and architecture have not previously been explored. To study mutation in-situ within biofilms, we transformed Pseudomonas aeruginosa cells with a green fluorescent protein gene containing a +1 frameshift mutation. Transformed P. aeruginosa cells were non-fluorescent until a mutation causing reversion to the wildtype sequence occurs. Fluorescence-inducing mutations were observed in microcolony structures, but not in other biofilm cells, or in planktonic cultures of P. aeruginosa cells. Thus microcolonies may represent important foci for mutation and evolution within biofilms. We calculated that microcolony-specific increases in mutation frequency were at least 100-fold compared with planktonically grown cultures. We also observed that mutator phenotypes can enhance microcolony-based growth of P. aeruginosa cells. For P. aeruginosa strains defective in DNA fidelity and error repair, we found that microcolony initiation and growth was enhanced with increased mutation frequency of the organism. We suggest that microcolony-based growth can involve mutation and subsequent selection of mutants better adapted to grow on surfaces within crowded-cell environments. This model for biofilm growth is analogous to mutation selection that occurs during neoplastic progression and tumor

  1. Detecting clusters of mutations.

    Directory of Open Access Journals (Sweden)

    Tong Zhou

    Full Text Available Positive selection for protein function can lead to multiple mutations within a small stretch of DNA, i.e., to a cluster of mutations. Recently, Wagner proposed a method to detect such mutation clusters. His method, however, did not take into account that residues with high solvent accessibility are inherently more variable than residues with low solvent accessibility. Here, we propose a new algorithm to detect clustered evolution. Our algorithm controls for different substitution probabilities at buried and exposed sites in the tertiary protein structure, and uses random permutations to calculate accurate P values for inferred clusters. We apply the algorithm to genomes of bacteria, fly, and mammals, and find several clusters of mutations in functionally important regions of proteins. Surprisingly, clustered evolution is a relatively rare phenomenon. Only between 2% and 10% of the genes we analyze contain a statistically significant mutation cluster. We also find that not controlling for solvent accessibility leads to an excess of clusters in terminal and solvent-exposed regions of proteins. Our algorithm provides a novel method to identify functionally relevant divergence between groups of species. Moreover, it could also be useful to detect artifacts in automatically assembled genomes.

  2. Leveraging Distant Relatedness to Quantify Human Mutation and Gene-Conversion Rates

    NARCIS (Netherlands)

    Palamara, Pier Francesco; Francioli, Laurent C; Wilton, Peter R; Genovese, Giulio; Gusev, Alexander; Finucane, Hilary K; Sankararaman, Sriram; Sunyaev, Shamil R; de Bakker, Paul I W; Wakeley, John; Pe'er, Itsik; Price, Alkes L

    2015-01-01

    The rate at which human genomes mutate is a central biological parameter that has many implications for our ability to understand demographic and evolutionary phenomena. We present a method for inferring mutation and gene-conversion rates by using the number of sequence differences observed in

  3. Genetic Testing for Long-QT Syndrome Distinguishing Pathogenic Mutations From Benign Variants

    NARCIS (Netherlands)

    Kapa, Suraj; Tester, David J.; Salisbury, Benjamin A.; Harris-Kerr, Carole; Pungliya, Manish S.; Alders, Marielle; Wilde, Arthur A. M.; Ackerman, Michael J.

    2009-01-01

    Background-Genetic testing for long-QT syndrome (LQTS) has diagnostic, prognostic, and therapeutic implications. Hundreds of causative mutations in 12 known LQTS-susceptibility genes have been identified. Genetic testing that includes the 3 most commonly mutated genes is available clinically.

  4. De novo mutations in the genome organizer CTCF cause intellectual disability

    DEFF Research Database (Denmark)

    Gregor, Anne; Oti, Martin; Kouwenhoven, Evelyn N

    2013-01-01

    An increasing number of genes involved in chromatin structure and epigenetic regulation has been implicated in a variety of developmental disorders, often including intellectual disability. By trio exome sequencing and subsequent mutational screening we now identified two de novo frameshift mutat...

  5. Model and test in a fungus of the probability that beneficial mutations survive drift

    NARCIS (Netherlands)

    Gifford, D.R.; Visser, de J.A.G.M.; Wahl, L.M.

    2013-01-01

    Determining the probability of fixation of beneficial mutations is critically important for building predictive models of adaptive evolution. Despite considerable theoretical work, models of fixation probability have stood untested for nearly a century. However, recent advances in experimental and

  6. Spontaneous mutation rate is a plastic trait associated with population density across domains of life

    National Research Council Canada - National Science Library

    Rok Krašovec; Huw Richards; Danna R Gifford; Charlie Hatcher; Katy J Faulkner; Roman V Belavkin; Alastair Channon; Elizabeth Aston; Andrew J McBain; Christopher G Knight

    2017-01-01

    .... Such plasticity affects evolutionary trajectories and may be adaptive. We recently identified an inverse plastic association between mutation rate and population density at 1 locus in 1 species of bacterium...

  7. Ambiguous Adaptation

    DEFF Research Database (Denmark)

    Møller Larsen, Marcus; Lyngsie, Jacob

    We investigate why some exchange relationships terminate prematurely. We argue that investments in informal governance structures induce premature termination in relationships already governed by formal contracts. The formalized adaptive behavior of formal governance structures and the flexible...... 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...

  8. [PRRT2 mutation and infantile convulsions].

    Science.gov (United States)

    Mathot, M; Lederer, D; Gerard, S; Gueulette, E; Deprez, M

    2017-10-01

    New genetic techniques have made it possible to better understand the implications of the PRRT2 gene (proline rich transmembrane protein 2) in various neurological disorders. Mutations within this gene are responsible for kinesigenic paroxysmal dyskinesias (PKD) as well as for benign familial infantile epilepsy (BFIE), a disease associating infantile convulsions and choreoathetosis (ICCA), a form of familial hemiplegic migraine (FHM type 4), paroxysmal benign torticollis of childhood, and episodic ataxia. We describe the case of an infant, carrying a mutation of the PRRT2 gene, with a classical presentation. Through her progression over time, we raise the question of systematic use of anti-epileptic drugs. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  9. 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.

  10. 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...... approach shaped the prototype and we discuss the ethical implications of creating a self-adaptive, semiautonomous treatment game....

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

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Genetics; Volume 93; Issue 1. 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 C. R. Srikumari Srisailapathy. Research Note Volume ...

  12. Stalled replication forks generate a distinct mutational signature in yeast

    DEFF Research Database (Denmark)

    Larsen, Nicolai B.; Liberti, Sascha E.; Vogel, Ivan

    2017-01-01

    Proliferating cells acquire genome alterations during the act of DNA replication. This leads to mutation accumulation and somatic cell mosaicism in multicellular organisms, and is also implicated as an underlying cause of aging and tumorigenesis. The molecular mechanisms of DNA replication-associ...

  13. An overview about mitochondrial DNA mutations in ovarian cancer ...

    African Journals Online (AJOL)

    Result: Furthermore, this review offers some perspective as to the mtDNA origin of these mutations in ovarian cancer, their functional consequences in ovarian cancer development, to check for incidence rate for transmission of the disease through maternal lineages and possible diagnostic marker implication.

  14. Interaction between Mutations and Regulation of Gene Expression during Development of de novo Antibiotic Resistance

    NARCIS (Netherlands)

    Händel, N.; Schuurmans, J.M.; Feng, Y.; Brul, S.; ter Kuile, B.H.

    2014-01-01

    Bacteria can become resistant not only by horizontal gene transfer or other forms of exchange of genetic information, but also de novo by adaptation at the gene expression level and through DNA mutations. The interrelationship between changes in gene expression and DNA mutations during acquisition

  15. ALS2 mutations

    Science.gov (United States)

    Schneider, Susanne A.; Carr, Lucinda; Deuschl, Guenther; Hopfner, Franziska; Stamelou, Maria; Wood, Nicholas W.; Bhatia, Kailash P.

    2014-01-01

    Objective: To determine the genetic etiology in 2 consanguineous families who presented a novel phenotype of autosomal recessive juvenile amyotrophic lateral sclerosis associated with generalized dystonia. Methods: A combination of homozygosity mapping and whole-exome sequencing in the first family and Sanger sequencing of candidate genes in the second family were used. Results: Both families were found to have homozygous loss-of-function mutations in the amyotrophic lateral sclerosis 2 (juvenile) (ALS2) gene. Conclusions: We report generalized dystonia and cerebellar signs in association with ALS2-related disease. We suggest that the ALS2 gene should be screened for mutations in patients who present with a similar phenotype. PMID:24562058

  16. 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 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....

  17. 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.

  18. Mutators and hypermutability in bacteria: the Escherichia coli ...

    Indian Academy of Sciences (India)

    Being a mutator is advantageous to the organism when adapting to environmental changes or stressful situations, such as moving from one habitat to another, ... mismatch repair, oxidative DNA damage, mistranslation etc., as well as phenomena associated with these processes, using Escherichia coli as a paradigmatic ...

  19. Identical skin toxins by convergent molecular adaptation in frogs.

    Science.gov (United States)

    Roelants, Kim; Fry, Bryan G; Norman, Janette A; Clynen, Elke; Schoofs, Liliane; Bossuyt, Franky

    2010-01-26

    The Tree of Life is rife with adaptive convergences at all scales and biological levels of complexity. However, natural selection is not likely to result in the independent evolution of identical gene products. Here we report such a striking example of evolutionary convergence in the toxic skin secretions of two distantly related frog lineages. Caeruleins are important decapeptides in pharmacological and clinical research [1] and are commonly believed to represent a single evolutionary class of peptides [2-4]. Instead, our phylogenetic analyses combining transcriptome and genome data reveal that independently evolved precursor genes encode identical caeruleins in Xenopus and Litoria frogs. The former arose by duplication from the cholecystokinin (cck) gene, whereas the latter was derived from the gastrin gene. These hormone genes that are involved in many physiological processes diverged early in vertebrate evolution, after a segmental duplication during the Cambrian period. Besides implicating convergent mutations of the peptide-encoding sequence, recurrent caerulein origins entail parallel shifts of expression from the gut-brain axis to skin secretory glands. These results highlight extreme structural convergence in anciently diverged genes as an evolutionary mechanism through which recurrent adaptation is attained across large phylogenetic distances. Copyright 2010 Elsevier Ltd. All rights reserved.

  20. 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 ...

  1. Factor V Leiden Mutation and PT 20210 Mutation Test

    Science.gov (United States)

    ... Patient Resources For Health Professionals Subscribe Search Factor V Leiden Mutation and PT 20210 Mutation Send Us ... As Activated Protein C Resistance APC Resistance Factor V R506Q PT G20210A Factor II 20210 Factor II ...

  2. Antagonistic changes in sensitivity to antifungal drugs by mutations of an important ABC transporter gene in a fungal pathogen.

    Directory of Open Access Journals (Sweden)

    Wenjun Guan

    Full Text Available Fungal pathogens can be lethal, especially among immunocompromised populations, such as patients with AIDS and recipients of tissue transplantation or chemotherapy. Prolonged usage of antifungal reagents can lead to drug resistance and treatment failure. Understanding mechanisms that underlie drug resistance by pathogenic microorganisms is thus vital for dealing with this emerging issue. In this study, we show that dramatic sequence changes in PDR5, an ABC (ATP-binding cassette efflux transporter protein gene in an opportunistic fungal pathogen, caused the organism to become hypersensitive to azole, a widely used antifungal drug. Surprisingly, the same mutations conferred growth advantages to the organism on polyenes, which are also commonly used antimycotics. Our results indicate that Pdr5p might be important for ergosterol homeostasis. The observed remarkable sequence divergence in the PDR5 gene in yeast strain YJM789 may represent an interesting case of adaptive loss of gene function with significant clinical implications.

  3. 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.

  4. Msx1 Mutations

    Science.gov (United States)

    Wang, Y.; Kong, H.; Mues, G.; D’Souza, R.

    2011-01-01

    Mutations in the transcription factors PAX9 and MSX1 cause selective tooth agenesis in humans. In tooth bud mesenchyme of mice, both proteins are required for the expression of Bmp4, which is the key signaling factor for progression to the next step of tooth development. We have previously shown that Pax9 can transactivate a 2.4-kb Bmp4 promoter construct, and that most tooth-agenesis-causing PAX9 mutations impair DNA binding and Bmp4 promoter activation. We also found that Msx1 by itself represses transcription from this proximal Bmp4 promoter, and that, in combination with Pax9, it acts as a potentiator of Pax9-induced Bmp4 transactivation. This synergism of Msx1 with Pax9 is significant, because it is currently the only documented mechanism for Msx1-mediated activation of Bmp4. In this study, we investigated whether the 5 known tooth-agenesis-causing MSX1 missense mutations disrupt this Pax9-potentiation effect, or if they lead to deficiencies in protein stability, protein-protein interactions, nuclear translocation, and DNA-binding. We found that none of the studied molecular mechanisms yielded a satisfactory explanation for the pathogenic effects of the Msx1 mutations, calling for an entirely different approach to the investigation of this step of odontogenesis on the molecular level. PMID:21297014